Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease

Eikelboom, John W.; Connolly, Stuart J.; Bosch, Jackie; Dagenais, Gilles R.; Hart, Robert G.; Shestakovska, Olga; Dı́az, Rafael; Alings, Marco; Lonn, Eva; Anand, Sonia S.; Widimský, Petr; Hori, Masatsugu; Avezum, Álvaro; Piegas, Leopoldo Soares; Branch, Kelley R.; Probstfield, Jeffrey L.; Bhatt, Deepak L.; Zhu, Jun; Liang, Yan; Maggioni, Aldo P.; López‐Jaramillo, Patricio; O’Donnell, Martin J.; Kakkar, Ajay K.; Fox, Keith A.A.; Parkhomenko, Alexander; Ertl, Georg; Störk, Stefan; Keltai, Mátyás; Rydén, Lars; Pogosova, Nana; Dans, Antonio L.; Lanas, Fernando; Commerford, Patrick; Torp‐Pedersen, Christian; Guzik, Tomasz J.; Verhamme, Peter; Vinereanu, Dragoş; Kim, Jae-Hyung; Tonkin, Andrew; Lewis, Basil S.; Félix, Camilo; Yusoff, Khalid; Steg, Ph. Gabriel; Metsärinne, Kaj; Bruns, Nancy Cook; Misselwitz, Frank; Chen, Edmond; Leong, Darryl P.; Yusuf, Salim

doi:10.1056/nejmoa1709118

Cited by 1,798 publications

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“…These results are also consistent with the results of the overall trial, which have been reported separately. 18 Collectively, these results show that in patients with arterial vascular disease, low dose anticoagulants and aspirin have an additive effect. The subgroup of patients with peripheral artery disease but no coronary artery disease was too small to show significance on its own, but the results were directionally consistent with the rest of the patients in the analysis, and the test for heterogeneity was not significant.…”

Section: Discussionmentioning

confidence: 86%

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Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

et al. 2018

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BACKGROUND Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications. METHODS This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. FINDINGS Between March 12, 2013, and May 10, 2016, we ; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043). INTERPRETATION Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding. FUNDING Bayer AG. Methods This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, i...

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Section: Discussionmentioning

confidence: 86%

“…Details are provided elsewhere. 17,18 This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.…”

Section: Resultsmentioning

confidence: 99%

Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

et al. 2018

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“…The SMART‐REACH model, incorporated in an online calculator (eg, Supplemental Calculator and http://www.U-Prevent.com), may support clinical decision making on (novel) therapeutic options by estimating an individual's anticipated treatment benefit in terms of life expectancy without recurrent cardiovascular events. This may particularly be of value for novel effective but costly agents such as PCSK9 inhibitors, potent antithrombotics, and anti‐inflammatory agents 23, 35, 36, 37. Ideally, such treatment effect estimations are validated on the basis of the original trial data of such novel therapies.…”

Section: Discussionmentioning

confidence: 99%

Estimated Life Expectancy Without Recurrent Cardiovascular Events in Patients With Vascular Disease: The SMART‐REACH Model

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Dorresteijn

et al. 2018

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BackgroundIn patients with vascular disease, risk models may support decision making on novel risk reducing interventions, such as proprotein convertase subtilisin/kexin type 9 inhibitors or anti‐inflammatory agents. We developed and validated an innovative model to estimate life expectancy without recurrent cardiovascular events for individuals with coronary, cerebrovascular, and/or peripheral artery disease that enables estimation of preventive treatment effect in lifetime gained.Methods and ResultsStudy participants originated from prospective cohort studies: the SMART (Secondary Manifestations of Arterial Disease) cohort and REACH (Reduction of Atherothrombosis for Continued Health) cohorts of 14 259 (REACH Western Europe), 19 170 (REACH North America) and 6959 (SMART, The Netherlands) patients with cardiovascular disease. The SMART‐REACH model to estimate life expectancy without recurrent events was developed in REACH Western Europe as a Fine and Gray competing risk model incorporating cardiovascular risk factors. Validation was performed in REACH North America and SMART. Outcomes were (1) cardiovascular events (myocardial infarction, stroke, cardiovascular death) and (2) noncardiovascular death. Predictors were sex, smoking, diabetes mellitus, systolic blood pressure, total cholesterol, creatinine, number of cardiovascular disease locations, atrial fibrillation, and heart failure. Calibration plots showed high agreement between estimated and observed prognosis in SMART and REACH North America. C‐statistics were 0.68 (95% confidence interval, 0.67–0.70) in SMART and 0.67 (95% confidence interval, 0.66–0.68) in REACH North America. Performance of the SMART‐REACH model was better compared with existing risk scores and adds the possibility of estimating lifetime gained by novel therapies.ConclusionsThe externally validated SMART‐REACH model could be used for estimation of anticipated improvements in life expectancy without recurrent cardiovascular events in individual patients with cardiovascular disease in Western Europe and North America.

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“…Analogous to other trials, a combined end point of MACE and MALE was examined. 14,18 Prespecified safety end points as defined in the primary analysis were included for the PAD subgroup.…”

Section: What Are the Clinical Implications?mentioning

confidence: 99%

Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease

et al. 2018

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BACKGROUND:The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events. METHODS:FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia. RESULTS:Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80-0.93; P=0.0003; P interaction =0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91; P=0.0040) for those with PAD and 0.81 (0.73-0.90; P<0.0001) for those without PAD (P interaction =0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL. CONCLUSIONS:Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events.

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Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease

Cited by 1,798 publications

References 17 publications

Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

Estimated Life Expectancy Without Recurrent Cardiovascular Events in Patients With Vascular Disease: The SMART‐REACH Model

Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease

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