Cardiovascular Outcomes For People Using Anticoagulation Strategies Research Articles

CHA2DS2-VASc and CHADS2 scores for risk stratification of major adverse cardiovascular events in the COMPASS trial

Abstract Background The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial demonstrated that the combination therapy of rivaroxaban and aspirin reduced major adverse cardiovascular events (MACE) compared to aspirin alone in patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD). Purpose We assessed whether the CHA2DS2-VASc (congestive heart failure (CHF), hypertension, age ≥75 years, diabetes, stroke/transient ischemic attack (TIA)/thromboembolism, vascular disease, age 65–75 years, and sex category) and CHADS2 (CHF, hypertension, age ≥75 years, diabetes, stroke/TIA) scores used to predict the risk of stroke in patients with atrial fibrillation, can be used identify vascular patients at highest risk of recurrent events who may derive greatest benefits of treatment. Methods In COMPASS patients, the predictive accuracy of CHA2DS2-VASc and CHADS2 scores were assessed for MACE, bleeding and net clinical benefit using Cox proportional hazards model. Kaplan-Meier estimates of cumulative risk and absolute risk differences were used to examine the effects of rivaroxaban plus aspirin compared with aspirin alone over 30 months according to risk score categories. Results In 27,395 participants with CAD and/or PAD, a high CHA2DS2-VASc score (6–9) was associated with 3 times greater absolute risk of MACE compared to a low score (1–2) (hazard ratio=3.39, 95% CI: 2.54–4.51, p<0.0001). The effects of combination therapy with rivaroxaban and aspirin on MACE, bleeding and net clinical benefit were consistent across CHA2DS2-VASc and CHADS2 score categories, with the greatest benefit in those with the highest risk scores (Figure 1). The greatest reduction in MACE with rivaroxaban and aspirin compared to aspirin only was observed in patients treated for 30 months with highest CHA2DS2-VASc score (6–9) (23 events per 1000 patients prevented) or highest CHADS2 score (3–6) (25 events per 1000 patients prevented). There was increased bleeding in patients with higher CHA2DS2-VASc and CHADS2 scores, but net clinical benefit was preserved across all risk categories and was greatest in those with the highest risk scores. Conclusion The CHA2DS2-VASc or CHADS2 scores can be used in patients with chronic CAD and/or PAD to identify patients who are at highest risk of MACE, and therefore likely to achieve the greatest benefit of dual pathway inhibition with the combination of rivaroxaban and aspirin compared with aspirin alone. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): This study was sponsored by Bayer AG.

ASSESSMENT OF IMPLEMENTING THE COMPASS TRIAL RESULTS IN ROUTINE CLINICAL PRACTICE IN ONTARIO, CANADA: INSIGHTS FROM THE CARDIOVASCULAR HEALTH IN AMBULATORY CARE RESEARCH TEAM (CANHEART) STUDY

The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial showed a decrease in major adverse cardiovascular events (MACE) with low-dose rivaroxaban and aspirin vs aspirin alone in patients with a history of CAD and/or PAD. The aim of this study was to examine a) the applicability of the COMPASS trial’s population and b) potential impact of this strategy on MACE and bleeding outcomes in a North American routine clinical practice context.

Oral factor Xa inhibitors and risk of subdural hematoma: COMPASS trial results and meta-analysis.

Subdural hematomas (SDHs) are an uncommon, but important, complication of anticoagulation therapy. We hypothesized that the risks of SDH would be similar during treatment with oral factor Xa inhibitors compared with aspirin. We assessed the frequency and the effects of antithrombotic treatments on SDHs in the recent international Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial comparing aspirin 100 mg daily, rivaroxaban 5 mg twice daily, and rivaroxaban 2.5 mg twice daily plus aspirin. A systematic review/meta-analysis of randomized trials comparing oral factor Xa inhibitors vs aspirin on SDH risk was undertaken. Among 27,395 COMPASS participants, 28 patients with SDHs were identified (mean age 72 years). SDH-associated mortality was 7%. Incidence was 0.06 per 100 patient-years (11 SDH/17,492 years observation) during the mean 23-month follow-up among aspirin-assigned patients and did not differ significantly between treatments. Three additional randomized controlled trials including 16,177 participants reported a total of 14 SDHs with an incidence ranging from 0.06 to 0.1 per 100 patient-years. Factor Xa inhibitor use was not associated with an increased risk of SDH compared to aspirin (odds ratio, 0.97; 95% confidence interval, 0.52-1.81; I2 = 0%). The frequency of SDH was similar in all 3 treatment arms of the COMPASS trial. The COMPASS trial results markedly increase the available evidence from randomized comparisons of oral factor Xa inhibitors with aspirin regarding SDH. From available, albeit limited, evidence from 4 randomized trials, therapeutic dosages of factor Xa inhibitors do not appear to increase the risk of SDH compared with aspirin. NCT01776424.

The COMPASS trial: practical considerations for application after coronary artery bypass surgery.

We review the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial with particular emphasis on patients with a history of remote coronary artery bypass grafting (CABG) and those who were enrolled 4-14 days after CABG. We provide practical guidance for selecting patients with the greatest potential to benefit who have acceptable bleeding risk. In particular, we address concerns about postoperative bleeding and discuss the relative merits of rivaroxaban and aspirin versus P2Y12 inhibition and aspirin. The COMPASS trial demonstrated that rivaroxaban and aspirin reduce myocardial infarction, stroke, and cardiovascular death in patients with coronary artery disease, without a demonstrated effect on bypass graft patency in the first postoperative year. After CABG, cardiac surgeons should consider using the COMPASS regimen in patients at high risk of thrombosis whose risk of bleeding is acceptable. If used, the COMPASS regimen should be continued indefinitely in conjunction with other pharmacological risk reduction therapies to prevent long-term atherothrombotic events.

Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial.

Patients with peripheral artery disease (PAD) are at a high risk not only for the classical cardiovascular (CV) outcomes (major adverse cardiovascular events; MACE) but also for vascular limb events (major adverse limb events; MALE). Therefore, a comprehensive approach for these patients should include both goals. However, the traditional antithrombotic approach with only antiplatelet agents (single or dual antiplatelet therapy) does not sufficiently reduce the risk of recurrent thrombotic events. Importantly, the underlying cause of atherosclerosis in patients with PAD implies both platelet activation and the initiation and promotion of coagulation cascade, in which Factor Xa plays a key role. Therefore, to reduce residual vascular risk, it is necessary to address both targets. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial that included patients with stable atherosclerotic vascular disease, the rivaroxaban plus aspirin strategy (versus aspirin) markedly reduced the risk of both CV and limb outcomes, and related complications, with a good safety profile. In fact, the net clinical benefit outcome composed of MACE; MALE, including major amputation, and fatal or critical organ bleeding was significantly reduced by 28% with the COMPASS strategy, (hazard ratio: 0.72; 95% confidence interval: 0.59–0.87). Therefore, the rivaroxaban plus aspirin approach provides comprehensive protection and should be considered for most patients with PAD at high risk of such events.

COMPASS criteria applied to a contemporary cohort of unselected patients with stable coronary artery diseases: insights from the START registry.

Recently, the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial demonstrated that dual therapy reduced cardiovascular outcomes compared with aspirin alone in patients with stable atherosclerotic disease. We sought to assess the proportion of patients eligible for the COMPASS trial and to compare the epidemiology and outcome of these patients with those without COMPASS inclusion or with any exclusion criteria in a contemporary, nationwide cohort of patients with stable coronary artery disease. Among the 4068 patients with detailed information allowing evaluation of eligibility, 1416 (34.8%) did not fulfil the inclusion criteria (COMPASS-Not-Included), 841 (20.7%) had exclusion criteria (COMPASS-Excluded), and the remaining 1811 (44.5%) were classified as COMPASS-Like. At 1 year, the incidence of major adverse cardiovascular event (MACE), a composite of cardiovascular death, myocardial infarction, and stroke, was 0.9% in the COMPASS-Not-Included and 2.0% in the COMPASS-Like (P = 0.01), and 5.0% in the COMPASS-Excluded group (P < 0.0001 for all comparisons). Among the COMPASS-Like population, patients with multiple COMPASS enrichment criteria presented a significant increase in the risk of MACE (from 1.0% to 3.3% in those with 1 and ≥3 criteria, respectively; P = 0.012), and a modest absolute increase in major bleeding risk (from 0.2% to 0.4%, respectively; P = 0.46). In a contemporary real-world cohort registry of stable coronary artery disease, most patients resulted as eligible for the COMPASS. These patients presented a considerable annual risk of MACE that consistently increases in the presence of multiple risk factors.

ASSESSMENT OF IMPLEMENTING THE COMPASS TRIAL RESULTS IN ROUTINE CLINICAL PRACTICE IN ONTARIO, CANADA: INSIGHTS FROM THE CARDIOVASCULAR HEALTH IN AMBULATORY CARE RESEARCH TEAM (CANHEART) STUDY

The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial showed decrease in major adverse cardiovascular events (MACE) with low-dose rivaroxaban (riva) and ASA vs ASA alone in patients (pts) with a history of CAD and/or PAD. The aim of this study was to examine a) the

New possibilities of antithrombotic therapy improving prognosis in patients with stenosing atherosclerosis of carotid arteries

The purpose of the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial was to evaluate a regimen of a two-way impact on thrombus formation in patients presenting with ischaemic heart disease and peripheral artery diseases. The study included a total of 1,919 patients with stenosis of carotid arteries and 1,032 patients with a history of stroke. Many patients with disease of peripheral arteries (including carotid arteries) enrolled into the COMPASS trial appeared to have additional risk factors for stroke such as, for instance, current or former smoking, diabetes mellitus, or ischaemic heart disease. An additionally carried out analysis for strokes revealed that supplementing rivaroxaban at a dose of 2.5 mg twice daily to acetylsalicylic acid decreased the risk for the development of ischaemic stroke by 49% (p<0.001), without increasing the risk for haemorrhagic transformation on the background of combined therapy (HR=0.35; 95% CI: 0.13-0.99; p=0.04), whereas the risk for haemorrhagic strokes remained at a low level and did not differ between the groups (HR=1.49; 95% CI: 0.67-3.31; p=0.33). The composite risk for major ischaemic and haemorrhagic events was significantly lower in the group of combined therapy. Adding rivaroxaban to acetylsalicylic acid appeared to result in a decrease in the risk of all-cause mortality in patients with ischaemic heart disease and peripheral artery disease by 18%. Thus, the addition of rivaroxaban at a dose of 2.5 mg twice daily to acetylsalicylic acid made it possible to decrease the risks of both primary and secondary strokes, and hence may be considered in patients with significant stenoses of carotid arteries for primary prevention, whereas in patients with endured ischaemic stroke - for secondary prevention, as well as after open endovascular reconstructive operations on carotid arteries.

023 Risk Stratification Using CHA2DS2-VASc and CHADS2 Scores in Patients With Chronic Atherosclerotic Cardiovascular Disease Receiving Aspirin With or Without Rivaroxaban: An Analysis of the COMPASS Trial

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that rivaroxaban plus aspirin reduced major adverse cardiovascular events (MACE) in patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD). We explored whether the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke/transient ischemic attack/thromboembolism, vascular disease, age 65-75 years, and sex category) and CHADS2 scores can identify vascular patients at highest risk of recurrent events who may derive greatest benefits of treatment. The predictive accuracies of the CHA2DS2-VASc and CHADS2 scores for the primary outcome, MACE, were assessed in COMPASS patients. Kaplan-Meier estimates of cumulative risk were used to compare the effects of rivaroxaban plus aspirin with aspirin alone according to risk score categories. A high CHA2DS2-VASc score (6-9) was associated with 3 times greater absolute risk of MACE compared to a low score (1-2) (hazard ratio=3.39, 95% CI: 2.54-4.51, p<0.0001). The effects of rivaroxaban plus aspirin compared with aspirin alone were consistent across CHA2DS2-VASc and CHADS2 score categories for MACE, bleeding and net clinical benefit, with greatest reduction in MACE observed in patients treated for 30 months with highest CHA2DS2-VASc score (6-9) (23 events per 1000 patients prevented) or highest CHADS2 score (3-6) (25 events per 1000 patients prevented). The CHA2DS2-VASc and CHADS2 scores can be used in patients with chronic CAD and/or PAD to identify patients who are at highest risk of MACE, and who achieve the greatest benefit of dual pathway inhibition with rivaroxaban and aspirin.

Net Clinical Benefit of Low Dose Rivaroxaban in Coronary Heart Disease: A Systematic Review and Meta-Analysis

Introduction US Food and Drug Administration has recently approved the use of rivaroxaban 2.5mg BID in patients with coronary heart disease based on Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial. However, it's unclear whether there is net clinical benefit with use of rivaroxaban in such patients. Therefore, we did a systematic review and meta-analysis to evaluate the effects of rivaroxaban on clinical outcomes in coronary heart disease patients. Methods: Embase, Ovid, Pubmed and Scopus were extensively searched from inception of these databases to April 2019 by two independent reviewers. Only randomized controlled trials of low dose rivaroxaban (2.5 mg BID) reporting mortality and cardiovascular outcomes of interest in baseline coronary heart disease patients (≥ 18 years) with at least 1000 patients and follow-up of ≥ 1 year were included. The co-primary outcomes were cardiovascular mortality and all-cause mortality. The secondary endpoints were myocardial infarction (MI), stroke, major adverse cardiovascular events, major bleeding and cerebral nervous system (CNS) bleeding. Cochrane Collaboration's tool was used for risk of bias assessment. Statistical heterogeneity was quantified using I2 statistics whereas publication bias was assessed with Eggers regression test. We combined estimates using DerSimonian and Laird random effects models. Outcomes were reported as hazard ratios (HR) with 95% confidence intervals (CI). Results: Five randomized control trials including 39,979 patients were included in our meta-analysis. Trials ATLAS and Commander HF used placebo as their control while COMPASS and GEMINI ACS-1 used aspirin as control. Pioneer AF-PCI used vitamin K antagonist as the control. Mean age (SD) of the patients was 65.6 ± 3.7 years with 74.3% females. Mean follow up in years was 1.6 ±0.5. Majority of the patients in each trial had hypertension. Our pooled analysis showed reduction in all-cause mortality (HR, 0.85, 95% CI, 0.72-1.00, P=0.05), cardiovascular mortality (HR, 0.83, 95% CI, 0.70-1.00, P=0.05), MI (HR, 0.88, 95% CI, 0.78-1.00, P=0.05) and stroke (HR, 0.70, 95% CI, 0.53-0.94, P=0.02) with low dose rivaroxaban. No significant difference in risk of bleeding was observed (HR, 1.45, 95% CI, 0.83-2.51, P=0.19). Our pooled analysis also showed reduction in major cardiovascular events (HR, 0.91, 95% CI, 0.85-0.98, P=0.01). CNS bleeding was only reported by ATLAS and COMPASS trials and net effect showed no statistically significant bleeding risk (HR, 1.63, 95% CI, 0.70-3.79, P=0.26). Conclusion: Our data suggest that the use of rivaroxaban is associated with reduction in all-cause and cardiovascular mortality in coronary heart disease patients without significantly increasing the risk of bleeding. To further decrease the residual risk of cardiovascular events in coronary heart disease patients, low dose rivaroxaban can be considered by clinicians. Disclosures No relevant conflicts of interest to declare.

Risk factors and clinical outcomes in chronic coronary and peripheral artery disease: An analysis of the randomized, double-blind COMPASS trial.

Secondary prevention in patients with coronary artery disease and peripheral artery disease involves antithrombotic therapy and optimal control of cardiovascular risk factors. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) study, adding low-dose rivaroxaban on top of aspirin lowered cardiovascular events, but there is limited data about risk factor control in secondary prevention. We studied the association between risk factor status and outcomes, and the impact of risk factor status on the treatment effect of rivaroxaban, in a large contemporary population of patients with coronary artery disease or peripheral artery disease. We reported ischemic events (cardiovascular death, stroke, or myocardial infarction) in participants from the randomized, double-blind COMPASS study by individual risk factor (blood pressure, smoking status, cholesterol level, presence of diabetes, body mass index, and level of physical activity), and by number of risk factors. We compared rates and hazard ratios of patients treated with rivaroxaban plus aspirin vs aspirin alone within each risk factor category and tested for interaction between risk factor status and antithrombotic regimen. Complete baseline risk factor status was available in 27,117 (99%) patients. Status and number of risk factors were both associated with increased risk of ischemic events. Rates of ischemic events (hazard ratio 2.2; 95% confidence interval 1.8-2.6) and cardiovascular death (hazard ratio 2.0; 1.5-2.7) were more than twofold higher in patients with 4-6 compared with 0-1 risk factors (p < 0.0001 for both). Rivaroxaban reduced event rates independently of the number of risk factors (p interaction 0.93), with the largest absolute benefit in patients with the highest number of risk factors. More favorable risk factor status and low-dose rivaroxaban were independently associated with lower risk of cardiovascular events.

2180Estimating individual lifetime benefit and bleeding risk of adding rivaroxaban to aspirin for patients with stable cardiovascular disease: results from the COMPASS trial

Abstract Background The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial has demonstrated that adding low-dose rivaroxaban to aspirin in patients with stable atherosclerotic disease on average reduces recurrence of cardiovascular disease (CVD) events, but increases the risk of major bleeding. For clinical practice, it is important to be able to weigh the absolute benefit from the intervention in terms of lower cardiovascular risk against the absolute increase in risk for major bleeding. Purpose The aim of this study was to estimate the individual lifetime benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease by predicting individual months free from CVD events gained and individual months free from major bleeding lost. Methods Analyses were based on data of patients with established CVD in the COMPASS trial (n=27,390) and SMART prospective cohort study (n=8,139). The externally validated lifetime SMART-REACH model for recurrent CVD was used to predict life expectancy free of stroke and myocardial infarction, based on the following predictors: sex, current smoking, diabetes mellitus, systolic blood pressure, total cholesterol, creatinine, number of locations of CVD, history of atrial fibrillation, and history of congestive heart failure. A new Fine &amp; Gray competing-risk adjusted Cox proportional hazard model was derived in the COMPASS study population for prediction of life expectancy free from major bleeding, including the same predictors as the SMART-REACH model and additionally ethnicity, geographical region, and history of bleeding requiring transfusion. These lifetime estimates were then combined with hazard ratios from the COMPASS trial to estimate lifetime treatment effects from adding low-dose rivaroxaban to aspirin, expressed in terms of 1) months free from stroke or myocardial infarction gained, and 2) months free from major bleeding lost. Results External goodness-of-fit of the SMART-REACH model in the COMPASS study was sufficient. The newly developed major bleeding risk model also showed sufficient external goodness-of-fit in the SMART cohort. The median predicted individual gain in life-expectancy free of stroke or MI from added low-dose rivaroxaban was 16 months (range 1–48 months), while the median predicted individualized lifetime lost in terms of major bleeding was 2 months (range 0–20 months) (Figure 1A). Predicted benefit was higher than predicted harm in more than 90% of the study population. An interactive calculator for use in clinical practice will be made available (example in figure 1B). Figure 1 Conclusions There is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable CVD. Using these lifetime models, benefits and bleeding risk can be weighed for and with each individual patient, to support treatment decision making in clinical practice.

Association Between Low-Dose Rivaroxaban With or Without Aspirin and Ischemic Stroke Subtypes

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) randomized clinical trial was stopped early owing to the efficacy of low-dose rivaroxaban plus aspirin in preventing major cardiovascular events. The main reason for early trial termination was the effect of combination therapy on reducing ischemic strokes. To analyze the association between low-dose rivaroxaban with or without aspirin and different ischemic stroke subtypes. This is a secondary analysis of a multicenter, double-blind, randomized, placebo-controlled study that was performed in 33 countries from March 12, 2013, to May 10, 2016. Patients with stable atherosclerotic vascular disease were eligible, and a total of 27 395 participants were randomized and followed up to February 6, 2017. All first ischemic strokes and uncertain strokes that occurred by this date were adjudicated using TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. The analysis of ischemic stroke subtypes was evaluated using an intention-to-treat principle. Statistical analysis was performed from March 12, 2013, to February 6, 2017. Participants received rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice a day), or aspirin (100 mg once a day). Risk of ischemic stroke subtypes during follow-up. A total of 291 patients (66 women; mean [SD] age, 69.4 [8.5] years; 43 [14.8%] had a previous nonlacunar stroke) experienced an ischemic stroke. During the study, 49 patients (16.8%) received a diagnosis of atrial fibrillation. Applying TOAST criteria, 59 strokes (20.3%) were cardioembolic, 54 strokes (18.6%) were secondary to greater than 50% stenosis of the ipsilateral internal carotid artery, 42 strokes (14.4%) had a negative evaluation that met criteria for embolic stroke of undetermined source, and 21 strokes (7.2%) were secondary to small vessel disease. There were significantly fewer cardioembolic strokes (hazard ratio [HR], 0.40 [95% CI, 0.20-0.78]; P = .005) and embolic strokes of undetermined source (HR, 0.30 [95% CI, 0.12-0.74]; P = .006) in the combination therapy group compared with the aspirin-only group. A trend for reduction in strokes secondary to small vessel disease (HR, 0.36 [95% CI, 0.12-1.14]; P = .07) was not statistically significant. No significant difference was observed between the 2 groups in strokes secondary to greater than 50% carotid artery stenosis (HR, 0.85 [95% CI, 0.45-1.60]; P = .61). Rivaroxaban, 5 mg, twice daily showed a trend for reducing cardioembolic strokes compared with aspirin (HR, 0.57 [95% CI, 0.31-1.03]; P = .06) but was not associated with reducing other stroke subtypes. For patients with systemic atherosclerosis, low-dose rivaroxaban plus aspirin was associated with large, significant reductions in cardioembolic strokes and embolic strokes of undetermined source. However, these results of exploratory analysis need to be independently confirmed before influencing clinical practice. ClinicalTrials.gov identifier: NCT01776424.

Major Bleeding in Patients With Coronary or Peripheral Artery Disease Treated With Rivaroxaban Plus Aspirin

BackgroundIn patients with coronary or peripheral artery disease, the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced major adverse cardiovascular events and mortality and increased bleeding. ObjectivesThis study sought to explore the effects of the combination of rivaroxaban and aspirin compared with aspirin on sites, timing, severity, and management of bleeding in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) study. MethodsThis study reports, by treatment group, the number and proportion of patients; hazard rate ratios for bleeding according to site and severity; the timing of bleeding using landmark analyses; and the number and proportion of patients who received blood products and other hemostatic treatments. ResultsOf 27,395 patients enrolled (mean age 68 years, 22% women), 18,278 were randomized to the combination of rivaroxaban and aspirin or to aspirin alone and followed for a mean of 23 months. Compared with aspirin alone, the combination increased modified International Society on Thrombosis and Hemostasis major bleeding (288 of 9,152 [3.1%] vs. 170 of 9,126 [1.9%]), (HR: 1.70; 95% CI: 1.40 to 2.05; p < 0.001), International Society on Thrombosis and Hemostasis major bleeding (206 of 9,152 [2.3%] vs. 116 of 9,126 [1.3%]), (HR: 1.78; 95% CI: 1.41 to 2.23; p < 0.0001), and minor bleeding (838 of 9,152 [9.2%] vs. 503 of 9,126 [5.5%]), (HR: 1.70; 95% CI 1.52 to 1.90; p < 0.0001); the combination also increased the need for any red cell transfusion (87 of 9,152 [1.0%] vs. 44 of 9,126 [0.5%]), (HR: 1.97; 95% CI 1.37 to 2.83, p = 0.0002). The gastrointestinal (GI) tract was the most common site of increased major bleeding (140 of 9,152 [1.5%] vs. 65 of 9,126 [0.7%]), (HR: 2.15; 95% CI: 1.60 to 2.89; p < 0.001), and the increase in bleeding was predominantly in the first year after randomization. Approximately one-third of major GI bleeding was gastric or duodenal, one-third was colonic or rectal, and one-third was from an unknown GI site. The study investigators reported that approximately three-quarters of major bleeding episodes were of mild or moderate intensity. A similar proportion of patients in each treatment group who experienced major bleeding received platelets, clotting factors, or other hemostatic agents. ConclusionsThe combination of rivaroxaban and aspirin compared with aspirin alone increased major bleeding, mainly from the GI tract. Most excess bleeding occurred during the first year after randomization, was of mild or moderate intensity, and was managed with conventional supportive therapy. (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease [COMPASS]; NCT01776424)

Rivaroxaban Plus Aspirin Versus Aspirin in Relation to Vascular Risk in the COMPASS Trial

BackgroundThe COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the combination of low-dose rivaroxaban and aspirin reduced major vascular events in patients with stable vascular disease. ObjectivesThe purpose of this study was to identify subsets of patients at higher risk of recurrent vascular events, which may help focus the use of rivaroxaban and aspirin therapy. MethodsCOMPASS patients with vascular disease were risk stratified using 2 methods: the REACH (REduction of Atherothrombosis for Continued Health) atherothrombosis risk score and CART (Classification and Regression Tree) analysis. The absolute risk differences for rivaroxaban with aspirin were compared to aspirin alone over 30 months for the composite of cardiovascular death, myocardial infarction, stroke, acute limb ischemia, or vascular amputation; for severe bleeding; and for the net clinical benefit. ResultsHigh-risk patients using the REACH score were those with 2 or more vascular beds affected, history of heart failure (HF), or renal insufficiency, and by CART analysis were those with ≥2 vascular beds affected, history of HF, or diabetes. Rivaroxaban and aspirin combination reduced the serious vascular event incidence by 25% (4.48% vs. 5.95%, hazard ratio: 0.75; 95% confidence interval: 0.66 to 0.85), equivalent to 23 events prevented per 1,000 patients treated for 30 months, at the cost of a nonsignificant 34% increase in severe bleeding (1.34; 95% confidence interval: 0.95 to 1.88), or 2 events caused per 1,000 patients treated. Among patients with ≥1 high-risk feature identified from the CART analysis, rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months. ConclusionsIn patients with vascular disease, further risk stratification can identify higher-risk patients (≥2 vascular beds affected, HF, renal insufficiency, or diabetes). The net clinical benefit remains favorable for most patients treated with rivaroxaban and aspirin compared with aspirin.

Association of Multiple Enrichment Criteria With Ischemic and Bleeding Risks Among COMPASS-Eligible Patients

BackgroundThe COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial found clinical benefit of low-dose rivaroxaban plus aspirin, but at the expense of increased bleeding risk in patients with stable vascular disease. ObjectivesThis study evaluated the balance of ischemic and bleeding risks according to the presence of ≥1 enrichment criteria in “COMPASS-eligible” patients. MethodsKey COMPASS selection criteria were applied to identify a COMPASS-eligible population (n = 16,875) from the REACH (REduction of Atherothrombosis for Continued Health) Registry of stable atherothrombotic patients. Ischemic outcome was the composite of cardiovascular death, myocardial infarction, or stroke. Bleeding outcome was serious bleeding (hemorrhagic stroke, hospitalization for bleeding, transfusion). ResultsPatients were categorized according to the enrichment criteria: age >65 years (81.5%), diabetes (41.0%), moderate renal failure (40.2%), peripheral artery disease (33.7%), current smoker (13.8%), heart failure (13.3%), ischemic stroke (11.1%), and asymptomatic carotid stenosis (8.7%). Each criterion was associated with a consistent increase in ischemic and bleeding events, but no individual subgroup derived a more favorable trade-off. Patients with multiple criteria had a dramatic increase in ischemic risk (7.0% [95% confidence interval (CI): 5.6% to 8.7%], 12.5% [95% CI: 11.1% to 14.1%], 16.6% [95% CI: 14.7% to 18.6%], and 21.8% [95% CI: 19.9% to 23.9%] with 1, 2, 3, and ≥4 enrichment criteria, respectively), but a more modest absolute increase in bleeding risk (1.5% [95% CI: 0.9% to 2.1%], 1.8% [95% CI: 1.3% to 2.2%], 2.0% [95% CI: 1.5% to 2.6%], 3.2% [95% CI: 2.6% to 3.9%]). ConclusionsIn a population of stable vascular patients at high risk of atherothrombotic events, the subset with multiple enrichment criteria had a greater absolute increase in ischemic than in bleeding risk and may be good candidates for low-dose rivaroxaban in addition to aspirin.

Rivaroxaban Plus Aspirin in Patients With Vascular Disease and Renal Dysfunction: From the COMPASS Trial

BackgroundChronic kidney disease is associated with an increased risk of both bleeding and ischemic cardiovascular events. ObjectiveThe purpose of this study was to determine the balance of risks and benefits from the dual pathway antithrombotic regimen (rivaroxaban 2.5 mg twice daily [bd] plus aspirin, compared with aspirin) in vascular patients with or without moderate renal dysfunction. MethodsThis was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial involving 27,395 patients with chronic coronary or peripheral artery disease. ResultsIn COMPASS, 21,111 patients had an estimated glomerular filtration rate (GFR) at baseline of ≥60 ml/min, 6,276 had a GRF of <60 ml/min. Both the primary efficacy outcome (cardiovascular death, myocardial infarction, or stroke) and major bleeding were more frequent in those with renal dysfunction, and the frequency of these outcome events was inversely related to GFR. However, the primary outcome was consistently reduced with rivaroxaban 2.5 mg bd plus aspirin, irrespective of GFR category (GFR ≥60 ml/min, 3.5% rivaroxaban plus aspirin, 4.5% aspirin alone, hazard ratio [HR]: 0.76, 95% confidence interval [CI]: 0.64 to 0.90; GFR <60 ml/min, 6.4% rivaroxaban plus aspirin, 8.4% aspirin alone, HR: 0.75; 95% CI: 0.60 to 0.94). Major bleeding was more frequent with rivaroxaban 2.5 mg plus aspirin versus aspirin alone in those with GFR ≥60 ml/min (2.9% rivaroxaban plus aspirin, 1.6% aspirin alone, HR: 1.81; 95% CI: 1.44 to 2.28) and similarly in those with GFR <60 ml/min (3.9% rivaroxaban plus aspirin, 2.7% aspirin alone, HR: 1.47, 95% CI: 1.05 to 2.07). ConclusionsThe benefits of the dual pathway COMPASS regimen (rivaroxaban 2.5 mg bd plus aspirin), versus aspirin alone, are preserved in patients with moderate renal dysfunction without evidence of an excess hazard of bleeding.

COMPASS for Vascular Surgeons: Practical Considerations.

To suggest a practical approach for the application of data from the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial in patients with peripheral artery disease (PAD). The COMPASS trial showed that low-dose rivaroxaban 2.5 mg twice daily plus daily aspirin was superior to aspirin alone in reducing major adverse cardiovascular and cerebrovascular events, and major adverse limb events among patients with stable atherosclerotic vascular disease, including those with PAD. The risk for major bleeding, however, was higher with rivaroxaban plus aspirin. Critical limb ischemia at baseline (rest pain, ulcer, or gangrene), previous limb or foot amputation, or a history of peripheral revascularization surgery or stenting were independently associated with increased major adverse limb events within the trial. Intensification of antithrombotic therapy with low-dose rivaroxaban plus aspirin should be considered in low bleeding risk PAD patients who are at increased risk for ischemic and/or limb events. A practical approach for clinicians is presented to help incorporate COMPASS data into practice.

Rivaroxaban, Aspirin, or Both to Prevent Early Coronary Bypass Graft Occlusion: The COMPASS-CABG Study

BackgroundPatients with recent coronary artery bypass graft (CABG) surgery are at risk for early graft failure, which is associated with a risk of myocardial infarction and death. In the COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) trial, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced the primary major adverse cardiovascular events (MACE) outcome of cardiovascular death, stroke, or myocardial infarction. Rivaroxaban 5 mg twice daily alone did not significantly reduce MACE. ObjectivesThis pre-planned substudy sought to determine whether the COMPASS treatments are more effective than aspirin alone for preventing graft failure and MACE after CABG surgery. MethodsThe substudy randomized 1,448 COMPASS trial patients 4 to 14 days after CABG surgery to receive the combination of rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone. The primary outcome was graft failure, diagnosed by computed tomography angiogram 1 year after surgery. ResultsThe combination of rivaroxaban and aspirin and the regimen of rivaroxaban alone did not reduce the graft failure rates compared with aspirin alone (combination vs. aspirin: 113 [9.1%] vs. 91 [8.0%] failed grafts; odds ratio [OR]: 1.13; 95% confidence interval [CI]: 0.82 to 1.57; p = 0.45; rivaroxaban alone vs. aspirin: 92 [7.8%] vs. 92 [8.0%] failed grafts; OR: 0.95; 95% CI: 0.67 to 1.33; p = 0.75). Compared with aspirin, the combination was associated with fewer MACE (12 [2.4%] vs. 16 [3.5%]; hazard ratio [HR]: 0.69; 95% CI: 0.33 to 1.47; p = 0.34), whereas rivaroxaban alone was not (16 [3.3%] vs. 16 [3.5%]; HR: 0.99, CI: 0.50 to 1.99; p = 0.98). There was no fatal bleeding or tamponade within 30 days of randomization. ConclusionsThe combination of rivaroxaban 2.5 mg twice daily plus aspirin or rivaroxaban 5 mg twice daily alone compared with aspirin alone did not reduce graft failure in patients with recent CABG surgery, but the combination of rivaroxaban 2.5 mg twice daily plus aspirin was associated with similar reductions in MACE, as observed in the larger COMPASS trial. (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS [COMPASS]; NCT01776424)

CE1 - Cost-Effectiveness of Rivaroxaban and Aspirin Compared to Aspirin Alone in Patients with Stable Cardiovascular Disease: An Australian Perspective

Abstract Objective In light of the Cardiovascular Outcomes for People using Anticoagulation Strategies (COMPASS) trial, our objective was to assess the cost-effectiveness, from the Australian healthcare perspective, of rivaroxaban in combination with aspirin versus aspirin alone for the prevention of recurrent cardiovascular disease among patients with stable atherosclerotic vascular disease. Methods A Markov model was developed using input data from the COMPASS trial to predict the clinical course and costs of patients over a 20-year time-horizon. The model comprised of three health states: ‘Alive without recurrent CVD’, ‘Alive after recurrent CVD’ and ‘Dead’. Costs were from the Australian public healthcare system perspective, and estimated from published sources, as were utility data. The costs of rivaroxaban were based on current acquisition prices on the Australian Pharmaceutical Benefits Schedule (PBS) and assumed as AUD$3.09/day. The main outcome of interest was the incremental cost-effectiveness ratio (ICER) in terms of cost per quality adjusted life year (QALY) gained, and cost per year of life saved (YoLS). Costs and benefits were discounted by 5.0% per year. Results Compared to aspirin alone, rivaroxaban plus aspirin was estimated to cost an additional AUD$12,156 (discounted) per person, but lead to 0.516 YoLS (discounted) and 0.386 QALYs gained (discounted), over 20 years. These equated to ICERs of AUD$23,560/YoLS and AUD$31,436/QALY gained. We have assumed a threshold of AUD$50,000/QALY gained to signify cost-effectiveness. Conclusion Compared to aspirin, rivaroxaban in combination with aspirin is likely to be cost-effective in preventing recurrent cardiovascular events in patients with stable atherosclerotic vascular disease.