Major Clinical Trial Clopidogrel Plus Aspirin Versus Warfarin in Patients With Stroke and Aortic Arch Plaques Pierre Amarenco, MD; Stephen Davis, MD; Elizabeth F. Jones, MD, PhD; Ariel A. Cohen, MD, PhD; Wolf-Dieter Heiss, MD; Markku Kaste, MD; Cédric Laouénan, MD; Dennis Young; Malcolm Macleod, MD, PhD, FRCP; Geoffrey A. Donnan, MD; The Aortic Arch Related Cerebral Hazard Trial Investigators*
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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. (Stroke. 2014;45:1248-1257.) Key Words: aorta ◼ atherosclerosis ◼ cerebral infarction
See related article, p 1239.
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
A
therosclerosis 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 18 years and had a nondisabling (modified Rankin Scale 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).
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.
Randomization
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
1250 Stroke May 2014
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of o n-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 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
1254 Stroke May 2014 Table 2. Efficacy and Safety Outcome Aspirin+Clopidogrel (n=172)
Warfarin (n=177)
Events
Rates*
Events
Rates*
Adjusted HR (95% CI)
P Value
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%)
…
…
… …
Treatment
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
11 (6.4%)
…
9 (5.1%)
…
1.82 (0.66–5.00)
0.2 …
Ischemic stroke, n (%)
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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%)
…
…
…
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%)
…
…
…
Cerebral infarction
1 (0.6%)
…
2 (1.1%)
…
…
…
Primary end point or death from all causes, n (%)
Revascularization procedures
20 (11.6%)
…
27 (15.3%)
…
0.91 (0.48–1.73)
0.8
Primary end point
13 (7.5%)
…
20 (11.3%)
…
…
…
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%)
…
…
…
0
…
2 (1.1%)
…
…
…
Death from all causes
Revascularization procedure
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.
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 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.
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.
1256 Stroke May 2014 Biostatistics: France Mentré, Cédric Laouénan, Simon Gosset (France), Leonid Churilov (Australia).
Centers (Number of Inclusion) and Investigators
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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, SaintEtienne (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-enProvence (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).
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–ClaudeBernard. The trial coordinator at the Florey Institute in Melbourne, Australia, was Dennis Young and assisted by Sandra Petrolo.
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 a rms-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.
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.
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Clopidogrel Plus Aspirin Versus Warfarin in Patients With Stroke and Aortic Arch Plaques Pierre Amarenco, Stephen Davis, Elizabeth F. Jones, Ariel A. Cohen, Wolf-Dieter Heiss, Markku Kaste, Cédric Laouénan, Dennis Young, Malcolm Macleod and Geoffrey A. Donnan The Aortic Arch Related Cerebral Hazard Trial Investigators Downloaded from http://stroke.ahajournals.org/ by guest on July 13, 2017
Stroke. 2014;45:1248-1257; originally published online April 3, 2014; doi: 10.1161/STROKEAHA.113.004251 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
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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. (Stroke. 2014;45:1248-1257.) Key Words: aorta ◼ atherosclerosis ◼ cerebral infarction
See related article, p 1239.
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
A
therosclerosis 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 18 years and had a nondisabling (modified Rankin Scale 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).
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.
Randomization
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
1250 Stroke May 2014
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of o n-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 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
1254 Stroke May 2014 Table 2. Efficacy and Safety Outcome Aspirin+Clopidogrel (n=172)
Warfarin (n=177)
Events
Rates*
Events
Rates*
Adjusted HR (95% CI)
P Value
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%)
…
…
… …
Treatment
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
11 (6.4%)
…
9 (5.1%)
…
1.82 (0.66–5.00)
0.2 …
Ischemic stroke, n (%)
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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%)
…
…
…
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%)
…
…
…
Cerebral infarction
1 (0.6%)
…
2 (1.1%)
…
…
…
Primary end point or death from all causes, n (%)
Revascularization procedures
20 (11.6%)
…
27 (15.3%)
…
0.91 (0.48–1.73)
0.8
Primary end point
13 (7.5%)
…
20 (11.3%)
…
…
…
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%)
…
…
…
0
…
2 (1.1%)
…
…
…
Death from all causes
Revascularization procedure
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.
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 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.
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.
1256 Stroke May 2014 Biostatistics: France Mentré, Cédric Laouénan, Simon Gosset (France), Leonid Churilov (Australia).
Centers (Number of Inclusion) and Investigators
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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, SaintEtienne (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-enProvence (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).
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–ClaudeBernard. The trial coordinator at the Florey Institute in Melbourne, Australia, was Dennis Young and assisted by Sandra Petrolo.
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 a rms-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.
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.
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Clopidogrel Plus Aspirin Versus Warfarin in Patients With Stroke and Aortic Arch Plaques Pierre Amarenco, Stephen Davis, Elizabeth F. Jones, Ariel A. Cohen, Wolf-Dieter Heiss, Markku Kaste, Cédric Laouénan, Dennis Young, Malcolm Macleod and Geoffrey A. Donnan The Aortic Arch Related Cerebral Hazard Trial Investigators Downloaded from http://stroke.ahajournals.org/ by guest on July 13, 2017
Stroke. 2014;45:1248-1257; originally published online April 3, 2014; doi: 10.1161/STROKEAHA.113.004251 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
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