Abstract
Introduction
Stable angina is usually caused by coronary atherosclerosis, and affects up to 16% of men and 10% of women aged 65–74 years in the UK. Risk factors include hypertension, elevated serum cholesterol levels, smoking, physical inactivity, and overweight. People with angina are at increased risk of other cardiovascular events and mortality compared with people without angina. Among people not thought to need coronary artery revascularisation, annual mortality is 1–2% and the annual non-fatal myocardial infarction (MI) rate is 2–3%.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are effects of long-term drug treatment for stable angina? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ 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 nine systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the long-term effectiveness and safety of the following interventions: beta-blockers, calcium channel blockers, long-acting nitrates, potassium channel openers, combinations of these anti-anginal drug treatments and the use of these anti-anginal drug treatment as an adjunct to existing therapies.
Key Points
Stable angina is a sensation of discomfort or pain in the chest, arm, or jaw brought on predictably by factors that increase myocardial oxygen demand, such as exertion, and relieved by rest or nitroglycerin.
Stable angina is usually caused by coronary atherosclerosis, and affects up to 16% of men and 10% of women aged 65–74 years in the UK. Risk factors include hypertension, elevated serum cholesterol levels, smoking, physical inactivity, and overweight.
People with angina are at increased risk of other cardiovascular events and mortality compared with people without angina.
Among people not thought to need coronary artery revascularisation, annual mortality is 1–2% and annual non-fatal MI rates are 2–3%.
We found no long-term, adequately powered RCTs of anti-anginal drugs versus placebo or comparing the use of a single anti-anginal drug versus combinations of anti-anginal drug classes. There is a consensus that monotherapy with beta-blockers, calcium channel blockers, nitrates, and potassium channel openers are effective for treating the symptoms of stable angina in the long term, although we found few studies to confirm this. There is also consensus that the concurrent use of two of these classes of drug has an additional beneficial effect on anginal symptoms and quality of life. It has not been established that this approach reduces cardiovascular events.
Monotherapy with beta-blockers or calcium channel blockers seems equally effective at reducing angina attacks, and they are equally well tolerated in the long term.
Adding a calcium channel blocker to existing anti-anginal drug treatments slightly reduces the need for coronary artery surgery, but has no effect on other cardiovascular events.
Monotherapy with nitrates may be as effective as monotherapy with calcium channel blockers at reducing angina attacks and improving quality of life.
We found no RCTs on the effects of long-term monotherapy with potassium channel openers in people with stable angina, but a large RCT of a potassium channel opener as an adjunct to existing anti-anginal drug treatments found a reduction the number of cardiovascular events compared with placebo.
Clinical context
About this condition
Definition
Angina pectoris, often simply known as angina, is a clinical syndrome characterised by discomfort in the chest, shoulder, back, arm, or jaw. Angina is usually caused by coronary artery atherosclerotic disease. Rarer causes include valvular heart disease, hypertrophic cardiomyopathy, uncontrolled hypertension, or vasospasm or endothelial dysfunction not related to atherosclerosis. The differential diagnosis of angina includes non-cardiac conditions affecting the chest wall, oesophagus, and lungs. Angina may be classified as stable or unstable. Stable angina is defined as regular or predictable angina symptoms that have been occurring for over 2 months. Symptoms are transient and typically provoked by exertion, and alleviated by rest or nitroglycerin. Other precipitants include cold weather, eating, or emotional distress. This review deals specifically with stable angina caused by coronary artery atherosclerotic disease. For management of unstable angina, see separate review on acute coronary syndromes.
Incidence/ Prevalence
The prevalence of stable angina remains unclear. Epidemiological studies in the UK estimate that 6–16% of men and 3–10% of women aged 65–74 years have experienced angina. Annually, about 1% of the population visit their general practitioner with symptoms of angina, and 23,000 people with new anginal symptoms present to their general practitioner each year in the UK. These studies did not distinguish between stable and unstable angina.
Aetiology/ Risk factors
Stable angina resulting from coronary artery disease is characterised by focal atherosclerotic plaques in the intimal layer of the epicardial coronary artery. The plaques encroach on the coronary lumen and may limit blood flow to the myocardium, especially during periods of increased myocardial oxygen demand. The major risk factors that lead to the development of stable angina are similar to those that predispose to CHD. These risk factors include increasing age, male sex, overweight, hypertension, elevated serum cholesterol level, smoking, and relative physical inactivity.
Prognosis
Stable angina is a marker of underlying CHD, which accounts for 1 in 4 deaths in the UK. People with angina are 2–5 times more likely to develop other manifestations of CHD than people who do not have angina. One population-based study (7100 men aged 51–59 years at entry) found that people with angina had higher mortality than people with no history of coronary artery disease at baseline (16-year survival rate: 53% with angina v 72% without coronary artery disease v 34% with a history of MI). Clinical trials in people with stable angina have tended to recruit participants who were not felt to be in need of coronary revascularisation, and prognosis is better in these people, with an annual mortality of 1–2%, and an annual rate of non-fatal MI of 2–3%. Features that indicate a poorer prognosis include: more-severe symptoms, male sex, abnormal resting ECG (present in about 50% of people with angina), previous MI, left ventricular dysfunction, easily provoked or widespread coronary ischaemia on stress testing (present in about a third of people referred to hospital with stable angina), and significant stenosis of all three major coronary arteries or the left main coronary artery. In addition, the standard coronary risk factors continue to exert a detrimental and additive effect on prognosis in people with stable angina. Control of these risk factors is dealt with in the Clinical Evidence review on secondary prevention of ischaemic cardiac events.
Aims of intervention
To prevent death and future cardiovascular events, and to improve symptoms, exercise capacity, and quality of life.
Outcomes
Primary outcomes: mortality, non-fatal MI, and unstable angina. Secondary outcomes: anti-anginal efficacy (as determined by symptom frequency and total exercise time on treadmill testing), quality of life (assessed by questionnaire), and adverse effects of treatment.
Methods
BMJ Clinical Evidence search and appraisal June 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2007, Embase 1980 to June 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 where possible, and containing more than 50 people, of whom more than 80% were followed up for a minimum of 6 months. We excluded all studies described as “open”, “open label”, or not blinded. We included RCTs that compared single-drug anti-anginal treatment versus placebo or another single-drug anti-anginal treatment, single drug-class treatment versus dual drug-class treatment, and single drug-class treatment used as an adjunct to existing treatment versus existing treatment alone in people with stable angina believed to be caused by coronary artery atherosclerotic disease. The anti-anginal drug classes covered by the search were beta-blockers, calcium channel blockers, long-acting nitrate preparations, and potassium channel openers. 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. 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 have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table 1.
GRADE evaluation of interventions for angina (chronic stable)
| Important outcomes | Symptom improvement, mortality, quality of life | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of long-term single-drug treatment for stable angina? | |||||||||
| 1 (112) | Symptom improvement | Beta-blockers v placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for no statistical comparison between groups for one outcome |
| 5 (1542) . | Symptom improvement | Beta-blockers v calcium channel blockers | 4 | –2 | 0 | –1 | 0 | Very low | Quality point deducted for incomplete reporting and high rate of withdrawals in 1 RCT. Directness point deducted for composite outcome in 2 RCTs |
| 1 (809) | Mortality | Beta-blockers v calcium channel blockers | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (809) | Quality of life | Beta-blockers v calcium channel blockers | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (112) | Symptom improvement | Calcium channel blockers v placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for no statistical comparison between groups for one outcome |
| 1 (196) | Symptom improvement | Calcium channel blockers v nitrates | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (196) | Quality of life | Calcium channel blockers v nitrates | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| What are the effects of long-term combination drug treatment for stable angina? | |||||||||
| 1 (450) | Symptom improvement | Beta-blockers plus calcium channel blockers v beta-blockers alone | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for use of composite outcome and limited outcomes reported |
| 1 (456) | Symptom improvement | Calcium channel blockers plus beta-blockers v calcium channel blockers alone | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for use of composite outcome and limited outcomes reported |
| What are the effects of long-term adjunctive treatment in people with stable angina? | |||||||||
| 1 (7665) | Symptom improvement | Calcium channel blockers in addition to existing anti-anginal drug treatment v adding placebo to existing anti-anginal drug treatment | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for use of compositie outcome |
| 1 (7665) | Mortality | Calcium channel blockers in addition to existinganti-anginal drug treatment v adding placebo to existing anti-anginal drug treatment | 4 | 0 | 0 | 0 | 0 | High | |
| 1(5126) | Symptom improvement | Potassium channel openers in addition to existing anti-anginal drug treatment v adding placebo to existing anti-anginal drug treatment | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for composite outcome |
| 1(5126) | Mortality | Potassium channel openers in addition to existing anti-anginal drug treatment v adding placebo to existing anti-anginal drug treatment | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted as trial not adequately powered for this outcome |
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
- Exercise stress testing
is widely used in the evaluation of people with chest pain. The person walks on a treadmill, the speed and slope of which are varied according to protocol, while being monitored by ECG. Exercise-induced horizontal or down-sloping ST segment depression is strongly suggestive of myocardial ischaemia, particularly when associated with typical chest pain. ST segment depression at a low workload usually indicates severe coronary artery disease, as may exercise-induced ventricular arrhythmia or a fall in blood pressure.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- 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.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Secondary prevention of ischaemic cardiac events.
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.
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