Abstract
Introduction
In people with acute coronary syndrome (ACS) the incidence of serious adverse outcomes (such as death, acute myocardial infarction [MI], or refractory angina requiring emergency revascularisation) is 5-10% within the first 7 days and about 15% at 30 days. Between 5-14% of people with acute coronary syndrome die in the year after diagnosis, with about half of these deaths occurring within 4 weeks of diagnosis.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of: antiplatelet; antithrombin; anti-ischaemic; lipid-lowering; and invasive treatments? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 32 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aspirin, beta-blockers, calcium channel blockers, clopidogrel, direct thrombin inhibitors, glycoprotein IIb/IIIa inhibitors (oral or intravenous), heparin (low molecular weight, unfractionated), nitrates, routine early cardiac catheterisation and revascularisation, statins, and warfarin.
Key Points
Acute coronary syndrome (ACS, here defined as unstable angina and non-ST elevation MI) is characterised by episodes of chest pain at rest or with minimal exertion, which are increasing in frequency or severity often with dynamic ECG changes.
Aspirin reduces the risk of death, MI, and stroke compared with placebo in people with ACS at doses up to 325 mg daily; higher doses of aspirin are no more effective, and increase the risk of complications.
Adding clopidogrel to aspirin may reduce the combined outcome of mortality and MI, but may increase the risk of bleeding.
Intravenous glycoprotein IIb/IIIa platelet receptor inhibitors reduce the combined end point of death and MI at 6 months in people with ACS, but increase the risk of bleeding.
Unfractionated or low molecular weight heparin plus aspirin may reduce death or MI at 1 week, but longer-term benefits are unclear.
Low molecular weight heparin may reduce MI compared with unfractionated heparin
Direct thrombin inhibitors (hirudin and bivalirudin) may reduce death or MI compared with unfractionated heparin.
Warfarin has not been shown to be beneficial and increases the risk of major bleeding.
We don't know whether intravenous nitrates, beta-blockers, or calcium channel blockers reduce the risk of MI or death, although they may reduce the frequency and severity of chest pain.
CAUTION: Short-acting dihydropyridine calcium channel blockers may increase mortality in people with CHD.
Early routine cardiac catheterisation and revascularisation may reduce death and non-fatal MI compared with conservative strategies (medical treatment with or without later cardiac catheterisation and revascularisation).
About this condition
Definition
Acute coronary syndrome (ACS) is term that encompasses unstable angina, non-ST elevation MI (new term for non-Q wave MI, often referred to as non-STEMI), and ST elevation MI (new term for Q wave MI, often referred to as STEMI). Unstable angina and non-STEMI are overlapping entities and will be discussed together in this review. STEMI is discussed elsewhere (see review on acute myocardial infarction). Unstable angina and non-STEMI is a spectrum of disease that involves an imbalance of supply and demand of oxygen available to the myocardium. This balance is sometimes disrupted, causing symptoms such as new-onset exertional angina, pre-existing angina that is refractory to nitroglycerin, or angina at rest. The pathophysiology governing anginal symptoms is usually due to atherosclerotic plaque that nearly obstructs coronary vessels. The distinguishing feature between unstable angina and non-STEMI is the presence of elevated cardiac markers such as troponin, which imply myocardial damage. Patient history alone is insufficient to make a diagnosis of ACS. The clinical dilemma of distinguishing between cardiac and non-cardiac pain requires a combination of patient history, ECG, and biomarkers. Overlapping clinical entities in the ACS spectrum of disease allows for similar treatment strategies, and many trials include people with either unstable angina or non-STEMI. We have included systematic reviews and RCTs in a mixed population of people with unstable angina, non-STEMI, or both, which we will refer to here as ACS.
Incidence/ Prevalence
In the USA, ACS accounts for more than 1.4 million hospital admissions a year. In industrialised countries, the annual incidence of unstable angina is about 6/10,000 people in the general population.
Aetiology/ Risk factors
Risk factors are the same as for other manifestations of ischaemic heart disease — older age, previous atheromatous CVD, diabetes mellitus, smoking, hypertension, hypercholesterolaemia, male sex, and a family history of premature ischaemic heart disease. ACS can also occur in association with other disorders of the circulation, including valvular disease, arrhythmias, and cardiomyopathies.
Prognosis
Between 9-19% of people with ACS die in the first 6 months after diagnosis, with about half of these deaths occurring within 30 days of diagnosis.Several risk factors may indicate poor prognosis and include severity of presentation (e.g. duration of pain, speed of progression, evidence of heart failure), medical history (e.g. previous ACS, acute MI, left ventricular dysfunction), other clinical parameters (e.g. age, diabetes), ECG changes (e.g. severity of ST segment depression and deep T wave inversion), biomarkers (e.g. presence of troponin concentration elevation), and change in clinical status (e.g. recurrent chest pain, silent ischaemia, haemodynamic instability). However, several key prognostic indicators associated with adverse outcomes may be used to aid clinical decision making. Variables including age 65 or over, at least three risk factors for coronary artery disease, known significant coronary stenosis, degree of ST segment deviation, recurrent anginal symptoms in 24 hours, use of aspirin in last 7 days, and elevated cardiac biomarkers can be used to generate a scoring system to predict high-risk patients who may experience true ischaemic cardiac events and death (TIMI [thrombolysis in MI] risk score). The more of these factors that are present, the greater the likelihood of adverse ischaemic events. This helps in stratifying patients according to risk, and in identifying high-risk patients.
Aims of intervention
To relieve pain and ischaemia; to prevent death and MI; to identify people at high risk who require revascularisation; to facilitate early hospital discharge in people at low and medium risk; to modify risk factors; to prevent death, MI, and recurrent ischaemia after discharge from hospital, with minimum adverse effects.
Outcomes
Mortality, MI, refractory ischaemia or readmission for ACS, adverse effects of treatment.
Methods
Clinical Evidence search and appraisal May 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2007, Embase 1980 to May 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We report outcomes of treatment from onset of symptoms up to 6 months in this review. We would also include systematic reviews which combine outcomes from both before and after 6 months. Systematic reviews and RCTs that cover secondary prevention in mixed manifestations of atherosclerotic coronary artery disease are reported in the review on Secondary prevention of ischaemic cardiac events. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs.
Table.
GRADE evaluation of interventions for acute coronary syndrome
| Important outcomes | Mortality, MI, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of antiplatelet treatments in people with acute coronary syndrome? | |||||||||
| 12 (5031) | Cardiovascular events | Aspirin v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of different interventions |
| 12 (5031) | Bleeding | Aspirin v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of different interventions |
| 1 (12,562) | Cardiovascular events | Clopidogrel v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (12,562) | Bleeding | Clopidogrel v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of antithrombin treatments in people with acute coronary syndrome? | |||||||||
| 6 (31,402) | Cardiovascular events | Intravenous glycoprotein IIB/IIIA inhibitors v placebo | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for high use of surgery in participants, and not using other standard medical treatments by current practice |
| 6 (31,402) | Bleeding | Intravenous glycoprotein IIB/IIIA inhibitors v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for not using current standard medical treatments |
| 6 (1353) | Cardiovascular events | Unfractionated heparin plus aspirin v aspirin alone | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for different results at different times |
| 1 (1353) | Bleeding | Unfractionated heparin plus aspirin v aspirin alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data due to low event rate |
| 7 (13,738) | Cardiovascular events | LMWH v no heparin | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for different results at different times |
| 7 (13,738) | Bleeding | LMWH v no heparin | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for different results at different times |
| 7 (11,092) | Mortality | LMWH v unfractionated heparin | 4 | 0 | 0 | 0 | 0 | High | |
| 7 (11,092) | MI | LMWH v unfractionated heparin | 4 | 0 | 0 | 0 | 0 | High | |
| 7 (11,092) | Bleeding | LMWH v unfractionated heparin | 4 | 0 | 0 | 0 | 0 | High | |
| 11 (35,070) | Cardiovascular events | Direct thrombin inhibitors v unfractionated heparin | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for heterogeneity of RCTs |
| 11 (35,070) | Bleeding | Direct thrombin inhibitors v unfractionated heparin | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for heterogeneity of RCTs |
| 5 (4567) [11, 12, 13, 14] | Cardiovascular events | Warfarin v no warfarin | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for different definitions of combined outcome |
| 1 (3712) [13] | Bleeding | Warfarin v no warfarin | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of anti-ischaemic treatments in people with acute coronary syndrome? | |||||||||
| 1 (338) [15] | MI | Beta-blockers v placebo | 4 | –2 | 0 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results and short follow-up. Directness point deducted for narrow range of beta-blockers studies |
| 1 (81) [16] | Mortality | Beta-blockers v placebo | 4 | –2 | 0 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results and short follow-up. Directness point deducted for narrow range of beta-blockers studies |
| 1 (162) [17] | Adverse effects | Nitrate v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 6 (856) [19] | Mortality | Calcium channel blockers v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 6 (856) [19] | MI | Calcium channel blockers v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 6 (303) [19] | Mortality | Calcium channel blockers v beta-blockers | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 6 (303) [19] | MI | Calcium channel blockers v beta-blockers | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| What are the effects of lipid-lowering treatments in people with acute coronary syndrome? | |||||||||
| 1 (3086) [22] | Mortality or MI | Statins v placebo | 4 | 0 | 0 | –1 | 0 | High | Directness point deducted for narrow range of interventions studied |
| What are the effects of invasive treatments in people with acute coronary syndrome? | |||||||||
| 7 (8375) [23] | Mortality | Routine early surgical revascularisation v more conservative management | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of different interventions |
| 7 (8375) [23] | MI | Routine early surgical revascularisation v more conservative management | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of different interventions |
| 2 (4677) [24, 25] | Bleeding | Routine early surgical revascularisation v more conservative management | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio
Glossary
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- International normalised ratio (INR)
A value derived from a standardised laboratory test that measures the effect of an anticoagulant. The laboratory materials used in the test are calibrated against internationally accepted standard reference preparations, so that variability between laboratories and different reagents is minimised. Normal blood has an international normalised ratio of 1.0. Therapeutic anticoagulation often aims to achieve an international normalised ratio value of 2.0–3.5.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Acute myocardial infarction
Secondary prevention of ischaemic cardiac events
Angina (chronic stable)
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Michael L Sarkees, Cleveland Clinic, Cleveland, USA.
Anthony A Bavry, University of Florida, Florida, USA.
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