Featured Publications

As a learning organization committed to enhancing the health of current and future generations through research, the CVC relentlessly pursues the generation, translation, and dissemination of new knowledge addressing unmet clinical needs. This section highlights important publications produced by the CVC faculty and our body of research in recent months.

View CVC’s full publication archive here.

Impact of prior oral anticoagulant use and outcomes on patients from secondary analysis in the AUGUSTUS trial

Welsh RC, Dehghani P, Lopes R, Wojdyla DM, Aronson R, Granger CB, Windecker S, Vora AN, Vinereanu D, Halvorsen S, Parkhomenko A, Mehran R, Alexander JH, Goodman S.
Open Heart . 2022 Feb;9:e001892.

Managing antithrombotic therapy in patients with atrial fibrillation (AF) and an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) is challenging and can be affected by prior oral anticoagulant (OAC) treatment.

The AUGUSTUS trial (An Open-Label, 2-by-2 Factorial, Randomised, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs VKA and Aspirin vs Aspirin Placebo in Patients With AF and ACS and/or PCI) compared vitamin K antagonists (VKA) with a non-vitamin K antagonist oral anticoagulant (NOAC). In this study, the authors performed a prespecified subgroup analysis of the AUGUSTUS trial to describe the patient characteristics, clinical events and potential interaction with randomised treatment arms comparing patients with or without prior OAC, with prior OAC separated into those receiving an NOAC or VKA.

This research found that, although patients enrolled in AUGUSTUS with prior OAC use, compared with those without, had increased comorbidities with an associated higher probability of stroke and clinically relevant bleeding; however, they had no increased risk of bleeding complications and a lower risk of ischaemic complications. In patients with AF and ACS and/or elective PCI, clinicians can be assured that the results of the AUGUSTUS trial can be applied to patients regardless of their prior OAC status.

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Vericiguat in Patients with Coronary Artery Disease and Heart Failure with Reduced Ejection Fraction.

Saldarriaga C, Atar D, Stebbins A, Lewis BS, Zainal Abidin I, Blaustein RO, Butler J, Ezekowitz JA, Hernandez AF, Lam CSP, O'Connor CM, Pieske B, Ponikowski P, Roessig L, Voors AA, Anstrom KJ, Armstrong PW; VICTORIA Study Group.
Eur J Heart Fail. 2022;24:782-790.

This study of over 5,000 patients with heart failure and reduced ejection fraction (HFrEF) found that the presence of coronary artery disease (CAD) had a major impact on increasing the rates of both cardiovascular death and heart failure hospitalization in the high-risk patients in the VICTORIA trial. It also showed that vericiguat was equally well tolerated in both patients with and without CAD, and the treatment benefit was similar in both cohorts.

The authors of this paper found that although the 58% of patients with CAD have worse outcomes in heart failure, the beneficial effect and safety profile of vericiguat was similar irrespective of CAD.

The 3.1% absolute increase in sudden cardiac death in patients with CAD ( 8.6) vs. 5.5% in non-CAD patients occurred despite a much greater overall use of implantable cardiovascular devices (ICDs) in these patients. However, when ICD’s were employed their use was associated with significantly less sudden death. Interestingly, the incidence of sudden death in patients without CAD was similar irrespective of the presence of an ICD. These findings also have implications both for the care of patients with HFrEF and for gauging the potential mortality outcomes in the planning of future research to address the continuing unmet needs of patients with HFrEF.

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Laboratory Markers of Acidosis and Mortality in Cardiogenic Shock: Developing a Definition of Hemometabolic Shock.

Jentzer JC, Kashani KB, Wiley BM, Patel PC, Baran DA, Barsness GW, Henry TD, van Diepen S.
Shock. 2022;57:31-40.

In patients with cardiogenic shock (CS), accumulated metabolic derangements such as acidosis and organ failure can create a downward spiral of worsening shock and hypoperfusion, causing some patients to develop a treatment-resistant shock state that has been termed “hemometabolic shock.”

Few studies have examined admission laboratory markers to fully characterize the association between metabolic acidosis severity at initial presentation and outcomes in patients with CS, and the best acidosis marker for prediction of mortality in CS remains uncertain. As such, the authors sought to determine whether overall acidosis severity on admission predicted in-hospital mortality in CS patients.

This research showed that among CS patients from various etiologies, greater acidosis severity on CICU admission was strongly associated with increased shock severity, more non-cardiovascular organ failure and higher in-hospital mortality in CS patients. Further, despite the multitude of admission laboratory values that differed between hospital survivors and inpatient deaths, markers of acidosis were among the only admission laboratory values that were significantly associated with in-hospital mortality after multivariable adjustment, with the admission lactate level being the strongest predictor.

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Association between maternal glucose and large for gestational outcomes: Real-world evidence to support Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study findings.

Kaul P, Savu A, Yeung RO, Ryan EA.
Diabet Med. 2022;39:e14786.

The landmark Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) Study established the association between increasing maternal glucose and large for gestational age (LGA) rates, but found no individual measure from the oral glucose tolerance tests (OGTT) to be superior in predicting LGA. However, there is some evidence to suggest that elevated fasting plasma glucose (FPG) may be of more prognostic importance for LGA outcomes than post-load glucose elevations among women with gestational diabetes mellitus (GDM).

In this article, the authors used a large pregnancy-birth cohort to examine real-world rates of LGA according to the FPG and compare with those from the HAPO study. They further examined the independent association between FPG versus post-load elevation and LGA outcomes, after accounting for other maternal factors.

The authors confirmed the HAPO study findings that increases in maternal glycaemia are associated with an increase in LGA rates at lower levels of glucose elevation. Further, they found that GDM diagnosis and treatment appear to be effective in reducing rates of LGA in pregnancies with post-load glucose elevations, but not elevated FPG. However, elevated FPG was shown to be a stronger predictor of LGA than post-load glucose elevations.

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Prevalence of Cardiovascular Disease in a Population-Based Cohort of High-Cost Healthcare Services Users.

Kaul P, Klassen N, Dover DC, Sepehrvand N, Sandhu RK, van Diepen S, Bainey K, McMurtry MS, Welsh RC, Ezekowitz JA, Goodman SG, Armstrong PW, McAlister FA.
CJC Open. 2021;4:180-188.

A small proportion of patients account for a large proportion of healthcare costs. There are limited data on the prevalence of cardiovascular disease (CVD) and multimorbidity in contemporary cohorts of these high-cost users (HCUs) in Canada. In a cohort of complex HCUs between 2011-2012 and 2014-2015 in Alberta, Canada this study compared health expenditures among HCUs with and without CVD.

Almost a third of the HCUs were hospitalized with a primary diagnosis of CVD, and an additional half were hospitalized with a secondary diagnosis of CVD, leading to a prevalence of CVD of over 75%. Healthcare costs among HCUs with CVD accounted for $7.7 billion of the total $9.7 billion for all HCUs in Alberta during the 4-year time period. Hospitalization costs accounted for 80% of healthcare expenditures among HCUs with CVD, and costs of physician services, ambulatory care, and drugs accounted for the remaining 20% of total healthcare costs. Frailty and multi-morbidity were major drivers of both costs and mortality among HCUs with CVD.

The researchers concluded that CVD accounts for a large proportion of healthcare costs among HCUs. Additionally, HCUs with CVD have high rates of other comorbidities that contribute substantially to healthcare costs and adverse outcomes. Further research is needed to identify and intervene earlier, in order to flatten the cost curve in these complex patients.

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A Population-Based Study of Unexplained/Lone Atrial Fibrillation: Temporal Trends, Management, and Outcomes.

Roston TM, Islam S, Hawkins NM, Krahn AD, Sandhu R, Kaul P.
CJC Open. 2021;4:65-74.

Atrial fibrillation and atrial flutter (AF) are common arrhythmias that affect ∼2% of the population and lead to substantial morbidity and mortality. In most, AF occurs “secondary” to a comorbid condition, either cardiac in origin, such as coronary artery disease and heart failure, or extracardiac in nature, such as infectious and chronic pulmonary disease. However, in a proportion of predominantly young individuals, AF develops as a primary disorder without an identifiable trigger, often termed unexplained, idiopathic, or lone AF.

In this study, the authors characterized unexplained AF in a dataset from a large population, using a stringent contemporary definition, which accounted for a multitude of potentially AF-predisposing comorbidities, and compared it to secondary AF.

Using a strict contemporary definition of unexplained AF, this study shows that the condition is rare, predominantly male, and has excellent event-free survival. However, the high rate of acute hospital utilization after diagnosis is concerning. Additional studies are needed to provide an explanation for AF in these individuals and to identify factors that lead to recurrent hospitalization.

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Statins and SARS-CoV-2 Infection: Results of a Population-Based Prospective Cohort Study of 469 749 Adults From 2 Canadian Provinces.

McAlister FA, Wang T, Wang X, Chu A, Goodman SG, van Diepen S, Jackevicius CA, Kaul P, Udell J, Ko DT, Kwong JC, Austin PC, Lee DS; CORONA Collaboration *.
J Am Heart Assoc. 2021;10:e022330.

A few small observational studies have suggested that statin users had a lower risk of severe COVID‐19 and exhibited faster recovery times. To further investigate this hypothesis, the authors designed this study to test whether current use of statins is associated with decreased susceptibility of adults to SARS‐CoV‐2 infection and/or better outcomes in those with a positive SARS‐CoV‐2 test. Using large‐scale, population‐based cohorts in Alberta and Ontario, the authors measured the association between current use of statins and infection rates among adults who underwent SARS‐CoV‐2 testing; they also assessed the association of current statin use with outcomes in adults with laboratory‐confirmed SARS‐CoV‐2 infection.

In stark contrast to the previous observational studies, this research found that compared with statin nonusers, patients taking statins exhibit the same risk of testing positive for SARS‐CoV‐2 and those younger than 75 years exhibit similar outcomes within 30 days of a positive test. Patients older than 75 years with a positive SARS‐CoV‐2 test and who were taking statins had more emergency department visits and hospitalizations, but exhibited lower 30‐day all‐cause mortality risk.

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Hemoglobin and Clinical Outcomes in the VerICiguaT Global Study in Patients With Heart Failure and Reduced Ejection Fraction (VICTORIA).

Ezekowitz JA, Zheng Y, Cohen-Solal A, Melenovský V, Escobedo J, Butler J, Hernandez AF, Lam CSP, O'Connor CM, Pieske B, Ponikowski P, Voors AA, deFilippi C, Westerhout CM, McMullan C, Roessig L, Armstrong PW; VICTORIA Study Group.
Circulation. 2021;144:1489-1499.

In this newest publication from the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the authors explored the relationship between markers of anemia (including hemoglobin, hematocrit, and other metrics) and vericiguat or placebo. They further explored changes in hemoglobin and hematocrit over the course of the trial and their relationship with the primary composite endpoint and its components. Finally, they examined whether biomarkers, including those signaling inflammation and hemodilution, provided insight into any observed declines in hemoglobin.

This analysis found that anemia was common among patients at randomization and a lower hemoglobin was associated with a greater frequency of clinical events. Although vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further progress nor was it related to the treatment benefit of vericiguat. The authors advise that further mechanistic studies are warranted to understand the basis for anemia associated with vericiguat and any potential interaction between the sGC pathway and hemoglobin.

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Remote ischaemic conditioning in ST elevation myocardial infarction: a registry-based randomised trial.

Bainey KR, Zheng Y, Coulden R, Sonnex E, Thompson R, Mei J, Bastiany A, Welsh R.
Heart. 2022;108:703-709.

Remote ischaemic conditioning (RIC) has been tested as a possible strategy for mitigating reperfusion injury in ST elevation myocardial infarction (STEMI) with primary percutaneous coronary intervention (PPCI). However, surrogate outcomes have shown inconsistent effects with lack of clinical correlation.

The Remote Ischemic Conditioning in ST-Elevation Myocardial Infarction (RemCon-STEMI) registry-based randomised trial evaluated the use of RIC as an adjunct to contemporary therapy for STEMI, measuring the effects on myocardial perfusion, left ventricle performance, infarct size, and clinical outcomes within 1 year.

The authors found that, in a contemporary registry-based randomised study of patients with STEMI presenting within 6 hours of ischaemic symptoms undergoing PPCI, adjunctive therapy with RIC compared with standard of care did not improve myocardial perfusion, reduce infarct size or alter left ventricle geometry or function. Consequently, there was no difference in clinical outcomes while in hospital or within 1 year of follow-up. Accordingly, the results of this analysis do not support the use of RIC in STEMI.

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Ticagrelor or clopidogrel dual antiplatelet therapy following a pharmacoinvasive strategy in ST-segment elevation myocardial infarction.

Welsh RC, Shavadia JS, Zheng Y, Tyrrell BD, Leung R, Bainey KR.
Clin Cardiol. 2021;44:1543-1550.

Many ST-elevation myocardial infarction (STEMI) patients worldwide cannot achieve timely percutaneous coronary intervention (PCI) and therefore require fibrinolysis. Although comparable 30-day and 1-year safety was shown with clopidogrel or ticagrelor in a previous study, there is paucity of long-term outcomes in pharmacoinvasive treated STEMI.

This research sought to describe the pattern of in-hospital P2Y12 antagonist switching following fibrinolysis and evaluate associated clinical outcomes of pharmaco-invasively treated STEMI patients discharged on ticagrelor compared to clopidogrel within a comprehensive STEMI network of care.

The authors found that, in a large prospective STEMI registry, switching patients to ticagrelor compared with sustaining clopidogrel therapy following fibrinolysis pharmacoinvasive reperfusion was associated with reduced recurrent ischemic events at 1-year. Additionally, switching was not associated with differences in major bleeding or intracranial hemorrhage. Aligned with randomized data, these findings provide support to switch pharmaco-invasively treated STEMI patients.

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