Sunday, April 12, 2009
HEART FAIIURE:
What is heart failure?Heart failure is when the heart loses its ability to pump blood efficiently through your body. Oxygen and nutrients in blood provide your body with the energy it needs to operate normally.Heart failure may affect the left, right or both sides of the heart.
If the left half of the heart fails (left ventricular failure), fluid will build up in the lungs due to congestion of the veins in the lungs.
If the right half of the heart fails (right ventricular failure), general body vein pressure will increase and fluid will accumulate in the body, especially in the legs and in the abdominal organs, with the liver most likely to be affected. Often left heart failure leads to right heart failure, causing biventricular failure (failure on both sides). What causes heart failure? Heart failure can be caused by many different diseases. Some of which happen as an acute, sudden effect, while others are chronic, long-term conditions.
High blood pressure
Diseases of the heart valves.
Ischaemic heart disease - a blood clot in one of the coronary arteries can cause injury and irreversible damage to the heart muscle.
Cardiomyopathy (chronic heart muscle disease).
Congenital heart diseases.
Endocrine disorders, including decreased metabolism due to abnormal thyroid function (rare) and also increased metabolism due to abnormal thyroid function (rare).
Severe anaemia (rare).What are the symptoms of heart failure?
Left-sided heart failure
Shortness of breath together with a reduction in mobility.
In less severe cases, breathing problems only start upon exertion.
A dry cough may develop that doesn't go away.
Fatigue.
Right-sided heart failure and biventricular failure
Swelling in the legs (oedema).
Oedema may lead to dry skin on the lower part of the legs because of pressure from inside the tissue.
There may be an eczema-type rash on legs, which can be complicated by ulcers that do not heal (venous leg ulcers).
Possible accumulation of fluid in the abdominal cavity and organs, especially the liver. The organs swell and the abdominal wall might expand.How does the doctor diagnose heart failure?
The diagnosis is usually based on medical history combined with an examination that will look for an increased heart rate, abnormal heart sounds, the presence of heart murmurs, swollen legs, fluid in the lungs, swollen neck veins and liver enlargement.
To determine the extent of the heart failure, a chest X-ray is done.
To establish whether a previous heart attack may be associated with the development of heart failure, an electrocardiogram (ECG) will be taken.
Blood samples are usually taken to check for metabolic upset and kidney function.To find out what caused the heart failure, further investigations are required. These can include:
additional blood tests to check for recent viral infections and for rare metabolic causes of heart failure
an ultrasound examination of the heart (echocardiograph)
an exercise test using a treadmill
an examination of the coronary arteries by injecting a dye into the left and right coronary arteries so any blockages show up on an X-ray
measurement of pressure and valve function in between both the chambers of the heart and the great blood vessels (cardiac catheterisation)
taking a small sample of heart muscle (biopsy) if heart muscle disease (cardiomyopathy) is suspected at the time of catheterisation
additional non-invasive imaging to look at the heart muscle using magnetic resonance imaging (MRI).In the long termHeart failure is a progressive disease, with the potential for gradual deterioration. Treatment can often slow the progression of the illness and substantially increase your quality of life.
What are the signs of deterioration?
Left-sided heart failure
Increasing difficulty in moving around.
Breathlessness at rest or when lying flat (orthopnoea).
Waking up at night with breathlessness (paroxysmal nocturnal dyspnoea).
A cough with frothy sputum (lung oedema).
Right-sided heart failure
Venous leg ulcers.
General swelling of the legs, abdomen and, in men, the scrotum.
Possible liver enlargement if severe.What can the doctor do?
Investigate with a view to coronary artery widening (revascularisation) and valve replacement if necessary.
Treat any obvious causes of heart failure.
Give advice regarding risk factors such as smoking, excessive weight and high blood pressure.
Refer you for further investigation to identify the cause of the heart failure.
Prescribe medication.
Monitor your health on a regular basis.Which medication is used afterwards?
AspirinAspirin (eg Nu-seals 75mg) is always prescribed unless it can't be tolerated. It has a mildly blood-thinning effect and goes some way to prevent further cardiac events. Aspirin must be taken for the rest of your life.Clopidogrel (Plavix) can be given instead of aspirin.
Agents for increasing cardiac function Digoxin (eg Lanoxin) helps the heart contract more vigorously.
Nitroglycerin and other nitrates Nitrates such as glyceryl trinitrate or isosorbide mononitrate (eg Imdur) make the veins and arteries relax and widen (dilate). When the blood vessels dilate in this way there is more space inside them and so less resistance. This makes it easier for the heart to pump blood around the body.
Beta blockers Beta blockers block the action of adrenaline hormones on the heart. They reduce the energy used by the heart to pump blood around the body, so it doesn't have to work so hard.
ACE inhibitors ACE inhibitors prevent the formation of a hormone that makes the blood vessels contract. This means that less effort is needed by the heart to pump blood.
Diuretics Diuretics help the body excrete excessive fluid and salts, reducing the strain on the heart and blood vessels. If you take diuretics, you may need to take a potassium supplement because some diuretics cause a loss of potassium.What can be done to avoid heart failure?
Stop smoking.
Avoid overeating.
Exercise regularly.
Eat a healthy, low-fat diet.
If you are suffering from a disease that can cause heart failure, such as high blood pressure, it is important to have it treated as soon as possible. The risk of developing heart failure will then be greatly reduced.
What is heart failure?Heart failure is when the heart loses its ability to pump blood efficiently through your body. Oxygen and nutrients in blood provide your body with the energy it needs to operate normally.Heart failure may affect the left, right or both sides of the heart.
If the left half of the heart fails (left ventricular failure), fluid will build up in the lungs due to congestion of the veins in the lungs.
If the right half of the heart fails (right ventricular failure), general body vein pressure will increase and fluid will accumulate in the body, especially in the legs and in the abdominal organs, with the liver most likely to be affected. Often left heart failure leads to right heart failure, causing biventricular failure (failure on both sides). What causes heart failure? Heart failure can be caused by many different diseases. Some of which happen as an acute, sudden effect, while others are chronic, long-term conditions.
High blood pressure
Diseases of the heart valves.
Ischaemic heart disease - a blood clot in one of the coronary arteries can cause injury and irreversible damage to the heart muscle.
Cardiomyopathy (chronic heart muscle disease).
Congenital heart diseases.
Endocrine disorders, including decreased metabolism due to abnormal thyroid function (rare) and also increased metabolism due to abnormal thyroid function (rare).
Severe anaemia (rare).What are the symptoms of heart failure?
Left-sided heart failure
Shortness of breath together with a reduction in mobility.
In less severe cases, breathing problems only start upon exertion.
A dry cough may develop that doesn't go away.
Fatigue.
Right-sided heart failure and biventricular failure
Swelling in the legs (oedema).
Oedema may lead to dry skin on the lower part of the legs because of pressure from inside the tissue.
There may be an eczema-type rash on legs, which can be complicated by ulcers that do not heal (venous leg ulcers).
Possible accumulation of fluid in the abdominal cavity and organs, especially the liver. The organs swell and the abdominal wall might expand.How does the doctor diagnose heart failure?
The diagnosis is usually based on medical history combined with an examination that will look for an increased heart rate, abnormal heart sounds, the presence of heart murmurs, swollen legs, fluid in the lungs, swollen neck veins and liver enlargement.
To determine the extent of the heart failure, a chest X-ray is done.
To establish whether a previous heart attack may be associated with the development of heart failure, an electrocardiogram (ECG) will be taken.
Blood samples are usually taken to check for metabolic upset and kidney function.To find out what caused the heart failure, further investigations are required. These can include:
additional blood tests to check for recent viral infections and for rare metabolic causes of heart failure
an ultrasound examination of the heart (echocardiograph)
an exercise test using a treadmill
an examination of the coronary arteries by injecting a dye into the left and right coronary arteries so any blockages show up on an X-ray
measurement of pressure and valve function in between both the chambers of the heart and the great blood vessels (cardiac catheterisation)
taking a small sample of heart muscle (biopsy) if heart muscle disease (cardiomyopathy) is suspected at the time of catheterisation
additional non-invasive imaging to look at the heart muscle using magnetic resonance imaging (MRI).In the long termHeart failure is a progressive disease, with the potential for gradual deterioration. Treatment can often slow the progression of the illness and substantially increase your quality of life.
What are the signs of deterioration?
Left-sided heart failure
Increasing difficulty in moving around.
Breathlessness at rest or when lying flat (orthopnoea).
Waking up at night with breathlessness (paroxysmal nocturnal dyspnoea).
A cough with frothy sputum (lung oedema).
Right-sided heart failure
Venous leg ulcers.
General swelling of the legs, abdomen and, in men, the scrotum.
Possible liver enlargement if severe.What can the doctor do?
Investigate with a view to coronary artery widening (revascularisation) and valve replacement if necessary.
Treat any obvious causes of heart failure.
Give advice regarding risk factors such as smoking, excessive weight and high blood pressure.
Refer you for further investigation to identify the cause of the heart failure.
Prescribe medication.
Monitor your health on a regular basis.Which medication is used afterwards?
AspirinAspirin (eg Nu-seals 75mg) is always prescribed unless it can't be tolerated. It has a mildly blood-thinning effect and goes some way to prevent further cardiac events. Aspirin must be taken for the rest of your life.Clopidogrel (Plavix) can be given instead of aspirin.
Agents for increasing cardiac function Digoxin (eg Lanoxin) helps the heart contract more vigorously.
Nitroglycerin and other nitrates Nitrates such as glyceryl trinitrate or isosorbide mononitrate (eg Imdur) make the veins and arteries relax and widen (dilate). When the blood vessels dilate in this way there is more space inside them and so less resistance. This makes it easier for the heart to pump blood around the body.
Beta blockers Beta blockers block the action of adrenaline hormones on the heart. They reduce the energy used by the heart to pump blood around the body, so it doesn't have to work so hard.
ACE inhibitors ACE inhibitors prevent the formation of a hormone that makes the blood vessels contract. This means that less effort is needed by the heart to pump blood.
Diuretics Diuretics help the body excrete excessive fluid and salts, reducing the strain on the heart and blood vessels. If you take diuretics, you may need to take a potassium supplement because some diuretics cause a loss of potassium.What can be done to avoid heart failure?
Stop smoking.
Avoid overeating.
Exercise regularly.
Eat a healthy, low-fat diet.
If you are suffering from a disease that can cause heart failure, such as high blood pressure, it is important to have it treated as soon as possible. The risk of developing heart failure will then be greatly reduced.
الجلطة القلبيةلماذا هي قاتلة
الجلطة القلبية التي يمكن تعريفها بلغة مبسطة أنها عبارة عن انسداد حاد بشكل تام أو شبه تام لأحد شرايين القلب التاجية الرئيسة والذي يؤدي إلى منع تدفق الدم إلى عضلة القلب وعدم تزويدها بالأوكسجين والمواد الضرورية الأخرى مما يسبب موت الخلايا وتلفها وتحولها إلى نسيج ضعيف وغير حي أو فعال، والمعروف علمياً من فسيولوجية خلايا القلب أنها إذا ماتت لايمكن أعادتها إلى الحياة مالم تتدخل القدرة الإلهية على يد الطبيب بأسرع وقت ممكن قبل أن تصل إلى مرحلة اللاعودة، ومن هنا يتبين لنا كم هي غالية كل ثانية ودقيقة في حياة هذه الخلايا وبالتالي حياة القلب وعامل الزمن هذا هو ماتحرص عليه وتشدد كل الأنظمة الصحية المتطورة حينما تواجه مثل هذه المشكلة القاتلة .وهنا أسرد مثالاً مختصراً يبين كيف يتعامل العالم المتحضر الذي يحترم ويقدر الحياة الإنسانية بغض النظر عن الجنس والعرق والدين والانتماء والغرض من هذا المثال هو لفت القارئ العزيز لأهمية عامل الوقت فحين يدخل المريض إلى الطوارئ وهو يشكو من ألم في الصدر ويشتبه أنها ذبحة صدرية فإن كل الطاقم الطبي من أطباء وممرضين مؤهلين يستنفرون ويعملون في نفس اللحظة بسرعة وتناغم، حيث إنه يجب عليهم خلال العشر الدقائق الأولى (حسب الإرشادات العالمية لأمراض القلب) أخذ تاريخ المريض بشكل دقيق ومركز وأخذ العلامات الحيوية من ضغط ونبض وتنفس وإعطاء المريض الإسبرين مضغاً وموسع الشرايين تحت اللسان والأكسجين ووضع إبرة وريدية وإعطاء المورفين لتسكين الألم وحقنة أخرى لتمييع الدم وعمل تخطيط القلب وأخذ الفحوصات المخبرية اللازمة ووضع المريض على جهاز مراقبة القلب المستمرة وتحضيره لأي قسطرة محتملة مع إعادة التخطيط كل 10-5 دقائق، فإذا تبين أن هناك دلائل مؤكدة على وجود جلطة قلبية (احتشاء عضلة القلب) فيتم إضافة بعض الأدوية المهمة وريدياً والتي لامجال لذكرها الآن ثم ينقل المريض إلى قسم القسطرة، حيث يكون طبيب القلب والممرضون المؤهلون على أهبة من الاستعداد لاستقباله، فيجب أن نعلن أنه حسب الإرشادات الطبية العالمية فإن الفترة التي تبدأ منذ دخول المريض إلى الطوارئ حتى يوضع على طاولة القسطرة يجب أن تكون بحدود التسعين دقيقة .ولم نستعرض هنا خيار إعطاء الحقن التي تذيب الجلطة المسماة (إبرة الحياة) والتي يجب توافرها في كل مستشفى لايتواجد في قسم القسطرة، ولكني أشير إلى أن الدراسات العالمية كافة تثبت أفضلية القسطرة العلاجية (التداخلية) على هذه الحقن وبمضاعفات أقل كنزيف الدماغ أو احتمالية تكرار الجلطة .والآن ماعلاقة مدينة عدن بما سبق ذكره في مشكلة طبية بحتة ؟ هذا السؤال يقودنا إلى أسئلة عديدة ولعل أهمها هو هل يعقل أن تكون مدينة بحجم عدن (على سبيل المثال وليس الحصر) بهذا العدد المتزايد من السكان والكثافة السكانية المكتظة لايوجد فيها حتى مركز واحد متخصص في أمراض القلب مجهز بكوادر طبية وقدرات تشخيصية عالية من مختبرات وأشعة وأقسام القسطرة التشخيصية والتداخلية مدعمة بغرف عمليات القلب المفتوح فهل يعقل هذا ؟فكم أتمنى أن أرى عدن وهي تفخر بهكذا إنجاز وصرح طبي يساند ويخفف الضغط عن مدينة صنعاء التي على الرغم من ازدحامها بالكثير من مراكز القلب الحكومية والخاصة، فإنها تتحمل مشكورة النصيب الأكبر من هذا الجهد للتخفيف من وطأة هذه المعضلة الصحية والاجتماعية . ومن هنا وبالنظر إلى ماقد أسلفنا ذكره من أهمية بالغة للثواني والدقائق في إنقاد حياة الإنسان من هذا المرض الفتاك نتساءل بحسرة وأسف هل سيتمكن هذا المريض المسكين والمنهك من أن يصل إلى صنعاء في الوقت المناسب وهو على قيد الحياة ؟ الله أعلم
الجلطة القلبية وطرق علاجها
الجلطة أو النوبة القلبية هو مايحدث عندما تنقطع التروية
الجلطة أو النوبة القلبية هو مايحدث عندما تنقطع التروية
التاجية عن جزء من قلب الإنسان لفترة معينة مما يؤدي إلى " موت " أو إنحلال للخلايا في هذا الجزء من القلبسبب هذا الأنقطاع في التروية التاجية هو أنسداد كامل أو جزئي في أحد الشرايين التاجية الثلاث المغذية لعضلة القلب وهى : 1- الشريان الأمامي النازل . 2- الشريان التاجي الأيمن . 3- الشريان التاجي الخلفي . وفي بعض الحالات النادرة تحدث الجلطة على الرغم من كون الشرايين التاجية " كاملة الأنفتاح " وذلك إما بسبب تشنج وأنقباض حاد في جدار الشريان أو أنسداد هذا الشريان جراء تكون خثرة دموية داخله . - أعراض الجلطة القلبية : عبارة عن آلام صدرية عميقة تتبلور في منتصف الصدر عادة وقد تكون في موضع آخر وقد تنتشر هذه الآلام إلى الجهة اليسرى من الصدر أو المرفق الأيسر حتى الرسغ أو إصبعي الخنصر والبنصر ، وقد تمتد هذه الألام إلى الرقبة أو الفك الأسفل أو الظهر أو أعلى المعدة وتستمر هذه الآلام نصف ساعة أو أكثر وقد تكون مصحوبة بالعرق البارد مع شحوب أو أصفرار في الوجه وضيق في التنفس ، كما قد يحدث غثيان وتقيؤ وأنحطاط في الجسم أو حالة إغماء . - المضاعفات الناتجة عن الجلطة القلبية : لكون الوظيفة الأساسية للقلب هى عمله كمضخة للدم على مدار الساعة بدون أنقطاع ولأن هذه العضلة تعتمد في " ترويتها " على الشرايين التاجية الثلاث الآنف ذكرها فإن أي أنسداد في أحد هذه الشرايين يؤدي إلى نوعين من المضاعفات : 1- مضاعفات كهربية مما يؤدي إلى أضطراب في نظم ضربات القلب . 2- مضاعفات عضلية كقصور في وظائف " المضخة " مما يؤدي إلى هبوط في وظائف القلب أو لاسمح الله للصدمة القلبية . وتختلف درجات الهبوط في وظائف القلب بأختلاف حجم الجلطة القلبية وبوجود جلطة أو جلطات قلبية سابقة ، كلما كبر حجم الجلطة كان الهبوط أشد وكلما كان هناك جلطة سابقة كان الخطر من الهبوط الحاصل من الجلطة المستجدة أكثر وأكبر . وتختلف أعراض هبوط وظائف القلب بأختلاف شدته ، أهم هذه الأعراض هو وعي المريض بضربات القلب أو تسارع ضربات القلب أو رفه في القلب أو آلام الصدر وضيق النفس سواء بعد جهد أو خلال الراحة كما قد يحدث سعال وضيق في التنفس عند الأستلقاء أو النوم يزولان عند الجلوس أو الأستيقاظ ، وفي أقصى حالاته يتضخم الكبد وتنتفخ البطن وتتورم القدمين . وأما في حالة حدوث جلطة كبيرة مؤدية إلى تلف أكثر من 40% من حجم عضلة القلب وخصوصاً البطين الأيسر فقد ينشأ مايعرف بحالة " الصدمة القلبية " وفي هذه الحالة يحصل نقص حاد في تروية أعضاء الجسم كله ناتج عن " فشل المضخة " القلبية مما يؤدي عادة إلى أنخفاض شديد في الضغط الشرياني مع برودة وأزرقاق في الأطراف وضعف حاد في وظائف الكلى . 3- السكتة القلبية :هى موت مفاجى ء وغير منتظر يقع خلال مدة لاتتجاوز الساعة من أصابة الشخص بالأعراض القلبية كألام الصدر أو ضيق التنفس أو حالة الأنحطاط العام ، مع أن هناك العديد من الأسباب المؤدية للسكتة القلبية فإن تصلب الشرايين التاجية هو أهمها وأكبرها على الإطلاق ( السبب في 90% من حالات السكتة ) . وبينما يوجد تصلب في شريان تاجي فقط لدى 10% من ضحايا السكتة يوجد تصلب في شريانين لدى 10% من هؤلاء ويوجد بتصلب شديد في الشرايين التاجية الثلاثة لدى 75% من الحالات . وتنتج السكتة القلبية نتيجة عدم أستقرار كهربي بسبب النقص الشديد في التروية التاجية ، وعدم الأستقرار هذا يحدث فوضىتامة لاتستقر إلا بعد إعطاء الصدمة الكهربائية اللازمة في الوقت المناسب . أما الأعراض التي قد تسبب السكتة القلبية ففي الغالبية هى شعور برفه في القلب أو ألم شديد في الصدر أو ضيق في التنفس أو إنزعاج ما في الصدر أو أنحطاط شديد في الجسم . من هم المرضى المعرضون أكثر من غيرهم للسكتة القلبية ؟ - الرجال فوق سن الخامسة والثلاثين . - المصابون بتصلب الشرايين التاجية بغض النظر عن الشكوي . - الذين يشكون من أرتفاع في ضغط الدم . - من لديهم أرتفاع في نسبة الكولستيرول والدهنيات الثلاثية . - المصابون بداء السكري . - الذين يشكون من زيادة الوزن أو السمنة . علاج الجلطة القلبية : من أهم مباديء العلاج هو التشخيص الدقيق للداء وأسباب هذا الداء ومع أن السبب الحقيقي لتصلب الشرايين التاجية لايزال غامضاً ، فإننا بدأنا بالتعرف على عوامل خطيرة ومهيئة له ، وقد أظهرت الدراسات العلمية بما لايدعوا للشك أن علاج هذه العوامل الخطيرة والمهيئة لتصلب الشرايين والسيطرة على هذه العوامل يؤدي بالضرورة إلى خفض واضح وصريح لهذا المرض ومضاعفاته الخطيرة . كما أتضح من الدراسات الموثقة والتي أستخدمت فيها القسطرة التاجية وجود تناسب طردي بين عدد الشرايين التاجية المتصلبة وبقاء المريض على قيد الحياة ، كما أظهرت هذه الدراسات كذلك وجود علاقة تناسب بين مدى تصلب الشرايين التاجية وحدة الأعراض الناتجة عن هذا التصلب . - الأهداف العامة لعلاج الجلطة القلبية : 1- إزالة آلام الصدر ( الذبحة الصدرية ) والوقاية منها . 2- تخفيف خطورة المرض ومضاعفاته الحادة والمزمنة . 3- ( إذا جاز التعبير ) إطالة عمر المريض إذا شاء الله . - أنواع العلاج : أولاً : العلاج بالأدوية : 1- الأدوية التي تعطى بشكل عاجل ومنها الأدوية المذيبة للخثرة الدموية وهى تحقن بالوريد ، مثل دواء (TPA ) وألـ ( STREPTOKINASE ) وألـ ( HEPARIN ) . 2- الأدوية المنظمة لضربات القلب كالـ ( LIGNOCAINE ) . 3- الأدوية المستخدمة في حالة حصول سكتة قلبية لاسمح الله . 4- الأدوية المعطاة لتخفيف الآم الصدر كالنترات والمورفين . 5- الأدوية المفيدة لتهدئة عضلة القلب مثل المضادة لمستقبلات ( بيتا ) والمثبطة للكالسيوم . 6- أخيراً وليس آخراً الأسبرين الذي أثبت جدواه الأكيدة في تخفيض مضاعفات الجلطة وحد أنتشارها . ثانياً : العلاج بالقسطرة : وهذه النوعية من العلاج أثبتت نجاحها ودورها الهام في تحسين حالة مرضى الجلطات القلبية ، ويبدأ الأمر بعمل قسطرة تشخيصية تتكون من حقن للشرايين التاجية بواسطة قساطر ( أنابيب بلاستيكية ) دقيقة بأستعمال صبغة ملونة مما يساعد في معرفة مكان ودرجة تضيق أو أنسداد الشرايين التاجية . وعند كون الحالة مناسبة " للعلاج بالقسطرة " يقوم الطبيب بإدخال بالون في الجزء المتضيق من الشرايين ونفخه لكي يتسع ، كذلك في بعض الحالات يجري تركيب دعامة شريانية للمحافظة على أنفتاح الشريان التاجي والتقليل من مخاطر أنكماشة أو عودة التضيق له مرة أخرى . ثالثاً : العلاج الجراحي : وهى في الحقيقة جراحة خارج القلب ، على الشرايين ، والخطر في هذه النوع من الجراحة ضئيلة لاتتعدى 2% ونتائج هذه العملية جيدة إلى ممتاز في أكثر من 80% من الحالات من ناحية تحسن أعراض الذبحة الصدرية وتجنب الجلطات المستقبلية وإطالة عمر المريض إذا شاء الله . أما الشروط الموجبة لعملية الشرايين التاجية فهى : 1- أن يكون هناك على الأقل شريانان متضيقان تضيقاً شديداً أو متوسطاً . 2- أن يكون التضيق في أول الشريان أو على الأكثر في منتصفه إذا أن الجراحة على شريان متضيق في نهايته غير مجدية . 3- أن يكون التضيق موضعياً وغير منتشر على طول الشريان . 4- أن تكون عضلة القلب سليمة أو شبه سليمة . 5- أن تكون الحالة العامة للمريض جيدة . 6- تضيق الشريان لأيسر الرئيسي ( الجذع ) قبل أنقسامه . هو مرض خطير ويجب أجراء زراعة الشرايين في أقرب فرصة . 7- تدرس كل حالة على حدة . وكما يقال فإن درهم وقاية خير من قنطار علاج فأنجح السبل لتخفيف أخطار هذا المرض هو الوقاية من وذلك من خلال : 1- حملة للتوعية العامة بهذا المرض ومسبباته موجهة بشكل مكثف للنشء في المدارس والمعاهد . 2- تشجيع الأشخاص على قياس ضغط الدم والبحث عن داء السكرى وأرتفاع مستوى الكولسترول . 3- عمل حملة عامة للتوعية بفوائد الغذاء المتزن وممارسة الرياضة المنتظمة . 4- شن حملة مكثفة شعواء على ممارسة كافة أنواع التدخين ومساندة عيادات الإقلاع عنه .
myocardial infaraction
This term refers to the death of a certain segment of the heart muscle (myocardium), usually the result of a focal complete blockage in one of the main coronary arteries or a branch thereof.
The main cause of myocardial infarction is atherosclerosis in the coronary arteries. Refer for the pathogenesis of myocardial infarction. This event results in impaired contractility of the heart muscle within seconds, and is initially restricted to the affected segment.
The myocardial ischemia or infarction begins in the endocardium (the inner lining of the heart) and spreads to the epicardium (the outer lining of the heart). Irreversible heart damage will occur if the blockage is complete for at least 15-20 minutes. Irreversible damage occurs maximally in the area at risk, and when the occlusion is maintained for 4-6 hours. Most of the damage occurs in the first 2-3 hours. Restoration of flow within the first 4-5 hours is associated with salvage of the heart muscle, but the salvage is greater if flow is restored in the first 1-2 hours. A major determinant of death and illness is the size of the infarct. Increasing the oxygen supply to the involved site of blockage by coronary reperfusion (angioplastystents, figures atherectomy, see figures is more effective in salvaging the myocardium than decreasing oxygen demand.
The onset of acute Q-wave myocardial infarction for normal EKG with a normal Q-wave, which is sharply inscribed, narrow in time of inscription and small in depth compared to the abnormal acute Q-wave type in myocardial infarction, which is deeper and wider in inscription time) occurs commonly in the morning hours shortly after arising, when there is increasing adrenergic activity, as well as increased blood fibrinogen levels and increased platelet (blood cell) adhesiveness. Non Q wave infarction does not show this circadian rhythm.
The traditional concept that myocardial infarctions can be classified as transmural or nontransmural on the basis of the presence or absence of Q waves is misleading, since autopsy studies have demonstrated convincingly that pathologic Q waves may be associated with nontransmural infarction and may be absent with transmural infarction. These misnomers have been replaced by the terms Q-wave infarction and nonQ-wave infarction for transmural and nontransmural infarction, respectively.
The evolution of a non-Q-wave infarction is charcterized by a lack of development of an abnormal Q wave and by the appearance of reversible ST-T-wave changes with ST depression that usually returns to normal over a few days, but occasionally is permanent. Differentiation between these two types of infarctions has become entrenched, since there are major differences in their pathogenesis, clinical manifestations, treatment, and prognosis. The initiating events in the pathogenesis of Q-wave and non-Q-wave infarction are thought to be identical, namely, coronary occlusion induced by thrombus superimposed on a plaque together with vasoconstriction.
There is considerable evidence, however, to indicate that in non-Q-wave infarction, early spontaneus reperfusion occurs, the mechanism of which remains uncertain. In contrast, in Q-wave infarction, the coronary occlusion is sustained at least for a long enough period to result in extensive necrosis.One explanation for early spontaneous reperfusion is the lack of sustained vasoconstriction, which may contribute to ocusion. The evidence supporting the existence of early spontaneous reperfusion in non-Q-wave infarction is as follows:
1. Coronary angiographic studies performed in the early hours after onset show that only 20-30% of patients have complete coronary occlusion of the infarct-related vessels;but for Q-wave infarction it is about 80 to 90%.
2. Infarct size is routinely much less than observed with Q wave infarction, which is consistent with salvage by early reperfusion.3. Peak plasma CK levels are reached on an average of 12 to 13 h after onset of symptoms, indicating early washout of the enzyme, as opposed to about 27 h after Q-wave infarction.4. Reperfusion-induced contraction necrosis is extremely common, as it is in patients who undergo early reperfusion induced by thrombolytic therapy.5. Acute mortality rates are around 2 to 3 percent, compared with 10 percent for Q-wave infarction.6. The complications are minimal compared with those after a Q-wave infarction.7. Finally, the long-term prognosis is characterized by recurrent episodes of reinfarction, so that after about 2 years, survival is the same as that after Q-wave infarction.
Quite often with the initial heart attack over half of the patients have significant obstructive atherosclerosis in only one vessel. However, in a recent study two fifths of the patients with acute myocardial infarction had angiographic evidence of multiple complex coronary plaques, which were associated with a less favorable in-hospital course. The presence of these plaques with complex morphologic features is the angiographic hallmark of unstable coronary syndromes and correlates with pathologic plaque and thrombus.
Other causes of myocardial infarction
Carbon monoxide poisoning is one of the occupational toxic risk factors for not only myocardial infarction but also cardiomyopathy.
Firefighters '"chronic" occupational exposure to carbon monoxide results in increased blood concentrations of carboxyhemoglobin, even in nonsmoking firefighters; changes in cardiac serum enzyme levels in one study suggested myocardial (heart) damage.
Increase symptoms in patients known to have coronary disease occur with exposure to carbon monoxide. Carbon monoxide has an affinity for hemoglobin that is much greater than that of oxygen. The cardiac effects are the results of hypoxia. These effects are determined by the degree of carbon monoxide exposure, the hemoglobin concentration, and the presence or absence of coronary or myocardial disease.
A decrease in exercise performance occurs even in normal individuals with low level exposure. Patients with angina pectoris have a greater reduction in exercise tolerance.
Carbon monoxide poisoning causes myocardial ischemia most commnoly manifest as ST- and T-wave changes on the ECG and atrial and ventricular arrhythmias. Severe exposure can cause extensive myocardial necrosis and cardiomyopathy. Myocardial infarction may occur as a result of myocardial necrosis without coronary occlusion.
Signs of acute CO intoxication include headache, confusion, visual disturbance, unconsciousness, seizures and lung edema. If untreated severe intoxication can lead to death.
Patients with mild intoxication are likely to recover without specific treatment other than removal from the noxious gas environment. The outlook is uncertain in those severely intoxicated. The severity of the illness often does not correlate with the measured carboxyhemoglobin level but corresponds more closely to the extent and the duration of the exposure.
Patients with any form of CNS impairment, evidence of myocardial ischemia,or carboxyhemoglobin levels above 25% merit aggressive therapeutic intervention. The rationale for treatment with hyperbaric oxygen is based on more rapid removal of the CO from hemoglobin and tissue sites. Because O-2 and CO compete for hemoglobin and many tissue binding sites, hyperbaric oxygenation greatly acclerates CO elimination. Furthermore, O-2 dissolved in plasma under hyperbaric conditions effectively bypasses any impediment to oxygen transport imposed by carboxyhemoglobin. Potentially lethal cerebral hypoxia may be averted as a consequence.Twenty minutes of exposure to 100% oxygen at 2.4 atm absolute will be accompanied by release of CO from the blood equivalent to that obtained after 5 hours of breathing uncontaminated air. Sixty to 90 min of hyperbaric oxygen therapy at this pressure is sufficient to reduce carboxyhemoglobin saturation to well below 10%. Prompt recovery is the rule if treatment can be initiated before extensive irreversible brain injury has occuuued.
CORONARY ARTERY DISSECTION
Separation of the media by hemorrhage with or without an associated intimal tear is termed coronary artery dissection. The medial separation forces the intimal-medial layer (wall of the true channel) toward the true coronary lumen and producesdistal myocardial ischemia/infarction Coronary artery dissections may be primary or secondary .
A. Post-or peripartumB. With or without eosinophiliaC. IdiopathicD. Systemic hypertensionE. Coronary spasmF. Aortic root dissection (hypertension, medial degeneration)G. ArteritisH. Fibromuscular hyperplasia
2.Trauma
A. Post- or peripartumB. Blunt chest (penetrating, nonpenetrating)C. Coronary-~angiographyD. Coronary interventions (angioplasty, atherectomy laser, stenting, rotablade)E. Cardiac surgery (coronary bypass, coronary ostial cannulation, endarterectomy)F. Aortic root dissection(surgery, non-penetrating, penetrating
Secondary coronary artery dissections are more frequent, especially those associated as an extension from aortic root dissection (8 percent). Primary coronary artery dissections may occur spontaneously or as a consequence of coronary angioplasty or angiography, cardiac surgery, or chest trauma (0.3 percent). Most spontaneous coronary artery dissections occur in women who are most commonly postpartum: they may be associated with coronary artery wall eosinophils. The left anterior descending artery is the one most frequently involved. Systemic hypertension does not appear to provide a significant factor of risk.Spontaneous coronary artery dissection may result in sudden death or acute myocardial infarction and subsequent death. Parenthetically, localized and limited coronary artery dissection te (i.e., intimal-medial tear) appears necessary for a clinically successful coronary artery balloon angioplasty procedure.Coronary angioplasty dissections viewed in short- or long-axis tomographic images help distinguish dissections that are therapeutic (mechanism) from those which are complications of angioplasty (complications). In the short-axis image, dissection involving more than 50 percent of the coronary medial circumference has been considered a complication. Similarly, in the long-axis image, dissections (antegrade, retrograde, or a both) longer than 1 cm in length also have been defined as a complication of angioplasty A combination of dissection greater than 50 percent of the short-axis circumference and greater than 1 cm antegrade or retrograde of long-axis length may result in "intussusception" of intimal-medial tissue. Spiral dissections ("the ugly") are among the most serious dissection injuries after balloon angioplasty The spiral dissection as reviewed angiographically appears to alternate from side to side, extending antegrade and retrograde or it has an unaltered dissection course but appears alternating from limited angiographic views.
MANAGEMENT OF MYOCARDIAL INFARCTION(HEART ATTACK)
Objects of early treatment
1). Provide cardiac resuscitation if necessary.
2). Immediate hospitalization.
3). Treat life threatening arrhythmias.
4). Alleviate pain and suffering.
5). Preserve as much myocardium as possible by the following:
Cardioprotection by Increasing Coronary Flow:Thrombolysis (Dissolution of Blood Clot or Thrombus Blocking Lumen of Coronary Artery)
Thrombolysis is based on the following facts:
A). The evolution of myocardial necrosis (death) following coronary occlusion is time-dependent over 4-6 hours.
B). The restoration of coronary blood flow within this 4-6 hour period salvages myocardium, but in a time related fashion.
C). The proximate cause of myocardial infarction is generally an occlusive thrombus within the coronary artery.
Clinical trials have shown that Early Reperfusion Induced by a Thrombolytic Agent --- Recombinant Tissue Plasminogen Activator, Streptokinase, Urokinase, or Anisoylated Plasminogen Streptokinase Activator Complex --- is associated with Limitation of Infarct Size, Preservation of Ventricular Function, and Improved Survival.
Sustained Patency and the Impact of Reocclusion
The incidence of coronary reocclusion from rethrombosis is about 20 per cent, and the incidence of reinfarction is about 10 per cent, occurring mainly in the first 24 hours.
Contraindications to Thrombolytic Therapy
1). Cerebral vascular accident (stroke) within the last 3 months
2). Recent major surgery
3). Pregnancy, aortic dissection, recent head trauma, brain tumor
Risks of Thrombolytic Therapy: Possible Intracranial Bleeding (Stroke)
Conjunctive and Adjunctive Therapy
1). Heparin (an anticlotting drug) is given intravenously to prevent rethrombosis and reocclusion: 5000 units as a bolus, followed by an infusion of 1000 to1200 units/h to keep the PTT (a measure of the clotting time of blood) at 1.5 to2.0 times normal for the first 24-48 hours.
2a). Aspirin is more effective than heparin after 24 to 48h, because the plasma thrombin levels have returned to normal by this time. Aspirin reduces the incidence of reocclusion and reinfarction. It should be given as soon as possible and continued indefinitely.
2b). The antiplatelet agent clopidogrel has been found to lower the number of nonfatal myocardial infarction or stroke in patients with acute coronary syndromes without ST-segment elevation to 9.3% compared to placebo and aspirin with 11.4% over a 3 to 12 month period. Also, the above or refractory ischemia occurred in 16.5% in the clopidogrel group compared to 18.8 % in the placebo group. But there were significantly more patients with major bleeding in the clopidogrel group (3.7%) than in the placebo group (2.7%), but there were not significantly more patients with life-threatening bleeding (2.1% versus 1.8%) or hemorrhagic stroke.
Reference:Clopidogrel in Unstable Angina to Prevent Recurrent Events trial Investigators,Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes Without ST-Segment Elevation,N Engl J Med,Vol.345,No.7,August 16,2001 ,Pp.494-502.
3). Beta-Adrenergic Blockers ( medications like metoprolol, atenolol) effects :
a) Reduces ventricular ectopy, atrial fibrillation, and nonfatal cardiac arrest
b) Reduces frequency of progression of threatened infarction to completed infarction
c) Reduces recurrent ischemia and infarction during first 6 weeks after initial event
4). Magnesium has the following effects:
a) reduces all causes of death and coronary care mortality rates;
b) reduces congestive heart failure in the coronary care unit;
c) preserves myocardium;
d) may reduce ventricular arrhythmias.
Angioplasty and Surgical Revascularization as Primary or Adjunctive Therapy to ThrombolysisRisk of Thrombolytic Therapy: Hemorrhagic strokengioAdjunctive Theray to Thrombolyses in which angioplasty may be per
1). Direct angioplasty as the primary reperfusion technique.
2). Immediate angioplasty after thrombolytic agent.
3). Rescue angioplasty if thrombolysis fails.
4). Delayed angioplasty routinely after thrombolysis.
5). Elective angioplasty if ischemia occurs after reperfusion.
Use of Glycoprotein IIb/IIIa Inhibitors
A recent study has shown that the use of the platelet glycoprotein IIb//IIIa inhibitor tirofiban in patients with unstable coronary syndromes (unstable angina and myocardial infarction without ST elevation) and early invasive strategy including percutaneous coronary revascularization and intracoronary stents reduce the risk of death, myocardial infarction or recurrent angina. The benefit of the early invasive strategy was greater in patients with troponin T levels (markers of myocardial injury) of more than 0.01ng per milliliter than in patients with levels of 0.01ng per milliliter or less.
The benefits of early invasive strategy, similarly, were largely confined to patients with ST-segment depression on the admission electrocardiogram. The advent of "point of care" measurements of troponin levels in the emergency room, together with the routine electrocardiogram, has made the goal of rapid identification of high risk patients most likely to benefit from an early invasive approach readily attainable. It is thus unnecessary to recommend the use of such an approach for all patients with acute coronary syndromes, especially those without elevated levels of cardiac enzymes or troponins or ST-segment depression.
Reference:Cannon,C.P.,M.D. and others,Comparison of early invasive and conservative strategies in patients wit unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban,N.Engl.J.Med.,Vol.344,No.25.June 21,2001,PP.1879-1887.
Reference:Boden,W.E. andMackay,R.G.,Optimal treatment of acute coronary syndromes-An evolving strategy,N.Engl.J.Med.,Vol.344,No.25.June 21,2001,PP.1939-1942.
Another study showed that tirofiban offerred less protection from major ischemic events with percutaneous coronary revascularization than did abciximab, another platelet inhibitor.
Reference:Topol,E.J. and others,Comparison of two platelet glycoprotein IIa/IIIb inhibitors,tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization,N.Engl.J.Med.,Vol.344,No.25.June 21,2001,PP.1888-1893
There is also a recent report that early administration of abciximab in patients with acute myocardial infarction improves coronary patency before stenting, the success rate of stenting procedure, and the rate of coronary patency at six months, left ventricular function, and clinical outcomes.
Reference:Montalescot,G. and others,Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction,N.Engl.J.Med.,Vol.344,No.25.June 21,2001,PP.1895-903.
Troponin Measurements in Ischemic Heart Disease
Current nomenclature categorizes patients with ischemic discomfort into those who present with ST elevation of the twelve lead electrocardiogram (E CG) versus those who do not present with ST elevation. Patients presenting with ST-segment elevation are, of course, easy to recognize using the ECG. The majority of such patients will develop a Q wave on the ECG and will ultimately be diagnosed as having sustained a Q-wave myocardial infarction(MI). Patients who present without ST elevation are experiencing either unstable angina(UA) or a non-ST- segment elevation MI (NSTEMI). Most patients who present with NSTEMI do not develop a Q wave on the ECG. The distinction between unstable angina and NSTEMI is based on the presence or absence of a cardiac marker in the blood. When such a cardiac marker is detected in a patient's blood, the patient is ultimately diagnosed as having a non-Q wave myocardial infarction.
Biochemical markers of myocyte necrosis are useful not only for making the diagnosis of an MI, but also with estimating prognosis. Of interst are the macromolecules that diffuse out of necrosing myocytes as membrane integrity is lost. Once outside the myocyte, the macromolecules are cleared from the interstitium by cardiac lymphatics. Eventually when the capacity of lymphatics to clear the macromolecules is exceeded, the markers become detectable in the peripheral circulation. Both clinical chemical laboratory of assays and bedside assays are available to measure several biochemical cardiac markers, notably myoglobin and the MB fraction of creatine kinase( CK-MB) and cardiac specific troponins T and I (cTnT and cTn I).
Although myoglobin and CK.-MB are familiar to physicians and provide reasonable sensitivity for detecting MI, they lack specificity in the setting of skeletal muscle disease or injury. Hence, there is intense interest in cTnT and cTn I as markers that are found in high concentration in the myocardium and are released with a stoichiometric relationship proportional to the amount of myocardial injury. Monoclonal-antibody-based assays are available that capitalize on the fact that the amino acid sequences of the cardiac and skeletal muscle forms of troponins T and I are sufficiently dissimilar. After much debate and discussion expert panels have declared cTnT and cTnI to be the preferred biomarkers for detection of myocardial damage.
Myocardial necrosis (i.e.MI) is said to be present if the maximal concentration of cTnT or cTnI exceeds the decision limit (99 percent of the values for a reference control group) on at least one occasion during the 24 hours after the index clinical event. It is important to note that patients may have an episode of microinfarction where cTnT or cTnI measurements exceed the decision limits and yet CK-MB even by mass assay remains in the normal range. It is estimated that about 1/3 of patients presenting without ST elevation who would previously have been diagnosed as experiencing unstable angina on the basis of normal CK-M B levels are now diagnosed as experiencing NSTEMI because of detectable troponin levels.
In a recent study the results of several trials reported that the relative risk of troponin positive patients (compared with troponin negative patients)was 3.9 for mortality and 3.8 for death or nonfatal recurrent MI. The adverse prognostic significance of a positive troponin test has been demonstrated by multiple chemical investigators across multiple trials, involving multiple patient groups from different countries, indicating that the observation is a robust one.
Part of the answer to why the patients with a positive troponin test have a worse prognosis may simply be that the positive troponin is indicative of myocardial necrosis. Because it is well established that left ventricular(LV) function is a pivotal determinant of prognosis, it is possible that loss of functioning myocardium is associated with a worse outcome. Several investigators have reported dichotomous analysis showing that the patients who present with UA/ NSTEMI and a positive troponin test are significantly more likely to have high-risk angographic anatomy of the culprit lesion. Troponin-positive patients are more likely to have visible thrombus in the culprit lesion,complex lesions, and worse thrombolysis in myocardial infarction flow grade. It has been argued that these anatomical findings put troponin-positive patients at risk for downstream embolization of atherothrombotic debris, occluding the microvasculature and causing foci of microinfarction-hence the release of troponin.
This line of reasoning leads to the oft-repeated recommendation by several investigators that patients with positive troponin test should be treated aggressively with antithrombotic therapy with particular emphasis on the intravenous IIb/IIIa inhibitors. It also been argued that troponin-positive patients should be selected for referral for early invasive strategy. Clearly ,not all troponin positive patients are at the same level of risk. Note that there is a highly significant gradient of increasing risk of mortality with increasing troponin levels. In a recent study patients with increasing cTnT levels tended to have progressively greater delays from the onset of symptoms to blood sampling, were significantly more likely to present a ST depression or abnormal Q-waves on their ECG. And were progressively more likely to have depressed LV function on echocardiography (ejection fraction less than 45 percent). In the subset patients who were randomized to an early invasive strategy, angiography did not show any correlation between the severity of underlying coronary artery disease in the cTnT level but did show a progressive increase in the odds of visible thrombus and a progressive decrease in the odds of TIMI flow grade 3 with increasing cTnT levels.
Complementing the angiographic finding from the early invasive strategy are the interesting clinical findings in the early noninvasive cohort. The 12-month mortality was numerical lowest in the cTnT negative group and was slightly higher in the cTnT positive patients, but there was no clear trend toward increasing mortality with increasing troponin levels when analyze by tertilesof positive cTnT. However, a U-shaped relationship was observed between troponin measurements and the rate of MI through one year;MI occurred in 5.5% of cTnT negative patients (<0.01>0.63ng/ml. A similar U-shaped relationship was found with referral for revascularization: 38.8%,51.9%,46.1% and 34.3%, respectively, in the same four groups.
In another study patients with either undetectable or only slightly elevated levels of cTnT or cTnI showed no benefit of tirofiban with respect to prevention of death or nonfatal MI by 30 days. Those with intermediate elevations of either cTnT or cTnI had the maximal benefit, whereas those with higher biomarker levels showed progressive less benefit compared with the intermediately elevated group.
Those patients with negative tests (below the decision limit) or just barely elevated quantitative results are at low risk.They are unlikely to benefit from IV glycoprotein IIb/IIIa inhibitors. In general, they are managed equally well with either an early conservative or early invasive strategy (depending on patient and physician preferences). Multiple clinical factors other than the results of biomarkers should be included in the decision about referral for revascularization. Those patients with an intermediately elevated troponin levels have not yet lost substantial amounts of myocardium and are excellent candidates for effective antithrombotic therapy (e.g.,enoxaparin in place of unfractionated heparin) and prompt referral for an early invasive approach supported by IV glycoproteins inhibitors in the catheterization laboratory.
Those patients with the highest level of troponin have already lost substantial amounts of myocardium.It is not clear it is not so clear that aggressive antithrombotic therapy with glycoprotein inhibitors will be helpful in such patients. The focus should be early diagnostic coronary arteriography. Some patients may have a completed left circumflex infarction masquerading as / NSTEMI . Others may have severe multivessel disease or other r high risk coronary anatomy in association with depressed LV function (as suggested by high troponin levels); this group is likely to be best served by referral for coronary artery bypass surgery.
Because of the uncertainty about the best course of action for patients with highest level of troponin upstream use of IV glycoproteinIIb/IIIa inhibitors is not favored. Instead, diagnostic catheterization is advised to determine whether revascularization is needed, art in the in and if so, whether referral for surgery is best without IV glycoproteins or whether a percutaneous intervention supported by the inhibitors is
Reference:Antman,E.M., Troponin Measurements in Ischemic heart Heart Disease:More Than Just a Black and White Picture,AmericanCollege Cardiology ,Vol.38,N.4 2001,PP.987990
ACC/AHA 2002 Guideline Updatefor the Management of Patients WithUnstable Angina and Non-ST-SegmentElevation Myocardial Infarction-Summary Article
A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)
INTRODUCTION
The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) were published in Septemher 2000 (1). Since then, a number of clinical trials and observational studies have been published or presented that, when taken together, alter significantly the recommendations made in that document. Therefore, the ACC/AHA
The ACC/AHA Task Force on Practice Guidelines makes every effort to avoid any actual or potential conflicts of interest that might arise as a result of an outside relationship or personal interest of a member of the writing panel. Specifically, all members of the writing panel are asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. These statements are reviewed by the parent task force, reported orally to all members of the writing panel at the first meeting, and updated as changes occur.
This document was approved by the American College of Cardiology Foundation Board of Trustees in September 2002 and by the American Heart Association Science Advisory and Coordinating Committee in August 2002.
When citing this document, the American College of Cardiology Foundation and the American Heart Association would appreciate the following citation format: Braunwald E, Anturan EM, Beasley JW, Califf RM, Cheitlin MD, IIochman JS, Jones RI- I, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE III, Steward DE, Theroux P.ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2002;40:1366-74.
This document is available on the World Wide Web sites of the ACC (wow. acc.org) and the AHA (www.americanheartorg). Single copies of this document arc available for $5 each by calling 800-253-4636 (US only) or writing the American College of Cardiology Foundation, Resource Center, 9111 Old Georgetown Road, Bethesda, MD 20814-1699 (product code 71-0227).This document and the companion full-text guidelines (product code 71-0240), are available on the ACC Web site at www.acc.org and the AHA Web site at www.anieiicauheart.org. To purchase additional reprints (specify version): up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1,000 or more copies, call 214-706-1466, fax 214-691-6342; or E-mail pubauth©heart.org
Committee on the Management of Patients With Unstable Angina, with the concurrence of the ACC/AHA Task Force on Practice Guidelines, revised these guidelines. These revisions were prepared in December 2001, reviewed and approved, and then published on the ACC World Wide Web site (www.acc.org) and AHA World Wide Web site (www.americanheart.org) on March 15, 2002. The present article describes these revisions and provides further updates in this rapidly moving field. Minor clarifications in the wording of three recommendations that now appear differently from those that were previously published on the ACC and AHA Web sites are noted in footnotes.
The ACC/AHA classifications I, II, and III are used to summarize indications as follows:ClassI:Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective. ClassII:Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment.IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.IIb: Usefulness/efficacy is less well established by evidence/opinion.ClassIII: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful.The weight of the evidence was ranked highest (A) if the data were derived from multiple randomized clinical trials that involved large numbers of patients and intermediate (B) if the data were derived from a limited number of randomized trials that involved small numbers of patients or from careful analyses of nonrandomized studies or observational registries. A lower rank (C) was given when expert consensus was the primary basis for the recommendation.
RISK ASSESSMENT
Clinical Features
Unstable angina and NSTEMI are heterogeneous disorders in which patients have widely varying risks. Risk is an important "driver" of management decisions, and accurate yet simple methods of risk assessment are important for patient care.
Risk was assessed by multivariable regression techniques in patients presenting with UA/NSTEMI in several large clinical trials. Boersma et al. analyzed the relation between baseline characteristics and the incidence of death and the composite of death or myocardial (re)infarction at 30 days in patients who entered the PURSUIT (Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial (2). The most important baseline features associated with death were age, heart rate, systolic blood pressure, ST-segment depression, signs of heart failure, andelevation of cardiac biomarkers. From this analysis, a simple risk estimation score was developed.
Antman et al. developed a 7-point risk score, the "TIMI Risk Score," (age greater than or equal to 65 years, more than 3 coronary risk factors, prior angiographic coronary obstruction, ST-segment deviation, more than 2 angina events within 24 h, use of aspirin [ASA] within 7 days, and elevated cardiac markers) (3). The score was defined as the simple sum of these individual prognostic variables. The risk of developing an adverse outcome-death, (re)infarction, or recurrent severe ischemia that required revascularizationranged from 5% with a score of 0 or 1 to 41% with a score of 6 or 7. The score was derived from data in the TIMI 11B (Thrombolysis In Myocardial Infarction 11B) trial (4) and then validated in 3 additional trials-ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events study) (5), and PRISM-PLUS (Platelet Receptor inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms) (6) and prospectively in one TACTICS-TIMI 18 (Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction) 18 (7). A progressively greater benefit from newer therapies such as low-molecular-weight heparin (LMWH) (4,5), platelet glycoprotein (GP) IIb/IIIa receptor antagonists (6), and an invasive strategy (7) with increasing risk score have been reported.
Biomarkers
The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction (8) emphasized the use of troponins as critical markers of the presence of myocardial necrosis. Although troponins are accurate in identifying myocardial necrosis, the latter is not always secondary to atherosclerotic coronary artery disease. Therefore, in establishing the diagnosis of NSTEMI, cardiac troponins should be used in conjunction with appropriate clinical features and electrocardiographic changes. Myocardial injury of diverse origins (e.g., myocarditis, trauma, or cardioversion) may cause necrosis and release of troponins. Although these may be considered instances of NSTEMI, they should be distinguished on clinical grounds from the more common form of NSTEMI secondary to coronary atherosclerosis.
Antiplatelet Therapy
Antiplatelet therapy is a cornerstone in the management of UA/NSTEMI. Three classes of antiplatelet drugs (ASA, thienopyridines, and GP Ilb/IIIa antagonists) have been found useful in the management of these patients and are the subject of continued intensive investigation and analysis. Clopidogrel. Given its more rapid onset of action (9,10) and better safety profile compared with ticlopidine, clopidogrel is now the preferred thienopyridine. The CURE (Clopidogrel in Unstable angina to prevent Recurrent ischemic Events) trial (11) randomized 12,562 patients withUA/STEMI who presented within 24 h to placebo or clopidogrel (loading dose of 300 mg followed by 75 mg daily) and followed them for 3 to 12 months; all patients were given aspirin. Cardiovascular death, myocardial infarction (MI), or stroke occurred in 11.5% of patients assigned to placebo and 9.3% of those assigned to clopidogrel (relative risk [RR] 0.80; p less than 0.001). Looking at the individual components of the primary composite and end point, there was a trend in favor of clopidogrel for cardiovascular death and stroke (5.5% and 1.4%, respectively, for placebo vs. 5.1% and 1.2% for clopidogrel), and there was a significant reduction in MI (6.7% vs. 5.2% R.R. = 0.77, p less than 0.001). However, there was no significant difference in the incidence of non-Q-wave MI (3.8% vs. 3.5%). A reduction in recurrent ischemia was noted within the first few hours after randomization. These salutary results were observed across all subgroups of patients. There was, however, a significant excess of major bleeding (2.7% in the placebo group versus 3.7% in the clopidogrel group; p = 0.003) and of minor bleeding, as well as a (nonsignificant) trend for an increase in life-threatening bleeding. The risk of bleeding was increased in patients who underwent coronary artery bypass grafting (CABG) within the first 5 days after clopidogrel was discontinued.The CURE trial was performed in hospitals in which there was no routine policy of early invasive procedures, and therefore, revascularization was performed during the initial admission in only 23% of the patients, a substantially lower percentage than currently receive this therapy at most US hospitals. Although the addition of a GP IIb/IIIa antagonist appeared to be well tolerated in patients who were given ASA, clopidogrel, and heparin in CURE, fewer than 10% of patients received this combination. Therefore, additional information on the safety of "quadruple therapy" (heparin [unfractionated or low molecular weight], ASA, clopidogrel, and a GP 11b/111a antagonist) should be obtained.The CURE trial provides strong support for the addition of clopidogrel to ASA on admission in the management of patients with UA and NSTEMI. Clopidogrel appears to be especially useful in hospitals that do not have a routine policy of early invasive procedures and in patients who are not candidates or who do not wish to be considered for revascularization. The optimal duration of therapy with clopidogrel has not been determined. The major benefits in CURE were observed at 30 days, with small additional benefits observed over the subsequent treatment period, which averaged 8 months.
In PCI-CURE, a substudy of CURE, 2,658 patients who underwent percutaneous coronary intervention (PCI) had been randomly assigned to double-blind treatment with clopidogrel (n = 1,313) or placebo (n = 1,345) (12); all patients also received ASA. Patients were pretreated with placebo or study drug for a median of 10 days before PCI. After the procedure, most patients received open-label thienopyridine (clopidogrel or ticlopidine) for approximately 4 weeks, after which the study drug (placebo orclopidogrel) was again administered for an average of 8 months. The primary end point, a composite of cardiovascular death, MI, or urgent target-vessel revascularization within 30 days of PCI, occurred in 86 patients (6.4%) in the placebo group compared with 59 (4.5%) in the clopidogrel group (RR 0.70; p = 0.03). When events that occurred before and after PCI were considered, there was a 31% reduction in cardiovascular death or MI with assignment to clopidogrel (p = 0.002). Thus, in patients with UA and NSTEMI who are given ASA and are undergoing PCI, a strategy of clopidogrel pretreatment followed by at least 1 month and probably longer-term therapy is beneficial in reducing major cardiovascular events (12).
There now appears to be an important role for clopidogrel in patients with UA/NSTEMI, both those who are managed conservatively and those who undergo PCI, especially stenting. However, it is not entirely clear how long therapy should be maintained. Because clopidogrel, when added to ASA, increases the risk of bleeding during major surgery in patients who are scheduled for CABG, if possible, clopidogrel should be withheld for at least 5 days (11) and preferably for 7 days before surgery (13). In many hospitals in which patients with UA/NSTEMI undergo diagnostic catheterization within 24 to 36 h of admission, clopidogrel is not started until it is clear that CABG will not be scheduled within the next several days. A loading dose of clopidogrel can be given to a patient on the catheterization table if a PCI is to be performed immediately. If PCI is not performed, clopidogrel can be begun after the catheterization.
Glycoprotein IIb/IIIa antagonists in PCI.
The introduction of platelet GP IIb/IIIa antagonists represents an important advance in the treatment of patients with UA/ NSTEMI who are undergoing PCI. These drugs take advantage of the fact that platelets play an important role in the development of ischemic complications that may occur in patients with UA/NSTEMI during coronary revascularization procedures. The September 2000 guidelines emphasized the value of GP Ilb/IIIa antagonists in patients with UA/NSTEMI who were undergoing PCI (1).Two trials of GP IIb/IIIa inhibitors have been published since September 2000. The ESPRIT trial (Enhanced Suppression of the Platelet IIb/Illa Receptor with Integrilin Therapy) was a placebo-controlled trial designed to assess whether eptifibatide improved outcome in patients undergoing stenting (14). Fourteen percent of the 2,064 patients enrolled in ESPRIT had UA/NSTEMI. The primary end point (the composite of death, MI, target-vessel revascularization, and "bailout" GP Ilb/Illa antagonist therapy) was reduced from 10.5% to 6.6% with treatment (p = 0.0015). There was consistency in the reduction of events in all components of the end point and in all major subgroups, including patients with UA/NSTEMI. Major bleeding occurred more frequently in patients who received eptifibatide (1.3%) than in those who received placebo (0.4%; p = 0.027); however, no significant difference in thetransfusion rate occurred. At 1 year of follow-up, death or MI occurred in 12.4% of patients assigned to placebo and 8.0% of eptifibatide-treated patients (hazard ratio 0.63; 95% confidence interval [CI] 0.48 to 0.83; p = 0.001) (15).In the only head-to-head comparison of GP Ilb/lila antagonists, the TARGET trial (Do Tirofiban and ReoPro Give similar Efficacy? Trial) randomized 5,308 patients to tirofiban or abciximab before PCI with the intent to perform stenting (16). The primary end point, a composite of death, nonfatal MI, and urgent target-vessel revascularization at 30 days, occurred less frequently in those given abciximab than in those given tirofiban (6.0% vs. 7.6%; p = 0.038). There was a similar direction and magnitude for each component of the end point. The difference in outcome between the 2 treatment groups may be related to a suboptimal dose of tirofiban resulting in inadequate platelet inhibition. However, by six months, the primary end point occurred in a similar percentage of patients in each group (14.9% tirofiban vs. 14.3 % abciximab, NS). Mortality was also similar (1.9% vs. 1.7%, NS) (17). Glycoprotein IIb/IIIa antagonists without scheduled PCI. The Global Utilization of Strategies to Open Occluded Coronary Arteries IV-Acute Coronary Syndromes (GUSTO IV-ACS) trial (18) enrolled 7,800 patients with UA/NSTEMI who were admitted to the hospital with more than 5 min of chest pain and ST-segment depression and/or elevated troponin T or I concentration and in whom early (less than 48 h) revascularization was not intended to be conducted. All received ASA and either unfractionated heparin (UFH) or LMWH. They were randomized to placebo, an abciximab bolus and 24-h infusion, or an abciximab bolus and 48-h infusion. The primary end point, death or MI at 30 days, occurred in 8.0% of patients given placebo, 8.2% given 24-h abciximab, and 9.1% given 48-h abciximab, differences that were not statistically significant. At 48 h, death occurred in 0.3%, 0.7%, and 0.9% in these groups, respectively (placebo vs. abciximab 48 h, p = 0.008). The lack of benefit of abciximab was observed in most subgroups, including patients with elevated concentrations of troponin who were at higher risk. Although the explanation for these results is not clear, they indicate that abciximab, at least at the dosing regimen used in GUSTO IV-ACS, is not indicated in the management of patients with UA or NSTEMI in whom an early invasive management strategy is not planned.In the PRISM-PLUS trial, 1,069 patients did not undergo early PCI. Although tirofiban treatment was associated with a lower incidence of death, MI or death, and MI or refractory ischemia at 30 days, these reductions were not statistically significant (19). In a high-risk subgroup of these patients not undergoing PCI (TIMI risk score greater than or equal to 4) (3), tirofiban appeared to be beneficial whether they underwent PCI (odds ratio [OR] 0.60, 95% CI 0.35 to 1.01) or not (OR 0.69, 95% CI 0.49 to 0.99). However, no benefit was observed in the patients at lower risk (6). In the PURSUIT trial, eptifibatide reduced theincidence of death or MI from 15.7% to 14.2% (RR 0.91; 95% CI 0.79 to 1.00; p = 0.032) (20).
Boersma et al performed a meta-analysis of GP IIb/IIIa antagonists in all 6 large, randomized, placebo-controlled trials, including GUSTO IV-ACS (18), which involved 31,402 patients with UA/NSTEMI who were not routinely scheduled to undergo coronary revascularization (21). A small reduction in the odds of death or MI in the active treatment arm (11.8% vs 10.8%; OR 0.91, 95% CI 0.84 to 0.98; p = 0.015) was observed. Unexpectedly, no benefit was observed in women (test for interaction between treatment assignment and gender, p less than 0.0001). However, women with positive troponins derived a treatment benefit that was similar to men. In the meta-analysis, reductions in the end points of death or nonfatal MI considered individually did not achieve statistical significance.Although not scheduled for coronary revascularization procedures, 11,965 of the 31,402 patients (38%) actually underwent PCI or CABG within 30 days, and in this subgroup, the OR for death or MI in patients assigned to GP IIb/IIIa antagonists was 0.89 (95% CI 0.80 to 0.98). In the other 19,416 patients who did not undergo coronary revascularization, the OR for death or MI in the GP IIb/IIIa group was 0.95 (95% CI 0.86 to 1.05, p = NS). Major bleeding complications were increased in the GP IIb/IIIa antagonist-treated group compared with those who received placebo (1.4% vs. 2.4%, p less than 0.0001). The authors concluded that in patients with UA/NSTEMI who were not routinely scheduled for early revascularization and who were at high risk of thrombotic complications, "treatment with a GP Ilb/Illa inhibitor might therefore be considered" (21). Thus, GP Ilb/Illa inhibitors are of benefit in high-risk patients with UA/NSTEMI, and their administration, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned received a Class I recommendation. These agents are of questionable benefit in patients who do not undergo PCI. However, the revised guidelines recommend broader indications for a routine invasive strategy (see following text).Thus, clopidogrel (in addition to aspirin and heparin or low molecular weight heparin) is recommended for patients with UA/NSTEMI in whom a noninterventional approach is planned (Class I recommendation). In patients in whom an interventional approach is planned, a GP IIb/IIIa inhibitor (in addition to aspirin and heparin or low molecular weight heparin) is recommended (Class I recommendation). No head-to-head comparison of clopidogrel, a GP IIb/IIIa inhibitor, and their combination has been reported. The addition of a GP IIb/IIIa inhibitor to a subset of patients in the CURE trial who were receiving aspirin, clopidogrel, and heparin appeared to be well tolerated, and current practice frequently involves the use of this combination of drugs. However, until further information on the safety and efficacy of such quadruple therapy becomes available, a Class Ila recommendation is made for the addition of a GP IIb/IIIa inhibitor for patients with UA/NSTEMI who are transfusion rate occurred. At 1 year of follow-up, death or MI occurred in 12.4% of patients assigned to placebo and 8.0% of eptifibatide-treated patients (hazard ratio 0.63; 95% confidence interval [CI] 0.48 to 0.83; p = 0.001) (15).
In the only head-to-head comparison of GP Ilb/lila antagonists, the TARGET trial (Do Tirofiban and ReoPro Give similar Efficacy? Trial) randomized 5,308 patients to tirofiban or abciximab before PCI with the intent to perform stenting (16). The primary end point, a composite of death, nonfatal MI, and urgent target-vessel revascularization at 30 days, occurred less frequently in those given abciximab than in those given tirofiban (6.0% vs. 7.6%; p = 0.038). There was a similar direction and magnitude for each component of the end point. The difference in outcome between the 2 treatment groups may be related to a suboptimal dose of tirofiban resulting in inadequate platelet inhibition. However, by six months, the primary end point occurred in a similar percentage of patients in each group (14.9% tirofiban vs. 14.3 % abciximab, NS). Mortality was also similar (1.9% vs. 1.7%, NS) (17). Glycoprotein IIb/IIIa antagonists without scheduled PCI. The Global Utilization of Strategies to Open Occluded Coronary Arteries IV-Acute Coronary Syndromes (GUSTO IV-ACS) trial (18) enrolled 7,800 patients with UA/NSTEMI who were admitted to the hospital with more than 5 min of chest pain and ST-segment depression and/or elevated troponin T or I concentration and in whom early (less than 48 h) revascularization was not intended to be conducted. All received ASA and either unfractionated heparin (UFH) or LMWH. They were randomized to placebo, an abciximab bolus and 24-h infusion, or an abciximab bolus and 48-h infusion. The primary end point, death or MI at 30 days, occurred in 8.0% of patients given placebo, 8.2% given 24-h abciximab, and 9.1% given 48-h abciximab, differences that were not statistically significant. At 48 h, death occurred in 0.3%, 0.7%, and 0.9% in these groups, respectively (placebo vs. abciximab 48 h, p = 0.008). The lack of benefit of abciximab was observed in most subgroups, including patients with elevated concentrations of troponin who were at higher risk. Although the explanation for these results is not clear, they indicate that abciximab, at least at the dosing regimen used in GUSTO IV-ACS, is not indicated in the management of patients with UA or NSTEMI in whom an early invasive management strategy is not planned.
In the PRISM-PLUS trial, 1,069 patients did not undergo early PCI. Although tirofiban treatment was associated with a lower incidence of death, MI or death, and MI or refractory ischemia at 30 days, these reductions were not statistically significant (19). In a high-risk subgroup of these patients not undergoing PCI (TIMI risk score greater than or equal to 4) (3), tirofiban appeared to be beneficial whether they underwent PCI (odds ratio [OR] 0.60, 95% CI 0.35 to 1.01) or not (OR 0.69, 95% CI 0.49 to 0.99). However, no benefit was observed in the patients at lower risk (6). In the PURSUIT trial, eptifibatide reduced theincidence of death or MI from 15.7% to 14.2% (RR 0.91; 95% CI 0.79 to 1.00; p = 0.032) (20).
Boersma et al performed a meta-analysis of GP IIb/IIIa antagonists in all 6 large, randomized, placebo-controlled trials, including GUSTO IV-ACS (18), which involved 31,402 patients with UA/NSTEMI who were not routinely scheduled to undergo coronary revascularization (21). A small reduction in the odds of death or MI in the active treatment arm (11.8% vs 10.8%; OR 0.91, 95% CI 0.84 to 0.98; p = 0.015) was observed. Unexpectedly, no benefit was observed in women (test for interaction between treatment assignment and gender, p less than 0.0001). However, women with positive troponins derived a treatment benefit that was similar to men. In the meta-analysis, reductions in the end points of death or nonfatal MI considered individually did not achieve statistical significance.
Although not scheduled for coronary revascularization procedures, 11,965 of the 31,402 patients (38%) actually underwent PCI or CABG within 30 days, and in this subgroup, the OR for death or MI in patients assigned to GP IIb/IIIa antagonists was 0.89 (95% CI 0.80 to 0.98). In the other 19,416 patients who did not undergo coronary revascularization, the OR for death or MI in the GP IIb/IIIa group was 0.95 (95% CI 0.86 to 1.05, p = NS). Major bleeding complications were increased in the GP IIb/IIIa antagonist-treated group compared with those who received placebo (1.4% vs. 2.4%, p less than 0.0001). The authors concluded that in patients with UA/NSTEMI who were not routinely scheduled for early revascularization and who were at high risk of thrombotic complications, "treatment with a GP Ilb/Illa inhibitor might therefore be considered" (21). Thus, GP Ilb/Illa inhibitors are of benefit in high-risk patients with UA/NSTEMI, and their administration, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned received a Class I recommendation. These agents are of questionable benefit in patients who do not undergo PCI. However, the revised guidelines recommend broader indications for a routine invasive strategy (see following text).
Thus, clopidogrel (in addition to aspirin and heparin or low molecular weight heparin) is recommended for patients with UA/NSTEMI in whom a noninterventional approach is planned (Class I recommendation). In patients in whom an interventional approach is planned, a GP IIb/IIIa inhibitor (in addition to aspirin and heparin or low molecular weight heparin) is recommended (Class I recommendation). No head-to-head comparison of clopidogrel, a GP IIb/IIIa inhibitor, and their combination has been reported. The addition of a GP IIb/IIIa inhibitor to a subset of patients in the CURE trial who were receiving aspirin, clopidogrel, and heparin appeared to be well tolerated, and current practice frequently involves the use of this combination of drugs. However, until further information on the safety and efficacy of such quadruple therapy becomes available, a Class Ila recommendation is made for the addition of a GP IIb/IIIa inhibitor for patients with UA/NSTEMI who are receiving aspirin, clopidogrel, and unfractionated or low molecular weight heparin and who are referred for an invasive strategy. A Class I recommendation is made for a GP Ilb/Illa inhibitor at the time of PCI in patients receiving heparin and aspirin. Specific updated recommendations for the use of antiplatelet regimens in the revised guidelines are as follows:
Class I
1. Antiplatelet therapy should be initiated promptly. ASA should be administered as soon as possible after presentation and continued indefinitely. (Level of Evidence: A)
2. Clopidogrel should be administered to hospitalized patients who are unable to take ASA because of hypersensitivity or major gastrointestinal intolerance. (Level of Evidence: A)
*3. In hospitalized patients in whom an early noninterventional approach is planned, clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month (Level of Evidence: A), and for up to 9 months. (Level of Evidence: B)
*4. A platelet GP IIb/IIIa antagonist should be administered, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI. (Level of Evidence: A)
*.5. In patients for whom a PCI is planned and who are not at high risk for bleeding, clopidogrel should be started and continued for at least 1 month (Level of Evidence: A) and for up to 9 months. (Level of Evidence: B)
*6. In patients taking clopidogrel in whom elective CABG is planned, the drug should be withheld for 5 to 7 days. (Level of Evidence: B)
Class Ila
*1. Eptifibatide or tirofiban should be administered, in addition to ASA and LMWH or UFH, to patients with continuing ischemia, an elevated troponin, or with other high-risk features in whom an invasive management strategy is not planned. (Level of Evidence: A)
*2. A platelet GP IIb/IIIa antagonist should be administered to patients already receiving heparin, ASA, and clopidogrel in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI. (Level of Evidence: B)
Class IIb
*1. Eptifibatide or tirofiban, in addition to ASA and LM" or UFH, to patients without continuing ischemia who have no other high-risk features and in whom PCI is not planned. (Level of Evidence: A)
Class III1. Intravenous fibrinolytic therapy in patients without acute ST-segment elevation, a true posterior MI, or a presumed new left bundle-branch block. (Level of Evidence: A)*2. Abciximab administration in patients in whom PCI is not planned. (Level of Evidence: A)
*New indication, not included in the September 2000 guidelines.
'Minor clarification different from full-text version on web site.
Anticoagulant Therapy
The September 2000 guidelines (1) reviewed the evidence regarding the use of intravenous UFH or subcutaneous LMWH. It provided the following Class I recommendation:
"Parenteral anticoagulation with intravenous UFH orsubcutaneous LMWH should be added to antiplatelettherapy with ASA or a thienopyridine. (bevel of Evidence: B)"
In the interim, a number of studies have appeared that support the use of enoxaparin. In the EVET trial (Enoxaparin VErsus Tinzaparin in the management of unstable coronary artery disease), 2 LMWHs, enoxaparin and tinzaparin, administered for 7 days, were compared in 438 patients with UA/NSTEMI. A preliminary report stated that both the recurrence of unstable angina and the need for revascularization were significantly lower in the enoxaparin group (22). Because the level of anticoagulant activity cannot be easily measured in patients given LMWH (e.g., activated partial thromboplastin time or activated clotting time), interventional cardiologists have expressed concern about the substitution of LMWH for UFH in patients scheduled for catheterization with possible PCI. However, Collet et al. (23) have shown in a small nonrandomized observation study in 293 patients that PCI can be performed safely with UA/NSTEMI patients who received the usual dose of enoxaparin. In NICE-1 (National Investigators Collaborating on Enoxaparin), an observational study, intravenous enoxaparin (1.0 mg/kg) was used in 828 patients undergoing elective PCI without an intravenous GP IIb/ IIIa antagonist (24). The rates of bleeding (L1% major bleeding and 6.2% minor bleeding in 30 days) were comparable to those observed in historical controls with UFH.
An alternative approach is to use LMWH during the period of initial stabilization and to withhold the dose on the morning of the procedure. If an intervention is required and more than 8 h has elapsed since the last dose of LMWH, UFH can be used for PCI according to usual practice patterns. Because the anticoagulant effect of UFH can be more readily reversed than that of LMWH, UFH is preferred in patients likely to undergo CABG within 24h.Class II1. Intravenous fibrinolytic therapy in patients without acute ST-segment elevation, a true posterior MI, or a presumed new left bundle-branch block. (Level of Evidence: A)*2. Abciximab administration in patients in whom PCI is not planned. (Level of Evidence: A)
JACC Vol. 40, No. 7, 2002 October 2, 2002:1366-74
The September 2000 guidelines reflected concern regarding the combined use of LMWH and GP IIb/lila antagonists. Although the data are not definitive, it now appears that GP IIb/IIIa antagonists can be used with LMWH. In the ACUTE II (Anti-thrombotic Combination Using Tirofiban and Enoxaparin II) study (25), UFH and enoxaparin were compared in patients with UA/NSTEMI who were given tirofiban. The frequencies of both major and minor bleeding were similar, and there was a trend to fewer adverse events in the patients given enoxaparin. A number of other open-label studies have examined the safety of combining enoxaparin with abciximab, eptifibatide, or tirofiban in patients with UA/NSTEMI who are treated with PCI or conservatively; of combining enoxaparin with abciximab in patients undergoing elective PCI (26); and of combining dalteparin with abciximab in patients with UAINSTEMI who are treated conservatively and during PCI (27). Although the majority of these studies relied on historical controls, none suggested that the combination of enoxaparin and a GP Ilb/Illa antagonist was associated with excess bleeding, whether or not the patient also underwent PCI.Specific recommendations for the use of heparins in the revised guidelines are as follows:Class I*1. Anticoagulation with subcutaneous LMWH or intravenous UFH should be added to antiplatelet therapy with ASA and/or clopidogrel. (Level of Evidence: A)Class Ila*fl. Enoxaparin is preferable to UFH as an anticoagulant in patients with UA/NSTEMI, in the absence of renal failure and unless CABG is planned within 24 h. (Level of Evidence: A)
*New indication, not included in the September 2000 guidelines.*Minor clarification different from full-text version on web site.
EARLY CONSERVATIVE VS. EARLY INVASIVE STRATEGIES
The September 2000 guidelines indicated that 2 different treatment strategies, termed "early conservative" and "early invasive," may be used in patients with UA/NSTEMI (1). In the early conservative strategy, coronary angiography is reserved for patients with evidence of recurrent ischemia (angina at rest or with minimal activity or dynamic STsegment changes) or a strongly positive stress test despite vigorous medical therapy. In the early invasive strategy, patients without clinically obvious contraindications to coronary revascularization are routinely recommended for coronary angiography and angiographically directed revascularization, if possible.
Several trials comparing these 2 strategies were reviewed,but greatest attention was paid to the then-most-recent trial, FRISC II (Fragmin and Fast Revascularization during InStability in Coronary artery disease II) (28). At 1 year, the mortality rate in the invasive strategy group was 2.2% compared with 3.9% in the noninvasive strategy group (p = 0.016) (29). However, in FRISC II, the invasive strategy involved treatment for an average of 6 days in the hospital with LMWH, ASA, nitrates, and beta-blockers before coronary angiography, an approach that would be difficult to adopt in U.S. hospitals.
In the interim, the TACTICS-TIMI 18 trial was reported (7). In this trial, 2,220 patients with UA or NSTEMI were treated with ASA, heparin, and the GP IIb/IIIa antagonist tirofiban. They were then randomized to an early invasive strategy with routine coronary angiography within 48 h followed by revascularization if the coronary anatomy was deemed suitable, or to a more conservative strategy. In the latter, catheterization was performed only if the patient had recurrent ischemia or a strongly positive stress test. Death, myocardial (re)infarction, or rehospitalization for an acute coronary syndrome at 6 months occurred in 19.4% of patients assigned to the conservative strategy vs. 15.9% assigned to the invasive strategy (OR 0.78; 95% CI 0.62 to 0.97; p = 0.025). Occurrence of death or MI was also reduced at 6 months (9.5 % vs 7.3%; p less than 0.05). The beneficial effects on outcome were particularly evident in medium- and high-risk patients, as defined by an elevation of troponin T greater than 0.01 ng/ml or of troponin I greater than 0.1 ng/ml, the presence of STsegment deviation, or a TIMI risk score greater than or equal to 3 (7,30). In the absence of these high-risk features, outcomes in patients assigned to the 2 strategies were similar. Rates of major bleeding were similar, and lengths of hospital stay were reduced in patients assigned to the invasive strategy. The benefits of the invasive strategy were achieved at no significant increase in the cost of care over the 6-month follow-up period.Thus, both the FRISC 11 (28,29) and TACTICS-TIMI 18 (7,30) trials, the 2 most recent trials comparing invasive vs. conservative strategies in patients with UA/NSTEMI, showed a benefit in patients assigned to the invasive strategy. In contrast to earlier trials, a large majority of patients undergoing PCI in these 2 trials received coronary stents as opposed to balloon angioplasty alone. In TACTICS-TIMI 18, treatment included the GP IIb/IIIa antagonist tirofiban, which was administered for an average of 22 h before coronary angiography. The routine use of the GP IIb/IIIa antagonist in this trial may have eliminated the excess risk of early (within 7 days) acute MI in the invasive arm, an excess risk that was observed in FRISC II and other trials in which there was no routine "upstream" use of a GP Ilb/Illa antagonist. Therefore, an invasive strategy is associated with a better outcome in UA/NSTEMI patients at high risk who receive a GP Ilb/Illa antagonist (7). Although the benefit of GP Ilb/Illa antagonists is well established for patients with UA/NSTEMI who undergo PCI, the optimumtime of commencing these drugs-as early as possible after presentation, i.e. "upstream," as in TACTICS-TIMI 18, or just before the PCI-has not been established.Specific recommendations for the use of an invasive strategy in the revised guidelines are as follows:
Class I*1. An early invasive strategy in patients with UA/ NSTEMI without serious comorbidity and who have any of the following high-risk indicators:
(Level of Evidence: A)*a) Recurrent angina/ischemia at rest or with lowlevel activities despite intensive anti-ischemic therapy.*b) Elevated TnT or TnI*c) New or presumably new ST-segment depressiond) Recurrent angina/ischemia with CHF symptoms, an S3 gallop, pulmonary edema, worsening rales, or new or worsening MRe) High-risk findings on noninvasive stress testingf) Depressed LV systolic function (e.g., EF lessthan 0.40 on noninvasive study) g) Hemodynamic instabilityh) Sustained ventricular tachycardia i) PCI within 6 monthsj) Prior CABG
2. In the absence of any of these findings, either an early conservative or an early invasive strategy may be offered in hospitalized patients without contraindications for revascularization. (Level of Evidence: B)
*New indication, not included in the September 2000guidelines.*Minor clarification different from full-text version on website.
RISK FACTOR MODIFICATION
The September 2000 guidelines pointed out that despite the overwhelming evidence for the benefits of beta-hydroxybeta-methylglutaryl-coenzyme A (HMG-CoA) reductase (statin) therapy in patients with elevated low-density lipoprotein (LDL) cholesterol levels, almost no data existed about the timing of initiation of therapy in patients with acute coronary syndromes (1). Indeed, the secondary prevention trials of statins specifically excluded patients with UA/NSTEMI in the acute phase. Fewer than 300 patients had been entered into the trials within 4 months of an acute coronary syndrome.
The Lipid-Coronary Artery Disease (L-CAD) study was a small trial that randomized 126 patients with an acute coronary syndrome to early treatment with pravastatin, alone or in combination with cholestyramine or niacin, or to usual care. At 24 months, the patients who received early aggressive treatment had a lower incidence of clinical events(23%) than the usual-care group (52%; p = 0.005) (31). In the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) trial, 3,086 patients were randomized to treatment with an aggressive lipid-lowering regimen of atorvastatin 80 mg per day or placebo 24 to 96 h after an acute coronary syndrome (32). At 16 weeks of follow-up, the primary end point of death, nonfatal MI, resuscitated cardiac arrest, or recurrent severe myocardial ischemia was reduced from 17.4% in the placebo group to 14.8% in the atorvastatin group (p = 0.048). There were no significant differences between the 2 groups in the risk of the following individual end points: death, nonfatal MI, cardiac arrest, or worsening heart failure; however, there were fewer strokes and a lower risk of severe recurrent ischemia in patients assigned to atorvastatin.
Although the evidence from these 2 trials of a beneficial effect of predischarge initiation of lipid-lowering therapy is not yet robust or definitive, observational studies support this policy. In the Swedish Registry of Cardiac Intensive Care of almost 20,000 patients, the adjusted relative risk of mortality was 25% lower in patients in whom statin therapy was initiated before hospital discharge (33). In addition, patients in whom lipid-lowering therapy is begun in the hospital are much more likely to be undergoing such therapy at a later time. In one demonstration project, the Cardiovascular Hospitalization Atherosclerosis Management Program (CHAMP), the in-hospital initiation of lipidlowering therapy was associated with an increased percentage of patients treated with statins 1 year later (from 10% to 91%) and with a higher frequency of patients whose LDL cholesterol was less than 100 mg/dl (from 6% to 58%) (34). Although additional trials are ongoing, there appear to be no adverse effects and substantial advantages to the initiation of lipid-lowering therapy before hospital discharge (35-37). Such early initiation of therapy has also been recommended in the third report of the National Cholesterol Education Program (NCEP III), which also raised the threshold of high-density lipoprotein cholesterol concentration that required therapy (38). Similar considerations apply to the early initiation of statin therapy following PCI. In the Lescol Intervention Prevention Study (LIPS), 1,669 patients were randomized to receive 80 mg fluvastatin or placebo, beginning two days after PCI. After a follow-up of 3.9 years, the statin-treated group had a lower incidence of clinical events (21.4%) than the placebo group (26.7%), p = 0.01 (39).
In addition to maintaining the original Class I recommendations for LDL cholesterol reduction, specific additional recommendations for the use of lipid-lowering therapy in UA/NSTEMI in the revised guidelines are as follows:Class I*1. A fibrate or niacin if high-density lipoprotein cholesterol is less than 40 mg per dl, occurring asan isolated finding or in combination with other lipid abnormalities. (Level of Evidence: B)
Class Ila*1. HMG-CoA reductase inhibitors and diet for LDL cholesterol greater than 100 mg per dl begun 24 to 96 h after admission and continued at hospital discharge. (Level of Evidence: B)*New indication, not included in the September 2000 guidelines.
CONCLUSIONS
These guidelines address the diagnosis and management of patients with UA and the closely related condition NSTEMI. These life-threatening disorders are a major cause of emergency medical care and are responsible for more than 1.4 million hospitalizations annually in the United States (40). Nearly 60% of these admissions are among persons greater than 65 years old, and almost half occur in women. In 1997, there were 5,315,000 visits to US emergency departments for the evaluation of chest pain and related symptoms (41).
Because of the high incidence of UA/NSTEMI and the seriousness of this condition (approximately 15% rate of death or [re]infarction at 30 days) (1,20), continued research in this field is of the greatest importance. It is encouraging that in the 21 months since the publication of the September 2000 guidelines, a considerable body of additional useful information about these conditions has emerged. Indeed, the progress between September 2000 and June 2002 equals that between 1994, when the first guidelines were published (42), and September 2000.
Editorial:N Engl Med,Vol.347,No.13,September26,2002,Pp 1019-1021
ANTITHROMBOTIC THERAPY AFTER MYOCARDIAL INFARCTION
DESPITE encouraging trends over the past three decades, coronary heart disease remains the leading cause of death in the United States and other industrialized countries. Recent data from the National Center for Health Statistics and the National Heart, Lung, and Blood Institute emphasize the full dimensions of this health problem, revealing that nearly 13 million Americans have coronary heart disease and that 7.5 million have had a myocardial infarction. Because there are 1.1 million myocardial infarctions in the United States alone each year and because 450,000 of them represent recurrent infarctions, which carry an inherently greater risk of death and disability than first events, the importance of secondary-prevention strategies that can be widely implemented is unparalleled in health care.
In this issue of the Journal, the potential role of oral anticoagulant therapy as secondary prevention is highlighted in the Warfarin, Aspirin, Reinfarction Study (WARIS II), reported by Hurlen et al. In this open-label study, patients hospitalized in 20 Norwegian centers for acute myocardial infarction were randomly assigned to long-term treatment with either warfarin (at a dose targeted to achieve an international normalized ratio [INR] of 2.8 to 4.2), 160 mg of aspirin daily, or 75 mg of aspirin daily plus warfarin (INR, 2.0 to 2.5). The primary outcome - a composite of death, nonfatal reinfarction, or thromboembolic stroke - occurred in 20.0 percent of the patients in the aspirin-only group, 16.7 percent of those in the warfarin-only group, and 15.0 percent of those in the combination-therapy group. The overall risk reduction was 29 percent in the combination-therapy group (P=0.001 for the comparison with the aspirin-only group) and 19 percent in the warfarin-only group (P=0.03). The incidence of nonfatal major hemorrhage among the patients receiving warfarin (either alone or in combination) was three to four times that among the patients receiving aspirin alone.
Does the hypothesis that oral anticoagulant therapy may be effective for secondary prevention after myocardial infarction have a sound scientific basis? Angioscopic studies have documented residual thrombosis and soft (vulnerable) plaques in the majority of patients for several months after myocardial infarction, with coexisting evidence of thrombin generation. Thrombin that is incorporated into plasma fibrin clots, and its subsequent binding to purified fibrin, is saturable and reversible. Thrombin activity, determined by in situ zymography, is approximately 4.5 IU per gram (wet weight) of thrombus . Although there is firm evidence that thrombin is the primary procoagulant enzyme in both physiologic hemostasis and pathologic thrombosis, its mechanism of generation and regulatory functions represent critical considerations in the development of effective therapies for cardiovascular thrombotic disorders.
A cell-based model of vascular thrombosis, which fosters a functional, physiologic view of complex biochemical events on cell surfaces, identifies tissue factor-bearing cells (monocytes and endothelial cells) as the initiating sites of coagulation (Fig. 1). The complexing of tissue factor with factor Vila (from plasma) leads to thrombin generation, which in turn activates platelets by way of protease-activated receptors. The final phase takes place on platelet surfaces after the assembly of tenase complex (factor Villa and tissue factor-factor VIIa complex) and prothrombinase complex (factors Va and Xa, calcium, and phospholipid).
The recognized contribution of inflammation to atherothrombosis also underscores the importance of coagulation proteases and thrombin generation on nonplatelet surfaces. Inflammatory cytokines, including tumor necrosis factor a and interleukin-1, facilitate thrombin generation by stimulating the release of tissue factor from monocytes and vascular endothelial cells. In addition, they impair fibrinolysis through the provoked release of thrombin-activatable fibrinolysis inhibitor and plasminogen-activator inhibitor type 1. Inflammatory cytokines, by reducing the concentration of endothelial-cell-surface thrombomodulin and the formation of thrombomodulin-activated protein C complex, compromise thromboresistance to factors Va and VIIla. Lastly, leukocytes adhered to activated endothelial cells by P-selectin glycoprotein ligand 1 in regions of variable shear stress7 promote thrombosis by several unique pathways, such as the de-encryption of tissue factor, the binding of macrophage antigen 1 (CD11b-CD18) to coagulation factor Xa, and the capture of fibrin protofibrils.
It is the direct involvement of coagulation proteases in thrombotic, inflammatory, and cellular regulatory processes that provides a scientific underpinning to the consideration of anticoagulant agents in secondary prevention. The four hydroxycoumarin compounds used currently in clinical practice - warfarin, phenprocoumon, acenocoumarol, and dicumarol - inhibit the vitamin K-dependent, post-translational carboxylation of coagulation factors II, VII, IX, and X (which is required for calcium-mediated binding of these factors to the negatively charged phospholipids found in platelets and injured endothelial cells). The ability to inhibit thrombin generation offers consid
Figure 1. A Cell-Based Paradigm of Arterial Thrombosis.Arterial thrombosis, though traditionally viewed as a platelet-dependent process, occurs on a variety of other cell surfaces, including the surfaces of activated endothelial cells and monocytes, which are tissue factor (TF)-bearing cells. Inflammatory cytokines (tumor necrosis factor a [TNF-a] and interleukin-1) impair surface fibrinolysis by the provoked release of thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen-activator inhibitor type 1 (PAT-1). Oral anticoagulants potentially interrupt several prothrombotic, inflammatory, and regulatory processes.
erable appeal; however, inhibition of one or more specific coagulation proteases may also prove beneficial. Tissue factor requires a cofactor, factor VIIa from plasma, to fulfill its enzymatic capabilities. Factor Xa, a vital component of prothrombinase-mediated conversion of prothrombin to thrombin, induces the expression of tissue factor from endothelial cells, smooth-muscle cells, and macrophages; increases endothelial-cell expression of E-selectin, intercellular adhesion molecule 1, and vascular-cell adhesion molecule 1, with subsequent leukocyte adhesion; and stimulates the synthesis and release of interleukin-6, interleukin-8, and monocyte chemotactic protein 1.9 Thus, our knowledge of atherosclerosis, inflammation, and thrombosis firmly supports a hypothesis designed to test oral anticoagulant therapy for the secondary prevention of cardiovascular events after myocardial infarction.
The evolution of oral anticoagulant agents for the management of acute coronary syndromes has taken a circuitous path, although much insight has been achieved along the way. In WARIS I,10 patients with myocardial infarction received either warfarin (INR, 2.8 to 4.8) or placebo. With warfarin, the incidence of major hemorrhage was twice that with placebo, but mortality and the rate of reinfarction were reduced by 24 percent and 34 percent, respectively. Interest in oral anticoagulant therapy then waned during the 1990s because two large-scale trials, the Coumadin Aspirin Reinfarction Study (CARS) (median INR, 1.3)" and the Combination Hemotherapy and Mortality Prevention (CHAMP) study (median INR, 1.8)12 found no reduction in mortality, in the rate of reinfarction, or in the rate of stroke with warfarin (alone or in combination with aspirin) as compared with aspirin monotherapy.
The favorable results observed in WARTS I, coupled with the disappointing findings of CARS and CHAMP, not only established the need for a definitive trial of anticoagulant therapy in acute coronary syndromes but also raised the important possibility of a "threshold" level of anticoagulation for benefit (as previously observed in venous thromboembolic disorders and atrial fibrillation). Indeed, WARTS II,2 the recently published Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis 2 study, 13 and the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis 2 trial 14 support a target level of anticoagulation approaching an INR of 3.0 (range, 2.5 to 3.5) for anticoagulation monotherapy and of 2.5 (range, 2.0 to 3.0) for combination therapy with aspirin. Thus, the available data, based on nearly 20,000 patients participating in randomized clinical trials, are strong and show that oral anticoagulants, when given in adequate doses, reduce the rates of reinfarction and thromboembolic stroke but at the cost of increased rates of hemorrhagic events.Maximizing the benefit associated with oral anticoagulant therapy while minimizing the risk is a key consideration in management strategies designed to achieve and maintain a target level of inhibition. Because coumarin compounds have complex pharmacokinetic and pharmacodynamic properties and are among the most challenging drugs to regulate, coordinated anticoagulation clinics may be the preferred means to provide safe and effective care. Accumulating data show a 50 percent reduction in the rate of thromboembolism, major hemorrhage, and emergency medical visits with the use of this strategy; the use of portable, point-of-care coagulation monitors, by allowing frequent testing, may improve outcomes further." Even under ideal circumstances, the complexities of coumarin therapy create real obstacles for clinicians and their patients. In WARTS II, the INR in approximately one third of the patients receiving warfarin alone was below the target range; one third discontinued warfarin treatment at some point during the 80-month study period; 5 to 7 percent were withdrawn from treatment because of hemorrhagic complications; and 2 to 3 percent were deemed noncompliant. The exclusion of patients 75 years of age or older undoubtedly reduced the warfarin-associated risk of hemorrhage.
In the United States, percutaneous coronary intervention and stenting are performed in 15 to 20 percent of patients who have myocardial infarction with ST-segment elevation, and an additional 20 to 40 percent undergo percutaneous coronary intervention within the subsequent six weeks. The proportion of patients who have myocardial infarction without ST-segment elevation and who undergo percutaneous coronary intervention is even higher. Histologic examination reveals platelets and leukocytes clustered around the stent struts, and electron microscopy identifies fibrinogen, prothrombin, thrombin, and tissue factor on the outer surface of the platelet monolayer. Therapies designed primarily to inhibit platelet activation and aggregation take existing pathobiologic processes into consideration and are preferred to anticoagulant therapy in this setting.
The contribution of WARTS II to our current knowledge base is multidimensional. First, targeted inhibition of one or more coagulation proteases (and, potentially, of their proinflammatory or cell-regulatory properties) represents an important physiological concept in arterial thrombosis. Second, a threshold level of inhibition is required for benefit:. Third, close monitoring and meticulous dose adjustment are absolute prerequisites for safe and effective treatment. Fourth, oral anticoagulant agents with .more predictable pharmacokinetic and pharmacodynamic properties than coumarin compounds and with a broader therapeutic index should be developed.
Although it is likely that antiplatelet therapy will remain the standard of care in many countries for secondary prevention after myocardial infarction, the findings of WARTS II must not be overlooked. Oral anticoagulant therapy should be strongly considered for patients at risk for thromboembolic events, those with thrombophilia involving the arterial system (e.g., the antiphospholipid syndrome), and - pending further investigation of combination antiplatelet therapy in acute coronary syndromes associated with ST-segment elevation - patients with possible aspirin resistance. Advances in pharmacogenomics will ultimately permit patient-specific antithrombotic therapy for patients with acute coronary syndromes and other thrombotic disorders.
This term refers to the death of a certain segment of the heart muscle (myocardium), usually the result of a focal complete blockage in one of the main coronary arteries or a branch thereof.
The main cause of myocardial infarction is atherosclerosis in the coronary arteries. Refer for the pathogenesis of myocardial infarction. This event results in impaired contractility of the heart muscle within seconds, and is initially restricted to the affected segment.
The myocardial ischemia or infarction begins in the endocardium (the inner lining of the heart) and spreads to the epicardium (the outer lining of the heart). Irreversible heart damage will occur if the blockage is complete for at least 15-20 minutes. Irreversible damage occurs maximally in the area at risk, and when the occlusion is maintained for 4-6 hours. Most of the damage occurs in the first 2-3 hours. Restoration of flow within the first 4-5 hours is associated with salvage of the heart muscle, but the salvage is greater if flow is restored in the first 1-2 hours. A major determinant of death and illness is the size of the infarct. Increasing the oxygen supply to the involved site of blockage by coronary reperfusion (angioplastystents, figures atherectomy, see figures is more effective in salvaging the myocardium than decreasing oxygen demand.
The onset of acute Q-wave myocardial infarction for normal EKG with a normal Q-wave, which is sharply inscribed, narrow in time of inscription and small in depth compared to the abnormal acute Q-wave type in myocardial infarction, which is deeper and wider in inscription time) occurs commonly in the morning hours shortly after arising, when there is increasing adrenergic activity, as well as increased blood fibrinogen levels and increased platelet (blood cell) adhesiveness. Non Q wave infarction does not show this circadian rhythm.
The traditional concept that myocardial infarctions can be classified as transmural or nontransmural on the basis of the presence or absence of Q waves is misleading, since autopsy studies have demonstrated convincingly that pathologic Q waves may be associated with nontransmural infarction and may be absent with transmural infarction. These misnomers have been replaced by the terms Q-wave infarction and nonQ-wave infarction for transmural and nontransmural infarction, respectively.
The evolution of a non-Q-wave infarction is charcterized by a lack of development of an abnormal Q wave and by the appearance of reversible ST-T-wave changes with ST depression that usually returns to normal over a few days, but occasionally is permanent. Differentiation between these two types of infarctions has become entrenched, since there are major differences in their pathogenesis, clinical manifestations, treatment, and prognosis. The initiating events in the pathogenesis of Q-wave and non-Q-wave infarction are thought to be identical, namely, coronary occlusion induced by thrombus superimposed on a plaque together with vasoconstriction.
There is considerable evidence, however, to indicate that in non-Q-wave infarction, early spontaneus reperfusion occurs, the mechanism of which remains uncertain. In contrast, in Q-wave infarction, the coronary occlusion is sustained at least for a long enough period to result in extensive necrosis.One explanation for early spontaneous reperfusion is the lack of sustained vasoconstriction, which may contribute to ocusion. The evidence supporting the existence of early spontaneous reperfusion in non-Q-wave infarction is as follows:
1. Coronary angiographic studies performed in the early hours after onset show that only 20-30% of patients have complete coronary occlusion of the infarct-related vessels;but for Q-wave infarction it is about 80 to 90%.
2. Infarct size is routinely much less than observed with Q wave infarction, which is consistent with salvage by early reperfusion.3. Peak plasma CK levels are reached on an average of 12 to 13 h after onset of symptoms, indicating early washout of the enzyme, as opposed to about 27 h after Q-wave infarction.4. Reperfusion-induced contraction necrosis is extremely common, as it is in patients who undergo early reperfusion induced by thrombolytic therapy.5. Acute mortality rates are around 2 to 3 percent, compared with 10 percent for Q-wave infarction.6. The complications are minimal compared with those after a Q-wave infarction.7. Finally, the long-term prognosis is characterized by recurrent episodes of reinfarction, so that after about 2 years, survival is the same as that after Q-wave infarction.
Quite often with the initial heart attack over half of the patients have significant obstructive atherosclerosis in only one vessel. However, in a recent study two fifths of the patients with acute myocardial infarction had angiographic evidence of multiple complex coronary plaques, which were associated with a less favorable in-hospital course. The presence of these plaques with complex morphologic features is the angiographic hallmark of unstable coronary syndromes and correlates with pathologic plaque and thrombus.
Other causes of myocardial infarction
Carbon monoxide poisoning is one of the occupational toxic risk factors for not only myocardial infarction but also cardiomyopathy.
Firefighters '"chronic" occupational exposure to carbon monoxide results in increased blood concentrations of carboxyhemoglobin, even in nonsmoking firefighters; changes in cardiac serum enzyme levels in one study suggested myocardial (heart) damage.
Increase symptoms in patients known to have coronary disease occur with exposure to carbon monoxide. Carbon monoxide has an affinity for hemoglobin that is much greater than that of oxygen. The cardiac effects are the results of hypoxia. These effects are determined by the degree of carbon monoxide exposure, the hemoglobin concentration, and the presence or absence of coronary or myocardial disease.
A decrease in exercise performance occurs even in normal individuals with low level exposure. Patients with angina pectoris have a greater reduction in exercise tolerance.
Carbon monoxide poisoning causes myocardial ischemia most commnoly manifest as ST- and T-wave changes on the ECG and atrial and ventricular arrhythmias. Severe exposure can cause extensive myocardial necrosis and cardiomyopathy. Myocardial infarction may occur as a result of myocardial necrosis without coronary occlusion.
Signs of acute CO intoxication include headache, confusion, visual disturbance, unconsciousness, seizures and lung edema. If untreated severe intoxication can lead to death.
Patients with mild intoxication are likely to recover without specific treatment other than removal from the noxious gas environment. The outlook is uncertain in those severely intoxicated. The severity of the illness often does not correlate with the measured carboxyhemoglobin level but corresponds more closely to the extent and the duration of the exposure.
Patients with any form of CNS impairment, evidence of myocardial ischemia,or carboxyhemoglobin levels above 25% merit aggressive therapeutic intervention. The rationale for treatment with hyperbaric oxygen is based on more rapid removal of the CO from hemoglobin and tissue sites. Because O-2 and CO compete for hemoglobin and many tissue binding sites, hyperbaric oxygenation greatly acclerates CO elimination. Furthermore, O-2 dissolved in plasma under hyperbaric conditions effectively bypasses any impediment to oxygen transport imposed by carboxyhemoglobin. Potentially lethal cerebral hypoxia may be averted as a consequence.Twenty minutes of exposure to 100% oxygen at 2.4 atm absolute will be accompanied by release of CO from the blood equivalent to that obtained after 5 hours of breathing uncontaminated air. Sixty to 90 min of hyperbaric oxygen therapy at this pressure is sufficient to reduce carboxyhemoglobin saturation to well below 10%. Prompt recovery is the rule if treatment can be initiated before extensive irreversible brain injury has occuuued.
CORONARY ARTERY DISSECTION
Separation of the media by hemorrhage with or without an associated intimal tear is termed coronary artery dissection. The medial separation forces the intimal-medial layer (wall of the true channel) toward the true coronary lumen and producesdistal myocardial ischemia/infarction Coronary artery dissections may be primary or secondary .
A. Post-or peripartumB. With or without eosinophiliaC. IdiopathicD. Systemic hypertensionE. Coronary spasmF. Aortic root dissection (hypertension, medial degeneration)G. ArteritisH. Fibromuscular hyperplasia
2.Trauma
A. Post- or peripartumB. Blunt chest (penetrating, nonpenetrating)C. Coronary-~angiographyD. Coronary interventions (angioplasty, atherectomy laser, stenting, rotablade)E. Cardiac surgery (coronary bypass, coronary ostial cannulation, endarterectomy)F. Aortic root dissection(surgery, non-penetrating, penetrating
Secondary coronary artery dissections are more frequent, especially those associated as an extension from aortic root dissection (8 percent). Primary coronary artery dissections may occur spontaneously or as a consequence of coronary angioplasty or angiography, cardiac surgery, or chest trauma (0.3 percent). Most spontaneous coronary artery dissections occur in women who are most commonly postpartum: they may be associated with coronary artery wall eosinophils. The left anterior descending artery is the one most frequently involved. Systemic hypertension does not appear to provide a significant factor of risk.Spontaneous coronary artery dissection may result in sudden death or acute myocardial infarction and subsequent death. Parenthetically, localized and limited coronary artery dissection te (i.e., intimal-medial tear) appears necessary for a clinically successful coronary artery balloon angioplasty procedure.Coronary angioplasty dissections viewed in short- or long-axis tomographic images help distinguish dissections that are therapeutic (mechanism) from those which are complications of angioplasty (complications). In the short-axis image, dissection involving more than 50 percent of the coronary medial circumference has been considered a complication. Similarly, in the long-axis image, dissections (antegrade, retrograde, or a both) longer than 1 cm in length also have been defined as a complication of angioplasty A combination of dissection greater than 50 percent of the short-axis circumference and greater than 1 cm antegrade or retrograde of long-axis length may result in "intussusception" of intimal-medial tissue. Spiral dissections ("the ugly") are among the most serious dissection injuries after balloon angioplasty The spiral dissection as reviewed angiographically appears to alternate from side to side, extending antegrade and retrograde or it has an unaltered dissection course but appears alternating from limited angiographic views.
MANAGEMENT OF MYOCARDIAL INFARCTION(HEART ATTACK)
Objects of early treatment
1). Provide cardiac resuscitation if necessary.
2). Immediate hospitalization.
3). Treat life threatening arrhythmias.
4). Alleviate pain and suffering.
5). Preserve as much myocardium as possible by the following:
Cardioprotection by Increasing Coronary Flow:Thrombolysis (Dissolution of Blood Clot or Thrombus Blocking Lumen of Coronary Artery)
Thrombolysis is based on the following facts:
A). The evolution of myocardial necrosis (death) following coronary occlusion is time-dependent over 4-6 hours.
B). The restoration of coronary blood flow within this 4-6 hour period salvages myocardium, but in a time related fashion.
C). The proximate cause of myocardial infarction is generally an occlusive thrombus within the coronary artery.
Clinical trials have shown that Early Reperfusion Induced by a Thrombolytic Agent --- Recombinant Tissue Plasminogen Activator, Streptokinase, Urokinase, or Anisoylated Plasminogen Streptokinase Activator Complex --- is associated with Limitation of Infarct Size, Preservation of Ventricular Function, and Improved Survival.
Sustained Patency and the Impact of Reocclusion
The incidence of coronary reocclusion from rethrombosis is about 20 per cent, and the incidence of reinfarction is about 10 per cent, occurring mainly in the first 24 hours.
Contraindications to Thrombolytic Therapy
1). Cerebral vascular accident (stroke) within the last 3 months
2). Recent major surgery
3). Pregnancy, aortic dissection, recent head trauma, brain tumor
Risks of Thrombolytic Therapy: Possible Intracranial Bleeding (Stroke)
Conjunctive and Adjunctive Therapy
1). Heparin (an anticlotting drug) is given intravenously to prevent rethrombosis and reocclusion: 5000 units as a bolus, followed by an infusion of 1000 to1200 units/h to keep the PTT (a measure of the clotting time of blood) at 1.5 to2.0 times normal for the first 24-48 hours.
2a). Aspirin is more effective than heparin after 24 to 48h, because the plasma thrombin levels have returned to normal by this time. Aspirin reduces the incidence of reocclusion and reinfarction. It should be given as soon as possible and continued indefinitely.
2b). The antiplatelet agent clopidogrel has been found to lower the number of nonfatal myocardial infarction or stroke in patients with acute coronary syndromes without ST-segment elevation to 9.3% compared to placebo and aspirin with 11.4% over a 3 to 12 month period. Also, the above or refractory ischemia occurred in 16.5% in the clopidogrel group compared to 18.8 % in the placebo group. But there were significantly more patients with major bleeding in the clopidogrel group (3.7%) than in the placebo group (2.7%), but there were not significantly more patients with life-threatening bleeding (2.1% versus 1.8%) or hemorrhagic stroke.
Reference:Clopidogrel in Unstable Angina to Prevent Recurrent Events trial Investigators,Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes Without ST-Segment Elevation,N Engl J Med,Vol.345,No.7,August 16,2001 ,Pp.494-502.
3). Beta-Adrenergic Blockers ( medications like metoprolol, atenolol) effects :
a) Reduces ventricular ectopy, atrial fibrillation, and nonfatal cardiac arrest
b) Reduces frequency of progression of threatened infarction to completed infarction
c) Reduces recurrent ischemia and infarction during first 6 weeks after initial event
4). Magnesium has the following effects:
a) reduces all causes of death and coronary care mortality rates;
b) reduces congestive heart failure in the coronary care unit;
c) preserves myocardium;
d) may reduce ventricular arrhythmias.
Angioplasty and Surgical Revascularization as Primary or Adjunctive Therapy to ThrombolysisRisk of Thrombolytic Therapy: Hemorrhagic strokengioAdjunctive Theray to Thrombolyses in which angioplasty may be per
1). Direct angioplasty as the primary reperfusion technique.
2). Immediate angioplasty after thrombolytic agent.
3). Rescue angioplasty if thrombolysis fails.
4). Delayed angioplasty routinely after thrombolysis.
5). Elective angioplasty if ischemia occurs after reperfusion.
Use of Glycoprotein IIb/IIIa Inhibitors
A recent study has shown that the use of the platelet glycoprotein IIb//IIIa inhibitor tirofiban in patients with unstable coronary syndromes (unstable angina and myocardial infarction without ST elevation) and early invasive strategy including percutaneous coronary revascularization and intracoronary stents reduce the risk of death, myocardial infarction or recurrent angina. The benefit of the early invasive strategy was greater in patients with troponin T levels (markers of myocardial injury) of more than 0.01ng per milliliter than in patients with levels of 0.01ng per milliliter or less.
The benefits of early invasive strategy, similarly, were largely confined to patients with ST-segment depression on the admission electrocardiogram. The advent of "point of care" measurements of troponin levels in the emergency room, together with the routine electrocardiogram, has made the goal of rapid identification of high risk patients most likely to benefit from an early invasive approach readily attainable. It is thus unnecessary to recommend the use of such an approach for all patients with acute coronary syndromes, especially those without elevated levels of cardiac enzymes or troponins or ST-segment depression.
Reference:Cannon,C.P.,M.D. and others,Comparison of early invasive and conservative strategies in patients wit unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban,N.Engl.J.Med.,Vol.344,No.25.June 21,2001,PP.1879-1887.
Reference:Boden,W.E. andMackay,R.G.,Optimal treatment of acute coronary syndromes-An evolving strategy,N.Engl.J.Med.,Vol.344,No.25.June 21,2001,PP.1939-1942.
Another study showed that tirofiban offerred less protection from major ischemic events with percutaneous coronary revascularization than did abciximab, another platelet inhibitor.
Reference:Topol,E.J. and others,Comparison of two platelet glycoprotein IIa/IIIb inhibitors,tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization,N.Engl.J.Med.,Vol.344,No.25.June 21,2001,PP.1888-1893
There is also a recent report that early administration of abciximab in patients with acute myocardial infarction improves coronary patency before stenting, the success rate of stenting procedure, and the rate of coronary patency at six months, left ventricular function, and clinical outcomes.
Reference:Montalescot,G. and others,Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction,N.Engl.J.Med.,Vol.344,No.25.June 21,2001,PP.1895-903.
Troponin Measurements in Ischemic Heart Disease
Current nomenclature categorizes patients with ischemic discomfort into those who present with ST elevation of the twelve lead electrocardiogram (E CG) versus those who do not present with ST elevation. Patients presenting with ST-segment elevation are, of course, easy to recognize using the ECG. The majority of such patients will develop a Q wave on the ECG and will ultimately be diagnosed as having sustained a Q-wave myocardial infarction(MI). Patients who present without ST elevation are experiencing either unstable angina(UA) or a non-ST- segment elevation MI (NSTEMI). Most patients who present with NSTEMI do not develop a Q wave on the ECG. The distinction between unstable angina and NSTEMI is based on the presence or absence of a cardiac marker in the blood. When such a cardiac marker is detected in a patient's blood, the patient is ultimately diagnosed as having a non-Q wave myocardial infarction.
Biochemical markers of myocyte necrosis are useful not only for making the diagnosis of an MI, but also with estimating prognosis. Of interst are the macromolecules that diffuse out of necrosing myocytes as membrane integrity is lost. Once outside the myocyte, the macromolecules are cleared from the interstitium by cardiac lymphatics. Eventually when the capacity of lymphatics to clear the macromolecules is exceeded, the markers become detectable in the peripheral circulation. Both clinical chemical laboratory of assays and bedside assays are available to measure several biochemical cardiac markers, notably myoglobin and the MB fraction of creatine kinase( CK-MB) and cardiac specific troponins T and I (cTnT and cTn I).
Although myoglobin and CK.-MB are familiar to physicians and provide reasonable sensitivity for detecting MI, they lack specificity in the setting of skeletal muscle disease or injury. Hence, there is intense interest in cTnT and cTn I as markers that are found in high concentration in the myocardium and are released with a stoichiometric relationship proportional to the amount of myocardial injury. Monoclonal-antibody-based assays are available that capitalize on the fact that the amino acid sequences of the cardiac and skeletal muscle forms of troponins T and I are sufficiently dissimilar. After much debate and discussion expert panels have declared cTnT and cTnI to be the preferred biomarkers for detection of myocardial damage.
Myocardial necrosis (i.e.MI) is said to be present if the maximal concentration of cTnT or cTnI exceeds the decision limit (99 percent of the values for a reference control group) on at least one occasion during the 24 hours after the index clinical event. It is important to note that patients may have an episode of microinfarction where cTnT or cTnI measurements exceed the decision limits and yet CK-MB even by mass assay remains in the normal range. It is estimated that about 1/3 of patients presenting without ST elevation who would previously have been diagnosed as experiencing unstable angina on the basis of normal CK-M B levels are now diagnosed as experiencing NSTEMI because of detectable troponin levels.
In a recent study the results of several trials reported that the relative risk of troponin positive patients (compared with troponin negative patients)was 3.9 for mortality and 3.8 for death or nonfatal recurrent MI. The adverse prognostic significance of a positive troponin test has been demonstrated by multiple chemical investigators across multiple trials, involving multiple patient groups from different countries, indicating that the observation is a robust one.
Part of the answer to why the patients with a positive troponin test have a worse prognosis may simply be that the positive troponin is indicative of myocardial necrosis. Because it is well established that left ventricular(LV) function is a pivotal determinant of prognosis, it is possible that loss of functioning myocardium is associated with a worse outcome. Several investigators have reported dichotomous analysis showing that the patients who present with UA/ NSTEMI and a positive troponin test are significantly more likely to have high-risk angographic anatomy of the culprit lesion. Troponin-positive patients are more likely to have visible thrombus in the culprit lesion,complex lesions, and worse thrombolysis in myocardial infarction flow grade. It has been argued that these anatomical findings put troponin-positive patients at risk for downstream embolization of atherothrombotic debris, occluding the microvasculature and causing foci of microinfarction-hence the release of troponin.
This line of reasoning leads to the oft-repeated recommendation by several investigators that patients with positive troponin test should be treated aggressively with antithrombotic therapy with particular emphasis on the intravenous IIb/IIIa inhibitors. It also been argued that troponin-positive patients should be selected for referral for early invasive strategy. Clearly ,not all troponin positive patients are at the same level of risk. Note that there is a highly significant gradient of increasing risk of mortality with increasing troponin levels. In a recent study patients with increasing cTnT levels tended to have progressively greater delays from the onset of symptoms to blood sampling, were significantly more likely to present a ST depression or abnormal Q-waves on their ECG. And were progressively more likely to have depressed LV function on echocardiography (ejection fraction less than 45 percent). In the subset patients who were randomized to an early invasive strategy, angiography did not show any correlation between the severity of underlying coronary artery disease in the cTnT level but did show a progressive increase in the odds of visible thrombus and a progressive decrease in the odds of TIMI flow grade 3 with increasing cTnT levels.
Complementing the angiographic finding from the early invasive strategy are the interesting clinical findings in the early noninvasive cohort. The 12-month mortality was numerical lowest in the cTnT negative group and was slightly higher in the cTnT positive patients, but there was no clear trend toward increasing mortality with increasing troponin levels when analyze by tertilesof positive cTnT. However, a U-shaped relationship was observed between troponin measurements and the rate of MI through one year;MI occurred in 5.5% of cTnT negative patients (<0.01>0.63ng/ml. A similar U-shaped relationship was found with referral for revascularization: 38.8%,51.9%,46.1% and 34.3%, respectively, in the same four groups.
In another study patients with either undetectable or only slightly elevated levels of cTnT or cTnI showed no benefit of tirofiban with respect to prevention of death or nonfatal MI by 30 days. Those with intermediate elevations of either cTnT or cTnI had the maximal benefit, whereas those with higher biomarker levels showed progressive less benefit compared with the intermediately elevated group.
Those patients with negative tests (below the decision limit) or just barely elevated quantitative results are at low risk.They are unlikely to benefit from IV glycoprotein IIb/IIIa inhibitors. In general, they are managed equally well with either an early conservative or early invasive strategy (depending on patient and physician preferences). Multiple clinical factors other than the results of biomarkers should be included in the decision about referral for revascularization. Those patients with an intermediately elevated troponin levels have not yet lost substantial amounts of myocardium and are excellent candidates for effective antithrombotic therapy (e.g.,enoxaparin in place of unfractionated heparin) and prompt referral for an early invasive approach supported by IV glycoproteins inhibitors in the catheterization laboratory.
Those patients with the highest level of troponin have already lost substantial amounts of myocardium.It is not clear it is not so clear that aggressive antithrombotic therapy with glycoprotein inhibitors will be helpful in such patients. The focus should be early diagnostic coronary arteriography. Some patients may have a completed left circumflex infarction masquerading as / NSTEMI . Others may have severe multivessel disease or other r high risk coronary anatomy in association with depressed LV function (as suggested by high troponin levels); this group is likely to be best served by referral for coronary artery bypass surgery.
Because of the uncertainty about the best course of action for patients with highest level of troponin upstream use of IV glycoproteinIIb/IIIa inhibitors is not favored. Instead, diagnostic catheterization is advised to determine whether revascularization is needed, art in the in and if so, whether referral for surgery is best without IV glycoproteins or whether a percutaneous intervention supported by the inhibitors is
Reference:Antman,E.M., Troponin Measurements in Ischemic heart Heart Disease:More Than Just a Black and White Picture,AmericanCollege Cardiology ,Vol.38,N.4 2001,PP.987990
ACC/AHA 2002 Guideline Updatefor the Management of Patients WithUnstable Angina and Non-ST-SegmentElevation Myocardial Infarction-Summary Article
A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)
INTRODUCTION
The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) were published in Septemher 2000 (1). Since then, a number of clinical trials and observational studies have been published or presented that, when taken together, alter significantly the recommendations made in that document. Therefore, the ACC/AHA
The ACC/AHA Task Force on Practice Guidelines makes every effort to avoid any actual or potential conflicts of interest that might arise as a result of an outside relationship or personal interest of a member of the writing panel. Specifically, all members of the writing panel are asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. These statements are reviewed by the parent task force, reported orally to all members of the writing panel at the first meeting, and updated as changes occur.
This document was approved by the American College of Cardiology Foundation Board of Trustees in September 2002 and by the American Heart Association Science Advisory and Coordinating Committee in August 2002.
When citing this document, the American College of Cardiology Foundation and the American Heart Association would appreciate the following citation format: Braunwald E, Anturan EM, Beasley JW, Califf RM, Cheitlin MD, IIochman JS, Jones RI- I, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE III, Steward DE, Theroux P.ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2002;40:1366-74.
This document is available on the World Wide Web sites of the ACC (wow. acc.org) and the AHA (www.americanheartorg). Single copies of this document arc available for $5 each by calling 800-253-4636 (US only) or writing the American College of Cardiology Foundation, Resource Center, 9111 Old Georgetown Road, Bethesda, MD 20814-1699 (product code 71-0227).This document and the companion full-text guidelines (product code 71-0240), are available on the ACC Web site at www.acc.org and the AHA Web site at www.anieiicauheart.org. To purchase additional reprints (specify version): up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1,000 or more copies, call 214-706-1466, fax 214-691-6342; or E-mail pubauth©heart.org
Committee on the Management of Patients With Unstable Angina, with the concurrence of the ACC/AHA Task Force on Practice Guidelines, revised these guidelines. These revisions were prepared in December 2001, reviewed and approved, and then published on the ACC World Wide Web site (www.acc.org) and AHA World Wide Web site (www.americanheart.org) on March 15, 2002. The present article describes these revisions and provides further updates in this rapidly moving field. Minor clarifications in the wording of three recommendations that now appear differently from those that were previously published on the ACC and AHA Web sites are noted in footnotes.
The ACC/AHA classifications I, II, and III are used to summarize indications as follows:ClassI:Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective. ClassII:Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment.IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.IIb: Usefulness/efficacy is less well established by evidence/opinion.ClassIII: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful.The weight of the evidence was ranked highest (A) if the data were derived from multiple randomized clinical trials that involved large numbers of patients and intermediate (B) if the data were derived from a limited number of randomized trials that involved small numbers of patients or from careful analyses of nonrandomized studies or observational registries. A lower rank (C) was given when expert consensus was the primary basis for the recommendation.
RISK ASSESSMENT
Clinical Features
Unstable angina and NSTEMI are heterogeneous disorders in which patients have widely varying risks. Risk is an important "driver" of management decisions, and accurate yet simple methods of risk assessment are important for patient care.
Risk was assessed by multivariable regression techniques in patients presenting with UA/NSTEMI in several large clinical trials. Boersma et al. analyzed the relation between baseline characteristics and the incidence of death and the composite of death or myocardial (re)infarction at 30 days in patients who entered the PURSUIT (Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial (2). The most important baseline features associated with death were age, heart rate, systolic blood pressure, ST-segment depression, signs of heart failure, andelevation of cardiac biomarkers. From this analysis, a simple risk estimation score was developed.
Antman et al. developed a 7-point risk score, the "TIMI Risk Score," (age greater than or equal to 65 years, more than 3 coronary risk factors, prior angiographic coronary obstruction, ST-segment deviation, more than 2 angina events within 24 h, use of aspirin [ASA] within 7 days, and elevated cardiac markers) (3). The score was defined as the simple sum of these individual prognostic variables. The risk of developing an adverse outcome-death, (re)infarction, or recurrent severe ischemia that required revascularizationranged from 5% with a score of 0 or 1 to 41% with a score of 6 or 7. The score was derived from data in the TIMI 11B (Thrombolysis In Myocardial Infarction 11B) trial (4) and then validated in 3 additional trials-ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events study) (5), and PRISM-PLUS (Platelet Receptor inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms) (6) and prospectively in one TACTICS-TIMI 18 (Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction) 18 (7). A progressively greater benefit from newer therapies such as low-molecular-weight heparin (LMWH) (4,5), platelet glycoprotein (GP) IIb/IIIa receptor antagonists (6), and an invasive strategy (7) with increasing risk score have been reported.
Biomarkers
The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction (8) emphasized the use of troponins as critical markers of the presence of myocardial necrosis. Although troponins are accurate in identifying myocardial necrosis, the latter is not always secondary to atherosclerotic coronary artery disease. Therefore, in establishing the diagnosis of NSTEMI, cardiac troponins should be used in conjunction with appropriate clinical features and electrocardiographic changes. Myocardial injury of diverse origins (e.g., myocarditis, trauma, or cardioversion) may cause necrosis and release of troponins. Although these may be considered instances of NSTEMI, they should be distinguished on clinical grounds from the more common form of NSTEMI secondary to coronary atherosclerosis.
Antiplatelet Therapy
Antiplatelet therapy is a cornerstone in the management of UA/NSTEMI. Three classes of antiplatelet drugs (ASA, thienopyridines, and GP Ilb/IIIa antagonists) have been found useful in the management of these patients and are the subject of continued intensive investigation and analysis. Clopidogrel. Given its more rapid onset of action (9,10) and better safety profile compared with ticlopidine, clopidogrel is now the preferred thienopyridine. The CURE (Clopidogrel in Unstable angina to prevent Recurrent ischemic Events) trial (11) randomized 12,562 patients withUA/STEMI who presented within 24 h to placebo or clopidogrel (loading dose of 300 mg followed by 75 mg daily) and followed them for 3 to 12 months; all patients were given aspirin. Cardiovascular death, myocardial infarction (MI), or stroke occurred in 11.5% of patients assigned to placebo and 9.3% of those assigned to clopidogrel (relative risk [RR] 0.80; p less than 0.001). Looking at the individual components of the primary composite and end point, there was a trend in favor of clopidogrel for cardiovascular death and stroke (5.5% and 1.4%, respectively, for placebo vs. 5.1% and 1.2% for clopidogrel), and there was a significant reduction in MI (6.7% vs. 5.2% R.R. = 0.77, p less than 0.001). However, there was no significant difference in the incidence of non-Q-wave MI (3.8% vs. 3.5%). A reduction in recurrent ischemia was noted within the first few hours after randomization. These salutary results were observed across all subgroups of patients. There was, however, a significant excess of major bleeding (2.7% in the placebo group versus 3.7% in the clopidogrel group; p = 0.003) and of minor bleeding, as well as a (nonsignificant) trend for an increase in life-threatening bleeding. The risk of bleeding was increased in patients who underwent coronary artery bypass grafting (CABG) within the first 5 days after clopidogrel was discontinued.The CURE trial was performed in hospitals in which there was no routine policy of early invasive procedures, and therefore, revascularization was performed during the initial admission in only 23% of the patients, a substantially lower percentage than currently receive this therapy at most US hospitals. Although the addition of a GP IIb/IIIa antagonist appeared to be well tolerated in patients who were given ASA, clopidogrel, and heparin in CURE, fewer than 10% of patients received this combination. Therefore, additional information on the safety of "quadruple therapy" (heparin [unfractionated or low molecular weight], ASA, clopidogrel, and a GP 11b/111a antagonist) should be obtained.The CURE trial provides strong support for the addition of clopidogrel to ASA on admission in the management of patients with UA and NSTEMI. Clopidogrel appears to be especially useful in hospitals that do not have a routine policy of early invasive procedures and in patients who are not candidates or who do not wish to be considered for revascularization. The optimal duration of therapy with clopidogrel has not been determined. The major benefits in CURE were observed at 30 days, with small additional benefits observed over the subsequent treatment period, which averaged 8 months.
In PCI-CURE, a substudy of CURE, 2,658 patients who underwent percutaneous coronary intervention (PCI) had been randomly assigned to double-blind treatment with clopidogrel (n = 1,313) or placebo (n = 1,345) (12); all patients also received ASA. Patients were pretreated with placebo or study drug for a median of 10 days before PCI. After the procedure, most patients received open-label thienopyridine (clopidogrel or ticlopidine) for approximately 4 weeks, after which the study drug (placebo orclopidogrel) was again administered for an average of 8 months. The primary end point, a composite of cardiovascular death, MI, or urgent target-vessel revascularization within 30 days of PCI, occurred in 86 patients (6.4%) in the placebo group compared with 59 (4.5%) in the clopidogrel group (RR 0.70; p = 0.03). When events that occurred before and after PCI were considered, there was a 31% reduction in cardiovascular death or MI with assignment to clopidogrel (p = 0.002). Thus, in patients with UA and NSTEMI who are given ASA and are undergoing PCI, a strategy of clopidogrel pretreatment followed by at least 1 month and probably longer-term therapy is beneficial in reducing major cardiovascular events (12).
There now appears to be an important role for clopidogrel in patients with UA/NSTEMI, both those who are managed conservatively and those who undergo PCI, especially stenting. However, it is not entirely clear how long therapy should be maintained. Because clopidogrel, when added to ASA, increases the risk of bleeding during major surgery in patients who are scheduled for CABG, if possible, clopidogrel should be withheld for at least 5 days (11) and preferably for 7 days before surgery (13). In many hospitals in which patients with UA/NSTEMI undergo diagnostic catheterization within 24 to 36 h of admission, clopidogrel is not started until it is clear that CABG will not be scheduled within the next several days. A loading dose of clopidogrel can be given to a patient on the catheterization table if a PCI is to be performed immediately. If PCI is not performed, clopidogrel can be begun after the catheterization.
Glycoprotein IIb/IIIa antagonists in PCI.
The introduction of platelet GP IIb/IIIa antagonists represents an important advance in the treatment of patients with UA/ NSTEMI who are undergoing PCI. These drugs take advantage of the fact that platelets play an important role in the development of ischemic complications that may occur in patients with UA/NSTEMI during coronary revascularization procedures. The September 2000 guidelines emphasized the value of GP Ilb/IIIa antagonists in patients with UA/NSTEMI who were undergoing PCI (1).Two trials of GP IIb/IIIa inhibitors have been published since September 2000. The ESPRIT trial (Enhanced Suppression of the Platelet IIb/Illa Receptor with Integrilin Therapy) was a placebo-controlled trial designed to assess whether eptifibatide improved outcome in patients undergoing stenting (14). Fourteen percent of the 2,064 patients enrolled in ESPRIT had UA/NSTEMI. The primary end point (the composite of death, MI, target-vessel revascularization, and "bailout" GP Ilb/Illa antagonist therapy) was reduced from 10.5% to 6.6% with treatment (p = 0.0015). There was consistency in the reduction of events in all components of the end point and in all major subgroups, including patients with UA/NSTEMI. Major bleeding occurred more frequently in patients who received eptifibatide (1.3%) than in those who received placebo (0.4%; p = 0.027); however, no significant difference in thetransfusion rate occurred. At 1 year of follow-up, death or MI occurred in 12.4% of patients assigned to placebo and 8.0% of eptifibatide-treated patients (hazard ratio 0.63; 95% confidence interval [CI] 0.48 to 0.83; p = 0.001) (15).In the only head-to-head comparison of GP Ilb/lila antagonists, the TARGET trial (Do Tirofiban and ReoPro Give similar Efficacy? Trial) randomized 5,308 patients to tirofiban or abciximab before PCI with the intent to perform stenting (16). The primary end point, a composite of death, nonfatal MI, and urgent target-vessel revascularization at 30 days, occurred less frequently in those given abciximab than in those given tirofiban (6.0% vs. 7.6%; p = 0.038). There was a similar direction and magnitude for each component of the end point. The difference in outcome between the 2 treatment groups may be related to a suboptimal dose of tirofiban resulting in inadequate platelet inhibition. However, by six months, the primary end point occurred in a similar percentage of patients in each group (14.9% tirofiban vs. 14.3 % abciximab, NS). Mortality was also similar (1.9% vs. 1.7%, NS) (17). Glycoprotein IIb/IIIa antagonists without scheduled PCI. The Global Utilization of Strategies to Open Occluded Coronary Arteries IV-Acute Coronary Syndromes (GUSTO IV-ACS) trial (18) enrolled 7,800 patients with UA/NSTEMI who were admitted to the hospital with more than 5 min of chest pain and ST-segment depression and/or elevated troponin T or I concentration and in whom early (less than 48 h) revascularization was not intended to be conducted. All received ASA and either unfractionated heparin (UFH) or LMWH. They were randomized to placebo, an abciximab bolus and 24-h infusion, or an abciximab bolus and 48-h infusion. The primary end point, death or MI at 30 days, occurred in 8.0% of patients given placebo, 8.2% given 24-h abciximab, and 9.1% given 48-h abciximab, differences that were not statistically significant. At 48 h, death occurred in 0.3%, 0.7%, and 0.9% in these groups, respectively (placebo vs. abciximab 48 h, p = 0.008). The lack of benefit of abciximab was observed in most subgroups, including patients with elevated concentrations of troponin who were at higher risk. Although the explanation for these results is not clear, they indicate that abciximab, at least at the dosing regimen used in GUSTO IV-ACS, is not indicated in the management of patients with UA or NSTEMI in whom an early invasive management strategy is not planned.In the PRISM-PLUS trial, 1,069 patients did not undergo early PCI. Although tirofiban treatment was associated with a lower incidence of death, MI or death, and MI or refractory ischemia at 30 days, these reductions were not statistically significant (19). In a high-risk subgroup of these patients not undergoing PCI (TIMI risk score greater than or equal to 4) (3), tirofiban appeared to be beneficial whether they underwent PCI (odds ratio [OR] 0.60, 95% CI 0.35 to 1.01) or not (OR 0.69, 95% CI 0.49 to 0.99). However, no benefit was observed in the patients at lower risk (6). In the PURSUIT trial, eptifibatide reduced theincidence of death or MI from 15.7% to 14.2% (RR 0.91; 95% CI 0.79 to 1.00; p = 0.032) (20).
Boersma et al performed a meta-analysis of GP IIb/IIIa antagonists in all 6 large, randomized, placebo-controlled trials, including GUSTO IV-ACS (18), which involved 31,402 patients with UA/NSTEMI who were not routinely scheduled to undergo coronary revascularization (21). A small reduction in the odds of death or MI in the active treatment arm (11.8% vs 10.8%; OR 0.91, 95% CI 0.84 to 0.98; p = 0.015) was observed. Unexpectedly, no benefit was observed in women (test for interaction between treatment assignment and gender, p less than 0.0001). However, women with positive troponins derived a treatment benefit that was similar to men. In the meta-analysis, reductions in the end points of death or nonfatal MI considered individually did not achieve statistical significance.Although not scheduled for coronary revascularization procedures, 11,965 of the 31,402 patients (38%) actually underwent PCI or CABG within 30 days, and in this subgroup, the OR for death or MI in patients assigned to GP IIb/IIIa antagonists was 0.89 (95% CI 0.80 to 0.98). In the other 19,416 patients who did not undergo coronary revascularization, the OR for death or MI in the GP IIb/IIIa group was 0.95 (95% CI 0.86 to 1.05, p = NS). Major bleeding complications were increased in the GP IIb/IIIa antagonist-treated group compared with those who received placebo (1.4% vs. 2.4%, p less than 0.0001). The authors concluded that in patients with UA/NSTEMI who were not routinely scheduled for early revascularization and who were at high risk of thrombotic complications, "treatment with a GP Ilb/Illa inhibitor might therefore be considered" (21). Thus, GP Ilb/Illa inhibitors are of benefit in high-risk patients with UA/NSTEMI, and their administration, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned received a Class I recommendation. These agents are of questionable benefit in patients who do not undergo PCI. However, the revised guidelines recommend broader indications for a routine invasive strategy (see following text).Thus, clopidogrel (in addition to aspirin and heparin or low molecular weight heparin) is recommended for patients with UA/NSTEMI in whom a noninterventional approach is planned (Class I recommendation). In patients in whom an interventional approach is planned, a GP IIb/IIIa inhibitor (in addition to aspirin and heparin or low molecular weight heparin) is recommended (Class I recommendation). No head-to-head comparison of clopidogrel, a GP IIb/IIIa inhibitor, and their combination has been reported. The addition of a GP IIb/IIIa inhibitor to a subset of patients in the CURE trial who were receiving aspirin, clopidogrel, and heparin appeared to be well tolerated, and current practice frequently involves the use of this combination of drugs. However, until further information on the safety and efficacy of such quadruple therapy becomes available, a Class Ila recommendation is made for the addition of a GP IIb/IIIa inhibitor for patients with UA/NSTEMI who are transfusion rate occurred. At 1 year of follow-up, death or MI occurred in 12.4% of patients assigned to placebo and 8.0% of eptifibatide-treated patients (hazard ratio 0.63; 95% confidence interval [CI] 0.48 to 0.83; p = 0.001) (15).
In the only head-to-head comparison of GP Ilb/lila antagonists, the TARGET trial (Do Tirofiban and ReoPro Give similar Efficacy? Trial) randomized 5,308 patients to tirofiban or abciximab before PCI with the intent to perform stenting (16). The primary end point, a composite of death, nonfatal MI, and urgent target-vessel revascularization at 30 days, occurred less frequently in those given abciximab than in those given tirofiban (6.0% vs. 7.6%; p = 0.038). There was a similar direction and magnitude for each component of the end point. The difference in outcome between the 2 treatment groups may be related to a suboptimal dose of tirofiban resulting in inadequate platelet inhibition. However, by six months, the primary end point occurred in a similar percentage of patients in each group (14.9% tirofiban vs. 14.3 % abciximab, NS). Mortality was also similar (1.9% vs. 1.7%, NS) (17). Glycoprotein IIb/IIIa antagonists without scheduled PCI. The Global Utilization of Strategies to Open Occluded Coronary Arteries IV-Acute Coronary Syndromes (GUSTO IV-ACS) trial (18) enrolled 7,800 patients with UA/NSTEMI who were admitted to the hospital with more than 5 min of chest pain and ST-segment depression and/or elevated troponin T or I concentration and in whom early (less than 48 h) revascularization was not intended to be conducted. All received ASA and either unfractionated heparin (UFH) or LMWH. They were randomized to placebo, an abciximab bolus and 24-h infusion, or an abciximab bolus and 48-h infusion. The primary end point, death or MI at 30 days, occurred in 8.0% of patients given placebo, 8.2% given 24-h abciximab, and 9.1% given 48-h abciximab, differences that were not statistically significant. At 48 h, death occurred in 0.3%, 0.7%, and 0.9% in these groups, respectively (placebo vs. abciximab 48 h, p = 0.008). The lack of benefit of abciximab was observed in most subgroups, including patients with elevated concentrations of troponin who were at higher risk. Although the explanation for these results is not clear, they indicate that abciximab, at least at the dosing regimen used in GUSTO IV-ACS, is not indicated in the management of patients with UA or NSTEMI in whom an early invasive management strategy is not planned.
In the PRISM-PLUS trial, 1,069 patients did not undergo early PCI. Although tirofiban treatment was associated with a lower incidence of death, MI or death, and MI or refractory ischemia at 30 days, these reductions were not statistically significant (19). In a high-risk subgroup of these patients not undergoing PCI (TIMI risk score greater than or equal to 4) (3), tirofiban appeared to be beneficial whether they underwent PCI (odds ratio [OR] 0.60, 95% CI 0.35 to 1.01) or not (OR 0.69, 95% CI 0.49 to 0.99). However, no benefit was observed in the patients at lower risk (6). In the PURSUIT trial, eptifibatide reduced theincidence of death or MI from 15.7% to 14.2% (RR 0.91; 95% CI 0.79 to 1.00; p = 0.032) (20).
Boersma et al performed a meta-analysis of GP IIb/IIIa antagonists in all 6 large, randomized, placebo-controlled trials, including GUSTO IV-ACS (18), which involved 31,402 patients with UA/NSTEMI who were not routinely scheduled to undergo coronary revascularization (21). A small reduction in the odds of death or MI in the active treatment arm (11.8% vs 10.8%; OR 0.91, 95% CI 0.84 to 0.98; p = 0.015) was observed. Unexpectedly, no benefit was observed in women (test for interaction between treatment assignment and gender, p less than 0.0001). However, women with positive troponins derived a treatment benefit that was similar to men. In the meta-analysis, reductions in the end points of death or nonfatal MI considered individually did not achieve statistical significance.
Although not scheduled for coronary revascularization procedures, 11,965 of the 31,402 patients (38%) actually underwent PCI or CABG within 30 days, and in this subgroup, the OR for death or MI in patients assigned to GP IIb/IIIa antagonists was 0.89 (95% CI 0.80 to 0.98). In the other 19,416 patients who did not undergo coronary revascularization, the OR for death or MI in the GP IIb/IIIa group was 0.95 (95% CI 0.86 to 1.05, p = NS). Major bleeding complications were increased in the GP IIb/IIIa antagonist-treated group compared with those who received placebo (1.4% vs. 2.4%, p less than 0.0001). The authors concluded that in patients with UA/NSTEMI who were not routinely scheduled for early revascularization and who were at high risk of thrombotic complications, "treatment with a GP Ilb/Illa inhibitor might therefore be considered" (21). Thus, GP Ilb/Illa inhibitors are of benefit in high-risk patients with UA/NSTEMI, and their administration, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned received a Class I recommendation. These agents are of questionable benefit in patients who do not undergo PCI. However, the revised guidelines recommend broader indications for a routine invasive strategy (see following text).
Thus, clopidogrel (in addition to aspirin and heparin or low molecular weight heparin) is recommended for patients with UA/NSTEMI in whom a noninterventional approach is planned (Class I recommendation). In patients in whom an interventional approach is planned, a GP IIb/IIIa inhibitor (in addition to aspirin and heparin or low molecular weight heparin) is recommended (Class I recommendation). No head-to-head comparison of clopidogrel, a GP IIb/IIIa inhibitor, and their combination has been reported. The addition of a GP IIb/IIIa inhibitor to a subset of patients in the CURE trial who were receiving aspirin, clopidogrel, and heparin appeared to be well tolerated, and current practice frequently involves the use of this combination of drugs. However, until further information on the safety and efficacy of such quadruple therapy becomes available, a Class Ila recommendation is made for the addition of a GP IIb/IIIa inhibitor for patients with UA/NSTEMI who are receiving aspirin, clopidogrel, and unfractionated or low molecular weight heparin and who are referred for an invasive strategy. A Class I recommendation is made for a GP Ilb/Illa inhibitor at the time of PCI in patients receiving heparin and aspirin. Specific updated recommendations for the use of antiplatelet regimens in the revised guidelines are as follows:
Class I
1. Antiplatelet therapy should be initiated promptly. ASA should be administered as soon as possible after presentation and continued indefinitely. (Level of Evidence: A)
2. Clopidogrel should be administered to hospitalized patients who are unable to take ASA because of hypersensitivity or major gastrointestinal intolerance. (Level of Evidence: A)
*3. In hospitalized patients in whom an early noninterventional approach is planned, clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month (Level of Evidence: A), and for up to 9 months. (Level of Evidence: B)
*4. A platelet GP IIb/IIIa antagonist should be administered, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI. (Level of Evidence: A)
*.5. In patients for whom a PCI is planned and who are not at high risk for bleeding, clopidogrel should be started and continued for at least 1 month (Level of Evidence: A) and for up to 9 months. (Level of Evidence: B)
*6. In patients taking clopidogrel in whom elective CABG is planned, the drug should be withheld for 5 to 7 days. (Level of Evidence: B)
Class Ila
*1. Eptifibatide or tirofiban should be administered, in addition to ASA and LMWH or UFH, to patients with continuing ischemia, an elevated troponin, or with other high-risk features in whom an invasive management strategy is not planned. (Level of Evidence: A)
*2. A platelet GP IIb/IIIa antagonist should be administered to patients already receiving heparin, ASA, and clopidogrel in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI. (Level of Evidence: B)
Class IIb
*1. Eptifibatide or tirofiban, in addition to ASA and LM" or UFH, to patients without continuing ischemia who have no other high-risk features and in whom PCI is not planned. (Level of Evidence: A)
Class III1. Intravenous fibrinolytic therapy in patients without acute ST-segment elevation, a true posterior MI, or a presumed new left bundle-branch block. (Level of Evidence: A)*2. Abciximab administration in patients in whom PCI is not planned. (Level of Evidence: A)
*New indication, not included in the September 2000 guidelines.
'Minor clarification different from full-text version on web site.
Anticoagulant Therapy
The September 2000 guidelines (1) reviewed the evidence regarding the use of intravenous UFH or subcutaneous LMWH. It provided the following Class I recommendation:
"Parenteral anticoagulation with intravenous UFH orsubcutaneous LMWH should be added to antiplatelettherapy with ASA or a thienopyridine. (bevel of Evidence: B)"
In the interim, a number of studies have appeared that support the use of enoxaparin. In the EVET trial (Enoxaparin VErsus Tinzaparin in the management of unstable coronary artery disease), 2 LMWHs, enoxaparin and tinzaparin, administered for 7 days, were compared in 438 patients with UA/NSTEMI. A preliminary report stated that both the recurrence of unstable angina and the need for revascularization were significantly lower in the enoxaparin group (22). Because the level of anticoagulant activity cannot be easily measured in patients given LMWH (e.g., activated partial thromboplastin time or activated clotting time), interventional cardiologists have expressed concern about the substitution of LMWH for UFH in patients scheduled for catheterization with possible PCI. However, Collet et al. (23) have shown in a small nonrandomized observation study in 293 patients that PCI can be performed safely with UA/NSTEMI patients who received the usual dose of enoxaparin. In NICE-1 (National Investigators Collaborating on Enoxaparin), an observational study, intravenous enoxaparin (1.0 mg/kg) was used in 828 patients undergoing elective PCI without an intravenous GP IIb/ IIIa antagonist (24). The rates of bleeding (L1% major bleeding and 6.2% minor bleeding in 30 days) were comparable to those observed in historical controls with UFH.
An alternative approach is to use LMWH during the period of initial stabilization and to withhold the dose on the morning of the procedure. If an intervention is required and more than 8 h has elapsed since the last dose of LMWH, UFH can be used for PCI according to usual practice patterns. Because the anticoagulant effect of UFH can be more readily reversed than that of LMWH, UFH is preferred in patients likely to undergo CABG within 24h.Class II1. Intravenous fibrinolytic therapy in patients without acute ST-segment elevation, a true posterior MI, or a presumed new left bundle-branch block. (Level of Evidence: A)*2. Abciximab administration in patients in whom PCI is not planned. (Level of Evidence: A)
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The September 2000 guidelines reflected concern regarding the combined use of LMWH and GP IIb/lila antagonists. Although the data are not definitive, it now appears that GP IIb/IIIa antagonists can be used with LMWH. In the ACUTE II (Anti-thrombotic Combination Using Tirofiban and Enoxaparin II) study (25), UFH and enoxaparin were compared in patients with UA/NSTEMI who were given tirofiban. The frequencies of both major and minor bleeding were similar, and there was a trend to fewer adverse events in the patients given enoxaparin. A number of other open-label studies have examined the safety of combining enoxaparin with abciximab, eptifibatide, or tirofiban in patients with UA/NSTEMI who are treated with PCI or conservatively; of combining enoxaparin with abciximab in patients undergoing elective PCI (26); and of combining dalteparin with abciximab in patients with UAINSTEMI who are treated conservatively and during PCI (27). Although the majority of these studies relied on historical controls, none suggested that the combination of enoxaparin and a GP Ilb/Illa antagonist was associated with excess bleeding, whether or not the patient also underwent PCI.Specific recommendations for the use of heparins in the revised guidelines are as follows:Class I*1. Anticoagulation with subcutaneous LMWH or intravenous UFH should be added to antiplatelet therapy with ASA and/or clopidogrel. (Level of Evidence: A)Class Ila*fl. Enoxaparin is preferable to UFH as an anticoagulant in patients with UA/NSTEMI, in the absence of renal failure and unless CABG is planned within 24 h. (Level of Evidence: A)
*New indication, not included in the September 2000 guidelines.*Minor clarification different from full-text version on web site.
EARLY CONSERVATIVE VS. EARLY INVASIVE STRATEGIES
The September 2000 guidelines indicated that 2 different treatment strategies, termed "early conservative" and "early invasive," may be used in patients with UA/NSTEMI (1). In the early conservative strategy, coronary angiography is reserved for patients with evidence of recurrent ischemia (angina at rest or with minimal activity or dynamic STsegment changes) or a strongly positive stress test despite vigorous medical therapy. In the early invasive strategy, patients without clinically obvious contraindications to coronary revascularization are routinely recommended for coronary angiography and angiographically directed revascularization, if possible.
Several trials comparing these 2 strategies were reviewed,but greatest attention was paid to the then-most-recent trial, FRISC II (Fragmin and Fast Revascularization during InStability in Coronary artery disease II) (28). At 1 year, the mortality rate in the invasive strategy group was 2.2% compared with 3.9% in the noninvasive strategy group (p = 0.016) (29). However, in FRISC II, the invasive strategy involved treatment for an average of 6 days in the hospital with LMWH, ASA, nitrates, and beta-blockers before coronary angiography, an approach that would be difficult to adopt in U.S. hospitals.
In the interim, the TACTICS-TIMI 18 trial was reported (7). In this trial, 2,220 patients with UA or NSTEMI were treated with ASA, heparin, and the GP IIb/IIIa antagonist tirofiban. They were then randomized to an early invasive strategy with routine coronary angiography within 48 h followed by revascularization if the coronary anatomy was deemed suitable, or to a more conservative strategy. In the latter, catheterization was performed only if the patient had recurrent ischemia or a strongly positive stress test. Death, myocardial (re)infarction, or rehospitalization for an acute coronary syndrome at 6 months occurred in 19.4% of patients assigned to the conservative strategy vs. 15.9% assigned to the invasive strategy (OR 0.78; 95% CI 0.62 to 0.97; p = 0.025). Occurrence of death or MI was also reduced at 6 months (9.5 % vs 7.3%; p less than 0.05). The beneficial effects on outcome were particularly evident in medium- and high-risk patients, as defined by an elevation of troponin T greater than 0.01 ng/ml or of troponin I greater than 0.1 ng/ml, the presence of STsegment deviation, or a TIMI risk score greater than or equal to 3 (7,30). In the absence of these high-risk features, outcomes in patients assigned to the 2 strategies were similar. Rates of major bleeding were similar, and lengths of hospital stay were reduced in patients assigned to the invasive strategy. The benefits of the invasive strategy were achieved at no significant increase in the cost of care over the 6-month follow-up period.Thus, both the FRISC 11 (28,29) and TACTICS-TIMI 18 (7,30) trials, the 2 most recent trials comparing invasive vs. conservative strategies in patients with UA/NSTEMI, showed a benefit in patients assigned to the invasive strategy. In contrast to earlier trials, a large majority of patients undergoing PCI in these 2 trials received coronary stents as opposed to balloon angioplasty alone. In TACTICS-TIMI 18, treatment included the GP IIb/IIIa antagonist tirofiban, which was administered for an average of 22 h before coronary angiography. The routine use of the GP IIb/IIIa antagonist in this trial may have eliminated the excess risk of early (within 7 days) acute MI in the invasive arm, an excess risk that was observed in FRISC II and other trials in which there was no routine "upstream" use of a GP Ilb/Illa antagonist. Therefore, an invasive strategy is associated with a better outcome in UA/NSTEMI patients at high risk who receive a GP Ilb/Illa antagonist (7). Although the benefit of GP Ilb/Illa antagonists is well established for patients with UA/NSTEMI who undergo PCI, the optimumtime of commencing these drugs-as early as possible after presentation, i.e. "upstream," as in TACTICS-TIMI 18, or just before the PCI-has not been established.Specific recommendations for the use of an invasive strategy in the revised guidelines are as follows:
Class I*1. An early invasive strategy in patients with UA/ NSTEMI without serious comorbidity and who have any of the following high-risk indicators:
(Level of Evidence: A)*a) Recurrent angina/ischemia at rest or with lowlevel activities despite intensive anti-ischemic therapy.*b) Elevated TnT or TnI*c) New or presumably new ST-segment depressiond) Recurrent angina/ischemia with CHF symptoms, an S3 gallop, pulmonary edema, worsening rales, or new or worsening MRe) High-risk findings on noninvasive stress testingf) Depressed LV systolic function (e.g., EF lessthan 0.40 on noninvasive study) g) Hemodynamic instabilityh) Sustained ventricular tachycardia i) PCI within 6 monthsj) Prior CABG
2. In the absence of any of these findings, either an early conservative or an early invasive strategy may be offered in hospitalized patients without contraindications for revascularization. (Level of Evidence: B)
*New indication, not included in the September 2000guidelines.*Minor clarification different from full-text version on website.
RISK FACTOR MODIFICATION
The September 2000 guidelines pointed out that despite the overwhelming evidence for the benefits of beta-hydroxybeta-methylglutaryl-coenzyme A (HMG-CoA) reductase (statin) therapy in patients with elevated low-density lipoprotein (LDL) cholesterol levels, almost no data existed about the timing of initiation of therapy in patients with acute coronary syndromes (1). Indeed, the secondary prevention trials of statins specifically excluded patients with UA/NSTEMI in the acute phase. Fewer than 300 patients had been entered into the trials within 4 months of an acute coronary syndrome.
The Lipid-Coronary Artery Disease (L-CAD) study was a small trial that randomized 126 patients with an acute coronary syndrome to early treatment with pravastatin, alone or in combination with cholestyramine or niacin, or to usual care. At 24 months, the patients who received early aggressive treatment had a lower incidence of clinical events(23%) than the usual-care group (52%; p = 0.005) (31). In the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) trial, 3,086 patients were randomized to treatment with an aggressive lipid-lowering regimen of atorvastatin 80 mg per day or placebo 24 to 96 h after an acute coronary syndrome (32). At 16 weeks of follow-up, the primary end point of death, nonfatal MI, resuscitated cardiac arrest, or recurrent severe myocardial ischemia was reduced from 17.4% in the placebo group to 14.8% in the atorvastatin group (p = 0.048). There were no significant differences between the 2 groups in the risk of the following individual end points: death, nonfatal MI, cardiac arrest, or worsening heart failure; however, there were fewer strokes and a lower risk of severe recurrent ischemia in patients assigned to atorvastatin.
Although the evidence from these 2 trials of a beneficial effect of predischarge initiation of lipid-lowering therapy is not yet robust or definitive, observational studies support this policy. In the Swedish Registry of Cardiac Intensive Care of almost 20,000 patients, the adjusted relative risk of mortality was 25% lower in patients in whom statin therapy was initiated before hospital discharge (33). In addition, patients in whom lipid-lowering therapy is begun in the hospital are much more likely to be undergoing such therapy at a later time. In one demonstration project, the Cardiovascular Hospitalization Atherosclerosis Management Program (CHAMP), the in-hospital initiation of lipidlowering therapy was associated with an increased percentage of patients treated with statins 1 year later (from 10% to 91%) and with a higher frequency of patients whose LDL cholesterol was less than 100 mg/dl (from 6% to 58%) (34). Although additional trials are ongoing, there appear to be no adverse effects and substantial advantages to the initiation of lipid-lowering therapy before hospital discharge (35-37). Such early initiation of therapy has also been recommended in the third report of the National Cholesterol Education Program (NCEP III), which also raised the threshold of high-density lipoprotein cholesterol concentration that required therapy (38). Similar considerations apply to the early initiation of statin therapy following PCI. In the Lescol Intervention Prevention Study (LIPS), 1,669 patients were randomized to receive 80 mg fluvastatin or placebo, beginning two days after PCI. After a follow-up of 3.9 years, the statin-treated group had a lower incidence of clinical events (21.4%) than the placebo group (26.7%), p = 0.01 (39).
In addition to maintaining the original Class I recommendations for LDL cholesterol reduction, specific additional recommendations for the use of lipid-lowering therapy in UA/NSTEMI in the revised guidelines are as follows:Class I*1. A fibrate or niacin if high-density lipoprotein cholesterol is less than 40 mg per dl, occurring asan isolated finding or in combination with other lipid abnormalities. (Level of Evidence: B)
Class Ila*1. HMG-CoA reductase inhibitors and diet for LDL cholesterol greater than 100 mg per dl begun 24 to 96 h after admission and continued at hospital discharge. (Level of Evidence: B)*New indication, not included in the September 2000 guidelines.
CONCLUSIONS
These guidelines address the diagnosis and management of patients with UA and the closely related condition NSTEMI. These life-threatening disorders are a major cause of emergency medical care and are responsible for more than 1.4 million hospitalizations annually in the United States (40). Nearly 60% of these admissions are among persons greater than 65 years old, and almost half occur in women. In 1997, there were 5,315,000 visits to US emergency departments for the evaluation of chest pain and related symptoms (41).
Because of the high incidence of UA/NSTEMI and the seriousness of this condition (approximately 15% rate of death or [re]infarction at 30 days) (1,20), continued research in this field is of the greatest importance. It is encouraging that in the 21 months since the publication of the September 2000 guidelines, a considerable body of additional useful information about these conditions has emerged. Indeed, the progress between September 2000 and June 2002 equals that between 1994, when the first guidelines were published (42), and September 2000.
Editorial:N Engl Med,Vol.347,No.13,September26,2002,Pp 1019-1021
ANTITHROMBOTIC THERAPY AFTER MYOCARDIAL INFARCTION
DESPITE encouraging trends over the past three decades, coronary heart disease remains the leading cause of death in the United States and other industrialized countries. Recent data from the National Center for Health Statistics and the National Heart, Lung, and Blood Institute emphasize the full dimensions of this health problem, revealing that nearly 13 million Americans have coronary heart disease and that 7.5 million have had a myocardial infarction. Because there are 1.1 million myocardial infarctions in the United States alone each year and because 450,000 of them represent recurrent infarctions, which carry an inherently greater risk of death and disability than first events, the importance of secondary-prevention strategies that can be widely implemented is unparalleled in health care.
In this issue of the Journal, the potential role of oral anticoagulant therapy as secondary prevention is highlighted in the Warfarin, Aspirin, Reinfarction Study (WARIS II), reported by Hurlen et al. In this open-label study, patients hospitalized in 20 Norwegian centers for acute myocardial infarction were randomly assigned to long-term treatment with either warfarin (at a dose targeted to achieve an international normalized ratio [INR] of 2.8 to 4.2), 160 mg of aspirin daily, or 75 mg of aspirin daily plus warfarin (INR, 2.0 to 2.5). The primary outcome - a composite of death, nonfatal reinfarction, or thromboembolic stroke - occurred in 20.0 percent of the patients in the aspirin-only group, 16.7 percent of those in the warfarin-only group, and 15.0 percent of those in the combination-therapy group. The overall risk reduction was 29 percent in the combination-therapy group (P=0.001 for the comparison with the aspirin-only group) and 19 percent in the warfarin-only group (P=0.03). The incidence of nonfatal major hemorrhage among the patients receiving warfarin (either alone or in combination) was three to four times that among the patients receiving aspirin alone.
Does the hypothesis that oral anticoagulant therapy may be effective for secondary prevention after myocardial infarction have a sound scientific basis? Angioscopic studies have documented residual thrombosis and soft (vulnerable) plaques in the majority of patients for several months after myocardial infarction, with coexisting evidence of thrombin generation. Thrombin that is incorporated into plasma fibrin clots, and its subsequent binding to purified fibrin, is saturable and reversible. Thrombin activity, determined by in situ zymography, is approximately 4.5 IU per gram (wet weight) of thrombus . Although there is firm evidence that thrombin is the primary procoagulant enzyme in both physiologic hemostasis and pathologic thrombosis, its mechanism of generation and regulatory functions represent critical considerations in the development of effective therapies for cardiovascular thrombotic disorders.
A cell-based model of vascular thrombosis, which fosters a functional, physiologic view of complex biochemical events on cell surfaces, identifies tissue factor-bearing cells (monocytes and endothelial cells) as the initiating sites of coagulation (Fig. 1). The complexing of tissue factor with factor Vila (from plasma) leads to thrombin generation, which in turn activates platelets by way of protease-activated receptors. The final phase takes place on platelet surfaces after the assembly of tenase complex (factor Villa and tissue factor-factor VIIa complex) and prothrombinase complex (factors Va and Xa, calcium, and phospholipid).
The recognized contribution of inflammation to atherothrombosis also underscores the importance of coagulation proteases and thrombin generation on nonplatelet surfaces. Inflammatory cytokines, including tumor necrosis factor a and interleukin-1, facilitate thrombin generation by stimulating the release of tissue factor from monocytes and vascular endothelial cells. In addition, they impair fibrinolysis through the provoked release of thrombin-activatable fibrinolysis inhibitor and plasminogen-activator inhibitor type 1. Inflammatory cytokines, by reducing the concentration of endothelial-cell-surface thrombomodulin and the formation of thrombomodulin-activated protein C complex, compromise thromboresistance to factors Va and VIIla. Lastly, leukocytes adhered to activated endothelial cells by P-selectin glycoprotein ligand 1 in regions of variable shear stress7 promote thrombosis by several unique pathways, such as the de-encryption of tissue factor, the binding of macrophage antigen 1 (CD11b-CD18) to coagulation factor Xa, and the capture of fibrin protofibrils.
It is the direct involvement of coagulation proteases in thrombotic, inflammatory, and cellular regulatory processes that provides a scientific underpinning to the consideration of anticoagulant agents in secondary prevention. The four hydroxycoumarin compounds used currently in clinical practice - warfarin, phenprocoumon, acenocoumarol, and dicumarol - inhibit the vitamin K-dependent, post-translational carboxylation of coagulation factors II, VII, IX, and X (which is required for calcium-mediated binding of these factors to the negatively charged phospholipids found in platelets and injured endothelial cells). The ability to inhibit thrombin generation offers consid
Figure 1. A Cell-Based Paradigm of Arterial Thrombosis.Arterial thrombosis, though traditionally viewed as a platelet-dependent process, occurs on a variety of other cell surfaces, including the surfaces of activated endothelial cells and monocytes, which are tissue factor (TF)-bearing cells. Inflammatory cytokines (tumor necrosis factor a [TNF-a] and interleukin-1) impair surface fibrinolysis by the provoked release of thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen-activator inhibitor type 1 (PAT-1). Oral anticoagulants potentially interrupt several prothrombotic, inflammatory, and regulatory processes.
erable appeal; however, inhibition of one or more specific coagulation proteases may also prove beneficial. Tissue factor requires a cofactor, factor VIIa from plasma, to fulfill its enzymatic capabilities. Factor Xa, a vital component of prothrombinase-mediated conversion of prothrombin to thrombin, induces the expression of tissue factor from endothelial cells, smooth-muscle cells, and macrophages; increases endothelial-cell expression of E-selectin, intercellular adhesion molecule 1, and vascular-cell adhesion molecule 1, with subsequent leukocyte adhesion; and stimulates the synthesis and release of interleukin-6, interleukin-8, and monocyte chemotactic protein 1.9 Thus, our knowledge of atherosclerosis, inflammation, and thrombosis firmly supports a hypothesis designed to test oral anticoagulant therapy for the secondary prevention of cardiovascular events after myocardial infarction.
The evolution of oral anticoagulant agents for the management of acute coronary syndromes has taken a circuitous path, although much insight has been achieved along the way. In WARIS I,10 patients with myocardial infarction received either warfarin (INR, 2.8 to 4.8) or placebo. With warfarin, the incidence of major hemorrhage was twice that with placebo, but mortality and the rate of reinfarction were reduced by 24 percent and 34 percent, respectively. Interest in oral anticoagulant therapy then waned during the 1990s because two large-scale trials, the Coumadin Aspirin Reinfarction Study (CARS) (median INR, 1.3)" and the Combination Hemotherapy and Mortality Prevention (CHAMP) study (median INR, 1.8)12 found no reduction in mortality, in the rate of reinfarction, or in the rate of stroke with warfarin (alone or in combination with aspirin) as compared with aspirin monotherapy.
The favorable results observed in WARTS I, coupled with the disappointing findings of CARS and CHAMP, not only established the need for a definitive trial of anticoagulant therapy in acute coronary syndromes but also raised the important possibility of a "threshold" level of anticoagulation for benefit (as previously observed in venous thromboembolic disorders and atrial fibrillation). Indeed, WARTS II,2 the recently published Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis 2 study, 13 and the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis 2 trial 14 support a target level of anticoagulation approaching an INR of 3.0 (range, 2.5 to 3.5) for anticoagulation monotherapy and of 2.5 (range, 2.0 to 3.0) for combination therapy with aspirin. Thus, the available data, based on nearly 20,000 patients participating in randomized clinical trials, are strong and show that oral anticoagulants, when given in adequate doses, reduce the rates of reinfarction and thromboembolic stroke but at the cost of increased rates of hemorrhagic events.Maximizing the benefit associated with oral anticoagulant therapy while minimizing the risk is a key consideration in management strategies designed to achieve and maintain a target level of inhibition. Because coumarin compounds have complex pharmacokinetic and pharmacodynamic properties and are among the most challenging drugs to regulate, coordinated anticoagulation clinics may be the preferred means to provide safe and effective care. Accumulating data show a 50 percent reduction in the rate of thromboembolism, major hemorrhage, and emergency medical visits with the use of this strategy; the use of portable, point-of-care coagulation monitors, by allowing frequent testing, may improve outcomes further." Even under ideal circumstances, the complexities of coumarin therapy create real obstacles for clinicians and their patients. In WARTS II, the INR in approximately one third of the patients receiving warfarin alone was below the target range; one third discontinued warfarin treatment at some point during the 80-month study period; 5 to 7 percent were withdrawn from treatment because of hemorrhagic complications; and 2 to 3 percent were deemed noncompliant. The exclusion of patients 75 years of age or older undoubtedly reduced the warfarin-associated risk of hemorrhage.
In the United States, percutaneous coronary intervention and stenting are performed in 15 to 20 percent of patients who have myocardial infarction with ST-segment elevation, and an additional 20 to 40 percent undergo percutaneous coronary intervention within the subsequent six weeks. The proportion of patients who have myocardial infarction without ST-segment elevation and who undergo percutaneous coronary intervention is even higher. Histologic examination reveals platelets and leukocytes clustered around the stent struts, and electron microscopy identifies fibrinogen, prothrombin, thrombin, and tissue factor on the outer surface of the platelet monolayer. Therapies designed primarily to inhibit platelet activation and aggregation take existing pathobiologic processes into consideration and are preferred to anticoagulant therapy in this setting.
The contribution of WARTS II to our current knowledge base is multidimensional. First, targeted inhibition of one or more coagulation proteases (and, potentially, of their proinflammatory or cell-regulatory properties) represents an important physiological concept in arterial thrombosis. Second, a threshold level of inhibition is required for benefit:. Third, close monitoring and meticulous dose adjustment are absolute prerequisites for safe and effective treatment. Fourth, oral anticoagulant agents with .more predictable pharmacokinetic and pharmacodynamic properties than coumarin compounds and with a broader therapeutic index should be developed.
Although it is likely that antiplatelet therapy will remain the standard of care in many countries for secondary prevention after myocardial infarction, the findings of WARTS II must not be overlooked. Oral anticoagulant therapy should be strongly considered for patients at risk for thromboembolic events, those with thrombophilia involving the arterial system (e.g., the antiphospholipid syndrome), and - pending further investigation of combination antiplatelet therapy in acute coronary syndromes associated with ST-segment elevation - patients with possible aspirin resistance. Advances in pharmacogenomics will ultimately permit patient-specific antithrombotic therapy for patients with acute coronary syndromes and other thrombotic disorders.
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