Clopidogrel Plus Aspirin Versus Warfarin in Patients With Stroke and Aortic Arch Plaques
Abstract
Background and Purpose—
Severe atherosclerosis in the aortic arch is associated with a high risk of recurrent vascular events, but the optimal antithrombotic strategy is unclear.
Methods—
This prospective randomized controlled, open-labeled trial, with blinded end point evaluation (PROBE design) tested superiority of aspirin 75 to 150 mg/d plus clopidogrel 75 mg/d (A+C) over warfarin therapy (international normalized ratio 2–3) in patients with ischemic stroke, transient ischemic attack, or peripheral embolism with plaque in the thoracic aorta >4 mm and no other identified embolic source. The primary end point included cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage. Follow-up visits occurred at 1 month and then every 4 months post randomization.
Results—
The trial was stopped after 349 patients were randomized during a period of 8 years and 3 months. After a median follow-up of 3.4 years, the primary end point occurred in 7.6% (13/172) and 11.3% (20/177) of patients on A+C and on warfarin, respectively (log-rank, P=0.2). The adjusted hazard ratio was 0.76 (95% confidence interval, 0.36–1.61; P=0.5). Major hemorrhages including intracranial hemorrhages occurred in 4 and 6 patients in the A+C and warfarin groups, respectively. Vascular deaths occurred in 0 patients in A+C arm compared with 6 (3.4%) patients in the warfarin arm (log-rank, P=0.013). Time in therapeutic range (67% of the time for international normalized ratio 2–3) analysis by tertiles showed no significant differences across groups.
Conclusions—
Because of lack of power, this trial was inconclusive and results should be taken as hypothesis generating.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00235248.
See related article, p 1239.
Atherosclerosis in the aortic arch is an important source of cerebral embolism,1,2 particularly where atherosclerotic plaque is ≥4 mm in thickness.3–5 In patients with prior ischemic stroke, the risk of recurrent stroke or other vascular events has consistently been reported to be 3- to 4-fold higher than in those with plaques <4 mm or no plaque in the aortic arch.6–10 In 1996, it was reported to be as high as 26% per year, the highest rate of recurrence among ischemic stroke pathogenesis.11 Given this high risk observed in cohorts of patients who are generally treated with single antiplatelet therapy, together with the frequent finding of mobile thrombus superimposed on the aortic arch plaque, empirical use of either warfarin or dual antiplatelet therapy combining clopidogrel plus aspirin has been proposed.12 Retrospective, unblinded, nonrandomized comparisons between these 2 strategies have been inconclusive13 and no randomized evaluation of these strategies has been conducted.14 We hypothesized that the combination of aspirin plus clopidogrel was 25% superior to dose-adjusted warfarin on prevention of new vascular events. To test this hypothesis, we performed a multicenter prospective randomized, controlled trial, open-labeled with blinded end point evaluation of aspirin 75 mg/d plus clopidogrel 75 mg/d versus warfarin (international normalized ratio [INR] 2–3) in patients with ischemic stroke, transient ischemic attack (TIA), or peripheral embolism associated with thoracic aortic plaque ≥4 mm and no other identified embolic source while on best medical therapy. The study was an academic, investigator-driven trial, funded by the French government (PHRC AOM 97211/P991205) and the Australian National Health and Medical Research Council. The study drugs were supplied by Sanofi and Bristol-Myers Squibb. These companies were not involved in the design, conduct, analysis, or interpretation of the trial.
Methods
The Aortic Arch Related Cerebral Hazard (ARCH) trial was a prospective randomized, open-labeled, controlled, superiority trial with blinded end point evaluation (PROBE design).15
The research protocol was approved by the Ethics Committee in France and Human Ethics Committees at each Australian center. All subjects provided informed consent. The ARCH trial was registered on ClinicalTrials.gov (NCT00235248).
Study Population
Patients were aged >18 years and had a nondisabling (modified Rankin Scale <4) ischemic stroke, TIA or peripheral embolism, and an atherosclerotic plaque in the thoracic aorta, diagnosed by transesophageal echocardiography without any other recognized embolic source. We included patients with an embolic event downstream from the observed atherosclerotic plaque.10 Women with childbearing potential were excluded, as were patients considered unlikely to return for follow-up study visits for 3 years. Other exclusions involved patients with an overt cardiac source of embolism (eg, mitral stenosis, endocarditis, and atrial fibrillation), with extracranial or intracranial atherosclerotic stenosis ≥70%, those scheduled for carotid revascularization, with cerebral artery dissection or other uncommon cause of ischemic stroke. Patients with an absolute indication for oral anticoagulant (eg, atrial fibrillation, prosthetic heart valve), or with a contraindication to aspirin or to clopidogrel, or to investigation with transesophageal echocardiography, were excluded.
Randomization
Patients were randomized 1:1 to either aspirin 75 to 150 mg/d (according to local rules) plus clopidogrel 75 mg/d (A+C), or warfarin with a target INR 2.5 (2–3).
Collection of Data and Risk Factor Definition
Patient demographics, physical examination findings (weight, height, and current blood pressure reading), medical history (medical treatments, atherothrombotic and cardiac history), and laboratory measurements (fasting blood glucose, low-density lipoprotein-cholesterol [LDL-C]) were recorded at baseline.
Risk factors included hypertension, diabetes mellitus (type 1 or 2), dyslipidemia, and smoking habits (current smoking was defined as consuming ≥5 cigarettes/d on average in the 3 months before entering the study; former smoking was defined as >5 cigarettes/d on average ≥1 month before entering the study). Hypertension, diabetes mellitus, and dyslipidemia were defined as the use of medications for these conditions at hospital discharge or at the time of study enrollment based on elevated systolic blood pressure ≥140 mm Hg and diastolic blood pressure ≥90 mm Hg and fasting hyperglycemia ≥7 mmol/L (126 mg/dL) and LDL-C ≥160 mg/dL (4 mmol/L).
Follow-Up
Follow-up visits were conducted 1 month post randomization, and then every 4 months. Accrual was initially planned for a 2-year period, with total follow-up planned per patient of 3 years. Given the difficulties in recruitment, the Steering Committee decided to continue the follow-up every 4 months for all randomized patients until the end of the trial to maximize the number of outcome events recorded.
Outcome Measure
The primary end point was a composite of the first occurrence of ischemic stroke, myocardial infarction, peripheral embolism, vascular death, or hemorrhagic stroke. We used the tissue-based definition of TIA, meaning that any transient neurological deficit with positive diffusion-weighted imaging in the appropriate area corresponding to the symptoms was defined as cerebral infarction.16 Secondary end points included ischemic stroke or TIA; myocardial infarction; vascular death; total death; primary end point plus major hemorrhage (ie, net benefit); primary end point or revascularization procedures; primary end points, revascularization procedures or TIA; primary end point or total death. Vascular death included fatal stroke, fatal myocardial infarction, and other causes of cardiovascular death, including any unobserved and unexpected sudden death; death after vascular surgery, vascular procedure, or amputation (except for trauma or malignancy); and death attributed to heart failure, visceral or limb infarction. Any myocardial infarction or stroke followed within 28 days by death, of whatever cause, was considered to be a fatal myocardial infarction or fatal stroke. Cardiac events included myocardial infarction, resuscitation after cardiac arrest, and hospitalization for unstable angina or heart failure. Major peripheral events included all events related to noncoronary or cervicocephalic arterial disease leading to hospitalization or revascularization (eg, new or worsening claudication leading to revascularization, surgery for ruptured aneurysm, cholesterol emboli syndrome).
All end points were adjudicated by an independent clinical event committee. Safety end points were reviewed by a data safety monitoring committee.
Sample Size
We hypothesized that the combination of aspirin plus clopidogrel is 25% superior to dose-adjusted warfarin. Observational data have shown that the risk of stroke, myocardial infarction, and vascular death was as high as 26% per year. Given that event rates in clinical trials are typically much lower than expected, we predicted an event rate in the warfarin group of 12% per year. To test our hypothesis and assuming a type 1 error of 5%, a power of 90%, a drop out rate of 15%, a sequential triangular design,17 2-year accrual, and 3-year follow-up, we calculated that we required a mean of 372 patients per treatment arm, with a probability of 5.8% for a maximal inclusion of 744 patients per treatment arm.
Study Conduct
The first patient was enrolled on February 1, 2002, the last patient was randomized on May 6, 2010, and the last study visit was May 19, 2011. An electronic case report form was developed to collect baseline characteristics and follow-up data at every study visit, including blood pressure in a seating position, LDL-C, and INR.
Analyses
All analyses were performed using intention to treat. We compared the time to first vascular event of the primary and secondary end points using the Kaplan–Meier method and the log-rank test. Patients who died from nonvascular causes were censored at the time of death. Estimates of hazard ratio were calculated from a Cox proportional hazards model with a priori adjustment on age, sex, country (France or Australia), on-treatment systolic and diastolic blood pressure as time-dependent covariates (because of the important impact of on-treatment blood pressure control on stroke risk recurrence and that there were no interaction expected between blood pressure control and both treatment strategies), as well as on variables included in the baseline characteristics that would be significantly imbalanced between groups. Continuous variables were expressed as mean (SD) or median (interquartile range). Categorical variables were expressed as frequencies and percentages.
Further exploratory analyses were performed using the proportion of patients on warfarin who were in therapeutic range (INR 2–3, then INR 1.8–3.2), that is, time in therapeutic range (TTR).18 TTR was calculated for every patient on warfarin using all collected INR at every study visit (3 measures were collected within the preceding 4 months: highest INR, lowest INR, and last INR). In case of missing INR value, INR value at the next visit was considered. We then had a mean INR per patient per visit and a patient TTR. We then calculated a center TTR (cTTR), which gave us a distribution of centers classified by their TTR in increasing order. We then grouped the centers per tertiles of cTTR. For each tertiles, we attributed the corresponding patients on C+A randomized in the same centers. We then computed for the primary end point a hazard ratio for each tertile of cTTR.
Statistical testing was done at the 2-tailed type 1 error level of 0.05. Data were analyzed using the SAS software package, release 9.3 (SAS Institute, Cary, NC).
Results
Among 382 screened patients, 349 signed informed consent and were randomized (Figure 1) during a period of 8 years and 3 months. In May 2010, the steering committee decided to stop the trial because no more funding was available because of the much longer than expected accrual time. With 349 patients and 33 primary end points, we had not met the criteria for the first planned interim analysis in our sequential design (based on ≥70 primary outcome events) and were unable to perform a futility analysis. Mean follow-up was 3.4 years (range, 1–8 years). Permanent discontinuation of study drugs occurred in 15% of patients on combined aspirin+clopidogrel and 21% of patients on warfarin. The qualifying event was ischemic stroke in 67% of cases and TIA in 32% of cases. Only 1 patient was randomized with a peripheral embolism.
Baseline Characteristics
Table 1 shows a rate of male sex (72%), hypercholesterolemia (66%), and current smoking (66%) to be higher than usually observed in other location of cerebral atherosclerosis in a white population. The proportion of hypertension (73%) and diabetes mellitus (22%) was within the expected range. Baseline systolic and diastolic blood pressure were <140/90 mm Hg, that is, already controlled (Table 1). LDL-C, measured in a subset of 166 patients, was between 120 and 130 mg/dL, which is within the usual range for an ischemic stroke population. There was an imbalance in the proportion of patients with a history of myocardial infarction (8% in the aspirin+clopidogrel versus 17.3% in the warfarin arm).
| Aspirin+Clopidogrel (n=172) | Warfarin (n=177) | Total | |
|---|---|---|---|
| Sex: male, n (%) | 119 (69.2) | 131 (74.0) | 250 |
| Age,* y | 69.2±9.2 | 69.7±9.0 | 69.4±9.1 |
| Country, n (%) | |||
| France | 100 (58.1) | 111 (62.7) | 211 |
| Australia | 70 (40.7) | 66 (37.3) | 136 |
| Switzerland | 2 (1.2) | 0 (0.0) | 2 |
| Blood pressure,* mm Hg | |||
| Systolic | 135.5±15.9 | 135.2±18.9 | 135.3±17.5 |
| Diastolic | 76.0±10.4 | 76.3±11.1 | 76.1±10.7 |
| LDL cholesterol,* mg/dL | 122±40 | 125±50 | 123±50 |
| Ischemic stroke, n (%) | |||
| No | 125 (72.7) | 126 (71.2) | 251 |
| 1 | 40 (23.2) | 46 (26.0) | 86 |
| 2 | 7 (4.1) | 5 (2.8) | 12 |
| ≥3 | 0 | 0 | 0 |
| Hemorrhagic stroke, n (%) | |||
| No | 171 (100.0) | 171 (99.4) | 342 |
| 1 | 0 | 1 (0.6) | 1 |
| 2 | 0 | 0 | 0 |
| ≥3 | 0 | 0 | 0 |
| TIA, n (%) | |||
| No | 139 (81.3) | 143 (82.7) | 282 |
| 1 | 18 (10.5) | 20 (11.5) | 38 |
| 2 | 8 (4.7) | 5 (2.9) | 13 |
| ≥3 | 6 (3.5) | 5 (2.9) | 11 |
| Peripheral embolism, n (%) | |||
| No | 170 (99.4) | 169 (98.3) | 339 |
| 1 | 1 (0.6) | 1 (0.6) | 2 |
| 2 | 0 (0.0) | 2 (1.1) | 2 |
| ≥3 | 0 (0.0) | 0 | 0 |
| Hypertension, n (%) | |||
| Yes | 127 (74.3) | 129 (74.5) | 256 |
| Hypercholesterolemia, n (%) | |||
| Yes | 119 (69.6) | 113 (66.1) | 232 |
| Smoking habit, n (%) | |||
| Yes | 112 (65.5) | 118 (68.2) | 230 |
| Diabetes mellitus, n (%) | |||
| Type 1 | 7 (4.2) | 2 (1.2) | 9 |
| Type 2 | 35 (20.8) | 32 (18.9) | 67 |
| Angina, n (%) | |||
| Yes | 13 (7.6) | 15 (8.9) | 28 |
| Revascularization, n (%) | |||
| Yes | 11 (6.5) | 13 (7.7) | 24 |
| Myocardial infarction, n (%) | |||
| Yes | 13 (8.0) | 28 (17.3) | 41 |
| Qualifying event, n (%) | |||
| Ischemic stroke | 113 (65.7) | 122 (68.9) | 235 |
| Transient ischemic attack | 58 (33.7) | 55 (31.1) | 113 |
| Peripheral embolism | 1 (0.6) | 0 (0.0) | 1 |
| Time between qualifying event and inclusion, mo | 2.16±2.16 | 2.16±1.92 | 2.16±2.04 |
LDL indicates low-density lipoprotein; and TIA, transient ischemic attack.
*
Values represent mean±SD.
On-Treatment Characteristics
Figure 2 shows the evolution of key drivers of the risk of recurrent stroke. During the follow-up period, systolic blood pressure fell by 2 and 5 mm Hg in the aspirin+clopidogrel (from 135.5 to 133.4 mm Hg) and warfarin arms (from 135.2 to 130.7 mm Hg), respectively, and diastolic blood pressure fell by 2.2 and 3.5 mm Hg in the aspirin+clopidogrel (from 76.0 to 73.8 mm Hg) and warfarin arms (from 73.3 to 72.8 mm Hg), respectively. LDL-C was reduced by 39 mg/dL (ie, 1 mmol/L) from 122 to 83 mg/dL in the aspirin+clopidogrel arm and by 41 mg/dL, from 125 to 84 mg/dL in the warfarin arm.
Efficacy Outcome
A primary outcome event occurred in 7.6% (13/172) of patients in the aspirin+clopidogrel arm and in 11.3% (20/174) of patients in the warfarin arm (unadjusted hazard ratio, 0.65 [95% confidence interval, 0.32–1.30]; P=0.2), a nonsignificant 24% relative risk reduction after prespecified adjustment for age, sex, country, on-treatment systolic and diastolic blood pressure as time-dependent covariates, and history of myocardial infarction (hazard ratio, 0.76 [95% confidence interval, 0.36–1.61]; P=0.5; Figure 3; Table 2). Among secondary end points (Table 2), only vascular death was significantly different between groups with 0 (0%) in the aspirin+clopidogrel arm and 6 (3.4%) in the warfarin arm (log-rank, P=0.013). Vascular deaths included 1 myocardial infarction, 1 intracranial hemorrhage, 1 major (nonintracranial) hemorrhage, 1 fatal coronary heart failure, 1 aortic aneurysm rupture, and 1 sudden death.
| Treatment | Aspirin+Clopidogrel (n=172) | Warfarin (n=177) | Adjusted HR (95% CI) | P Value | ||
|---|---|---|---|---|---|---|
| Events | Rates* | Events | Rates* | |||
| Primary end point, n (%) | 13 (7.6%) | 2.17 | 20 (11.3%) | 3.49 | 0.76 (0.36–1.61) | 0.5 |
| Ischemic stroke | 11 (6.4%) | … | 9 (5.1%) | … | … | … |
| Myocardial infarction | 0 | … | 3 (1.7%) | … | … | … |
| Peripheral embolism | 0 | … | 1 (0.6%) | … | … | … |
| Vascular death | 0 | … | 6 (3.4%) | … | … | … |
| Intracranial hemorrhage | 2 (1.2%) | … | 1 (0.6%) | … | … | … |
| Total death, n (%) | 8 (4.7%) | … | 15 (8.4%) | … | 0.58 (0.22–1.50) | 0.3 |
| Ischemic stroke, n (%) | 11 (6.4%) | … | 9 (5.1%) | … | 1.82 (0.66–5.00) | 0.2 |
| Myocardial infarction, n (%) | 0 | … | 3 (1.7%) | … | … | … |
| Vascular death, n (%) | 0 | … | 6 (3.4%) | … | … | … |
| Primary end point or major hemorrhage (net benefit), n (%) | 17 (9.9%) | … | 24 (13.6%) | … | 0.79 (0.41–1.54) | 0.5 |
| Primary end point | 13 (7.6%) | … | 18 (10.2%) | … | … | … |
| Major hemorrhage | 4 (2.3%) | … | 6 (3.4%) | … | … | … |
| Transient ischemic attack or cerebral infarction, n (%) | 21 (12.2%) | … | 19 (10.7%) | … | 1.27 (0.65–2.48) | 0.5 |
| Transient ischemic attack | 11 (6.3%) | … | 10 (5.6%) | … | … | … |
| Cerebral infarction | 8 (4.7%) | … | 11 (6.2%) | … | … | … |
| Primary end point or revascularization procedures, n (%) | 14 (8.1%) | … | 22 (12.4%) | … | 0.8 (0.39–1.65) | 0.5 |
| Primary end point | 13 (7.6%) | … | 20 (11.3%) | … | … | … |
| Revascularization procedures | 1 (0.6%) | … | 2 (1.1%) | … | … | … |
| Primary end point or death from all causes, n (%) | 20 (11.6%) | … | 27 (15.3%) | … | 0.91 (0.48–1.73) | 0.8 |
| Primary end point | 13 (7.5%) | … | 20 (11.3%) | … | … | … |
| Death from all causes | 7 (4.1%) | … | 7 (4.0%) | … | … | … |
| Primary end point or TIA or revascularization procedure, n (%) | 23 (13.4%) | … | 32 (18.1%) | … | 0.8 (0.45–1.40) | 0.4 |
| Primary end point | 12 (7.0%) | … | 20 (11.3%) | … | … | … |
| Transient ischemic attack | 11 (6.4%) | … | 10 (5.6%) | … | … | … |
| Revascularization procedure | 0 | … | 2 (1.1%) | … | … | … |
HR was adjusted by age, sex, country, history of myocardial infarction, and systolic and diastolic blood pressure as time-dependent covariates. CI indicates confidence interval; and HR, hazard ratio.
*
Rate per 100 person-years.
Safety Outcomes
Total death occurred in 4.7% and 8.4% in the aspirin+ clopidogrel and warfarin arms, respectively (log-rank P=0.1; adjusted P=0.3). Major hemorrhages occurred in 2.3% (4/172) and 3.4% (6/177), respectively (log-rank P=0.17; adjusted P=0.2). An intracranial hemorrhage was observed in 2 patients on aspirin+clopidogrel (which were nonfatal) and in 1 patient on warfarin (which was fatal).
Net benefit combining primary end point events and major hemorrhages was not significant between both groups (9.9% versus 13.6% in the aspirin+clopidogrel and warfarin arms, respectively, log-rank P=0.3; adjusted P=0.5; Table 2).
TTR Analysis
Patients on warfarin spent 67% of their time in therapeutic range (INR 2–3). TTR (Figure I in the online-only Data Supplement) was 76% for INR 1.8 to 3.2. When the primary end point was analyzed by tertiles of cTTR, there was a tendency for a better efficacy of aspirin+clopidogrel strategy for low cTTR, and a better efficacy for warfarin therapy at high or super high cTTR (Figure 4). None of these differences were significant and tests for heterogeneity for treatment by cTTR group interaction were not significant.
Discussion
We found that patients with an ischemic stroke and aortic arch plaques ≥4 mm treated with aspirin plus clopidogrel had a nonsignificant 24% reduction in the rate of recurrent stroke (including intracerebral hemorrhage), myocardial infarction, peripheral embolism, and vascular death (adjusted P=0.5) but had a significant reduction in vascular death compared with patients on warfarin (log-rank, P=0.013). These results, however, may have been obtained by a play of chance as the number of patients recruited and the number of primary outcomes did not meet the numbers required to perform the first interim futility analysis. The long duration of the trial is also a limitation. Therefore, the results should be treated with caution, including the imbalance of fatal vascular events that could have merely been obtained by chance. Failure to recruit the expected number of patients in the trial had mixed causes including lack of motivation (none of the centers in France received honorarium fee or any financial support except for drug supply, centers in Australia received only $500 per patient and no other honoraria), limited number of centers (we failed to open centers in other European of North American countries, because of the limited budget).
The baseline characteristics confirmed that patients with stroke with aortic arch plaques ≥4 mm have a particularly severe risk factor profile with 66% being current smokers, 73% with hypercholesterolemia, 73% with hypertension, and 22% with diabetes mellitus. There was a previous history of cerebral infarction or TIA in >40% and of coronary artery disease in >20% of cases, which is approximately double the rates usually observed in recent noncardioembolic ischemic stroke populations.19,20 Plaques ≥4 mm in thickness are important markers for a high vascular risk.11,21
Despite, the observed event rate in the control (warfarin) group was 3.5% per year (Table 2) as opposed to 12% per year expected from observational data. This was despite a conservative hypothesis, because the observed rate in 1996 was 26% per year for the primary end point.11 The observed event rate was similar to the 3.6% per year observed in the Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial and likely reflects the much improved background treatment in modern secondary prevention trials.22 Indeed, with an on-treatment blood pressure as low as 130.7/72.8 mm Hg and an on-treatment LDL-C 41 mg/dL (>1 mmol/L) lower than baseline value, the ARCH trial population was generally treated in accord with the 2008 European Stroke Organization guidelines and 2011 recommendations of the American Heart Association/American Stroke Association and even preceded them, implementing the results of the PROGRESS and SPARCL trials.22,23 Furthermore, TTR was 67% for an INR 2 to 3 and 76% for an INR 1.8 to 3.2, which indicated a similar standard of warfarin treatment to the recent atrial fibrillation mega-trials in which the best mean TTRs were between 55% and 68%.24–26
The choice of warfarin as the comparator was based on empirical practice in 1996. Because transesophageal echocardiography can demonstrate complex aortic plaques with superimposed, often mobile, thrombus, warfarin therapy has become a standard for most cardiologists and vascular neurologists. In the Stroke Prevention in Atrial Fibrillation (SPAF) trial, in patients with atrial fibrillation, the mere presence of aortic arch plaques ≥4 mm in thickness tripled the risk compared with atrial fibrillation patients without aortic plaques or with plaques <4 mm.27 However, even with long-term warfarin, mobile thrombi in the aortic arch usually persist.28 Within the neurological community, considerable caution with warfarin therapy in atherothombotic strokes has emerged because of the results of the SPIRIT trial.29 This showed a doubling in the risk of bleeding complications on warfarin (INR 3.5) compared with aspirin 30 mg/d in patients with atherothrombotic strokes and similar efficacy for recurrent ischemic events. These concerns were further intensified by the Warfarin-Aspirin in Recurrent Stroke Study (WARSS) and the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trials.30,31 However, clopidogrel monotherapy was shown to be superior to aspirin in a previously symptomatic atherothrombotic population (although 55% of patients with stroke had small vessel disease).32 Aspirin+clopidogrel combination therapy has been shown to be superior to aspirin monotherapy in patients with acute coronary syndromes33,34 and to some extent in patients with stable, previously symptomatic, atherosclerotic disease in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial.35 Therefore, in the late 1990s when the ARCH trial was designed, we considered that the combination of aspirin+clopidogrel could be 25% superior to warfarin, provided intracranial hemorrhage was included as a component of the primary end point.
This choice of aspirin+clopidogrel can be discussed in retrospect. One could argue that a third arm with aspirin 75 mg/d was missing. However, the cost of a third arm was not feasible. Given the expected high 26% risk that we had reported on antithrombotic monotherapy,11 we preferred to use dual antiplatelet therapy with aspirin+clopidogrel. For these reasons, it was argued at the time that an aspirin monotherapy arm may have been unethical. During the conduct of the ARCH trial, results of studies such as the Management of Atherothrombosis With Clopidogrel in High Risk Patients With Recurrent Transient Ischemic Attack or Ischemic Stroke (MATCH) provided evidence that the combination of aspirin+clopidogrel was no better than clopidogrel alone while having a significant increase in the risk of intracranial hemorrhage.36 However, as in the CAPRIE trial,32 the MATCH trial included >55% of the patients with a lacunar (small vessel disease) stroke,36 which are more likely to develop an intracranial bleeding.37,38 We speculated that the results of the MATCH trial were driven by this skewed recruitment toward more small vessel disease, which is a population different from the patients with aortic arch plaques ≥4 mm.39 The later SPS-3 results seemed to confirm that long-term aspirin+clopidogrel in small vessel disease patients is no better and less well tolerated than aspirin alone.38 Conversely, the CHANCE trial showed that short-term (21 days) aspirin+clopidogrel followed by clopidogrel alone was more effective and as well tolerated as aspirin alone at 90 days, regardless of the ischemic stroke subtype.40 In the ARCH trial, there were no apparent safety issues with the combination of aspirin+clopidogrel compared with warfarin, without any increase in major hemorrhages, intracranial hemorrhages, vascular deaths, and total deaths. But again, we should take this safety result with caution given that the statistical power of this trial cannot exclude a true difference between arms.
We acknowledge that the lack of statistical power makes the ARCH trial inconclusive, and that any interpretation is hypothesis generating. We then cautiously suggest that, given the significant increase in vascular death observed on well-conducted warfarin therapy and the complexity involved in INR-adjusted dosing, the antiplatelet strategy should be preferred in practice. Because in our trial we also observed the well-known signal of more intracranial hemorrhages with long-term aspirin+clopidogrel, we suggest a short-term use (such as 3 months) of aspirin+clopidogrel, followed by long-term clopidogrel monotherapy.
However, the TTR analysis (which is a surrogate for quality of medical care) seemed to indicate that groups with the highest TTR in the warfarin arm did much better than aspirin+clopidogrel, although tests for interaction were not significant and power was again lacking for this analysis. Future trials are needed to clarify optimal therapy for ischemic stroke attributed to aortic arch atheroma. An optimized antiplatelet strategy should be compared with one of the novel anticoagulants, shown to be much safer than warfarin in stroke prevention in atrial fibrillation, with substantially lower risk of intracranial hemorrhage.24–26 A suggested design would be to compare an antiplatelet strategy with one of the new anticoagulants.
Acknowledgments
We are indebted to all patients included in the Aortic Arch Related Cerebral Hazard trial. Staff trial coordinators at Bichat hospital: Genevieve Pétré, and research Nurses, as well as research assistant Agnes Kemmel and Anu Eräkanto were deeply involved. We thank Unité de Recherche Clinique Paris Nord, Hôpital Bichat–Claude-Bernard. The trial coordinator at the Florey Institute in Melbourne, Australia, was Dennis Young and assisted by Sandra Petrolo.
Appendix
Writing Committee
Pierre Amarenco (Principal Investigator), Stephen Davis (Principal Investigator), Elizabeth F. Jones, Ariel A. Cohen, Wolf Dieter Heiss (Chair Safety Committee), Markku Kaste (Chair End point Committee), Cédric Laouénan, Dennis Young, Malcolm Macleod, Geoffrey A. Donnan (Principal Investigator).
Steering Committee
Australia: Geoffrey A. Donnan (Chair), Stephen Davis (Co-Chair), Elizabeth F. Jones, Christopher F. Bladin, Brian R. Chambers, Judith Frayne, Graeme J. Hankey, Christopher R. Levi, Stephen J. Read. France: Pierre Amarenco (Chair), Ariel A. Cohen, Philippe Ravaud (methodologist).
End Point Committee
Markku Kaste (Chair), Turgut Tatlisumak, Lauri Soinne (neurologists), Mika Laine, Mikko Syvänne (cardiologists), Pirkka Vikatmaa, Mauri Lepäntalo (vascular surgeons).
Safety review: Wolf-Dieter Heiss.
Biostatistics: France Mentré, Cédric Laouénan, Simon Gosset (France), Leonid Churilov (Australia).
Centers (Number of Inclusion) and Investigators
France (211): Pierre Amarenco, Paris, Hospital Bichat (86); Thomas De Broucker, Saint-Denis (16); Pascal Favrole, Jérôme Mawet, Paris, Hôpital Lariboisière (15); Yves Mocquard, Brest (14); Pascal Favrole, Paris, Hôpital Tenon (11); Michael Obadia, Paris, Fondation Rothschild (9); Olivier Godefroy, Amiens (7); Hassan Hosseini, Créteil (7); Fernando Pico, Versailles (6); Pierre Garnier, Saint- Etienne (6); Marcel Malbec (5); Jean-François Pinel, Rennes (5); Olivier Ille, Mantes la Jolie (4); Xavier Vadamme, La Rochelle (4); Francisco Macian-Montoro, Limoges (3); Jérôme Servan, Pontoise (3); François Viallet, Aix-en- Provence (3); Thierry Rosolacci, Maubeuge (2); Patrick Lecoz, Arras (1); Pierre Clavelou, Clermont Ferrand (1); Olivier Detante, Grenoble (1); Tae-Hee Cho, Lyon (1); Denis Saudeau, Tours (1).
Switzerland (2): Patrik Michel, Suzette D’Ombrogio, Lausane, CHUV (2).
Australia (136): Geoffrey Donnan, Austin Health Melbourne (74); Stephen Davis, Royal Melbourne Hospital (20); David Serisier, Wollongong Hospital (12); Graeme Hankey, Royal Perth Hospital (6); Christopher Levi, John Hunter Hospital Newcastle (4); Jonathon Sturm, Central Coast Hospital Gosford (4); Thomas Kimber, Royal Adelaide Hospital (3); Romesh Marcus, St Vincents Hospital, Sydney (3); Stephen Read, Royal Brisbane Hospital (3); Christopher Bladin, Box Hill Hospital (2); Ray Schwartz, Southern Neurology Sydney (2), Rob Helme, Western Hospital Melbourne (2); Judith Frayne, Alfred Hospital Melbourne (1); David Blacker, Sir Charles Gairdner Hospital, Perth (1); Jonathan Wood, Nepean Hospital Penrith (1).
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© 2014 American Heart Association, Inc.
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History
Received: 26 November 2013
Revision received: 13 January 2014
Accepted: 14 January 2014
Published online: 3 April 2014
Published in print: May 2014
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Disclosures
Dr Amarenco reports receipt of research grant support and lecture fees from Pfizer, Sanofi, Bristol-Myers-Squibb, Merck, AstraZeneca, Boehringer-Ingelheim, and consultancy fees from Pfizer, BMS, Merck, Boehringer-Ingelheim, AstraZeneca, Bayer, Daiichi-Sankyo, Lundbeck, Edwards, Boston Scientific, Kowa, lecture fees from Bayer, Boston Scientific, St. Jude Medical, and research grants from the French government. Dr Davis reports modest consultancy fees and lecture fees for Boehringer Ingelheim, Ever NeuroPharma, Sanofi Aventis, and Pfizer. Dr Cohen reports research grant support Réseau Insuffisance Cardiaque (RESICARD), consultant, and lecture fees from AstraZeneca, Bayer Pharma, Boehringer-Ingelheim, Daiichi Sankyo, Glaxo-Smith-Kline, Sanofi. Dr Kaste reports having received honoraria, travel expenses, and consultation fees from Boehringer Ingelheim for attending the Steering Committee meetings of the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial and from Sanofi-Aventis for attending the Steering Committee meetings of the MATCH trial. Dr Donnan reports receipt of a research grant from Sanofi and consultancy fees from Sanofi, Bristol Myers-Squibb, Merck, AstraZeneca, Boehringer-Ingelheim, Bayer, Pfizer, and Lundbeck. He has received research grants from the Australian Government. The other authors report no conflicts.
Sources of Funding
This trial was supported by a research grant from the French government (Programme Hospitalier de Recherche Clinique: AOM-97211/P991205; Eudract: 2007-003644-30) and the Département à la Recherche Clinique et au Développement, Assistance Publique–Hôpitaux de Paris, the Australian National Health and Medical Research Council, and supported by SOS-Attaque Cerebrale association. Sanofi and Bristol-Myers Squibb provided study drugs free of charge. Sanofi Australia provided a small, unrestricted arms-length grant to Aortic Arch Related Cerebral Hazard-Australia team. The investigators were fully responsible for the protocol design, conduct of the study, data collection, monitoring, data management, analysis and interpretation of the data, and writing of the article, without any pharmaceutical company involvement.
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