Systematic Review and Meta-analysis of Adverse Events of Low-dose Aspirin and Clopidogrel in Randomized Controlled Trials

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1 The American Journal of Medicine (2006) 119, REVIEW Systematic Review and Meta-analysis of Adverse Events of Low-dose Aspirin and Clopidogrel in Randomized Controlled Trials Kenneth R. McQuaid, MD, a,b Loren Laine, MD c a Veterans Affairs Medical Center, San Francisco, Ca; b Department of Medicine, University of California San Francisco; c Department of Medicine, University of Southern California, Los Angeles. ABSTRACT PURPOSE: We performed a systematic review to define the relative and absolute risk of clinically relevant adverse events with the antiplatelet agents, aspirin and clopidogrel. MATERIALS AND METHODS: Databases were searched for randomized controlled trials of low-dose aspirin ( mg/dayay) or clopidogrel administered for cardiovascular prophylaxis. Relative risks (RR) were determined by meta-analysis of 22 trials for aspirin versus placebo and from single studies for aspirin versus clopidogrel, aspirin versus aspirin/clopidogrel, and clopidogrel versus aspirin/clopidogrel. Absolute risk increase was calculated by multiplying RR increase by the pooled weighted incidence of the control. RESULTS: Aspirin increased the risk of major bleeding (RR 1.71; 95% confidence interval [CI], ), major gastrointestinal (GI) bleeding (RR 2.07; 95% CI, ), and intracranial bleeding (RR 1.65; 95% CI, ) versus placebo. No difference between mg/day and mg/day aspirin versus placebo was seen. The absolute annual increases attributable to aspirin were major bleeding: 0.13% (95% CI, ); major GI bleeding: 0.12% (95% CI, ), intracranial bleeding: 0.03% (95% CI, ). No study compared clopidogrel with placebo. One study showed increased major GI bleeding (but not non-gi bleeding endpoints) with aspirin versus clopidogrel (RR 1.45; 95% CI, ). The absolute annual increase was 0.12% (95% CI, ). CONCLUSIONS: Low-dose aspirin increases the risk of major bleeding by 70%, but the absolute increase is modest: 769 patients (95% CI, ) need to be treated with aspirin to cause one additional major bleeding episode annually. Compared with clopidogrel, aspirin increases the risk of GI bleeding but not other bleeding; however, 883 patients (95% CI, 357- ) would need to be treated with clopidogrel versus aspirin to prevent one major GI bleeding episode annually at a cost of over 1 million dollars Elsevier Inc. All rights reserved. KEYWORDS: Aspirin; Clopidogrel; Meta-analysis; Systematic review; Cardiovascular diseases Aspirin is an antiplatelet agent that inhibits platelet thromboxane A 2 production and is the most important and widely used drug for the primary and secondary prevention of atherothrombotic disease. 1-3 However, low-dose aspirin used for the prevention and treatment of cardiovascular Supported by a grant from Bayer Healthcare LLC, Morristown, NJ. Requests for reprints should be addressed to Kenneth R. McQuaid, MD, GI Section 111-B-1, VA Medical Center, 4150 Clement Street, San Francisco, CA address: enneth.mcquaid@med.va.gov disease may cause side effects due to its antiplatelet activity, as well as its effects on the gastrointestinal (GI) tract mucosa. 4-6 The relative contribution of these 2 mechanisms to the induction of clinical events is uncertain. Clopidogrel is an alternative antiplatelet agent that inhibits adenosine diphosphate (ADP)-induced platelet aggregation through irreversible inhibition of P2 nucleotide receptors on the platelet surface. 7 It is commonly used for secondary prevention of atherothrombotic disease in place of low-dose aspirin in patients who have experienced gastrointestinal intolerance to aspirin-related adverse events or /$ -see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 McQuaid and Laine Complications of Low-dose Aspirin and Clopidogrel 625 with aspirin allergy. 8 Because clopidogrel and aspirin inhibit platelet aggregation through independent but complementary mechanisms, they also are sometimes used in combination (eg, after coronary stenting or in patients with acute coronary syndrome). 7 Like aspirin, clopidogrel may cause adverse bleeding events via its antiplatelet activity. Although clopidogrel has not been considered to be injurious to the GI mucosa, the results of a recent randomized trial assessing recurrent GI bleeding with clopidogrel led the authors of the article and an accompanying editorial to raise this possibility. 9,10 As the population ages and increasing numbers of patients receive antiplatelet agents, knowledge of the potential negative effects of treatment will be crucial to health care providers as they attempt to develop management strategies for patients with cardiovascular disease. We therefore sought to define the risk of bleeding events and other noncardiovascular adverse events with these 2 widely used antiplatelet agents through a systematic review of the literature. CLINICAL SIGNIFICANCE Although several recent systematic reviews of the GI complications of aspirin are available, 4,5,11-13 their selection criteria and analysis are less clinically relevant than the present review. They include studies with doses outside the range of low-dose aspirin commonly used for cardiovascular prophylaxis ( mg daily), 4,5,11-13 data from studies in which aspirin was given concurrently with anticoagulants, 11 they exclude studies with duration of less than 12 months 4,5 or include short-term studies in which the length of follow-up may be inadequate to observe rare outcomes; 11,13 they do not provide information on clinically important major bleeding or other relevant side effects of antiplatelet therapy, and they don t provide information about bleeding rates based on duration of exposure. 12,13 Furthermore, some systematic reviews include studies in which aspirin was administered for a single limited indication, ie, primary cardiovascular prevention 5 or secondary cardiovascular prevention. 12 Although these reviews provide data in specific populations of interest, they may have limited precision for estimating risk because of the limited number of studies included; furthermore, it is not clear that differences in the study populations (eg, primary vs secondary prevention) lead to significant differences in incidences of GI bleeding. 14 Most importantly, prior meta-analyses provide relative risks, or odds ratios as measures of the effect of aspirin on the development of bleeding. However, information on the absolute increase in incidence with antiplatelet agents and the number of patients who would need to be treated to cause an additional serious Among patients enrolled in long-term controlled trials of antiplatelet agents for cardiovascular prophylaxis, low-dose aspirin increases the risk of major bleeding 2-fold compared with placebo. However, the annual incidence of major bleeding due to low-dose aspirin is modest only 1.3 patients per thousand higher than what is observed with placebo treatment. Treatment of approximately 800 patients with low-dose aspirin annually for cardiovascular prophylaxis will result in only 1 additional major bleeding episode. adverse event may be more useful information for clinicians. We made these clinically relevant measures a focus of this systematic review. METHODS Search Strategy We performed a systematic review of the medical literature for randomized controlled trials of aspirin or clopidogrel administered for the primary or secondary prophylaxis of cardiovascular disease. We searched the PubMed and CENTRAL (Cochrane Central Register of Controlled Trials) computerized bibliographic databases (1966 to December 2004), as well as bibliographies from prior systematic reviews. 4,5,11,15 We did not search for abstracts or attempt to identify unpublished data (eg, pharmaceutical companies, other funding sources, the U.S. Food and Drug Administration). The search of PubMed was performed by combining the MESH headings ( aspirin, platelet aggregation inhibitors, ticlopidine/analogs and derivatives ), or the substance name or text word clopidogrel and the publication type randomized controlled trials. This strategy yielded 2835 references. Two searches of CENTRAL were conducted by searching the term aspirin and the terms ticlopidine/ analogs and derivatives or clopidogrel. These searches yielded 2900 and 215 references, respectively. The searches were not limited by language. The 2 authors independently screened the titles and abstracts for eligibility. Full articles were retrieved for all titles for which abstracts were not available and for all abstracts that appeared to potentially fulfill the inclusion and exclusion criteria. Study Inclusion Criteria Population. Studies of adults assigned to antiplatelet therapy for primary or secondary prevention of cardiovascular disease were included. This included studies in which the stated indication for therapy was for primary prevention in patients without known disease and primary or secondary prophylaxis in patients with, hypertension, atrial fibrillation, valvular heart disease, postcoronary artery bypass graft surgery, postcoronary artery angioplasty or stent placement, cerebral vascular disease (stroke or transient ischemic attack), operative or nonoperative management of peripheral artery disease, or prophylaxis of deep venous thrombosis.

3 626 The American Journal of Medicine, Vol 119, No 8, August 2006 Intervention: Antiplatelet therapy with low-dose aspirin (defined as mg/day or mg every other day) or clopidogrel was required for inclusion, provided the indication for antiplatelet therapy was primary or secondary prophylaxis of cardiovascular disease. Outcome: Studies were included if they provided information on the following adverse events: bleeding, non-cardiovascular deaths, discontinuations due to adverse events, or symptoms other than bleeding or cardiovascular events. Study: Randomized controlled trials assessing cardiovascular outcomes were included if at least one study arm included low-dose aspirin or clopidogrel and a comparator study arm included placebo, low-dose aspirin (compared with clopidogrel), clopidogrel (compared with aspirin), or combined aspirin and clopidogrel. Because antiplatelet agents commonly are administered long term for cardiovascular prophylaxis and because many side effects may require a longer duration of therapy to develop, trials were included only if the planned duration of therapy was 2 months. In addition, because many of the important side effects of antiplatelet agents are uncommon, we included only studies with 100 patients in the antiplatelet arm(s) in order to exclude smaller studies with imprecise estimates of uncommon events. Data Abstraction and Validity Assessment The full texts of all selected articles were reviewed independently by the authors to confirm study eligibility, to assess study quality, and to extract data using a predesigned extraction form. Disagreement between reviewers was resolved by consensus. Trials fulfilling the inclusion criteria were scored for quality using the criteria established by Jadad et al on a scale of For each treatment arm the total number of patients enrolled and the mean or median length of follow-up (in months) were recorded. If available, the person-years of follow-up also were recorded. For each treatment arm we attempted to determine the total number of patients with bleeding originating from any site or unspecified sites ( any bleeding ), GI bleeding, intracranial bleeding (intracerebral, subarachnoid, or subdural), and non-gi/nonintracranial bleeding. For all bleeding categories, we attempted to determine the total number of patients with bleeding of any severity ( all bleeding ), as well as the number with major bleeding, fatal bleeding, and minor bleeding. Bleeding events were classified as major or minor in accordance with a priori definitions established in some studies. For studies lacking such definitions, we defined as major those bleeding events that were listed as fatal or required hospitalization or transfusion. The primary outcome assessments were any major bleeding, major GI bleeding, or intracranial bleeding. Additional bleeding outcome assessments were any bleeding (irrespective of severity), any fatal bleeding, or any minor bleeding; GI bleeding (irrespective of severity), fatal GI bleeding, or minor GI bleeding; fatal intracranial bleeding; all non-gi/ non-intracranial bleeding (irrespective of severity), major non-gi/non-intracranial bleeding, fatal non-gi/non-intracranial bleeding, and minor non-gi/non-intracranial bleeding. Bruising and ecchymoses were excluded from tabulations of minor bleeding (both any bleeding and non-gi/ non-intracranial bleeding). Other non-bleeding outcome assessments included noncardiovascular deaths; GI adverse events (including dyspepsia, diarrhea, and constipation); non-gi adverse events (including rash); and discontinuations of therapy due to all adverse events and GI adverse events. Data Analysis Individual studies providing head-to-head comparisons of therapies (placebo, low-dose aspirin, clopidogrel, or combined aspirin and clopidogrel) were pooled by meta-analysis. For each study, we calculated the crude proportion of patients with each endpoint using an intent-to-treat analysis of all patients randomized to each study arm. Data pertaining to the number of bleeding events (rather than the number of patients with bleeding) were not included when the provided tabulations suggested that there was more than 1 event per patient ( double-counting ). For each endpoint, meta-analysis was performed when at least 2 studies provided head-to-head comparisons of therapies. A summary relative risk with 95% confidence intervals (CI) was calculated using a random effects model (Review Manager software, Version 4.2.7; Oxford, UK: Cochrane Collaboration). Heterogeneity was calculated using the chi-squared test with n-1 degrees of freedom, where n represented the number of studies contributing to the meta-analysis. Significant heterogeneity was defined as a P value of.10 or less. When only 1 study provided head-to-head comparison for an endpoint, a Fisher s exact test was used for statistical analysis. For primary endpoints, we also performed a planned subgroup analysis assessing the results for low low-dose aspirin ( mg daily) and high low-dose aspirin ( mg daily) versus placebo. For the primary endpoints, we determined the absolute risk increase (ie, the attributable incidence) of bleeding due to low-dose aspirin above the comparator (placebo or clopidogrel). To determine this, we first calculated the bleeding incidence (event per person-month) in patients treated with placebo by dividing the number of placebo-treated patients with the bleeding event by the patient-months of follow-up (where provided) or the crude proportion of placebo-treated patients with the event by the mean or median months of follow-up. Where neither mean nor median follow-up was provided, the study duration was used. A pooled incidence for each bleeding endpoint among patients treated with placebo was then calculated by sample-size weighted pooling. To calculate the absolute risk increase (attributable incidence) of bleeding due to low-dose aspirin above placebo, we multiplied the relative risk increase associated with aspirin versus placebo derived from the meta-analysis by the pooled weighted incidence for the placebo studies in the meta-analysis. When only one study provided a head-

4 McQuaid and Laine Complications of Low-dose Aspirin and Clopidogrel 627 Table 1 Bleeding Complications: Meta-analyses of Trials with Direct Comparisons of Aspirin versus Endpoint Number of Studies Reference # Aspirin/ Subjects Compared: Relative Risk (95% CI) Primary bleeding endpoints Any major bleeding 9 22,23,26,27,29,33,36,46,52,58 26,673/26, ( ) Lower-dose aspirin 5 27,33,36,46,52 14,578/14, ( ) Higher-dose aspirin 3 23,26,29, / ( ) Major GI bleeding 14 22,27-29,33,36,38,40,42,46,52,54,58,64,65 28,686/28, ( ) Lower-dose aspirin 6 27,33,36,46,52,64 14,778/14, ( ) Higher-dose aspirin 7 28,29,38,40,42,54,58, / ( ) Intracranial bleeding 11 22,23,26-29,33,36,38,46, 52,58,65 27,671/27, ( ) Lower-dose aspirin 5 27,33,36,46,52 14,578/14, ( ) Higher dose aspirin 5 23,26,28,29,38,58, / ( ) Additional bleeding endpoints Any bleeding 8 22,27-29,46,52,61,64,65 23,871/23, ( )* Lower-dose aspirin 5 27,46,52,61,64 11,620/11, ( ) Higher-dose aspirin 2 28,29, / ( ) All GI bleeding 11 22,24,27-29,33,40,46,58, 61,64,65 25,036/25, ( )* Lower-dose aspirin 6 24,27,33,46,61,64 12,068/12, ( ) Higher-dose aspirin 4 28,29,40,58, / ( ) All non-gi/non-intracranial bleeding 5 27,29,46,58,61 10,917/10, ( ) Major non-gi/non-intracranial bleeding 7 27,29,33,46,52,55,58 12,975/12, ( ) Any fatal bleeding 10 22,23,26,27,36,38,46,52,58, 64,67 25,497/25, ( ) Fatal GI bleeding 12 22,23,26-28,33,38,40,46,52,58,64,65,67 25,964/25, ( ) Fatal intracranial bleeding 12 23,26-29,38,46,52,58,62,64,65,67,74 13,802/13, ( ) Fatal non-gi/non- intracranial bleeding 8 23,26,27,33,46,52,58,64,67 13,314/13, ( ) *Heterogeneity: P.10. to-head comparison, we used the absolute risk difference directly from the study divided by the duration of follow-up to determine the attributable incidence. We then calculated the number needed to harm at 1 year based on these absolute incidence increases. RESULTS Our searches identified 58 original articles pertaining to 55 randomized controlled trials that met our initial inclusion and exclusion criteria and provided sufficient information to determine the proportion of patients with any of the primary or secondary endpoints In these trials there were 75,005 patients treated with low-dose aspirin, 13,401 with clopidogrel, 11,247 with combined aspirin and clopidogrel, and 30,515 with placebo. The characteristics of these clinical trials are provided in the Appendix. Twenty-five of these trials were included in this metaanalysis. Two trials included a clopidogrel treatment arm: one trial compared clopidogrel (9599 patients) to low-dose aspirin (9586 patients) 17 and 1 trial compared clopidogrel (3802 patients) to combined clopidogrel and aspirin (3797 patients). 19 Twenty-four trials included a low-dose aspirin treatment arm: 1 trial compared aspirin with clopidogrel (as above); 17 1 trial compared aspirin (6303 patients) with combined clopidogrel and aspirin (6259 patients); 18 and 22 compared aspirin ( patients) with placebo ( patients) ,26-29,33,36,38,40,42,43,46,52,54,55,61,62,64,67,74,75 Twentythree of the studies eligible for this meta-analysis had a Jadad score of 3, and 19 had a score of 4, reflecting good quality study design. Meta-analyses: Aspirin versus Meta-analyses of bleeding complications (Table 1) and nonbleeding complications (Table 2) were performed on trials comparing aspirin versus placebo. In nine comparative trials comprising over 53,000 patients, the relative risk of any major bleeding among patients treated with aspirin was 1.71 (95% CI ) (Table 1, Figure 1). The point estimates of all but one relatively small trial 23 lay on the same side of unity, and the test for heterogeneity was not significant (P.47). To assess major GI bleeding complications we performed a meta-analysis of 14 studies comprising over 57,000 patients. This analysis included the Physicians Health Study, in which over 22,000 patients were randomized to aspirin or placebo treatment. 22 This study did not specify the numbers of patients who developed major GI bleeding but did report the numbers with melena, hematemesis, and transfusion-requiring bleeding. We considered 2 scenarios for tabulating the major GI bleeding episodes for this study. Our primary analysis assumed that the transfusion-requiring bleeding episodes comprised the major GI bleeding episodes (48 for aspirin and 28 for placebo). We also performed a sensitivity analysis using a worst case scenario that assigned all patients with hematemesis or melena as having major GI bleeding (402 for aspirin and 274 for placebo). This number appears to have included a small number of double-counting (ie, patients with both hematemesis and melena) and likely includes a number of patients who were not hospitalized. It is noteworthy that the meta-analysis by Derry and Loke (which did not assess major GI bleeding) used the combination of hematemesis and melena from the Physicians

5 628 The American Journal of Medicine, Vol 119, No 8, August 2006 Table 2 Non-Bleeding Outcomes: Meta-analysis of Trials with Direct Comparisons of Aspirin versus Outcome Studies Subjects Compared Aspirin/ Relative Risk (95% CI) Noncardiovascular deaths 16 22,23,27-29,33,36,38,46,52,55,58,62,64,65,67,74 28,450/28, ( ) Discontinuations due to adverse events All events 5 28,29,54,55,61, / ( ) GI events 7 23,28,38,42,54,55,65, / ( ) Non-GI events 4 28,38,54,55, / ( ) Adverse events Dyspepsia 5 22,28,42,61,64,65 12,510/12, ( ) Diarrhea 2 28,64, / ( ) Constipation 2 28,64, / ( ) Rash 1 28,65 810/ ( ) Health Study to calculate the GI bleeding proportion. 4 In contrast, the meta-analysis of Hayden et al 5 used the number of subjects with peptic ulcers to calculate GI bleeding in the Physicians Health Study and did not use the reported bleeding events. Based upon our primary analysis, there was a significant increase in major GI bleeding episodes among patients treated with aspirin versus placebo (relative risk [RR] 2.07; 95% CI, ) (Table 1, Figure 2). When the metaanalysis was recalculated using the worst case scenario for the Physicians Health Study, the relative risk was lower but remained significant (RR 1.59; 95% CI, ). Significantly increased risks of intracranial bleeding (RR 1.65; 95% CI, ) and fatal intracranial bleeding (RR 2.52; 95% CI, ) were also observed among patients taking aspirin versus placebo in separate meta-analyses (Table 1, Figure 3). Separate subset analyses of trials comparing low lowdose aspirin versus placebo or high low-dose aspirin with placebo demonstrated overlapping confidence intervals for the relative risks for all bleeding endpoints assessed (Table 1). However, firm conclusions are limited by the relatively small number of patients treated with high low-dose aspirin versus placebo. Meta-analysis of 16 trials including almost 57,000 subjects detected no difference in risk of noncardiovascular death among patients treated with aspirin versus placebo (RR 0.92; 95% CI, ) (Table 2). Few studies that assessed nonbleeding adverse events were available for meta-analysis (Table 2). Based on 5 studies, low-dose aspirin was not associated with a significant increase in dyspepsia versus placebo (RR 1.09; 95% CI, ). Interestingly, 2 relatively small studies detected an increased risk of both diarrhea (RR 3.30; 95% CI, ) and constipation (RR 1.98; 95% CI, ) in the same study populations. Meta-analyses of a small number of studies and patients did not detect a significantly increased risk of discontinuations for all adverse events (RR 1.16; 95% CI, ) or GI adverse events (RR 1.26; 95% CI, ) among patients taking aspirin versus placebo. References 22 23/ Summary Relative RR (random) Risk Weight Relative RR (random) Risk (95% CI) % (95% 95% CI) CI [1.08, 2.73] [0.33, 1.64] [1.03, 4.90] [0.40, 4.93] [0.68, 4.96] [1.32, 6.05] [1.32, 2.30] [0.78, 3.13] Not estimable [1.41, 2.08] Favors Favours Aspirin treatment Favours Favors control Figure 1 Meta-analysis of major bleeding: aspirin vs placebo.

6 McQuaid and Laine Complications of Low-dose Aspirin and Clopidogrel 629 References / Summary Relative Risk RR (random) Weight Relative RR (random) Risk (95% 95% CI) % (95% 95% CI) CI [1.08, 2.73] [0.70, 7.36] [0.17, 20.55] [0.61, 14.88] [0.06, 15.53] [1.28, 9.38] Not estimable [1.11, 22.92] [0.21, 89.36] [1.41, 3.07] [0.69, 5.02] [0.31, 6.09] [0.12, 73.20] Not estimable [1.61, 2.66] Favors Favours Aspirin treatment Favours Favors control Figure 2 Meta-analysis of major GI bleeding: aspirin vs placebo. Based upon the weighted incidence of bleeding among patients treated with placebo in the meta-analyses, we determined the rate of bleeding attributable to aspirin (ie, the absolute increase in annual bleeding incidence for aspirin vs placebo) for the 3 primary bleeding endpoints. Nine studies comparing treatment with aspirin versus placebo provided data pertaining to any major bleeding (Table 1, Figure 1). The median duration of 1 study with 192 patients was 3 months, 75 while the mean or median duration of the other 8 studies (53,193 patients) ranged from 15 to 76 months. Among patients given placebo, the weighted incidence of any major bleeding was 0.18% per year. The absolute rate increase with aspirin above placebo was 0.13% per year (95% CI, % per year), and the number needed to harm (NNH) at 1 year was 769 (95% CI, ). Fourteen comparative studies provided data for major GI bleeding (Table 1, Figure 2). The median duration of 2 studies 54,75 (1458 patients) was 3 months, whereas the mean or median duration of the other 12 studies (55,947 patients) ranged from 12 to 76 months. The weighted incidence of major GI bleeding with placebo was 0.12% per year. The absolute rate increase with aspirin above placebo was 0.12% per year (95% CI, % per year), and the NNH at 1 year was 833 (95% CI, ). Eleven comparative studies provided data for intracranial bleeding (Table 1, Figure 3). The median duration of 1 study 75 (192 patients) was 3 months, while the average duration of the other References / Summary RR Relative (random) Risk Relative RR (random) Risk (95% CI) (95% 95% CI) CI 1.92 [0.95, 3.85] 1.03 [0.15, 7.28] 3.37 [0.93, 12.20] 1.87 [0.17, 20.55] 1.50 [0.25, 8.99] Not estimable 1.36 [0.30, 6.07] 3.53 [0.73, 16.92] 0.93 [0.45, 1.93] 3.05 [0.62, 15.08] Not estimable 1.65 [1.12, 2.44] Favors Favours Aspirin treatment Favours Favors control Figure 3 Meta-analysis of intracranial bleeding: aspirin vs placebo.

7 630 The American Journal of Medicine, Vol 119, No 8, August 2006 Table 3 Trials Comparing Clopidogrel, Aspirin, Combined Aspirin and Clopidogrel, or Aspirin vs. Clopidogrel (CAPRIE Study) 17 (CURE Study) 18,77 (MATCH Study) 19 Aspirin vs. Aspirin Clopidogrel Clopidogrel vs. Aspirin Clopidogrel Aspirin Clopidogrel Aspirin Clopidogrel Clopidogrel Aspirin Clopidogrel Aspirin Total enrolled Outcome n (%) n (%) RR (95% CI) n (%) n (%) RR (95% CI) n (%) n (%) RR (95% CI) Any bleeding 890 (9.28%) 890 (9.27%) 1.00 ( ) 317 (5.03%) 533 (8.52%) 0.59 ( ) 110 (2.89%) 289 (7.61%) 0.38 ( ) Any major bleeding % 132 (1.38%) 1.13 ( ) 169 (2.68%) 231 (3.69%) 0.73 ( ) 71 (1.87%) 169 (4.45%) 0.42 ( ) Any fatal bleeding 27 (0.28%) 23 (0.24%) 1.18 ( ) 15 (0.238%) 11 (0.176%) 1.35 ( ) 11 (0.289%) 16 (0.421%) 0.69 ( ) All GI bleeding 255 (2.66%) 191 (1.99%) 1.34 ( ) Major GI bleeding 68 (0.71%) 47 (0.49%) 1.45 ( ) 47 (0.75%) 83 (1.33%) 0.56 ( ) 32 (0.84%) 93 (2.45%) 0.34 ( ) Fatal GI bleeding 2 (0.021%) 1 (0.010%) 2.00 ( ) Intracranial bleeding 47 (0.49%) 34 (0.35%) 1.38 ( ) 5 (0.08%) 7 (0.11%) 0.71 ( ) 25 (0.66%) 40 (1.05%) 0.62 ( ) Fatal intracranial bleeding 16 (0.167%) 16 (0.167%) 1.00 ( ) Major non-gi, non-intracranial bleeding 40 (0.42%) 55 (0.57%) 0.73 ( ) 10 (0.16%) 12 (0.19%) 0.83 ( ) 14 (0.37%) 36 (0.95%) 0.39 ( ) Noncardiovascular death 193 (2.01%) 210 (2.19%) 0.92 ( ) 45 (0.71%) 41 (0.66%) 1.09 ( ) 80 (2.10%) 77 (2.03%) 1.04 ( ) Dyspepsia 588 (6.10%) 501 (5.22%) 1.18 ( ) Diarrhea 322 (3.36%) 428 (4.46%) 0.75 ( ) Constipation 319 (3.33%) 229 (2.38%) 1.39 ( ) Rash 442 (4.61%) % 0.77 ( ) 10 studies (55,191 patients) ranged from 15 to 76 months. Among patients allocated to placebo therapy, the weighted incidence of any intracranial bleeding was 0.05% per year. The absolute rate increase with aspirin above placebo was 0.03% per year (95% CI, % per year), and the NNH at 1 year was 3333 (95% CI, ,000). Aspirin versus Clopidogrel No studies were identified comparing clopidogrel with placebo. A single randomized controlled trial did compare clopidogrel with aspirin 325 mg daily 17 (Table 3). The relative risks of all GI bleeding (RR 1.34; 95% CI, ) and major ( severe ) GI bleeding (RR 1.45; 95% CI, ) were increased in patients taking aspirin, while the risks of all other bleeding endpoints (eg, all major bleeding and intracranial bleeding) and of non-cardiovascular deaths were not significantly increased. 17 A separate safety report from this study provided additional data on the proportion of patients hospitalized with GI bleeding with aspirin versus clopidogrel: 1.08% vs 0.74%; RR 1.47; 95% CI, ). 76 Aspirin was associated with a small but significant increase in dyspepsia (RR 1.18; 95% CI, ) and constipation (RR 1.39; 95% CI, ) but a decreased risk of diarrhea (RR 0.75; 95% CI, ) and rash (RR 0.77; 95% CI, ). Absolute rate increases are calculated only for endpoints with significant differences. The absolute risk increase in major ( severe ) GI bleeding with aspirin versus clopidogrel was 0.22% (95% CI, %) over a mean duration of 1.91 years. The yearly absolute increase in incidence is therefore 0.12% per year (95% CI, %), with an NNH at 1 year of 833 (95% CI, 357- ). Aspirin plus Clopidogrel versus Aspirin or Clopidogrel Alone One trial comparing aspirin versus combined aspirin and clopidogrel (CURE study) 18,77 and one study comparing clopidogrel versus combined aspirin and clopidogrel (MATCH study) 19 were identified (Table 3). Both aspirin alone and clopidogrel alone were associated with a reduced risk of any bleeding, any major bleeding, and major GI bleeding compared with combined therapy with aspirin and clopidogrel. Compared with combined aspirin and clopidogrel therapy, the relative risk reduction (RRR) for any major bleeding was greater in the MATCH study with clopidogrel therapy alone (RRR 0.58; 95% CI, ) than in the CURE study with aspirin therapy alone (RRR 0.27; 95% CI, ) with non-overlapping confidence intervals. For major GI bleeding the relative risk reduction was also greater in the MATCH study with clopidogrel alone (RRR 0.66; 95% CI, ) than in the CURE study with aspirin alone (RRR 0.44; 95% CI, ), although the 95% CIs overlapped between the 2 studies. Combined therapy was not associated with a significantly increased risk of any fatal bleeding or intracranial bleeding in either study, although the number of these events in the 2 trials was small.

8 McQuaid and Laine Complications of Low-dose Aspirin and Clopidogrel 631 DISCUSSION When used for primary or secondary prevention of atherothrombotic disease, low-dose aspirin ( mg/day) increases the risk of any major bleeding, major GI bleeding, and intracranial bleeding fold compared with placebo. Although these reflect significant increases in the relative risks of these major bleeding endpoints, the absolute increases in risk are small. The absolute increased risk of any major bleeding attributable to aspirin is 0.13%/year. Hence, the number of patients that would need to be treated with aspirin instead of placebo for 1 year in order to induce 1 additional major bleeding event is 769 (95% CI, ). Likewise, the absolute increased risk per year of major GI bleeding with aspirin instead of placebo is 0.12% (NNH 833) and it is 0.03% (NNH 3333) for intracranial bleeding. This review did not find evidence of an increased risk of bleeding with high low-dose aspirin ( to 325 mg daily) versus low low-dose aspirin (75 to mg daily). The higher doses of low-dose aspirin did not result in an increased relative risk of any of the major bleeding endpoints, including intracranial bleeding or the secondary endpoints of any bleeding or all GI bleeding. These findings are consistent with the results of meta-regression analyses by Derry and Loke, which did not find a relationship between the odds ratio for all gastrointestinal bleeding and daily aspirin dose ( mg/day) among controlled trials of long-term aspirin therapy. 4 Only one study in our systematic review included a randomized head-to-head comparison of lower dose (81 mg) and higher dose (325 mg) low-dose aspirin: rates of all GI bleeding (1.1% vs 1.1%) and intracranial hemorrhage (0.6% vs 0.8%) were not significantly different in this 3-month trial in 1417 patients after carotid endarterectomy. 66 A double-blind trial of colon neoplasm chemoprevention with 33 months mean follow-up also included a randomized head-to-head comparison of 81 and 325 mg of aspirin. 78 The proportions with GI bleeding were not significantly different between the 81 mg group (2/377 [0.5%]) and the 325 mg group (4/372 [1.1%]; 95% CI of the difference 0.7% to 1.8%). Another recent review did conclude that increasing doses of low-dose aspirin are associated with an increased risk of bleeding. 13 This review pooled cohorts of aspirin users from both randomized controlled trials and nonrandomized cohort studies and calculated the weighted crude proportions of events for doses of aspirin 100 mg, mg, and 200 mg. Patients included in this analysis were given aspirin for widely variable durations and disparate indications (sometimes with other anticoagulants or thrombolytic agents that may induce bleeding) and were pooled without adjustment for duration of exposure or for potential confounding factors. Furthermore, studies using aspirin doses up to 1200 mg daily (well above the accepted low dose of 325 mg) were included. Limitations of this analysis preclude legitimate conclusions regarding dose effects of aspirin. A systematic review of randomized controlled trials of lower low-dose aspirin versus higher lowdose aspirin or of these doses versus placebo, as done in our review and meta-analysis, is an appropriate way to examine the potential dose response of low-dose aspirin. Ultimately, larger randomized comparisons are required to definitively determine whether a dose-response is present across the range of lowdose aspirin. Aspirin did not increase the risk of noncardiovascular deaths as compared with placebo. Consistent with this observation, the risk among aspirin users of any fatal bleeding, fatal GI bleeding, or fatal non-gi/non-intracranial bleeding was not significantly increased, although there was a significant increased risk of fatal intracranial bleeding (RR 2.52; 95% CI, ). Although low-dose aspirin did appear to increase the risk of dyspepsia, diarrhea, and constipation compared with placebo, discontinuations due to all adverse events or GI adverse events were not significantly increased with aspirin compared with placebo. We caution that conclusions are limited by the relatively small number of studies and patients available for analysis of theses endpoints. Conclusions about the risks of clopidogrel therapy are limited by the paucity of trials pertaining to the use of this agent for secondary prevention of atherothrombotic disease No trials compared clopidogrel with placebo. Only one eligible trial performed a head-to-head comparison of clopidogrel alone versus aspirin. 17 This large, well-designed study showed an increase in all GI bleeding (RR 1.34; 95% CI, ) and major GI bleeding (RR 1.45; 95% CI, ). However, it did not find a significant increase in the relative risk of any of the other bleeding endpoints or non-cardiovascular death. The absolute increased risk associated with low-dose aspirin therapy versus clopidogrel for major GI bleeding was 0.12%/year; ie, 833 patients would have to be treated with aspirin in place of clopidogrel to cause one additional major GI bleeding episode in 1 year. Assuming an incremental retail cost of $1460 for clopidogrel versus aspirin therapy for 1 year, the cost to prevent one major GI bleeding episode from aspirin in 1 year by substituting clopidogrel therapy would be $1,216,180 (95% CI, $521,220- ). The minimal increased risk of GI bleeding with low-dose aspirin as compared with clopidogrel may appear surprising given the known importance of high-dose aspirin as a causal agent in peptic ulcer disease. However, there has been little study of low-dose aspirin in ulcer pathogenesis. In a randomized, prospective, double-blind endoscopic study of 768 patients 50 years of age treated with low-dose enteric aspirin (81 mg daily) versus placebo, the 12-week cumulative incidence of ulcers 5 mm was 4.9% (95% CI, %) in aspirin-treated patients versus 4.2% (95% CI, %) with placebo treatment, suggesting that low low-dose aspirin has little ulcerogenic potential. 79 Similar to aspirin, clopidogrel may potentiate bleeding complications through its inhibition of platelet aggregation, but it has not been considered to be injurious to the GI mucosa. An 8-day endoscopic study showed no evidence of GI tract mucosal injury with clopidogrel in human volunteers. 80 However, a recent study in rats reported that an ADP receptor antagonist impaired gastric ulcer healing, likely due to suppression of the release of platelet-

9 632 The American Journal of Medicine, Vol 119, No 8, August 2006 derived growth factors, 81 leading to speculation that in patients with ulcer disease, clopidogrel may cause bleeding through induction of recurrent ulcers in previously damaged gastric mucosa, as well as through its antiplatelet effects. 10 In possible support of this hypothesis, a 1-year double-blind comparison of aspirin (80 mg daily) plus esomeprazole (20 mg twice daily) versus clopidogrel (75 mg daily) in 320 H. pylori-negative patients with recent low-dose aspirin-associated ulcer bleeding revealed recurrent ulcer bleeding in 0.7% with aspirin plus esomeprazole versus 8.6% with clopidogrel alone (95% CI of the difference 3.4 to 12.4%). 9 In summary, these data suggest that the anti-platelet effect of low-dose aspirin and clopidogrel is likely the most important determinant of GI bleeding; the mucosal damaging effect of low-dose aspirin (81 mg daily) appears to be small, and further study is required to determine whether clopidogrel has an injurious effect on the GI mucosa. Based upon 2 large, well-designed comparative studies, combined therapy with aspirin and clopidogrel is associated with significant increased risk of complications compared with aspirin alone or clopidogrel alone. 18,19 These significant increases were seen for any bleeding, any major bleeding, and major GI bleeding but not for any fatal bleeding, intracranial bleeding, or non-cardiovascular death. Whether there is a difference when combined aspirin plus clopidogrel is compared with aspirin alone versus clopidogrel alone has not been studied. As compared with combined therapy, the relative risk reduction of any major bleeding was larger with clopidogrel in the CURE study than with aspirin in the MATCH study and the 95% CIs of the RRs from the two studies did not overlap. A similar trend was seen for major GI bleeding, although the 95% CIs did overlap. Although these results raise the possibility that addition of aspirin to clopidogrel may increase major bleeding more than the addition of clopidogrel to aspirin, an appropriately designed trial would be required to reach such a conclusion. In conducting this systematic review we defined low-dose aspirin as mg/day. This dose range was based on FDA-approved labeling and current recommendations for primary and secondary prophylaxis of. 2,3,82-86 Although aspirin doses 75 mg do inhibit platelet aggregation, 84 the Antithrombotic Trialists Collaboration meta-analysis of randomized trials of antiplatelet therapy revealed a nonsignificant reduction in vascular events (including cardiac and neurological) with daily aspirin doses 75 mg/day (13%) than mg/day (32%) or mg/day (26%) as compared with no aspirin. The authors concluded that uncertainty remained about whether aspirin doses 75 mg/day are as effective as doses 75 mg/day for vascular prophylaxis. 15 However, for prophylaxis of ischemic transient ischemic attack (TIA) and stroke, aspirin doses of mg/day currently are recommended and consistent with FDA-approved labeling. 86,87 Data in support of aspirin doses 75 mg/day for secondary neurologic prophylaxis derive from 2 large randomized controlled trials: the Dutch TIA trial and the European Stroke Prevention Study 2 (ESPS-2). 25,88 The Dutch TIA trial demonstrated similar efficacy of aspirin 30 mg/day versus 283 mg/day in the secondary prevention of vascular events in 3131 patients with a history of TIA or minor stroke. This study was not included in our meta-analysis because it did not include a placebo arm. Consistent with the results of our present analysis, no significant difference in major bleeding complications was seen in patients receiving the lower dose (30 mg) versus the higher dose (283 mg) of aspirin (hazard ratio 0.84; 95% CI, ). 25 ESPS-2 was a randomized, double-blind, placebo-controlled study that compared aspirin 50 mg/day, dipyridamole 400 mg/day, both agents, and placebo for secondary prevention in 6602 patients with prior stroke or TIA followed for 2 years. 88 The odds ratio of recurrent stroke or death was 0.84 (95% CI, ) for aspirin versus placebo. Severe bleeding (not further defined) from any site occurred during the 2-year follow up in 7/1649 (0.21% per year) placebo-treated patients versus 20/1649 (0.61% per year) aspirin-treated patients. This absolute rate increase of 0.40% per year for any severe bleeding with aspirin 50 mg/day compared with placebo is higher than the absolute rate increase of 0.13% per year observed in our systematic review for the endpoint of any major bleeding. Addition of the results of ESPS-2 to the 9 other placebo-controlled trials included in our original meta-analysis does not appreciably change the relative risk of any major bleeding with aspirin (1.76, 95% CI, ), nor does it change our original estimate of the absolute increase in bleeding incidence attributable to aspirin of 0.13% per year. Another randomized study of aspirin that was dosed below our inclusion criteria was published after completion of our systematic review. The Women s Health Study compared aspirin 100 mg every other day versus placebo in the primary prevention of cardiovascular disease in over 39,000 women followed for an average of 10.1 years. 89 This study did not report the incidence of major bleeding from any site, but it did report the incidence of transfusion-requiring GI bleeding and hemorrhagic stroke. Among patients treated with aspirin, the relative risk of transfusion-requiring GI bleeding versus placebo was 1.4 (95% CI, ), and the annualized increase in absolute incidence attributable to aspirin was 0.018%. The risk of hemorrhagic stroke was not significantly increased among subjects treated with aspirin versus placebo (RR 1.24; 95% CI, ). Possible explanations for the somewhat lower relative risks of major GI bleeding and intracranial bleeding in the Women s Health Study and the markedly lower absolute risk of major GI bleeding compared with the results of our meta-analysis include the very low dose of aspirin (which was used every other day), the relatively young age of the study population (90% were aged years), and the good baseline health status of the study population (professional women without a history of cardiovascular disease). Addition of the Women s Health Study to the 14 placebocontrolled studies included in our original meta-analyses reduces the relative risk of major GI bleeding with aspirin versus placebo (RR 1.72; 95% CI, ), as well as the absolute increase in incidence of major GI bleeding attributable to aspirin (0.06% per year; 95% CI, % per year). For

10 McQuaid and Laine Complications of Low-dose Aspirin and Clopidogrel 633 major GI bleeding, the NNH with aspirin therapy is 1667 per year (95% CI, per year). When added to the 11 placebo-controlled studies in our original meta-analysis, the results of the Women s Health Study also reduce the relative risk of intracranial bleeding for aspirin versus placebo (RR 1.44; 95% CI, ). The absolute rate increase was reduced to only 0.02% per year ( % per year), and the NNH at 1 year with aspirin therapy was increased to 5000 (95% CI, ,000). Thus, the results of the Women s Health Study serve to strengthen the conclusions derived from our original meta-analyses. Although the relative risks of these 2 major bleeding endpoints remain significant, the absolute increases in risk of major GI bleeding or intracranial bleeding with aspirin versus placebo are very small. Three other published studies not included in this systematic review provide important information on the rate of upper GI bleeding and the effect of prophylactic therapy in patients at high risk for upper GI bleeding. These include the previously discussed study by Chan et al, 9 as well as 2 other double-blind randomized trials from Hong Kong. 9,90,91 These studies were not included in our systematic review because there was no nonaspirin comparator arm 90,91 and because they were not designed to assess cardiovascular prevention but rather to evaluate therapy to prevent GI bleeding. 9,90,91 All three studies included patients with ulcer complications ( 99% bleeding) whose ulcers were healed before randomization and re-initiation of their anti-platelet therapy. A comparison of H. pylori eradication therapy versus maintenance omeprazole therapy (20 mg daily) for 6 months in 250 H. pylori-positive patients given aspirin (80 mg daily) revealed an annualized incidence of recurrent bleeding of 3.8% with H. pylori therapy versus 1.8% with omeprazole. 90 A comparison of placebo and lansoprazole (30 mg daily) after H. pylori eradication in 123 patients followed for a median of 1 year on aspirin (100 mg daily) found ulcer bleeding in 14.8% given placebo versus 1.6% treated with lansoprazole (95% CI of difference 3.7% to 22.6%). 91 Comparison of these studies with the studies of aspirin and clopidogrel included in our systematic review indicate that the risk of upper GI bleeding with anti-platelet agents is far higher in patients with prior ulcer bleeding on low-dose aspirin. Cotherapy with a proton pump inhibitor decreases the risk of GI bleeding with chronic low-dose aspirin therapy, although the risk still remains higher than the average-risk population. Furthermore, patients with prior upper GI bleeding on aspirin appear to have an increased risk of bleeding even when the anti-platelet agent is changed to clopidogrel. In calculating the incidences of our primary endpoints, we preferentially used either the patient-months of follow-up (where provided) or the mean or median months of follow-up. However, where none of this information was provided, the study duration was used. Use of the study duration may overestimate the true length of follow-up and, therefore, potentially could lead to an underestimation of the incidence of bleeding. Although this would decrease estimates of both aspirin and placebo incidences, the absolute difference might still be affected. Among all patients in trials comparing aspirin versus placebo in our review, only 3% were from trials that used study duration as a surrogate for follow-up. 42,43,67,24,61 However, none of these studies provided results for the primary endpoints of any major bleeding or intracranial bleeding and, therefore, none were included in the meta-analyses of these endpoints. For the meta-analysis of 14 studies that assessed major GI bleeding, only 1 study was included for which follow-up was uncertain, comprising only 0.4% of the 57,000 patients analyzed. 42 Therefore, the use of study duration should have minimal or no influence on our estimates of risk over time. In conclusion, the use of low-dose aspirin increases the risk of clinically important major bleeding endpoints by approximately 2-fold compared with placebo, although the absolute increase in the annual incidence of any major bleeding event due to aspirin use is rather modest at 1.3 patients per thousand. As compared with clopidogrel, low-dose aspirin causes an increased relative risk of major GI bleeding, although non-gi endpoints were not significantly greater. Again, the absolute increase in annual incidence of major GI bleeding with aspirin versus clopidogrel is quite small at 1.2 patients per thousand, and the use of clopidogrel in place of low-dose aspirin for the purpose of decreasing bleeding does not approach traditional levels of cost-effectiveness. The combination of low-dose aspirin plus clopidogrel increases the risk of bleeding as compared with either agent alone. When instituting antiplatelet therapy for individual patients, health care providers need to consider the absolute risk attributable to treatment in concert with the established absolute benefit in cardiovascular outcomes. References 1. Sanderson S, Emery J, Baglin T, Kinmonth AL. Narrative review: aspirin resistance and its clinical implications. Ann Intern Med. 2005; 142: U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular events: recommendation and rationale. Ann Intern Med. 2002;136: Pearson TA, Blair SN, Daniels SR, et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation. 2002;106: Derry S, Loke YK. Risk of gastrointestinal haemorrhge with long term use of aspirin: meta-analysis. BMJ. 2000;321: Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136: Serrano P, Lanas A, Arroyo MT, Ferreira IJ. Risk of upper gastrointestinal bleeding in patients taking low-dose aspirin for the prevention of cardiovascular diseases. Aliment Pharmacol Ther. 2002;16: CURE study investigators. The clopidogrel in unstable angina to prevent recurrent events (CURE) trial programme. Rationale, design, and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J. 2000;21: Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-st segment elevation myocardial infarction 2002: summary article: a report of the American College of Cardiology/American Heart

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