Adding Heparin to Aspirin Reduces the Incidence of Myocardial Infarction and Death in Patients With Unstable Angina A Meta-analysis Allison Oler, MD; Mary A. Whooley, MD; Jacqueline Oler, PhD; Deborah Grady, MD, MPH Objective.\p=m-\Toestimate the risk of myocardial infarction (MI) and death in pa- lows time for endogenous fibrinolysis to tients with unstable angina who are treated with aspirin plus heparin compared with occur. In theory, adding heparin to aspi¬ treated with alone. rin should reduce intracoronary obstruc¬ patients aspirin blood reduce Data Sources.\p=m-\Studieswere retrieved using MEDLINE, bibliographies, and tion, improve coronary flow, consultation with myocardial ischemia, and ultimately de¬ experts. crease cardiac and in that enrolled with unstable morbidity mortality Study Selection.\p=m-\Onlypublished trials patients an- patients with unstable angina.9 Several gina, randomized participants to aspirin plus heparin vs aspirin alone, and reported randomized clinical trials have demon¬ incidence of myocardial infarction or death were included in the meta-analysis. strated a trend toward reduced risk of Data Extraction.\p=m-\Patientoutcomes including MI or death, recurrent ischemic death or nonfatal myocardial infarction in pain, and major bleeding during randomized treatment; revascularization proce- patients with unstable angina treated with dures after randomization; and MI or death during the 2 to 12 weeks following ran- aspirin plus intravenous heparin com¬ domization were extracted by 2 authors, 1 of whom was blinded to the journal, in- pared with patients treated with aspirin stitution, and author of each study. alone.7·10"14 However, it has not been es¬ tablished that the combina¬ Data randomized trials were included. The overall summary definitively Synthesis.\p=m-\Six tion of is to relative risk of MI or death randomized treatment was 0.67 con- aspirin plus heparin superior (RR) during (95% alone. We a fidence interval in with unstable treated with aspirin performed meta-analy¬ [CI], 0.44-1.02) patients angina aspirin sis of published randomized trials to de¬ plus heparin compared with those treated with aspirin alone. The summary RRs for termine whether treatment with intra¬ in treated with with secondary endpoints patients aspirin plus heparin compared venous heparin and aspirin is more those treated with aspirin alone were 0.68 (95% CI, 0.40-1.17) for recurrent ische- effective than treatment with aspirin mic pain; 0.82 (95% CI, 0.56-1.20) for MI or death 2 to 12 weeks following random- alone in preventing MI or death in pa¬ ization; 1.03 (95% CI, 0.74-1.43) for revascularization; and 1.99 (95% CI, 0.52-7.65) tients with unstable angina. for major bleeding. We found no statistically significant heterogeneity among indi- vidual study findings. METHODS Conclusions.\p=m-\Ourfindings are consistent with a 33% reduction in risk of MI or Literature Review death in patients with unstable treated with aspirin plus heparin compared angina We performed a literature search us¬ with those treated with aspirin alone. The bulk of evidence suggests that most pa- ing the MEDLINE database (January tients with unstable angina should be treated with both heparin and aspirin. 1966 to September 1995) with the key¬ JAMA. 1996;276:811-815 words "aspirin," "heparin," and "unstable angina." The search was not restricted to UNSTABLE ANGINA, ranging from of patients admitted to the hospital with citations in the English-language litera¬ progressive angina to angina at rest, unstable angina progress to myocardial ture. In addition, a manual search was results from intracoronary plaque dis¬ infarction (MI) within 2 weeks of diag¬ done using reference lists from identified ruption causing increased stenosis and, nosis.2·3 One-year mortality of patients articles and consultation with experts. in some cases, intermittent thrombosis.1 with unstable angina ranges from 5% to Studies included in the meta-analysis Prospective studies have found that 12% 14% with approximately half of these met the following criteria: (1) a random¬ deaths occurring within 4 weeks of di¬ ized clinical trial; (2) eligible participants In patients with unstable an¬ were admitted to the hospital with the A. agnosis.4 From the Departments of Medicine (Drs Oler, reduces the risk of throm¬ of unstable or non-Q- Whooley, and Grady) and Epidemiology and Biostatis- gina, aspirin diagnosis angina tics (Dr Grady), University of California, San Francisco, bosis by inhibiting platelet aggregation wave myocardial infarction; (3) partici¬ School of Medicine; the General Internal Medicine and decreases the risk of cardiac death pants were assigned either to intrave¬ Section, San Francisco Veterans Affairs Medical Cen- or nonfatal MI by 30% to 51% 7 nous heparin and aspirin or to aspirin ter (Drs Whooley and Grady); and the Department of incidence of Quantitative Methods, Drexel University, Philadelphia, Heparin binds to antithrombin III and alone; and (4) the myocar¬ Pa (Dr J. Oler). induces a conformational change that re¬ dial infarction (prolonged chest pain as¬ Reprints: Deborah Grady, MD, MPH, General Inter- sults in inhibition ofthrombin.8 This sociated with waves or ST nal Medicine Section, San Francisco Veterans Affairs rapid Q persistent Medical Center, 111A1, 4150 Clement St, San Fran- inhibition of thrombin prevents propaga¬ changes on electrocardiogram and/or a cisco, CA 94121. tion of an established thrombus and al- 2-fold increase over baseline creatine Downloaded from www.jama.com at New York State Psychiatric Institute on August 3, 2009 kinase levels with elevated MB fractions) Table 1.—Characteristics of 6 Randomized Trials of Aspirin Plus Heparin vs Aspirin Alone to Prevent or death while on randomized treatment Myocardial Infarction and Death in Patients Admitted to the Hospital With Unstable Angina was reported. Clinical trials were in¬ Goal Partial cluded regardless of whether they in¬ Aspirin Thromboplastin Duration of Source d cluded a heparin placebo in the aspirin Blinding Dose, mg Time Heparin Therapy, et and 325 twice 1.5-2 X normal or the had been tak¬ Theroux al, 1988'° Participants daily only group patients investigators to admission. ing aspirin prior hospital RISC Group, 19907 None 75 daily Not stated Data Extraction Cohen et al, 1990" None 80/325 dally* Cohen et al, 1994" Participants 162.5 daily 2 x normal 3-4 Two of us and inde¬ (A.O. M.A.W.) et 150 1.5-2 x normal pendently reviewed each study that met Holdright al, 1994" Participants daily Gurfinkel et al, 1995" and 200 2 normal 5-7 the inclusion criteria. One of us ab¬ Participants daily investigators stracted data in an unblinded fashion; the other was blinded to journal, year of *Aspirin dose was 80 mg/d in the heparin plus aspirin group and 325 mg/d in the aspirin only group. publication, authors, and institution. We evaluated each study with regard to pa¬ tient selection, blinding, and adequacy measure, or estimated overall RR, was RESULTS of randomization, and recorded the dos¬ calculated using the DerSimonian and Study Selection age and duration of each treatment. Dis¬ Laird model which uses a random effects crepant findings between reviewers model to incorporate variance between An initial search using MEDLINE, ref¬ were settled by discussion. study findings in a weighted average of erence review, and expert consultation Heparin was given as a continuous in¬ rate ratios.18·19 Approximate 95% CIs were yielded 135 citations. Of these, 19 were fusion in 5 of 6 studies1044 with the rate obtained on the natural log transforma¬ randomized trials.7·9"14·22^3 Amongthese tri¬ adjusted to achieve a goal partial throm- tion scale and the limits reexpressed us¬ als, we found 8 that enrolled participants boplastin time (PTT) of 1.5 to 2 times ing the natural antilog transformation. A with unstable angina, randomized par¬ normal (Table 1). In the sixth study, hep¬ 2 statistic summing the squared devia¬ ticipants to aspirin or heparin plus aspi¬ arin was administered as intermittent in¬ tion ofeach ofthe study natural log trans¬ rin, and reported the risk of MI or death travenous boluses and a goal PTT was not formations ofthe OR from their weighted during randomized treatment.7·9"14·80 One stated.7 The duration of heparin therapy average was used to test whether a sum¬ of the 8 trials was excluded because we was 2 to 7 days in all studies. Aspirin was mary OR was appropriate for each end- could not determine whether all patients given orally in the doses shown in Table point. These calculations were substan¬ were treated with aspirin.30 Another was 1 and continued indefinitely. tiated using the log linear fits discussed excluded because only a portion of the Incidence of MI or death during ran¬ next, and obtained using BMDP statis¬ patients in the study received aspirin.9 domized treatment was abstracted as the tical software.20 Thus, 6 trials with a total of 1353 patients primary outcome. In addition, data were The primary endpoint in this meta- met all inclusion criteria for the meta- abstracted on incidence of recurrent is¬ analysis was MI or death while on ran¬ analysis.7·10"14 Characteristics of these tri¬ chemie pain (anginal chest pain with is¬ domized treatment. Relationships among als are shown in Table 1. chemie ST-T changes on electrocardio¬ the 3 dichotomous factors—myocardial All 6 trials excluded participants who gram) and major bleeding (bleeding infarction or death, treatment regimen, had evolving Q-wave MI on admission; requiring transfusion or fall in hemoglo¬ and study—were explored furtherby fit¬ coronary artery bypass grafting within bin by at least 20 g/L) during randomized ting a hierarchical log-linear model to the 12 months prior to admission; a contra¬ treatment. We also abstracted data on cell counts.21 This approach models the indication to aspirin or anticoagulation; MI or death between discontinuation of natural log cell frequencies as linear com¬ or had already been anticoagulated at ad¬ randomized treatment and 12 weeks fol¬ binations of main effects, and second-or¬ mission.