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September 11, 1996, Vol 276, No. 10 >
ARTICLE | September 11, 1996

Adding Heparin to Aspirin Reduces the Incidence of Myocardial Infarction and Death in Patients With Unstable Angina: Title and subTitle BreakA Meta-analysis FREE

Allison Oler, MD; Mary A. Whooley, MD; Jacqueline Oler, PhD; Deborah Grady, MD, MPH
[+] Author Affiliations

Reprints: Deborah Grady, MD, MPH, General Internal Medicine Section, San Francisco Veterans Affairs Medical Center, 111A1, 4150 Clement St, San Francisco, CA 94121.


JAMA. 1996;276(10):811-815. doi:10.1001/jama.1996.03540100055028
Text Size: A A A
Published online
Article
References

Objective.  —To estimate the risk of myocardial infarction (MI) and death in patients with unstable angina who are treated with aspirin plus heparin compared with patients treated with aspirin alone.

Data Sources.  —Studies were retrieved using MEDLINE, bibliographies, and consultation with experts.

Study Selection.  —Only published trials that enrolled patients with unstable angina, randomized participants to aspirin plus heparin vs aspirin alone, and reported incidence of myocardial infarction or death were included in the meta-analysis.

Data Extraction.  —Patient outcomes including MI or death, recurrent ischemic pain, and major bleeding during randomized treatment; revascularization procedures after randomization; and MI or death during the 2 to 12 weeks following randomization were extracted by 2 authors, 1 of whom was blinded to the journal, institution, and author of each study.

Data Synthesis.  —Six randomized trials were included. The overall summary relative risk (RR) of MI or death during randomized treatment was 0.67 (95% confidence interval [CI], 0.44-1.02) in patients with unstable angina treated with aspirin plus heparin compared with those treated with aspirin alone. The summary RRs for secondary endpoints in patients treated with aspirin plus heparin compared with those treated with aspirin alone were 0.68 (95% CI, 0.40-1.17) for recurrent ischemic pain; 0.82 (95% CI, 0.56-1.20) for MI or death 2 to 12 weeks following randomization; 1.03 (95% CI, 0.74-1.43) for revascularization; and 1.99 (95% CI, 0.52-7.65) for major bleeding. We found no statistically significant heterogeneity among individual study findings.

Conclusions.  —Our findings are consistent with a 33% reduction in risk of MI or death in patients with unstable angina treated with aspirin plus heparin compared with those treated with aspirin alone. The bulk of evidence suggests that most patients with unstable angina should be treated with both heparin and aspirin.

REFERENCES

1 +
Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J.  Insights into the pathogenesis of acute ischemic syndromes . Circulation . 1988;;77:1213-1220.
2 +
Gazes PC, Mobley E Jr, Faris H Jr, Duncan RC, Humphries GB.  Preinfarctional (unstable) angina—a prospective study—ten year follow-up: prognostic significance of electrocardiographic changes . Circulation . 1973;;48:331-337.
3 +
Duncan B, Fulton M, Morrison SL, et al.  Prognosis of new and worsening angina pectoris . BMJ . 1976;;1:981-985.
4 +
Rahimtoola SH.  Coronary bypass surgery for unstable angina . Circulation . 1984;;69:842-848.
5 +
Cairns JA, Gent M, Singer J, et al.  Aspirin, sulfinpyrazone, or both in unstable angina: results of a Canadian multicenter trial . N Engl J Med . 1985;;313:1369-1375.
6 +
Lewis H Jr, Davis JW, Archibald DG, et al.  Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a Veterans Administration Cooperative Study . N Engl J Med . 1983;;309:396-403.
7 +
The RISC Group.  Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease: the RISC Group . Lancet . 1990;;336:827-830.
8 +
Rosenberg RD.  Actions and interactions of antithrombin and heparin . N Engl J Med . 1975;;292:146-151.
9 +
Wallis DE, Boden WE, Califf R, et al.  Failure of adjuvant heparin to reduce myocardial ischemia in the early treatment of patients with unstable angina . Am Heart J . 1991;;122:949-954.
10 +
Theroux P, Ouimet H, McCans J, et al.  Aspirin, heparin, or both to treat acute unstable angina . N Engl J Med . 1988;;319:1105-1111.
11 +
Cohen M, Adams PC, Hawkins L, Bach M, Fuster V.  Usefulness of antithrombotic therapy in resting angina pectoris or non-Q-wave myocardial infarction in preventing death and myocardial infarction (a pilot study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group) . Am J Cardiol . 1990;;66:1287-1292.
12 +
Cohen M, Adams PC, Parry G, et al.  Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users: primary end points analysis from the ATACS trial: Antithrombotic Therapy in Acute Coronary Syndromes Research Group . Circulation . 1994;;89:81-88.
13 +
Holdright D, Patel D, Cunningham D, et al.  Comparison of the effect of heparin and aspirin versus aspirin alone on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina . J Am Coll Cardiol . 1994;;24:39-45.
14 +
Gurfinkel EP, Manos EJ, Mejail RI, et al.  Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia . J Am Coll Cardiol . 1995;;26:313-318.
15 +
Walter S, Cook R.  A comparison of several point estimators of the odds ratios in a single 2× contingency table . Biometrics . 1991;;47:795-811.
16 +
Fleiss JL. Statistical Methods for Rates and Proportions . 2nd ed. New York, NY: John Wiley & Sons Inc; 1981;.
17 +
Fisher LD, van Belle G. Biostatistics: A Methodology for the Health Sciences . New York, NY: John Wiley & Sons Inc; 1993;.
18 +
Berlin JA, Laird NM, Sacks HS, Chalmers TC.  A comparison of statistical methods for combining event rates from clinical trials . Stat Med . 1989;;8:141-151.
19 +
Fleiss JL.  The statistical basis of meta-analysis . Stat Methods Med Res . 1993;;2:121-145.
20 +
BMDP Statistical Software, Inc. PC90 ed. Los Angeles: University of California Press; 1990.
21 +
Bishop YMM, Feinberg SE, Holland PW. Discrete Multivariate Analysis: Theory and Practice . Cambridge, Mass: MIT Press; 1975;.
22 +
Cohen M, Parry G, Adams PC, et al.  Prospective evaluation of a prostacyclin-sparing aspirin formulation and heparin/warfarin in aspirin users with unstable angina or non-Q wave myocardial infarction at rest . Eur Heart J . 1994;;15:1196-1203.
23 +
Fuchs J, Cannon CP.  Hirulog in the treatment of unstable angina: results of the Thrombin Inhibition in Myocardial Ischemia (TIMI) 7 trial . Circulation . 1995;;92:727-733.
24 +
Serneri GGN, Modesti PA, Gensini GF, et al.  Randomised comparison of subcutaneous heparin, intravenous heparin, and aspirin in unstable angina: Studio Epoorine Sottocutanea nell'Angina Instobile (SESAIR) Refrattorie Group . Lancet . 1995;;345:1201-1204.
25 +
Moise A, Roos M, Roos M.  Aspirin versus heparin in the acute phase of unstable angina . Circulation . 1994;;90:1107.
26 +
Theroux P, Waters D, Qiu S, et al.  Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina . Circulation . 1993;;88:2045-2048.
27 +
Cohen M Xiong J, Parry G, et al.  Prospective comparison of unstable angina versus non-Q wave myocardial infarction during antithrombotic therapy: Antithrombotic Therapy in Acute Coronary Syndromes Research Group . J Am Coll Cardiol . 1993;;22:1338-1343.
28 +
Averkov OV, Zateishchikov DA, Gratsianskii NA, Dobrovol'skii AV.  Unstable angina: tissue-type plasminogen activator inhibitor and other hemostatic factors in aspirin and intravenous heparin administration . Kardiologiia . 1993;;33:16-22.
29 +
Averkov OV, Zateishchikov DA, Gratsianskii NA, Logutov I, Iavelov IS, Ianus V.  Unstable angina: effect of aspirin and heparin on treatment outcome in hospital patients (a double-blind, placebocontrolled study) . Kardiologiia . 1993;;33:4-9.
30 +
Zwerner PL, Gore JM, Corrao JM, et al.  Heparin in the treatment of unstable angina: a randomized prospective trial . Circulation . 1987;;76( (IV) ):180.
31 +
Charvat J, Fiserova J.  Anticoagulation and antiaggregation therapy in patients with unstable angina pectoris . Vnitr Lek . 1990;;36:537-543.
32 +
Serneri GGN, Gensini GF, Poggesi L, et al.  Effect of heparin, aspirin, or alteplase in reduction of myocardial ischaemia in refractory unstable angina . Lancet . 1990;;335:615-618.
33 +
Correction: Lancet . 1990;;335:868.
34 +
OASIS.  Comparison of hirudin with heparin and warfarin with control for unstable angina and non q wave MI in a randomized controlled trial . Circulation . 1995;;92:416.
35 +
Hirsh J, Raschke R, Warkentin TE, Dalen JE, Deykin D, Poller L.  Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety . Chest . 1995;;108:258S-275S.
36 +
Williams DO, Kirby MG, McPherson K, Phear DN.  Anticoagulant treatment of unstable angina . Br J Clin Pract . 1986;;40:114-116.
37 +
Theroux P, Waters D, Lam J, Juneau M, McCans J.  Reactivation of unstable angina after the discontinuation of heparin . N Engl J Med . 1992;;327:141-145.
38 +
Granger CB, Armstrong PW.  Reinfarction following discontinuation of intravenous heparin or hirudin for unstable angina and acute myocardial infarction . Circulation . 1995;;92( (81) ):460.
39 +
Moher D, Olkin I.  Meta-analysis of randomized controlled trials . JAMA . 1995;;274:1962-1964.
40 +
Unstable Angina Panel. Unstable Angina: Diagnosis and Management. Clinical Practice Guideline . Washington, DC: US Dept of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research; 1994;. AHCPR 94-0602.
41 +
The FRISC Study Group.  Low-molecularweight heparin during instability in coronary artery disease: Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group . Lancet . 1996;;347:561-568.
42 +
Barrowcliffe TW.  Low molecular weight heparin(s) . Br J Haematol . 1995;;90:1-7.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J.  Insights into the pathogenesis of acute ischemic syndromes . Circulation . 1988;;77:1213-1220.
2 +
Gazes PC, Mobley E Jr, Faris H Jr, Duncan RC, Humphries GB.  Preinfarctional (unstable) angina—a prospective study—ten year follow-up: prognostic significance of electrocardiographic changes . Circulation . 1973;;48:331-337.
3 +
Duncan B, Fulton M, Morrison SL, et al.  Prognosis of new and worsening angina pectoris . BMJ . 1976;;1:981-985.
4 +
Rahimtoola SH.  Coronary bypass surgery for unstable angina . Circulation . 1984;;69:842-848.
5 +
Cairns JA, Gent M, Singer J, et al.  Aspirin, sulfinpyrazone, or both in unstable angina: results of a Canadian multicenter trial . N Engl J Med . 1985;;313:1369-1375.
6 +
Lewis H Jr, Davis JW, Archibald DG, et al.  Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a Veterans Administration Cooperative Study . N Engl J Med . 1983;;309:396-403.
7 +
The RISC Group.  Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease: the RISC Group . Lancet . 1990;;336:827-830.
8 +
Rosenberg RD.  Actions and interactions of antithrombin and heparin . N Engl J Med . 1975;;292:146-151.
9 +
Wallis DE, Boden WE, Califf R, et al.  Failure of adjuvant heparin to reduce myocardial ischemia in the early treatment of patients with unstable angina . Am Heart J . 1991;;122:949-954.
10 +
Theroux P, Ouimet H, McCans J, et al.  Aspirin, heparin, or both to treat acute unstable angina . N Engl J Med . 1988;;319:1105-1111.
11 +
Cohen M, Adams PC, Hawkins L, Bach M, Fuster V.  Usefulness of antithrombotic therapy in resting angina pectoris or non-Q-wave myocardial infarction in preventing death and myocardial infarction (a pilot study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group) . Am J Cardiol . 1990;;66:1287-1292.
12 +
Cohen M, Adams PC, Parry G, et al.  Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users: primary end points analysis from the ATACS trial: Antithrombotic Therapy in Acute Coronary Syndromes Research Group . Circulation . 1994;;89:81-88.
13 +
Holdright D, Patel D, Cunningham D, et al.  Comparison of the effect of heparin and aspirin versus aspirin alone on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina . J Am Coll Cardiol . 1994;;24:39-45.
14 +
Gurfinkel EP, Manos EJ, Mejail RI, et al.  Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia . J Am Coll Cardiol . 1995;;26:313-318.
15 +
Walter S, Cook R.  A comparison of several point estimators of the odds ratios in a single 2× contingency table . Biometrics . 1991;;47:795-811.
16 +
Fleiss JL. Statistical Methods for Rates and Proportions . 2nd ed. New York, NY: John Wiley & Sons Inc; 1981;.
17 +
Fisher LD, van Belle G. Biostatistics: A Methodology for the Health Sciences . New York, NY: John Wiley & Sons Inc; 1993;.
18 +
Berlin JA, Laird NM, Sacks HS, Chalmers TC.  A comparison of statistical methods for combining event rates from clinical trials . Stat Med . 1989;;8:141-151.
19 +
Fleiss JL.  The statistical basis of meta-analysis . Stat Methods Med Res . 1993;;2:121-145.
20 +
BMDP Statistical Software, Inc. PC90 ed. Los Angeles: University of California Press; 1990.
21 +
Bishop YMM, Feinberg SE, Holland PW. Discrete Multivariate Analysis: Theory and Practice . Cambridge, Mass: MIT Press; 1975;.
22 +
Cohen M, Parry G, Adams PC, et al.  Prospective evaluation of a prostacyclin-sparing aspirin formulation and heparin/warfarin in aspirin users with unstable angina or non-Q wave myocardial infarction at rest . Eur Heart J . 1994;;15:1196-1203.
23 +
Fuchs J, Cannon CP.  Hirulog in the treatment of unstable angina: results of the Thrombin Inhibition in Myocardial Ischemia (TIMI) 7 trial . Circulation . 1995;;92:727-733.
24 +
Serneri GGN, Modesti PA, Gensini GF, et al.  Randomised comparison of subcutaneous heparin, intravenous heparin, and aspirin in unstable angina: Studio Epoorine Sottocutanea nell'Angina Instobile (SESAIR) Refrattorie Group . Lancet . 1995;;345:1201-1204.
25 +
Moise A, Roos M, Roos M.  Aspirin versus heparin in the acute phase of unstable angina . Circulation . 1994;;90:1107.
26 +
Theroux P, Waters D, Qiu S, et al.  Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina . Circulation . 1993;;88:2045-2048.
27 +
Cohen M Xiong J, Parry G, et al.  Prospective comparison of unstable angina versus non-Q wave myocardial infarction during antithrombotic therapy: Antithrombotic Therapy in Acute Coronary Syndromes Research Group . J Am Coll Cardiol . 1993;;22:1338-1343.
28 +
Averkov OV, Zateishchikov DA, Gratsianskii NA, Dobrovol'skii AV.  Unstable angina: tissue-type plasminogen activator inhibitor and other hemostatic factors in aspirin and intravenous heparin administration . Kardiologiia . 1993;;33:16-22.
29 +
Averkov OV, Zateishchikov DA, Gratsianskii NA, Logutov I, Iavelov IS, Ianus V.  Unstable angina: effect of aspirin and heparin on treatment outcome in hospital patients (a double-blind, placebocontrolled study) . Kardiologiia . 1993;;33:4-9.
30 +
Zwerner PL, Gore JM, Corrao JM, et al.  Heparin in the treatment of unstable angina: a randomized prospective trial . Circulation . 1987;;76( (IV) ):180.
31 +
Charvat J, Fiserova J.  Anticoagulation and antiaggregation therapy in patients with unstable angina pectoris . Vnitr Lek . 1990;;36:537-543.
32 +
Serneri GGN, Gensini GF, Poggesi L, et al.  Effect of heparin, aspirin, or alteplase in reduction of myocardial ischaemia in refractory unstable angina . Lancet . 1990;;335:615-618.
33 +
Correction: Lancet . 1990;;335:868.
34 +
OASIS.  Comparison of hirudin with heparin and warfarin with control for unstable angina and non q wave MI in a randomized controlled trial . Circulation . 1995;;92:416.
35 +
Hirsh J, Raschke R, Warkentin TE, Dalen JE, Deykin D, Poller L.  Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety . Chest . 1995;;108:258S-275S.
36 +
Williams DO, Kirby MG, McPherson K, Phear DN.  Anticoagulant treatment of unstable angina . Br J Clin Pract . 1986;;40:114-116.
37 +
Theroux P, Waters D, Lam J, Juneau M, McCans J.  Reactivation of unstable angina after the discontinuation of heparin . N Engl J Med . 1992;;327:141-145.
38 +
Granger CB, Armstrong PW.  Reinfarction following discontinuation of intravenous heparin or hirudin for unstable angina and acute myocardial infarction . Circulation . 1995;;92( (81) ):460.
39 +
Moher D, Olkin I.  Meta-analysis of randomized controlled trials . JAMA . 1995;;274:1962-1964.
40 +
Unstable Angina Panel. Unstable Angina: Diagnosis and Management. Clinical Practice Guideline . Washington, DC: US Dept of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research; 1994;. AHCPR 94-0602.
41 +
The FRISC Study Group.  Low-molecularweight heparin during instability in coronary artery disease: Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group . Lancet . 1996;;347:561-568.
42 +
Barrowcliffe TW.  Low molecular weight heparin(s) . Br J Haematol . 1995;;90:1-7.

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