CARDIOVASCULAR DISEASES

Health Evidence Bulletins - Wales (logo)
Team Leader: Dr David Fone

Date of completion: 30.9.98

3: Unstable angina

This bulletin is a supplement to, not a substitute for, professional skills and experience. Users are advised to consult the supporting evidence for a consideration of all the implications of a recommendation.

The Statements The Evidence
3.1 Clinical guidelines
3.1a. The clinical syndrome of unstable angina includes patients within a spectrum ranging from stable angina through to myocardial infarction (MI). Patients present with symptoms of angina at rest (usually more than 20 minutes), new onset of exertional angina with marked limitation of ordinary physical activity, or recent (<2 months) increase in the severity of angina. The risk of death or complications in patients with unstable angina is lower than in patients with MI but higher than with stable angina. Around 5% to 10% of patients with unstable angina progress to MI, of which in 1% the outcome will be fatali. Evidence-based guidelines for the diagnosis and management of unstable angina are availablei.
(Health gain notation - 1 "beneficial")
i. Braunwald E, Mark DB, Jones RH, et al. Unstable Angina: Diagnosis and Management. Clinical Practice Guideline Number 10 (amended) AHCPR. Rockville, MD: Agency for Health Care Policy and Research and the National Heart, Lung, and Blood Institute, Public Health Service, U.S. Department of Health and Human Services, 1994
http://www.ahcpr.gov/clinic/
(Type V evidence - expert opinion)

 

3.2 Thrombolytic therapy
3.2a. There is no evidence that thrombolytic therapy is of benefit in patients without acute ST-segment elevation or left bundle branch block on 12-lead ECG, and is associated with a non-significant 1.7% (95% CI: -2.4%, 5.8%) increased risk of acute myocardial infarction (MI)i. (Health gain notation - 5 "unlikely to be beneficial")

 

i. Braunwald E, Mark DB, Jones RH, et al. Unstable Angina: Diagnosis and Management. Clinical Practice Guideline Number 10 (amended) AHCPR. Rockville, MD: Agency for Health Care Policy and Research and the National Heart, Lung, and Blood Institute, Public Health Service, U.S. Department of Health and Human Services, 1994
http://www.ahcpr.gov/clinic/
(Type I evidence - systematic review and AHCPR meta-analysis of eight trials)

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3.3 Antiplatelet and anticoagulant therapy
3.3a. Antiplatelet therapy is likely to reduce the odds of MI, stroke or vascular death in patients with unstable angina by around 25% at six to twelve month follow-up. Review of different doses of aspirin in long-term treatment suggests equal efficacy of daily doses 75mg to 324mg per dayi.
(Health gain notation - 2 "likely to be beneficial")

Caveat: Based on a meta-analysis of antiplatelet therapy in 14 sub-categories of high risk patients, including stable and unstable angina, which showed an odds reduction of 27% (SD 2%) for MI, stroke or vascular death without significant heterogeneity.

i. Antiplatelet Trialist's Collaboration. Collaborative overview of randomised trials of antiplatelet therapy - I: Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. British Medical Journal 1994; 308: 81-106.
http://www.bmj.com/cgi/content/full/308/6943/1540
In: Database of Reviews of Effectiveness. The Cochrane Library, Issue 4. Oxford: Update Software, 1998
(Type I evidence - systematic review and meta-analysis of 4000 patients in seven trials of antiplatelet therapy in patients with unstable angina)

 

3.3b. Intravenous heparin during the acute phase of unstable angina significantly reduces the risk of MI (fatal or non-fatal) at mean follow-up of 5.7 days compared to aspirin (0.8% of heparin patients vs. 3.7% of aspirin patients, p = 0.035: absolute risk difference 2.9%; 95% CI: 0.3%, 5.6%)i.
(Health gain notation - 1 "beneficial")
i. Theroux P, Waters D, Qiu S, et al. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation 1993;88:2045-48
(Type II evidence - randomised controlled trial of 484 patients with unstable angina randomised to 325mg aspirin twice daily or dose-adjusted heparin)
3.3c. There is some evidence that combination therapy of oral aspirin and intravenous heparin in the initial management of unstable angina may reduce the incidence of MI and death compared to aspirin alone both during treatment (odds ratio 0.67; 95% CI: 0.44, 1.02; p=0.06) and at 12 week follow-up (odds ratio ratio 0.82; 95% CI: 0.56, 1.20; p=NS)i.
(Health gain notation - 4 "unknown")

Caveat: It is not clear that all relevant studies were included, and follow-up was short. A large randomised controlled trial with long-term follow-up is necessary.

i. Oler A, Whooley MA, Oler J, Grady D. Adding aspirin to heparin reduces the incidence of myocardial infarction and death in patients with unstable angina. Journal of the American Medical Association 1996;276:811-15. In: Database of Reviews of Effectiveness. The Cochrane Library, Issue 4. Oxford: Update Software, 1998
(Type I evidence - systematic review and meta-analysis of 1353 patients in six randomised controlled trials comparing combination therapy of aspirin and heparin to aspirin alone)

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3.3d. In view of the evidence for the efficacy of heparin and aspirin as monotherapy, in the absence of contra-indications it is recommended that all patients with unstable angina should be treated with both heparin in the acute phase and long-term aspirini.
(Health gain notation - 1 "beneficial")

 

i. Braunwald E, Mark DB, Jones RH et al. Unstable Angina: Diagnosis and Management. Clinical Practice Guideline Number 10 (amended) AHCPR. Rockville, MD: Agency for Health Care Policy and Research and the National Heart, Lung, and Blood Institute, Public Health Service, U.S. Department of Health and Human Services, 1994
http://www.ahcpr.gov/clinic/
(Type V evidence - expert opinion)
3.3e. There is accumulating evidence that antithrombotic therapy with low-molecular weight heparins in combination with aspirin is at least as effectivei or more effectiveii - iv as unfractionated heparin and aspirin in reducing the incidence at up to four month follow-up of ischaemic events (death, new infarct or recurrent angina) or revascularisation in patients with unstable angina. Enoxaparin is associated with an excess risk of both minorii and major haemorrhage at catheterisation sitesiii.
(Health gain notation - 3 "trade-off between beneficial and adverse effects")

Caveat: Further assessment of relative effectiveness, cost-effectiveness and safety is required.

 

i. Klein W, Buchwald A, Hillis S, et al. Comparison of low-molecular weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary disease. Fragmin in Unstable Coronary Artery Disease Study (FRIC). Circulation 1997;96:61-68
(Type II evidence - randomised controlled trial of 1482 patients with unstable angina randomised to a maximum of 45 days of 7500 IU dalteparin daily or continuous dose-adjusted heparin)
ii. Cohen M, Demers C, Gurfinkel E, et al, for the ESSENCE study group. A comparison of low-molecular weight heparin with unfractionated heparin for unstable coronary disease. New England Journal of Medicine 1997;337:447-52
(Type II evidence - randomised controlled trial of 3171 patients with unstable angina randomised to a maximum of 8 days 1mg/kg body weight of sub-cutaneous enoxaparin twice daily or continuous dose-adjusted heparin)
iii. The Thrombolysis in Myocardial Infarction (TIMI) IIA Trial Investigators. Dose-ranging trial of enoxaparin for unstable angina: results of TIMI IIA. Journal of the American College of Cardiology 1997;29:474-82
(Type II evidence - randomised controlled trial of 630 patients with unstable angina randomised to 1.25mg/kg or 1.0mg/kg body weight enoxaparin for 14 days)
iv. Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group. Low-molecular weight heparin during instability in coronary artery disease. Lancet 1996;347:561-68
(Type II evidence - randomised controlled trial of 1506 patients with unstable angina randomised to a maximum of 45 days of 7500 IU dalteparin daily or placebo)

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3.3f. Abciximab therapy in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) with severe unstable angina or evolving MIi or refractory unstable anginaii or stable anginaiii is associated with reduced occurrence of death, non-fatal MI or re-intervention at 30 days compared to placebo (11.3% vs. 15.9%, p=0.012)ii. Major bleeding was more frequent with abciximabi,ii (3.8% vs. 1.9%, p=0.04)ii. There was no difference in death, MI or repeat intervention between abciximab and placebo in one trial at six-month follow-upii: another trial found no significant difference in major bleeding and a small advantage in the cumulative incidence of death, MI or repeat revascularisation in the abciximab groupiii.
(Health gain notation - 4 "unknown")

Caveat: Further trials of clinical and cost-effectiveness are required. Evidence that other glycoprotein IIb/IIIa inhibitors (tirofiban, eptifibatide and lamifiban) are also effective is accumulating, and trials are in progress to clarify the benefits in patients undergoing stenting or as an adjunct to thrombolytic therapy or primary angioplastyiv.

i. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. New England Journal of Medicine 1994;330:956-61
(Type II evidence - randomised controlled trial of 2099 patients with severe unstable angina or evolving MI randomised to abciximab or placebo pre-PTCA)
ii. The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997;349:1429-35
(Type II evidence - randomised controlled trial of 1265 patients with refractory unstable angina randomised to abciximab or placebo pre-PTCA)
iii. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularisation. New England Journal of Medicine 1997;336:1689-96
(Type II evidence - randomised controlled trial of 2792 patients with stable angina randomised to abciximab with standard dose or low dose heparin, or placebo pre-PTCA)
iv. Adgey AAJ. An overview of the results of clinical trials with glycoprotein IIb/IIIa inhibitors. European Heart Journal 1998;19 (suppl D):D10-21
(Type II evidence - narrative overview of randomised controlled trials)
3.4 Coronary revascularisation
3.4a. "High risk" patients with unstable angina - failure to stabilise with medical treatment, recurrent ischaemia, congestive heart failure or left ventricular (LV) dysfunction - are at increased risk of MI or cardiac death and should be considered for prompt revascularisationi.
(Health gain notation - 2 "likely to be beneficial")

3.4b. Patients found at catheterisation to have significant left main disease (>50% stenosis) or significant (>70%) three-vessel disease with depressed LV function (ejection fraction <0.50) should be referred promptly for coronary artery bypass graftingi.
(Health gain notation - 1 "beneficial")

3.4c. Patients with two-vessel disease, with proximal severe subtotal stenosis (>95%) of the left anterior descending coronary artery and depressed LV function should be referred promptly for revascularisationi.
(Health gain notation - 2 "likely to be beneficial")

i. Braunwald E, Mark DB, Jones RH et al. Unstable Angina: Diagnosis and Management. Clinical Practice Guideline Number 10 (amended) AHCPR. Rockville, MD: Agency for Health Care Policy and Research and the National Heart, Lung, and Blood Institute, Public Health Service, U.S. Department of Health and Human Services, 1994
http://www.ahcpr.gov/clinic
(Type II evidence - narrative review of randomised controlled trials)

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3.4d. An Early Invasive Strategy of routine cardiac catheterisation of all patients without contra-indications does not achieve significantly different outcomes at 42 days of death, non-fatal MI or positive six-week exercise test compared to an Early Conservative Strategy of selective catheterisation of high risk patients (prior revascularisation, reduced LV function, recurrent ischaemia or ventricular arrhythmia) 15.5% vs. 17.7%; p =0.26i.
(Health gain notation - 3 "trade-off between beneficial and adverse effects")

 

i. TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-q wave myocardial infarction. Circulation 1994; 89:1545-56
(Type II evidence - 1473 patients randomised to early invasive or early conservative catheterisation strategy)

 

3.4e. A USA cost-effectiveness analysis based on the TIMI III data suggests the costs of Early Invasive Strategy are similar to the Early Conservative Strategy; either strategy is acceptable from the economic viewpointi.
(Health gain notation - 3 "trade-off between beneficial and adverse effects")
i. Conti CR. Unstable angina: cost of conservative and invasive strategies using TIMI 3B as a model. Clinical Cardiology 1995; 18:187-88
(Type II evidence - analysis of 1995 USA health care costs based on results of trial of 1473 patients randomised to early invasive or early conservative catheterisation strategy)
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Health Evidence Bulletins: Wales, Duthie Library, UWCM, Cardiff CF14 4XN. e-mail: weightmanal@cardiff.ac.uk