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Abstract Aims: 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. Methods and results: 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 1.82.6) and cardiovascular death (hazard ratio 2.0; 1.52.7) were more than twofold higher in patients with 46 compared with 01 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. Conclusion: More favorable risk factor status and low-dose rivaroxaban were independently associated with lower risk of cardiovascular events. (AU)
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Doença da Artéria Coronariana , Prevenção SecundáriaRESUMO
SUMMARY 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 anklebrachial 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 enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·570·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·350·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·691·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·451·00, 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 1·122·31, 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 1·172·40; 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.
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Doença da Artéria Coronariana , Inibidores da Agregação Plaquetária , Doenças das Artérias Carótidas , Doença Arterial Periférica , RivaroxabanaRESUMO
The pattern of atrial fibrillation (AF) occurrenceparoxysmal, persistent, or permanentis associated with progressivestages of atrial dysfunction and structural changes and may therefore be associated with progressively higher stroke risk.However, previous studies have not consistently shown AF pattern to predict stroke but have been hampered bymethodological shortcomings of low power, variable event ascertainment, and variable anticoagulant use.Methodsand resultsWe analysed the rates of stroke and systemic embolism in 6563 aspirin-treated patients with AF from the ACTIVE-A/AVERROESdatabases. Therewas thorough searching for events and adjudication. Multivariable analyses were performedwith the adjustment for known risk factors for stroke. Mean age of patients with paroxysmal, persistent, and permanentAFwas 69.0+9.9, 68.6+10.2, and 71.9+9.8 years (P , 0.001). TheCHA2DS2-VASc scorewas similar in patients withparoxysmal and persistent AF (3.1+1.4), but was higher in patients with permanent AF (3.6+1.5, P , 0.001). Yearlyischaemic stroke rates were 2.1, 3.0, and 4.2% for paroxysmal, persistent, and permanent AF, respectively, with adjustedhazard ratio of 1.83 (P , 0.001) for permanent vs. paroxysmal and 1.44 (P » 0.02) for persistent vs. paroxysmal.Multivariable analysis identified age ≥ 75 year, sex, history of stroke or TIA, and AF pattern as independent predictorsof stroke, with AF pattern being the second strongest predictor after prior stroke or TIA.Conclusion In a large population of non-anticoagulated AF patients, pattern of AF was a strong independent predictor of stroke riskand may be helpful to assess the risk/benefit for anticoagulant therapy, especially in lower risk patients.
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Acidente Vascular Cerebral , Anticoagulantes , Fibrilação AtrialRESUMO
The pattern of atrial fibrillation (AF) occurrenceparoxysmal, persistent, or permanentis associated with progressivestages of atrial dysfunction and structural changes and may therefore be associated with progressively higher stroke risk.However, previous studies have not consistently shown AF pattern to predict stroke but have been hampered by methodologicalshortcomings of low power, variable event ascertainment, and variable anticoagulant use.Methodsand resultsWe analysed the rates of stroke and systemic embolism in 6563 aspirin-treated patients with AF from the ACTIVE-A/AVERROESdatabases. Therewas thorough searching for events and adjudication. Multivariable analyses were performedwith the adjustment for known risk factors for stroke. Mean age of patients with paroxysmal, persistent, and permanentAFwas 69.0+9.9, 68.6+10.2, and 71.9+9.8 years (P , 0.001). TheCHA2DS2-VASc scorewas similar in patients withparoxysmal and persistent AF (3.1+1.4), but was higher in patients with permanent AF (3.6+1.5, P , 0.001). Yearlyischaemic stroke rates were 2.1, 3.0, and 4.2% for paroxysmal, persistent, and permanent AF, respectively, with adjustedhazard ratio of 1.83 (P , 0.001) for permanent vs. paroxysmal and 1.44 (P » 0.02) for persistent vs. paroxysmal. Multivariableanalysis identified age ≥ 75 year, sex, history of stroke or TIA, and AF pattern as independent predictors ofstroke, with AF pattern being the second strongest predictor after prior stroke or TIA.Conclusion In a large population of non-anticoagulated AF patients, pattern of AF was a strong independent predictor of stroke riskand may be helpful to assess the risk/benefit for anticoagulant therapy, especially in lower risk patients.