Effect of Addition of Clopidogrel to Aspirin on Mortality Systematic Review of Randomized Trials

Abstract

Background and Purpose

In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, addition of clopidogrel to aspirin was associated with an unexpected increase in mortality in patients with lacunar strokes. We assessed the effect of the addition of clopidogrel to aspirin on mortality in a meta-analysis of published randomized trials.

Methods

Randomized trials in which clopidogrel was added to aspirin in subjects with vascular disease or vascular risk factors were identified. Trials were restricted to those with a mean follow-up of ≥14 days in which both the combination of aspirin and clopidogrel was tested and mortality was reported.

Results

Twelve trials included 90 934 participants (mean age, 63 years; 70% men; median follow-up, 1 year) with 6849 observed deaths. There was no significant increase in mortality with the combination therapy either in 4 short-term (14 days–3 months; OR, 0.93; 95% CI, 0.87– 0.99) or in 7 long-term (>3 months; hazard ratio, 0.97; 95% CI, 0.91–1.04) trials after 1 long-term trial (the SPS3 trial) was excluded because of heterogeneity. Addition of clopidogrel was associated with an increase in fatal hemorrhage (OR, 1.35; 95% CI, 0.97–1.90) and a reduction in myocardial infarction (OR, 0.82; 95% CI, 0.74–0.91).

Conclusions

The addition of clopidogrel to aspirin has no overall effect on mortality. The SPS3 trial results are outliers, possibly because of a lower prevalence of coronary artery ischemia. Addition of clopidogrel to aspirin increases fatal bleeding and reduces myocardial infarction.

Dual antiplatelet therapy of clopidogrel combined with aspirin is standard antithrombotic therapy after coronary and carotid arteries stent placement and for patients with acute coronary syndromes. In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial involving patients with recent lacunar strokes, the addition of clopidogrel 75 mg daily to aspirin 325 mg daily was associated with an unexpected increase in all-cause mortality (hazard ratio, 1.5; P=0.005).¹

We sought to determine the effect of addition of clopidogrel to aspirin on mortality in patients with a wide spectrum of vascular disease; we conducted systematic identification of all randomized trials comparing these agents and meta-analysis of their results. To understand further the effects on mortality, we examined the effects of addition of clopidogrel on vascular versus nonvascular death, fatal bleeding, and myocardial infarction. Adverse mortality effects of combining clopidogrel with aspirin are relevant to ongoing randomized trials testing this combination.^2,3

Methods

Search and Selection Process

Randomized trials in which clopidogrel in any dosage was added to aspirin in any dosage and in which all-cause mortality was reported were included. Trials were excluded if follow-up averaged <14 days or if published only in abstract. Trials were identified by computerized search of the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov Web site, and Pubmed using the keywords of clopidogrel plus aspirin combined with clinical trial; inquiry to the manufacturer of Plavix brand of clopidogrel was also made.

Data Extraction

Two physician reviewers (S.P., R.G.H.) independently extracted the following from published sources: data on methodological features; number of patients treated; total follow-up exposure; and occurrence of all-cause mortality, causes of death, death caused by hemorrhage, myocardial infarction, and intracranial hemorrhage. Disagreements were resolved by joint review and consensus. If the years of exposure for each treatment arm were not provided, they were estimated from the number of primary events divided by the annualized event rate; if the overall mortality rate was not provided, then the mean follow-up multiplied by the number of participants was used. The biostatistician reviewer (L.A.P.) extracted available data on hazard ratios (HR) and their 95% CIs for the long-term trials.

Outcomes

We accepted the definitions of vascular versus nonvascular causes of death as reported in the individual clinical trials. For these analyses, deaths categorized as of unknown cause were combined with vascular deaths (ie, vascular deaths included all deaths that were not determined to be nonvascular). We accepted the diagnosis of myocardial infarction as reported in individual trials.

Data Synthesis

Intention-to-treat results were used for the analyses when available (and footnoted when not available). Meta-analyses of the trial results are presented as ORs comparing dual antiplatelet versus aspirin, with the exception of all-cause mortality results for longer-term trials, in which the HR was estimated instead. (Meta-analysis of other long-term trial results as an HR was not performed, as data were less available.) Each meta-analysis OR was computed assuming a random effects model, and the assumption of statistical homogeneity of the treatment effect (across trials) was tested using the Q_L statistic for the relative odds scale. If the count in 1 or more of the cells for a trial was 0, then 0.5 was added to each of the 4 cells. The meta-analysis HR for all-cause mortality in longer-term trials was computed using a generic inverse variance method for continuous data. The log (HR) and standard error for each trial result were calculated from the published HR and 95% CI. For 1 trial (CURE), HR data for overall mortality were not reported, so OR data were used; and for a relatively small trial (CASCADE), total deaths numbered 1, so data were excluded.⁴ Heterogeneity across trials was evaluated using the I² index (percentage of the total variability in a set of effect sizes because of between-studies variability) and the χ² test for heterogeneity. All tests and CIs are 2-sided. Software used for meta-analysis of ORs and HRs were MedCalc for Windows, version 12.1.4.0 (MedCalc Software) and RevMan 5.0 (the Cochrane Collaboration), respectively.⁵

Results

Twelve randomized trials published between 2001 and 2012 were included, with a total of 90 934 randomized participants with a mean age of 63 years, a mean follow-up of 1 year per patient, and 6849 total deaths.^1,6–16 (Table 1) Numbers of participants ranged from 113 to 45 852 and average follow-up from 15 days to 2.3 years. Trial cohorts mainly included patients with vascular diseases (acute coronary syndromes, coronary artery bypass grafting, peripheral vascular revascularization, atrial fibrillation, recent lacunar stroke), but 1 trial (CHARISMA) also included patients with vascular risk factors without clinically manifest vascular disease¹⁰ (Table 1). In the 8 trials in which follow-up averaged >3 months, clopidogrel versus placebo were administered double-blind.

Table 1.

Design Features and Baseline Characteristics Participants

	N	Mean Age, y	Men %	DM %	Previous Stroke/TIA %	Main Inclusion	Primary Outcome	ASA Dose, mg/d	CPD Dose, mg/d	Average Follow-Up	% Lost to Follow-Up
Short-Term Trials (14 d–3 mo)
CPD and ASA after surgery in CAD6 2007–2009	249	59	83	40	5	Elective CABG	Graft occlusion at 3 mo	100	75	3 mo	3.6
ASA vs ASA and CPD in lower limb angioplasty7 2002–2003	132	66	77	12	NR	Leg atherosclerosis undergoing revascularization	Platelet responsiveness to stimulation	75	300 ×1 then 75	30 d	none
PROCLAIM8 2005–2006	181	56	43	NR	NR	Metabolic syndrome	Inflammatory markers	81	75	6 wk	none
COMMIT9 1999–2005	45 852	61	72	NR	NR	Acute MI with ST changes	Death/reinfarction/stroke and death from any cause	162	75	15 d	<1
Long-Term Trials (>3 mo)
SPS31 2003–2012	3020	63	63	37	NR	Recent lacunar stroke	Recurrent stroke	325	75	3.5 y	NR
CHARISMA10 2002–2004	15 603	64	70	42	25	CV disease or multiple risk factors	Stroke, MI, and vascular death	75–162	75	2.3 y	<1
CURE11 1998–2000	12 562	64	62	23	4	Acute coronary syndrome	Stroke, MI, and vascular death	75–325	300 ×1 then 75	9 mo	<1
ACTIVE A12 2003–2008	7554	71	58	19	13	AF+1 risk factor	Stroke, MI, and vascular death	96%: 75–100 3.5 %>100	75	3.6 y	<1
CASCADE13 2006–2009	113	67	89	29	NR	CABG with saphenous vein	Graft hyperplasia at 1 y	162	75	1 y	none
CREDO14 1999–2001	2116	62	71	26	7	Elective PCI	All death, stroke, MI	325×28 d; then 81–325	300 ×1 then 75	1 y	4
REAL-LATE/ZEST-LATE15 2007–2010	2701	62	70	26	4	Drug-eluting stents for 12 mo	MI or death from cardiac causes	100–200	75	1.6 y	<1
CASPAR16 2004–2006	851	66	76	38	NR	Bypass for PVD	Graft occlusion or revascularization, amputation or death	75–100	75	1 y	2
All trials	90 934	63	70			⋯	⋯	⋯	75	⋯	⋯

DM indicates diabetes mellitus; TIA, transient ischemic attack; ASA, aspirin; CPD, clopidogrel; CAD, coronary artery disease; CABG, coronary artery bypass graft; NR, not reported; MI, myocardial infarction; CV, cardiovascular; AF, atrial fibrillation; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease.

Mortality

Four trials with short duration of follow-up (14 days–3 months) included 46 414 participants with 3572 deaths, and were dominated by the large COMMIT trial.⁹ (Table 2) Meta-analysis of these trials showed all-cause mortality was reduced by dual antiplatelet therapy versus aspirin alone (OR, 0.93; 95% CI, 0.87– 0.99; I² index, 0%; P=0.94 for heterogeneity).

Table 2.

All-Cause Mortality in Randomized Trials Testing Clopidogrel Added to Aspirin

		#Deaths/#Randomized
Short-Term Trials (14 d–3 mo)	Population	Combination	Aspirin Alone	OR (95% CI)
Clopidogrel and aspirin after surgery in CAD6	CABG surgery	0/124	1/125	0.33* (0.01–8.26)
Aspirin vs aspirin and clopidogrel in lower limb angioplasty7	Leg atherosclerosis undergoing revascularization	0/67	0/65	0.97* (0.02–50)
PROCLAIM8	Metabolic syndrome	0/89	0/92	1.03* (0.02–53)
COMMIT9	Acute MI with ST changes	1726/22 961	1845/22 891	0.93 (0.87–0.99)
All short-term trials		1726/23 241	1846/23 173	0.93 (0.87–0.99)†
		#Deaths/#Randomized (Annualized Mortality Rate)		Hazard Ratio (95% CI)
Long-Term Trials (> 3 mo)	Population	Combination	Aspirin Alone
SPS31	Recent lacunar stroke	113/1517 (2.1%/pt-yr)	77/1503 (1.4%/pt-yr)	1.49 (1.11–2.01)
CHARISMA10	Vascular disease or risk factors	371/7802 (2.0%/pt-yr)	374/7801 (2.1%/pt-yr)	0.99 (0.86–1.14)
CURE11	Acute coronary syndromes	359/6259 (7.6%/pt-yr)	390/6303 (8.3%/pt-yr)	0.92 (0.80–1.07)‡
ACTIVE A12	Atrial fibrillation unsuitable for warfarin	825/3772 (6.4%/pt-yr)	841/3782 (6.6%/pt-yr)	0.98 (0.89–1.08)
CASCADE13	Coronary artery bypass grafting	0/56 (0%/pt-yr)	1/57 (1.8%/pt-yr)	⋯
CREDO14	Percutaneous coronary intervention	18/1053 (≈1.7%/pt-yr)	24/1063 (≈2.3%/pt-yr)	0.75 (0.41–1.39)
REAL-LATE / ZEST-LATE15	Drug-eluting stents >12 mo	20/1357 (0.9%/pt-yr)	13/1344 (0.6%/pt-yr)	1.52 (0.75–3.50)
CASPAR16	Lower extremity bypass	24/425 (5.6%/pt-yr)	17/426 (4.0%/pt-yr)	1.44 (0.70–2.68)
All longer-term trials		1730/22 241	1737/22 279	1.03 (0.91–1.16)§
Longer-term trials except SPS3	⋯	1617/20 724	1660/20 776	0.97 (0.91–1.04)¶

CAD indicates coronary artery disease; CABG, coronary artery bypass graft; MI, myocardial infarction.

^*Estimated by adding 0.5 to each cell.

^†I² index, 0%; P=0.94 for heterogeneity.

^‡OR reported for mortality.

^§I² index, 48%; P=0.07 for heterogeneity.

^¶I² index, 0%; P=0.56 for heterogeneity.

Eight trials with longer duration of average follow-up (>3 months) included 44 520 participants with 3467 deaths (Table 2). Meta-analysis of these trials showed no effect on mortality of dual antiplatelet therapy versus aspirin alone (HR, 1.03; 95% CI, 0.91–1.16; Table 2); however, there was moderate heterogeneity among the results (I² index, 48%; P=0.07 for heterogeneity). After excluding the SPS3 trial, meta-analysis of the remaining 7 trials showed no effect of dual antiplatelet therapy versus aspirin alone on mortality (HR, 0.97; 95% CI, 0.91–1.04) with no indication of heterogeneity of results across trials (I² index, 0%; P=0.56 for heterogeneity; Figure 1).

Figure.

Meta-analysis of long-term (>3 months) trials.

Cause of death was reported as vascular versus nonvascular in 6 longer-term follow-up trials. (Table 3) The OR by meta-analysis for vascular death by dual antiplatelet therapy versus aspirin alone was 1.05 (95% CI 0.91–1.20); however, there was moderate heterogeneity among the trial results (I² index, 43%, P=0.12 for heterogeneity). Excluding the SPS3 trial (OR, 1.61, 95% CI, 1.11–2.36), the OR estimate was 0.99 (95% CI, 0.91–1.08; I² index, 0%; P=0.61 for heterogeneity). There was no evidence of heterogeneity across the trials for nonvascular death, and the OR estimate by meta-analysis was 0.95 (95% CI 0.83–1.09; I² index, 0%; P=0.83 for heterogeneity).

Table 3.

Etiologies of Death: Vascular Versus Nonvascular in Longer-Term Follow-Up Trials

Trial	Etiology	Combination # of Deaths	Aspirin Alone # of Deaths	OR (95% CI)
SPS31	Vascular	72*	45*	1.61 (1.11–2.36)
	Nonvascular	41	32	1.28 (0.80–2.04)
CHARISMA10	Vascular	238	229	1.04 (0.87–1.25)
	Nonvascular	133	145	0.92 (0.72–1.16)
CURE11	Vascular	318	345	0.92 (0.79–1.08)
	Nonvascular	41	45	0.92 (0.60–1.40)
ACTIVE A12	Vascular	600	599	1.01 (0.89–1.14)
	Nonvascular	225	242	0.93 (0.77–1.12)
CASCADE13	Vascular	0	1	0.33† (0.01–8.36)
	Nonvascular	0	0	1.02† (0.02–52)
CREDO14	Vascular	NR	NR
	Nonvascular	NR	NR
REAL-LATE/ZEST-LATE15	Vascular	13‡	8‡	1.62 (0.67–3.91)
	Nonvascular	7	5	1.39 (0.44–4.39)
CASPAR16	Vascular	NR	NR
	Nonvascular	NR	NR
All longer-term trials	Vascular	1241	1227	1.05 (0.91–1.20)
	Excluding SPS3	1169	1182	0.99 (0.91–1.08)
	Nonvascular	447	469	0.95 (0.83–1.09)

NR indicates not reported.

^*Vascular includes probable vascular and unknown causes.

^†Estimated by adding 0.5 to each cell.

^‡Cardiac causes assumed to be vascular.

Fatal Bleeding

Six longer-term follow-up trials reported the number of fatal hemorrhages (Table 4). Results for SPS3 were not available. The OR by meta-analysis for fatal hemorrhage among patients assigned to dual antiplatelet therapy was 1.35 (95% CI, 0.97–1.90; I² index, 0%; P=0.57 for heterogeneity).

Table 4.

Effect of Clopidogrel Added to Aspirin on Fatal Hemorrhage in Longer-Term Follow-Up Trials

Trial	Combination # of Events	Aspirin Alone # of Events	OR (95% CI)
SPS31	NR	NR	⋯
CHARISMA10	26	17	1.53 (0.83–2.82)
CURE11	11	15	0.74 (0.34–1.61)
ACTIVE A12	42	27	1.57 (0.96–2.55)
CASCADE13	0	0	1.02* (0.02–52)
CREDO14	NR	NR	⋯
REAL LATE-ZEST LATE15	NR	NR	⋯
CASPAR16	2	1	2.01 (0.18–22)
All longer-term trials	81	60	1.35 (0.97–1.90)

NR indicates not reported.

^*Estimated by adding 0.5 to each cell.

Myocardial Infarction

Myocardial infarctions were significantly reduced (OR, 0.82; 95% CI, 0.74–0.91; I² index, 2%; P=0.41 for heterogeneity) when clopidogrel was added to aspirin based on meta-analysis of 7 longer-term follow-up trials (Table 5). The effect was of similar magnitude, but no longer significant when 3 trials involving patients with acute coronary syndromes (CURE) or undergoing coronary stent placement (CREDO, REAL–LATE/ZEST-LATE) were excluded (OR, 0.87; 95% CI, 0.73–1.04; I² index, 9%; P=0.35 for heterogeneity). Fatal myocardial infarctions were not reported in any trial.

Table 5.

Effect of Clopidogrel Added to Aspirin on Myocardial Infarction in Longer-Term Follow-Up Trials

Trial	Combination # of MIs	Aspirin Alone # of MIs	OR (95% CI)
SPS31	30	38	0.78 (0.48 –1.26)
CHARISMA*10	185	197	0.94 (0.77–1.15)
CURE11	324	419	0.77 (0.66–0.89)
ACTIVE A12	90	115	0.78 (0.59–1.03)
CASCADE13	4	1	4.31 (0.47–40)
CREDO14	70	90	0.77 (0.56–1.07)
REAL LATE-ZEST LATE15	10	7	1.42 (0.54–3.74)
CASPAR†16	NR	NR
All longer-term Trials	713	867	0.82 (0.74–0.91)

MI indicates myocardial infarction; NR, not reported.

^*Only nonfatal MIs reported in the main results article; all MIs estimated from Table 3 in the Berger PB, et al. (6).

^†Hazard ratio reported: combination vs aspirin alone: HR, 0.81; 95% CI, 0.32–2.06; P=0.66.

Excluded Trials

Trials that were excluded from these analyses and the reasons for exclusion are given in Appendix I (online data). For example, in 1 trial involving participants with acute myocardial infarction, 30-day mortality data are available, but randomly assigned clopidogrel versus aspirin was given only for the initial 2 to 4 days before coronary intervention was undertaken.¹⁷ A small trial involving 392 patients with acute transient ischemic attack or minor ischemic stroke followed for 90 days did not report total mortality.¹⁸

Discussion

Based on analysis of all published randomized trials, addition of clopidogrel to aspirin does not affect overall mortality. In trials with long-term follow-up, a trend toward an increase in fatal hemorrhage with dual antiplatelet therapy (35%; 95% CI, −3% to 90%) was offset by a significant reduction in myocardial infarction (18%; 95% CI, 9%–26%). There was no impact on vascular death as reported in a subset of the trials. The 50% increase (P=0.005) in mortality associated with addition of clopidogrel to aspirin in the SPS3 trial involving patients with recent lacunar stroke was an outlier when considered in the context of the other randomized trials.

Several subgroup analyses dealing with mortality from the large CHARISMA (2002–2006) trial have been published and may shed light on the aberrant mortality results reported from the SPS3 trial. The CHARISMA trial included 15 603 patients with vascular disease or multiple vascular risk factors randomized to aspirin (dose range, 75–162 mg daily) alone versus combined with clopidogrel 75 mg daily, administered double-blind. There was no difference in all-cause mortality (371 deaths with dual antiplatelet therapy versus 374 deaths with aspirin alone, 2.0%/pt-yr versus 2.1%/pt-yr; HR, 0.99) during the mean follow-up of 2.3 years. The investigators published 3 subsequent secondary analyses addressing the issue of clopidogrel added to aspirin and mortality. Wang et al¹⁹ reported mortality rates according to whether participants enrolled with asymptomatic (n=3284) versus symptomatic vascular disease (n=12 153) and found an unanticipated interaction (P for interaction=0.02) between symptom status and effect of addition of clopidogrel on all-cause mortality: all-cause mortality was increased in asymptomatic patients by dual antiplatelet therapy (HR, 1.4; P=0.04) versus decreased in those with symptoms (HR, 0.91 P=0.27).¹⁹ Asymptomatic participants were much more often diabetic (83%) than were symptomatic patients (31%); fatal bleeding did not account for the excess in deaths among asymptomatic patients. A second post hoc analysis considered diabetes and diabetic nephropathy (microalbuminuria ≥30 µg/mL as reported by local investigators) and concluded that patients having diabetic nephropathy was related to increased mortality in patients assigned to clopidogrel.²⁰ A third analysis examined bleeding complications and found a strong independent relationship between moderate bleeding and all-cause mortality (HR, 2.9; P<0.0001).²¹

The aspirin dosage (325 mg daily, enteric-coated) used in SPS3 is higher than that used in most other randomized trials testing dual antiplatelet therapy. Higher aspirin doses have been associated with increased rates of life-threatening bleeding when combined with clopidogrel.^22,23 However, in a large trial involving 12 566 patients with acute coronary syndromes, participants randomly assigned to aspirin 300 to 325 mg daily versus 75 to 100 mg daily combined with clopidogrel 75 mg daily had no increase in mortality (143 deaths with high-dose aspirin, 156 deaths with low-dose aspirin; HR, 0.93; 95% CI, 0.74–1.16).²⁴

Limitations of this meta-analysis include that it is based on published data and not on pooling of individual patient data, and therefore it was not possible to perform subgroup analyses according to history of coronary heart disease or to explore consistency of the treatment effects on mortality in key subgroups.

We hypothesize that in cohorts with a sufficiently high frequency of coronary artery disease, addition of clopidogrel to aspirin results in a neutral effect on mortality, explained by a reduction in myocardial infarction being offset by increases in fatal hemorrhage and moderate hemorrhage that are associated with death. Cohorts with overall low mortality rates and low frequencies of coronary artery disease, such as the SPS3 cohort and asymptomatic subgroup of the CHARISMA trial, may have increased mortality with dual antiplatelet therapy because the absolute reduction in coronary events does not offset death related directly or indirectly to bleeding complications.

However, we cannot exclude that the results of SPS3 could be caused by extreme play of chance. Nevertheless, we hypothesize that the chronic use of dual antiplatelet therapy with clopidogrel and aspirin may adversely affect mortality compared with aspirin monotherapy in cohorts with low rates of coronary artery ischemia, such as those participating in the SPS3 trial.