Publications by authors named "John Eikelboom"

561 Publications

Urinary fatty acid binding protein 3 (uFABP3) is a potential biomarker for peripheral arterial disease.

Sci Rep 2021 May 26;11(1):11061. Epub 2021 May 26.

Division of Vascular Surgery, St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada.

Plasma levels of fatty acid binding protein 3 (pFABP3) are elevated in patients with peripheral artery disease (PAD). Since the kidney filters FABP3 from circulation, we investigated whether urinary fatty acid binding protein 3 (uFABP3) is associated with PAD, and also explored its potential as a diagnostic biomarker for this disease state. A total of 130 patients were recruited from outpatient clinics at St. Michael's Hospital, comprising of 65 patients with PAD and 65 patients without PAD (non-PAD). Levels of uFABP3 normalized for urine creatinine (uFABP3/uCr) were 1.7-folds higher in patients with PAD [median (IQR) 4.41 (2.79-8.08)] compared with non-PAD controls [median (IQR) 2.49 (1.78-3.12), p-value = 0.001]. Subgroup analysis demonstrated no significant effect of cardiovascular risk factors (age, sex, hypertension, hypercholesteremia, diabetes and smoking) on uFABP3/uCr in both PAD and non-PAD patients. Spearmen correlation studies demonstrated a significant negative correlation between uFABP3/uCr and ABI (ρ = - 0.436; p-value = 0.001). Regression analysis demonstrated that uFABP3/Cr levels were associated with PAD independently of age, sex, hypercholesterolemia, smoking, prior history of coronary arterial disease and Estimated Glomerular Filtration rate (eGFR) [odds ratio: 2.34 (95% confidence interval: 1.47-3.75) p-value < 0.001]. Lastly, receiver operator curve (ROC) analysis demonstrated unadjusted area under the curve (AUC) for uFABP3/Cr of 0.79, which improved to 0.86 after adjusting for eGFR, age, hypercholesteremia, smoking and diabetes. In conclusion, our results demonstrate a strong association between uFABP3/Cr and PAD and suggest the potential of uFABP3/Cr in identifying patients with PAD.
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http://dx.doi.org/10.1038/s41598-021-90395-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155078PMC
May 2021

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

Heart 2021 May 21. 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
May 2021

What is the role of growth-differentiation factor-15 in biomarker-based prediction of mortality in patients with atrial fibrillation?

Eur J Intern Med 2021 Jun 11;88:23-24. Epub 2021 May 11.

Population Health Research Institute, Hamilton Health Sciences and McMaster University, 20 Copeland Avenue, Hamilton, ON L8L 2 × 2, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ejim.2021.04.011DOI Listing
June 2021

Risk stratification of cardiovascular complications using CHADS-VASc and CHADS scores in chronic atherosclerotic cardiovascular disease.

Int J Cardiol 2021 May 3. Epub 2021 May 3.

Cardiology Research Unit, University Hospital Geelong, Barwon Health, Geelong, Australia.

Background The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that rivaroxaban plus aspirin reduced major adverse cardiovascular events (MACE) in patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD). We explored whether CHADS-VASc or CHADS scores, well-validated tools for assessing risk of thromboembolic events in atrial fibrillation, can identify vascular patients at highest risk of recurrent events who may derive greatest benefits of treatment. Methods Predictive accuracies of the CHADS-VASc and CHADS scores for MACE, were assessed in this analysis of the COMPASS trial. Kaplan-Meier estimates of cumulative risk were used to compare the effects of rivaroxaban plus aspirin (n = 9152) with aspirin alone (n = 9126) according to risk scores. Results High CHADS-VASc (6-9) or CHADS (3-6) scores were associated with over three times greater absolute risk of MACE compared with CHADS-VASc score of 1-2 or CHADS score of 0. The effects of rivaroxaban plus aspirin compared with aspirin alone were consistent across CHADS-VASc and CHADS score categories for MACE, bleeding and net clinical benefit, with greatest reduction in MACE observed in patients treated for 30 months with highest CHADS score (3-6) (hazard ratio = 0.67, 95% CI: 0.53-0.86, p = 0.0012, 25 events per 1000 patients prevented). Conclusion The CHADS-VASc and CHADS scores can be used in patients with chronic CAD and/or PAD to identify patients who are at highest risk of MACE. Those identified at highest risk by CHADS scores had greatest benefit from dual pathway inhibition with rivaroxaban plus aspirin. Clinical Trial Registration: NCT01776424.
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http://dx.doi.org/10.1016/j.ijcard.2021.04.067DOI Listing
May 2021

Biomarker-Based Risk Prediction With the ABC-AF Scores in Patients With Atrial Fibrillation Not Receiving Oral Anticoagulation.

Circulation 2021 May 14;143(19):1863-1873. Epub 2021 Apr 14.

Uppsala Clinical Research Center (Z.H., J.L., J.O., A.S., L.W.), Uppsala University, Sweden.

Background: The novel ABC (Age, Biomarkers, Clinical History) scores outperform traditional risk scores for stroke, major bleeding, and death in patients with atrial fibrillation (AF) receiving oral anticoagulation. To refine their utility, the ABC-AF scores needed to be validated in patients not receiving oral anticoagulation.

Methods: We measured plasma levels of the ABC biomarkers (N-terminal pro-B-type natriuretic peptide, cardiac troponin-T, and growth-differentiation factor 15) to apply the previously developed ABC-AF scores in patients with AF receiving aspirin (n=3195) or aspirin and clopidogrel (n=1110) in 2 large clinical trials. Calibration was assessed by comparing estimated with observed 1-year risks. Cox regression models were used for recalibration. Discrimination was evaluated separately for the aspirin-only and the overall cohort (n=4305).

Results: The ABC-AF-stroke score yielded a c-index of 0.70 (95% CI, 0.67-0.73) in both cohorts. The ABC-AF-bleeding score had a c-index of 0.76 (95% CI, 0.71-0.81) in the aspirin-only cohort and 0.73 (95% CI, 0.69-0.77) overall. Both scores were superior to risk scores recommended by current guidelines. The ABC-AF-death score yielded a c-index of 0.78 (95% CI, 0.76-0.80) overall. Calibrated in patients receiving oral anticoagulation, the ABC-AF-stroke score underestimated and the ABC-AF-bleeding score overestimated the risk of events in both cohorts. These scores were recalibrated for prediction of absolute event rates in the absence of oral anticoagulation.

Conclusions: The biomarker-based ABC-AF scores showed better discrimination than traditional risk scores and were recalibrated for precise risk estimation in patients not receiving oral anticoagulation. They can now provide improved decision support on treatment of an individual patient with AF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.053100DOI Listing
May 2021

Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials.

Eur Heart J 2021 Mar 26. Epub 2021 Mar 26.

Dutch Network for Cardiovascular Research (WCN), Utrecht, The Netherlands.

Aims: Recent randomized trials demonstrated a benefit of low-dose colchicine added to guideline-based treatment in patients with recent myocardial infarction or chronic coronary disease. We performed a systematic review and meta-analysis to obtain best estimates of the effects of colchicine on major adverse cardiovascular events (MACE).

Methods And Results: We searched the literature for randomized clinical trials of long-term colchicine in patients with atherosclerosis published up to 1 September 2020. The primary efficacy endpoint was MACE, the composite of myocardial infarction, stroke, or cardiovascular death. We combined the results of five trials that included 11 816 patients. The primary endpoint occurred in 578 patients. Colchicine reduced the risk for the primary endpoint by 25% [relative risk (RR) 0.75, 95% confidence interval (CI) 0.61-0.92; P = 0.005], myocardial infarction by 22% (RR 0.78, 95% CI 0.64-0.94; P = 0.010), stroke by 46% (RR 0.54, 95% CI 0.34-0.86; P = 0.009), and coronary revascularization by 23% (RR 0.77, 95% CI 0.66-0.90; P < 0.001). We observed no difference in all-cause death (RR 1.08, 95% CI 0.71-1.62; P = 0.73), with a lower incidence of cardiovascular death (RR 0.82, 95% CI 0.55-1.23; P = 0.34) counterbalanced by a higher incidence of non-cardiovascular death (RR 1.38, 95% CI 0.99-1.92; P = 0.060).

Conclusion: Our meta-analysis indicates that low-dose colchicine reduced the risk of MACE as well as that of myocardial infarction, stroke, and the need for coronary revascularization in a broad spectrum of patients with coronary disease. There was no difference in all-cause mortality and fewer cardiovascular deaths were counterbalanced by more non-cardiovascular deaths.
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http://dx.doi.org/10.1093/eurheartj/ehab115DOI Listing
March 2021

Cardiovascular Outcomes According to Polypharmacy and Drug Adherence in Patients with Atrial Fibrillation on Long-Term Anticoagulation (from the RE-LY Trial).

Am J Cardiol 2021 Mar 20. Epub 2021 Mar 20.

Klinik für Innere Medizin III - Kardiologie, Angiologie, Internistische Intensivmedizin.

Prevalence of atrial fibrillation (AF) increases with age, along with comorbidities and, thus, polypharmacy. Non-adherence is associated with polypharmacy. This study aimed to identify patients at risk for cardiovascular events according to their pharmacological treatment intensity and adherence. Patients (n = 18,113) with a mean age of 71.5 ± 8.7 years, at high cardiovascular risk were followed between December 2005 until December 2007 for a median time of 2 years. The association between polypharmacy and adherence and their impact on cardiovascular and bleeding events were explored. Adherence was defined as a study drug intake of ≥80%. Patients with more co-medications had a higher body mass index, higher prevalence of hypertension, coronary heart disease, heart failure, and diabetes mellitus (all p < 0.0001) compared to ≤4 or 5-8 co-medications, but no differences in history of stroke (p = 0.68) or transient ischemic attack (p = 0.065). Across all treatments, the adjusted hazard ratios (HRs) increased in patients with more co-medications (≥9 vs ≤4) for all-cause death (HR 1.30; 1.06-1.59), major bleeding (HR 1.65; 1.33-2.05), and all bleeding events (HR 1.44; 1.31-1.59). Yearly event rates were higher in non-adherent than adherent patients for stroke and systemic embolism (SSE) (3.14 vs 1.00), all-cause death (7.76 vs 2.66), major bleeding (6.21 vs 2.65), and all bleeding (28.71 vs 19.05; all p < 0.0001). After an event the patients were more likely to become non-adherent (adherence after SSE 30.3%, after major bleeding 33.4%, after all bleeding 66.7%; all p < 0.0001). The treatment effects were consistent to the overall group in the different polypharmacy groups. In conclusion, polypharmacy and non-adherence are risk indicators for increased adverse cardiovascular and bleeding events. Dabigatran is safe to use across the full spectrum of AF patients, independent of the number of co-medications and adherence. Patients with co-medications and comorbidities require special attention and encouragement to adhere to oral anticoagulation.
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http://dx.doi.org/10.1016/j.amjcard.2021.03.024DOI Listing
March 2021

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 04 16;77(15):1903-1921. Epub 2021 Mar 16.

Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; Center for Outcomes Research and Evaluation (CORE), Yale School of Medicine, New Haven, Connecticut, USA. Electronic address:

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.
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http://dx.doi.org/10.1016/j.jacc.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963001PMC
April 2021

Rosuvastatin for the prevention of venous thromboembolism: a pooled analysis of the HOPE-3 and JUPITER randomized controlled trials.

Cardiovasc Res 2021 Mar 10. Epub 2021 Mar 10.

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

Aims: To examine the association between rosuvastatin and VTE risk, and whether effects vary in different subpopulations stratified by key demographic, cardiovascular disease (CVD) risk factors and other risk factors associated with VTE.

Methods And Results: An individual participant data meta-analysis was conducted across two randomized controlled trials in 30,507 participants over a mean follow up of 3.62 years, Individuals had no prior history of vascular disease but were at intermediate CV risk. In both trials, participants were randomized to receive rosuvastatin or matching placebo. The primary outcome was VTE during follow-up, defined as either deep vein thrombosis or pulmonary embolism. Associations between rosuvastatin and VTE were examined in the overall pooled cohort, and subpopulations stratified by demographic risk factors (i.e. age, sex), CVD risk factors (i.e. obesity, smoking, lipid levels, blood pressure levels, C-reactive protein level), and a history of cancer.Mean age was 65.96 (SD 7.19) years of age, and 17,832 (58.45%) were male. 5,434 (17.82%) were smokers, median BMI was 27.6 (Interquartile range [IQR] 24.7 - 31.1) kg/m2, and median CRP level was 3.4 (IQR 2.1 - 6.0) mg/L. There were 139 VTE events. In the pooled cohort, rosuvastatin was associated with a large proportional reduction in the risk of VTE (hazard ratio 0.53, 95% CI 0.37 - 0.75). No significant interactions were observed between treatment with rosuvastatin and the risk of VTE across subpopulations stratified by demographic, CVD risk factors or a history of cancer (p-values for interactions >0.05 for all subgroups).

Conclusions: Rosuvastatin is associated with a 47% proportional reduction in the risk of VTE, and its effect is consistent both in the presence or absence of VTE related clinical risk factors.

Translational Perspective: In this individual participant data meta-analysis of two large randomized controlled trials comparing rosuvastatin to placebo, rosuvastatin was associated with a 47% proportional reduction in the risk of VTE. The effect of rosuvastatin was consistent across a broad range of demographic factors, cardiovascular risk factors, and a history of cancer. This study demonstrates that rosuvastatin is broadly affective at reducing the risk of VTE both in the presence or absence of VTE associated clinical risk factors. Results inform future research on the use of statins for this indication.
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http://dx.doi.org/10.1093/cvr/cvab078DOI Listing
March 2021

Plasma Rivaroxaban Level to Identify Patients at Risk of Drug Overexposure: Is a Single Measurement of Drug Level Reliable?

TH Open 2021 Jan 25;5(1):e84-e88. Epub 2021 Feb 25.

Population Health Research Institute, Hamilton, Ontario, Canada.

 Dose adjustment based on laboratory monitoring is not routinely recommended for patients treated with rivaroxaban but because an association has been reported between high drug level and bleeding, it would be of interest to know if measuring drug level once could identify patients at risk of bleeding who might benefit from a dose reduction.  This study was aimed to investigate the reliability of a single measurement of rivaroxaban level to identify clinic patients with persistently high levels, defined as levels that remained in the upper quintile of drug-level distribution.  In this prospective cohort study of 100 patients with atrial fibrillation or venous thromboembolism, peak and trough rivaroxaban levels were measured using the STA-Liquid Anti-Xa assay at baseline and after 2 months. Values of 395.8 and 60.2 ng/mL corresponded to the 80th percentile for peak and trough levels, respectively, and levels above these cut-offs were categorized as high for our analyses.  Among patients with a peak or trough level in the upper quintile at baseline, only 26.7% (95% confidence interval [CI]: 10.9-52.0%), and 13.3% (95% CI: 2.4-37.9%), respectively, remained above these thresholds.  Our findings do not support the use of a single rivaroxaban level measurement to identify patients who would benefit from a dose reduction because such an approach is unable to reliably identify patients with high levels.
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http://dx.doi.org/10.1055/s-0040-1721734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906835PMC
January 2021

Restart of Anticoagulant Therapy and Risk of Thrombosis, Rebleeding, and Death after Factor Xa Inhibitor Reversal in Major Bleeding Patients.

Thromb Haemost 2021 Feb 25. Epub 2021 Feb 25.

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

Background:  Lack of data on balancing bleeding and thrombosis risk causes uncertainty about restarting anticoagulants after major bleeding. Anticoagulant reversal trials offer prospectively gathered data after major bleeding with well-documented safety events and restarting behavior.

Objectives:  To examine the relationship of restarting anticoagulation with thrombosis, rebleeding, and death.

Methods:  This is a posthoc analysis of a prospective factor Xa inhibitor reversal study at 63 centers in North America and Europe. We compared outcomes of restarted patients with those not restarted using landmark and time-dependent Cox proportional hazards models. Outcomes included thrombotic and bleeding events and death and a composite of all three.

Results:  Of 352 patients enrolled, oral anticoagulation was restarted in 100 (28%) during 30-day follow-up. Thirty-four (9.7%) had thrombotic events, 15 (4.3%) had bleeding events (after day 3), and 49 (14%) died. In the landmark analysis comparing patients restarted within 14 days to those not, restarting was associated with decreased thrombotic events (hazard ratio [HR] = 0.112; 95% confidence interval [CI]: 0.001-0.944;  = 0.043) and increased rebleeding (HR = 8.39; 95% CI: 1.13-62.29;  = 0.037). The time-dependent Cox model showed evidence for a reduction in a composite (thrombotic events, bleeding, and death) attempting to capture net benefit (HR = 0.384; 95% CI: 0.161-0.915;  = 0.031).

Conclusion:  This analysis provides modest evidence that restarting anticoagulation in factor Xa inhibitor-associated major bleeding patients is correlated with reduced risk of thrombotic events and increased risk of rebleeding. There is low-level evidence of net benefit for restarting. A randomized trial of restarting would be appropriate.
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http://dx.doi.org/10.1055/a-1400-6159DOI Listing
February 2021

Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention: A North American Perspective: 2021 Update.

Circulation 2021 Feb 8;143(6):583-596. Epub 2021 Feb 8.

Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA (D.L.B., C.P.C., D.P.F.).

A growing number of patients undergoing percutaneous coronary intervention (PCI) with stent implantation also have atrial fibrillation. This poses challenges for their optimal antithrombotic management because patients with atrial fibrillation undergoing PCI require oral anticoagulation for the prevention of cardiac thromboembolism and dual antiplatelet therapy for the prevention of coronary thrombotic complications. The combination of oral anticoagulation and dual antiplatelet therapy substantially increases the risk of bleeding. Over the last decade, a series of North American Consensus Statements on the Management of Antithrombotic Therapy in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention have been reported. Since the last update in 2018, several pivotal clinical trials in the field have been published. This document provides a focused updated of the 2018 recommendations. The group recommends that in patients with atrial fibrillation undergoing PCI, a non-vitamin K antagonist oral anticoagulant is the oral anticoagulation of choice. Dual antiplatelet therapy with aspirin and a P2Y inhibitor should be given to all patients during the peri-PCI period (during inpatient stay, until time of discharge, up to 1 week after PCI, at the discretion of the treating physician), after which the default strategy is to stop aspirin and continue treatment with a P2Y inhibitor, preferably clopidogrel, in combination with a non-vitamin K antagonist oral anticoagulant (ie, double therapy). In patients at increased thrombotic risk who have an acceptable risk of bleeding, it is reasonable to continue aspirin (ie, triple therapy) for up to 1 month. Double therapy should be given for 6 to 12 months with the actual duration depending on the ischemic and bleeding risk profile of the patient, after which patients should discontinue antiplatelet therapy and receive oral anticoagulation alone.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050438DOI Listing
February 2021

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

J Am Coll Cardiol 2021 Feb;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

The Indirect Consequences of the Response to the COVID-19 Pandemic.

J Am Coll Cardiol 2021 01;77(2):186-188

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

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http://dx.doi.org/10.1016/j.jacc.2020.11.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837132PMC
January 2021

Stroke risk prediction in patients with atrial fibrillation with and without rheumatic heart disease.

Cardiovasc Res 2021 Jan 2. Epub 2021 Jan 2.

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

Aims: Patients with atrial fibrillation (AF) and rheumatic heart disease (RHD), especially mitral stenosis, are assumed to be at high risk of stroke, irrespective of other factors. We aimed to re-evaluate stroke risk factors in a contemporary cohort of AF patients.

Methods And Results: We analyzed data of 15,400 AF patients presenting to an emergency department and who were enrolled in the global RE-LY AF registry, representing 47 countries from all inhabited continents. Follow-up occurred at 1 year after enrollment. A total of 1,788 (11.6%) patients had RHD. These patients were younger (51.4 ± 15.7 vs. 67.8 ± 13.6 years), more likely to be female (66.2% vs. 44.7%) and had a lower mean CHA2DS2-VASc score (2.1 ± 1.7 vs. 3.7 ± 2.2) as compared to patients without RHD (all p < 0.001). Significant mitral stenosis (average mean transmitral gradient 11.5 ± 6.5 mmHg) was the predominant valve lesion in those with RHD (59.6%). Patients with RHD had a higher baseline rate of anticoagulation use (60.4% vs. 45.2%, p < 0.001). Unadjusted stroke rates at 1 year were 2.8% and 4.1% for patients with and without RHD, respectively. The performance of the CHA2DS2-VASc score was modest in both groups (stroke at 1 year, c-statistics 0.69, 95% confidence interval [CI] 0.60-0.78 and 0.63, 95% CI 0.61-0.66, respectively). In the overall cohort, advanced age, female sex, prior stroke, tobacco use and non-use of anticoagulation were predictors for stroke (all p < 0.05). Mitral stenosis was not associated with stroke risk (adjusted odds ratio 1.07, 95% CI 0.67-1.72, p = 0.764).

Conclusions: The performance of the CHA2DS2-VASc score was modest in AF patients both with and without RHD. In this cohort, moderate-to-severe mitral stenosis was not an independent risk factor for stroke.

Translational Perspective: Based on studies conducted several decades ago, the presence of moderate-to-severe mitral stenosis has been associated with a very high risk of stroke in patients with AF. Our results, based on a large, global sample of contemporary patients with AF that contained a significant proportion of individuals with RHD, challenge the assumption that mitral stenosis is a major, independent risk factor for stroke. The performance of the widely used CHA2DS2-VASc score was modest in both patients with and without RHD. At least one ongoing randomized trial is evaluating the optimal antithrombotic strategy in patients with AF and RHD.
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http://dx.doi.org/10.1093/cvr/cvaa344DOI Listing
January 2021

Post-operative pain following cardiac implantable electronic device implantation: insights from the BRUISE CONTROL trials.

Europace 2021 May;23(5):748-756

Division of Cardiology, Department of Medicine, University of Calgary, Libin Cardiovascular Institute, Calgary, AB, Canada.

Aims : Post-operative pain following cardiac implantable electronic device (CIED) insertion is associated with patient dissatisfaction, emotional distress, and emergency department visits. We sought to identify factors associated with post-operative pain and develop a prediction score for post-operative pain.

Methods And Results : All patients from the BRUISE CONTROL-1 and 2 trials were included in this analysis. A validated Visual Analogue Scale (VAS) was used to assess the severity of pain related to CIED implant procedures. Patients were asked to grade the most severe post-operative pain, average post-operative pain, and pain on the day of the first post-operative clinic. Multivariable regression analyses were performed to identify predictors of significant post-operative pain and to develop a pain-prediction score. A total of 1308 patients were included. Multivariable regression analysis found that the presence of post-operative clinically significant haematoma {CSH; P value < 0.001; odds ratio (OR) 3.82 [95% confidence interval (CI): 2.37-6.16]}, de novo CIED implantation [P value < 0.001; OR 1.90 (95% CI: 1.47-2.46)], female sex [P value < 0.001; OR 1.61 (95% CI: 1.22-2.12)], younger age [<65 years; P value < 0.001; OR 1.54 (95% CI: 1.14-2.10)], and lower body mass index [<20 kg/m2; P value < 0.05; OR 2.05 (95% CI: 0.98-4.28)] demonstrated strong and independent associations with increased post-operative pain. An 11-point post-operative pain prediction score was developed using the data.

Conclusion : Our study has identified multiple predictors of post-operative pain after CIED insertion. We have developed a prediction score for post-operative pain that can be used to identify individuals at risk of experiencing significant post-operative pain.
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http://dx.doi.org/10.1093/europace/euaa349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139821PMC
May 2021

Individual Patient Data from the Pivotal Randomized Controlled Trials of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation (COMBINE AF): Design and Rationale: From the COMBINE AF (A Collaboration between Multiple institutions to Better Investigate Non-vitamin K antagonist oral anticoagulant use in Atrial Fibrillation) Investigators.

Am Heart J 2021 03 6;233:48-58. Epub 2020 Dec 6.

Duke Clinical Research Institute, 200 Morris St, Durham, NC 27701.

Background: Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date.

Design: COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771).

Conclusion: In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes.
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http://dx.doi.org/10.1016/j.ahj.2020.12.002DOI Listing
March 2021

Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation.

J Am Heart Assoc 2020 12 9;9(24):e018984. Epub 2020 Dec 9.

Uppsala Clinical Research Center Uppsala University Uppsala Sweden.

Background To explore the pathophysiological features of ischemic stroke in patients with atrial fibrillation (AF), we evaluated the association between 268 plasma proteins and subsequent ischemic stroke in 2 large AF cohorts receiving oral anticoagulation. Methods and Results A case-cohort sample of patients with AF from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, including 282 cases with ischemic stroke or systemic embolism and a random sample of 4124 without these events, during 1.9 years of follow-up was used for identification. Validation was provided by a similar case-cohort sample of patients with AF from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, including 149 cases with ischemic stroke/systemic embolism and a random sample of 1062 without these events. In plasma obtained before randomization, 268 unique biomarkers were measured with OLINK proximity extension assay panels (CVD II, CVD III, and Inflammation) and conventional immunoassays. The association between biomarkers and outcomes was evaluated by random survival forest and adjusted Cox regression. According to random survival forest or Cox regression analyses, the biomarkers most strongly and consistently associated with ischemic stroke/systemic embolism were matrix metalloproteinase-9, NT-proBNP (N-terminal pro-B-type natriuretic peptide), osteopontin, sortilin, soluble suppression of tumorigenesis 2, and trefoil factor-3. The corresponding hazard ratios (95% CIs) for an interquartile difference were as follows: 1.18 (1.00-1.38), 1.55 (1.28-1.88), 1.28 (1.07-1.53), 1.19 (1.02-1.39), 1.23 (1.05-1.45), and 1.19 (0.97-1.45), respectively. Conclusions In patients with AF, of 268 unique biomarkers, the 6 biomarkers most strongly associated with subsequent ischemic stroke/systemic embolism represent fibrosis/remodeling (matrix metalloproteinase-9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT-proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor-3). Registration URL: https://www.clinicaltrials.gov. Unique Identifiers: NCT00412984 and NCT00262600.
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http://dx.doi.org/10.1161/JAHA.120.018984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955358PMC
December 2020

Direct oral anticoagulants: evidence and unresolved issues.

Lancet 2020 11;396(10264):1767-1776

Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada; Population Health Research Institute, Hamilton, ON, Canada; Hamilton General Hospital and McMaster University, Hamilton, ON, Canada.

Currently licenced direct oral anticoagulants selectively target thrombin (eg, dabigatran) or coagulation factor Xa (eg, apixaban, betrixaban, edoxaban, and rivaroxaban). Designed to be given in fixed doses without routine monitoring, direct oral anticoagulants have a lower propensity for food and drug interactions than do vitamin K antagonists, and in randomised controlled trials involving around 250 000 patients, they were at least as effective for prevention and treatment of thrombosis and were associated with a lower risk of life-threatening bleeding. The absolute benefits of direct oral anticoagulants over vitamin K antagonists are modest; however, guidelines recommend them in preference to vitamin K antagonists for most indications because of their ease of use and superior safety. The greatest benefits of direct oral anticoagulants are likely to be in patients who were previously deemed unsuitable for vitamin K antagonist therapy. The emergence of generic preparations is expected to further increase the uptake of direct oral anticoagulants, particularly in countries where they are currently not widely used because of cost. Direct oral anticoagulants are contraindicated in patients with mechanical heart valves and should be used with caution or avoided in patients with advanced kidney or liver disease. In this Therapeutics paper, we review the pharmacology of direct oral anticoagulants, summarise the evidence that led to their approval and incorporation into treatment guidelines, and explore key unresolved issues. We also briefly discuss future perspectives for the development of oral anticoagulants.
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http://dx.doi.org/10.1016/S0140-6736(20)32439-9DOI Listing
November 2020

Mortality benefits of thromboprophylaxis.

Authors:
John Eikelboom

Lancet Haematol 2020 11;7(11):e783

Department of Medicine, McMaster University, Hamilton, ON L9K 1H8, Canada. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(20)30285-4DOI Listing
November 2020

Sulodexide versus Control and the Risk of Thrombotic and Hemorrhagic Events: Meta-Analysis of Randomized Trials.

Semin Thromb Hemost 2020 Nov 21;46(8):908-918. Epub 2020 Oct 21.

Clinical Trials Center, Cardiovascular Research Foundation, New York, New York.

Thrombotic cardiovascular disease (myocardial infarction [MI], stroke, and venous thromboembolism [VTE]) remains a major cause of death and disability. Sulodexide is an oral glycosaminoglycan containing heparan sulfate and dermatan sulfate. We conducted a systematic review and meta-analysis to determine the cardiovascular efficacy, and safety of sulodexide versus control in randomized controlled trials (RCTs). We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for RCTs reporting cardiovascular outcomes in patients receiving sulodexide versus control (placebo or no treatment). Outcomes included all-cause mortality, cardiovascular mortality, MI, stroke, deep vein thrombosis (DVT), pulmonary embolism, and bleeding. We used inverse variance random-effects models with odds ratio (OR) as the effect measure. After screening 360 records, 6 RCTs including 7,596 patients (median follow-up duration: 11.6 months) were included. Patients were enrolled for history of MI, VTE, peripheral arterial disease, or cardiovascular risk factors plus nephropathy. Use of sulodexide compared with control was associated with reduced odds of all-cause mortality (OR 0.67, 95% confidence interval [CI] 0.52-0.85,  = 0.001), cardiovascular mortality (OR 0.44, 95% CI 0.22-0.89,  = 0.02), and MI (OR 0.70, 95% CI 0.51-0.96,  = 0.03), and nonsignificantly reduced odds of stroke (OR 0.78, 95% CI 0.45-1.35,  = 0.38). Sulodexide was associated with significantly reduced odds of VTE (OR 0.44, 95% CI 0.24-0.81,  = 0.008), including DVT (OR 0.41, 95% CI 0.26-0.65,  < 0.001), but not pulmonary embolism (OR 0.92, 95% CI 0.40-2.15,  = 0.86). Bleeding events were not significantly different in the two groups (OR 1.14, 95% CI 0.47-2.74,  = 0.48). In six RCTs across a variety of clinical indications, use of sulodexide compared with placebo or no treatment was associated with reduced odds of all-cause mortality, cardiovascular mortality, MI, and DVT, without a significant increase in bleeding. Additional studies with this agent are warranted.
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http://dx.doi.org/10.1055/s-0040-1716874DOI Listing
November 2020

Long-Term Treatment with Apixaban in Patients with Atrial Fibrillation: Outcomes during the Open-Label Extension following AVERROES.

Thromb Haemost 2021 Apr 4;121(4):518-528. Epub 2020 Oct 4.

Population Health Research Institute, Hamilton, Ontario, Canada.

Background:  AVERROES, a randomized controlled trial in high-risk patients with atrial fibrillation, unsuitable for vitamin K antagonist therapy, demonstrated efficacy and safety of apixaban compared with aspirin. At the conclusion of the double-blind phase, an open-label extension was initiated to allow study participants to receive apixaban until it became locally available. This study reports outcomes of patients on apixaban during the open-label extension.

Methods:  Rates of stroke or systemic embolism, hemorrhagic stroke, major bleeding, and other outcomes during the open-label extension are reported.

Results:  Of the 5,599 participants enrolled in AVERROES, 3,275 (58.5%) received apixaban during the open-label extension. Median (interquartile range) follow-up in the open-label extension was 3.0 (2.5-3.5) years. The rate of stroke or systemic embolism during the open-label extension was 1.0% per year, and the annual rates of hemorrhagic stroke and major bleeding were 0.3 and 1.2%, respectively. After adjustment for imbalances in patient variables, event rates in patients on apixaban during the open-label extension were similar to those of patients receiving apixaban during AVERROES. Additional analyses in all patients who received apixaban, at any time from the start of AVERROES to the end of the open-label extension, were performed. This cohort ( = 4,414) showed annual event rates of 1.1% for stroke or systemic embolism, 0.3% for hemorrhagic stroke, and 1.2% for major bleeding.

Conclusion:  During the open-label extension, annual rates of stroke or systemic embolism, hemorrhagic stroke, and major bleeding remained as low as those observed during apixaban treatment in AVERROES. These data support the long-term efficacy and safety of apixaban in patients with atrial fibrillation.
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http://dx.doi.org/10.1055/s-0040-1717115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982299PMC
April 2021

Quality of early evidence on the pathogenesis, diagnosis, prognosis and treatment of COVID-19.

BMJ Evid Based Med 2020 Sep 30. Epub 2020 Sep 30.

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

Since the initial description of the SARS-CoV-2 outbreak and its declaration as a worldwide pandemic, the number of publications on the novel virus has increased rapidly. We studied the trends and quality of evidence in early SARS-CoV-2 publications. A comprehensive search of MEDLINE and EMBASE was performed for papers published between 1 January 2020 and 21 April 2020. Two reviewers independently screened titles and abstracts and subsequently full texts for eligibility in this systematic review. The search yielded 2504 citations published between January and February 2020 or an unspecified date, 109 of which remained for extraction after screening. Data extracted included study design, year of publication, country of basis, journal of publication, impact factor of publishing journal, study sample size, number of citations and topic of investigation. Study design-specific critical appraisal tools were used to evaluate the scientific rigour of all included papers: the Joanna Briggs Institute checklist was used for case series, Scale for the Assessment of Narrative Review Articles scale for narrative reviews, Newcastle-Ottawa scale for cohort studies and AMSTAR 2 for systematic reviews. The overall quality of the literature was low-moderate. Of 541 papers that reported clinical characteristics, 295 were commentaries/expert opinions and 36 were case reports. There were no randomised clinical trials, 45 case series studies, 58 narrative reviews, 1 cohort study and 5 systematic reviews. We encourage clinicians to be attentive to these findings when utilising early SARS-CoV-2 evidence in their practices.
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http://dx.doi.org/10.1136/bmjebm-2020-111499DOI Listing
September 2020

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

Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation.

Eur Heart J 2020 11;41(41):4037-4046

Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.

Aims: The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability.

Methods And Results: Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level.

Conclusions: Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.
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http://dx.doi.org/10.1093/eurheartj/ehaa697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543499PMC
November 2020

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