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. Unstable angina was diagnosed lowing randomization, and revasculariza¬ der and third-order interactions. A like¬ using the following criteria: (1) recent on¬ tion procedures (angioplasty or surgical lihood ratio 2 statistic was used to test set (less than 1 month) of prolonged or bypass) during the 12 weeks following the statistical significance of the third- recurrent chest pain suggestive of myo¬ randomization. order interaction parameter, effectively cardial ischemia7·11"14; (2) pain of increas¬ a test for in the ORs across at rest or with minimal ef¬ Statistical heterogeneity ing severity, Analysis studies. Likelihood ratio x2s were exam¬ fort7·10"14; and (3) last episode of pain Rate ratios from each study were used ined to identify the most parsimonious occurring within 48 hours ofadmission.10"14 as measures of effect in these analyses. "best" fit to the cell counts. For these Patients thought to be having non-Q- The total numbers of patient outcomes data, the likelihood ratio 2 statistic pro¬ wave MI on admission were included un¬ in both the aspirin and aspirin plus hep¬ vided a test of the statistical significance der the definition of unstable angina. arin groups were recorded in 2 X 2 tables. of the second-order interaction param¬ Effect Ml and Death To improve bias and precision proper¬ eter, which measured the variation in MI Summary on ties, 0.5 was added to every cell in any and death rate across treatment regimen, The findings of each of the 6 trials table containing a zero.15 Relative risks controlling for study. demonstrated a trend toward improved (RRs) with 95% confidence intervals We examined potential for publica¬ outcome using aspirin plus heparin com¬ (CIs) were calculated individually for tion bias using the correlation between pared with aspirin alone, but none of the each study.16 number ofsubjects and RR in each study. findings reached statistical significance The summary measure of effect in the If small studies with negative results (Table 2). The incidence of MI or death meta-analysis for each endpoint is the were less likely to be published, then during heparin therapy was 7.9% (55/ odds ratio (OR).17 Since the sample cross- the correlation between number of sub¬ 698) in participants treated with aspirin product has a highly skewed distribution, jects and RR would be high. If publi¬ plus heparin, and 10.4% (68/655) in par¬ its natural log transformation is appro¬ cation bias does not exist, then no sig¬ ticipants treated with aspirin alone. The priate for purposes of estimation and hy¬ nificant correlation between number of summary RR of MI or death during ran¬ pothesis testing.15 The summary effect subjects and RR would be evident. domized treatment was 0.67 (95% CI, Downloaded from www.jama.com at New York State Psychiatric Institute on August 3, 2009 Table 2.—Incidence of Myocardial Infarction or Death and Relative Risk of Myocardial Infarction or Death During Treatment With Heparin From 6 Randomized Trials in Patients Admitted to the Hospital With Favors Unstable Angina Heparin Favors Source Plus Aspirin Aspirin Myocardial Infarction or Death, No.* (%) Therouxetal, 198810 Source Aspirin Aspirin Plus Heparin RR (95% Cl)t Theroux et al, 19 4/121 (3) 2/122 (2) 0.50 (0.18-2.66) RISC Group, 19907 RISC Group, 19907 7/189(4) 3/210(1) 0.39(0.18-1.47) Cohen et al, 199011 Cohen et al, 1990" 1/32 (3) 0/37 (0) 0.29 (0.06-6.87) Cohen et al, 199412 Cohen et al, 19941: 9/109(8) 4/105(4) 0.46(0.24-1.45) Holdright et al, 199413 et al, 1994'= 40/131 Holdright (31) 42/154(27) 0.89(0.66-1.29) Gurfinkel et al, 199514 Gurfinkel et al, 1995" 7/73(10) 4/70 (6) 0.60 (0.29-1.95) Summary Relative Risk Summary 68/655(10) 55/698 (8) 0.67 (0.44-1.02) ~r ™f "Number of patients who had a myocardial infarction or died during randomized treatment/total number 0.01 0.1 1 10 to the treatment of participants assigned group. Relative Risk ¡ RR indicates relative risk; and CI, confidence interval for myocardial Infarction or death in the aspirin plus heparin compared with the aspirin group. ^Summary RR estimate and 95% CI from meta-analysis. Relative risk of myocardial infarction or death dur¬ 0.44-1.02; P=.06) in patients treated with RR for recurrent ischemie pain was 0.68 ing hospitalization. aspirin plus heparin compared with those (95% CI, 0.4-1.17; for test of heteroge¬ treated with aspirin alone (Figure 1). neity, P=.08) in patients treated with but none of the trials was large enough The result of a test for heterogeneity aspirin plus heparin compared with those to demonstrate a statistically significant was not statistically significant (P=.78). treated with aspirin alone. benefit. Combining data from these 6 Incidence of MI or death from dis¬ Five studies10"14 reported the number trials using formal meta-analytic tech¬ continuation of randomized therapy to of patients in each treatment group who niques resulted in a summary RR esti¬ 12 weeks after randomization was re¬ underwent coronary arterybypass graft¬ mate of 0.67 (95% CI, 0.44-1.02), sug¬ ported in 4 studies (Table 3).7·10·12·13 Based ing or percutaneous transluminal coro¬ gesting a 33% reduction in MI or death on data from these 4 studies, the risk of nary angioplasty within 12 weeks after during heparin therapy in patients late MI or death was 12.4% (73/591) in randomization (Table 3). Of participants treated with heparin plus aspirin com¬ participants treated with aspirin plus treated with aspirin plus heparin, 23.8% pared with patients treated with aspirin heparin and 13.8% (76/550) in partici¬ (116/488) underwent revascularization, alone. This result closely approached sta¬ pants treated with aspirin alone. The compared with 23.4% (109/466) of those tistical significance. summary RR for MI or death from dis¬ treated with aspirin alone. The summary In 1 trial,13 31% (40/131) of participants continuation of randomized therapy to RR for revascularization procedures was in the aspirin group and 27% (42/154) of 12 weeks after randomization was 0.82 1.03 (95% CI, 0.84-1.43; for test of het¬ participants in the aspirin plus heparin (95% CI, 0.56-1.20; for test of heteroge¬ erogeneity, P=.41) in patients treated group developed MI or died during ran¬ neity, =.76) in patients treated with with aspirin plus heparin compared with domized treatment. This incidence of MI aspirin plus heparin compared with those those treated with aspirin alone. or death was markedly higher than the treated with aspirin alone. Of note, 1 of Overall, 0.4% (3/655) of patients treated average incidence of 5.3% (28/254) in the these 4 studies continued anticoagula- with aspirin alone and 1.5% (10/698) of aspirin groups and 2.4% (13/544) in the tion therapy with warfarin in the hep¬ patients treated with aspirin plus hep¬ aspirin plus heparin groups reported in arin plus aspirin group after heparin was arin developed major bleeding during the 5 other trials. The explanation for this discontinued.12 Removing the findings randomized treatment. Based on data increased risk of death or MI is unclear. of this trial from the summary results from all 6 trials, the summary RR for It is possible that participants in this trial did not significantly alter the summary major bleeding was 1.89 (95% CI, 0.66- were sicker at baseline, or that the in¬ RR estimate. 5.38; for test of heterogeneity, =.68) vestigators used a more sensitive defini¬ in patients treated with aspirin plus hep¬ tion of MI. When we performed a post Summary Effects on Ischemie Pain, arin compared with those treated with hoc meta-analysis excluding this trial, the Revascularization and Procedures, aspirin alone (Table 3). summary RR was 0.45 (95% CI, 0.23-0.89), Major Bleeding suggesting a55% reductionin MI ordeath COMMENT Recurrence of ischemie pain was re¬ in patients treated with aspirin plus hep¬ ported in 5 of the 6 studies (Table 3).1014 Unstable angina is an important medi¬ arin compared with patients treated with The within study effect of heparin plus cal problem associated with a high in¬ aspirin alone. This result was statistically aspirin compared with aspirin alone for cidence of MI and death. Many physi¬ significant, but because it was a post hoc recurrent ischemie pain was heterog¬ cians routinely treat patients with analysis, the findings should be viewed eneous across studies (for test of het¬ unstable angina with both aspirin and with caution. erogeneity, P=.02). Heterogeneity was heparin, but adding heparin to aspirin Depending on whether the 1 trial with primarily due to 1 trial11 that used 80 mg has not been demonstrated to reduce a markedly high incidence of MI or death of aspirin daily in the group receiving the incidence of MI and death compared is excluded, the average risk of MI or heparin and 325 mg of aspirin daily in with treatment with aspirin alone. death in the combined studies is either the group not receiving heparin (Table We found 6 randomized trials oftreat¬ 5.3% or 10.4% for patients treated with 1). With this study excluded from the ment with aspirin plus intravenous hep¬ aspirin alone. If we assume that adding analysis, the incidence of recurrent is¬ arin compared with treatment with as¬ heparin to aspirin reduces the risk of MI chemie pain during randomized treat¬ pirin alone in patients with unstable or death by 33% to 55% (depending on ment was 17.3% (78/451) in participants angina. Each of these trials reported a whether the 1 trial was excluded), the treated with aspirin plus heparin, and trend toward decreased risk of MI or absolute risk reduction of MI or death 22.6% (98/434) in participants treated death in patients with unstable angina during treatment is 2.9% to 3.4% for with aspirin alone, and the summary treated with both heparin and aspirin, patients with unstable angina treated Downloaded from www.jama.com at New York State Psychiatric Institute on August 3, 2009 Table 3.—Relative Risk of Recurrent Ischemie Pain and Major Bleeding During Treatment With Heparin, pared with the 0.4% incidence of major Relative Risk of Revascularization Procedures Following Randomization, and Relative Risk of Myocardial bleeding reported in patients treated Infarction or Death During the 2-12 Weeks Following Randomization in Patients With Unstable Angina* with aspirin alone does not justify with¬ RR (95% CI) RR (95% CI) RR (95% CI) RR (95% CI) holding heparin from patients with un¬ of Recurrent of Major of CABG of Ml or Death stable angina. Source Ischemie Pain Bleeding or PTCA at 2-12 wk Several limitations ofthis meta-analy¬ Theroux 198810 0.50(0.25-1.60) étal, 0.64(0.41-1.24) 1.98(0.50-10.63) 0.97(0.75-1.28) sis deserve comment. The summary RR RISC Group, 19907_NA_NB_NA_0.77 (0.46-1 63) may be overestimated ifpublication bias NA Cohen et al, 1990" 1.98 (1.01-4.19)t NB 0.59(0.93-2.67) makes it more likely that studies show¬ Cohen étal, 1994'2_0.36(0.23-0.82) 7.06(0.46-135.15) 0.78(0.47-1.57) 0.75(0.41-1.80) ing benefit are published while those Holdright et al, 1994'3 0.74(0.52-1.17) 0.85(0.12-13.47) 1.08(0.65-2.03) 0.97(0.72-1.36) showing no benefit are not. If publica¬ Gurfinkel et al, 1995" 1.20(0.82-1.78) 5.21(0.34-106.67) 0.81(0.42-2.06)_NA tion bias exists, small studies with nega¬ Summary 0.68(0.40-1.17) 1.89(0.66-5.38) 1.03(0.84-1.43) 0.82(0.56-1.20) tive findings are unlikely to be published, while small studies with find¬ *RR Indicates relative risk; 95% CI, confidence interval for patients treated with aspirin plus heparin compared positive with those treated with aspirin alone; Ml, myocardial infarction; CABG, coronary artery bypass grafting; PTCA, ings are likely to be published. This could percutaneous translumlnal coronary angioplasty; NA, not available; and NB, no major bleeding in the aspirin group result in a correlation between study or the group. aspirin plus heparin and estimate. We found no such tResults from this trial were excluded from the meta-analysis of recurrent ischemie pain because of heterogeneity size RR (see text). correlation among the 6 randomized tri¬ als in our meta-analysis (r=0.25; P= .64). with heparin plus aspirin compared with moved from the meta-analysis, the sum¬ The validity of results from a meta- those treated with aspirin alone. There¬ mary RR was 0.68 (95% CI, 0.40-1.17), analysis depends on the quality of the tri¬ fore, 29 to 34 patients would need to be suggesting a 32% risk reduction which als included.38 Formal weighting of the treated with heparin for every 1 MI or is similar to the risk reduction found for quality of individual studies in this meta- death prevented. Despite the risks of MI or death. This finding is consistent analysis was not done because all 6 were intravenous heparin therapy including with the results of 2 other studies that well-performed randomized controlled tri¬ bleeding, thrombocytopenia, skin necro¬ reported increased infarction rate and als. A strength of these trials is that the sis, hypersensitivity reactions, and cath¬ reactivation of unstable angina follow¬ primary outcomes (MI and death) were eter-related infections,34 we believe that ing discontinuation of heparin.36·37 objective, and MI was diagnosed using this low number needed to treat justi¬ Because the anticoagulant effects of standard criteria. In addition, follow-up fies treating patients with unstable an¬ heparin are brief, any benefit of therapy among all 6 studies was excellent. Only 1 gina with 2 to 7 days of heparin added is unlikely to last beyond the duration of study11 reported incomplete follow-up: 2 to aspirin. However, it should be noted treatment. Consistent with this theory, patients were lost to follow-up at 12 weeks. that the majority of primary outcome we found no reduction in risk of MI or Bias may result from inadequate blind¬ events in the 4 studies that reported MI death between 2 and 12 weeks following ing in randomized controlled trials. Table and death separately were nonfatal MI. randomization in patients with unstable 1 shows that only 2 trials were double- The number of deaths in these studies angina who received heparin and aspirin blinded,10·14 2 blinded only the partici¬ was too low to calculate a meaningful compared with those who received aspi¬ pants,12·13 and 2 were unblinded.7·11 The difference between therapies for death rin alone. This result underscores that trial by Cohen et al12 was stopped early alone. The enhanced risk of bleeding on heparin is a short-acting, temporizing due to high withdrawal rates, particu¬ heparin might not be worth the benefit therapy, and not an intervention that al¬ larly in the aspirin plus heparin arm. Bi¬ ofreduced nonfatal MI for some patients. ters underlying atherosclerotic disease. ased findings from this trial are unlikely, Any benefit of adding heparin to aspi¬ A high percentage of patients who are however, because most of the difference rinmostlikely occurs because heparin pre¬ admitted to the hospital with unstable in withdrawal between the 2 groups was vents propagation of established throm¬ angina go on to have coronary angiogra- due to medication intolerance or patient bus and allows time for endogenous phy. The decision to revascularize is based request and not to an increased rate of fibrinolysis to occur. In theory, preven¬ on coronary anatomy and the degree of events in the aspirin plus heparin group. tion offurther thrombus formation should underlying atherosclerotic disease. Be¬ The trial by Gurfinkel et al14 was stopped act synergistically with the antiplatelet cause heparin does not change underly¬ prematurely because of much greater effects of aspirin to reduce intracoronary ing atherosclerotic disease, we did not efficacy of a third arm, low-molecular- obstruction and reduce myocardial ische¬ expect heparin to reduce the incidence of weight heparin plus aspirin. While ter¬ mia in patients with unstable angina. coronary artery bypass grafting or per¬ minating the trial early might have re¬ Heparin alone has been demonstrated cutaneous transluminal coronary angio- duced the power of the study (and our to reduce the incidence of recurrent is¬ plasty following treatment for unstable meta-analysis) to detect a difference be¬ chemie pain in patients with unstable angina. The results of our meta-analysis tween unfractionated heparin and aspi¬ angina.32·35 There was heterogeneity in support this theory. rin compared with aspirin alone, it should the findings of the 6 clinical trials re¬ We found a RR of 1.89 (95% CI, 0.66- not have biased the outcomes. garding the benefit of adding heparin to 5.38) for major bleeding in patients with The Agency for Health Care Policy and aspirin for the prevention of recurrent unstable angina treated with aspirin plus Research Clinical Practice Guideline39 ischemie pain. Much of this heterogene¬ heparin compared with those treated has recommended that, unless contrain- ity was due to the findings of 1 trial11 with aspirin alone. This result is not dicated, patients with unstable angina be that used 80 mg of aspirin per day in the statistically significant but is consistent treated with heparin for 2 to 5 days. This aspirin plus heparin group, but 325 mg with the results of other studies of the recommendation was based on a panel per day in the aspirin only group. While adverse effects associated with heparin consensus in the absence of directly each dose should have provided adequate therapy. If adding heparin to aspirin applicable clinical studies (strength of antiplatelet therapy, it is possible the reduces the risk of MI or death by one evidence = C). This meta-analysis pro¬ higher dose also provided analgesia, re¬ third, we believe that the 1.5% incidence vides statistical evidence to support the ducing the observed benefit of heparin of major bleeding reported in patients recommendation stated in this guideline. on recurrent pain. With this study re- treated with aspirin plus heparin com- Our conclusion is further supported by Downloaded from www.jama.com at New York State Psychiatric Institute on August 3, 2009 2 randomized controlled trials dence that unless heparin is 21. Bishop YMM, Feinberg SE, Holland PW. Dis- comparing suggests crete Multivariate and Practice. most with un¬ Analysis: Theory low-molecular-weight heparin plus aspi¬ contraindicated, patients Cambridge, Mass: MIT Press; 1975. rin with aspirin alone in patients with stable angina should be treated with both 22. Cohen M, Parry G, Adams PC, et al. Prospec- unstable angina.14·40 The first study ran¬ aspirin and heparin. tive evaluation of a prostacyclin-sparing aspirin for- domized patients to 3 arms (low-molecu¬ mulation and heparin/warfarin in aspirin users with unfrac¬ unstable angina or non-Q wave myocardial infarc- lar-weight heparin plus aspirin, References tion at rest. Eur Heart J. 1994;15:1196-1203. tionated heparin plus aspirin, or aspirin 1. Fuster V, Badimon L, Cohen M, Ambrose JA, 23. Fuchs J, Cannon CP. Hirulog in the treatment alone) and found a RR of 0.07 (95% CI, Badimon JJ, Chesebro J. Insights into the patho- of unstable angina: results of the Thrombin Inhi- 0.0-1.28) for MI and death in 68 patients genesis of acute ischemic syndromes. Circulation. bition in Myocardial Ischemia (TIMI) 7 trial. Cir- treated with 1988;77:1213-1220. culation. 1995;92:727-733. low-molecular-weight hep¬ 2. Gazes PC, Mobley E Jr, Faris H Jr, Duncan RC, 24. Serneri GGN, Modesti PA, Gensini GF, et al. arin compared with 73 patients treated Humphries GB. Preinfarctional (unstable) angina\p=m-\a Randomised comparison of subcutaneous heparin, with aspirin alone.14 This trial also com¬ prospective study\p=m-\tenyear follow-up: prognostic intravenous heparin, and aspirin in unstable an- pared low-molecular-weight heparin to significance of electrocardiographic changes. Cir- gina: Studio Epoorine Sottocutanea nell'Angina In- culation. stobile Refrattorie Lancet. unfractionated and found a RR 1973;48:331-337. (SESAIR) Group. 1995; heparin Fulton Morrison et al. 345:1201-1204. of MI and 3. Duncan B, M, SL, Prog- 0.11 (95% CI, 0.01-2.17) for nosis of new and worsening angina pectoris. BMJ. 25. Moise A, Roos M, Roos M. Aspirin versus hep- death in patients treated with low-mo¬ 1976;1:981-985. arin in the acute phase of unstable angina. Circu- lecular-weight heparin plus aspirin com¬ 4. Rahimtoola SH. Coronary bypass surgery for lation. 1994;90:1107. with unfractionated unstable angina. Circulation. 1984;69:842-848. 26. Theroux P, Waters D, Qiu S, et al. Aspirin pared heparin plus et sul- versus to infarction second 5. Cairns JA, Gent M, Singer J, al. Aspirin, heparin prevent myocardial aspirin. The study randomized pa¬ finpyrazone, or both in unstable angina: results of during the acute phase of unstable angina. Circu- tients to 2 arms (low-molecular-weight a Canadian multicenter trial. N Engl J Med. 1985; lation. 1993;88:2045-2048. heparin plus aspirin or aspirin alone) and 313:1369-1375. 27. Cohen M Xiong J, Parry G, et al. Prospective 6. Lewis H Davis Archibald et al. of unstable versus non-Q wave found a RR of 0.37 (95% 0.20-0.68) for Jr, JW, DG, comparison angina CI, Protective effects of acute myocardial infarction during antithrombotic ther- MI and death in 741 treated with aspirin against myocar- patients dial infarction and death in men with unstable an- apy: Antithrombotic Therapy in Acute Coronary low-molecular-weight heparin plus aspi¬ gina: results of a Veterans Administration Coop- Syndromes Research Group. J Am Coll Cardiol. rin compared with 757 patients treated erative Study. N Engl J Med. 1983;309:396-403. 1993;22:1338-1343. with In this 7. The RISC Group. Risk of myocardial infarction 28. Averkov OV, Zateishchikov DA, Gratsianskii aspirin alone.40 large trial, death with low dose NA, Dobrovol'skii AV. Unstable in of the and during treatment aspirin angina: tissue-type major bleeding occurred 0.5% and intravenous heparin in men with unstable coro- plasminogen activator inhibitor and other hemo- aspirin group and 0.8% of the low-mo¬ nary artery disease: the RISC Group. Lancet. 1990; static factors in aspirin and intravenous heparin lecular-weight heparin group (RR, 1.53, 336:827-830. administration. Kardiologiia. 1993;33:16-22. 95% 0.43-5.44). 8. Rosenberg RD. Actions and interactions of an- 29. Averkov OV, Zateishchikov DA, Gratsianskii CI, tithrombin and heparin. N Engl J Med. 1975;292: NA, Logutov I, Iavelov IS, Ianus V. Unstable an- If therapeutically equivalent, low-mo¬ 146-151. gina: effect of aspirin and heparin on treatment lecular-weight heparin might be preferred 9. Wallis DE, Boden WE, Califf R, et al. 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