Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction.

BACKGROUND: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking. METHODS: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first. RESULTS: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group. CONCLUSIONS: Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).

Influence of Weight and Body Size on the Pharmacokinetics of Heart Failure Pharmacotherapy: A Systematic Review.

OBJECTIVE: To conduct a review of studies evaluating the influence of body size and weight (WT) on the pharmacokinetics (PK) of drugs recommended for heart failure (HF) treatment. DATA SOURCES: A systematic search of the MEDLINE (1946 to April 2023) and EMBASE (1974 to April 2023) databases was conducted for articles that focused on the impact of WT or body size on the PK of drugs of interest used in HF patients. STUDY SELECTION AND DATA EXTRACTION: Articles written in English or French related to the aim of our study were retained for analysis. DATA SYNTHESIS: Of 6493 articles, 20 were retained for analysis. Weight was associated with the clearance of digoxin, carvedilol, enalapril, and candesartan as well as the volume of distribution of eplerenone and bisoprolol. There was no documented direct impact of WT on the PK of furosemide, valsartan, and metoprolol, although these studies were limited or confounded by the small sample size, adjustment of PK factors by WT, or the use of the Cockroff-Gault equation for the evaluation of creatinine clearance, which includes WT. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review highlights and summarizes the available data on the importance of WT on the PK of HF treatment. CONCLUSION: Considering the significant impact of WT on most HF drugs in this review, it may be important to further investigate it in the context of personalized therapy, particularly in patients presenting extreme WTs.

The Effects of Angiotensin Receptor-Neprilysin Inhibition on Major Coronary Events in Patients With Acute Myocardial Infarction: Insights From the PARADISE-MI Trial.

BACKGROUND: In patients who survive an acute myocardial infarction (AMI), angiotensin-converting enzyme inhibitors decrease the risk of subsequent major cardiovascular events. Whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan reduce major coronary events more effectively than angiotensin-converting enzyme inhibitors in high-risk patients with recent AMI remains unknown. We aimed to compare the effects of sacubitril/valsartan on coronary outcomes in patients with AMI. METHODS: We conducted a prespecified analysis of the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitors Trial to Determine Superiority in Reducing Heart Failure Events After MI), which compared sacubitril/valsartan (97/103 mg twice daily) with ramipril (5 mg twice daily) for reducing heart failure events after myocardial infarction in 5661 patients with AMI complicated by left ventricular systolic dysfunction, pulmonary congestion, or both. In the present analysis, the prespecified composite coronary outcome was the first occurrence of death from coronary heart disease, nonfatal myocardial infarction, hospitalization for angina, or postrandomization coronary revascularization. RESULTS: Patients were randomly assigned at a median of 4.4 [3.0-5.8] days after index AMI (ST-segment-elevation myocardial infarction 76%, non-ST-segment-elevation myocardial infarction 24%), by which time 89% of patients had undergone coronary reperfusion. Compared with ramipril, sacubitril/valsartan decreased the risk of coronary outcomes (hazard ratio, 0.86 [95% CI, 0.74-0.99], P=0.04) over a median follow-up of 22 months. Rates of the components of the composite outcomes were lower in patients on sacubitril/valsartan but were not individually significantly different. CONCLUSIONS: In survivors of an AMI with left ventricular systolic dysfunction and pulmonary congestion, sacubitril/valsartan-compared with ramipril-reduced the risk of a prespecified major coronary composite outcome. Dedicated studies are necessary to confirm this finding and elucidate its mechanism. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02924727.

Global Variations in Heart Failure Etiology, Management, and Outcomes.

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries. Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development. Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years. Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death. Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a ß-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies. Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.

A disease-specific comorbidity index for predicting mortality in patients admitted to hospital with a cardiac condition.

BACKGROUND: Comorbidity indexes derived from administrative databases are essential tools of research in global health. We sought to develop and validate a novel cardiac-specific comorbidity index, and to compare its accuracy with the generic Charlson-Deyo and Elixhauser comorbidity indexes. METHODS: We derived the cardiac-specific comorbidity index from consecutive patients who were admitted to hospital at a tertiary-care cardiology hospital in Quebec. We used logistic regression analysis and incorporated age, sex and 22 clinically relevant comorbidities to build the index. We compared the cardiac-specific comorbidity index with refitted Charlson-Deyo and Elixhauser comorbidity indexes using the C-statistic and net reclassification improvement to predict in-hospital death, and the Akaike information criterion to predict length of stay. We validated our findings externally in an independent cohort obtained from a provincial registry of coronary disease in Alberta. RESULTS: The novel cardiac-specific comorbidity index outperformed the refitted generic Charlson-Deyo and Elixhauser comorbidity indexes for predicting in-hospital mortality in the derivation population (n = 10 137): C-statistic 0.95 (95% confidence interval [CI] 0.94-0.9) v. 0.81 (95% CI 0.77-0.84) and 0.86 (95% CI 0.82-0.89), respectively. In the validation population (n = 17 877), the cardiac-specific comorbidity index was similarly better: C-statistic 0.92 (95% CI 0.89-0.94) v. 0.76 (95% CI 0.71-0.81) and 0.82 (95% CI 0.78-0.86), respectively, and also numerically outperformed the Charlson-Deyo and Elixhauser comorbidity indexes for predicting 1-year mortality (C-statistic 0.78 [95% CI 0.76-0.80] v. 0.75 [95% CI 0.73-0.77] and 0.77 [95% CI 0.75-0.79], respectively). Similarly, the cardiac-specific comorbidity index showed better fit for the prediction of length of stay. The net reclassification improvement using the cardiac-specific comorbidity index for the prediction of death was 0.290 compared with the Charlson-Deyo comorbidity index and 0.192 compared with the Elixhauser comorbidity index. INTERPRETATION: The cardiac-specific comorbidity index predicted in-hospital and 1-year death and length of stay in cardiovascular populations better than existing generic models. This novel index may be useful for research of cardiology outcomes performed with large administrative databases.

Is there a potential association between spironolactone and the risk of new-onset diabetes in a cohort of older patients with heart failure?

PURPOSE: Some evidence suggests that spironolactone may have a deleterious effect on glucose homeostasis. The objective of this study was to assess whether spironolactone use is associated with a higher risk of developing diabetes in a large cohort of patients with heart failure (HF). METHODS: Two Quebec government administrative databases were used to identify a cohort of hospitalized patients discharged between January 1995 and December 2009 with a primary discharge diagnosis of HF and without secondary discharge diagnosis of diabetes. Patients were categorized as new users of spironolactone and non-users. The primary outcome was defined as new-onset diabetes (NOD) during 5 years of follow-up and was ascertained using ICD codes for diabetes or use of hypoglycemic agents. RESULTS: Among the 2974 patients that were included in the cohort analysis, 769 were given a new prescription of spironolactone. The incidence rate of NOD was similar among spironolactone users (5.0 per 100 person-years) and non-users (4.9 per 100 person-years). There was no significant association between the use of spironolactone and NOD in the crude, unadjusted model (hazard ratio (HR) 1.01; 95% confidence interval (CI) 0.80-1.28; p = 0.9217), and it remained unchanged in the adjusted Cox proportional hazard model (HR = 0.92; 95% CI = 0.72-1.18; p = 0.5227). The results were consistent with those observed in sensitivity analyses of a 1:3 propensity score-matched cohort (HR = 0.97; CI = 0.76-1.25; p = 0.8169). CONCLUSION: We found no evidence supporting the claim that use of spironolactone is associated with a higher risk of diabetes among patients hospitalized for HF.

A comparison of the effects of selective and non-selective mineralocorticoid antagonism on glucose homeostasis of heart failure patients with glucose intolerance or type II diabetes: A randomized controlled double-blind trial.

Mineralocorticoid receptor antagonists (MRAs) decrease morbidity and mortality in patients with heart failure (HF). However, spironolactone, a non-selective MRA, has been shown to exert a harmful effect on glucose homeostasis. The objective of this multicenter, randomized, controlled, double-blind trial was to compare the effects of spironolactone to those of the selective MRA eplerenone on glucose homeostasis among 62 HF patients with glucose intolerance or type II diabetes. Trial registration number:NCT01586442.

The Leadership and Organizational Context Required to Support Patient Partnerships.

Healthcare providers and managers typically design programs based on what they believe patients need and want. Yet patients have knowledge and insight into how the system can be changed to better meet their needs, improve outcomes and reduce costs. We describe challenges in creating a culture of patient partnerships and the leadership actions and organizational context required now and in the future to support engagement-capable environments at the organizational and policy levels in Canada. Case examples illustrate the need for leaders to set clear expectations, develop the infrastructure to support patient partnerships and provide education to staff, physicians and patient partners.

Older adults with heart failure treated with carvedilol, bisoprolol, or metoprolol tartrate: risk of mortality.

PURPOSE: The long-term use of ß-blockers has been shown to improve clinical outcomes among patients with heart failure (HF). However, a lack of data persists in assessing whether carvedilol or bisoprolol are superior to metoprolol tartrate in clinical practice. We endeavored to compare the effectiveness of ß-blockers among older adults following a primary hospital admission for HF. METHODS: We conducted a cohort study using Quebec administrative databases to identify patients who were using ß-blockers, carvedilol, bisoprolol, or metoprolol tartrate after the diagnosis of HF. We characterized the patients by the type of ß-blocker prescribed at discharge of their first HF hospitalization. An adjusted multivariate Cox proportional hazards model was used to compare the primary outcome of all-cause mortality. We also conducted analyses by matching for a propensity score for initiation of ß-blocker therapy and assessed the effect on primary outcome. RESULTS: Among 3197 patients with HF with a median follow-up of 2.8 years, the crude annual mortality rates (per 100 person-years) were at 16, 14.9, and 17.7 for metoprolol tartrate, carvedilol, and bisoprolol, respectively. Adjusted hazard ratios of carvedilol (hazard ratio 0.92; 0.78-1.09) and bisoprolol (hazard ratio 1.04; 0.93-1.16) were not significantly different from that of metoprolol tartrate in improving survival. After matching for propensity score, carvedilol and bisoprolol showed no additional benefit with respect to all-cause mortality compared with metoprolol tartrate. CONCLUSIONS: Our evidence suggests no differential effect of ß-blockers on all-cause mortality among older adults with HF. Copyright © 2016 John Wiley & Sons, Ltd.

Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial.

BACKGROUND: Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an ≈4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas). METHODS AND RESULTS: To better understand this regional difference in clinical outcomes, demographic characteristics of these populations and their responses to spironolactone were explored. Patients from Russia/Georgia were younger, had less atrial fibrillation and diabetes mellitus, but were more likely to have had prior myocardial infarction or a hospitalization for heart failure. Russia/Georgia patients also had lower left ventricular ejection fraction and creatinine but higher diastolic blood pressure (all P<0.001). Hyperkalemia and doubling of creatinine were more likely and hypokalemia was less likely in patients receiving spironolactone in the Americas with no significant treatment effects in Russia/Georgia. All clinical event rates were markedly lower in Russia/Georgia, and there was no detectable impact of spironolactone on any outcomes. In contrast, in the Americas, the rates of the primary outcome, cardiovascular death, and hospitalization for heart failure were significantly reduced by spironolactone. CONCLUSIONS: This post hoc analysis demonstrated greater potassium and creatinine changes and possible clinical benefits with spironolactone in patients with heart failure and preserved ejection fraction from the Americas. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Coronary-artery bypass surgery in patients with left ventricular dysfunction.

BACKGROUND: The role of coronary-artery bypass grafting (CABG) in the treatment of patients with coronary artery disease and heart failure has not been clearly established. METHODS: Between July 2002 and May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). The primary outcome was the rate of death from any cause. Major secondary outcomes included the rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. RESULTS: The primary outcome occurred in 244 patients (41%) in the medical-therapy group and 218 (36%) in the CABG group (hazard ratio with CABG, 0.86; 95% confidence interval [CI], 0.72 to 1.04; P=0.12). A total of 201 patients (33%) in the medical-therapy group and 168 (28%) in the CABG group died from an adjudicated cardiovascular cause (hazard ratio with CABG, 0.81; 95% CI, 0.66 to 1.00; P=0.05). Death from any cause or hospitalization for cardiovascular causes occurred in 411 patients (68%) in the medical-therapy group and 351 (58%) in the CABG group (hazard ratio with CABG, 0.74; 95% CI, 0.64 to 0.85; P<0.001). By the end of the follow-up period (median, 56 months), 100 patients in the medical-therapy group (17%) underwent CABG, and 555 patients in the CABG group (91%) underwent CABG. CONCLUSIONS: In this randomized trial, there was no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary end point of death from any cause. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; STICH ClinicalTrials.gov number, NCT00023595.).

A Genome-Wide Association Study of Oxypurinol Concentrations in Patients Treated with Allopurinol.

Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10-8). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy.

Sacubitril/valsartan compared to ramipril in high-risk post-myocardial infarction patients stratified according to use of mineralocorticoid receptor antagonists: Insight from the PARADISE MI trial.

AIM: It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high-risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. METHODS AND RESULTS: Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR]MRA 0.96, 95% confidence interval [CI] 0.77-1.19 and HRMRA- 0.87, 95% CI 0.71-1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator-reported endpoints were evaluated (p = 0.61 for interaction). CONCLUSIONS: Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post-MI setting in patients with LVSD and/or congestion.

Angiotensin Receptor-Neprilysin Inhibition in Patients With STEMI vs NSTEMI.

BACKGROUND: Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), remain at high risk for heart failure (HF), coronary events, and death. Angiotensin-converting enzyme inhibitors have been shown to significantly decrease the risk for cardiovascular events in both STEMI and NSTEMI patients. OBJECTIVES: The objectives were to determine whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan, compared with ramipril, has impact on reducing cardiovascular events according to the type of AMI. METHODS: The PARADISE-MI (Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) trial enrolled patients with AMI complicated by left ventricular dysfunction and/or pulmonary congestion and at least 1 risk-enhancing factor. Patients were randomized to either sacubitril/valsartan or ramipril. The primary endpoint was death from cardiovascular causes or incident HF. In this prespecified analysis, we stratified patients according to AMI type. RESULTS: Of 5,661 enrolled patients, 4,291 (75.8%) had STEMI. These patients were younger and had fewer comorbidities and cardiovascular risk factors than NSTEMI patients. After adjustment for potential confounders, the risk for the primary outcome was marginally higher in NSTEMI vs STEMI patients (adjusted HR: 1.19; 95% CI: 1.00-1.41), with borderline statistical significance (P = 0.05). The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan vs ramipril in STEMI (10% vs 12%; HR: 0.87; 95% CI: 0.73-1.04; P = 0.13) and NSTEMI patients (17% vs 17%; HR: 0.97; 95% CI: 0.75-1.25; P = 0.80; P interaction = 0.53). CONCLUSIONS: Compared with ramipril, sacubitril/valsartan did not significantly decrease the risk for cardiovascular death and HF in patients with AMI complicated by left ventricular dysfunction, irrespective of the type of AMI. (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI; NCT02924727).

Circulating biomarkers in patients with heart failure and preserved ejection fraction.

Patients with heart failure with preserved ejection fraction (HF-PEF) comprise a growing proportion of the overall HF burden. The pathophysiology of HF-PEF is complex, and relates to the interplay between cardiac risk factors (notably diabetes/insulin resistance, hypertension), systemic inflammation, and comorbid medical illness (e.g. chronic kidney disease) that conspire to promote endothelial dysfunction, ventricular-vascular stiffening, and diastolic dysfunction. Efficient diagnosis and optimal therapy remain challenging in this population. Imaging, electrocardiographic, and circulating biomarkers, as well as pharmacogenetics, may help to facilitate HF diagnosis, stratify risk, and individualize therapy. In this review, we focus on established and emerging circulating biomarkers in HF-PE, including circulating biomarkers of myocyte stress, myocyte injury, renal function, systemic inflammation, and fibrosis. Such markers have contributed to better understanding of the pathophysiologic mechanisms relevant to HF-PEF, and may eventually help to facilitate more effective and personalized management of this syndrome.

Females present higher dose-adjusted drug concentrations of metoprolol and allopurinol/oxypurinol than males.

Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross-sectional studies. Participants were self-described "White" adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age- and dose-adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age-adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10-4 ). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype-inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose-adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex-specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.

Design of the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor Versus Placebo in Patients With Congenital Systemic Right Ventricle Heart Failure (PARACYS-RV) Trial.

The presence of a systemic right ventricle (sRV) with biventricular physiology (biV) is associated with increased patient morbidity and mortality. To date, no pharmacologic therapy for heart failure has been proven effective for patients with systolic dysfunction of the sRV-biV. We designed a randomized, double-blind, placebo-controlled crossover trial to compare sacubitril/valsartan treatment to placebo in adults (aged ≥ 18 years) with moderate-to-severe sRV-biV dysfunction and New York Heart Association functional class II to III symptoms. Two primary efficacy endpoints are assessed in the trial: exercise capacity (submaximal exercise duration) and neurohormonal activation (N-terminal prohormone brain natriuretic peptide). Secondary objectives include assessing a change in the Kansas City Cardiomyopathy Questionnaire score and evaluating the safety and tolerance of sacubitril/valsartan. A 6-week open run-in phase identifies the maximum tolerated dose of sacubitril/valsartan, up to 97 mg/103 mg twice daily. After a 2-week washout period, patients are randomized 1:1 to sacubitril/valsartan treatment vs placebo for a 24-week phase, followed by another 2-week washout period and subsequent crossover to the alternative treatment arm for an additional 24-week phase. Data to assess primary and secondary endpoints are collected at baseline and at the end of each phase. A total of 48 patients is required to provide > 80% power to detect a 30% difference in distance walked and in N-terminal prohormone brain natriuretic peptide levels with sacubitril/valsartan treatment vs placebo, each with a 2-sided P-value of 0.025. In summary, the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor vs Placebo in Patients With Congenital Systemic Right Ventricular Heart Failure Trial (PARACYS-RV) should determine the role of sacubitril/valsartan in treating heart failure in patients with sRV-biV and carries the potential to alter management of this patient population.

La présence d'un ventricule droit systémique (VDs) avec physiologie biventriculaire (PbiV) est associée à une morbidité et une mortalité accrues chez les patients. À ce jour, aucune pharmacothérapie de l'insuffisance cardiaque ne s'est révélée efficace chez les patients atteints d'une dysfonction systolique du VDs-PbiV. Nous avons conçu un essai croisé, à répartition aléatoire et à double insu, contrôlé par placebo pour comparer la bithérapie sacubitril-valsartan au placebo chez les adultes (≥ 18 ans) ayant une dysfonction modérée ou sévère du VDs-PbiV et des symptômes de la classe fonctionnelle II à III de la New York Heart Association. Deux paramètres d'évaluation principaux de l'efficacité sont définis pour l'essai : tolérance à l'effort (durée d'effort sous-maximal) et activation neurohormonale (propeptide natriurétique de type B N-Terminal [NT-proBNP]). La mesure d'une variation du score au questionnaire sur la cardiomyopathie de Kansas City de même que l'évaluation de l'innocuité et de la tolérance de la bithérapie sacubitril-valsartan sont des objectifs secondaires. Une phase préparatoire de six semaines en mode ouvert permet d'établir la dose maximale tolérée de sacubitril-valsartan, jusqu'à concurrence de 97 mg/103 mg deux fois par jour. Après une période de repos thérapeutique de deux semaines, les patients sont affectés au hasard, dans un rapport 1:1, à la bithérapie sacubitril-valsartan ou au placebo pendant une phase de traitement de 24 semaines, suivie d'une autre période de repos thérapeutique de deux semaines et d'un passage subséquent à l'autre groupe de traitement pendant une phase additionnelle de 24 semaines. Les données sur les paramètres d'évaluation principaux et secondaires sont recueillies au début de l'essai et à la fin de chaque phase. Il faut un total de 48 patients afin d'obtenir une puissance supérieure à 80 % pour détecter une différence de 30 % entre la bithérapie sacubitril-valsartan et le placebo quant à la distance parcourue à la marche et aux taux de NT-proBNP, la valeur p bilatérale étant de 0,025 pour les deux valeurs. En résumé, l'essai PARACYS-RV (Prospective Comparison ofAngiotensinReceptor-Neprilysin Inhibitor vs Placebo in Patients WithCongenital SystemicRightVentricular Heart Failure) doit déterminer le rôle de la bithérapie sacubitril-valsartan dans le traitement de l'insuffisance cardiaque chez les patients ayant un VDs-PbiV et pourrait modifier la prise en charge de cette population de patients.

STICH3C: Rationale and Study Protocol.

BACKGROUND: Coronary artery bypass grafting (CABG) is the recommended mode of revascularization in patients with ischemic left ventricular dysfunction (iLVSD) and multivessel disease. However, contemporary percutaneous coronary intervention (PCI) outcomes have improved with the integration of novel technologies and refinement of revascularization strategies, and PCI is often used in clinical practice in this population. There is a lack of evidence from randomized trials comparing contemporary state-of-the-art PCI versus CABG for the treatment of iLVSD and multivessel disease. This was the impetus for the STICH3C trial (Canadian CABG or PCI in Patients With Ischemic Cardiomyopathy), described here. METHODS: The STICH3C trial is a prospective, unblinded, international, multicenter trial with an expected sample size of 754 participants from ≈45 centers. Patients with multivessel/left main coronary artery disease and iLVSD with left ventricular ejection fraction ≤40% considered by the local Heart Team appropriate for and amenable to revascularization by both modes of revascularization will be randomized in a 1:1 ratio to state-of-the-art PCI or CABG. RESULTS: The primary end point is the composite of death from any cause, stroke, spontaneous myocardial infarction, urgent repeat revascularization, or heart failure readmission, summarized as a time-to-event outcome. The key hierarchical end point is time to death and frequency of hospitalizations for heart failure. The key safety outcome is a composite of major adverse events. Disease-specific quality-of-life and health economics measures will be compared between groups. Participants will be followed for a median of 5 years, with a minimum follow-up of 4 years. CONCLUSIONS: STICH3C will directly inform patients, clinicians, and international practice guidelines about the efficacy and safety of CABG versus PCI in patients with iLVSD. The results will provide novel and broad evidence, including clinical events, health status, and economic assessments, to guide care for patients with iLVSD and severe coronary artery disease. REGISTRATION: URL: https://clinicaltrials.gov/; Unique identifier: NCT05427370.