Publications by authors named "Olga Shestakovska"

30 Publications

  • Page 1 of 1

Mortality Benefit of Rivaroxaban Plus Aspirin in Patients With Chronic Coronary or Peripheral Artery Disease.

J Am Coll Cardiol 2021 07;78(1):14-23

Population Health Research Institute, Hamilton Ontario, Canada; Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Background: The combination of 2.5 mg rivaroxaban twice daily and 100 mg aspirin once daily compared with 100 mg aspirin once daily reduces major adverse cardiovascular (CV) events in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).

Objectives: The aim of this work was to report the effects of the combination on overall and cause-specific mortality.

Methods: The COMPASS trial enrolled 27,395 patients of whom 18,278 were randomized to the combination (n = 9,152) or aspirin alone (n = 9,126). Deaths were adjudicated by a committee blinded to treatment allocation. Previously identified high-risk baseline features were polyvascular disease, chronic kidney disease, mild or moderate heart failure, and diabetes.

Results: During a median of 23 months of follow-up (maximum 47 months), 313 patients (3.4%) allocated to the combination and 378 patients (4.1%) allocated to aspirin alone died (hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.71-0.96; P = 0.01). Compared with aspirin, the combination reduced CV death (160 [1.7%] vs 203 [2.2%]; HR: 0.78; 95% CI: 0.64-0.96; P = 0.02) but not non-CV death. There were fewer deaths following MI, stroke, and CV procedures, as well as fewer sudden cardiac, other, and unknown causes of CV deaths and coronary heart disease deaths. Patients with 0, 1, 2, and 3 or 4 high-risk features at baseline had 4.2, 4.8, 25.0, and 53.9 fewer deaths, respectively, per 1000 patients treated for 30 months.

Conclusions: The combination of rivaroxaban and aspirin compared with aspirin reduced overall and CV mortality with consistent reductions in cause specific CV mortality in patients with chronic CAD or PAD. The absolute mortality benefits are greater with increasing baseline risk. (Cardiovascular Outcomes for People Using Anticoagulant Strategies [COMPASS]; NCT01776424).
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http://dx.doi.org/10.1016/j.jacc.2021.04.083DOI Listing
July 2021

Low-dose rivaroxaban plus aspirin in patients with polypharmacy and multimorbidity: an analysis from the COMPASS trial.

Eur Heart J Cardiovasc Pharmacother 2021 Jun 30. Epub 2021 Jun 30.

Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada.

Background: In patients with coronary or peripheral arterial disease, adding low dose rivaroxaban to aspirin reduces cardiovascular events and mortality. Polypharmacy and multimorbidity are frequent in such patients.

Aims: To analyze whether the benefits and risks of rivaroxaban plus aspirin varies in patients with comorbidities and receiving multiple drugs.

Methods And Results: We describe ischemic events (cardiovascular death, stroke, or myocardial infarction) and major bleeding in participants from the randomised, double-blind COMPASS study by number of cardiovascular medications and concomitant medical conditions. We compared event rates and hazard ratios (HR) for rivaroxaban plus aspirin versus aspirin alone by the number of medications and concomitant conditions, and tested for interaction between polypharmacy or multimorbidity and the antithrombotic regimen.The risk of ischemic events was higher in patients with more concomitant drugs (HR 1.7, 95%CI 1.5-2.1 for >4 vs 0-2) and with more comorbidities (HR 2.3, 1.8-2.1 for >3 vs 0-1). Multimorbidity, but not polypharmacy, was associated with a higher risk of major bleeding. The relative efficacy, safety, and net clinical benefit of rivaroxaban were not affected by the number of drugs or comorbidities. Patients taking more concomitant medications derived the largest absolute reduction in the net clinical outcome with added rivaroxaban (1.1% vs 0.4% reduction with >4 vs 0-2 cardiovascular drugs, NNT 91 vs 250).

Conclusion: Adding low-dose rivaroxaban to aspirin resulted in benefits irrespective of the number of concomitant drugs or comorbidities. Multiple comorbidities and/or polypharmacy should not dissuade the addition of rivaroxaban to aspirin in otherwise eligible patients.
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http://dx.doi.org/10.1093/ehjcvp/pvab050DOI Listing
June 2021

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

Neurology 2020 08 10;95(5):e480-e487. Epub 2020 Jul 10.

From the Department of Medicine (Neurology) (L.C., K.N., S.N., K.S.P., A.S., M.S., R.G.H.), Department of Medicine (Division of Hematology & Thromboembolism) (J.W.E.), and School of Rehabilitation Science (J.B.), McMaster University/Hamilton Health Sciences/Population Health Research Institute (O.S.), Hamilton, Canada.

Objective: 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.

Methods: 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.

Results: 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; I = 0%).

Conclusion: 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.

Clinical Trial Identifier Number: NCT01776424.
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http://dx.doi.org/10.1212/WNL.0000000000009826DOI Listing
August 2020

The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared With Aspirin in Patients With Chronic Vascular Disease.

Circulation 2020 07 21;142(1):40-48. Epub 2020 May 21.

Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (K.A.A.F.).

Background: Rivaroxaban 2.5 mg twice daily plus acetylsalicylic acid (aspirin; ASA) 100 mg reduced the risk of cardiovascular events as compared with ASA monotherapy in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) but increased the risk of major bleedings. Analysis of net clinical benefit (NCB) is of key clinical relevance and represents an integrated measure of overall patient outcome.

Methods: The current prespecified analysis was performed to assess the NCB of adding rivaroxaban 2.5 mg twice daily to ASA monotherapy in patients with chronic vascular disease in the COMPASS study cohort (intention-to-treat study population), with a specific focus on high-risk subgroups. The predefined NCB outcome was the composite of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ.

Results: A lower number of NCB adverse outcomes was observed with rivaroxaban 2.5 mg twice daily plus ASA versus ASA alone (hazard ratio, 0.80 [95% CI, 0.70-0.91], =0.0005), which became increasingly favorable with longer treatment duration. The main drivers of NCB outcomes were "efficacy" events, in particular stroke (0.5%/y versus 0.8%/y; hazard ratio, 0.58 [95% CI, 0.44-0.76], <0.0001) and cardiovascular death (0.9%/y versus 1.2%/y; hazard ratio, 0.78 [95% CI, 0.64-0.96], =0.02), whereas the bleeding components of the NCB, in particular fatal bleeding (0.09%/y versus 0.06%/y; hazard ratio, 1.49 [95% CI 0.67-3.33], =0.32), only represented a minority of NCB events. In selected high-risk subgroups, including patients with polyvascular disease (≥2 vascular beds affected with atherosclerosis), impaired renal function, heart failure, and/or diabetes mellitus, a larger absolute risk reduction for experiencing a NCB event was observed.

Conclusions: Compared with ASA monotherapy, the combination of rivaroxaban 2.5 mg twice daily plus ASA resulted in fewer NCB events primarily by preventing adverse efficacy events, particularly stroke and cardiovascular mortality, whereas severe bleedings were less frequent and with less clinical impact. The NCB was particularly favorable in high-risk subgroups and those with multiple risk characteristics. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046048DOI Listing
July 2020

Efficacy and safety of rivaroxaban plus aspirin in women and men with chronic coronary or peripheral artery disease.

Cardiovasc Res 2021 02;117(3):942-949

Department of Medicine, Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada.

Aims: The COMPASS trial demonstrated that 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 (MACE) in patients with chronic coronary artery disease or peripheral artery disease by 24% during a mean follow-up of 23 months. We explored whether this effect varies by sex.

Methods And Results: The effects were examined in women and men using log-rank tests and Kaplan-Meier curve. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were obtained from stratified Cox proportional hazards models to explore subgroup effects including subgroup of women and men according to baseline modified REACH risk score. Of 27 395 patients randomized, 18 278 were allocated to receive rivaroxaban plus aspirin (n = 9152) or aspirin alone (n = 9126), and of these, 22.1% were women. Women compared with men had similar incidence rates for MACE and major bleeding but borderline lower rates for myocardial infarction (1.7% vs. 2.2%, P = 0.05). The effect of combination therapy compared with aspirin in women and men was consistent for MACE (women: 3.8% vs. 5.2%, HR 0.72, 95% CI 0.54-0.97; men: 4.2% vs. 5.5%, HR 0.76, 95% CI 0.66-0.89; P interaction 0.75) and major bleeding (women: 3.1% vs. 1.4%, HR 2.22, 95% CI 1.42-3.46; men: 3.2% vs. 2.0%, HR 1.60, 95% CI 1.29-1.97; P interaction 0.19). There was no significant interaction between randomized treatment and baseline modified REACH score above or below the median for MACE or major bleeding.

Conclusion: In patients with stable coronary artery disease or peripheral artery disease, the combination of rivaroxaban (2.5 mg twice daily) and aspirin compared with aspirin alone appears to produce consistent benefits in women and men, independent of baseline cardiovascular risk.
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http://dx.doi.org/10.1093/cvr/cvaa100DOI Listing
February 2021

Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease: Insights From the COMPASS Trial.

Circulation 2020 06 28;141(23):1841-1854. Epub 2020 Mar 28.

Population Health Research Institute, McMaster University and Hamilton Health Sciences, Ontario, Canada (J.W.E., S.J.C., S.S.A., J.B., O.S., S.Y.).

Background: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events.

Methods: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding.

Results: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, =0.002; and hazard ratio, 0.77, =0.005, respectively, =0.77) and all-cause mortality (hazard ratio, 0.81, =0.05; and hazard ratio, 0.84, =0.09, respectively; =0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative <0.0001; 1.9% versus 0.6% for all-cause mortality, =0.02; 2.7% versus 1.7% for major vascular events, <0.0001). Because the bleeding hazards were similar among patients with and without diabetes mellitus, the prespecified net benefit for rivaroxaban appeared particularly favorable in the patients with diabetes mellitus (2.7% versus 1.0%; Gail-Simon qualitative =0.001).

Conclusions: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314494PMC
June 2020

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

Eur J Prev Cardiol 2020 02 15;27(3):296-307. Epub 2019 Oct 15.

Population Health Research Institute, McMaster University and Hamilton Health Sciences, Canada.

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 1.8-2.6) 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 ( < 0.0001 for both). Rivaroxaban reduced event rates independently of the number of risk factors ( 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.
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http://dx.doi.org/10.1177/2047487319882154DOI Listing
February 2020

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

J Am Coll Cardiol 2019 09;74(12):1519-1528

Hamilton Health Sciences, Hamilton, Ontario, Canada; McMaster University, Hamilton, Ontario, Canada; Population Health Research Institute, Hamilton, Ontario, Canada.

Background: In 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.

Objectives: This 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.

Methods: This 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.

Results: Of 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.

Conclusions: The 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).
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http://dx.doi.org/10.1016/j.jacc.2019.07.065DOI Listing
September 2019

Bleeding and New Cancer Diagnosis in Patients With Atherosclerosis.

Circulation 2019 10 12;140(18):1451-1459. Epub 2019 Sep 12.

Population Health Research Institute, McMaster University and Hamilton Health Sciences, Ontario, Canada (J.W.E., S.J.C., J.B., O.S., S.S.A., R.G.H., P.M., S.Y.).

Background: Patients treated with antithrombotic drugs are at risk of bleeding. Bleeding may be the first manifestation of underlying cancer.

Methods: We examined new cancers diagnosed in relation to gastrointestinal or genitourinary bleeding among patients enrolled in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) and determined the hazard of new cancer diagnosis after bleeding at these sites.

Results: Of 27 395 patients enrolled (mean age, 68 years; women, 21%), 2678 (9.8%) experienced any (major or minor) bleeding, 713 (2.6%) experienced major bleeding, and 1084 (4.0%) were diagnosed with cancer during a mean follow-up of 23 months. Among 2678 who experienced bleeding, 257 (9.9%) were subsequently diagnosed with cancer. Gastrointestinal bleeding was associated with a 20-fold higher hazard of new gastrointestinal cancer diagnosis (7.4% versus 0.5%; hazard ratio [HR], 20.6 [95% CI, 15.2-27.8]) and 1.7-fold higher hazard of new nongastrointestinal cancer diagnosis (3.8% versus 3.1%; HR, 1.70 [95% CI, 1.20-2.40]). Genitourinary bleeding was associated with a 32-fold higher hazard of new genitourinary cancer diagnosis (15.8% versus 0.8%; HR, 32.5 [95% CI, 24.7-42.9]), and urinary bleeding was associated with a 98-fold higher hazard of new urinary cancer diagnosis (14.2% versus 0.2%; HR, 98.5; 95% CI, 68.0-142.7). Nongastrointestinal, nongenitourinary bleeding was associated with a 3-fold higher hazard of nongastrointestinal, nongenitourinary cancers (4.4% versus 1.9%; HR, 3.02 [95% CI, 2.32-3.91]).

Conclusions: In patients with atherosclerosis treated with antithrombotic drugs, any gastrointestinal or genitourinary bleeding was associated with higher rates of new cancer diagnosis. Any gastrointestinal or genitourinary bleeding should prompt investigation for cancers at these sites.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041949DOI Listing
October 2019

Rivaroxaban With or Without Aspirin in Patients With Heart Failure and Chronic Coronary or Peripheral Artery Disease.

Circulation 2019 08 5;140(7):529-537. Epub 2019 Jun 5.

Population Health Research Institute, McMaster University and Hamilton Health Sciences, ON, Canada (J.W.E., J.B., S.J.C., O.S., S.Y.).

Background: Patients with chronic coronary artery disease or peripheral artery disease and history of heart failure (HF) are at high risk for major adverse cardiovascular events. We explored the effects of rivaroxaban with or without aspirin in these patients.

Methods: The COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) randomized 27 395 participants with chronic coronary artery disease or peripheral artery disease to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg alone. Patients with New York Heart Association functional class III or IV HF or left ventricular ejection fraction (EF) <30% were excluded. The primary major adverse cardiovascular events outcome comprised cardiovascular death, stroke, or myocardial infarction, and the primary safety outcome was major bleeding using modified International Society of Thrombosis and Haemostasis criteria. Investigators recorded a history of HF and EF at baseline, if available. We examined the effects of rivaroxaban on major adverse cardiovascular events and major bleeding in patients with or without a history of HF and an EF <40% or ≥40% at baseline.

Results: Of the 5902 participants (22%) with a history of HF, 4971 (84%) had EF recorded at baseline, and 12% had EF <40%. Rivaroxaban and aspirin had similar relative reduction in major adverse cardiovascular events compared with aspirin in participants with HF (5.5% versus 7.9%; hazard ratio [HR], 0.68; 95% CI, 0.53-0.86) and those without HF (3.8% versus 4.7%; HR, 0.79; 95% CI, 0.68-0.93; P for interaction 0.28) but larger absolute risk reduction in those with HF (HF absolute risk reduction 2.4%, number needed to treat=42; no HF absolute risk reduction 1.0%, number needed to treat=103). The primary major adverse cardiovascular events outcome was not statistically different between those with EF <40% (HR, 0.88; 95% CI, 0.55-1.42) and ≥40% (HR, 0.81; 95% CI, 0.67-0.98; P for interaction 0.36). The excess hazard for major bleeding was not different in participants with HF (2.5% versus 1.8%; HR, 1.36; 95% CI, 0.88-2.09) than in those without HF (3.3% versus 1.9%; HR, 1.79; 95% CI, 1.45-2.21; P for interaction 0.26). There were no significant differences in the primary outcomes with rivaroxaban alone.

Conclusions: In patients with chronic coronary artery disease or peripheral artery disease and a history of mild or moderate HF, combination rivaroxaban and aspirin compared with aspirin alone produces similar relative but larger absolute benefits than in those without HF.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.039609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693980PMC
August 2019

Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin.

Gastroenterology 2019 09 29;157(3):682-691.e2. Epub 2019 May 29.

University of Washington, Seattle, Washington.

Background & Aims: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.

Methods: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.

Results: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.

Conclusions: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.
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http://dx.doi.org/10.1053/j.gastro.2019.05.056DOI Listing
September 2019

Monitoring Emerging Data From the COMPASS Trial of an Antithrombotic Agent.

J Am Coll Cardiol 2019 06;73(21):2769-2772

Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin.

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http://dx.doi.org/10.1016/j.jacc.2019.03.479DOI Listing
June 2019

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

J Am Coll Cardiol 2019 05;73(18):2243-2250

Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Population Health Research Institute, Hamilton, Ontario, Canada.

Background: Chronic kidney disease is associated with an increased risk of both bleeding and ischemic cardiovascular events.

Objective: The 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.

Methods: This 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.

Results: In 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).

Conclusions: The 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.
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http://dx.doi.org/10.1016/j.jacc.2019.02.048DOI Listing
May 2019

Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial.

Gastroenterology 2019 08 2;157(2):403-412.e5. Epub 2019 May 2.

University of Washington, Seattle, Washington.

Background & Aims: Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. We evaluated whether proton pump inhibitor therapy could reduce this risk.

Methods: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation.

Results: There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88; 95% confidence interval [CI], 0.67-1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52; 95% confidence interval, 0.28-0.94; P = .03); this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45; 95% confidence interval, 0.27-0.74), although the number needed to treat still was high (n = 982; 95% confidence interval, 609-2528).

Conclusions: In a randomized placebo-controlled trial, we found that routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions. ClinicalTrials.gov ID: NCT01776424.
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http://dx.doi.org/10.1053/j.gastro.2019.04.041DOI Listing
August 2019

Stroke Outcomes in the COMPASS Trial.

Circulation 2019 02;139(9):1134-1145

McMaster University/Population Health Research Institute, Hamilton, Canada (M.S., R.G.H., S.J.C., J.B., O.S., K.K.H.N., L.C., S.Y., J.W.E.).

Background: Strokes were significantly reduced by the combination of rivaroxaban plus aspirin in comparison with aspirin in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies). We present detailed analyses of stroke by type, predictors, and antithrombotic effects in key subgroups.

Methods: Participants had stable coronary artery or peripheral artery disease and were randomly assigned to receive aspirin 100 mg once daily (n=9126), rivaroxaban 5 mg twice daily (n=9117), or rivaroxaban 2.5 mg twice daily plus aspirin (n=9152). Patients who required anticoagulation or had a stroke within 1 month, previous lacunar stroke, or intracerebral hemorrhage were excluded.

Results: During a mean follow-up of 23 months, fewer patients had strokes in the rivaroxaban plus aspirin group than in the aspirin group (83 [0.9% per year] versus 142 [1.6% per year]; hazard ratio [HR], 0.58; 95% CI, 0.44-0.76; P<0.0001). Ischemic/uncertain strokes were reduced by nearly half (68 [0.7% per year] versus 132 [1.4% per year]; HR, 0.51; 95% CI, 0.38-0.68; P<0.0001) by the combination in comparison with aspirin. No significant difference was noted in the occurrence of stroke in the rivaroxaban alone group in comparison with aspirin: annualized rate of 0.7% (HR, 0.82; 95% CI, 0.65-1.05). The occurrence of fatal and disabling stroke (modified Rankin Scale, 3-6) was decreased by the combination (32 [0.3% per year] versus 55 [0.6% per year]; HR, 0.58; 95% CI, 0.37-0.89; P=0.01). Independent predictors of stroke were prior stroke, hypertension, systolic blood pressure at baseline, age, diabetes mellitus, and Asian ethnicity. Prior stroke was the strongest predictor of incident stroke (HR, 3.63; 95% CI, 2.65-4.97; P<0.0001) and was associated with a 3.4% per year rate of stroke recurrence on aspirin. The effect of the combination in comparison with aspirin was consistent across subgroups with high stroke risk, including those with prior stroke.

Conclusions: Low-dose rivaroxaban plus aspirin is an important new antithrombotic option for primary and secondary stroke prevention in patients with clinical atherosclerosis.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01776424.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035864DOI Listing
February 2019

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease.

N Engl J Med 2017 10 27;377(14):1319-1330. Epub 2017 Aug 27.

From the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON (J.W.E., S.J.C., J.B., R.G.H., O.S., E.M.L., S.S.A., D.L., S.Y.), and Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, QC (G.R.D.) - both in Canada; Estudios Clínicos Latino América and Instituto Cardiovascular de Rosario, Rosario, Argentina (R.D.); Amphia Ziekenhuis and Werkgroep Cardiologische Centra Nederland (WCN), Utrecht, the Netherlands (M.A.); Cardiocenter, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic (P.W.); Osaka International Cancer Institute, Osaka, Japan (M.H.); Instituto Dante Pazzanese de Cardiologia (A.A.), and Hospital do Coração (L.S.P.), São Paulo; University of Washington Medical Center (K.R.H.B.) and University of Washington (J.P.), Seattle; Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston (D.L.B.); FuWai Hospital, Beijing (J.Z., Y.L.); National Association of Hospital Cardiologists Research Center (ANMCO), Florence, Italy (A.P.M.); Research Institute, Fundación Oftalmológica de Santander (FOSCAL)-Bucaramanga, Bucaramanga, Colombia (P.L.-J.); National University of Ireland, Galway (M.O.); Thrombosis Research Institute and University College London, London (A.K.K.), Centre for Cardiovascular Science, University of Edinburgh, Edinburgh (K.A.A.F.), and University of Glasgow, Glasgow (T.J.G.) - all in the United Kingdom; Collegium Medicum Jagiellonian University, Krakow, Poland (T.J.G); Institute of Cardiology, Kiev, Ukraine (A.N.P.); University of Würzburg and University Hospital, Würzburg (G.E., S.S.), and Bayer, Leverkusen (N.C.B., F.M., E.C.) - all in Germany; Semmelweis University, Budapest, Hungary (M.K.); Karolinska Institutet, Stockholm (L.R.); National Research Center for Preventative Medicine, Moscow (N.P.); University of Philippines, Manila (A.L.D.); Universidad de La Frontera, Temuco, Chile (F.L.); University of Cape Town, Cape Town, South Africa (P.J.C.); University of Aalborg, Copenhagen (C.T.-P.); University of Leuven, Leuven, Belgium (P.B.V.); University of Medicine and Pharmacology, Carol Davila University and Emergency Hospital, Bucharest, Romania (D.V.); Catholic University of Korea, Seoul, South Korea (J.-H.K.); Monash University, Melbourne, VIC, Australia (A.M.T.); Lady Davis Carmel Medical Center, Haifa, Israel (B.S.L.); Facultad de Ciencias de la Salud Eugenio Espejo-Universidad Tecnológica Equinoccial, Quito, Ecuador (C.F.); Universiti Teknologi Mara, Selangor, Malaysia (K.Y.); Université Paris Diderot, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris (P.G.S.); and Turku University Central Hospital and Turku University, Turku, Finland (K.P.M.).

Background: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone 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 once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months.

Results: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) 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 outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group.

Conclusions: Among 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) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).
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http://dx.doi.org/10.1056/NEJMoa1709118DOI Listing
October 2017

Optical Coherence Tomography-Guided Percutaneous Coronary Intervention in ST-Segment-Elevation Myocardial Infarction: A Prospective Propensity-Matched Cohort of the Thrombectomy Versus Percutaneous Coronary Intervention Alone Trial.

Circ Cardiovasc Interv 2016 Apr;9(4):e003414

From the Population Health Research Institute, McMaster University and Hamilton Health Science, Hamilton, Canada (T.N.S., M.K.N., O.S., R.T., B.M., S.S.J.); Heart Hospital, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland (O.A.K., K.N.); London Health Sciences Centre, London, Canada (S.L.); Royal North Shore Hospital, Sydney, Australia (R.B.), Southlake Regional Health Centre, University of Toronto, Newmarket, Canada (W.J.C.); St. Michael's Hospital, Toronto, Canada (A.N.C.); and Clinical Center of Serbia, Belgrade, Serbia (G.S.).

Background: Patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction are at increased risk for adverse events. It is unclear if image guidance by optical coherence tomography (OCT) can improve outcomes in these patients. We compared OCT-guided versus angiography-guided primary PCI for ST-segment-elevation myocardial infarction among patients in the Thrombectomy Versus PCI Alone (TOTAL) trial.

Methods And Results: Among 10 732 patients enrolled in the TOTAL trial, OCT was used for PCI guidance as a part of a prospective substudy in 214 patients. Using 2:1 propensity matching, we identified 428 patients in the trial who had PCI performed with angiography guidance alone. The primary outcome was a composite of cardiovascular death, myocardial infarction, stent thrombosis, and target-vessel revascularization at 1 year. Secondary outcomes included final in-stent angiographic minimum lumen diameter, procedure time, and contrast dose. The final in-stent angiographic minimum lumen diameter was 2.99±0.48 mm in the OCT-guided group versus 2.79±0.47 mm in the angiography-guided group (P<0.0001). OCT- and angiography-guided PCI had a median (interquartile range) procedure time of 58 (47, 71) minute versus 38 (28, 52) minute (P<0.0001) and total contrast dose of 239.7±81.1 mL versus 193.3±78.6 mL (P<0.0001). The primary outcome was observed in 7.5% of the OCT-guided group versus 9.8% of the angiography-guided group (hazard ratio, 0.76; 95% confidence interval, 0.43-1.34; P=0.34).

Conclusions: OCT-guided primary PCI for ST-segment-elevation myocardial infarction was associated with a larger final in-stent minimum lumen diameter. There was no significant difference in clinical outcomes at 1 year; however, the study was underpowered to detect a treatment effect.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01149044.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.115.003414DOI Listing
April 2016

Efficacy and safety of apixaban compared with aspirin in the elderly: a subgroup analysis from the AVERROES trial.

Age Ageing 2016 Jan 19;45(1):77-83. Epub 2015 Nov 19.

Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada.

Background: increasing age is associated with a higher prevalence of atrial fibrillation (AF), and higher risks of stroke and bleeding. We report the effects of apixaban versus acetylsalicylic acid (ASA) in older patients (≥75 years and ≥85 years) compared with younger patients with AF unsuitable for vitamin K antagonists.

Methods: AVERROES (Apixaban Versus ASA to Prevent Stroke In AF Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) trial (n = 5,599) included 1,898 patients ≥75 years and 366 patients ≥85 years. We compared the baseline characteristics and effects of apixaban compared with aspirin on clinical outcomes by age.

Results: compared with aspirin, apixaban was more efficacious for preventing strokes and systemic embolism in patients ≥85 years (absolute rate [AR] 1%/year on apixaban versus 7.5%/year on aspirin; hazard ratio [HR] 0.14, 95% confidence interval [CI] 0.02-0.48) compared with younger patients (AR 1.7%/year on apixaban versus 3.4%/year on aspirin; HR 0.50, 95% CI 0.35-0.69) (P-value for interaction = 0.05). Major haemorrhage was higher in patients ≥85 years compared with younger patients but similar with apixaban versus aspirin in both young and older individuals (4.9%/year versus 1.0%/year on aspirin and 4.7%/year versus 1.2%/year on apixaban) with no significant treatment-by-age interaction (P-value = 0.65).

Conclusions: older patients with AF are at particularly high risk of stroke if given aspirin and have substantially greater relative and absolute benefits from apixaban compared with younger patients with no greater risk of haemorrhage.

Clinical Trial Registration: ClinicalTrials.gov number: NCT00496769. URL: https://clinicaltrials.gov/ct2/show/NCT00496769.
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http://dx.doi.org/10.1093/ageing/afv156DOI Listing
January 2016

Culprit lesion thrombus burden after manual thrombectomy or percutaneous coronary intervention-alone in ST-segment elevation myocardial infarction: the optical coherence tomography sub-study of the TOTAL (ThrOmbecTomy versus PCI ALone) trial.

Eur Heart J 2015 Aug 20;36(29):1892-900. Epub 2015 May 20.

Population Health Research Institute and Department of Medicine, McMaster University and Hamilton Health Sciences, David Braley Cardiac, Vascular, and Stroke Research Institute, 237 Barton St E, Hamilton, ON, Canada L8L 2X4

Aims: Manual thrombectomy has been proposed as a strategy to reduce thrombus burden during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). However, the effectiveness of manual thrombectomy in reducing thrombus burden is uncertain. In this substudy of the TOTAL (ThrOmbecTomy versus PCI ALone) trial, we compared the thrombus burden at the culprit lesion using optical coherence tomography (OCT) in patients treated with thrombectomy vs. PCI-alone.

Methods And Results: The TOTAL trial (N = 10 732) was an international, multicentre, randomized trial of thrombectomy (using the Export catheter, Medtronic Cardiovascular, Santa Rosa, CA, USA) in STEMI patients treated with primary PCI. The OCT substudy prospectively enrolled 214 patients from 13 sites in 5 countries. Optical coherence tomography was performed immediately after thrombectomy or PCI-alone and then repeated after stent deployment. Thrombus quantification was performed by an independent core laboratory blinded to treatment assignment. The primary outcome of pre-stent thrombus burden as a percentage of segment analysed was 2.36% (95% CI: 1.73-3.22) in the thrombectomy group and 2.88% (95% CI: 2.12-3.90) in the PCI-alone group (P = 0.373). Absolute pre-stent thrombus volume was not different (2.99 vs. 3.74 mm(3), P = 0.329). Other secondary outcomes of pre-stent quadrants of thrombus, post-stent atherothrombotic burden, and post-stent atherothrombotic volume were not different between groups.

Conclusion: Manual thrombectomy did not reduce pre-stent thrombus burden at the culprit lesion compared with PCI-alone. Both strategies were associated with low thrombus burden at the lesion site after the initial intervention to restore flow.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061563PMC
http://dx.doi.org/10.1093/eurheartj/ehv176DOI Listing
August 2015

Randomized trial of primary PCI with or without routine manual thrombectomy.

N Engl J Med 2015 Apr 16;372(15):1389-98. Epub 2015 Mar 16.

From the Population Health Research Institute and Department of Medicine, McMaster University and Hamilton Health Sciences, Hamilton, ON (S.S.J., S.Y., B.M., J.P., M.J.R., L.T., M.K.N., O.S., P.G.), University of British Columbia, Vancouver (J.A.C.), London Health Sciences Centre, Department of Medicine, London, ON (S.L.), Southlake Regional Health Centre, Newmarket, ON (W.J.C.), Peter Munk Cardiac Centre, University Health Network (C.B.O., V.D.), and St. Michael's Hospital (A.N.C.), Toronto, Mazankowski Alberta Heart Institute, Department of Medicine, Edmonton (R.C.W.), and Quebec Heart-Lung Institute, Laval University, Quebec, QC (O.F.B.) - all in Canada; University Clinic of Cardiology, Sts. Cyril and Methodius University, Skopje, Macedonia (S.K.); Clinical Center of Serbia and Department of Cardiology, Medical Faculty, University of Belgrade, Belgrade, Serbia (G.S.); University Hospital La Paz, Madrid (R.M.); University Hospitals of Leicester, Department of Cardiovascular Sciences, Leicester (A.G.), and University Hospitals South Manchester, Manchester Academic Health Science Centre, Manchester (S.C.) - both in the United Kingdom; Heart Center, Tampere University Hospital, Tampere, Finland (K.N.); Université Paris-Diderot, Sorbonne Paris-Cité, INSERM Unité 1148, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris (P.G.S.); University Hospital and Faculty of Medicine Pilsen, Pilsen (I.B.), and the Third Faculty of Medicine, Charles University Prague, University Hospital Kralovske Vinohrady, Prague (P.W.) - both in the Czech Republic; the Tenth People's Hospital, Tongji University, Shanghai, China (Y.X.); Department of Cardiology and Angiology, Contilla Heart and Vascular Center, Elisabeth-Krankenhaus, Essen, Germany (C.K.N.); Dante Pazzanese Institute of Cardiology, São Paulo (A.A.); Royal North Shore Hospital, Sydney (R.B.); Northeast Clinical Trials Group, Scranton, PA (S.P.); Duke Clinical Research Institute, Durham, NC (S.V.R.); and Department

Background: During primary percutaneous coronary intervention (PCI), manual thrombectomy may reduce distal embolization and thus improve microvascular perfusion. Small trials have suggested that thrombectomy improves surrogate and clinical outcomes, but a larger trial has reported conflicting results.

Methods: We randomly assigned 10,732 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI to a strategy of routine upfront manual thrombectomy versus PCI alone. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key safety outcome was stroke within 30 days.

Results: The primary outcome occurred in 347 of 5033 patients (6.9%) in the thrombectomy group versus 351 of 5030 patients (7.0%) in the PCI-alone group (hazard ratio in the thrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P=0.86). The rates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone; hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P=0.34) and the primary outcome plus stent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio, 1.00; 95% CI, 0.89 to 1.14; P=0.95) were also similar. Stroke within 30 days occurred in 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%) in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P=0.02).

Conclusions: In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days. (Funded by Medtronic and the Canadian Institutes of Health Research; TOTAL ClinicalTrials.gov number, NCT01149044.).
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http://dx.doi.org/10.1056/NEJMoa1415098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995102PMC
April 2015

Risk of ischaemic stroke according to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A and AVERROES.

Eur Heart J 2015 Feb 3;36(5):281-7a. Epub 2014 Sep 3.

Population Health Research Institute, McMaster University and Hamilton Health Sciences, 237 Barton St. E., Hamilton, ON, Canada L8L 2X2.

Aims: The pattern of atrial fibrillation (AF) occurrence-paroxysmal, persistent, or permanent-is associated with progressive stages 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 methodological shortcomings of low power, variable event ascertainment, and variable anticoagulant use.

Methods And Results: We analysed the rates of stroke and systemic embolism in 6563 aspirin-treated patients with AF from the ACTIVE-A/AVERROES databases. There was thorough searching for events and adjudication. Multivariable analyses were performed with the adjustment for known risk factors for stroke. Mean age of patients with paroxysmal, persistent, and permanent AF was 69.0 ± 9.9, 68.6 ± 10.2, and 71.9 ± 9.8 years (P < 0.001). The CHA2DS2-VASc score was similar in patients with paroxysmal and persistent AF (3.1 ± 1.4), but was higher in patients with permanent AF (3.6 ± 1.5, P < 0.001). Yearly ischaemic stroke rates were 2.1, 3.0, and 4.2% for paroxysmal, persistent, and permanent AF, respectively, with adjusted hazard 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 predictors of 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 risk and may be helpful to assess the risk/benefit for anticoagulant therapy, especially in lower risk patients.
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http://dx.doi.org/10.1093/eurheartj/ehu307DOI Listing
February 2015

Modification of outcomes with aspirin or apixaban in relation to female and male sex in patients with atrial fibrillation: a secondary analysis of the AVERROES study.

Stroke 2014 Jul 10;45(7):2127-30. Epub 2014 Jun 10.

From the University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom (G.Y.H.L.); and Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada (J.E., S.Y., O.S., R.G.H., S.C.).

Background And Purpose: The main objective of the present analysis was to assess the effect of treatment with aspirin compared with apixaban on ischemic stroke and major bleeding in women compared with men. Female patients with atrial fibrillation are at increased stroke risk compared with male patients, and the underlying reasons for higher risk are uncertain.

Methods: Ancillary analysis of the Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial, comparing aspirin and apixaban, focused on sex differences. Mean follow-up was 1.1 years.

Results: Women compared with men tended to be older (aspirin, 71.8 versus 68.8 years; apixaban, 71.4 versus 68.6 years), with a higher proportion of those aged≥75 years. Also, women had less peripheral artery disease (aspirin, 2.4% versus 3.7%; apixaban, 1.4% versus 3.0%), more heart failure, and higher mean CHADS2 (congestive heart failure, hypertension, age of 75 years or older, diabetes [1 point each], stroke or transient ischemic attack [2 points]) scores (aspirin, 2.2 versus 2.0; apixaban, 2.1 versus 2.0). Women compared with men had higher ischemic stroke rates (aspirin, 3.99% versus 2.28%; apixaban, 1.55% versus 0.82%) but similar bleeding rates (aspirin, 1.29% versus 1.22%; apixaban, 1.15% versus 1.36%). The relative effect of apixaban compared with aspirin was similar in men and women for both ischemic stroke (women, 3.99% versus 1.55%; hazard ratio, 0.39; 95% confidence interval, 0.23-0.64; men, 2.28% versus 0.82%; hazard ratio, 0.36; 95% confidence interval, 0.19-0.63; Pint=0.84) and major bleeding (women, 1.29% versus 1.15%; hazard ratio, 1.15; 95% confidence interval, 0.59-2.23; men, 1.36% versus 1.22%; hazard ratio, 1.13; 95% confidence interval, 0.64-2.02; Pint=0.96).

Conclusions: Female patients with atrial fibrillation had higher ischemic stroke rates compared with male patients, but the relative effects of apixaban compared with aspirin on both ischemic stroke and bleeding were similar in men and women.
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http://dx.doi.org/10.1161/STROKEAHA.114.005746DOI Listing
July 2014

Design and rationale of the TOTAL trial: a randomized trial of routine aspiration ThrOmbecTomy with percutaneous coronary intervention (PCI) versus PCI ALone in patients with ST-elevation myocardial infarction undergoing primary PCI.

Am Heart J 2014 Mar 14;167(3):315-321.e1. Epub 2013 Dec 14.

Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Canada.

Background: A major limitation of primary percutaneous coronary intervention (PPCI) for the treatment of ST-elevation myocardial infarction (STEMI) is impaired microvascular perfusion due to embolization and obstruction of microcirculation with thrombus. Manual thrombectomy has the potential to reduce distal embolization and improve microvascular perfusion. Clinical trials have shown mixed results regarding thrombectomy.

Objective: The objective of this study is to evaluate the efficacy of routine upfront manual aspiration thrombectomy during PPCI compared with percutaneous coronary intervention alone in patients with STEMI.

Design: This is a multicenter, prospective, open, international, randomized trial with blinded assessment of outcomes. Patients with STEMI undergoing PPCI are randomized to upfront routine manual aspiration thrombectomy with the Export catheter (Medtronic CardioVascular, Santa Rosa, CA) or to percutaneous coronary intervention alone. The primary outcome is the composite of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or new or worsening New York Heart Association class IV heart failure up to 180 days. The trial uses an event-driven design and will recruit 10,700 patients.

Summary: The TOTAL trial will determine the effect of routine manual aspiration thrombectomy during PPCI on clinically important outcomes.
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http://dx.doi.org/10.1016/j.ahj.2013.12.002DOI Listing
March 2014

Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.

Eur Heart J 2014 Jul 25;35(28):1856-63. Epub 2014 Feb 25.

Population Health Research Institute, McMaster University, Hamilton, ON, Canada.

Aim: The AVERROES double-blinded, randomized trial demonstrated that apixaban reduces the risk of stroke or systemic embolism (SSE) by 55% compared with aspirin without an increase in major bleeding in patients with atrial fibrillation either who previously tried but failed vitamin K antagonists (VKA) therapy or who were expected to be unsuitable for VKA therapy. In this pre-specified analysis, we explored the consistency of the results in the subgroup of patients who tried but failed VKA therapy.

Methods And Results: Of 5599 patients, 2216 (40%) had previously failed VKA treatment [main reasons: poor international normalized ratio (INR) control 42%, refusal 37%, bleeding on VKA 8%]. Compared with those expected to be unsuitable for VKA therapy, those who had previously failed were older, more often male, had higher body mass index, more likely to have moderate renal impairment and a history of stroke and less likely to have heart failure or to be medically undertreated. The effects of apixaban compared with aspirin were consistent in those who previously failed and those who were expected to be unsuitable, for both SSE (P interaction 0.13) and major bleeding (P interaction 0.74) and were also consistent among different subgroups of patients who had previously failed VKA therapy defined by reasons for unsuitability, age, sex, renal function, CHADS2 score, aspirin dose, duration, indication, and quality of INR control of prior VKA use.

Conclusion: The efficacy and safety of apixaban compared with aspirin is consistent in subgroups of patients who have previously attempted but failed VKA therapy, irrespective of the reason for discontinuation.
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http://dx.doi.org/10.1093/eurheartj/ehu048DOI Listing
July 2014

The effects of apixaban on hospitalizations in patients with different types of atrial fibrillation: insights from the AVERROES trial.

Eur Heart J 2013 Sep 25;34(35):2752-9. Epub 2013 Jul 25.

Division of Clinical Electrophysiology, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, D 60590 Frankfurt, Germany.

Aims: The aim of this study was to evaluate the effects of apixaban, a novel oral factor Xa inhibitor, on the need for cardiovascular hospitalization.

Methods And Results: Our analysis is based on data from AVERROES, a randomized double-blind trial testing the efficacy and safety of apixaban against aspirin for the prevention of thrombo-embolism in 5599 atrial fibrillation (AF) patients unsuitable for vitamin K antagonist therapy. Hospitalizations were captured by dedicated case report forms and the outcome variable was time from randomization to the first hospitalization. Effects of treatment with apixaban on the rates of cardiovascular and non-cardiovascular hospitalizations were assessed using Cox proportional hazards regression models. During a mean follow-up of 1.1 years, 800 patients were hospitalized at least once for cardiovascular reasons, 442 (15.4%/year) in the aspirin group, 358 (12.3%) in the apixaban group [hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.69-0.92; P = 0.002]. The reduction in cardiovascular hospitalization in the apixaban arm was predominantly due to a reduction in hospitalization for strokes, but there were also fewer hospitalizations for other cardiovascular causes. Patients with paroxysmal AF were significantly more likely to be hospitalized for AF treatment, whereas more heart failure admissions occurred in patients with permanent AF. Assignment to apixaban was the only independent predictor for a reduction in hospitalization. Cardiovascular hospitalization was the strongest independent predictor of subsequent mortality (HR: 3.95, 95% CI: 3.06-5.09; P < 0.001).

Conclusion: In AVERROES, patients on apixaban therapy were less likely to be hospitalized. This may have important consequences for patients' well-being and for healthcare resources. This trial is registered underClinicalTrials.gov number, NCT00496769.
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http://dx.doi.org/10.1093/eurheartj/eht292DOI Listing
September 2013

Modification of outcomes with aspirin or apixaban in relation to CHADS(2) and CHA(2)DS(2)-VASc scores in patients with atrial fibrillation: a secondary analysis of the AVERROES study.

Circ Arrhythm Electrophysiol 2013 Feb 6;6(1):31-8. Epub 2013 Feb 6.

University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK.

Background: The impact of apixaban versus aspirin on ischemic stroke and major bleeding in relation to the CHADS(2) and CHA(2)DS(2)-VASc stroke risk scores in atrial fibrillation has not been investigated.

Methods And Results: In this secondary analysis of the AVERROES trial, our principal objective was to assess the effect of treatment with aspirin or apixaban on ischemic stroke and major bleeding, in relation to the CHADS(2)/CHA(2)DS(2)-VASc scores. We found no significant heterogeneity for treatment efficacy on ischemic stroke for apixaban when subdivided by stroke risk strata, based on CHADS(2)/CHA(2)DS(2)-VASc. Effects were consistent irrespective of baseline risk, and thus, absolute benefits were greatest in the high-risk groups. There was also no significant heterogeneity for apixaban versus aspirin with regard to major bleeding, when subdivided by CHADS(2)/CHA(2)DS(2)-VASc scores. In multivariable analysis, significant predictors of stroke on aspirin were age ≥75 years, prior stroke or transient ischemic attack, estimated glomerular filtration rate <60 mL/min, and nonparoxysmal atrial fibrillation. Proportions of the study cohort classified as low/moderate/high risk using the CHADS(2) and CHA(2)DS(2)-VASc scores were 0.3%/71.7%/28.1% and <0.1%/10.5%/89.5%, respectively.

Conclusions: In an atrial fibrillation population, apixaban was superior to aspirin for stroke prevention, with similar rates of major bleeding, in the presence of one or more stroke risk factors, with consistency of the treatment effect by CHADS(2)/CHA(2)DS(2)-VASc scores.
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http://dx.doi.org/10.1161/CIRCEP.112.975847DOI Listing
February 2013

Predicting myocardial infarction and other serious cardiac outcomes using high-sensitivity cardiac troponin T in a high-risk stable population.

Clin Biochem 2013 Jan 9;46(1-2):5-9. Epub 2012 Oct 9.

McMaster University and the Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada.

Objectives: Previous work on high-sensitivity troponin I (hs-cTnI) has demonstrated that it may identify patients with stable cardiovascular disease (CVD) at risk for future myocardial infarction (MI). In this study, we assessed if hs-cTnT concentrations could also identify those stable CVD patients at high risk for future MI and other ischemic cardiac outcomes.

Methods: hs-cTnT (lot:153-401) was measured in specimens obtained at randomisation in the Heart Outcomes Prevention Evaluation (HOPE) study (n=2941 stable CVD patients, 4.5 years follow-up). The primary outcome for the HOPE study (MI, stroke, or cardiovascular death) was used to identify cutoffs by receiver operating characteristic (ROC) curve analysis and was used in conjunction with the 95th and 99th percentile upper limits to construct different concentration ranges, which were assessed using log-rank tests and multivariable Cox proportional hazard models. These different concentration ranges were then assessed for the components of the primary outcome and for heart failure (HF).

Results: The ROC derived hs-cTnT cutoff was 8 ng/L for the primary outcome. Subjects with hs-cTnT either below (8 to <14 ng/L) or slightly above the published 99th from a healthy population (14 to 21 ng/L) had similar probability for the primary outcome. Those with hs-cTnT concentrations >31 ng/L had the highest probability and greatest risk for future MI, HF, and cardiovascular death as compared to those with hs-cTnT concentrations <8 ng/L.

Conclusion: In patients with stable CVD disease hs-cTnT measurement identifies those at risk for MI as well as HF and cardiovascular death.
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http://dx.doi.org/10.1016/j.clinbiochem.2012.10.003DOI Listing
January 2013

Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: the apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial.

Stroke 2012 Dec 2;43(12):3291-7. Epub 2012 Oct 2.

University of Missouri-Columbia, Five Hospital Drive, CE306, Columbia, MO 65212, USA.

Background And Purpose: Apixaban reduces stroke with comparable bleeding risks when compared with aspirin in patients with atrial fibrillation who are unsuitable for vitamin k antagonist therapy. This analysis explores patterns of bleeding and defines bleeding risks based on stroke risk with apixaban and aspirin.

Methods: The Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin k Antagonist Treatment (AVERROES) trial randomized 5599 patients with atrial fibrillation and risk factors to receive either apixaban or aspirin. Bleeding events were defined as the first occurrence of either major bleeding or clinically relevant nonmajor bleeding.

Results: The rate of a bleeding event was 3.8%/year with aspirin and 4.5%/year with apixaban (hazard ratio with apixaban, 1.18; 95% CI, 0.92-1.51; P=0.19). The anatomic site of bleeding did not differ between therapies. Risk factors for bleeding common to apixaban and aspirin were use of nonstudy aspirin>50% of the time and a history of daily/occasional nosebleeds. The rates of both stroke and bleeding increased with higher CHADS2 scores but apixaban compared with aspirin was associated with a similar relative risk of bleeding (P interaction 0.21) and a reduced relative risk of stroke (P interaction 0.37) irrespective of CHADS2 category.

Conclusions: Anatomic sites and predictors of bleeding are similar for apixaban and aspirin in these patients. Higher CHADS2 scores are associated with increasing rates of bleeding and stroke, but the balance between risks and benefits of apixaban compared with aspirin is favorable irrespective of baseline stroke risk. Clinical Trial Registration Information- www.clinicaltrials.gov. Unique identifier: NCT 00496769.
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http://dx.doi.org/10.1161/STROKEAHA.112.664144DOI Listing
December 2012

The CHA2DS2-VASc score identifies those patients with atrial fibrillation and a CHADS2 score of 1 who are unlikely to benefit from oral anticoagulant therapy.

Eur Heart J 2013 Jan 27;34(3):170-6. Epub 2012 Sep 27.

Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

Aims: The CHA(2)DS(2)-VASc score is a modification of the CHADS(2) score that aims to improve stroke risk prediction in patients with atrial fibrillation (AF) by adding three risk factors: age 65-74, female sex, and history of vascular disease. Whereas previous evaluations of the CHA(2)DS(2)-VASc score included all AF patients, the aim of this analysis was to evaluate its discriminative ability only in those patients for whom recommendations on antithrombotic treatment are uncertain (i.e. CHADS(2) score of 1).

Methods And Results: We selected all patients with a CHADS(2) score of 1 from the AVERROES and ACTIVE trials who were treated with acetylsalicylic acid with or without clopidogrel and calculated the incidences of ischaemic or unspecified stroke or systemic embolus (SSE) according to their CHA(2)DS(2)-VASc score. Of 4670 patients with a baseline CHADS(2) score of 1, 26% had a CHA(2)DS(2)-VASc score of 1 and 74% had a score of ≥ 2. After 11 414 patient-years of follow-up, the annual incidence of SSE was 0.9% (95% CI: 0.6-1.3) and 2.1% (95% CI: 1.8-2.5) for patients with a CHA(2)DS(2)-VASc score of 1 and ≥ 2, respectively. The c-statistic of the CHA(2)DS(2)-VASc score was 0.587 (95% CI: 0.550-0.624). Age 65 to <75 years was the strongest of the three new risk factors in the CHA(2)DS(2)-VASc score.

Conclusion: The CHA(2)DS(2)-VASc score reclassifies 26% of patients with a CHADS(2) score of 1 to a low annual risk of SSE of 1%. This risk seems low enough to consider withholding anticoagulant treatment.
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http://dx.doi.org/10.1093/eurheartj/ehs314DOI Listing
January 2013

Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial.

Lancet Neurol 2012 Mar 1;11(3):225-31. Epub 2012 Feb 1.

Department of Neurology, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany.

Background: In the AVERROES study, apixaban, a novel factor Xa inhibitor, reduced the risk of stroke or systemic embolism in patients with atrial fibrillation who were at high risk of stroke but unsuitable for vitamin K antagonist therapy. We aimed to investigate whether the subgroup of patients with previous stroke or transient ischaemic attack (TIA) would show a greater benefit from apixaban compared with aspirin than would patients without previous cerebrovascular events.

Methods: In AVERROES, 5599 patients (mean age 70 years) with atrial fibrillation who were at increased risk of stroke and unsuitable for vitamin K antagonist therapy were randomly assigned to receive apixaban (5 mg twice daily) or aspirin (81-324 mg per day). The mean follow-up was 1·1 years. The primary efficacy outcome was stroke or systemic embolism; the primary safety outcome was major bleeding. Patients and investigators were masked to study treatment. In this prespecified subgroup analysis, we used Kaplan-Meier estimates of 1-year event risk and Cox proportional hazards regression models to compare the effects of apixaban in patients with and without previous stroke or TIA. AVERROES is registered at ClinicalTrials.gov, number NCT00496769.

Findings: In patients with previous stroke or TIA, ten events of stroke or systemic embolism occurred in the apixaban group (n=390, cumulative hazard 2·39% per year) compared with 33 in the aspirin group (n=374, 9·16% per year; hazard ratio [HR] 0·29, 95% CI 0·15-0·60). In those without previous stroke or TIA, 41 events occurred in the apixaban group (n=2417, 1·68% per year) compared with 80 in the aspirin group (n=2415, 3·06% per year; HR 0·51, 95% CI 0·35-0·74). The p value for interaction of the effects of aspirin and apixaban with previous cerebrovascular events was 0·17. Major bleeding was more frequent in patients with history of stroke or TIA than in patients without (HR 2·88, 95% CI 1·77-4·55) but risk of this event did not differ between treatment groups.

Interpretation: In patients with atrial fibrillation, apixaban is similarly effective whether or not patients have had a previous stroke or TIA. Given that those with previous stroke or TIA have a higher risk of stroke, the absolute benefits might be greater in these patients.

Funding: Bristol-Myers Squibb and Pfizer.
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http://dx.doi.org/10.1016/S1474-4422(12)70017-0DOI Listing
March 2012
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