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| Team Leader: Dr David Fone |
Date of completion: 30.9.98 |
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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://text.nlm.nih.gov/ftrs/pick?dbName=angq&ftrsK=33426&cp=1&t=924603120&collect=ahcpr (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://text.nlm.nih.gov/ftrs/pick?dbName=angq&ftrsK=33426&cp=1&t=924603120&collect=ahcpr (Type I evidence - systematic review and AHCPR meta-analysis of eight trials) |
| 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. 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) |
| 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://text.nlm.nih.gov/ftrs/pick?dbName=angq&ftrsK=33426&cp=1&t=924603120&collect=ahcpr (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) |
| 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. 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. |
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://text.nlm.nih.gov/ftrs/pick?dbName=angq&ftrsK=33426&cp=1&t=924603120&collect=ahcpr (Type II evidence - narrative review of randomised controlled trials) |
| 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) |
Dr Alison Weightman, Protocol Enhancement Project, Duthie Library, UWCM, Cardiff CF4 4XN. e-mail: weightmanal@cardiff.ac.uk