Author + information
- Received March 20, 2015
- Revision received May 21, 2015
- Accepted June 4, 2015
- Published online August 18, 2015.
- Connie N. Hess, MD, MHS∗,
- Stefan James, MD, PhD†,
- Renato D. Lopes, MD, PhD∗,
- Daniel M. Wojdyla, MSc∗,
- Megan L. Neely, PhD∗,
- Danny Liaw, MD, PhD‡,
- Emil Hagstrom, MD, PhD∗,
- Deepak L. Bhatt, MD, MPH§,
- Steen Husted, MD, DSc‖,
- Shaun G. Goodman, MD, MSc¶,
- Basil S. Lewis, MD#,
- Freek W.A. Verheugt, MD∗∗,
- Raffaele De Caterina, MD, PhD††,
- Hisao Ogawa, MD‡‡,
- Lars Wallentin, MD, PhD† and
- John H. Alexander, MD, MHS∗∗ ()
- ∗Duke Clinical Research Institute, Duke Medicine, Durham, North Carolina
- †Uppsala Clinical Research Institute, Uppsala University, Uppsala, Sweden
- ‡Bristol-Myers Squibb, Princeton, New Jersey
- §Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts
- ‖Århus University Hospital, Århus, Denmark
- ¶Canadian Heart Research Centre and Terrence Donnelly Heart Centre, Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
- #Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel
- ∗∗University Medical Center of Nijmegen, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands
- ††Institute of Cardiology, G. d'Annunzio University–Chieti, Chieti, Italy
- ‡‡Division of Cardiology, Kumamoto University, School of Medicine, Kumamoto City, Japan
- ↵∗Reprint requests and correspondence:
Dr. John H. Alexander, Duke Clinical Research Institute, 2400 Pratt Street, Room 0311 Terrace Level, Durham, NC 27705.
Background Bleeding limits anticoagulant treatment in patients with acute coronary syndromes (ACS).
Objectives We investigated whether background concomitant antiplatelet therapy influences the effects of apixaban after ACS.
Methods This study examined high-risk ACS patients who were treated with aspirin or aspirin plus clopidogrel and who were randomized to apixaban 5 mg twice daily or placebo. In a post-hoc analysis, we assessed whether the effect of apixaban on efficacy and safety outcomes varied by the concomitant antiplatelet regimen by using simple Cox modeling and marginal structural models with propensity scores and antiplatelet therapy as a time-dependent covariate.
Results At baseline, of 7,364 patients, 16.3% (n = 1,202) were on aspirin alone, and 79.0% (n = 5,814) were on aspirin plus clopidogrel. A total of 19.2% (n = 1,415) switched antiplatelet therapy during follow-up. No differential effect of apixaban versus placebo was observed for the composite endpoint of cardiovascular death, myocardial infarction, and ischemic stroke in patients taking aspirin (12.21 per 100 patient-years vs. 13.21 per 100 patient-years; adjusted hazard ratio [HR]: 0.91; 95% confidence interval [CI]: 0.62 to 1.32) or aspirin plus clopidogrel (13.22 vs. 14.24; adjusted HR: 0.95; 95% CI: 0.78 to 1.14; pinteraction = 0.84). Compared with placebo, apixaban increased Thrombolysis In Myocardial Infarction major bleeding in patients taking aspirin (1.48 vs. 0.25; adjusted HR: 6.62; 95% CI: 0.75 to 51.73) and in patients taking aspirin plus clopidogrel (2.58 vs. 1.02; adjusted HR: 2.44; 95% CI: 1.34 to 4.45; pinteraction = 0.41). Similar results were obtained with marginal structural models and in patients treated with and without percutaneous coronary intervention.
Conclusions Post-ACS treatment with apixaban versus placebo showed no efficacy, but it increased bleeding regardless of concomitant therapy with aspirin alone or aspirin plus clopidogrel. (Apixaban for Prevention of Acute Ischemic Events 2 [APPRAISE-2]; NCT00831441)
Despite the significant benefits of antiplatelet therapy for reducing ischemic and thrombotic events in patients with acute coronary syndromes (ACS) (1–3), patients remain at high residual risk of repeat cardiovascular events after ACS, which is perhaps in part related to persistent thrombin generation (4). Consequently, there may be a role for long-term anticoagulants in addition to antiplatelet agents for the treatment of ACS. With respect to efficacy, studies of oral anticoagulation in the ACS population have provided mixed results; although warfarin and low-dose rivaroxaban were found to reduce recurrent ischemic and thrombotic events (5–7), apixaban and dabigatran did not provide any efficacy benefits compared with placebo (8,9). In contrast, studies have consistently demonstrated increased bleeding with the addition of anticoagulation to platelet inhibition in patients after an ACS (5,8).
Altering concomitant antiplatelet regimens, such as the use of mono rather than dual antiplatelet therapy, may mitigate some of the bleeding risks of novel oral anticoagulants in patients after an ACS, but these changes might also increase ischemic events. Although only rivaroxaban has an approved indication for secondary prevention after an ACS (10), exploration of this hypothesis in the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 51) trial was limited by the fact that only 7% of enrolled patients were on single antiplatelet therapy (5). Therefore, we studied apixaban, another factor Xa inhibitor, using data from the APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Events 2) trial (8). In this post-hoc analysis, our goals were 1) to describe overall patterns of mono and dual antiplatelet therapy use over time, and 2) to examine the rates of ischemic and bleeding events in patients randomized to apixaban versus placebo in addition to aspirin alone or aspirin plus clopidogrel in the overall population and in the subgroups of patients who underwent and who did not undergo percutaneous coronary intervention (PCI).
Data source and patient population
The trial design and main results of APPRAISE-2 have been published (8). In brief, APPRAISE-2 was a double-blind, placebo-controlled randomized clinical trial of patients who experienced ACS within the previous 7 days, with symptoms of myocardial ischemia at rest, elevated cardiac biomarkers, or dynamic ST-segment changes on the electrocardiogram, and who received aspirin or aspirin plus a P2Y12 receptor inhibitor. Patients were also required to have ≥2 of the following risk factors: age ≥65 years, diabetes, myocardial infarction (MI) within the previous 5 years, cerebrovascular disease, peripheral artery disease, clinical heart failure or a left ventricular ejection fraction (LVEF) <40% associated with the index event, creatinine clearance <60 ml/min, or no revascularization after the index event.
Patients were randomized to apixaban (5 mg twice daily or 2.5 mg twice daily for a creatinine clearance <40 ml/min) versus placebo. Other treatment decisions, including the use, choice, and duration of antiplatelet therapy, were left to the discretion of treating providers. The trial was stopped early at the recommendation of the independent data monitoring committee due to increased bleeding events with apixaban without any offsetting reduction in ischemic events. A total of 7,392 patients at 858 sites from 39 countries were randomized.
Outcomes and definitions
The median duration of follow-up was 241 days (25th, 75th percentiles: 131, 352). The primary efficacy endpoint for APPRAISE-2 and for this analysis was a composite endpoint of cardiovascular death, MI, and ischemic stroke. Secondary efficacy outcomes included cardiovascular death and all-cause mortality. Thrombolysis In Myocardial Infarction (TIMI) major bleeding was the primary safety endpoint, with TIMI major or minor bleeding assessed as a secondary safety outcome. All outcomes were adjudicated by a clinical events committee blinded to treatment assignment.
For the first study objective to describe antiplatelet therapy use in the overall trial population, we defined mono antiplatelet therapy as the use of any antiplatelet agent alone (aspirin, clopidogrel, prasugrel, or ticlopidine). Dual antiplatelet therapy was defined as use of aspirin plus at least 1 thienopyridine (clopidogrel, prasugrel, or ticlopidine). Due to the small numbers of patients on non-aspirin, single antiplatelet regimens, we examined specific regimens of aspirin alone and aspirin plus clopidogrel for our main analysis population and for modeling. Daily records for antiplatelet therapy use were summarized to weekly data. Patients were considered to be on a particular regimen if they received this regimen for >50% of the week. Dosage information regarding aspirin or P2Y12 receptor inhibitors was not available.
Mono (any antiplatelet agent alone) versus dual (aspirin plus any thienopyridine) antiplatelet therapy use was described over time among the overall APPRAISE-2 trial population. The proportion of patients on mono versus dual antiplatelet therapy of all available patients was calculated for each day since randomization. Due to a small number of patients (n = 23) not on aspirin or a P2Y12 receptor inhibitor at randomization, the proportions of mono and dual antiplatelet therapy use do not equal the sum of 1. Next, we assessed the proportion of patients on mono versus dual antiplatelet therapy before randomization, at randomization, and during the course of the trial. We calculated the number, direction, and timing of switch episodes, as well as the clinical rationale for switching between mono and dual antiplatelet therapy.
The main analysis population for our study included patients taking aspirin alone or aspirin plus clopidogrel. We examined patients according to their antiplatelet therapy regimens and according to whether they received treatment with PCI. Baseline categorical variables were presented as proportions and compared using the chi-square test; continuous variables were presented as medians with 25th and 75th percentiles and compared using the Wilcoxon rank-sum test.
Outcomes were presented as the number of events and rates per 100 patient-years. The impact of aspirin alone versus aspirin plus clopidogrel use at baseline on time-to-event for outcomes was characterized using the unadjusted hazard ratio (HR) and corresponding 95% confidence interval (CI) from a Cox proportional hazards model with a binary indicator for mono antiplatelet therapy. Next, we adjusted the Cox model for the following baseline variables that were associated with either the propensity to use aspirin or aspirin plus clopidogrel and the outcomes of interest: age; sex; body mass index; history of stroke; LVEF <40%; diabetes; hypertension; MI; peripheral artery disease; congestive heart failure; renal insufficiency; history of PCI; and history of coronary artery bypass graft surgery. To assess the impact of apixaban versus placebo according to baseline antiplatelet therapy, treatment effects within each baseline antiplatelet therapy group were characterized by adjusted HRs and associated 95% CIs of the binary treatment indicator for apixaban versus placebo (simple model), including an interaction term for assigned treatment (apixaban or placebo) by antiplatelet regimen (aspirin alone or aspirin plus clopidogrel). Although apixaban versus placebo was randomized, we adjusted for the same covariates associated with either the propensity to use aspirin or aspirin plus clopidogrel and the outcomes of interest, because this randomization was not performed within the antiplatelet therapy groups, nor was the use of aspirin or aspirin plus clopidogrel groups randomized. Adjustment was performed to ensure results were due to differences in assigned treatment and not to differences in case-mix between antiplatelet groups. Interactions were tested at a significance level of 0.05.
We next examined the influence of antiplatelet therapy on outcomes based on the actual antiplatelet regimen taken by patients during follow-up, instead of categorizing patients based on antiplatelet regimen at time of randomization, as was done for the simple model analyses. We achieved this by fitting a marginal structural model (MSM) involving a Cox model and propensity score methodology with antiplatelet therapy status as a time-dependent covariate (11). Rather than only considering baseline antiplatelet status, this approach allowed group membership to change during follow-up, and patients contributed information to the antiplatelet group depending on whether they were taking aspirin or aspirin plus clopidogrel at a particular time. This strategy allowed for estimation of a more accurate and clinically relevant effect of antiplatelet therapy on outcomes. In the MSM approach, the propensity for use of aspirin versus aspirin plus clopidogrel was modeled as a function of baseline and post-baseline characteristics, and inverse probability weights were used for covariate balancing. Through an iterative process, patients were re-weighted weekly during follow-up to balance the case-mix and to adjust for baseline covariates and post-baseline, time-dependent confounders related to both outcome and switching between aspirin and aspirin plus clopidogrel. In addition to the previously listed baseline covariates, the post-randomization, time-dependent confounders for which we adjusted for in the MSM included MI, angina, PCI, PCI with stent implantation, major bleeding, any bleeding, use of study drug, and use of dual antiplatelet therapy in the previous week. Similar to the main simple Cox model, adjusted MSMs were first used to assess the association of aspirin versus aspirin plus clopidogrel with outcomes and then to examine the impact of assigned treatment according to antiplatelet therapy and the interactions therein.
Finally, we repeated simple and MSM analyses according to treatment with PCI, because these patients might be expected to have differential risks of ischemic and bleeding outcomes. Simple model analyses could not be performed in the PCI subgroup due to insufficient patient numbers. The APPRAISE-2 trial was funded by Bristol-Myers Squibb (Princeton, New Jersey) and Pfizer, Inc. (New York, New York), and the sponsors participated in the trial design and data collection. Analyses presented in this analysis were designed by the authors and performed at the Duke Clinical Research Institute using SAS (version 9.2, SAS Institute, Cary, North Carolina).
Overall antiplatelet therapy use
Of the 7,392 patients randomized in APPRAISE-2, 23 patients were not on baseline aspirin or a P2Y12 receptor inhibitor, and 5 patients were not on a P2Y12 receptor inhibitor and were missing information on aspirin use, which left 7,364 patients with known baseline antiplatelet status (Figure 1). Of these 7,364 patients, 18.6% (n = 1,369) were on mono antiplatelet therapy, and 81.4% (n = 5,995) were on dual antiplatelet therapy at baseline. Among the patients on mono antiplatelet therapy, 87.8% (n = 1,202) were on aspirin alone, 11.8% (n = 162) were on clopidogrel alone, and a small minority was taking prasugrel or ticlopidine alone. Among the patients taking dual antiplatelet therapy, 97.2% (n = 5,826) were on clopidogrel, 2.6% (n = 155) were on prasugrel, and 0.4% (n = 26) were on ticlopidine.
Table 1 shows a summary of antiplatelet therapy switching in the overall population of 7,364 patients during the study period. Before the index ACS event, 54.1% (n = 3,987) of patients were not taking any antiplatelet therapy, 31.0% (n = 2,279) were on mono antiplatelet therapy, and 14.9% (n = 1,098) were on dual antiplatelet therapy. After randomization, 19.2% (n = 1,415) switched antiplatelet regimens. Among those who switched, the median times (25th, 75th percentiles) to first switch for patients on baseline mono and dual antiplatelet therapy were 19 days (4, 97) and 41 days (12, 109), respectively. Slightly more than one-half of the patients in both groups only switched therapies once. Most patients on monotherapy switched to dual therapy, with a PCI procedure listed as the most common indication for this occurrence. Among patients on dual antiplatelet therapy at baseline, almost all switches were to mono antiplatelet therapy. Bleeding was the most common reason for switching therapies, although 78.5% (n = 124) of the 224 patients on dual antiplatelet therapy at baseline with major bleeding events remained on dual antiplatelet regimens.
For our main analysis population, we were specifically interested in comparing the 2 most common antiplatelet regimens: aspirin alone versus aspirin plus clopidogrel. The mono antiplatelet therapy, or aspirin alone, group consisted of 1,202 patients. The dual antiplatelet therapy, or aspirin plus clopidogrel, group included 5,814 patients. Although Figure 1 shows that 5,826 patients were on aspirin plus clopidogrel, 9 patients on concomitant prasugrel and 3 patients also on ticlopidine were excluded from our analysis. Figure 2 shows the use of aspirin alone over time for the overall cohort and by treatment with or without PCI. Overall, 43.5% (n = 3,054) of patients were treated with PCI for their index ACS event; of the 56.5% (n = 3,962) of patients not treated with PCI, 99.0% (n = 3,924) received medical management, and 1.0% (n = 38) underwent coronary artery bypass graft surgery. Compared with patients without PCI, PCI-treated patients were more frequently taking dual antiplatelet therapy at randomization (98.9% vs. 70.5%). Over time, use of mono antiplatelet therapy increased, whereas use of dual antiplatelet therapy decreased.
As expected, baseline characteristics between randomized apixaban and placebo groups were well-matched. Therefore, we examined baseline characteristics according to use of aspirin versus aspirin plus clopidogrel. As shown in Table 2, the largest proportion of patients on aspirin only were enrolled in Eastern Europe, whereas enrollment of patients on aspirin plus clopidogrel was more even across geographic regions. Compared with patients on aspirin alone, patients on aspirin plus clopidogrel were more often male, had a greater burden of comorbidities (including diabetes, previous MI, peripheral artery disease, and previous coronary revascularization), and more frequently presented with MI (versus unstable angina). Patients on dual antiplatelet therapy were less likely to have previous or current heart failure and were referred more often for coronary angiography than patients on mono antiplatelet therapy.
Outcomes among patients on aspirin versus aspirin plus clopidogrel at baseline
From the simple Cox models adjusted for baseline characteristics, we found that the rates of the composite of cardiovascular death, MI, or ischemic stroke were similar between the dual and mono antiplatelet therapy groups (13.73 per 100 patient-years of follow-up [436 events] vs. 12.70 per 100 patient-years of follow-up [108 events]; adjusted HR: 1.07; 95% CI: 0.85 to 1.34). Observed rates of cardiovascular death (4.58 [151 events] vs. 6.47 [57 events]; adjusted HR: 0.81; 95% CI: 0.58 to 1.13) and all-cause mortality (6.21 [208 events] vs. 9.10 [81 events]; adjusted HR: 0.77; 95% CI: 0.58 to 1.02) were lower for dual versus mono antiplatelet therapy. In contrast, we observed higher rates of TIMI major bleeding (1.79 [52 events] vs. 0.87 [7 events]; adjusted HR: 1.47; 95% CI: 0.64 to 3.41) and higher rates of TIMI major or minor bleeding (3.13 [91 events] vs. 1.24 [10 events]; adjusted HR: 2.06; 95% CI: 1.04 to 4.07) for aspirin plus clopidogrel compared with aspirin therapy alone. Similar results were obtained using the MSM approach to adjust for baseline and post-baseline characteristics and to account for actual post-randomization antiplatelet therapy use.
Impact of antiplatelet regimen on treatment with apixaban versus placebo
Outcomes were examined among patients randomized to apixaban versus placebo taking aspirin alone or aspirin plus clopidogrel. Observed rates and unadjusted HRs for outcomes are listed in Table 3. More than 60% of the composite ischemic endpoint was comprised of MI events, and there were low numbers of ischemic stroke and stent thrombosis in the aspirin only group. Figure 3 and the Central Illustration show the adjusted effect estimates for apixaban versus placebo according to baseline antiplatelet therapy and in patients without PCI using simple Cox modeling. Apixaban versus placebo had similar effects on the risk of the composite of cardiovascular death, MI, or ischemic stroke among patients taking aspirin alone or aspirin plus clopidogrel (monotherapy: adjusted HR: 0.91; 95% CI: 0.62 to 1.32 vs. dual therapy: adjusted HR: 0.95; 95% CI: 0.78 to 1.14; pinteraction = 0.84). No differential effects of apixaban were observed for cardiovascular death (pinteraction = 0.74), all-cause mortality (pinteraction = 0.36), or any outcome among the no PCI subgroup according to concomitant antiplatelet therapy. Figure 4 shows that similar results were obtained, including among the PCI subgroup, after repeating the analyses using MSM.
Figure 3 also shows bleeding outcomes among patients assigned to apixaban versus placebo on aspirin alone or aspirin plus clopidogrel and according to PCI status. In general, bleeding rates for patients on aspirin plus clopidogrel were higher than for patients taking aspirin alone. Compared with placebo, apixaban increased both absolute and relative rates of TIMI major bleeding among patients taking aspirin only (1.48 per 100 patient-years follow-up vs. 0.25 per 100 patient-years follow-up; adjusted HR: 6.22; 95% CI: 0.75 to 51.73) and aspirin plus clopidogrel (2.58 vs. 1.02; adjusted HR: 2.44; 95% CI: 1.34 to 4.45; pinteraction = 0.41). We also found a significantly greater increase in apixaban-related TIMI major or minor bleeding in both the aspirin alone and aspirin plus clopidogrel groups (aspirin: 2.24 vs. 0.25; adjusted HR: 8.85; 95% CI: 1.12 to 69.89 vs. aspirin plus clopidogrel: 4.54 vs. 1.76; adjusted HR: 2.53; 95% CI: 1.61 to 4.00; pinteraction = 0.25). Figure 4 shows that similar results were obtained using MSM modeling.
Using data from the APPRAISE-2 trial, we found that approximately 20% of patients changed antiplatelet therapy regimen at least once after randomization. There was no effect on efficacy and increased bleeding risk for apixaban versus placebo among patients on aspirin alone or aspirin plus clopidogrel. We obtained similar results with MSM analyses to account for antiplatelet therapy switching during follow-up. These data suggest that use of novel oral anticoagulants with a strategy of concomitant aspirin alone compared with aspirin plus clopidogrel might not improve the safety of these agents. Further investigation with prospective studies evaluating other alterations in antithrombotic regimens, such as monotherapy with P2Y12 receptor inhibitors, should be pursued.
There is great interest in improving the safety of novel oral anticoagulant use in ACS, but there are limited data exploring the issue. A recent meta-analysis of 7 placebo-controlled randomized trials found that the addition of a novel oral anticoagulant to aspirin reduced the incidence of cardiovascular events (HR: 0.70; 95% CI: 0.59 to 0.84) but increased bleeding (HR: 1.79; 95% CI: 1.54 to 2.09) (12). Adding a novel oral anticoagulant to aspirin plus clopidogrel resulted in a modest decrease in cardiovascular events (HR: 0.87; 95% CI: 0.80 to 0.95) but also more than doubled the risk of bleeding (HR: 2.34; 95% CI: 2.06 to 2.66) (4). Although intriguing, the study was limited by the inclusion of anticoagulants such as ximelagatran that are no longer commercially available, as well as phase II clinical trials (including drug doses not evaluated in phase III studies). The meta-analysis was also not performed using patient-level data. The phase III clinical trials included in this analysis were ATLAS ACS-2 TIMI-51 and APPRAISE-2. On the basis of the results of ATLAS ACS-2 TIMI-51, rivaroxaban was approved for use in ACS patients in Europe, but this trial included a small percentage of patients on single antiplatelet therapy, precluding examination of concomitant aspirin-only use in the study.
We therefore examined the use of apixaban for ACS on the background of aspirin alone versus aspirin plus clopidogrel. In contrast to rivaroxaban, in APPRAISE-2, apixaban caused excess bleeding without ischemic benefit, which led to early trial termination. It should be noted that APPRAISE-2 tested the same dose of apixaban used for stroke prevention in nonvalvular atrial fibrillation and included higher risk patients than those patients in ATLAS ACS-2 TIMI-51, which studied one-quarter or one-half of the drug dose used for atrial fibrillation. These factors, as well as the shorter trial duration of APPRAISE-2 or chance, could potentially account for the differences in the trial results. Like rivaroxaban, apixaban is a factor Xa inhibitor. There appears to be a class effect on bleeding with the same 3- to 4-fold relative increase in bleeding relative to the baseline observed in phase II and phase III trials of these oral anticoagulants in this population (5,7,8,13). Thus, despite the early termination of APPRAISE-2, this analysis might provide hypothesis-generating insight into optimizing the use of novel oral anticoagulants such as rivaroxaban, especially because an analogous study from ATLAS ACS-2 TIMI-51 cannot be performed.
In our study, randomization of patients occurred at a median of 6 days after the index ACS event. In accordance with ACS treatment guidelines (14–17), almost all patients (97%) were on aspirin at baseline. However, 19% of patients were on a single antiplatelet agent at randomization, despite guidelines recommendations for dual antiplatelet therapy for ACS. This might be partially due to regional variation in practice patterns, because the majority of patients on baseline monotherapy were enrolled in Eastern Europe. Although we did not observe lower rates of ischemic events in patients treated with dual antiplatelet therapy versus monotherapy, as was demonstrated in randomized clinical trials (1), this was likely due to the nonrandomized use of antiplatelet medications and residual confounding in our study. These findings of underuse and regional variation in use of dual antiplatelet therapy in ACS deserve further exploration.
We also found that approximately 1 in 5 patients switched antiplatelet therapies after randomization. Because of these changes, we used statistical methodology to account for actual, not just baseline, use of aspirin versus aspirin plus clopidogrel in our analyses. We adjusted for not only baseline features, but we also weighted time-dependent covariates associated with antiplatelet therapy use and discontinuation. Using 2 statistical approaches and in subgroup analyses, we consistently found that apixaban versus placebo increased bleeding when added to either aspirin alone or aspirin plus clopidogrel. These findings suggested that this strategy might not improve the safety of novel oral anticoagulants for post-ACS treatment, although prospective studies are needed to confirm this.
Efforts to improve the safety of oral anticoagulation should continue to assess different combinations of antithrombotic agents. One potential approach might be to use concomitant single antiplatelet therapy. A previous study found that monotherapy with clopidogrel plus warfarin caused less bleeding and had no increase in thrombotic complications compared with clopidogrel plus aspirin in patients who underwent PCI (18). However, less than one-third of patients in this trial presented with ACS, and neither newer P2Y12 receptor antagonists, such as prasugrel or ticagrelor, nor novel oral anticoagulants, were studied. Additional insight into this area will come from the COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease; NCT01776424) trial, which will test rivaroxaban with versus without aspirin in patients with remote ACS. These results will have to be reconciled with those from the recent DAPT (Dual Antiplatelet Therapy) trial, which suggested benefit of prolonged dual antiplatelet therapy after PCI with a drug-eluting stent, and the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) trial, which showed benefit of ticagrelor for patients with previous remote MI, although patients on long-term anticoagulation were excluded from these trials (19,20). In addition, because of the increasing number of patients with multiple indications for anticoagulant and antiplatelet therapies, important data to help define optimal regimens for secondary prevention of ACS might also come from trials such as PIONEER AF-PCI (A Study Exploring Two Strategies of Rivaroxaban and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention; NCT01830543) and REDUAL PCI (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting; NCT02164864), which are studying the use of novel oral anticoagulants in patients with atrial fibrillation who are undergoing PCI.
The use of apixaban versus placebo was not randomized within antiplatelet therapy groups, nor was the use of aspirin alone or aspirin plus clopidogrel randomized. Despite adjustment for baseline and post-randomization variables, residual confounding likely exists. The use of concomitant antiplatelet therapy was not blinded, and there might have been differential post-baseline use of these therapies among patients on apixaban versus placebo. We did not have data regarding aspirin dosing, nor did we have a sufficient sample size to analyze patients on clopidogrel monotherapy. This analysis had limited power to detect modest, but still potentially clinically important differences, in the overall population and particularly in subgroups and for interactions between subgroups. Furthermore, this study was a subgroup analysis from a randomized clinical trial, and these results might not be applicable to the general population. Finally, APPRAISE-2 was terminated early, which would lead to an overestimation not only of the event rate leading to termination (bleeding) but also to the lack of efficacy seen with apixaban versus placebo.
Secondary prevention of ACS with novel oral anticoagulants on a background of antiplatelet therapy is limited by bleeding. Treatment after ACS with the factor Xa inhibitor apixaban versus placebo did not affect ischemic outcomes, but it did increase bleeding, regardless of concomitant aspirin alone or aspirin plus clopidogrel. A prospective study of alternative combinations of antithrombotic therapies, including use of novel oral anticoagulants with mono antiplatelet therapy, and different durations of treatment are needed to optimize the risk–benefit ratio of these drugs in this population.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Although antiplatelet therapy reduces the risk of ischemic and thrombotic events in patients with ACS, persistent thrombin generation may contribute to a residual risk of recurrent cardiovascular events. Addition of an anticoagulant may prevent ischemic events but increases the risk of bleeding. Greater bleeding was observed when the oral factor Xa inhibitor, apixaban, was given concomitantly with aspirin or with the combination of aspirin plus clopidogrel.
TRANSLATIONAL OUTLOOK: Additional studies are needed to develop safer and more effective antithrombotic strategies for secondary prevention of ischemic events in patients with ACS.
The authors thank Elizabeth Cook for her editorial contributions to this paper. Ms. Cook did not receive compensation for her contributions, apart from her employment at the institution where this study was conducted.
The APPRAISE-2 trial was funded by Bristol-Myers Squibb and Pfizer. Dr. Hess has received a research grant from Gilead Sciences, Inc. Dr. Lopes has received consulting fees and honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Glaxo-SmithKline, Portola, and Pfizer. Dr. Bhatt has received consulting fees and honoraria from Elsevier Practice Update Cardiology; research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, St. Jude Medical, The Medicines Company; is on the Advisory Board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; the Board of Directors for Boston VA Research Institute, Society of Cardiovascular Patient Care; is the Chair for the American Heart Association Get With The Guidelines Steering Committee; is a member of the Data Monitoring Committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; and has received additional honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), WebMD (CME steering committees), and Clinical Cardiology (Deputy Editor). Dr. Husted is a member of the Advisory Board for AstraZeneca, Bayer, Pfizer, Bristol-Myers Squibb, and Boehringer Ingelheim. Dr. Goodman has received research grant support and speaker/consulting honoraria from Bristol-Myers Squibb, Pfizer, Bayer, Johnson & Johnson, Boehringer Ingelheim, Daiichi-Sankyo, AstraZeneca, Eli Lilly, and Sanofi; and has received honoraria and is a member of the steering committee for the APPRAISE-2 trial (sponsored by Duke Clinical Research Institute and trial sponsors Bristol-Myers Squibb and Pfizer). Dr. Lewis has received consulting fees from and served as a speaker for Bristol-Myers Squibb and Pfizer; and is on the Advisory Boards for MSD and AstraZeneca. Dr. Verheugt has received consulting fees from Bristol-Myers Squibb, Pfizer, and Bayer Healthcare. Dr. De Caterina has received consulting fees from Bristol Myers-Squibb, Pfizer, Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Merck, Lilly, and Novartis. Dr. Ogawa has received honoraria from AstraZeneca, Bayer, Daiichi-Sankyo, MSD, Pfizer, Sanofi, and Takeda; and has received other research support from AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Dainippon Sumitomo Pharma, Kowa, MSD, Novartis, Otsuka, Pfizer, Sanofi, and Takeda. Dr. Wallentin has received consulting fees and honoraria from Abbott, AstraZeneca, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Regado Biosciences, Boehringer Ingelheim, and Athera Biotechnologies; has received research grants from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Merck/Schering-Plough, Bristol-Myers Squibb/Pfizer; has received lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Bristol-Myers Squibb/Pfizer; and has received travel support from AstraZeneca, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline. Dr. Alexander has received research grants from Bristol-Myers Squibb, Boehringer Ingelheim, CSL Behring, the National Institutes of Health, Regado Biosciences, Sanofi, Tenex Therapeutics, and Vivus Pharmaceuticals; and has received consulting fees from Portola Pharmaceuticals, Sohmalution, VA Cooperative Studies Program, and Bristol-Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Marc Sabatine, MD, MPH, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- confidence interval
- hazard ratio
- left ventricular ejection fraction
- myocardial infarction
- marginal structural model
- percutaneous coronary intervention
- Thrombolysis In Myocardial Infarction
- Received March 20, 2015.
- Revision received May 21, 2015.
- Accepted June 4, 2015.
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