Publications by authors named "Leanne Dyal"

28 Publications

  • Page 1 of 1

Low-dose rivaroxaban and aspirin among patients with peripheral artery disease: a meta-analysis of the COMPASS and VOYAGER trials.

Eur J Prev Cardiol 2021 Aug 31. Epub 2021 Aug 31.

Department of Cardiology, University of Colorado School of Medicine, 13001 E 17th Pl, Boulder, Colorado 80045, USA.

Aims: Peripheral artery disease (PAD) patients suffer a high risk of major cardiovascular (CV) events, with athero-thrombo-embolism as the underlying pathophysiologic mechanism. Recently, two large randomized clinical trials evaluated the efficacy and safety of low-dose rivaroxaban twice daily plus aspirin in stable PAD outpatients and those immediately after peripheral revascularization. We sought to determine if the effects of low-dose rivaroxaban and aspirin compared to aspirin alone are consistent across this broad spectrum of PAD patients.

Methods And Results: We conducted a random-effects meta-analysis of the COMPASS and VOYAGER randomized trials among 11 560 PAD patients (4996 from COMPASS and 6564 from VOYAGER) in the primary analysis and 9332 (2768 from COMPASS and 6564 from VOYAGER) with lower extremity (LE)-PAD in the secondary analysis. The hazard ratio (HR) for the composite of CV death, myocardial infarction, ischaemic stroke, acute limb ischaemia, or major vascular amputation was 0.79 (95% confidence interval, CI: 0.65-0.95) comparing low-dose rivaroxaban plus aspirin to aspirin alone. While the risk of major bleeding was increased with low-dose rivaroxaban plus aspirin compared to aspirin alone [HR: 1.51 (95% CI: 1.22-1.87)], there was no significant increase in severe bleeding [HR: 1.18 (95% CI: 0.79-1.76)]. Similar effects were observed in the subset with symptomatic LE-PAD.

Conclusions: Among PAD patients, low-dose rivaroxaban plus aspirin is superior to aspirin alone in reducing CV and limb outcomes including acute limb ischaemia and major vascular amputation. This reduction is offset by a relative increase in major bleeding, but not by an excess of fatal or critical organ bleeding. The consistency of findings of these trials supports the use of combination low-dose rivaroxaban plus aspirin in PAD patients across a broad spectrum of disease.
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http://dx.doi.org/10.1093/eurjpc/zwab128DOI Listing
August 2021

Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes.

N Engl J Med 2021 09 28;385(10):896-907. Epub 2021 Jun 28.

From the Population Health Research Institute, Hamilton Health Sciences (H.C.G., C.R., L.H., L.D.), and McMaster University (H.C.G.) - both in Hamilton, ON, Canada; the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (N.S.); the Dallas Diabetes Research Center at Medical City, Dallas (J.R.); AdventHealth Translational Research Institute, Orlando, FL (R.P.); Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (R.D.L.); National Heart Centre Singapore and Duke-National University of Singapore, Singapore (C.S.P.L.); Sanofi, Bridgewater, NJ (N.S.K.); the Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (S.D.P.); and the Division of Cardiology, University of Washington, Seattle (K.B.).

Background: Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events among persons with type 2 diabetes. The effect of an exendin-based GLP-1 receptor agonist, efpeglenatide, on cardiovascular and renal outcomes in patients with type 2 diabetes who are also at high risk for adverse cardiovascular events is uncertain.

Methods: In this randomized, placebo-controlled trial conducted at 344 sites across 28 countries, we evaluated efpeglenatide in participants with type 2 diabetes and either a history of cardiovascular disease or current kidney disease (defined as an estimated glomerular filtration rate of 25.0 to 59.9 ml per minute per 1.73 m of body-surface area) plus at least one other cardiovascular risk factor. Participants were randomly assigned in a 1:1:1 ratio to receive weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg or placebo. Randomization was stratified according to use of sodium-glucose cotransporter 2 inhibitors. The primary outcome was the first major adverse cardiovascular event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes).

Results: A total of 4076 participants were enrolled; 2717 were assigned to receive efpeglenatide and 1359 to receive placebo. During a median follow-up of 1.81 years, an incident MACE occurred in 189 participants (7.0%) assigned to receive efpeglenatide (3.9 events per 100 person-years) and 125 participants (9.2%) assigned to receive placebo (5.3 events per 100 person-years) (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P<0.001 for noninferiority; P = 0.007 for superiority). A composite renal outcome event (a decrease in kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (hazard ratio, 0.68; 95% CI, 0.57 to 0.79; P<0.001). Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than with placebo.

Conclusions: In this trial involving participants with type 2 diabetes who had either a history of cardiovascular disease or current kidney disease plus at least one other cardiovascular risk factor, the risk of cardiovascular events was lower among those who received weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg than among those who received placebo. (Funded by Sanofi; AMPLITUDE-O ClinicalTrials.gov number, NCT03496298.).
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http://dx.doi.org/10.1056/NEJMoa2108269DOI Listing
September 2021

Cardiovascular consequences of discontinuing low-dose rivaroxaban in people with chronic coronary or peripheral artery disease.

Heart 2021 07 21;107(14):1130-1137. Epub 2021 May 21.

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

Objective: In patients with chronic coronary or peripheral artery disease enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, randomised antithrombotic treatments were stopped after a median follow-up of 23 months because of benefits of the combination of rivaroxaban 2.5 mg two times per day and aspirin 100 mg once daily compared with aspirin 100 mg once daily. We assessed the effect of switching to non-study aspirin at the time of early stopping.

Methods: Incident composite of myocardial infarction, stroke or cardiovascular death was estimated per 100 person-years (py) during randomised treatment (n=18 278) and after study treatment discontinuation to non-study aspirin (n=14 068).

Results: During randomised treatment, the combination compared with aspirin reduced the composite (2.2 vs 2.9/100 py, HR: 0.76, 95% CI 0.66 to 0.86), stroke (0.5 vs 0.8/100 py, HR: 0.58, 95% CI 0.44 to 0.76) and cardiovascular death (0.9 vs 1.2/100 py, HR: 0.78, 95% CI 0.64 to 0.96). During 1.02 years after early stopping, participants originally randomised to the combination compared with those randomised to aspirin had similar rates of the composite (2.1 vs 2.0/100 py, HR: 1.08, 95% CI 0.84 to 1.39) and cardiovascular death (1.0 vs 0.8/100 py, HR: 1.26, 95% CI 0.85 to 1.86) but higher stroke rate (0.7 vs 0.4/100 py, HR: 1.74, 95% CI 1.05 to 2.87) including a significant increase in ischaemic stroke during the first 6 months after switching to non-study aspirin.

Conclusion: Discontinuing study rivaroxaban and aspirin to non-study aspirin was associated with the loss of cardiovascular benefits and a stroke excess.

Trial Registration Number: NCT01776424.
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http://dx.doi.org/10.1136/heartjnl-2020-318758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257559PMC
July 2021

Rivaroxaban Plus Aspirin in Obese and Overweight Patients With Vascular Disease in the COMPASS Trial.

J Am Coll Cardiol 2021 02;77(5):511-525

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

Background: Direct oral anticoagulants are administered in fixed doses irrespective of body weight, but guidelines recommend against their use in patients with extremes of body weight.

Objectives: This study determined the effects of dual-pathway inhibition antithrombotic regimen (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/day) compared with aspirin Halone across a range of patient body mass indexes (BMIs) and body weights.

Methods: This was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial, which included patients with chronic coronary artery disease or peripheral artery disease. Efficacy and safety outcomes were studied in relation to BMI: (normal 18.5 ≤BMI <25 kg/m, overweight 25 ≤BMI <30 kg/m, obese ≥30 kg/m) and body weight (≤70 kg, 70 < weight ≤90 kg, and >90 kg; as well as ≤120 kg vs. >120 kg).

Results: Among 27,395 randomized patients, 6,459 (24%) had normal BMI, 12,047 (44%) were overweight, and 8,701 (32%) were obese. The combination of rivaroxaban and aspirin compared with aspirin produced a consistent reduction in the primary outcome of cardiovascular death, stroke, or myocardial infarction, irrespective of BMI or body weight. For 18.5 ≤BMI <25 kg/m: 3.5% vs. 5.0%; hazard ratio (HR): 0.73 (95% credible interval [CrI]: 0.58 to 0.90); 25 ≤ BMI <30 kg/m: 4.3% vs. 5.1%; HR: 0.80 (95% CrI: 0.66 to 0.96); BMI ≥30 kg/m: 4.2% vs. 6.1%; HR: 0.71 (95% CrI: 0.57 to 0.86). For body weight ≤70 kg: 4.1% vs. 5.3%; HR: 0.75 (95% CrI: 0.62 to 0.91); 70 < weight ≤90 kg: 4.1% vs. 5.3%; HR: 0.76 (95% CrI: 0.65 to 0.89); >90 kg: 4.2% vs. 5.7%; HR: 0.74 (95% CrI: 0.61 to 0.90). Effects on bleeding, mortality, and net clinical benefit were consistent irrespective of BMI or bodyweight.

Conclusions: The effects of dual-pathway antithrombotic therapy are consistent irrespective of BMI or body weight, suggesting no need for dose adjustments in the ranges of weights and BMI of patients enrolled in the COMPASS trial. Further studies need to address this problem in relation to greater extremes of body weight. (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.2020.11.061DOI Listing
February 2021

Total cardiovascular or fatal events in people with type 2 diabetes and cardiovascular risk factors treated with dulaglutide in the REWIND trail: a post hoc analysis.

Cardiovasc Diabetol 2020 11 25;19(1):199. Epub 2020 Nov 25.

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

Background: The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants METHODS: We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models.

Results: Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82-0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80-0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87-0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82-0.99) p = 0.028].

Conclusions: These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk.

Clinical Trial Registration: https://www.clinicaltrials.gouv . Unique Identifier NCT01394952).
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http://dx.doi.org/10.1186/s12933-020-01179-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690176PMC
November 2020

Similar cardiovascular outcomes in patients with diabetes and established or high risk for coronary vascular disease treated with dulaglutide with and without baseline metformin.

Eur Heart J 2021 07;42(26):2565-2573

Department of Medicine K2, Karolinska Institutet, Solnavägen 1, Stockholm SE171 77, Sweden.

Objective: Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial.

Research Design And Methods: Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection.

Results: Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81-1.05) vs. 0.78 (CI 0.61-0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin.

Conclusion: This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy.
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http://dx.doi.org/10.1093/eurheartj/ehaa777DOI Listing
July 2021

Rivaroxaban and Aspirin in Patients With Symptomatic Lower Extremity Peripheral Artery Disease: A Subanalysis of the COMPASS Randomized Clinical Trial.

JAMA Cardiol 2021 Jan;6(1):21-29

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

Importance: Patients with symptomatic lower extremity peripheral artery disease (LE-PAD) experience an increased risk of major vascular events. There is limited information on what clinical features of symptomatic LE-PAD prognosticate major vascular events and whether patients at high risk have a greater absolute benefit from low-dose rivaroxaban and aspirin.

Objective: To quantify the risk of major vascular events and investigate the response to treatment with low-dose rivaroxaban and aspirin among patients with symptomatic LE-PAD based on clinical presentation and comorbidities.

Design, Setting, And Participants: This is a subanalysis of a previously reported subgroup of patients with symptomatic LE-PAD who were enrolled in a large, double-blind, placebo-controlled randomized clinical trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]) in 602 centers in 33 countries from March 2013 to January 2020. Data analysis was completed from May 2016 to June 2020.

Interventions: A combination of low-dose rivaroxaban and aspirin compared with aspirin alone.

Main Outcomes And Measures: Thirty-month incidence risk of myocardial infarction, stroke and cardiovascular death (MACE), major adverse limb events (MALE) including major vascular amputation, and bleeding.

Results: The COMPASS trial enrolled 4129 patients with symptomatic LE-PAD (mean [SD] age, 66.8 [8.8] years; 2932 men [71.0%]). The 30-month Kaplan-Meier incidence risk of MACE or MALE, including major amputation, was 22.6% in those with prior amputation (this outcome was observed in 54 patients), 17.6% (n = 15) in those with Fontaine III or IV symptoms, and 11.8% (n = 142) in those with previous peripheral artery revascularization, classifying these features as high-risk limb presentations. The 30-month incidence risk of MACE or MALE, including major amputation, was 14.1% (n = 118) in those with kidney dysfunction, 13.5% (n = 67) in those with heart failure, 13.4% (n = 199) in those with diabetes, and 12.8% (n = 222) in those with polyvascular disease, classifying these features as high-risk comorbidities. Among patients with either high-risk limb presentations or high-risk comorbidities, treatment with rivaroxaban and aspirin compared with aspirin alone was associated with an estimated 4.2% (95% CI, 1.9%-6.2%) absolute risk reduction for MACE or MALE, including major amputation, at 30 months. Although the estimated absolute risk increase of major bleeding was higher with rivaroxaban and aspirin in combination than aspirin alone (2.0% [95% CI, 0.5%-3.9%]) for patients with either high-risk limb presentation or high-risk comorbidity, the estimated absolute risk increase of fatal or critical organ bleeding was low in this high-risk group (0.4% [95% CI, 0.2%-1.8%]), such that the net clinical benefit was estimated to be 3.2% (95% CI, 0.6%-5.3%).

Conclusions And Relevance: Patients with LE-PAD with high-risk limb presentations or high-risk comorbidities had a high incidence of major vascular events. For these patients, treatment with rivaroxaban and aspirin in combination compared with aspirin alone led to a large absolute reduction in vascular risk.
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http://dx.doi.org/10.1001/jamacardio.2020.4390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527938PMC
January 2021

Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy.

Stroke 2020 10 21;51(10):2901-2909. Epub 2020 Sep 21.

ANMCO Research Center, Florence, Italy (A.P.M.).

Background And Purpose: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities.

Methods: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities.

Results: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38-0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37-1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27-1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests.

Conclusions: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.
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http://dx.doi.org/10.1161/STROKEAHA.120.029762DOI Listing
October 2020

The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial.

Lancet Diabetes Endocrinol 2020 02 7;8(2):106-114. Epub 2020 Jan 7.

Robert Koch Medical Center, Sofia, Bulgaria.

Background: Cardiovascular outcome trials have suggested that glucagon-like peptide 1 (GLP-1) receptor agonists might reduce strokes. We analysed the effect of dulaglutide on stroke within the researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial.

Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial done at 371 sites in 24 countries. Men and women (aged ≥50 years) with established or newly detected type 2 diabetes whose HbA was 9·5% or less (with no lower limit) on stable doses of up to two oral glucose-lowering drugs with or without basal insulin therapy were eligible if their body-mass index was at least 23 kg/m. Participants were randomly assigned (1:1) to weekly subcutaneous injections of either masked dulaglutide 1·5 mg or the same volume of masked placebo (containing the same excipients but without dulaglutide). Randomisation was done by a computer-generated random code with an interactive web response system with stratification by site. Participants, investigators, the trial leadership, and all other personnel were masked to treatment allocation until the trial was completed and the database was locked. During the treatment period, participants in both groups were instructed to inject study drug on the same day at around the same time, each week. Strokes were categorised as fatal or non-fatal, and as either ischaemic, haemorrhagic, or undetermined. Stroke severity was assessed using the modified Rankin scale. Participants were seen at 2 weeks, 3 months, 6 months, and then every 3 months for drug dispensing and every 6 months for detailed assessments, until 1200 confirmed primary outcomes accrued. The primary endpoint was the first occurrence of any component of the composite outcome, which comprised non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular or unknown causes. All analyses were done according to an intention-to-treat strategy that included all randomly assigned participants, irrespective of adherence. The trial is registered with ClinicalTrials.gov, number NCT01394952.

Findings: Between Aug 18, 2011, and Aug 14, 2013, we screened 12 133 patients, of whom 9901 with type 2 diabetes and additional cardiovascular risk factors were randomly assigned to either dulaglutide (n=4949) or an equal volume of placebo (n=4952). During a median follow-up of 5·4 years, cerebrovascular and other cardiovascular outcomes were ascertained and adjudicated. 158 (3·2%) of 4949 participants assigned to dulaglutide and 205 (4·1%) of 4952 participants assigned to placebo had a stroke during follow-up (hazard ratio [HR] 0·76, 95% CI 0·62-0·94; p=0·010). Dulaglutide reduced ischaemic stroke (0·75, 0·59-0·94, p=0·012) but had no effect on haemorrhagic stroke (1·05, 0·55-1·99; p=0·89). Dulaglutide also reduced the composite of non-fatal stroke or all-cause death (0·88, 0·79-0·98; p=0·017) and disabling stroke (0·74, 0·56-0·99; p=0·042). The degree of disability after stroke did not differ by treatment group.

Interpretation: Long-term dulaglutide use might reduce clinically relevant ischaemic stroke in people with type 2 diabetes but does not affect stroke severity.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S2213-8587(19)30423-1DOI Listing
February 2020

Association Between Low-Dose Rivaroxaban With or Without Aspirin and Ischemic Stroke Subtypes: A Secondary Analysis of the COMPASS Trial.

JAMA Neurol 2020 01;77(1):43-48

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

Importance: The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) randomized clinical trial was stopped early owing to the efficacy of low-dose rivaroxaban plus aspirin in preventing major cardiovascular events. The main reason for early trial termination was the effect of combination therapy on reducing ischemic strokes.

Objective: To analyze the association between low-dose rivaroxaban with or without aspirin and different ischemic stroke subtypes.

Design, Setting, And Participants: This is a secondary analysis of a multicenter, double-blind, randomized, placebo-controlled study that was performed in 33 countries from March 12, 2013, to May 10, 2016. Patients with stable atherosclerotic vascular disease were eligible, and a total of 27 395 participants were randomized and followed up to February 6, 2017. All first ischemic strokes and uncertain strokes that occurred by this date were adjudicated using TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. The analysis of ischemic stroke subtypes was evaluated using an intention-to-treat principle. Statistical analysis was performed from March 12, 2013, to February 6, 2017.

Interventions: Participants received rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice a day), or aspirin (100 mg once a day).

Main Outcomes And Measures: Risk of ischemic stroke subtypes during follow-up.

Results: A total of 291 patients (66 women; mean [SD] age, 69.4 [8.5] years; 43 [14.8%] had a previous nonlacunar stroke) experienced an ischemic stroke. During the study, 49 patients (16.8%) received a diagnosis of atrial fibrillation. Applying TOAST criteria, 59 strokes (20.3%) were cardioembolic, 54 strokes (18.6%) were secondary to greater than 50% stenosis of the ipsilateral internal carotid artery, 42 strokes (14.4%) had a negative evaluation that met criteria for embolic stroke of undetermined source, and 21 strokes (7.2%) were secondary to small vessel disease. There were significantly fewer cardioembolic strokes (hazard ratio [HR], 0.40 [95% CI, 0.20-0.78]; P = .005) and embolic strokes of undetermined source (HR, 0.30 [95% CI, 0.12-0.74]; P = .006) in the combination therapy group compared with the aspirin-only group. A trend for reduction in strokes secondary to small vessel disease (HR, 0.36 [95% CI, 0.12-1.14]; P = .07) was not statistically significant. No significant difference was observed between the 2 groups in strokes secondary to greater than 50% carotid artery stenosis (HR, 0.85 [95% CI, 0.45-1.60]; P = .61). Rivaroxaban, 5 mg, twice daily showed a trend for reducing cardioembolic strokes compared with aspirin (HR, 0.57 [95% CI, 0.31-1.03]; P = .06) but was not associated with reducing other stroke subtypes.

Conclusions And Relevance: For patients with systemic atherosclerosis, low-dose rivaroxaban plus aspirin was associated with large, significant reductions in cardioembolic strokes and embolic strokes of undetermined source. However, these results of exploratory analysis need to be independently confirmed before influencing clinical practice.

Trial Registration: ClinicalTrials.gov identifier: NCT01776424.
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http://dx.doi.org/10.1001/jamaneurol.2019.2984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749537PMC
January 2020

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

Eur Heart J 2019 12;40(46):3771-3778a

Department of Vascular Medicine, University Medical Center Utrecht, University Utrecht, GA Utrecht, The Netherlands.

Aims: Adding rivaroxaban to aspirin in patients with stable atherosclerotic disease reduces the recurrence of cardiovascular disease (CVD) but increases the risk of major bleeding. The aim of this study was to estimate the individual lifetime treatment benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease.

Methods And Results: Patients with established CVD from the COMPASS trial (n = 27 390) and SMART prospective cohort study (n = 8139) were used. Using the pre-existing lifetime SMART-REACH model for recurrent CVD, and a newly developed Fine and Gray competing risk-adjusted lifetime model for major bleeding, individual treatment effects from adding low-dose rivaroxaban to aspirin in patients with stable CVD were estimated, expressed in terms of (i) life-years free of stroke or myocardial infarction (MI) gained; and (ii) life-years free from major bleeding lost. Calibration of the SMART-REACH model for prediction of recurrent CVD events in the COMPASS study was good. The major bleeding risk model as derived in the COMPASS trial showed good external calibration in the SMART cohort. Predicted individual gain in life expectancy free of stroke or MI from added low-dose rivaroxaban had a median of 16 months (range 1-48 months), while predicted individualized lifetime lost in terms of major bleeding had a median of 2 months (range 0-20 months).

Conclusion: There is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable CVD. Using these lifetime models, benefits and bleeding risk can be weighed for each individual patient, which could facilitate treatment decisions in clinical practice.
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http://dx.doi.org/10.1093/eurheartj/ehz404DOI Listing
December 2019

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

J Am Coll Cardiol 2019 07;73(25):3271-3280

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

Background: The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the combination of low-dose rivaroxaban and aspirin reduced major vascular events in patients with stable vascular disease.

Objectives: The purpose of this study was to identify subsets of patients at higher risk of recurrent vascular events, which may help focus the use of rivaroxaban and aspirin therapy.

Methods: COMPASS patients with vascular disease were risk stratified using 2 methods: the REACH (REduction of Atherothrombosis for Continued Health) atherothrombosis risk score and CART (Classification and Regression Tree) analysis. The absolute risk differences for rivaroxaban with aspirin were compared to aspirin alone over 30 months for the composite of cardiovascular death, myocardial infarction, stroke, acute limb ischemia, or vascular amputation; for severe bleeding; and for the net clinical benefit.

Results: High-risk patients using the REACH score were those with 2 or more vascular beds affected, history of heart failure (HF), or renal insufficiency, and by CART analysis were those with ≥2 vascular beds affected, history of HF, or diabetes. Rivaroxaban and aspirin combination reduced the serious vascular event incidence by 25% (4.48% vs. 5.95%, hazard ratio: 0.75; 95% confidence interval: 0.66 to 0.85), equivalent to 23 events prevented per 1,000 patients treated for 30 months, at the cost of a nonsignificant 34% increase in severe bleeding (1.34; 95% confidence interval: 0.95 to 1.88), or 2 events caused per 1,000 patients treated. Among patients with ≥1 high-risk feature identified from the CART analysis, rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.

Conclusions: In patients with vascular disease, further risk stratification can identify higher-risk patients (≥2 vascular beds affected, HF, renal insufficiency, or diabetes). The net clinical benefit remains favorable for most patients treated with rivaroxaban and aspirin compared with aspirin.
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http://dx.doi.org/10.1016/j.jacc.2019.02.079DOI Listing
July 2019

Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.

Lancet 2019 07 9;394(10193):121-130. Epub 2019 Jun 9.

Research Institute, FOSCAL and Medical School, Universidad de Santander UDES, Bucaramanga, Colombia.

Background: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A (HbA) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control.

Methods: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952.

Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001).

Interpretation: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S0140-6736(19)31149-3DOI Listing
July 2019

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.

Lancet 2019 07 9;394(10193):131-138. Epub 2019 Jun 9.

Research Institute, FOSCAL and Medical School, Universidad de Santander UDES, Bucaramanga, Colombia.

Background: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease.

Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952.

Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy.

Interpretation: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S0140-6736(19)31150-XDOI Listing
July 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

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

Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease: The COMPASS Trial.

J Am Coll Cardiol 2018 05 11;71(20):2306-2315. Epub 2018 Mar 11.

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

Background: Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). There is limited information on the prognosis of patients who experience MALE.

Objectives: Among participants with lower extremity PAD, this study investigated: 1) if hospitalizations, MACE, amputations, and deaths are higher after the first episode of MALE compared with patients with PAD who do not experience MALE; and 2) the impact of treatment with low-dose rivaroxaban and aspirin compared with aspirin alone on the incidence of MALE, peripheral vascular interventions, and all peripheral vascular outcomes over a median follow-up of 21 months.

Methods: We analyzed outcomes in 6,391 patients with lower extremity PAD who were enrolled in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial. COMPASS was a randomized, double-blind placebo-controlled study of low-dose rivaroxaban and aspirin combination or rivaroxaban alone compared with aspirin alone. MALE was defined as severe limb ischemia leading to an intervention or major vascular amputation.

Results: A total of 128 patients experienced an incident of MALE. After MALE, the 1-year cumulative risk of a subsequent hospitalization was 61.5%; for vascular amputations, it was 20.5%; for death, it was 8.3%; and for MACE, it was 3.7%. The MALE index event significantly increased the risk of experiencing subsequent hospitalizations (hazard ratio [HR]: 7.21; p < 0.0001), subsequent amputations (HR: 197.5; p < 0.0001), and death (HR: 3.23; p < 0.001). Compared with aspirin alone, the combination of rivaroxaban 2.5 mg twice daily and aspirin lowered the incidence of MALE by 43% (p = 0.01), total vascular amputations by 58% (p = 0.01), peripheral vascular interventions by 24% (p = 0.03), and all peripheral vascular outcomes by 24% (p = 0.02).

Conclusions: Among individuals with lower extremity PAD, the development of MALE is associated with a poor prognosis, making prevention of this condition of utmost importance. The combination of rivaroxaban 2.5 mg twice daily and aspirin significantly lowered the incidence of MALE and the related complications, and this combination should be considered as an important therapy for patients with PAD. (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]; NCT01776424).
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http://dx.doi.org/10.1016/j.jacc.2018.03.008DOI Listing
May 2018

External applicability of the COMPASS trial: an analysis of the reduction of atherothrombosis for continued health (REACH) registry.

Eur Heart J 2018 03;39(9):750-757a

Département Hospitalo-Universitaire FIRE, FACT French Alliance for Cardiovascular Trials, 46 Rue Henri Huchard, Assistance Publique-Hôpitaux de Paris, 75018 Paris, France.

Aims: The aims of the present study were to describe the proportion of patients eligible for the COMPASS trial within the Reduction of Atherothrombosis for Continued Health (REACH) registry, the reasons for ineligibility, and to put in perspective the characteristics and outcomes of trial-eligible patients from the REACH registry compared with those of patients enrolled in the reference aspirin arm of the COMPASS trial.

Methods And Results: The COMPASS selection and exclusion criteria were applied to REACH patients with either coronary artery disease (CAD) or peripheral artery disease (PAD). We used the COMPASS primary composite outcome of cardiovascular (CV) death, myocardial infarction (MI), or stroke. In REACH, 31 873 patients had CAD or PAD and detailed information allowing evaluation of eligibility. Among these, 9518 (29.9%) patients had exclusion criteria and an additional 5480 patients (17.2%) did not fulfil the inclusion criteria and thus were not eligible. The 'COMPASS-Eligible' population therefore comprised 52.9% of the evaluable REACH patients (n = 16 875). The main reasons for exclusion were high-bleeding risk (51.8%), anticoagulant use (44.8%), requirement for dual antiplatelet therapy within 1 year of an ACS or PCI with stent, (25.9%), history of ischaemic stroke <1 year (12.4%), and severe renal failure (2.2%). Eligibility was highest among patients with PAD alone (68.4%). COMPASS-Eligible patients from REACH experienced higher annualized primary outcome event rates than patients actually enrolled in the reference aspirin arm of COMPASS (4.2% vs. 2.9% per year, P < 0.001).

Conclusion: COMPASS-Eligible patients represent a substantial fraction of stable CAD/PAD patients encountered in routine clinical practice in the large international REACH registry suggesting good external applicability. COMPASS-Eligible patients experienced a higher rate of the primary outcome compared with COMPASS participants in the aspirin alone treatment arm.
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http://dx.doi.org/10.1093/eurheartj/ehx658DOI Listing
March 2018

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

Lancet 2018 01 10;391(10117):205-218. Epub 2017 Nov 10.

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

Background: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.

Methods: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.

Findings: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78-1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37-2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23-1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65-0·90, p=0·0012).

Interpretation: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.

Funding: Bayer AG.
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http://dx.doi.org/10.1016/S0140-6736(17)32458-3DOI Listing
January 2018

Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial.

Lancet Diabetes Endocrinol 2014 Jul 2;2(7):562-72. Epub 2014 Jun 2.

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

Background: Diabetes and non-diabetic dysglycaemia are risk factors for accelerated cognitive decline. In this planned substudy of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, we assessed whether normalising glucose with insulin glargine or administering omega-3 fatty acids in this population may slow this process or affect the development of cognitive impairment.

Methods: The ORIGIN trial recruited participants older than 50 years with dysglycaemia who were taking either no or one oral glucose-lowering drug, who had additional risk factors for cardiovascular events, whose HbA1c was less than 9%, and who were not taking insulin. Participants were recruited from 573 sites in 40 countries. Participants were randomly assigned to either titrated basal insulin glargine targeting a fasting plasma glucose concentration of 5.3 mmol/L or lower or standard care and to either omega-3 fatty acid (1 g) or placebo by a factorial design. Outcome adjudicators and data analysts were masked to treatment allocation. Cognitive function was assessed by the Mini-Mental State Examination (MMS) and Digit Symbol Substitution (DSS). The effect of insulin glargine or omega-3 fatty * acid on cognitive function over time, the annualised change in test scores, and the development of probable cognitive impairment were measured. All analyses were restricted to those participants who had a cognitive measurement at both baseline and at least one follow-up visit. The ORIGIN trial is registered with ClinicalTrials.gov, NCT00069784.

Findings: Participants were randomly assigned between Sept 1, 2003, and Dec 15, 2005. MMSE and DSS were assessed in 11,685 and 3392 ORIGIN participants (mean age 63.4 years [SD 7.7]), who were followed up for a median of 6.2 years (IQR 5.8-6.7). There was no difference in the rate of change of cognitive test scores between the insulin glargine and standard care groups (for the MMSE 0.0046, 95% CI -0.0132 to 0.0224, p=0.39; and for the DSS -0.0362, -0.2180 to 0.1455, p=0.34) or between the omega-3 fatty acid and placebo groups (for the MMSE 0.0013, 95% CI -0.0165 to 0.0191, p=0.21; and for the DSS -0.0605, -0.2422 to 0.1212, p=0.72). Similarly, the incidence of probable cognitive impairment did not differ between the insulin glargine and standard care groups (p=0.065) or the omega-3 fatty acid and placebo groups (p=0.070). In a subgroup analysis, allocation to insulin glargine versus standard care seemed to reduce the decline in the MMSE (but not the DSS) in participants with dysglycaemia but without evidence of diabetes (pinteraction=0.024).

Interpretation: In this relatively young cohort of people with dysglycaemia, insulin mediated normoglycaemia and omega-3 fatty acid for over 6 years had a neutral effect on the rate of cognitive decline and on incident cognitive impairment. Future studies should assess the effect of these interventions in an older cohort or the effect of other glucometabolic interventions on cognitive decline.

Funding: Sanofi.
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http://dx.doi.org/10.1016/S2213-8587(14)70062-2DOI Listing
July 2014

Effect of insulin glargine and n-3FA on carotid intima-media thickness in people with dysglycemia at high risk for cardiovascular events: the glucose reduction and atherosclerosis continuing evaluation study (ORIGIN-GRACE).

Diabetes Care 2013 Sep 5;36(9):2466-74. Epub 2013 Apr 5.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Objective: To evaluate the effects of insulin glargine and n-3 polyunsaturated fatty acid (n-3FA) supplements on carotid intima-media thickness (CIMT).

Research Design And Methods: We enrolled 1,184 people with cardiovascular (CV) disease and/or CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes in a randomized multicenter 2 × 2 factorial design trial. Participants received open-label insulin glargine (targeting fasting glucose levels ≤ 5.3 mmol/L [95 mg/dL]) or standard glycemic care and double-blind therapy with a 1-g capsule of n-3FA or placebo. The primary trial outcome was the annualized rate of change in maximum CIMT for the common carotid, bifurcation, and internal carotid artery segments. Secondary outcomes were the annualized rates of change in maximum CIMT for the common carotid and the common carotid plus bifurcation, respectively. Baseline followed by annual ultrasounds were obtained during a median follow-up of 4.9 years.

Results: Compared with standard care, insulin glargine reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0030 ± 0.0021 mm/year; P = 0.145) and significantly reduced the secondary CIMT outcomes (differences of 0.0033 ± 0.0017 mm/year [P = 0.049] and 0.0045 ± 0.0021 mm/year [P = 0.032], respectively). There were no differences in the primary and secondary outcomes between the n-3FA supplement and placebo groups.

Conclusions: In people with CV disease and/or CV risk factors and dysglycemia, insulin glargine used to target normoglycemia modestly reduced CIMT progression, whereas daily supplementation with n-3FA had no effect on CIMT progression.
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http://dx.doi.org/10.2337/dc12-2129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747889PMC
September 2013

Influenza vaccination and major adverse vascular events in high-risk patients.

Circulation 2012 Jul 19;126(3):278-86. Epub 2012 Jun 19.

Department of Medicine, McMaster University, Hamilton, ON, Canada.

Background: We sought to determine the association between influenza vaccination and major adverse vascular events because the association remains uncertain.

Methods And Results: A total of 31 546 participants were enrolled from 40 countries. Eligibility included age ≥55 years and known vascular disease. The primary outcome was a composite of death resulting from cardiovascular causes, myocardial infarction, or stroke during 4 influenza seasons (2003-2007). Influenza vaccination was associated with a lower risk of the outcome during 3 influenza seasons (defined using World Health Organization FluNet reports): 2004 to 2005 (adjusted odds ratio [OR], 0.62; 95% confidence interval [CI], 0.50-0.77), 2005 to 2006 (adjusted OR, 0.69; 95% CI, 0.53-0.91), and 2006 to 2007 (adjusted OR, 0.52; 95% CI, 0.42-0.65), the same years that circulating influenza matched the vaccine antigen. In 2003 to 2004, there was an incomplete match between circulating influenza and the vaccine antigen, and there was no association between influenza vaccination and the outcome (adjusted OR, 0.96; 95% CI, 0.73-1.27). However, tests of potential biases in the analyses revealed associations between influenza vaccination and outcome during noninfluenza seasons except 2003 to 2004. The summary ORs in the influenza season (OR, 0.65; 95% CI, 0.58-0.74]) and noninfluenza season (OR, 0.66; 95% CI, 0.57-0.76) were almost identical. The reduction in risk of noncardiovascular death associated with the influenza vaccine ranged from 73% to 79%.

Conclusion: Although initial analyses suggest that influenza vaccination was associated with reduced risk of major adverse vascular events during influenza seasons when the influenza vaccine matched the circulating virus, sensitivity analyses revealed that risk of bias remained. A randomized trial is needed to definitively address this question.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.111.071100DOI Listing
July 2012

n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.

N Engl J Med 2012 Jul 11;367(4):309-18. Epub 2012 Jun 11.

Background: The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown.

Methods: In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here.

Results: During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups.

Conclusions: Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).
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http://dx.doi.org/10.1056/NEJMoa1203859DOI Listing
July 2012

Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies.

Lancet Neurol 2011 Jan 25;10(1):43-53. Epub 2010 Oct 25.

The George Institute for Global Health, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Background: cardiovascular risk factors are associated with dementia and cognitive decline. We investigated the effects of renin-angiotensin system blockade on cognitive function in patients aged 55 years and older with established atherosclerotic cardiovascular disease or diabetes with end-organ damage in two clinical trials.

Methods: in the main study, ONTARGET, a double-blind, double-dummy, randomised controlled trial, the effects on cardiovascular outcomes of standard doses of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), an angiotensin-receptor blocker (telmisartan), and a combination of the drugs were evaluated in 25 620 participants. In the parallel TRANSCEND trial, the effects of telmisartan were compared with those of placebo in 5926 participants intolerant to ACE inhibitors. Secondary outcomes included cognitive impairment (defined by investigator-reported diagnosis of dementia or significant cognitive dysfunction, or a score of ≤ 23 on the Mini-Mental State Examination [MMSE]) and cognitive decline (a decrease of ≤ 3 points on the MMSE from baseline during follow-up). Analyses were by intention to treat. We pooled data from these studies to identify baseline predictors of cognitive impairment and its frequency according to mean systolic blood pressure during follow-up. These studies were registered with ClinicalTrials.gov, number NCT00153101.

Findings: During a median duration of 56 months (IQR 51-64) of follow-up in ONTARGET, cognitive impairment occurred in 652 (8%) of 7865 patients allocated ramipril, 584 (7%) of 7797 allocated telmisartan, and 618 (8%) of 7807 allocated combination treatment (combination vs ramipril, odds ratio [OR] 0·95, 95% CI 0·85-1·07, p= 0·39; telmisartan vs ramipril, OR 0·90, 0·80-1·01, p = 0·06). Corresponding figures for cognitive decline were 1314 (17%), 1279 (17%), and 1240 (17%) in each of the groups, respectively (telmisartan vs ramipril, OR 0·97, 0·89-1·06, p= 0·53; combination vs ramipril, OR 0·95, 0·88-1·04, p=0·28). In TRANSCEND, cognitive impairment occurred in 239 (9%) of 2694 participants allocated telmisartan compared with 245 (9%) of 2689 allocated placebo (OR 0·97, 0·81-1·17, p= 0·76). The corresponding figures for cognitive decline were 454 (17%) and 412 (16%; OR 1·10, 0·95-1·27, p= 0·22).

Interpretation: In patients with cardiovascular disease or diabetes, different approaches to blocking of the renin-angiotensin system had no clear effects on cognitive outcomes. Although patients with the lowest systolic blood pressure had the greatest preservation of cognitive function, meta-regression analyses did not show any benefits of blood-pressure lowering on cognition over several years of treatment.
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http://dx.doi.org/10.1016/S1474-4422(10)70250-7DOI Listing
January 2011

Effect of telmisartan on renal outcomes: a randomized trial.

Ann Intern Med 2009 Jul 18;151(1):1-10, W1-2. Epub 2009 May 18.

Schwabing General Hospital, KfH Kidney Center, Ludwig Maximilians University, Munich, Germany.

Background: Angiotensin-receptor blockers (ARBs) blunt progression of advanced diabetic nephropathy, but their long-term renal effects in other patients are not clear.

Objective: To examine the long-term renal effects of telmisartan versus placebo in adults at high vascular risk.

Design: Randomized trial. Patients were randomly assigned by a central automated system between November 2001 and May 2004 and were followed until March 2008. Participants and investigators were blinded to intervention status.

Setting: Multicenter, multinational study.

Patients: 5927 adults with known cardiovascular disease or diabetes with end-organ damage but without macroalbuminuria or heart failure who cannot tolerate angiotensin-converting enzyme inhibitors.

Intervention: Telmisartan, 80 mg/d (n = 2954), or matching placebo (n = 2972) plus standard treatment for a mean of 56 months.

Measurements: Composite renal outcome of dialysis or doubling of serum creatinine, changes in estimated glomerular filtration rate (GFR), and changes in albuminuria.

Results: No important difference was found in the composite renal outcome with telmisartan (58 patients [1.96%]) versus placebo (46 patients [1.55%]) (hazard ratio, 1.29 [95% CI, 0.87 to 1.89]; P = 0.20). Among the telmisartan and placebo groups, 7 and 10 patients had dialysis and 56 and 36 patients had doubling of serum creatinine, respectively (hazard ratio, 1.59 [CI, 1.04 to 2.41]; P = 0.031). Albuminuria increased less with telmisartan than with placebo (32% [CI, 23% to 41%] vs. 63% [CI, 52% to 76%]; P < 0.001). Decreases in estimated GFR were greater with telmisartan than with placebo (mean change in estimated GFR, -3.2 mL/min per 1.73 m(2) [SD, 18.3] vs. -0.26 mL/min per 1.73 m(2) [SD, 18.0]; P < 0.001).

Limitation: Only 17 participants had dialysis.

Conclusion: In adults with vascular disease but without macroalbuminuria, the effects of telmisartan on major renal outcomes were similar to those of placebo.
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http://dx.doi.org/10.7326/0003-4819-151-1-200907070-00122DOI Listing
July 2009

Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial.

Lancet 2008 Aug;372(9638):547-53

Schwabing General Hospital, and KfH Kidney Centre, Ludwig Maximilians University Munchen, Germany.

Background: Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage.

Methods: The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101.

Findings: 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13.4%]) and ramipril (1150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01-1.18, p=0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89-1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01-1.51, p=0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2] mL/min/1.73 m(2)vs -4.12 [17.4], p<0.0001) or combination therapy (-6.11 [17.9], p<0.0001). The increase in urinary albumin excretion was less with telmisartan (p=0.004) or with combination therapy (p=0.001) than with ramipril.

Interpretation: In people at high vascular risk, telmisartan's effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.
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http://dx.doi.org/10.1016/S0140-6736(08)61236-2DOI Listing
August 2008

Telmisartan, ramipril, or both in patients at high risk for vascular events.

N Engl J Med 2008 Apr 31;358(15):1547-59. Epub 2008 Mar 31.

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

Background: In patients who have vascular disease or high-risk diabetes without heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and morbidity from cardiovascular causes, but the role of angiotensin-receptor blockers (ARBs) in such patients is unknown. We compared the ACE inhibitor ramipril, the ARB telmisartan, and the combination of the two drugs in patients with vascular disease or high-risk diabetes.

Methods: After a 3-week, single-blind run-in period, patients underwent double-blind randomization, with 8576 assigned to receive 10 mg of ramipril per day, 8542 assigned to receive 80 mg of telmisartan per day, and 8502 assigned to receive both drugs (combination therapy). The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure.

Results: Mean blood pressure was lower in both the telmisartan group (a 0.9/0.6 mm Hg greater reduction) and the combination-therapy group (a 2.4/1.4 mm Hg greater reduction) than in the ramipril group. At a median follow-up of 56 months, the primary outcome had occurred in 1412 patients in the ramipril group (16.5%), as compared with 1423 patients in the telmisartan group (16.7%; relative risk, 1.01; 95% confidence interval [CI], 0.94 to 1.09). As compared with the ramipril group, the telmisartan group had lower rates of cough (1.1% vs. 4.2%, P<0.001) and angioedema (0.1% vs. 0.3%, P=0.01) and a higher rate of hypotensive symptoms (2.6% vs. 1.7%, P<0.001); the rate of syncope was the same in the two groups (0.2%). In the combination-therapy group, the primary outcome occurred in 1386 patients (16.3%; relative risk, 0.99; 95% CI, 0.92 to 1.07); as compared with the ramipril group, there was an increased risk of hypotensive symptoms (4.8% vs. 1.7%, P<0.001), syncope (0.3% vs. 0.2%, P=0.03), and renal dysfunction (13.5% vs. 10.2%, P<0.001).

Conclusions: Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. The combination of the two drugs was associated with more adverse events without an increase in benefit. (ClinicalTrials.gov number, NCT00153101 [ClinicalTrials.gov].).
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http://dx.doi.org/10.1056/NEJMoa0801317DOI Listing
April 2008
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