Quantifying Improvement in V˙ o2peak and Exercise Thresholds in Cardiovascular Disease Using Reliable Change Indices.

PURPOSE: Improving aerobic fitness through exercise training is recommended for the treatment of cardiovascular disease (CVD). However, strong justifications for the criteria of assessing improvement in key parameters of aerobic function including estimated lactate threshold (θ LT ), respiratory compensation point (RCP), and peak oxygen uptake (V˙ o2peak ) at the individual level are not established. We applied reliable change index (RCI) statistics to determine minimal meaningful change (MMC RCI ) cutoffs of θ LT , RCP, and V˙ o2peak for individual patients with CVD. METHODS: Sixty-six stable patients post-cardiac event performed three exhaustive treadmill-based incremental exercise tests (modified Bruce) ∼1 wk apart (T1-T3). Breath-by-breath gas exchange and ventilatory variables were measured by metabolic cart and used to identify θ LT , RCP, and V˙ o2peak . Using test-retest reliability and mean difference scores to estimate error and test practice/exposure, respectively, MMC RCI values were calculated for V˙ o2 (mL·min -1. kg -1 ) at θ LT , RCP, and V˙ o2peak . RESULTS: There were no significant between-trial differences in V˙ o2 at θ LT ( P = .78), RCP ( P = .08), or V˙ o2peak ( P = .74) and each variable exhibited excellent test-retest variability (intraclass correlation: 0.97, 0.98, and 0.99; coefficient of variation: 6.5, 5.4, and 4.9% for θ LT , RCP, and V˙ o2peak , respectively). Derived from comparing T1-T2, T1-T3, and T2-T3, the MMC RCI for θ LT were 3.91, 3.56, and 2.64 mL·min -1. kg -1 ; 4.01, 2.80, and 2.79 mL·min -1. kg -1 for RCP; and 3.61, 3.83, and 2.81 mL·min -1. kg -1 for V˙ o2peak . For each variable, MMC RCI scores were lowest for T2-T3 comparisons. CONCLUSION: These MMC RCI scores may be used to establish cutoff criteria for determining meaningful changes for interventions designed to improve aerobic function in individuals with CVD.

Do Clinical Exercise Tests Permit Exercise Threshold Identification in Patients Referred to Cardiac Rehabilitation?

BACKGROUND: To evaluate the feasibility of "threshold-based" aerobic exercise prescription in cardiovascular disease, we aimed to quantify the proportion of patients whose clinical cardiopulmonary exercise test (CPET) permit identification of estimated lactate threshold (θLT) and respiratory compensation point (RCP) and to characterize the variability at which these thresholds occur. METHODS: Breath-by-breath CPET data of 1102 patients (65 ± 12 years) referred to cardiac rehabilitation were analyzed to identify peak O2 uptake (V˙O2peak; mL·min-1 and mL·kg-1·min-1) and θLT and RCP (reported as V˙O2, %V˙O2peak, and %peak heart rate [%HRpeak]). Patients were grouped by the presence or absence of thresholds: group 0: neither θLT nor RCP; group 1: θLT only; and group 2: both θLT and RCP. RESULTS: Mean V˙O2peak was 1523 ± 627 mL·min-1 (range: 315-3789 mL·min-1) or 18.0 ± 6.5 mL·kg-1·min-1 (5.2-46.5 mL·kg-1·min-1) and HRpeak was 123 ± 24 beats per minute (bpm) (52 bpm-207 bpm). There were 556 patients (50%) in group 0, 196 (18%) in group 1, and 350 (32%) in group 2. In group 1, mean θLT was 1240 ± 410 mL·min-1 (580-2560 mL·min-1), 75% ± 8%V˙O2peak (52%-92%V˙O2peak), or 84% ± 6%HRpeak (64%-96%HRpeak). In group 2, θLT was 1390 ± 360 mL·min-1 (640-2430 mL·min-1), 70% ± 8%V˙O2peak (41%-88%V˙O2peak), or 78% ± 7%HRpeak (52%-96%HRpeak), and RCP was 1680 ± 440 mL·min-1 (730-3090 mL·min-1), 84% ± 7%V˙O2peak (54%-99%V˙O2peak), or 87% ± 6%HRpeak (59%-99%HRpeak). Compared with group 1, θLT in group 2 occurred at a higher V˙O2 but lower %V˙O2peak and %HRpeak (P < 0.05). CONCLUSIONS: Only 32% of CPETs exhibited both θLT and RCP despite flexibility in protocol options. Commonly used step-based protocols are suboptimal for "threshold-based" exercise prescription.

Trial of an Intervention to Improve Acute Heart Failure Outcomes.

BACKGROUND: Patients with acute heart failure are frequently or systematically hospitalized, often because the risk of adverse events is uncertain and the options for rapid follow-up are inadequate. Whether the use of a strategy to support clinicians in making decisions about discharging or admitting patients, coupled with rapid follow-up in an outpatient clinic, would affect outcomes remains uncertain. METHODS: In a stepped-wedge, cluster-randomized trial conducted in Ontario, Canada, we randomly assigned 10 hospitals to staggered start dates for one-way crossover from the control phase (usual care) to the intervention phase, which involved the use of a point-of-care algorithm to stratify patients with acute heart failure according to the risk of death. During the intervention phase, low-risk patients were discharged early (in ≤3 days) and received standardized outpatient care, and high-risk patients were admitted to the hospital. The coprimary outcomes were a composite of death from any cause or hospitalization for cardiovascular causes within 30 days after presentation and the composite outcome within 20 months. RESULTS: A total of 5452 patients were enrolled in the trial (2972 during the control phase and 2480 during the intervention phase). Within 30 days, death from any cause or hospitalization for cardiovascular causes occurred in 301 patients (12.1%) who were enrolled during the intervention phase and in 430 patients (14.5%) who were enrolled during the control phase (adjusted hazard ratio, 0.88; 95% confidence interval [CI], 0.78 to 0.99; P = 0.04). Within 20 months, the cumulative incidence of primary-outcome events was 54.4% (95% CI, 48.6 to 59.9) among patients who were enrolled during the intervention phase and 56.2% (95% CI, 54.2 to 58.1) among patients who were enrolled during the control phase (adjusted hazard ratio, 0.95; 95% CI, 0.92 to 0.99). Fewer than six deaths or hospitalizations for any cause occurred in low- or intermediate-risk patients before the first outpatient visit within 30 days after discharge. CONCLUSIONS: Among patients with acute heart failure who were seeking emergency care, the use of a hospital-based strategy to support clinical decision making and rapid follow-up led to a lower risk of the composite of death from any cause or hospitalization for cardiovascular causes within 30 days than usual care. (Funded by the Ontario SPOR Support Unit and others; COACH ClinicalTrials.gov number, NCT02674438.).

Primary care-based integrated disease management for heart failure: a study protocol for a cluster randomised controlled trial.

INTRODUCTION: Heart failure (HF) is a common chronic disease that increases in prevalence with age. It is associated with high hospitalisation rates, poor quality of life and high mortality. Management is complex with most interactions occurring in primary care. Disease management programmes implemented during or after an HF hospitalisation have been shown to reduce hospitalisation and mortality rates. Evidence for integrated disease management (IDM) serving the primary care HF population has been investigated but is less conclusive. The aim of this study is to evaluate the efficacy of IDM, focused on, optimising medication, self-management and structured follow-up, in a high-risk primary care HF population. METHODS AND ANALYSIS: 100 family physician clusters will be recruited in this Canadian primary care multicentre cluster randomised controlled trial. Physicians will be randomised to IDM or to care as usual. The IDM programme under evaluation will include case management, medication management, education, and skills training delivered collaboratively by the family physician and a trained HF educator. The primary outcome will measure the combined rate (events/patient-years) of all-cause hospitalisations, emergency department visits and mortality over a 12-month follow-up. Secondary outcomes include other health service utilisation, quality of life, knowledge assessments and acute HF episodes. Two to three HF patients will be recruited per physician cluster to give a total sample size of 280. The study has 90% power to detect a 35% reduction in the primary outcome. The difference in primary outcome between IDM and usual care will be modelled using a negative binomial regression model adjusted for baseline, clustering and for individuals experiencing multiple events. ETHICS AND DISSEMINATION: The study has obtained approval from the Research Ethics Board at the University of Western Ontario, London, Canada (ID 114089). Findings will be disseminated through local reports, presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04066907.

Tissue Sodium Storage in Patients With Heart Failure: A New Therapeutic Target?

BACKGROUND: Preclinical data suggest sodium deposited (without water) in tissues may lead to aberrant remodeling and systemic inflammation, independently of fluid overload in patients with heart failure (HF). Tissue salt storage can be measured noninvasively and quantitatively with 23Na-magnetic resonance imaging. We aimed to investigate the possibility that patients with HF complicated by renal dysfunction are subject to higher tissue sodium concentration exposure than patients with chronic kidney disease alone. METHODS: We conducted an exploratory study including 18 patients with HF, 34 hemodialysis patients (with no meaningful renal clearance of sodium), and 31 patients with chronic kidney disease, with glomerular filtration rate matched to the patients with HF. Every patient underwent 23Na-magnetic resonance imaging of the calf, to quantify tissue sodium and allow comparison among the 3 patient groups. RESULTS: There were no differences in age, sex, and body mass index between groups. Median (interquartile range) skin sodium content in HF (31 [23-37] mmol/L) was very high and indistinguishable from skin sodium content in hemodialysis patients (30 [22-35] mmol/L), P=0.6. Patients with HF exhibited significantly higher skin sodium content than matched estimated glomerular filtration rate chronic kidney disease patients (22 [19-26] mmol/L), P=0.005. Median muscle sodium content in patients with HF was significantly higher than in patients with chronic kidney disease, P=0.002. There was no relationship with estimated glomerular filtration rate in patients with HF. We report a significant correlation between skin sodium and urinary sodium (P=0.04) but no correlation with muscle sodium. Patients who were assessed as being volume depleted (sodium excretion fraction <1%) had lower skin sodium content than patients with sodium excretion fraction >1% (P=0.03). CONCLUSIONS: We have demonstrated that patients with HF characteristically have very high levels of skin sodium storage, comparable to well-characterized extreme levels seen in patients with end-stage kidney disease requiring hemodialysis. 23Na-magnetic resonance imaging may allow precision medicine in the management of this challenging group of patients with HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03004547.

Assessments of Heart Failure and Frailty-Related Health Instability Provide Complementary and Useful Information for Home-Care Planning and Prognosis.

BACKGROUND: Health instability, measured with the Changes in Health and End-Stage Disease Signs and Symptoms (CHESS) scale, predicts hospitalizations and mortality in home-care clients. Heart failure (HF) is also common among home-care clients. We seek to understand how HF contributes to the odds of death, hospitalization, or worsening health among new home-care clients, depending on admission health instability. METHODS: We undertook a retrospective cohort study of home-care clients, aged 65 years and older, between January 1, 2010, and March 31, 2015 from Alberta, British Columbia, Ontario, and the Yukon, Canada. We used multistate Markov models to derive adjusted odds ratios (ORs) for transitions to different health instability states, hospitalization, and death. We examined the role of HF and CHESS at 6 months after home-care admission. RESULTS: The sample included 286,232 clients. Those with HF had greater odds of worsening health instability than those without HF. At low-to-moderate admission health instability (CHESS 0-2), clients with HF had greater odds of hospitalization and death than those without HF. Clients with HF and high health instability (CHESS≥3) had slightly greater odds of hospitalization (OR, 1.08; 95% confidence interval (CI), 1.02-1.13) but similar odds of death (OR, 1.024; 95% CI, 0.937-1.120) compared with clients without HF. CONCLUSIONS: Among new home-care clients, a diagnosis of HF predicts death, hospitalization, and worsening health, predominantly among those with low-to-moderate admission health instability. A diagnosis of HF and admission CHESS score provide complementary information to support care planning in this population.

Provision of a DAPT Score to Cardiologists and Extension of Dual Antiplatelet Therapy Beyond 1 Year After ACS: Randomized Substudy of the Prospective Canadian ACS Reflective II Study.

BACKGROUND: Extension of dual antiplatelet therapy (DAPT) beyond 1 year after acute coronary syndrome is associated with a reduction in ischemic events but also increased bleeding. The DAPT score identifies individuals likely to derive overall benefit or harm from DAPT extension. We sought to evaluate the impact of providing the DAPT score to treating physicians on the decision to extend DAPT beyond 1 year after non-ST-segment elevation myocardial infarction. METHODS: Moderate to high-risk non-ST-segment elevation myocardial infarction patients were enrolled from July 2016 to May 2018 in 13 Canadian hospitals by 52 cardiologists. Participating cardiologists were randomly assigned 1:1 to receive their individual patients' DAPT scores before the 1-year follow-up visit vs not receiving their patients' DAPT scores. Rates of DAPT extension were compared among the randomized groups. RESULTS: At 1 year, 370 of the 585 (63.2%) patients discharged on DAPT were receiving DAPT. Among patients on DAPT at 1 year, the median (25th, 75th percentile) DAPT score was 2 (1,3). DAPT was extended beyond 1 year in 36.2% randomly assigned to provision of DAPT score vs 35.7% in the control group (P = 0.93). In the subgroup of patients with DAPT score ≥ 2, DAPT extension was 49.5% in the DAPT score provision arm vs 40.4% in the control arm (P = 0.22); among patients with DAPT score < 2, DAPT termination was 78.6% in the DAPT score provision arm vs 70.6% in the control arm (P = 0.26) (P value for interaction = 0.1). CONCLUSIONS: In this exploratory randomized trial, provision of the DAPT score to treating physicians had no impact on the duration of DAPT treatment beyond 1 year.

INTRODUCTION: La prolongation de la bithérapie antiplaquettaire au-delà d'un an après un syndrome coronarien aigu est associée à la réduction des accidents ischémiques, mais aussi à l'augmentation des hémorragies. Le score de bithérapie antiplaquettaire permet de déterminer les individus susceptibles d'obtenir des avantages globaux ou des inconvénients de la prolongation de la bithérapie antiplaquettaire. Nous avons cherché à évaluer les répercussions de l'obtention du score de bithérapie antiplaquettaire par les médecins traitants sur la décision quant à la prolongation de la bithérapie antiplaquettaire au-delà d'un an après l'infarctus du myocarde sans élévation du segment ST. MÉTHODES: De juillet 2016 à mai 2018, 52 cardiologues de 13 hôpitaux du Canada ont inscrit des patients exposés à un risque modéré à élevé d'infarctus du myocarde sans élévation du segment ST. Nous avons réparti de façon aléatoire selon un rapport 1:1 les cardiologues participants qui recevaient les scores de bithérapie antiplaquettaire individuels de leurs patients avant la consultation de suivi après un an vs ceux qui ne recevaient pas les scores de bithérapie antiplaquettaire de leurs patients. Nous avons comparé les taux de prolongation de la bithérapie antiplaquettaire des groupes répartis de façon aléatoire. RÉSULTATS: Après un an, 370 (63,2 %) patients sur 585 qui avaient eu à la sortie de l'hôpital une bithérapie antiplaquettaire recevaient la bithérapie antiplaquettaire. Parmi les patients qui prenaient la bithérapie antiplaquettaire après un an, le score médian de bithérapie antiplaquettaire (25e, 75e percentiles) était de 2 (1, 3). La bithérapie antiplaquettaire était prolongée au-delà d'un an chez 36,2 % des patients répartis de façon aléatoire qui avaient un score de bithérapie antiplaquettaire vs 35,7 % dans le groupe témoin (P = 0,93). Dans le sous-groupe de patients qui avaient un score de bithérapie antiplaquettaire ≥ 2, la prolongation de la bithérapie antiplaquettaire était de 49,5 % dans le bras qui avait un score de bithérapie antiplaquettaire vs 40,4 % dans le bras témoin (P = 0,22); parmi les patients qui avaient un score de bithérapie antiplaquettaire < 2, la cessation de la bithérapie antiplaquettaire était de 78,6 % dans le bras qui avait un score de bithérapie antiplaquettaire vs 70,6 % dans le bras témoin (P = 0,26) (valeur P pour l'interaction = 0,1). CONCLUSIONS: Dans cet essai exploratoire à répartition aléatoire, l'obtention du score de la bithérapie antiplaquettaire par les médecins traitants n'a pas engendré de répercussions sur la durée de la bithérapie antiplaquettaire au-delà d'un an.

Developing and validating models to predict sudden death and pump failure death in patients with heart failure and preserved ejection fraction.

BACKGROUND: Sudden death (SD) and pump failure death (PFD) are leading modes of death in heart failure and preserved ejection fraction (HFpEF). Risk stratification for mode-specific death may aid in patient enrichment for new device trials in HFpEF. METHODS: Models were derived in 4116 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), using competing risks regression analysis. A series of models were built in a stepwise manner, and were validated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials. RESULTS: The clinical model for SD included older age, men, lower LVEF, higher heart rate, history of diabetes or myocardial infarction, and HF hospitalization within previous 6 months, all of which were associated with a higher SD risk. The clinical model predicting PFD included older age, men, lower LVEF or diastolic blood pressure, higher heart rate, and history of diabetes or atrial fibrillation, all for a higher PFD risk, and dyslipidaemia for a lower risk of PFD. In each model, the observed and predicted incidences were similar in each risk subgroup, suggesting good calibration. Model discrimination was good for SD and excellent for PFD with Harrell's C of 0.71 (95% CI 0.68-0.75) and 0.78 (95% CI 0.75-0.82), respectively. Both models were robust in external validation. Adding ECG and biochemical parameters, model performance improved little in the derivation cohort but decreased in validation. Including NT-proBNP substantially increased discrimination of the SD model, and simplified the PFD model with marginal increase in discrimination. CONCLUSIONS: The clinical models can predict risks for SD and PFD separately with good discrimination and calibration in HFpEF and are robust in external validation. Adding NT-proBNP further improved model performance. These models may help to identify high-risk individuals for device intervention in future trials. CLINICAL TRIAL REGISTRATION: I-Preserve: ClinicalTrials.gov NCT00095238; TOPCAT: ClinicalTrials.gov NCT00094302; CHARM-Preserved: ClinicalTrials.gov NCT00634712.

Optimal Usage of Sacubitril/Valsartan for the Treatment of Heart Failure: The Importance of Optimizing Heart Failure Care in Canada.

BACKGROUND: Heart failure (HF) with reduced ejection fraction represents approximately 50% of the 600,000 Canadians currently living with HF and over 90,000 new cases diagnosed each year. The angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, demonstrated superior efficacy in reducing cardiovascular death and HF hospitalization over standard of care therapy. METHODS: The potential magnitude of benefit in Canada with respect to preventing or postponing deaths and reducing hospitalizations resulting from its optimal implementation in patients with HF with an ejection fraction <40% was estimated based on published sources. RESULTS: Of the potentially eligible 225,562 patients, this would amount to the prevention of 4699 cardiovascular deaths and first HF hospitalizations, 3698 thirty-day HF readmissions, and 2820 deaths due to all-cause mortality. The number of patients receiving sacubitril/valsartan nationally in 2018 was 27,267. This represents approximately 12% of the calculated eligible population for this therapy in Canada. CONCLUSIONS: The findings from this analysis suggest that a substantial number of deaths, hospitalizations, and HF readmissions could potentially be avoided by optimal usage of sacubitril/valsartan therapy in Canada. This emphasizes the importance of rapidly and appropriately implementing evidence-based medications into routine clinical practice, to achieve the best possible outcomes for our patients with HF and to reduce the high burden and cost of HF in Canada.

CONTEXTE: L'insuffisance cardiaque (IC) avec diminution de la fraction d'éjection touche actuellement environ 50 % des 600 000 Canadiens qui sont atteints d'IC, et plus de 90 000 nouveaux cas de cette affection sont diagnostiqués chaque année. L'association sacubitril-valsartan (inhibiteur de la néprilysine et antagoniste des récepteurs de l'angiotensine) a démontré une efficacité supérieure à celle du traitement de référence au chapitre de la réduction de la mortalité d'origine cardiovasculaire et des hospitalisations dues à l'IC. MÉTHODOLOGIE: L'ampleur potentielle des bienfaits du médicament au Canada en matière de prévention ou de report des décès et de réduction des hospitalisations par suite de son utilisation optimale chez les patients atteints d'IC présentant une fraction d'éjection < 40 % a été estimée sur la base de sources publiées. RÉSULTATS: Chez les 225 562 patients potentiellement admissibles au traitement, le médicament permettrait de prévenir 4 699 décès d'origine cardiovasculaire et premières hospitalisations pour cause d'IC, 3 698 réhospitalisations pour cause d'IC dans les 30 jours suivant la sortie de l'hôpital et 2 820 décès toutes causes confondues. À l'échelle nationale en 2018, 27 267 patients ont été traités par l'association sacubitril-valsartan. Cela représente environ 12 % de la population admissible au traitement selon les calculs s'appliquant au Canada. CONCLUSIONS: Les résultats de cette analyse permettent de penser que beaucoup de décès, d'hospitalisations et de réhospitalisations pour cause d'IC pourraient être évités par suite de la mise en œuvre optimale du traitement par l'association sacubitril-valsartan au Canada. Sous cet éclairage, force est de constater l'importance que revêt l'intégration rapide et appropriée des pharmacothérapies factuelles à la pratique clinique courante, dans l'optique d'une démarche visant à obtenir les meilleurs résultats possible chez nos patients atteints d'IC et à réduire le lourd fardeau de cette affection au Canada.

CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation, SGLT2 Inhibitors, ARNI in HFpEF, and Tafamidis in Amyloidosis.

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.

Therapies for Advanced Heart Failure Patients Ineligible for Heart Transplantation: Beyond Pharmacotherapy.

Globally, there are ∼ 26 million people living with heart failure (HF), 50% of them with reduced ejection fraction, costing countries billions of dollars each year. Improvements in treatment of cardiovascular diseases, including advanced HF, have allowed an unprecedented number of patients to survive into old age. Despite these advances, patients with HF deteriorate and often require advanced therapies. As the proportion of elderly patients in the population increases, there will be an increasing number of patients to be evaluated for advanced therapies and an increasing number that do not qualify for, won't be considered for, or decline orthotopic heart transplantation. The purpose of this article is to review the benefits of palliative care (PC), exercise-based cardiac rehabilitation (ExCR), device therapy (cardiac resynchronization therapy and mitral clip), and mechanical circulatory support (MCS) in advanced HF patients who are transplant ineligible. PC interventions should be introduced early in the course of a patient's diagnosis to manage symptoms, address goals of care, and improve patient-centered outcomes. Further improvement in health-related quality of life as well as functional capacity can be achieved safely in patients with advanced HF through patient participation in ExCR. Device therapy and MCS can reduce HF hospitalizations and improve survival. In fact, early survival with MCS approaches that of heart transplantation. Despite their being transplant ineligible, there are a variety of treatment options available to patients to improve their quality of life, decrease hospitalizations, and potentially improve mortality.

DIVERT-Collaboration Action Research and Evaluation (CARE) Trial Protocol: a multiprovincial pragmatic cluster randomised trial of cardiorespiratory management in home care.

INTRODUCTION: Home care clients are increasingly medically complex, have limited access to effective chronic disease management and have very high emergency department (ED) visitation rates. There is a need for more appropriate and targeted supportive chronic disease management for home care clients. We aim to evaluate the effectiveness and preliminary cost effectiveness of a targeted, person-centred cardiorespiratory management model. METHODS AND ANALYSIS: The Detection of Indicators and Vulnerabilities of Emergency Room Trips (DIVERT) - Collaboration Action Research and Evaluation (CARE) trial is a pragmatic, cluster-randomised, multicentre superiority trial of a flexible multicomponent cardiorespiratory management model based on the best practice guidelines. The trial will be conducted in partnership with three regional, public-sector, home care providers across Canada. The primary outcome of the trial is the difference in time to first unplanned ED visit (hazard rate) within 6 months. Additional secondary outcomes are to identify changes in patient activation, changes in cardiorespiratory symptom frequencies and cost effectiveness over 6 months. We will also investigate the difference in the number of unplanned ED visits, number of inpatient hospitalisations and changes in health-related quality of life. Multilevel proportional hazard and generalised linear models will be used to test the primary and secondary hypotheses. Sample size simulations indicate that enrolling 1100 home care clients across 36 clusters (home care caseloads) will yield a power of 81% given an HR of 0.75. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Hamilton Integrated Research Ethics Board as well as each participating site's ethics board. Results will be submitted for publication in peer-reviewed journals and for presentation at relevant conferences. Home care service partners will also be informed of the study's results. The results will be used to inform future support strategies for older adults receiving home care services. TRIAL REGISTRATION NUMBER: NCT03012256.

Sex-Related Differences in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction. METHODS: Baseline characteristics (including biomarkers and quality of life) and outcomes (primary outcome: composite of first heart failure hospitalization or cardiovascular death) were compared in 4458 women and 4010 men enrolled in CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) (EF≥45%), I-Preserve (Irbesartan in heart failure with Preserved ejection fraction), and TOPCAT-Americas (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial). RESULTS: Women were older and more often obese and hypertensive but less likely to have coronary artery disease or atrial fibrillation. Women had more symptoms and signs of congestion and worse quality of life. Despite this, the risk of the primary outcome was lower in women (hazard ratio, 0.80 [95% CI, 0.73-0.88]), as was the risk of cardiovascular death (hazard ratio, 0.70 [95% CI, 0.62-0.80]), but there was no difference in the rate for first hospitalization for heart failure (hazard ratio, 0.92 [95% CI, 0.82-1.02]). The lower risk of cardiovascular death in women, compared with men, was in part explained by a substantially lower risk of sudden death (hazard ratio, 0.53 [0.43-0.65]; P<0.001). E/A ratio was lower in women (1.1 versus 1.2). CONCLUSIONS: There are significant differences between women and men with heart failure with preserved ejection fraction. Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men. Their risk of sudden death was half that of men. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00853658, NCT01035255.

Age-Related Characteristics and Outcomes of Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Although heart failure with preserved ejection fraction (HFpEF) is considered a disease of the elderly, younger patients are not spared from this syndrome. OBJECTIVES: This study therefore investigated the associations among age, clinical characteristics, and outcomes in patients with HFpEF. METHODS: Using data on patients with left ventricular ejection fraction ≥45% from 3 large HFpEF trials (TOPCAT [Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function], I-PRESERVE [Irbesartan in Heart Failure With Preserved Systolic Function], and CHARM Preserved [Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity]), patients were categorized according to age: ≤55 years (n = 522), 56 to 64 years (n = 1,679), 65 to 74 years (n = 3,405), 75 to 84 years (n = 2,464), and ≥85 years (n = 398). This study compared clinical and echocardiographic characteristics, as well as mortality and hospitalization rates, mode of death, and quality of life across age categories. RESULTS: Younger patients (age ≤55 years) with HFpEF were more often obese, nonwhite men, whereas older patients with HFpEF were more often white women with a higher prevalence of atrial fibrillation, hypertension, and chronic kidney disease (eGFR <60 ml/min/1.73 m2). Despite fewer comorbidities, younger patients had worse quality of life compared with older patients (age ≥85 years). Compared with patients age ≤55 years, patients age ≥85 years had higher mortality (hazard ratio: 6.9; 95% confidence interval: 4.2 to 11.4). However, among patients who died, sudden death was, proportionally, the most common mode of death (p < 0.001) in patients age ≤55 years. In contrast, older patients (age ≥85 years) died more often from noncardiovascular causes (34% vs. 20% in patients age ≤55 years; p < 0.001). CONCLUSIONS: Compared with the elderly, younger patients with HFpEF were less likely to be white, were more frequently obese men, and died more often of cardiovascular causes, particularly sudden death. In contrast, elderly patients with HFpEF had more comorbidities and died more often from noncardiovascular causes. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302; Irbesartan in Heart Failure With Preserved Systolic Function [I-PRESERVE]; NCT00095238; Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM Preserved]; NCT00634712).

Insulin treatment and clinical outcomes in patients with diabetes and heart failure with preserved ejection fraction.

AIMS: Insulin causes sodium retention and hypoglycaemia and its use is associated with worse outcomes in heart failure (HF) with reduced ejection fraction. We have investigated whether this is also the case in HF with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We examined the association between diabetes/diabetes treatments and the risk of the primary composite of cardiovascular death or HF hospitalization, as well as other outcomes in adjusted analyses in CHARM-Preserved (left ventricular ejection fraction ≥ 45%), I-Preserve and TOPCAT (Americas) pooled. Of 8466 patients, 2653 (31%) had diabetes, including 979 (37%) receiving insulin. Patients receiving insulin were younger, had a higher body mass index, prevalence of ischaemic aetiology, N-terminal pro-B-type natriuretic peptide and use of diuretics, worse New York Heart Association class and signs and symptoms, and worse quality of life and renal function, compared to patients with diabetes not on insulin. Among the 1398 patients with echocardiographic data, insulin use was associated with higher left ventricular end-diastolic pressure and more diastolic dysfunction than in other participants. The primary outcome occurred at a rate of 6.3 per 100 patient-years in patients without diabetes, and 10.2 and 17.1 per 100 patient-years in diabetes patients without and with insulin use, respectively [fully adjusted hazard ratio (aHR) insulin-treated diabetes vs. other diabetes: 1.41, 95% confidence interval (CI) 1.23-1.63, P < 0.001]. The adjusted HR is 1.67 (95% CI 1.20-2.32, p = 0.002) for sudden death (insulin-treated diabetes vs. other diabetes). CONCLUSIONS: Insulin use is associated with poor outcomes in HFpEF. Although we cannot conclude a causal association, the safety of insulin and alternative glucose-lowering treatments in HF needs to be evaluated in clinical trials.

Prior Pacemaker Implantation and Clinical Outcomes in Patients With Heart Failure and Preserved Ejection Fraction.

OBJECTIVES: This study examined the relationship between prior pacemaker implantation and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Conventional right ventricular pacing causes electrical and mechanical left ventricular dyssynchrony and may worsen left ventricular systolic dysfunction and HF. Whether conventional pacing is also associated with worse outcomes in HFpEF is unknown. METHODS: Patient data were pooled from the CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction), and TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial) studies and were examined for the association between having a pacemaker and the risk of the primary composite of cardiovascular death or HF hospitalization, the individual components of the composite, the 2 main modes of cardiovascular death (i.e., sudden death and pump failure death), and all-cause death in unadjusted and adjusted analyses. RESULTS: Of the 8,466 patients included, 682 patients (8%) had a pacemaker. Pacemaker patients were older and more often men and had lower body mass indexes, estimated glomerular filtration rates, and blood pressures but higher concentrations of N-terminal pro-B-type natriuretic peptide than those without a pacemaker. The rate of the primary composite outcome in pacemaker patients was almost twice that in patients without a pacemaker (13.6 vs. 7.6 per 100 patient-years of follow up, respectively), with a similar finding for HF hospitalizations (10.8 vs. 5.1 per 100 patient-years, respectively). This risk rate persisted after adjusting for other prognostic variables (hazard ratio [HR] for the composite outcome: 1.17; 95% confidence interval [CI]: 1.02 to 1.33; p = 0.026), driven mainly by HF hospitalization (HR: 1.37; 95% CI: 1.17 to 1.60; p < 0.001). The risk of death was not significantly higher in pacemaker patients in the adjusted analyses. CONCLUSIONS: These findings raise the possibility that right ventricular pacing-induced left ventricular dyssynchrony may be detrimental in HFpEF patients.