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Apixaban following acute coronary syndromes in patients with prior stroke: Insights from the APPRAISE-2 trial
Apixaban following acute coronary syndromes in patients with prior stroke: Insights from the APPRAISE-2 trial Matthew W. Sherwood MD, MHS, Renato D. Lopes MD, PhD, MHS, Jie Lena Sun MS, Danny Liaw MD, PhD, Robert A. Harrington MD, Lars Wallentin MD, PhD, Daniel T. Laskowitz MD, MHS, Stefan K. James MD, PhD, Shaun G. Goodman MD, MSc, Harald Darius MD, Basil S. Lewis MD, C. Michael Gibson MS, MD, Karen S. Pieper MS, John H. Alexander MD, MHS PII: DOI: Reference:
S0002-8703(17)30342-3 doi: 10.1016/j.ahj.2017.09.020 YMHJ 5556
To appear in:
American Heart Journal
Received date: Accepted date:
19 September 2017 19 September 2017
Please cite this article as: Sherwood Matthew W., Lopes Renato D., Sun Jie Lena, Liaw Danny, Harrington Robert A., Wallentin Lars, Laskowitz Daniel T., James Stefan K., Goodman Shaun G., Darius Harald, Lewis Basil S., Gibson C. Michael, Pieper Karen S., Alexander John H., Apixaban following acute coronary syndromes in patients with prior stroke: Insights from the APPRAISE-2 trial, American Heart Journal (2017), doi: 10.1016/j.ahj.2017.09.020
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ACCEPTED MANUSCRIPT Apixaban Following Acute Coronary Syndromes in Patients with Prior Stroke: Insights from
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the APPRAISE-2 Trial
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Matthew W. Sherwood, MD, MHS,1,2 Renato D. Lopes, MD, PhD, MHS,2 Jie Lena Sun, MS,2 Danny Liaw, MD, PhD,3 Robert A. Harrington, MD,4 Lars Wallentin, MD, PhD,5
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Daniel T. Laskowitz, MD, MHS,2 Stefan K. James, MD, PhD,5 Shaun G. Goodman, MD, MSc,6 Harald Darius, MD,7 Basil S. Lewis, MD,8 C. Michael Gibson, MS, MD,9 Karen S. Pieper, MS,2
Inova Heart and Vascular Institute, Falls Church, VA; 2Duke Clinical Research Institute, Duke University
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John H. Alexander, MD, MHS2
School of Medicine, Durham, NC; 3Bristol-Myers Squibb, Princeton, NJ; 4Stanford University School of
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Medicine, Stanford, CA; 5Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; Canadian Heart Research Center and University of Toronto, Toronto, Ontario, Canada; 7Vivantes
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Neukoelln Medical Center, Berlin, Germany; 8Lady Davis Carmel Medical Center, The Ruth and Bruce
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Rappaport School of Medicine of the Technion, Haifa, Israel; 9Harvard Medical School, Boston, MA.
Cover title: Apixaban Post-ACS in Patients with Prior Stroke Key words: stroke, non-VKA oral anticoagulant, acute coronary syndromes Subject codes: ischemic stroke; anticoagulants; acute coronary syndromes Word count: 4197
Address for correspondence: Matthew W. Sherwood, MD, MHS, Duke Clinical Research Institute, 2400 Pratt Street, P.O. Box 17969, Durham, NC 27715. Phone: 919-668-8033; Fax: 919-668-7057. Email: [email protected].
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ACCEPTED MANUSCRIPT Background and Purpose: Patients with prior stroke are at greater risk for recurrent cardiovascular events post-acute coronary syndromes (ACS) and may have a different risk/benefit profile with
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antithrombotic therapy than patients without prior stroke.
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Methods: We studied 7391 patients with ACS from APPRAISE-2, stratified by the presence or absence of prior stroke. Baseline characteristics and outcomes of cardiovascular death, myocardial infarction (MI),
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or stroke were compared between groups. Interactions between prior stroke, treatment assignment (apixaban vs. placebo), and outcomes were tested before and after multivariable adjustment with Cox
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proportional hazards models.
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Results: A total of 902 patients (12%) had prior stroke. Those with prior stroke were older (69 vs. 67 years), had more hypertension (91% vs. 77%), peripheral vascular disease (22% vs.18%), and impaired renal function (38% vs. 30%) but less diabetes (44% vs. 48%) than those without prior stroke. Patients
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with prior stroke vs. no prior stroke had higher unadjusted rates of cardiovascular death (4.8% vs. 4.0%),
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MI (11.2% vs. 7.1%), and ischemic stroke (3.2% vs. 0.9%). Patients with prior stroke assigned to apixaban had similar rates of the composite of cardiovascular death, MI, or stroke compared with those
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assigned to placebo (HR 1.39; 95% CI 0.92-2.08). Patients without prior stroke assigned to apixaban had similar rates of cardiovascular death, MI, or ischemic stroke compared with those assigned to placebo (HR
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0.87; 95% CI 0.73-1.04; p-interaction=0.041). Median follow-up was 240 days. Conclusions: Patients with prior stroke are at higher risk for recurrent cardiovascular events post-ACS and had a differential risk/benefit profile with oral anticoagulation. Clinical Trial Registration: ClinicalTrials.gov NCT00831441
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ACCEPTED MANUSCRIPT Patients with an acute coronary syndrome (ACS) are at increased risk for further vascular events, such as stroke, myocardial infarction (MI), and death during medical follow-up.1 Antithrombotic therapies are
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essential in the treatment of patients with ACS.2, 3 Previous investigations suggest that anticoagulant
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medications added to antiplatelet therapy may be effective in reducing further vascular events, but also increase the risk of bleeding.4-6 Healthcare providers are challenged to optimize antithrombotic treatment
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regimens to reduce the risk of further ischemic events without prohibitive increases in bleeding. Thus only a select population of patients may have a favorable risk benefit ratio for combination antithrombotic
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therapy.
A history of stroke is also a major risk factor for future vascular events.7-9 Patients with prior
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stroke often have other medical comorbidities that increase risk for subsequent cardiovascular events.8 Patients with prior stroke who experience an ACS event may benefit from further antithrombotic therapy
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despite bleeding risk; these patients have been included in recent trials evaluating direct oral
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anticoagulants in the setting of ACS.
The APPRAISE-2 trial evaluated the use of the direct, selective factor Xa inhibitor, apixaban, in
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addition to standard antiplatelet and other medical therapy, for secondary prevention of cardiovascular events in patients with an ACS,10 but without a specific indication (e.g., atrial fibrillation) for oral
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anticoagulation. The trial was terminated early due to an increase in major bleeding without a counterbalancing reduction in ischemic events in patients assigned to apixaban compared with those assigned placebo. These results ran counter to those seen in the ATLAS-2 trial of a post-ACS population that excluded patients with prior stroke in which patients treated with rivaroxaban had a reduction in cardiovascular death, MI, or stroke compared with those assigned placebo. In ATLAS-2, despite the use of lower dosing of rivaroxaban (than studied for stroke prevention in an atrial fibrillation population), there was also an increase in major and intracranial bleeding compared with placebo. Given these disparate results we aimed to study patients with and without prior stroke in the APPRAISE-2 trial to determine if there was a differential effect of apixaban in patients with and without prior stroke.
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ACCEPTED MANUSCRIPT METHODS The study design and primary results of the APPRAISE-2 trial have been published.10 In brief, the
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APPRAISE-2 trial was an international, multicenter, double-blind, randomized, controlled, trial
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comparing apixaban with placebo, in addition to standard antiplatelet therapy, for the reduction of cardiovascular death, MI, or ischemic stroke in high-risk patients with an ACS. Patients were required to
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have ≥2 of the following high-risk characteristics: age ≥65 years, diabetes mellitus, previous MI within the past 5 years, cerebrovascular disease (prior ischemic stroke or carotid endarterectomy), peripheral
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vascular disease, clinical heart failure or a left ventricular ejection fraction <40% in association with the
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index event, impaired renal function with a calculated creatinine clearance of <60 mL/min, and no revascularization after the index event. Key exclusion criteria were ischemic stroke within 7 days, any intracranial bleeding, and required ongoing treatment with a parenteral or oral anticoagulant. Of note
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there was a small, minority of patients with atrial fibrillation included in the trial (5.2% of population),
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who presumably were not candidates for long term anticoagulation, either due to very low stroke risk, high bleeding risk, or patient/physician determination.
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All patients provided written informed consent; ethics committees at participating institutions
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reviewed and approved the protocol.
Outcomes and Definitions
The primary efficacy outcome of the APPRAISE-2 trial was the composite of non-hemorrhagic cardiovascular death, MI, or ischemic stroke. The primary safety outcome was major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria. All-cause death was defined as all death. Cardiovascular death included deaths due to cardiogenic shock, heart failure, arrhythmia, sudden death, MI, cardiac rupture, ischemic stroke, pulmonary embolism, other venous and arterial thrombotic events, and other sudden deaths for which an alternative cause could not be identified. Importantly, fatal bleeding was considered a non-cardiovascular death, thus all references to CV death in the study are nonhemorrhagic. MI was defined as an elevation of cardiac biomarkers (CK-MB or troponin T or I) above 4
ACCEPTED MANUSCRIPT the upper reference limit plus either ischemic symptoms or ischemic electrocardiographic changes of STsegment elevation or depression or T-wave inversions, imaging evidence of new loss of viable
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myocardium, or new significant (≥0.04 second) Q waves in ≥2 contiguous leads. In the setting of
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revascularization using either percutaneous coronary intervention or coronary artery bypass graft surgery, a diagnosis of MI required an elevation of cardiac biomarkers ≥3 times or ≥5 times the upper limit of
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normal, respectively. Ischemic stroke was defined as a new, non-traumatic, focal neurological deficit of sudden onset, lasting at least 24 hours that was not due to a readily identifiable non-vascular cause and not
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due to primary intracranial bleeding based on cerebral imaging. TIMI major bleeding included fatal,
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intracranial, and clinically overt bleeding associated with a fall in hemoglobin of ≥5 g/dL accounting for transfusions.
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Statistical Methods
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Baseline characteristics were compared for patients with and without prior stroke. Continuous variables were reported as median (25th, 75th) and compared using the Wilcoxon rank sum test. Categorical
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variables were presented as frequencies and percentages, and compared using the Pearson Chi-square test or Fisher’s exact test. Survival distributions and event rates were compared across groups using the
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Kaplan-Meier method. Log-rank test was used to compare event rates between groups. Unadjusted and adjusted Cox proportional hazards regression models were used to evaluate the relationships between prior stroke groups, treatment groups, and all outcomes. The adjusted models included pre-specified variables either previously utilized for these outcomes or added per clinical judgment. The model for CV death, MI, stroke included Age, Female, Diabetes, Prior MI, Hypertension , Peripheral Vascular Disease, Enrolling MI, Heart Failure, Management of Index ACS event (pci,cabg,medical), Impaired Renal Function at Index ACS event. Model for ICH bleeding (due to very small number of events) included only age. The model for TIMI major and minor bleeding included Age, Management of Index ACS event (pci,cabg,medical), Smoking, Impaired Renal Function at Index ACS
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ACCEPTED MANUSCRIPT event, Dual Antiplatelet Therapy, White Blood Cell Count. The model for any bleeding included Age, Dual Antiplatelet Therapy, Bleed during Index ACS Event, Diastolic Blood Pressure, Management of
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Index ACS event (pci,cabg,medical), Prasugrel, Hypercholesterolemia, race, History of Atrial Fibrillation
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and Impaired Renal Function at Index ACS event.
Proportional hazards assumption and linearity assumption were tested. All statistical analyses
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were performed at the Duke Clinical Research Institute using SAS software (SAS Institute, Inc., Cary,
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NC).
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RESULTS
Of the 7391 patients in APPRAISE-2, 902 (12%) had prior stroke. While data were limited, the majority of patients (>90%) had their stroke event within 10 years of enrollment. Those with prior stroke were
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older, more frequently had hypertension, peripheral vascular disease, and impaired renal function, and less
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frequently had diabetes or congestive heart failure (
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ACCEPTED MANUSCRIPT Table 1). Use of dual antiplatelet therapy, statin therapy, and antihypertensive medications were similar in patients with and without prior stroke. Patients with prior stroke were less likely to receive prasugrel, but
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11 (1.2%) patients with prior stroke did receive prasugrel, despite this being a known contraindication for
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prasugrel therapy. Clinical Outcomes
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Prior Stroke
Over a median follow-up of 240 days, patients with prior stroke had higher rates of the composite of
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cardiovascular death, MI, or stroke than those without prior stroke (Figure 1). After adjustment, this
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increased risk persisted both for the composite outcome and for individual components of the composite (Table 2). There was no significant difference in all cause death, TIMI major or minor bleeding in patients with and without prior stroke. After adjustment for clinical risk factors, hazard ratios for all cause death,
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TIMI major or minor bleeding, as well as any bleeding, were similar in patients with and without stroke.
Apixaban vs. Placebo
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Among patients with prior stroke, after adjustment for clinical risk factors, apixaban was associated with a similar rate of cardiovascular death, MI, or stroke compared with placebo (HR 1.39; 95% CI 0.92-2.08)
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(Figure 2). Assignment to apixaban was associated with a similar composite ischemic endpoint risk vs. placebo in patients without prior stroke (HR 0.87; 95% CI 0.73-1.04). There was a borderline statistically significant interaction between prior stroke and apixaban effect on the primary composite outcome (pinteraction=0.041). For the individual outcomes of cardiovascular death, all cause death, and stroke there was no significant difference in risk in patients with prior stroke assigned apixaban and those assigned placebo (Figure 2). However, there was a similar trend towards higher risk of MI in patients with prior stroke on apixaban compared with placebo, with a borderline statistically significant interaction between apixaban assignment and stroke history (HR (Figure 2). For those assigned to apixaban or placebo there were no significant differences in rates or adjusted hazard ratios for TIMI major/minor bleeding outcomes (Figure 2). 7
ACCEPTED MANUSCRIPT DISCUSSION In a large, international cohort of patients with ACS, patients with prior stroke were at increased risk for
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subsequent adverse cardiovascular events, and there was an interaction between treatment assignment and
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ischemic outcomes. Patients without prior stroke showed a modest benefit from the addition of apixaban to antiplatelet therapy, while patients with prior stroke showed potential harm when apixaban was added.
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While antithrombotic therapy remains the mainstay for patients with ACS, further investigation is needed to determine the optimal combination of therapies for patients with and without prior stroke who
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experience an ACS.
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Given the increased risk imparted by a history of stroke, but the apparent lack of benefit with adding anticoagulation to antiplatelet therapy for secondary prevention in these patients, future studies on the use of anticoagulants in the post-ACS setting might consider exclusion of patients with prior stroke. In
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our study there was a significant interaction between prior stroke and treatment assignment regarding
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adverse cardiovascular outcomes, particularly myocardial (re)infarction. Patients without prior stroke showed a modest benefit from the addition of apixaban to standard antiplatelet therapy while patients with
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prior stroke showed potential harm with the addition of apixaban. In the ATLAS ACS 2-TIMI 51 trial, where patients with prior stroke were limited to antiplatelet monotherapy (or excluded from participation),
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there were qualitatively similar associations between prior stroke, treatment assignment, and adverse cardiovascular outcomes. Specifically, in those without prior stroke, rivaroxaban was associated with a lower risk of cardiovascular death/stroke/MI compared with placebo with a trend towards interaction between treatment assignment and the composite outcome (HR 0.82, 95% CI 0.72-0.94; pinteraction=0.10).6 In those with prior stroke, rivaroxaban-treated patients had a numerically higher hazard for cardiovascular death/stroke/MI compared with those treated with placebo (HR 1.57, 95% CI 0.753.31).11 Thus there may be a potential signal of harm for using DOACs in patients with prior stroke after ACS, conversely, there may be benefit in patients without stroke. In both cases, patients with prior stroke were at increased risk for MI specifically, rather than recurrent stroke or intracranial hemorrhage, but this
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ACCEPTED MANUSCRIPT risk was not mitigated by the addition of oral anticoagulation to antiplatelet therapy. This complex treatment interaction requires further investigation.
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Patients with ACS have a higher risk for stroke and other vascular events in follow-up.1, 8 Some
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of these risks can be mitigated by antiplatelet and statin therapy. However, the use of oral anticoagulant therapy for secondary prevention has been controversial. Trials such as WARIS-II4 and ASPECT-212
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showed a significant reduction in cardiovascular events with long-term anticoagulation compared with aspirin alone after presentation with an ACS event.4 However, anticoagulation was also associated with a
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significantly increased risk of bleeding in each of these studies. The APPRAISE-2 trial10 showed an
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increase in bleeding in patients with ACS given apixaban compared with those given placebo (HR 2.59, 95% CI 1.50-4.46; p=0.001), but failed to show a reduction in thrombotic events (HR 0.95; 95% CI 0.801.11; p=0.51). In contrast, the ATLAS ACS 2-TIMI 51 trial6 revealed that treatment with low-dose
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rivaroxaban after ACS decreased the risk of cardiovascular death/MI/stroke compared with placebo
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(combined rivaroxaban group HR 0.84, 95% CI 0.74-0.96; p=0.008). However, rivaroxaban also increased the risk for non-CABG related bleeding (2.1% vs. 0.6%; p<0.001). Of note, patients with prior stroke were
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limited to antiplatelet monotherapy in the ATLAS ACS 2-TIMI 51 trial, or were excluded from participation. This has led to limited use of rivaroxaban in the post-ACS setting in regions where it is
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approved. While patients with prior stroke are at higher risk for ischemic events, they may also have a higher risk for bleeding based on medical comorbidities. Thus the addition of an anticoagulant may have a net-clinical detriment. A recent meta-analysis of the phase II and phase III clinical trials of DOACs used in patients with recent ACS showed that addition of these agents modestly reduced the incidence of thrombotic events in follow up (HR 0.87, 95% CI 0.80-0.95).13 However, there was a more dramatic increase in clinical bleeding events, including both major and nonmajor clinically relevant bleeding (HR 2.34, 95%CI 2.06-2.66). Thus there remains uncertainty about the optimal antithrombotic regimen to achieve the balance of reduced ischemic events without unnecessarily high risk for bleeding.
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ACCEPTED MANUSCRIPT Patients with prior stroke have greater risk for subsequent stroke and other vascular events, but the use of anticoagulants and antiplatelet agents have not been beneficial in this setting. In a multicenter,
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randomized, double-blind trial of aspirin versus warfarin in the secondary prevention of non-
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cardioembolic, ischemic stroke in patients without ACS, Mohr and colleagues found no benefit of warfarin over aspirin (hazard ratio [HR] 1.13, 95% confidence interval [CI] 0.92-1.38; p=0.25).14 In
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addition, they found statistically similar rates of intracranial hemorrhage (2.22 vs. 1.49%; p=NS). While further studies have produced mixed results, a Cochrane database meta-analysis of the current literature,
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completed by De Schryver et al.,15 found that there was no overall benefit of vitamin K antagonist oral
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anticoagulants compared with antiplatelet therapy in the secondary prevention of non-cardioembolic ischemic stroke, regardless of degree of anticoagulation (medium intensity anticoagulation: relative risk [RR] 0.80; 95% CI 0.56-1.14; high intensity anticoagulation: RR 1.02; 95% CI 0.49-2.13), but there was
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an increased hazard for major bleeding (medium intensity anticoagulation: RR 1.93; 95% CI 1.27-2.94;
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high intensity anticoagulation: RR 9.0; 95% CI 3.9-21). Thus antiplatelet agents remain the mainstay of therapy,16 as recommended by the American Heart Association/American Stroke Association prevention
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of stroke guideline17 and American College of Chest Physicians guideline documents.18 Direct oral anticoagulant (DOAC) medications have been shown to be non-inferior, and in some
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cases superior to warfarin for the prevention of stroke/systemic embolism in patients with nonvalvular atrial fibrillation.19-22 In this setting, patients with prior stroke have been studied for a difference in treatment effect or safety between DOACs and warfarin. In all of these trials, RE-LY (dabigatran 110 mg: RR 0.84, 95% CI 0.58-1.20; 150 mg dabigatran: RR 0.75, 95% CI 0.52-1.08), ROCKET AF (HR 0.94, 95% CI 0.77-1.16), and ARISTOTLE (HR 0.76, 95% CI 0.56 to 1.03), patients with prior stroke experienced similar efficacy and safety from DOACs compared with dose-adjusted warfarin, and there was no interaction found between treatment assignment and a history of stroke in these large international cohorts of patients with nonvalvular atrial fibrillation.23-25
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Limitations
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There are several important limitations to this study. First, it was a post-hoc, subgroup analysis of the
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APPRAISE-2 trial. The trial was not powered to evaluate differences in clinical outcomes in patients with prior stroke, and the inclusion criteria of the trial may influence the ACS/prior stroke population (e.g.,
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exclusion of those with an indication for oral anticoagulation) making it less representative of the general population of those with prior stroke. In addition, there was little information about the characteristics of
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the prior stroke events and this limited further analyses of this heterogeneous group of patients. Finally,
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the APPRAISE-2 trial was stopped early in follow-up due to a signal of increased bleeding without significant reduction in ischemic events. This limited the time for observation of events and may bias
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towards an underestimation of difference in ischemic events over more long-term follow-up.
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Conclusions
In a large, international cohort of patients with ACS, patients with prior stroke are at greater risk for
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cardiovascular events, primarily MI, and may benefit less than patients without prior stroke from oral anticoagulation. Further investigation is needed to replicate these findings, understand the mechanism(s)
prior stroke.
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behind them, and determine the optimal antithrombotic therapy for patient post-ACS with and without
Funding Source APPRAISE-2 was funded by Bristol-Myers Squibb and Pfizer, Inc.
Disclosures Sherwood: Honoraria/Consulting fees from Boehringer Ingelheim and Janssen (<$10K). Lopes: Institutional research grants from Bristol-Myers Squibb and GlaxoSmithKline and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, and Portola. Sun: None. 12
ACCEPTED MANUSCRIPT Liaw: Employee of Bristol-Myers Squibb. Harrington: Consultant Fees/Honoraria: WebMD, GILEAD Sciences, Merck, Regado, Vox Media, CLS Behring, Fibrogen, Janssen R and D, BMS-Pfizer, Baxter,
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Daiichi-Lilly, Genentech, Adverse Events; Ownership/Partnership/Principal: MyoKardia, Revive;
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Research/Research Grants: The Medicines Company, AstraZeneca, GSK, Sanofi-aventis, Portola, Merck, Bristol Myers Squibb (BMS), BMS, CSL Behring. Wallentin: Institutional research grants from Bristol-
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Myers Squibb/Pfizer, AstraZeneca, Merck, Boehringer Ingelheim, and GlaxoSmithKline and consulting fees from GlaxoSmithKline, Bristol-Myers Squibb/Pfizer, Abbott, AstraZeneca, and Boehringer
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Ingelheim. Laskowitz: None. James: Research grants from Abbott Laboratories; AstraZeneca
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Pharmaceuticals LP; Boston Scientific; The Medicines Company. Goodman: Institutional research grants from Amylin, Bristol-Myers Squibb, Sanofi, Regeneron, HCor, Eli Lilly, Novartis, AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Amgen, Tenax
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Pharmaceuticals; Consulting/honoraria fees from Amylin, Bristol-Myers Squibb, Eli Lilly, AstraZeneca,
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Servier, Sanofi, Revalesio, Matrizyme Pharma, Ferring Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Bayer, Amgen, Boehringer Ingelheim, Merck. Darius: None. Lewis: Research Grant:
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Bristol-Myers Squibb; Speakers Bureau & Honoraria: Pfizer; Consultant/Advisory Board: Pfizer, Merck Sharp & Dohme, AstraZeneca. Gibson: Research grants from Angel Medical Corporation, Bayer Corp.,
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CSL Behring, Ikaria, Inc., Janssen Pharmaceuticals, Johnson & Johnson Corporation, Portola Pharmaceuticals, Stealth Peptides, Inc., St. Jude Medical; Consulting fees from Boston Clinical Research Institute, Cardiovascular Research Foundation, CSL Behring, Eli Lilly, Exeter Group, Gilead Sciences, Inc., Janssen Pharmaceuticals, Johnson & Johnson Corporation, The Medicines Company, Novo Nordisk, Ortho McNeil, Pfizer, St. Jude Medical, WebMD; Royalties from UpToDate in Cardiovascular Medicine. Pieper: None. Alexander: Institutional research grants from Bristol-Myers Squibb, Boehringer Ingelheim, CSL Behring, National Institutes of Health, Sanofi, and Tenax Therapeutics and consulting fees from Bristol-Myers Squibb, CSL Behring, Duke Private Diagnostic Clinic, Pfizer, Portola, VA Cooperative Studies Program.
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19.
Dabigatran versus warfarin in patients with atrial fibrillation. The New England journal of
20.
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medicine 2009;361(12):1139-51. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine 2013;369(22):2093-104. 21.
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine 2011;365(11):981-92.
22.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England journal of medicine 2011;365(10):883-91. 16
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Diener HC, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic
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attack or stroke: a subgroup analysis of the RE-LY trial. The Lancet Neurology
24.
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2010;9(12):1157-63.
Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, et al.
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Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. The Lancet
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Easton JD, Lopes RD, Bahit MC, Wojdyla DM, Granger CB, Wallentin L, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. The Lancet Neurology
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2012;11(6):503-11.
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25.
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Neurology 2012;11(4):315-22.
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ACCEPTED MANUSCRIPT Figure Legends Figure 1. Primary endpoint (composite of cardiovascular death, MI, or stroke) at 1 year of follow-up in
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patients with prior stroke who received apixaban compared with those who received placebo.
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Figure 2. Cardiovascular outcomes in patients with and without prior stroke.
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Prior Stroke
No Prior Stroke
(N=902)
(N=6489)
P-value
Age, median (25th, 75th), yrs
69 (62, 75)
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Table 1. Baseline characteristics
67 (58, 73)
<0.0001
Female sex, no. (%)
313 (34.7)
2065 (31.8)
0.0830
History of diabetes mellitus, no. (%)
394 (43.7)
3142 (48.4)
0.0076
Prior MI within 5 years, no. (%)
220 (24.4)
1716 (26.4)
0.1885
History of PVD, no. (%)
201 (22.3)
1137 (17.5)
0.0005
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Characteristic
300 (33.3)
2669 (41.1)
<0.0001
History of impaired renal function, no. (%)
315 (37.8)
1822 (29.8)
<0.0001
490 (54.3)
3604 (55.5)
0.4910
817 (90.6)
4996 (77.0)
<0.0001
162 (18.0)
1571 (24.2)
<0.0001
350 (38.8)
2386 (36.8)
0.2361
311 (34.5)
1765 (27.2)
<0.0001
297 (32.9)
1793 (27.6)
0.0009
220 (24.4)
1452 (22.4)
0.1755
119 (13.2)
515 (7.9)
<0.0001
68 (7.5)
317 (4.9)
0.0008
Coronary angiography
492 (54.5)
3358 (51.7)
0.1152
PCI
407 (45.1)
2848 (43.9)
0.4848
7 (0.8)
38 (0.6)
0.4909
490 (54.3)
3604 (55.5)
0.4910
869 (96.4)
6328 (97.6)
0.0475
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History of HF or LVEF <40% with index event, no. (%)
No revascularization for index ACS event, no. (%) Other medical history, no. (%)
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Hypertension
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Smoking MI
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HF
Prior coronary revascularization, no. (%)
PCI history CABG history
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Revascularization history
Atrial fibrillation ACS management, no. (%)
CABG Medical therapy Concomitant medications, no. (%) Aspirin
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Prior Stroke
No Prior Stroke
Characteristic
(N=902)
(N=6489)
P-value
Clopidogrel
741 (82.2)
5247 (80.9)
0.3344
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0.0398
11 (1.2)
148 (2.3)
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Prasugrel Dual antiplatelet therapy
726 (80.9)
5269 (81.5)
0.6975
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ACS indicates acute coronary syndrome; CABG, coronary artery bypass grafting; HF, heart failure; LVEF: leftventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease.
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ACCEPTED MANUSCRIPT Table 2. One-year unadjusted Kaplan-Meier event rates and adjusted hazard ratios for patients with and without prior stroke Prior Stroke
No Prior Stroke
(N=902)
(N=6489)
16.51. (94)
10.34 (478)
Cardiovascular death
4.75 (27)
3.96 (187)
MI
11.23 (62)
All stroke
4.40 (23)
Ischemic stroke
3.22 (16)
ICH
1.13 (5)
TIMI major/minor bleeding
All death
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0.90 (0.60, 1.35)
0.753
7.08 (314)
1.27 (0.97, 1.68)
0.004
1.24 (53)
2.87 (1.74, 4.72)
<0.0001
0.93 (41)
2.45 (1.37, 4.41)
0.0001
0.33 (10)
3.68 (1.24, 10.88)
0.009
4.04 (18)
2.13 (91)
1.34 (0.79, 2.25)
0.129
19.96 (123)
17.90 (861)
0.93 (0.77, 1.13)
0.571
5.73 (254)
1.05 (0.76, 1.46)
0.747
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0.0004
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Any bleeding
P-Value
1.49 (1.19, 1.86)
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Cardiovascular death, MI, or stroke
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Adjusted HR (95% CI)
7.96 (44)
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Cardiovascular death, by definition in the trial, does not include any fatal bleeding; CI indicates confidence interval; HR, hazard ratio; ICH, intracranial hemorrhage; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction. Model for CV death, MI, stroke included Age, Female, Diabetes, Prior MI, Hypertension , Peripheral Vascular Disease, Enrolling MI, Heart Failure, Management of Index ACS event (pci,cabg,medical), Impaired Renal Function at Index ACS event. Model for ICH bleeding (due to very small number of events) included only age. Model for TIMI major and minor bleeding included Age, Management of Index ACS event (pci,cabg,medical), Smoking, Impaired Renal Function at Index ACS event, Dual Antiplatelet Therapy, White Blood Cell Count. Model for any bleeding included Age, Dual Antiplatelet Therapy, Bleed during Index ACS Event, Diastolic Blood Pressure, Management of Index ACS event (pci,cabg,medical), Prasugrel, Hypercholesterolemia, race, History of Atrial Fibrillation and Impaired Renal Function at Index ACS event.
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Figure 1.
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Figure 2.
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S0002-8703(17)30342-3 doi: 10.1016/j.ahj.2017.09.020 YMHJ 5556
To appear in:
American Heart Journal
Received date: Accepted date:
19 September 2017 19 September 2017
Please cite this article as: Sherwood Matthew W., Lopes Renato D., Sun Jie Lena, Liaw Danny, Harrington Robert A., Wallentin Lars, Laskowitz Daniel T., James Stefan K., Goodman Shaun G., Darius Harald, Lewis Basil S., Gibson C. Michael, Pieper Karen S., Alexander John H., Apixaban following acute coronary syndromes in patients with prior stroke: Insights from the APPRAISE-2 trial, American Heart Journal (2017), doi: 10.1016/j.ahj.2017.09.020
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Apixaban Following Acute Coronary Syndromes in Patients with Prior Stroke: Insights from
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the APPRAISE-2 Trial
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Matthew W. Sherwood, MD, MHS,1,2 Renato D. Lopes, MD, PhD, MHS,2 Jie Lena Sun, MS,2 Danny Liaw, MD, PhD,3 Robert A. Harrington, MD,4 Lars Wallentin, MD, PhD,5
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Daniel T. Laskowitz, MD, MHS,2 Stefan K. James, MD, PhD,5 Shaun G. Goodman, MD, MSc,6 Harald Darius, MD,7 Basil S. Lewis, MD,8 C. Michael Gibson, MS, MD,9 Karen S. Pieper, MS,2
Inova Heart and Vascular Institute, Falls Church, VA; 2Duke Clinical Research Institute, Duke University
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1
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John H. Alexander, MD, MHS2
School of Medicine, Durham, NC; 3Bristol-Myers Squibb, Princeton, NJ; 4Stanford University School of
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Medicine, Stanford, CA; 5Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; Canadian Heart Research Center and University of Toronto, Toronto, Ontario, Canada; 7Vivantes
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Neukoelln Medical Center, Berlin, Germany; 8Lady Davis Carmel Medical Center, The Ruth and Bruce
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Rappaport School of Medicine of the Technion, Haifa, Israel; 9Harvard Medical School, Boston, MA.
Cover title: Apixaban Post-ACS in Patients with Prior Stroke Key words: stroke, non-VKA oral anticoagulant, acute coronary syndromes Subject codes: ischemic stroke; anticoagulants; acute coronary syndromes Word count: 4197
Address for correspondence: Matthew W. Sherwood, MD, MHS, Duke Clinical Research Institute, 2400 Pratt Street, P.O. Box 17969, Durham, NC 27715. Phone: 919-668-8033; Fax: 919-668-7057. Email: [email protected].
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ACCEPTED MANUSCRIPT Background and Purpose: Patients with prior stroke are at greater risk for recurrent cardiovascular events post-acute coronary syndromes (ACS) and may have a different risk/benefit profile with
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antithrombotic therapy than patients without prior stroke.
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Methods: We studied 7391 patients with ACS from APPRAISE-2, stratified by the presence or absence of prior stroke. Baseline characteristics and outcomes of cardiovascular death, myocardial infarction (MI),
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or stroke were compared between groups. Interactions between prior stroke, treatment assignment (apixaban vs. placebo), and outcomes were tested before and after multivariable adjustment with Cox
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proportional hazards models.
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Results: A total of 902 patients (12%) had prior stroke. Those with prior stroke were older (69 vs. 67 years), had more hypertension (91% vs. 77%), peripheral vascular disease (22% vs.18%), and impaired renal function (38% vs. 30%) but less diabetes (44% vs. 48%) than those without prior stroke. Patients
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with prior stroke vs. no prior stroke had higher unadjusted rates of cardiovascular death (4.8% vs. 4.0%),
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MI (11.2% vs. 7.1%), and ischemic stroke (3.2% vs. 0.9%). Patients with prior stroke assigned to apixaban had similar rates of the composite of cardiovascular death, MI, or stroke compared with those
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assigned to placebo (HR 1.39; 95% CI 0.92-2.08). Patients without prior stroke assigned to apixaban had similar rates of cardiovascular death, MI, or ischemic stroke compared with those assigned to placebo (HR
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0.87; 95% CI 0.73-1.04; p-interaction=0.041). Median follow-up was 240 days. Conclusions: Patients with prior stroke are at higher risk for recurrent cardiovascular events post-ACS and had a differential risk/benefit profile with oral anticoagulation. Clinical Trial Registration: ClinicalTrials.gov NCT00831441
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ACCEPTED MANUSCRIPT Patients with an acute coronary syndrome (ACS) are at increased risk for further vascular events, such as stroke, myocardial infarction (MI), and death during medical follow-up.1 Antithrombotic therapies are
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essential in the treatment of patients with ACS.2, 3 Previous investigations suggest that anticoagulant
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medications added to antiplatelet therapy may be effective in reducing further vascular events, but also increase the risk of bleeding.4-6 Healthcare providers are challenged to optimize antithrombotic treatment
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regimens to reduce the risk of further ischemic events without prohibitive increases in bleeding. Thus only a select population of patients may have a favorable risk benefit ratio for combination antithrombotic
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therapy.
A history of stroke is also a major risk factor for future vascular events.7-9 Patients with prior
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stroke often have other medical comorbidities that increase risk for subsequent cardiovascular events.8 Patients with prior stroke who experience an ACS event may benefit from further antithrombotic therapy
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despite bleeding risk; these patients have been included in recent trials evaluating direct oral
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anticoagulants in the setting of ACS.
The APPRAISE-2 trial evaluated the use of the direct, selective factor Xa inhibitor, apixaban, in
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addition to standard antiplatelet and other medical therapy, for secondary prevention of cardiovascular events in patients with an ACS,10 but without a specific indication (e.g., atrial fibrillation) for oral
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anticoagulation. The trial was terminated early due to an increase in major bleeding without a counterbalancing reduction in ischemic events in patients assigned to apixaban compared with those assigned placebo. These results ran counter to those seen in the ATLAS-2 trial of a post-ACS population that excluded patients with prior stroke in which patients treated with rivaroxaban had a reduction in cardiovascular death, MI, or stroke compared with those assigned placebo. In ATLAS-2, despite the use of lower dosing of rivaroxaban (than studied for stroke prevention in an atrial fibrillation population), there was also an increase in major and intracranial bleeding compared with placebo. Given these disparate results we aimed to study patients with and without prior stroke in the APPRAISE-2 trial to determine if there was a differential effect of apixaban in patients with and without prior stroke.
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ACCEPTED MANUSCRIPT METHODS The study design and primary results of the APPRAISE-2 trial have been published.10 In brief, the
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APPRAISE-2 trial was an international, multicenter, double-blind, randomized, controlled, trial
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comparing apixaban with placebo, in addition to standard antiplatelet therapy, for the reduction of cardiovascular death, MI, or ischemic stroke in high-risk patients with an ACS. Patients were required to
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have ≥2 of the following high-risk characteristics: age ≥65 years, diabetes mellitus, previous MI within the past 5 years, cerebrovascular disease (prior ischemic stroke or carotid endarterectomy), peripheral
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vascular disease, clinical heart failure or a left ventricular ejection fraction <40% in association with the
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index event, impaired renal function with a calculated creatinine clearance of <60 mL/min, and no revascularization after the index event. Key exclusion criteria were ischemic stroke within 7 days, any intracranial bleeding, and required ongoing treatment with a parenteral or oral anticoagulant. Of note
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there was a small, minority of patients with atrial fibrillation included in the trial (5.2% of population),
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who presumably were not candidates for long term anticoagulation, either due to very low stroke risk, high bleeding risk, or patient/physician determination.
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All patients provided written informed consent; ethics committees at participating institutions
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reviewed and approved the protocol.
Outcomes and Definitions
The primary efficacy outcome of the APPRAISE-2 trial was the composite of non-hemorrhagic cardiovascular death, MI, or ischemic stroke. The primary safety outcome was major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria. All-cause death was defined as all death. Cardiovascular death included deaths due to cardiogenic shock, heart failure, arrhythmia, sudden death, MI, cardiac rupture, ischemic stroke, pulmonary embolism, other venous and arterial thrombotic events, and other sudden deaths for which an alternative cause could not be identified. Importantly, fatal bleeding was considered a non-cardiovascular death, thus all references to CV death in the study are nonhemorrhagic. MI was defined as an elevation of cardiac biomarkers (CK-MB or troponin T or I) above 4
ACCEPTED MANUSCRIPT the upper reference limit plus either ischemic symptoms or ischemic electrocardiographic changes of STsegment elevation or depression or T-wave inversions, imaging evidence of new loss of viable
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myocardium, or new significant (≥0.04 second) Q waves in ≥2 contiguous leads. In the setting of
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revascularization using either percutaneous coronary intervention or coronary artery bypass graft surgery, a diagnosis of MI required an elevation of cardiac biomarkers ≥3 times or ≥5 times the upper limit of
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normal, respectively. Ischemic stroke was defined as a new, non-traumatic, focal neurological deficit of sudden onset, lasting at least 24 hours that was not due to a readily identifiable non-vascular cause and not
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due to primary intracranial bleeding based on cerebral imaging. TIMI major bleeding included fatal,
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intracranial, and clinically overt bleeding associated with a fall in hemoglobin of ≥5 g/dL accounting for transfusions.
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Statistical Methods
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Baseline characteristics were compared for patients with and without prior stroke. Continuous variables were reported as median (25th, 75th) and compared using the Wilcoxon rank sum test. Categorical
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variables were presented as frequencies and percentages, and compared using the Pearson Chi-square test or Fisher’s exact test. Survival distributions and event rates were compared across groups using the
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Kaplan-Meier method. Log-rank test was used to compare event rates between groups. Unadjusted and adjusted Cox proportional hazards regression models were used to evaluate the relationships between prior stroke groups, treatment groups, and all outcomes. The adjusted models included pre-specified variables either previously utilized for these outcomes or added per clinical judgment. The model for CV death, MI, stroke included Age, Female, Diabetes, Prior MI, Hypertension , Peripheral Vascular Disease, Enrolling MI, Heart Failure, Management of Index ACS event (pci,cabg,medical), Impaired Renal Function at Index ACS event. Model for ICH bleeding (due to very small number of events) included only age. The model for TIMI major and minor bleeding included Age, Management of Index ACS event (pci,cabg,medical), Smoking, Impaired Renal Function at Index ACS
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ACCEPTED MANUSCRIPT event, Dual Antiplatelet Therapy, White Blood Cell Count. The model for any bleeding included Age, Dual Antiplatelet Therapy, Bleed during Index ACS Event, Diastolic Blood Pressure, Management of
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Index ACS event (pci,cabg,medical), Prasugrel, Hypercholesterolemia, race, History of Atrial Fibrillation
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and Impaired Renal Function at Index ACS event.
Proportional hazards assumption and linearity assumption were tested. All statistical analyses
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were performed at the Duke Clinical Research Institute using SAS software (SAS Institute, Inc., Cary,
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NC).
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RESULTS
Of the 7391 patients in APPRAISE-2, 902 (12%) had prior stroke. While data were limited, the majority of patients (>90%) had their stroke event within 10 years of enrollment. Those with prior stroke were
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older, more frequently had hypertension, peripheral vascular disease, and impaired renal function, and less
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frequently had diabetes or congestive heart failure (
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ACCEPTED MANUSCRIPT Table 1). Use of dual antiplatelet therapy, statin therapy, and antihypertensive medications were similar in patients with and without prior stroke. Patients with prior stroke were less likely to receive prasugrel, but
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11 (1.2%) patients with prior stroke did receive prasugrel, despite this being a known contraindication for
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prasugrel therapy. Clinical Outcomes
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Prior Stroke
Over a median follow-up of 240 days, patients with prior stroke had higher rates of the composite of
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cardiovascular death, MI, or stroke than those without prior stroke (Figure 1). After adjustment, this
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increased risk persisted both for the composite outcome and for individual components of the composite (Table 2). There was no significant difference in all cause death, TIMI major or minor bleeding in patients with and without prior stroke. After adjustment for clinical risk factors, hazard ratios for all cause death,
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TIMI major or minor bleeding, as well as any bleeding, were similar in patients with and without stroke.
Apixaban vs. Placebo
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Among patients with prior stroke, after adjustment for clinical risk factors, apixaban was associated with a similar rate of cardiovascular death, MI, or stroke compared with placebo (HR 1.39; 95% CI 0.92-2.08)
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(Figure 2). Assignment to apixaban was associated with a similar composite ischemic endpoint risk vs. placebo in patients without prior stroke (HR 0.87; 95% CI 0.73-1.04). There was a borderline statistically significant interaction between prior stroke and apixaban effect on the primary composite outcome (pinteraction=0.041). For the individual outcomes of cardiovascular death, all cause death, and stroke there was no significant difference in risk in patients with prior stroke assigned apixaban and those assigned placebo (Figure 2). However, there was a similar trend towards higher risk of MI in patients with prior stroke on apixaban compared with placebo, with a borderline statistically significant interaction between apixaban assignment and stroke history (HR (Figure 2). For those assigned to apixaban or placebo there were no significant differences in rates or adjusted hazard ratios for TIMI major/minor bleeding outcomes (Figure 2). 7
ACCEPTED MANUSCRIPT DISCUSSION In a large, international cohort of patients with ACS, patients with prior stroke were at increased risk for
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subsequent adverse cardiovascular events, and there was an interaction between treatment assignment and
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ischemic outcomes. Patients without prior stroke showed a modest benefit from the addition of apixaban to antiplatelet therapy, while patients with prior stroke showed potential harm when apixaban was added.
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While antithrombotic therapy remains the mainstay for patients with ACS, further investigation is needed to determine the optimal combination of therapies for patients with and without prior stroke who
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experience an ACS.
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Given the increased risk imparted by a history of stroke, but the apparent lack of benefit with adding anticoagulation to antiplatelet therapy for secondary prevention in these patients, future studies on the use of anticoagulants in the post-ACS setting might consider exclusion of patients with prior stroke. In
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our study there was a significant interaction between prior stroke and treatment assignment regarding
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adverse cardiovascular outcomes, particularly myocardial (re)infarction. Patients without prior stroke showed a modest benefit from the addition of apixaban to standard antiplatelet therapy while patients with
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prior stroke showed potential harm with the addition of apixaban. In the ATLAS ACS 2-TIMI 51 trial, where patients with prior stroke were limited to antiplatelet monotherapy (or excluded from participation),
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there were qualitatively similar associations between prior stroke, treatment assignment, and adverse cardiovascular outcomes. Specifically, in those without prior stroke, rivaroxaban was associated with a lower risk of cardiovascular death/stroke/MI compared with placebo with a trend towards interaction between treatment assignment and the composite outcome (HR 0.82, 95% CI 0.72-0.94; pinteraction=0.10).6 In those with prior stroke, rivaroxaban-treated patients had a numerically higher hazard for cardiovascular death/stroke/MI compared with those treated with placebo (HR 1.57, 95% CI 0.753.31).11 Thus there may be a potential signal of harm for using DOACs in patients with prior stroke after ACS, conversely, there may be benefit in patients without stroke. In both cases, patients with prior stroke were at increased risk for MI specifically, rather than recurrent stroke or intracranial hemorrhage, but this
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ACCEPTED MANUSCRIPT risk was not mitigated by the addition of oral anticoagulation to antiplatelet therapy. This complex treatment interaction requires further investigation.
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Patients with ACS have a higher risk for stroke and other vascular events in follow-up.1, 8 Some
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of these risks can be mitigated by antiplatelet and statin therapy. However, the use of oral anticoagulant therapy for secondary prevention has been controversial. Trials such as WARIS-II4 and ASPECT-212
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showed a significant reduction in cardiovascular events with long-term anticoagulation compared with aspirin alone after presentation with an ACS event.4 However, anticoagulation was also associated with a
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significantly increased risk of bleeding in each of these studies. The APPRAISE-2 trial10 showed an
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increase in bleeding in patients with ACS given apixaban compared with those given placebo (HR 2.59, 95% CI 1.50-4.46; p=0.001), but failed to show a reduction in thrombotic events (HR 0.95; 95% CI 0.801.11; p=0.51). In contrast, the ATLAS ACS 2-TIMI 51 trial6 revealed that treatment with low-dose
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rivaroxaban after ACS decreased the risk of cardiovascular death/MI/stroke compared with placebo
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(combined rivaroxaban group HR 0.84, 95% CI 0.74-0.96; p=0.008). However, rivaroxaban also increased the risk for non-CABG related bleeding (2.1% vs. 0.6%; p<0.001). Of note, patients with prior stroke were
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limited to antiplatelet monotherapy in the ATLAS ACS 2-TIMI 51 trial, or were excluded from participation. This has led to limited use of rivaroxaban in the post-ACS setting in regions where it is
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approved. While patients with prior stroke are at higher risk for ischemic events, they may also have a higher risk for bleeding based on medical comorbidities. Thus the addition of an anticoagulant may have a net-clinical detriment. A recent meta-analysis of the phase II and phase III clinical trials of DOACs used in patients with recent ACS showed that addition of these agents modestly reduced the incidence of thrombotic events in follow up (HR 0.87, 95% CI 0.80-0.95).13 However, there was a more dramatic increase in clinical bleeding events, including both major and nonmajor clinically relevant bleeding (HR 2.34, 95%CI 2.06-2.66). Thus there remains uncertainty about the optimal antithrombotic regimen to achieve the balance of reduced ischemic events without unnecessarily high risk for bleeding.
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ACCEPTED MANUSCRIPT Patients with prior stroke have greater risk for subsequent stroke and other vascular events, but the use of anticoagulants and antiplatelet agents have not been beneficial in this setting. In a multicenter,
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randomized, double-blind trial of aspirin versus warfarin in the secondary prevention of non-
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cardioembolic, ischemic stroke in patients without ACS, Mohr and colleagues found no benefit of warfarin over aspirin (hazard ratio [HR] 1.13, 95% confidence interval [CI] 0.92-1.38; p=0.25).14 In
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addition, they found statistically similar rates of intracranial hemorrhage (2.22 vs. 1.49%; p=NS). While further studies have produced mixed results, a Cochrane database meta-analysis of the current literature,
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completed by De Schryver et al.,15 found that there was no overall benefit of vitamin K antagonist oral
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anticoagulants compared with antiplatelet therapy in the secondary prevention of non-cardioembolic ischemic stroke, regardless of degree of anticoagulation (medium intensity anticoagulation: relative risk [RR] 0.80; 95% CI 0.56-1.14; high intensity anticoagulation: RR 1.02; 95% CI 0.49-2.13), but there was
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an increased hazard for major bleeding (medium intensity anticoagulation: RR 1.93; 95% CI 1.27-2.94;
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high intensity anticoagulation: RR 9.0; 95% CI 3.9-21). Thus antiplatelet agents remain the mainstay of therapy,16 as recommended by the American Heart Association/American Stroke Association prevention
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of stroke guideline17 and American College of Chest Physicians guideline documents.18 Direct oral anticoagulant (DOAC) medications have been shown to be non-inferior, and in some
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cases superior to warfarin for the prevention of stroke/systemic embolism in patients with nonvalvular atrial fibrillation.19-22 In this setting, patients with prior stroke have been studied for a difference in treatment effect or safety between DOACs and warfarin. In all of these trials, RE-LY (dabigatran 110 mg: RR 0.84, 95% CI 0.58-1.20; 150 mg dabigatran: RR 0.75, 95% CI 0.52-1.08), ROCKET AF (HR 0.94, 95% CI 0.77-1.16), and ARISTOTLE (HR 0.76, 95% CI 0.56 to 1.03), patients with prior stroke experienced similar efficacy and safety from DOACs compared with dose-adjusted warfarin, and there was no interaction found between treatment assignment and a history of stroke in these large international cohorts of patients with nonvalvular atrial fibrillation.23-25
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Limitations
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There are several important limitations to this study. First, it was a post-hoc, subgroup analysis of the
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APPRAISE-2 trial. The trial was not powered to evaluate differences in clinical outcomes in patients with prior stroke, and the inclusion criteria of the trial may influence the ACS/prior stroke population (e.g.,
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exclusion of those with an indication for oral anticoagulation) making it less representative of the general population of those with prior stroke. In addition, there was little information about the characteristics of
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the prior stroke events and this limited further analyses of this heterogeneous group of patients. Finally,
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the APPRAISE-2 trial was stopped early in follow-up due to a signal of increased bleeding without significant reduction in ischemic events. This limited the time for observation of events and may bias
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towards an underestimation of difference in ischemic events over more long-term follow-up.
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Conclusions
In a large, international cohort of patients with ACS, patients with prior stroke are at greater risk for
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cardiovascular events, primarily MI, and may benefit less than patients without prior stroke from oral anticoagulation. Further investigation is needed to replicate these findings, understand the mechanism(s)
prior stroke.
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behind them, and determine the optimal antithrombotic therapy for patient post-ACS with and without
Funding Source APPRAISE-2 was funded by Bristol-Myers Squibb and Pfizer, Inc.
Disclosures Sherwood: Honoraria/Consulting fees from Boehringer Ingelheim and Janssen (<$10K). Lopes: Institutional research grants from Bristol-Myers Squibb and GlaxoSmithKline and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, and Portola. Sun: None. 12
ACCEPTED MANUSCRIPT Liaw: Employee of Bristol-Myers Squibb. Harrington: Consultant Fees/Honoraria: WebMD, GILEAD Sciences, Merck, Regado, Vox Media, CLS Behring, Fibrogen, Janssen R and D, BMS-Pfizer, Baxter,
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Daiichi-Lilly, Genentech, Adverse Events; Ownership/Partnership/Principal: MyoKardia, Revive;
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Research/Research Grants: The Medicines Company, AstraZeneca, GSK, Sanofi-aventis, Portola, Merck, Bristol Myers Squibb (BMS), BMS, CSL Behring. Wallentin: Institutional research grants from Bristol-
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Myers Squibb/Pfizer, AstraZeneca, Merck, Boehringer Ingelheim, and GlaxoSmithKline and consulting fees from GlaxoSmithKline, Bristol-Myers Squibb/Pfizer, Abbott, AstraZeneca, and Boehringer
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Ingelheim. Laskowitz: None. James: Research grants from Abbott Laboratories; AstraZeneca
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Pharmaceuticals LP; Boston Scientific; The Medicines Company. Goodman: Institutional research grants from Amylin, Bristol-Myers Squibb, Sanofi, Regeneron, HCor, Eli Lilly, Novartis, AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Amgen, Tenax
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Pharmaceuticals; Consulting/honoraria fees from Amylin, Bristol-Myers Squibb, Eli Lilly, AstraZeneca,
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Servier, Sanofi, Revalesio, Matrizyme Pharma, Ferring Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Bayer, Amgen, Boehringer Ingelheim, Merck. Darius: None. Lewis: Research Grant:
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Bristol-Myers Squibb; Speakers Bureau & Honoraria: Pfizer; Consultant/Advisory Board: Pfizer, Merck Sharp & Dohme, AstraZeneca. Gibson: Research grants from Angel Medical Corporation, Bayer Corp.,
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CSL Behring, Ikaria, Inc., Janssen Pharmaceuticals, Johnson & Johnson Corporation, Portola Pharmaceuticals, Stealth Peptides, Inc., St. Jude Medical; Consulting fees from Boston Clinical Research Institute, Cardiovascular Research Foundation, CSL Behring, Eli Lilly, Exeter Group, Gilead Sciences, Inc., Janssen Pharmaceuticals, Johnson & Johnson Corporation, The Medicines Company, Novo Nordisk, Ortho McNeil, Pfizer, St. Jude Medical, WebMD; Royalties from UpToDate in Cardiovascular Medicine. Pieper: None. Alexander: Institutional research grants from Bristol-Myers Squibb, Boehringer Ingelheim, CSL Behring, National Institutes of Health, Sanofi, and Tenax Therapeutics and consulting fees from Bristol-Myers Squibb, CSL Behring, Duke Private Diagnostic Clinic, Pfizer, Portola, VA Cooperative Studies Program.
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Diener HC, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic
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patients with prior stroke who received apixaban compared with those who received placebo.
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Figure 2. Cardiovascular outcomes in patients with and without prior stroke.
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Prior Stroke
No Prior Stroke
(N=902)
(N=6489)
P-value
Age, median (25th, 75th), yrs
69 (62, 75)
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Table 1. Baseline characteristics
67 (58, 73)
<0.0001
Female sex, no. (%)
313 (34.7)
2065 (31.8)
0.0830
History of diabetes mellitus, no. (%)
394 (43.7)
3142 (48.4)
0.0076
Prior MI within 5 years, no. (%)
220 (24.4)
1716 (26.4)
0.1885
History of PVD, no. (%)
201 (22.3)
1137 (17.5)
0.0005
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Characteristic
300 (33.3)
2669 (41.1)
<0.0001
History of impaired renal function, no. (%)
315 (37.8)
1822 (29.8)
<0.0001
490 (54.3)
3604 (55.5)
0.4910
817 (90.6)
4996 (77.0)
<0.0001
162 (18.0)
1571 (24.2)
<0.0001
350 (38.8)
2386 (36.8)
0.2361
311 (34.5)
1765 (27.2)
<0.0001
297 (32.9)
1793 (27.6)
0.0009
220 (24.4)
1452 (22.4)
0.1755
119 (13.2)
515 (7.9)
<0.0001
68 (7.5)
317 (4.9)
0.0008
Coronary angiography
492 (54.5)
3358 (51.7)
0.1152
PCI
407 (45.1)
2848 (43.9)
0.4848
7 (0.8)
38 (0.6)
0.4909
490 (54.3)
3604 (55.5)
0.4910
869 (96.4)
6328 (97.6)
0.0475
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History of HF or LVEF <40% with index event, no. (%)
No revascularization for index ACS event, no. (%) Other medical history, no. (%)
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Hypertension
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Smoking MI
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HF
Prior coronary revascularization, no. (%)
PCI history CABG history
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Revascularization history
Atrial fibrillation ACS management, no. (%)
CABG Medical therapy Concomitant medications, no. (%) Aspirin
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Prior Stroke
No Prior Stroke
Characteristic
(N=902)
(N=6489)
P-value
Clopidogrel
741 (82.2)
5247 (80.9)
0.3344
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0.0398
11 (1.2)
148 (2.3)
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Prasugrel Dual antiplatelet therapy
726 (80.9)
5269 (81.5)
0.6975
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ACS indicates acute coronary syndrome; CABG, coronary artery bypass grafting; HF, heart failure; LVEF: leftventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease.
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ACCEPTED MANUSCRIPT Table 2. One-year unadjusted Kaplan-Meier event rates and adjusted hazard ratios for patients with and without prior stroke Prior Stroke
No Prior Stroke
(N=902)
(N=6489)
16.51. (94)
10.34 (478)
Cardiovascular death
4.75 (27)
3.96 (187)
MI
11.23 (62)
All stroke
4.40 (23)
Ischemic stroke
3.22 (16)
ICH
1.13 (5)
TIMI major/minor bleeding
All death
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0.90 (0.60, 1.35)
0.753
7.08 (314)
1.27 (0.97, 1.68)
0.004
1.24 (53)
2.87 (1.74, 4.72)
<0.0001
0.93 (41)
2.45 (1.37, 4.41)
0.0001
0.33 (10)
3.68 (1.24, 10.88)
0.009
4.04 (18)
2.13 (91)
1.34 (0.79, 2.25)
0.129
19.96 (123)
17.90 (861)
0.93 (0.77, 1.13)
0.571
5.73 (254)
1.05 (0.76, 1.46)
0.747
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0.0004
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Any bleeding
P-Value
1.49 (1.19, 1.86)
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Cardiovascular death, MI, or stroke
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Adjusted HR (95% CI)
7.96 (44)
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Cardiovascular death, by definition in the trial, does not include any fatal bleeding; CI indicates confidence interval; HR, hazard ratio; ICH, intracranial hemorrhage; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction. Model for CV death, MI, stroke included Age, Female, Diabetes, Prior MI, Hypertension , Peripheral Vascular Disease, Enrolling MI, Heart Failure, Management of Index ACS event (pci,cabg,medical), Impaired Renal Function at Index ACS event. Model for ICH bleeding (due to very small number of events) included only age. Model for TIMI major and minor bleeding included Age, Management of Index ACS event (pci,cabg,medical), Smoking, Impaired Renal Function at Index ACS event, Dual Antiplatelet Therapy, White Blood Cell Count. Model for any bleeding included Age, Dual Antiplatelet Therapy, Bleed during Index ACS Event, Diastolic Blood Pressure, Management of Index ACS event (pci,cabg,medical), Prasugrel, Hypercholesterolemia, race, History of Atrial Fibrillation and Impaired Renal Function at Index ACS event.
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Figure 1.
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Figure 2.
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