د. حسين محمد جمعه
اختصاصي الامراض الباطنةالبورد العربي
كلية طب الموصل
2011
Secondary prevention of ischaemic cardiac events
BMJ 2011Incidence
Coronary artery disease is the leading cause of mortality in developed countries and is becoming a major cause of morbidity and mortality in developing countries. There are international, regional, and temporal differences in incidence, prevalence, and death rates. In the United States, the prevalence of coronary artery disease is over 6%, and the annual incidence is over 0.33%Aetiology
Most ischaemic cardiac events are associated with atheromatous plaques that can lead to acute obstruction of the coronary arteries.Coronary artery disease is more likely in people who are older or have risk factors, such as smoking, hypertension, high cholesterol, and diabetes mellitus.
What are the effects of antithrombotic treatments?
Aspirin
Reduce the risk of serious vascular events and reduced all cause mortality compared with placebo. One of the reviews found that doses of 75 to 325 mg daily were as effective as higher doses.
Harms
low dose aspirin (<100 mg/day) was associated with a lower rate of bleeding than that seen with higher doses of aspirin.
Comments
Among people at high risk of cardiac events, the absolute reductions in serious vascular events associated with aspirin far outweigh any absolute risks.
What are the effects of other drug treatments?
Beta blockersSystematic reviews have found strong evidence that beta blockers reduce the risk of all cause mortality, coronary mortality, recurrent non-fatal myocardial infarction, and sudden death in people after myocardial infarction. One systematic review found no differences in effect between men and women. In patients with heart failure and left ventricular dysfunction, beta blockers reduced mortality compared with placebo, and the relative benefit was not significantly different between people with and without diabetes.
Harms
One systematic review that examined the harms of beta blockers compared with placebo in people with previous myocardial infarction, heart failure, or hypertension found no significant difference between beta blockers and placebo in reported symptoms of depression or sexual dysfunction. However, it found a small but significant increase in fatigue with beta blockers compared to placebo.Angiotensin converting enzyme inhibitors (in people with and without left ventricular dysfunction)
Two systematic reviews found that angiotensin converting enzyme (ACE) inhibitors reduced the risk of serious cardiac events in stable people without left ventricular dysfunction or heart failure who were at high risk of cardiovascular events. Two systematic reviews found that ACE inhibitors reduced mortality in people with heart failure and/or left ventricular dysfunction, including patients with a recent myocardial infarction. One systematic review found a smaller benefit in women, but equal benefit in people with and without diabetes and in black and white people.
Harms
A systematic review reported adverse effects from three of five trials included in the review. Hypotension, renal dysfunction, and cough occurred more frequently with ACE inhibitors than with placebo. Hyperkalaemia also occurred more commonly in patients treated with ACE inhibitors.Angiotensin II receptor blockers
In patients with stable coronary artery disease without left ventricular dysfunction, there is less evidence for secondary prevention with an angiotensin II receptor antagonist than there is for ACE inhibitors.
However, one randomised controlled trial which recruited 406 patients found a reduction in the composite end point of cardiovascular death, non-fatal myocardial infarction, and revascularisation with the use of low dose candesartan, compared with usual care, in people with a past history of coronary intervention and no significant coronary stenosis on follow up coronary angiography six months after intervention, most of whom were not taking ACE inhibitors.
However, a more recent randomised controlled trial recruited 25 620 patients with coronary, cerebrovascular, or peripheral arterial disease or diabetes with end organ damage, and without heart failure.
Patients were randomised to telmisartan 80 mg daily (8542 patients), ramipril 10 mg daily (8576 patients), or the combination (8502 patients).
There was no significant difference in the primary outcome of cardiovascular death, MI, stroke, or hospitalisation for heart failure during a median follow up of 56 months between the three groups.
In view of the more recent evidence patients with stable coronary artery disease without heart failure and who are intolerant of ACE inhibitors, should be considered for an angiotension II receptor antagonist.
Harms
The randomised controlled trial of candesartan did not report adverse effects. However, 4% of participants were reported to be intolerant of candesartan. In the larger randomised controlled trial, the incidence of cough (4.2% versus 1.1%) and angio-oedema (0.3% versus 0.1%) was higher with ramipril compared to telmisartan, but hypotensive symptoms occurred less frequently (1.7% versus 2.6%).Angiotensin II receptor blockers added to ACE inhibitors
No systematic reviews were found. The randomised controlled trial of patients with coronary, cerebrovascular, or peripheral arterial disease or diabetes with end organ damage, and without heart failure which randomised patients to treatment with ramipril v telmisartan v the combination found no significant difference in the primary outcome of cardiovascular death, MI, stroke, or hospitalisation for heart failure during a median follow up of 56 months with the combination of telmisartan and ramipril compared to either drug alone.A subgroup analysis of the randomised controlled trial examining the efficacy of low dose candesartan in patients after coronary intervention found no additional significant reduction in cardiac events with candesartan in patients already treated with an ACE inhibitor, although the study may have lacked power.
A further randomised controlled trial in patients with chronic heart failure, in which 93% of patients were treated with an ACE inhibitor, found no overall difference in mortality with valsartan compared to placebo, although there was a reduction in mortality and morbidity with valsartan compared to placebo. However, in those already being treated with an ACE inhibitor and a beta blocker, valsartan had an adverse effect on mortality and a trend towards an increase in the combined end point of mortality and morbidity.
In contrast, a second randomised controlled trial in patients with chronic heart failure and left ventricular dysfunction, who were already being treated with ACE inhibitors, found a reduction in the composite of cardiovascular death and hospital admission for heart failure with treatment with candesartan compared to placebo, including patients treated with beta blockers at baseline.
In a randomised controlled trial in patients with
a recent myocardial infarction with heart failure and/or left ventricular dysfunction, the addition of valsartan to captopril resulted in no difference in all cause mortality compared to either valsartan or captopril alone.Calcium channel blockers
One systematic review found no significant difference in mortality between calcium channel blockers and placebo in people after myocardial infarction. However, subgroup analysis by drug type found that diltiazem and verapamil reduced rates of refractory angina in people without heart failure after myocardial infarction.The review found non-significantly higher mortality with dihydropyridines compared with placebo.
Harms
Three randomised controlled trials of either diltiazem or verapamil compared with placebo found a trend towards harm for people with clinical manifestations of heart failure.
Class I antiarrhythmic agents
(quinidine, procainamide, disopyramide, encainide, flecainide, and moracizine)One systematic review found that taking class I antiarrhythmic agents after myocardial infarction increased the risk of cardiovascular mortality and sudden death compared with placebo. One randomised controlled trial found that, in people who have had a myocardial infarction with ventricular ectopy which could be suppressed with flecainide, encainide, or moracizine, treatment with either flecainide or encainide compared to placebo increased the risk of cardiac arrest and death.
Amiodarone
Two systematic reviews found that amiodarone(a class III antiarrhythmic agent) significantly reduced the risk of all cause mortality and arrhythmic/sudden death, compared with placebo, in people with a recent myocardial infarction and a high risk of death from cardiac arrhythmia (including left ventricular dysfunction).
In one of the largest randomised controlled trials, there was no significant difference in all cause mortality (the primary outcome) or cardiac mortality, although there was a favourable interaction between the use of beta blockers and cardiac mortality. There was also a favourable interaction in a second randomised controlled trial between the use of beta blockers and the primary outcome of resuscitated ventricular fibrillation or arrhythmic death.
Harms
Adverse events leading to the discontinuation of amiodarone are hypothyroidism, hyperthyroidism, peripheral neuropathy, lung infiltrates, bradycardia, and liver dysfunction.
Comments
More recent trials have examined the efficacy of implantable cardioverter defibrillators (ICD). An ICD should be considered in patients with a past history of myocardial infarction who are at high risk of arrhythmic death and who fulfil prespecified criteria, rather than treatment with amiodarone.
Hormone replacement therapy
One randomised controlled trial found no overall significant difference between conjugated equine oestrogen plus medroxyprogesterone acetate and placebo in cardiac events among postmenopausal women with coronary artery disease after 4.1 years of follow up, although there was a pattern of an increased risk in coronary events in year 1, with fewer in years 4 and 5. Extension of the trial with open label treatment found that there remained no significant difference between the two groups.An additional randomised controlled trial in women with angiographically proved ischaemic heart disease also found no significant difference with transdermal beta oestradiol, with or without a cyclical progestogen, compared to placebo on coronary events. Furthermore, a third trial found no significant difference between oestradiol valerate and placebo on reinfarction, cardiac death, and all cause mortality in women after myocardial infarction
Harms
Combined oestrogen and progestogens versus placeboOne randomised controlled trial, with extended open label follow up, found an increase in the incidence of biliary tract surgery and of any venous thromboembolic event in women allocated to hormone replacement therapy, compared to placebo.
Oestrogen alone versus placebo
In one randomised controlled trial, 208 out of 373 women treated with oestradiol valerate, who had not had a hysterectomy, had vaginal bleeding during 24 months of treatment. There was no significant difference in venous thromboembolic events, stroke, transient ischaemic attack, breast cancer, endometrial cancer, or fracture in those treated with oestrogen compared to placebo, although the study may have been underpowered to detect these.39Comments
Contrary to decades of large observational studies, multiple randomised controlled trials show no cardiovascular benefit from oestrogen with or without progestogens in postmenopausal women.
Combinations of antiplatelet treatments
A randomised controlled trial in patients with non-ST elevation acute coronary syndromes, with a mean follow up of nine months, found that the combination of clopidogrel and aspirin reduced serious cardiovascular events compared with aspirin alone.Two randomised controlled trials in patients with ST elevation myocardial infarction, with a maximum follow up of 30 days, and excluding those treated with primary percutaneous coronary intervention (PCI), found that clopidogrel in addition to other standard treatment reduced adverse cardiovascular outcomes compared to placebo in addition to other standard treatment.
A randomised controlled trial comparing aspirin plus clopidogrel with aspirin alone in stable patients with vascular disease or multiple atherothrombotic risk factors, with a median follow up of 28 months, found no overall difference in major cardiovascular events between the two groups.
Prasugrel (60 mg loading dose, followed by 10 mg daily) is a new thienopyridine and was compared with clopidogrel (300 mg loading dose, followed by 75 mg daily) in a randomised controlled trial of 13 608 patients with moderate to high risk acute coronary syndrome scheduled for percutaneous coronary intervention. Prasugrel was more effective than clopidogrel in reducing the primary efficacy end point of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.
Harms
Aspirin plus thienopyridines: the addition of clopidogrel to aspirin after acute coronary syndrome, for a mean duration of nine months, significantly increased the risk of major bleeding, but did not significantly increase the risk of life threatening haemorrhage compared with aspirin alone.The addition of clopidogrel to aspirin in stable patients with vascular disease or multiple risk factors, compared to treatment with aspirin alone, for a median of 28 months, also increased the risk of moderate bleeding. Prasugrel in patients with moderate to high risk acute coronary syndrome, scheduled for percutaneous coronary intervention, increased the risk of major bleeding and life threatening bleeding compared to clopidogrel.
Oral anticoagulants in addition to antiplatelet treatments
A systematic review found that, after an acute coronary syndrome, warfarin with a target international normalised ratio (INR) of greater than 2 - target in the majority 2 to 2.5 - reduced the risk of myocardial infarction, ischaemic stroke, and revascularisation when added to aspirin, with no effect on mortality compared with aspirin alone. A randomised controlled trial of patients after acute myocardial infarction found that adding fixed, low dose warfarin to aspirin had no effect on cardiovascular outcomes compared with aspirin alone.Harms
Aspirin plus anticoagulants versus aspirin alone: a systematic review found a significant increase in major and minor bleeding in patients treated with warfarin (target INR >2) plus aspirin compared with aspirin alone, and in a randomised controlled trial, treatment with fixed low dose warfarin plus aspirin, compared to aspirin alone, was also associated with an increase in both serious and less serious bleeds.Oral anticoagulants in the absence of antiplatelet treatment
A systematic review found that high intensity oral anticoagulation (INR >2.8), compared with control, significantly reduced the risk of major cardiovascular events in people with coronary artery disease, with a non-significant reduction in events with moderate intensity oral anticoagulation (INR 2 to 3) compared with control.Harms
Oral anticoagulants versus placebo: the same review found that both high and moderate intensity anticoagulation substantially increased the risk of major bleeding compared with control.
Oral anticoagulants versus aspirin
A systematic review of six trials with 4155 patients found that moderate to high intensity oral anticoagulation was associated with a reduction in the composite of death, myocardial infarction, and stroke compared to aspirin.
A systematic review of 10 trials with 6655 patients found that moderate to high intensity oral anticoagulation was associated with an increased rate of major bleeding compared to aspirin.
Comments
Moderate to high intensity oral anticoagulation appears more effective than aspirin alone in reducing cardiovascular events, but is associated with an increased risk of haemorrhage.Aspirin is an effective agent for secondary prevention and is safer and more convenient, and compared to oral anticoagulation, is generally the preferred agent.
Following acute coronary syndrome or myocardial infarction without stenting in patients where the absolute risk of major cardiovascular events is higher than average, the benefits of moderate intensity oral anticoagulation plus aspirin may exceed the potential for harm, provided that the risk of bleeding is low. However, the combination of aspirin and a thienopyridine is likely to be preferred in this group, particularly as many will have had percutaneous coronary intervention, unless there are other indications for anticoagulation.
After an acute coronary syndrome, 12 months' treatment with the combination of aspirin and a thienopyridine is routinely recommended, irrespective of whether patients have percutaneous coronary intervention. This is particularly important in patients who have percutaneous coronary intervention with a drug eluting stent (in whom earlier discontinuation of dual treatment with antiplatelets increases the risk of stent thrombosis).
Clopidogrel
In a randomised controlled trial of patients with a history of myocardial infarction, stroke, or peripheral arterial disease, clopidogrel compared with aspirin reduced the risk of major cardiovascular events during a mean follow up of 1.91 years. The annual risk of ischaemic stroke, myocardial infarction, or vascular death was 5.32% with clopidogrel compared to 5.83% with aspirin.Harms
In a randomised controlled trial, clopidogrel 75 mg od was associated with less gastrointestinal haemorrhage and fewer upper gastrointestinal symptoms than aspirin 325 mg od, but the incidence of rash and diarrhoea was higher.
What are the effects of cholesterol reduction?
StatinsStatins have been studied in people both with vascular disease and at high risk of vascular disease in a large number of randomised controlled trials. A meta-analysis of 14 trials, including both primary and secondary prevention populations, found that statins compared to placebo reduce all cause mortality and major vascular events, with no adverse effect on non-vascular mortality.
The relative risk reduction was similar in those with and without previous vascular disease, in those with and without diabetes, in those who were older or younger than 65 years of age, and in both men and women.
A randomised controlled trial which recruited people aged 70 to 82 years with, or with risk factors for, vascular disease, found a significant reduction in the composite of coronary death, non-fatal myocardial infarction, and fatal and non-fatal stroke with treatment with pravastatin compared to placebo.
A meta-analysis of four randomised controlled trials comparing intensive with less intensive statin treatment in patients with coronary disease found a significant reduction in the combined outcome of coronary death or non-fatal myocardial infarction, and in the combined outcome of coronary death or any adverse cardiovascular event (myocardial infarction, stroke, hospitalisation for unstable angina, or any revascularisation), although there was no reduction in all cause mortality.
Harms
A systematic review has examined the safety of statins using data from cohort studies, randomised trials, voluntary notifications to national regulatory authorities, and published case reports. In two cohort studies, and supported by data from 20 randomised trials, the incidence of rhabdomyolysis was 3.4 per 100 000 person years in patients treated with statins, and the incidence of myopathy was 11 per 100 000 person years.Elevation in liver enzymes (alanine aminotransferase or aspartate aminotransferase) is more common with statin treatment than with placebo, but the incidence of clinical liver disease is rare, with an estimated rate of liver failure of about 0.5 per 100 000 person years.
Evidence from cohort studies and case reports estimates a small risk of peripheral neuropathy in people treated with statins of 12 per 100 000 person years.
Comments
People in the large statin trials in both treatment and placebo groups were also given dietary advice aimed at lowering cholesterol.A systematic review has examined the efficacy of any cholesterol lowering intervention on mortality, and in a meta-regression analysis, found that variability across trials was largely explained on the basis of differences in the amount by which cholesterol was reduced.
This is consistent with the meta-analysis of combined primary prevention and secondary prevention trials, in which relative risk reduction was greater, with greater reductions in low density lipoprotein cholesterol, and the absolute reduction in risk is dependent on the baseline risk of an ischaemic event in the population being treated.
What are the effects of non-drug treatments?
Antioxidant vitamin combinationsThree randomised controlled trials included in a systematic review found no benefit of antioxidant combinations on cardiovascular events or cardiac mortality.
Beta carotene
A systematic review found no reduction in cardiovascular risk from beta carotene supplementation. In a more recent randomised controlled trial of women aged 40 years or more with a prior cardiovascular event or three or more cardiovascular risk factors, treatment with beta carotene had no effect on the composite of cardiovascular mortality, myocardial infarction, stroke, or revascularisation.
Vitamin C
Evidence is limited on its efficacy. In a randomised controlled trial of women aged 40 years or more with a prior cardiovascular event or three or more cardiovascular risk factors, treatment with vitamin C had no effect on the composite of cardiovascular mortality, myocardial infarction, stroke, or revascularisation.
Vitamin E
Two systematic reviews found inconclusive evidence about the benefits of vitamin E. In a pooled analysis there was no beneficial or adverse effect. In a randomised controlled trial of women aged 40 years or more with a prior cardiovascular event or three or more cardiovascular risk factors, treatment with vitamin E had no effect on the composite of cardiovascular mortality, myocardial infarction, stroke, or revascularisation.Harms
The secondary prevention randomised controlled trials reported no consistent harms with vitamin supplementation, although in 1 in 1862 male smokers with a past history of myocardial infarction, beta carotene was associated with an increase in fatal coronary heart disease and fatal myocardial infarction. However, there was no effect on total coronary events and myocardial infarctions.This was a subgroup of a larger randomised controlled trial of 29 133 male smokers which examined the efficacy of daily supplementation with alpha-tocopherol or beta carotene, or both, compared to placebo in reducing the incidence of lung cancer or other cancers. It found evidence of an increase in lung cancer incidence and lung cancer mortality with beta carotene supplementation.
Cardiac rehabilitation including exercise
Two systematic reviews found that, compared with usual care, cardiac rehabilitation reduced mortality, and one found a reduction in recurrent myocardial infarction. The first review also reported a beneficial impact on modifiable risk factors, with reductions in total cholesterol, triglycerides, systolic blood pressure, and lower rates of self reported smoking with cardiac rehabilitation compared to usual care.Health related quality of life was assessed using a variety of outcome measures. Some of the trials included in the systematic reviews reported an improvement with cardiac rehabilitation compared to usual care, but effect sizes were generally small. Harms
Rates of adverse cardiovascular outcomes (syncope, arrhythmia, myocardial infarction, or sudden death) were low in supervised rehabilitation programmes, and rates of fatal cardiac events during or immediately after exercise training were reported in two older surveys as ranging from 1/116 400 person hours to 1/784 000 person hours.
Diet
Mediterranean dietOne randomised controlled trial found that advising people after a first myocardial infarction to eat a Mediterranean diet (more fruit and vegetables, bread, pasta, potatoes, olive oil, and rapeseed margarine), compared to a Western diet, led to a reduction in all cause and cardiovascular mortality, and the combination of recurrent myocardial infarction and cardiac death.
Advice to eat less fat
We found no strong evidence from randomised controlled trials on the effects of advising people to eat a low fat diet.
Advice to eat more fibre
There was no evidence from one randomised controlled trial, included in a systematic review, that a high fibre diet has any effect on cardiac or all cause mortality
Fish oil consumption (from oily fish or capsules)
Two of three randomised controlled trials, both involving people with a recent myocardial infarction, found a protective effect of increasing fish intake or taking a fish oil supplement, and two cohort studies were consistent with this. In the third randomised controlled trial of men with angina, those advised to eat oily fish, and in particular those supplied with fish oil capsules, had a higher risk of cardiac death.Harms
No major adverse effects of dietary advice have been reported, but very high doses of fish oil may increase the risk of bleeding.Smoking cessation
No randomised controlled trials of the effects of smoking cessation on cardiovascular events in people with coronary heart disease were found. Observational studies have found that smoking cessation significantly reduces the risk of myocardial infarction and death in people with coronary heart disease.
Harms
Two randomised controlled trials found no evidence that nicotine replacement, using transdermal patches, in people with stable coronary heart disease increases cardiovascular events.
Clopidogrel is a little more clinically effective than aspirin for reducing further cardiovascular events, but is currently more costly.
Clopidogrel is a particularly good option in patients who are allergic to aspirin.
In patients with a history of a myocardial infarction, ACE inhibitors such as ramipril have been found to reduce the risk of serious cardiac events, both in patients with preserved left ventricular function and in those with heart failure and/or left ventricular systolic dysfunction.
A meta-analysis compared the effectiveness of different doses of aspirin in reducing vascular events in high risk patients (excluding those with acute stroke), and the odds reduction (SE) in vascular events was 19% (3%) with 500 to 1500 mg daily, 26% (3%) with 160 to 325 mg daily, and 32% (6%) with 75 to 150 mg daily. The odds reduction with daily doses of less than 75 mg was fewer at 13% (8%).
Prognosis
Within one year of having a first myocardial infarction, it has been reported that 25% of men and 38% of women will die.
Within six years of having a first myocardial infarction, 18% of men and 35% of women will have another myocardial infarction, 22% of men and 46% of women will have heart failure, and 7% of men and 6% of women will have sudden death.
The patient's outcome after acute myocardial infarction has improved over recent years. Between 1999 and 2006, in patients with ST elevation myocardial infarction there was a fall in in-hospital deaths, congestive heart failure, and pulmonary oedema, and a fall in myocardial infarction diagnosed more than 24 hours after presentation to hospital or recurrent myocardial infarction.
Between hospital discharge and a time frame of six months, there was a reduction in the rate of myocardial infarction and stroke. In patients with non-ST elevation acute coronary syndrome, there was also a reduction in in-hospital deaths, congestive heart failure, and pulmonary oedema, and myocardial infarction diagnosed more than 24 hours or recurrent myocardial infarction. Between hospital discharge and a time frame of six months, there was a reduction in the rate of death and stroke. In both groups, there was an increase in evidence based interventions during the time period.
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