Association of Sacubitril/Valsartan vs Valsartan With Blood Pressure Changes and Symptomatic Hypotension: the PARAGLIDE-HF Trial.

BACKGROUND: In PARAGLIDE-HF, in patients with ejection fraction (EF) > 40%, stabilized after worsening heart failure (WHF), sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared to valsartan alone, despite more symptomatic hypotension (SH). Concern about SH may be limiting the use of sacubitril/valsartan in appropriate patients. METHODS: We characterized patients by the occurrence of SH (investigator-reported) after randomization to either sacubitril/valsartan or valsartan. A key trial inclusion criterion was systolic blood pressure (SBP) ≥ 100 mmHg for the preceding 6 hours and no SH. We also compared outcomes based on baseline SBP stratified by the median blood pressure. The primary endpoint was time-averaged proportional change in NT-proBNP levels from baseline through weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: (1) cardiovascular death; (2) hospitalizations due to HF; (3) urgent HF visits; and (4) change in NT-proBNP levels. RESULTS: Among 466 randomized patients, 92 (19.7%) experienced SH (sacubitril/valsartan, n = 56 [24.0%]; valsartan, n = 36 [15.5%]; P = 0.020). The median time to the first SH event was similar between treatment arms (18 days vs 15 days, respectively; P = 0.42) as was the proportion of first SH events classified as serious by investigators. Patients who experienced SH with sacubitril/valsartan were more likely to be white (OR 1.87 [95% CI: 0.31, 11.15]), to have a lower baseline SBP (per 10 mmHg increase, OR 0.68 [95% CI: 0.55, 0.85]), or to have a left ventricular ejection fraction (LVEF) of > 60% (OR 2.21 [95% CI: 1.05, 4.65]). Time-averaged change in NT-proBNP levels did not differ between patients with baseline SBP ≥ 128 mmHg vs SBP < 128 mmHg (interaction, P = 0.43). The composite hierarchical outcome for sacubitril/valsartan in patients with baseline SBP ≥ 128 mmHg had a win ratio of 1.34 ([95% CI: 0.91, 1.99]; P = 0.096) vs SBP < 128 mmHg with a win ratio of 1.09 ([95%CI: 0.73, 1.66]; P = 0 .62; interaction P value = 0.42). CONCLUSION: Among patients with LVEF > 40% stabilized after WHF, incident SH was more common with sacubitril/valsartan compared with valsartan. SH was associated with lower baseline SBP, being white, and having higher LVEF. Treatment benefits with sacubitril/valsartan may be more pronounced in patients with higher baseline SBP and lower LVEF (≤ 60%). (Funded by Novartis Pharmaceutical Corporation; ClinicalTrials.gov number, NCT03988634.).

Rationale, Design and Baseline Characteristics of the PARAGLIDE-HF Trial: Sacubitril/Valsartan vs Valsartan in HFmrEF and HFpEF With a Worsening Heart Failure Event.

BACKGROUND: The PARAGON-HF trial studied the effect of sacubitril/valsartan (Sac/Val) compared with valsartan (Val) on clinical outcomes in patients with chronic heart failure with preserved ejection fraction (HFpEF) or mildly reduced EF (HFmrEF). Further data are needed regarding the use of Sac/Val in these groups with EF and with recent worsening heart failure (WHF) events and in key populations not broadly represented in the PARAGON-HF trial, including those with de novo HF, the severely obese and Black patients. METHODS: The PARAGLIDE-HF trial is a multicenter, double-blind, randomized, controlled trial of Sac/Val vs Val that enrolled patients at 100 sites. Medically stable patients ≥ 18 years old with EF > 40%, amino terminal-pro B-type natriuretic peptide (NT-proBNP) levels ≥ 500 pg/mL and within 30 days of a WHF event were eligible for participation. Patients were randomly assigned 1:1 to Sac/Val vs Val. The primary efficacy endpoint is time-averaged proportional change in NT-proBNP from baseline through Weeks 4 and 8. Secondary endpoints include clinical outcomes during follow-up and additional biomarker assessments. Safety endpoints include symptomatic hypotension, worsening renal function and hyperkalemia. RESULTS: The trial enrolled 467 participants from June 2019 through October 2022 (52% women, 22% Black, age 70 ± 12 years, median (IQR) BMI 33 (27-40) kg/m2). The median (IQR) EF was 55% (50%-60%), 23% with HFmrEF (LVEF 41%-49%), 24% with EF > 60% and 33% with de novo HFpEF. Median screening NT-proBNP was 2009 (1291-3813) pg/mL, and 69% were enrolled in the hospital. CONCLUSIONS: The PARAGLIDE-HF trial enrolled a broad and diverse range of patients with heart failure with mildly reduced or preserved ejection fraction and will inform clinical practice by providing evidence about the safety, tolerability and efficacy of Sac/Val vs Val in those with a recent WHF event.

A First-in-Human Study of AMG 986, a Novel Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients.

PURPOSE: AMG 986 is a novel apelin receptor (APJ) agonist that improves cardiac contractility in animal models without adversely impacting hemodynamics. This phase 1b study evaluated the safety/tolerability, pharmacokinetics, and pharmacodynamics of AMG 986 in healthy subjects and patients with heart failure (HF). METHODS: Healthy adults (Parts A/B) and HF patients (Part C) aged 18-85 years were randomized 3:1 to single-dose oral/IV AMG 986 or placebo (Part A); multiple-dose oral/IV AMG 986 or placebo (Part B); or escalating-dose oral AMG 986 or placebo (Part C). PRIMARY ENDPOINT: treatment-emergent adverse events, laboratory values/vital signs/ECGs; others included AMG 986 pharmacokinetics, left ventricular (LV) function. RESULTS: Overall, 182 subjects were randomized (AMG 986/healthy: n = 116, placebo, n = 38; AMG 986/HF: n = 20, placebo, n = 8). AMG 986 had acceptable safety profile; no clinically significant dose-related impact on safety parameters up to 650 mg/day was observed. AMG 986 exposures increased nonlinearly with increasing doses; minimal accumulation was observed. In HF with reduced ejection fraction patients, there were numerical increases in percent changes from baseline in LV ejection fraction and stroke volume by volumetric assessment with AMG 986 vs placebo (stroke volume increase not recapitulated by Doppler). CONCLUSIONS: In healthy subjects and HF patients, short-term AMG 986 treatment was well tolerated. Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03276728. DATE OF REGISTRATION: September 8, 2017.

The effect of ASA, ticagrelor, and heparin in ST-segment myocardial infarction patients with prolonged transport times to primary percutaneous intervention.

OBJECTIVES: To investigate the effects of early upstream antithrombotic therapy administration (ATTA) in ST-segment elevation myocardial infarction (STEMI) patients with prolonged transport times to primary percutaneous intervention (PPCI) on major clinical outcomes. BACKGROUND: It remains unclear whether early upstream administration of aspirin, ticagrelor, and unfractionated heparin (UFH) confers additional benefits compared with in-hospital administration. METHODS: Between 2015 and 2018, we performed PPCI in 709 included consecutive STEMI patients. We compared 482 STEMI patients who received aspirin, ticagrelor, and UFH loading in a non-PCI capable spoke hospital before transfer (NPHT) versus 227 prehospital triage setting (PTS) STEMI patients who received in-ambulance aspirin, followed by ticagrelor and UFH in the hub catheterization laboratory. The primary outcome was the presence of a pre-PPCI TIMI flow 2-3 in the infarct related artery (IRA). The secondary outcomes included definite acute stent thrombosis and hemorrhagic complications. RESULTS: The median times from ticagrelor and heparin administration to angiography in the NPHT group and the PTS group were 80.5 min (Interquartile Range (IQR) 68.5-94) and 10 min (IQR 5-15) respectively (p < .0001). Using inverse probability of treatment weighting to minimize heterogeneity between groups, we showed significant differences for the primary outcome (44.6 versus 18.5%, p < .0001) and for definite acute stent thrombosis (0.6 versus 2.6%, p = .03), with no difference in the combined in-hospital BARC 2-5 bleeding events (1.9 versus 3.5%, p = .18) in the NPHT versus the PTS group, respectively. CONCLUSION: In this single-center retrospective cohort study, after adjusting for baseline covariates, early upstream ATTA with aspirin, ticagrelor, and UFH was associated with greater pre-PPCI TIMI flow and less definite acute stent thrombosis in STEMI patients, without increased bleeding risk.

The feasibility, reliability, and incremental value of two-dimensional speckle-tracking for the detection of significant coronary stenosis after treadmill stress echocardiography.

BACKGROUND: Two-dimensional speckle-tracking echocardiography (STE) may help detect coronary artery disease (CAD) when combined with dobutamine stress echocardiography. However, few studies have explored STE with exercise stress echocardiography (ESE). We aimed to evaluate the feasibility, reliability, and incremental value of STE combined with treadmill ESE compared to treadmill ESE alone to detect CAD. METHODS: We conducted a case-control study of all consecutive patients with abnormal ESE in 2018-2020 who subsequently underwent coronary angiography within a six-month interval. We 1:1 propensity score-matched these patients to those with a normal ESE. Two blinded operators generated a 17-segment bull's-eye map of longitudinal strain (LS). We utilized the mean differences between stress and baseline LS values in segments 13-17, segment 17, and segments 15-16 to create receiver operator curves for the overall examination, the left anterior descending artery (LAD), and the non-LAD territories, respectively. RESULTS: We excluded 61 STEs from 201 (30.3%) eligible ESEs; 47 (23.4%) because of suboptimal image quality and 14 (7.0%) because of excessive heart rate variability precluding the calculation of a bull's-eye map. After matching, a total of 102 patients were included (51 patients in each group). In the group with abnormal ESE patients (mean age 66.4 years, 39.2% female), 64.7% had significant CAD (> 70% stenosis) at coronary angiogram. In the group with normal ESE patients (mean age 65.1 years, 35.3% female), 3.9% were diagnosed with a new significant coronary stenosis within one year. The intra-class correlation for global LS was 0.87 at rest and 0.92 at stress, and 0.84 at rest, and 0.89 at stress for the apical segments. The diagnostic accuracy of combining ESE and STE was superior to visual assessment alone for the overall examination (area under the curve (AUC) = 0.89 vs. 0.84, p = 0.025), the non-LAD territory (AUC = 0.83 vs. 0.70, p = 0.006), but not the LAD territory (AUC = 0.79 vs. 0.73, p = 0.11). CONCLUSIONS: Two-dimensional speckle-tracking combined with treadmill ESE is relatively feasible, reliable, and may provide incremental diagnostic value for the detection and localization of significant CAD.

Effects of Sacubitril/Valsartan vs Valsartan in De Novo vs Acute on Chronic HFpEF and HFmrEF.

Background: Decompensated heart failure (HF) can be categorized as de novo or worsening of chronic HF. In PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF), among patients with an ejection fraction >40% that stabilized after worsening HF, sacubitril/valsartan led to a significantly greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and was associated with clinical benefit compared to valsartan. Objectives: This prespecified analysis characterized patients with de novo vs worsening chronic HF in PARAGLIDE-HF and assessed the interaction between HF chronicity and the effect of sacubitril/valsartan. Methods: Patients were classified as de novo (first diagnosis of HF) or chronic (known HF prior to the index event). Time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8 was analyzed using an analysis of covariance model. A win ratio consisting of time to cardiovascular death, number and times of HF hospitalizations during follow-up, number and times of urgent HF visits during follow-up, and time-averaged proportional change in NT-proBNP was assessed for each group. Results: Of the 466 participants, 153 (33%) had de novo HF and 313 (67%) had chronic HF. De novo patients had lower rates of atrial fibrillation/flutter and lower creatinine. There was a nonsignificant reduction in NT-proBNP with sacubitril/valsartan vs valsartan for de novo (0.82; 95% CI: 0.62-1.07) and chronic HF (0.88; 95% CI: 0.73-1.07), interaction P = 0.66. The win ratio was nominally in favor of sacubitril/valsartan for both de novo (1.12; 95% CI: 0.70-1.58) and chronic HF (1.24; 95% CI: 0.89-1.71). Conclusions: There is no interaction between HF chronicity and the effect of sacubitril-valsartan.

Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure.

BACKGROUND: The efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not been described. OBJECTIVES: Data from randomized trials of sacubitril/valsartan in HF patients with EF ≤40% (PIONEER-HF [Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode] trial) and >40% (PARAGLIDE-HF [Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF] trial) following recent worsening heart failure (WHF) were pooled to examine treatment effect across the EF spectrum. METHODS: The PIONEER-HF and PARAGLIDE-HF trials were double-blind, randomized trials of sacubitril/valsartan vs control therapy (enalapril or valsartan, respectively). All participants in the PIONEER-HF trial and 69.5% in the PARAGLIDE-HF trial were enrolled during hospitalization for HF after stabilization. The remainder in the PARAGLIDE-HF trial were enrolled ≤30 days after a WHF event. The primary endpoint of both trials was time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Adjudicated clinical endpoints were analyzed through the end of follow-up, adjusting for trial. RESULTS: The pooled analysis included 1,347 patients (881 from PIONEER-HF, 466 from PARAGLIDE-HF). Baseline characteristics included median age 66 years, 36% women, 31% Black, 34% de novo HF, and median EF 30%. The reduction in NT-proBNP was 24% greater with sacubitril/valsartan vs control therapy (n = 1,130; ratio of change = 0.76; 95% CI: 0.69-0.83; P < 0.0001). Cardiovascular death or hospitalization for HF was reduced by 30% with sacubitril/valsartan vs control therapy (HR: 0.70; 95% CI: 0.54-0.91; P = 0.0077). This effect was consistent across the spectrum of EF ≤60%. Sacubitril/valsartan increased symptomatic hypotension (risk ratio: 1.35; 95% CI: 1.05-1.72). CONCLUSIONS: In patients stabilized after WHF, sacubitril/valsartan led to a greater reduction in plasma NT-proBNP and improved clinical outcome compared with control therapy, in particular across the spectrum of EF ≤60%. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890; Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event [HFpEF Decompensation] Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation [PARAGLIDE-HF]; NCT03988634).

Access to heart failure care post emergency department visit: do we meet established benchmarks and does it matter?

BACKGROUND: The Canadian Cardiology Society recommends that patients should be seen within 2 weeks after an emergency department (ED) visit for heart failure (HF). We sought to investigate whether patients who had an ED visit for HF subsequently consult a physician within the current established benchmark, to explore factors related to physician consultation, and to examine whether delay in consultation is associated with adverse events (AEs) (death, hospitalization, or repeat ED visit). METHODS: Patients were recruited by nurses at 8 hospital EDs in Québec, Canada, and interviewed by telephone within 6 weeks of discharge and subsequently at 3 and 6 months. Clinical variables were extracted from medical charts by nurses. We used Cox regression in the analysis. RESULTS: We enrolled 410 patients (mean age 74.9 ± 11.1 years, 53% males) with a confirmed primary diagnosis of HF. Only 30% consulted with a physician within 2 weeks post-ED visit. By 4 weeks, 51% consulted a physician. Over the 6-month follow-up, 26% returned to the ED, 25% were hospitalized, and 9% died. Patients who were followed up within 4 weeks were more likely to be older and have higher education and a worse quality of life. Patients who consulted a physician within 4 weeks of ED discharge had a lower risk of AEs (hazard ratio 0.59, 95% CI 0.35-0.99). CONCLUSION: Prompt follow-up post-ED visit for HF is associated with lower risk for major AEs. Therefore, adherence to current HF guideline benchmarks for timely follow-up post-ED visit is crucial.

Canadian Cardiovascular Society-Canadian Heart Failure Society Focused Clinical Practice Update of Patients With Differing Heart Failure Phenotypes.

A number of societies produce heart failure (HF) management guidelines, comprising official recommendations on the basis of recent research discoveries, but their applicability to specific situations encountered in daily practice might be difficult. In this clinical practice update we aim to provide responses to fundamental questions that face health care providers, like appropriate timing for the introduction and optimization of different classes of medication according to specific patient phenotypes, when second-line therapies and valvular interventions should be considered, and management of difficult clinical scenarios such as cardiorenal syndrome and frailty. A consensus-based methodology was used. Approaches to 5 different phenotypes are presented: (1) The wet HF phenotype is the easiest to manage, decongestion being performed alongside introduction of guideline-directed medical therapy (GDMT); (2) The de novo HF phenotype requires the introduction of the 4 pillars of GDMT, personalizing the order on the basis of the individuals' biological and physiological characteristics; (3) The worsening HF phenotype is a marker of poor prognosis, and therefore should motivate optimization of GDMT, start second-line therapies, and/or reevaluate goals of care/advanced HF therapies; (4) The cardiorenal phenotypes require correct volume assessment, because renal function usually improves with decongestion; and (5) The frail HF phenotype require special attention, careful drug titration, and consideration of cardiac rehabilitation programs. In conclusion, specific common HF phenotypes call for a personalized approach to improve adoption of the HF guidelines into clinical practice.

Angiotensin-Neprilysin Inhibition in Patients With Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure.

BACKGROUND: U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly reduced or preserved ejection fraction (EF). Whether initiation is safe and effective in EF >40% after a worsening heart failure (WHF) event is unknown. OBJECTIVES: PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) assessed sacubitril/valsartan vs valsartan in EF >40% following a recent WHF event. METHODS: PARAGLIDE-HF is a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients with EF >40% enrolled within 30 days of a WHF event. The primary endpoint was time-averaged proportional change in amino terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: 1) cardiovascular death; 2) HF hospitalizations; 3) urgent HF visits; and 4) change in NT-proBNP. RESULTS: In 466 patients (233 sacubitril/valsartan; 233 valsartan), time-averaged reduction in the NT-proBNP was greater with sacubitril/valsartan (ratio of change: 0.85; 95% CI: 0.73-0.999; P = 0.049). The hierarchical outcome favored sacubitril/valsartan but was not significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P = 0.16). Sacubitril/valsartan reduced worsening renal function (OR: 0.61; 95% CI: 0.40-0.93) but increased symptomatic hypotension (OR: 1.73; 95% CI: 1.09-2.76). There was evidence of a larger treatment effect in the subgroup with EF ≤60% for NT-proBNP change (0.78; 95% CI: 0.61-0.98) and the hierarchical outcome (win ratio: 1.46; 95% CI: 1.09-1.95). CONCLUSIONS: Among patients with EF >40% stabilized after WHF, sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone, despite more symptomatic hypotension. (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634).

Optimization of pharmacotherapies for ambulatory patients with heart failure and reduced ejection fraction is associated with improved outcomes.

BACKGROUND: In heart failure, specific target doses for each drug are recommended, but some patients receive suboptimal dosing, others are undertreated or remain chronically in a titration phase, despite having no apparent contraindication or intolerance. We assessed the association of different levels of adherence to guidelines with outcomes in patients with heart failure and reduced ejection fraction (HFrEF). METHODS: Medical records of patients with HFrEF followed at our heart failure (HF) clinic for at least 6 months (n = 511) were reviewed and patients categorized as: 1) optimized (25.4%); 2) in-titration (29.0%); 3) undertreated (32.7%); and 4) intolerant/contraindicated (12.9%). Risk of mortality or HF events (hospitalization, emergency visit or ambulatory administration of intravenous diuretics) within one year was assessed using Cox regression models and Kaplan-Meier curves. RESULTS: Compared to optimized patients, those intolerant (HR: 4.60 [95%CI: 2.23-9.48]; p < 0.0001) had the highest risk of outcomes, followed by those undertreated (3.45 [1.78-6.67]; p = 0.0002) and in-titration (1.99 [0.97-4.06]; p = 0.0588). Overall predictors of outcomes included loop diuretics' use (4.54 [2.39-8.60]), undertreatment (2.38 [1.22-4.67]), intolerance/ contraindication to triple therapy (3.08 [1.47-6.42]), peripheral vascular disease (2.13 [1.29-3.50]) and NYHA class III-IV (1.89 [1.25-2.85]); all p < 0.05. CONCLUSION: Level of adherence to guidelines is associated with outcomes, with intolerant/contraindicated patients having the worst prognosis and those undertreated and in-titration at intermediate risk compared to those optimized. Up-titration of therapy should be attempted whenever possible, considering patients' limitations, to potentially improve outcomes.

CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction.

In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a ß-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.

The Status of Specialized Ambulatory Heart Failure Care in Canada: A Joint Canadian Heart Failure Society and Canadian Cardiovascular Society Heart Failure Guidelines Survey.

This joint Canadian Heart Failure Society and the CCS Heart Failure guidelines report has been developed to provide a pan-Canadian snapshot of the current state of clinic-based ambulatory heart failure (HF) care in Canada with specific reference to elements and processes of care associated with quality and high performing health systems. It includes the viewpoints of persons with lived experience, patient care providers, and administrators. It is imperative to build on the themes identified in this survey, through engaging all health care professionals, to develop integrated and shared care models that will allow better patient outcomes. Several patient and organizational barriers to care were identified in this survey, which must inform the development of regional care models and pragmatic solutions to improve transitions for this patient population. Unfortunately, we were unsuccessful in incorporating the perspectives of primary care providers and internal medicine specialists who provide the majority of HF care in Canada, which in turn limits our ability to comment on strategies for capacity building outside the HF clinic setting. These considerations must be taken into account when interpreting our findings. Engaging all HF care providers, to build on the themes identified in this survey, will be an important next step in developing integrated and shared care models known to improve patient outcomes.

Ce rapport conjoint des lignes directrices de la Société canadienne d'insuffisance cardiaque et de la Société canadienne de cardiologie (SCC) sur l'insuffisance cardiaque a été élaboré pour fournir un aperçu pancanadien de l'état actuel des soins ambulatoires de l'insuffisance cardiaque (IC) en clinique au Canada, en se référant spécifiquement aux éléments et aux processus de soins associés à des systèmes de santé très performants et de qualité. Il comprend les points de vue de personnes ayant une expérience vécue de l'IC, de prestataires de soins aux patients et d'administrateurs. Il est impératif de s'appuyer sur les thématiques identifiées dans cette enquête, en y engageant tous les professionnels de la santé, pour développer des modèles de soins intégrés et partagés qui permettront de meilleurs pronostics pour les patients. Plusieurs obstacles relatifs aux patients et organisationnels dont il faudra se soucier ont été identifiés dans cette enquête, qui doit servir de base à l'élaboration de modèles de soins régionaux et de solutions pragmatiques pour améliorer les transitions pour cette population de patients. Malheureusement, nous n'avons pas réussi à intégrer les points de vue des prestataires de soins primaires et des spécialistes en médecine interne qui fournissent la majorité des soins en IC au Canada, ce qui limite notre capacité à commenter les stratégies de renforcement des capacités en dehors du cadre des cliniques d'IC. Ces considérations doivent être prises en compte lors de l'interprétation de nos conclusions. L'engagement de tous les prestataires de soins de santé en IC à s'appuyer sur les thématiques identifiées dans cette enquête constituera une prochaine étape importante dans le développement de modèles de soins intégrés et partagés connus pour améliorer le pronostic des patients.

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.

Increased level of high-sensitivity cardiac Troponin T in a geriatric population is determined by comorbidities compared to age.

High level of cardiac Troponin T (hs-cTnT) in geriatric population has been considered as an age-related phenomenon, which may question the interpretation of the increase of hs-cTnT in this population. The challenge is what is the primary cause of the increased hs-cTnT levels in elderly patients without AMI. OBJECTIVE: The aim of the current study was to determine the impact of aging on hs-cTnT levels in elderly patients without acute cardiac events but in the presence of comorbidities. METHODS: Sociodemographic and clinical data were collected from 6977 medical records of patients aged ≥65 years without acute coronary events but for whom hs-cTnT measurements were available. The patients were stratified based on age, troponin levels and the number of comorbidities. RESULTS: The results suggested that the likelihood of increased hs-cTnT was related to the presence of comorbidities independently of their number (p < 0.05). The adjusted odds ratio (AOR) for both advanced age and having comorbidity was statistically significant, however for the old group (74 ≥ age ≥ 84 years) the chance of having elevated troponin regarding age compared to the presence of comorbidity was 1.070 vs. 1.216, whereas for the old-old group (≥85 years) it was found to be 1.071 vs. 1.311. Besides statistical significance for age, from a clinical standpoint, the AOR of 1.070 may not be considered clinically relevant. CONCLUSION: Increased hs-cTnT levels were associated with the presence of pre-existing comorbidities independently of age. Increased hs-cTnT levels in the elderly should always be considered as pathological, and a specific etiology should be searched.

Effects of AGTR1 A1166C gene polymorphism in patients with heart failure treated with candesartan.

BACKGROUND: The benefits of angiotensin II receptor blockers (ARBs) in patients with heart failure who are treated with standard pharmacotherapy, including an angiotensin-converting enzyme (ACE) inhibitor, were demonstrated in 2 large randomized trials. It is currently impossible to determine which patient will benefit from the addition of an ARB. OBJECTIVE: To explore the impact of selected candidate genes on the hemodynamic, neurohormonal, and antiinflammatory effects of candesartan in patients with heart failure who are already being treated with an ACE inhibitor. METHODS: We investigated the impact of 10 candidate genetic polymorphisms on the effects of candesartan in patients with heart failure who are treated with an ACE inhibitor. We evaluated their impact on acute (2 wk) and long-term (24 wk) changes in blood pressure and N-terminal proB-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) during treatment with candesartan. RESULTS: Thirty-one patients were included. Homozygotes of the AGTR1 A1166 allele (n = 13) had a greater decrease in systolic (-9.1 +/- 4.7 vs 1.1 +/- 3.3 mm Hg; p = 0.04 by analysis of variance [ANOVA], adjusting for dose) and diastolic blood pressure (-5.1 +/- 1.5 vs 1.9 +/- 1.9 mm Hg; p = 0.005 by ANOVA, adjusting for dose) compared with C1166 allele carriers (n = 18) following 2 weeks of treatment. After 6 months of treatment, C1166 carriers experienced a greater decrease in NT-proBNP (-151.4 [-207; -19.8] ng/L vs 147.3 [-61.3; 882.9] ng/L; p = 0.03) and hsCRP (-0.8 [-2.2; -0.03] mg/L) vs 0.2 [-1.8; 5.3] mg/L; p = 0.09) compared with patients carrying the AA1166 genotype. No other significant association was found. CONCLUSIONS: The results of this proof-of concept study provide the first evidence that the AGTR1 A1166C polymorphism could influence the response to candesartan in patients with heart failure who are receiving ACE inhibitors. Validation of these exploratory findings in larger populations is required before use of the AGTR1 A1166C genotype can be incorporated into clinical practice.

A prospective study of the impact of AGTR1 A1166C on the effects of candesartan in patients with heart failure.

AIM: To evaluate the impact of AGTR1 A1166C (rs5186) on the response to candesartan in patients with heart failure. MATERIALS & METHODS: Prospective, multicentre, open-label study. We studied 299 symptomatic patients with heart failure presenting a left ventricular ejection fraction ≤40%. RESULTS: Reductions in the primary end points of natriuretic peptides were not significantly associated with AGTR1 A1166C. Nevertheless, carrying the 1166C allele was associated with a greater compensatory increase in renin activity (p = 0.037) after 16 weeks of treatment with candesartan and a more modest effect on aldosterone concentrations (p = 0.022). CONCLUSION: AGTR1 1166C carriers may experience a greater long-term compensatory renin-angiotensin-aldosterone system activation following treatment with candesartan. Whether these associations ultimately influence clinical outcomes requires investigation. Clinicaltrials.gov : NCT00400582.

Effects of combined candesartan and ACE inhibitors on BNP, markers of inflammation and oxidative stress, and glucose regulation in patients with symptomatic heart failure.

BACKGROUND: We assessed the effects of candesartan in addition to angiotensin-converting enzyme (ACE) inhibitors on N-terminal pro-type natriuretic peptide (Nt-proBNP), systemic markers of inflammation and oxidative stress as well as on glucose regulation in patients with heart failure (HF). METHODS AND RESULTS: Eighty patients with HF ages 62.5 +/- 8.4 years presenting mostly with New York Heart Association class II symptoms (class II = 57.5%, III = 41.3%), and mean left ventricular ejection fraction 27.1 +/- 7.3% were recruited. The patients were randomized to receive candesartan titrated to 32 mg 1 per day versus placebo in double-blind fashion for 6 months. Nt-proBNP, markers of inflammation and oxidative stress, glucose, insulin, and fasting insulin resistance index were analyzed. Candesartan decreased Nt-proBNP (median value = 12.4% versus -20.4%; [candesartan] P = .05), and high-sensitivity C-reactive protein (hsCRP) (+5.32% versus -20.3% [candesartan]; P = 0.046), without significantly influencing serum interleukin-6, interleukin-18, adhesion molecules, or markers of oxidative stress. Blood glucose decreased in patients treated with candesartan with a significantly greater effect in patients with higher blood glucose levels (P < .01 for interaction). CONCLUSIONS: The addition of candesartan to ACE inhibitor and beta-blocker decreases Nt-proBNP and hsCRP, but does not change the other markers of inflammation or oxidative stress in patients with heart failure. Dual angiotensin-II suppression also decreased blood glucose with a greater impact in patients with higher blood glucose level.

Very late transcatheter heart valve thrombosis.

We describe a case of very late transcatheter heart valve (THV) thrombosis of a first-generation SAPIEN prosthesis (Edwards Lifesciences, Irvine, CA) implanted in a 64-year-old woman with severe symptomatic aortic stenosis. More than 54 mo after implantation, she presented with severe symptomatic prosthesis dysfunction (stenosis) which was successfully treated with oral anticoagulation. To our knowledge, this is the tardiest case of THV thrombosis ever reported. This case should increase clinical awareness for THV thrombosis even beyond the first two-year period following implantation.