Rivaroxaban With or Without Aspirin in Stable Cardiovascular Disease Peer Review
Original Article
Rivaroxaban with or without Aspirin in Stable Cardiovascular Affliction
Listing of authors.Abstract
Groundwork
We evaluated whether rivaroxaban solitary or in combination with aspirin would exist more effective than aspirin lone for secondary cardiovascular prevention.
Methods
In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg in one case daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a blended of cardiovascular expiry, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-upward of 23 months.
Results
The main outcome occurred in fewer patients in the rivaroxaban-plus-aspirin grouping than in the aspirin-lone group (379 patients [iv.1%] vs. 496 patients [5.iv%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=−4.126), only major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [iii.ane%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, i.40 to 2.05; P<0.001). There was no significant departure in intracranial or fatal bleeding between these 2 groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group every bit compared with 378 (iv.i%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary effect did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-lone group, just major bleeding events occurred in more patients in the rivaroxaban-alone group.
Conclusions
Amongst patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) lonely did not effect in improve cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424.)
Methods
Trial Conduct
The COMPASS trial, conducted at 602 centers in 33 countries, is a double-blind, double-dummy, randomized trial using a iii-by-2 partial factorial blueprint and involving patients with a history of stable atherosclerotic vascular disease.9 In one randomized comparison (now completed and reported here), rivaroxaban with or without aspirin was compared with aspirin alone. In the other randomized comparing (yet ongoing), pantoprazole is being compared with placebo in patients participating in the trial who are not receiving a proton-pump inhibitor. For an overview of the report design, run into Tabular array S1 in the Supplementary Appendix, available with the full text of this commodity at NEJM.org.
The trial sponsor is Bayer. The steering committee, comprising Population Wellness Research Establish (PHRI) investigators, study leaders in each country, and Bayer representatives, was responsible for the development of the protocol, which is available at NEJM.org, and for the acquit and oversight of the written report. The protocol was approved by the relevant health authorities and institutional review boards. A list of participating investigators and committee members is provided in the Supplementary Appendix. All the data analyses were independently performed at PHRI. The first author vouches for the abyss and accurateness of the data and analyses and for the fidelity of the trial to the protocol.
Eligibility
Patients were eligible if they provided written informed consent and met the criteria for coronary artery affliction, peripheral arterial disease, or both (see the Supplementary Appendix). Patients with coronary artery disease who were younger than 65 years of age were also required to have documentation of atherosclerosis involving at least 2 vascular beds or to have at to the lowest degree two boosted risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate [GFR] <60 ml per infinitesimal, heart failure, or nonlacunar ischemic stroke ≥i month earlier). Exclusion criteria were a loftier bleeding risk; a contempo stroke or previous hemorrhagic or lacunar stroke; severe eye failure; avant-garde stable kidney disease (estimated GFR <15 ml per minute); the employ of dual antiplatelet therapy, anticoagulation, or other antithrombotic therapy; and noncardiovascular weather condition deemed by the investigator to be associated with a poor prognosis. In improver, patients receiving a proton-pump inhibitor were not eligible for the pantoprazole randomization. Written informed consent was obtained from all the participants.
Randomization and Follow-up
Eligible participants (except those who underwent randomization four to fourteen days later coronary-artery bypass graft [CABG] surgery) entered a run-in stage during which they received a rivaroxaban-matched placebo twice daily and aspirin at a dose of 100 mg one time daily. The purpose of the run-in stage was to identify participants who were unwilling or unable to adhere to the trial regimen, who had adverse events, or who were otherwise not suitable for randomization. Patients who underwent randomization 4 to 14 days afterwards CABG surgery were not required to participate in the run-in phase considering thrombotic graft apoplexy is nearly mutual during the first few weeks afterward surgery and we sought to enroll such patients promptly.
Participants who adhered to the assigned regimen and who did not have agin events, as well every bit those enrolled 4 to 14 days subsequently CABG surgery, were randomly assigned in a 1:1:1 ratio to receive rivaroxaban (two.five mg twice daily) plus aspirin (100 mg in one case daily), rivaroxaban (5 mg twice daily) with an aspirin-matched placebo in one case daily, or aspirin (100 mg once daily) with a rivaroxaban-matched placebo twice daily, stratified according to center and the utilize of proton-pump inhibitor therapy at the time of randomization. Study aspirin was enteric-coated. Patients who were eligible for the proton-pump inhibitor randomization were likewise randomly assigned in a ane:1 ratio to receive pantoprazole (40 mg once daily) or matched placebo. Later on randomization, participants were seen at 1 and vi months and so at 6-month intervals.
Outcomes
The master efficacy outcome for the randomized comparison of rivaroxaban with or without aspirin versus aspirin solitary was the blended of cardiovascular expiry, stroke, or myocardial infarction. The main safety outcome was a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria for major bleeding and included fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization (including presentation to an astute care facility without an overnight stay). Dissimilar the ISTH criteria,10 we considered all bleeding that led to presentation to an acute care facility or hospitalization equally major.
3 secondary efficacy outcomes were specified: the composite of ischemic stroke, myocardial infarction, astute limb ischemia, or decease from coronary heart disease; the composite of ischemic stroke, myocardial infarction, acute limb ischemia, or cardiovascular death; and death from whatsoever cause. Tertiary efficacy outcomes included individual components of the primary and secondary outcomes, as well as hospitalization for cardiovascular causes, revascularization, limb amputation, stent thrombosis, angina, eye failure, venous thromboembolism, resuscitated cardiac arrest, and a new diagnosis of cancer. The cyberspace-clinical-benefit outcome was the composite of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a disquisitional organ. The primary outcome for the pantoprazole versus placebo randomization was upper gastrointestinal complications.ix Effect definitions and a full list of prespecified events included in this report are provided in the Supplementary Appendix.
Statistical Analysis
We planned on enrolling 27,400 participants. As an event-driven trial, with an expected control-group event rate of 3.3 per 100 person-years, it was designed to keep until at to the lowest degree 2200 participants had a confirmed primary efficacy effect, thereby providing ninety% ability to detect a 20% lower risk in each of the two comparisons of rivaroxaban versus aspirin.
An independent data and safety monitoring board monitored the study, with formal stopping guidelines for efficacy and nonformal guidelines for rubber. Two formal interim analyses of efficacy were planned, when 50% and 75% of main efficacy events had occurred. A modified Haybittle–Peto dominion was used, which required a deviation of iv SD at the first acting analysis that was consequent over a period of 3 months, and a consequent deviation of iii SD at the 2d interim analysis (see the Supplementary Appendix).
All the outcome events in all randomly assigned patients that occurred betwixt randomization and the appointment of stopping the trial were included in the assay, according to the intention-to-treat principle. Comparisons betwixt each of the rivaroxaban-based groups and the common aspirin command group were performed with the use of 2 separate log-rank tests stratified according to treatment with a proton-pump inhibitor (non randomly assigned to a proton-pump inhibitor, pantoprazole at a dose of 40 mg once daily, or a pantoprazole-matched placebo in one case daily). To address multiplicity related to testing ii primary and 6 secondary hypotheses, we planned to use a mixture gatekeeping process based on the Hochberg test to control the familywise error rate of 5%11 (meet the Supplementary Appendix). Nevertheless, an early stop of both antithrombotic treatment groups for efficacy had not been anticipated, and therefore a strategy for formal testing of secondary outcomes at the interim analysis was not prespecified.
Kaplan–Meier estimates of the cumulative chance were used to evaluate the timing of event occurrences in the three antithrombotic treatment groups. Gamble ratios and corresponding 95% confidence intervals were obtained from stratified Cox proportional-hazards models. The assumptions of the Cox models were verified with plots of log of negative log of the survival function against the log of time. All reported P values are two-sided.
Results
Participants
From March 2013 through May 2016, a full of 27,395 persons who successfully completed the run-in phase or who were enrolled 4 to 14 days later on CABG surgery were randomly assigned to rivaroxaban plus aspirin, rivaroxaban, or aspirin (Fig. S1 in the Supplementary Appendix). A total of 2320 participants did non successfully consummate the run-in phase and were excluded.
Table ane.
Table 1. Baseline Characteristics of the Participants. Baseline characteristics are presented in Table ane. The hateful historic period of participants was 68.ii years, and 22.0% were women. Lipid-lowering agents were used by 89.8%, and angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers past 71.ii%. The mean systolic blood pressure was 136 mm Hg, the mean diastolic blood pressure 78 mm Hg, and the mean total cholesterol level iv.ii mmol per liter (162 mg per deciliter). A total of ninety.6% of the participants had a history of coronary artery affliction, and 27.iii% had a history of peripheral arterial affliction.
Early on Termination, Follow-up, and Adherence
At the first formal acting analysis for efficacy (l% of planned events), the independent data and condom monitoring board recommended early termination of the randomized comparison of rivaroxaban with or without aspirin versus aspirin alone on February 6, 2017, having observed a consistent departure in the primary efficacy upshot in favor of rivaroxaban plus aspirin (z=−iv.592).
The z statistic for the comparison of rivaroxaban plus aspirin versus aspirin alone was larger than the prespecified 4 SD, but the z statistic for the comparison of rivaroxaban lone versus aspirin lone had not met this criterion (z=−2.44). Because at that place was a statistically pregnant consequence for both comparisons, the information and rubber monitoring board recommended stopping the rivaroxaban and aspirin groups of the trial.
Follow-upwards for the comparison of pantoprazole versus placebo connected and is ongoing. Vital status was available for 27,331 participants (99.8%) to February 6, 2017, and the mean duration of follow-upward of these participants was 23 months (maximum elapsing, 47 months). At the terminal visit for this component of the trial, the per centum of participants who had permanently discontinued study treatment was 16.5% in the rivaroxaban-plus-aspirin group, 17.0% in the rivaroxaban-alone group, and 15.7% in the aspirin-alone group.
Chief Efficacy Outcome
Tabular array 2.
Table ii. Efficacy Outcomes. Figure 1. 
Effigy 1. Cumulative Incidence of the Primary Efficacy Outcome among Participants Receiving Rivaroxaban plus Aspirin, Rivaroxaban Alone, or Aspirin Alone. Participants in the rivaroxaban-plus-aspirin group received ii.v mg of rivaroxaban twice daily and 100 mg of aspirin once daily. Participants in the rivaroxaban-alone grouping received 5 mg of rivaroxaban twice daily and an aspirin-matched placebo once daily. Participants in the aspirin-alone grouping received 100 mg of aspirin once daily and a rivaroxaban-matched placebo twice daily. The inset shows the same information on an expanded y axis.
A primary outcome event of cardiovascular death, stroke, or myocardial infarction occurred in 379 patients (iv.1%) who were assigned to rivaroxaban plus aspirin, 448 (four.9%) who were assigned to rivaroxaban lonely, and 496 (five.iv%) who were assigned to aspirin alone (Table 2 and Figure ane). For the comparison of rivaroxaban (two.5 mg twice daily) plus aspirin with aspirin alone, the hazard ratio for the main outcome was 0.76 (95% conviction interval [CI], 0.66 to 0.86; P<0.001; z=−iv.126). For the comparison of rivaroxaban (5 mg twice daily) alone with aspirin solitary, the hazard ratio was 0.90 (95% CI, 0.79 to 1.03; P=0.12; z=−one.575).
Secondary Efficacy Outcomes
The secondary blended outcome of ischemic stroke, myocardial infarction, acute limb ischemia, or death from coronary center illness occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (329 patients [iii.6%] vs. 450 patients [4.nine%]; hazard ratio, 0.72; 95% CI, 0.63 to 0.83; P<0.001) (Table 2). The secondary consequence of ischemic stroke, myocardial infarction, acute limb ischemia, or cardiovascular death as well occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (389 patients [four.3%] vs. 516 patients [v.vii%]; adventure ratio, 0.74; 95% CI, 0.65 to 0.85; P<0.001). There were 313 deaths (three.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (iv.ane%) in the aspirin-lonely grouping (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01). The threshold P value using the Hochberg procedure for each of the above comparisons was 0.0025. For the regimen of rivaroxaban alone as compared with aspirin solitary, because no meaning effect was seen for the primary composite outcome, formal testing of the secondary outcomes was not performed.
Haemorrhage and Other Adverse Events
Tabular array 3.
Table 3. Bleeding Events and Net Clinical Benefit. Major bleeding events occurred in more than patients in the rivaroxaban-plus-aspirin grouping than in the aspirin-lone group (288 patients [3.one%] vs. 170 patients [ane.9%]; hazard ratio, one.70; 95% CI, 1.40 to 2.05; P<0.001) (Table 3), mainly owing to a deviation in bleeding that led to presentation to an acute intendance facility or hospitalization. Virtually of the excess major bleeding was into the gastrointestinal tract, with no pregnant between-group difference in the charge per unit of fatal haemorrhage, intracranial bleeding, or symptomatic bleeding into a critical organ. The rate of major bleeding equally defined by the ISTH criteria (the composite of fatal haemorrhage, bleeding into a disquisitional organ, haemorrhage requiring ≥2 units of transfusion inside 48 hours, and bleeding associated with a decrease in the hemoglobin level of ≥ii k per deciliter) was significantly greater with rivaroxaban plus aspirin than with aspirin alone.
Major bleeding events occurred in more patients in the rivaroxaban-alone group than in the aspirin-solitary group (255 patients [2.8%] vs. 170 patients [1.9%]; hazard ratio, i.51; 95% CI, 1.25 to 1.84; P<0.001) (Table 3). The excess major haemorrhage included symptomatic bleeding into a disquisitional organ and bleeding that led to hospitalization.
Serious adverse events were reported in 721 patients (7.9%) assigned to rivaroxaban plus aspirin, 702 (seven.7%) assigned to rivaroxaban alone, and 662 (7.three%) assigned to aspirin alone. Details of serious adverse events co-ordinate to system organ class are shown in Table S2 in the Supplementary Appendix.
Internet Clinical Benefit
The risk of the blended net-clinical-benefit consequence of cardiovascular death, stroke, myocardial infarction, fatal haemorrhage, or symptomatic haemorrhage into a critical organ was lower with rivaroxaban plus aspirin than with aspirin lonely (431 patients [four.7%] vs. 534 patients [5.ix%]; chance ratio, 0.lxxx; 95% CI, 0.70 to 0.91; P<0.001) (Table iii). The take chances of the net-clinical-benefit consequence was not significantly lower with rivaroxaban alone than with aspirin alone.
Subgroup Analyses
Figure 2.
Figure 2. Subgroup Analyses for the Principal Outcome for the Comparing of Rivaroxaban plus Aspirin with Aspirin Alone. The size of each box is proportional to the number of events. Arrows indicate that the limits of the conviction interval are not shown. The subgroup labeled "Western Europe" also includes participants in Israel, Commonwealth of australia, and South Africa. GFR denotes glomerular filtration rate.
The effects of rivaroxaban plus aspirin as compared with aspirin lonely on the master upshot (Figure ii) and on major bleeding (Fig. S2 in the Supplementary Appendix) were consequent among subgroups that were defined co-ordinate to age, sex, geographic region, race or ethnic grouping, body weight, renal role, and history of cardiovascular risk factors (tobacco use, hypertension, diabetes, or dyslipidemia). Results in participants who met the eligibility criteria for coronary avenue disease and in those who met the eligibility criteria for peripheral arterial illness were also consequent and are being reported separately.12,13
Discussion
Amid patients with stable atherosclerotic vascular disease, a high proportion of whom were receiving proven secondary prevention therapies, the rate of the primary outcome (a blended of cardiovascular decease, stroke, or myocardial infarction) was lower by 24% with rivaroxaban (2.5 mg twice daily) plus aspirin than with aspirin solitary (four.1% vs. v.four%), but the charge per unit of major bleeding was higher by 70% (three.1% vs. 1.9%). The rate of the net-clinical-benefit issue was lower by 20% with rivaroxaban plus aspirin than with aspirin alone (four.7% vs. 5.9%). The comparison of rivaroxaban (five mg twice daily) lone with aspirin lone did not show a significant difference in the primary outcome or the cyberspace-clinical-benefit upshot, but the rate of major bleeding was higher with rivaroxaban lone.
Various antithrombotic regimens have been tested as alternatives to aspirin for long-term cardiovascular prevention. Trials of vitamin M antagonists involving patients with stable cardiovascular disease showed a reduction in the risk of subsequent cardiovascular events,3 merely there was no benefit in patients with peripheral arterial disease,xiv and at that place was a meaning increase in bleeding, including intracranial haemorrhage.iii,14 Among patients with stable cardiovascular disease, those who received clopidogrel had a lower risk of major agin cardiovascular events than those who received aspirin, but there was no significant difference in the risk of cardiovascular death or death from whatever cause.fifteen Among patients with symptomatic stable cardiovascular disease or multiple risk factors, the combination of clopidogrel and aspirin did not event in a significantly lower rate of major adverse cardiovascular events or expiry from any cause than aspirin solitary.16 Among patients who had had myocardial infarction 1 to 3 years previously, the combination of ticagrelor and aspirin resulted in a lower rate of major adverse cardiovascular events and a higher rate of major bleeding than aspirin alone, and at that place was no significant betwixt-grouping difference in mortality.17 Among patients with stable peripheral arterial affliction, ticagrelor did non issue in a significantly lower rate of major agin cardiovascular events than clopidogrel.18 Amid patients with stable cardiovascular affliction who were receiving unmarried or dual antiplatelet therapy, vorapaxar resulted in a lower rate of major adverse cardiovascular events and a higher rate of moderate or severe bleeding than placebo, with no significant between-group difference in mortality.19
The potential do good of rivaroxaban in patients with cardiovascular affliction was previously evaluated in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Astute Coronary Syndrome 2–Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2–TIMI 51) trial. This trial tested rivaroxaban on a background of single or dual antiplatelet therapy in patients with a recent acute coronary syndrome. Rivaroxaban at a dose of 2.5 mg twice daily or 5 mg twice daily resulted in a lower charge per unit of major adverse cardiovascular events than placebo, and the dose of 2.v mg twice daily resulted in lower bloodshed,8 findings consistent with the COMPASS results. The mean duration of rivaroxaban handling in the ATLAS ACS 2–TIMI 51 trial was xiii.3 months, whereas persons enrolled in the COMPASS trial who had a history of myocardial infarction were enrolled a hateful of 7.ane years after the astute event and continued to receive treatment for a mean of 23 months.
The definition of major bleeding in the COMPASS trial was based on the ISTH definition, which includes fatal haemorrhage, symptomatic haemorrhage into a critical area or organ, bleeding causing a subtract in the hemoglobin level of two g or more per deciliter, or bleeding that led to transfusion of two or more than units of whole blood or red cells. Even so, the definition used in the COMPASS trial, which had been adopted in response to a request from regulators, differed from the ISTH definition in that it did non take into account whether haemorrhage was associated with a decrease in the hemoglobin level or with claret transfusion, and it included any bleeding that led to hospitalization with or without an overnight stay, thus including events that would non be considered major bleeding in other trials. Although there was also a significant increase in the rate of major bleeding with rivaroxaban with the utilize of the ISTH scale, there were approximately one third fewer major bleeding events with this definition than with the utilise of the modified ISTH definition. Our definition of cyberspace clinical benefit counterbalanced the lower risk of cardiovascular death, stroke, or myocardial infarction against the most serious bleeding events and showed a significant benefit of combination therapy.
In that location are a few limitations of the trial that should exist considered. First, nosotros did not specifically written report patients with a previous stroke. All the same, of those enrolled, 1032 also had a history of stroke, and the benefits of the combination of rivaroxaban and aspirin in preventing cardiovascular expiry, stroke, or myocardial infarction were consequent in these patients. Furthermore, the combination of rivaroxaban and aspirin resulted in a lower rate of ischemic stroke than aspirin alone. 2nd, although the bulk of patients were receiving proven secondary prevention therapies, and the claret pressure and total cholesterol levels were serially recorded during the study, we did not specifically record statin use or low-density lipoprotein cholesterol levels at baseline, and the trial protocol did non specifically emphasize aggressive use of secondary prevention therapies to lower blood pressure and cholesterol levels. However, the results were consequent in patients with baseline claret pressure below or above the mean and in those with baseline cholesterol levels beneath or in a higher place the median, supporting the decision that the benefits of combination therapy are additive to those of other proven secondary preventive therapies. Third, trials that are stopped early on for efficacy may overestimate the treatment effect. However, before the time of stopping, the information and prophylactic monitoring lath had observed a progressive increase in do good of the combination of rivaroxaban and aspirin for more than ane twelvemonth. Furthermore, the data reported here include additional events that occurred before the cutoff simply were not reported at the time of stopping the written report and exclude some events that were refuted during adjudication. It is noteworthy that the results based on events reported by the sites and subsequently adjudication are well-nigh identical (Table S3 in the Supplementary Appendix).
In conclusion, in patients with stable atherosclerotic vascular disease, nosotros compared iii antiplatelet regimens: rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), and aspirin (100 mg once daily). The risk of major adverse cardiovascular events was significantly lower with the combination of rivaroxaban plus aspirin than with aspirin alone, and the risk of major bleeding was significantly college. Rivaroxaban alone did non result in a significantly lower hazard of major adverse cardiovascular events than aspirin alone and resulted in a significantly higher adventure of major bleeding.
Supplementary Textile
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