Stroke Volume

Contrary to prior recommendations, it looks like surgical repair of severely stenotic aortic valves produces better results when done early. James W. Mold, MD, MPH

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Background and aims: The question of when and how to treat truly asymptomatic patients with severe aortic stenosis (AS) and normal left ventricular (LV) systolic function is still subject to debate and ongoing research. Here, the results of extended follow-up of the AVATAR trial are reported (NCT02436655, clinical trials.gov).

Methods: The AVATAR trial randomly assigned patients with severe, asymptomatic AS and LV ejection fraction ≥50% to undergo either early surgical aortic valve replacement (AVR) or conservative treatment with watchful waiting strategy. All patients had negative exercise stress testing. The primary hypothesis was that early AVR will reduce a primary composite endpoint comprising all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure (HF), as compared to conservative treatment strategy.

Results: A total of 157 low-risk patients (mean age 67 years, 57% men, mean Society of Thoracic Surgeons score 1.7%) were randomly allocated to either early AVR group (n=78) or conservative treatment group (n=79). In an intention-to-treat analysis, after a median follow-up of 63 months, the primary composite endpoint outcome event occurred in 18/78 patients (23.1%) in the early surgery group and in 37/79 patients (46.8%) in the conservative treatment group (hazard ratio [HR] early surgery vs. conservative treatment 0.42; 95% confidence interval [CI] 0.24-0.73, p=0.002). The Kaplan-Meier estimates for individual endpoints of all-cause death and HF hospitalization were significantly lower in the early surgery compared with the conservative group (HR 0.44; 95% CI 0.23-0.85, p=0.012 for all-cause death, and HR 0.21; 95% CI 0.06-0.73, p=0.007 for HF hospitalizations).

Conclusions: The extended follow-up of the AVATAR trial demonstrates better clinical outcomes with early surgical AVR in truly asymptomatic patients with severe AS and normal LV ejection fraction compared with patients treated with conservative management on watchful waiting.

Author/s:

Marko Banovic, Svetozar Putnik, Bruno R Da Costa, Martin Penicka, Marek A Deja, Martin Kotrc

Estimating Lifetime Benefits of Comprehensive Disease-Modifying Pharmacological Therapies in Patients With Heart Failure With Reduced Ejection Fraction: A Comparative Analysis of Three Randomised Controlled Trials

John Bayhi — Tue, 26 May 2020 20:29:33 +0000

Date Added:

May 26, 2020

Journal/Publication:

Lancet

Publisher:

Elsevier Ltd

Publication Date:

May 21, 2020

Volume:

Online ahead of print

URL:

Estimating Lifetime Benefits of Comprehensive Disease-Modifying Pharmacological Therapies in Patients With Heart Failure With Reduced Ejection Fraction: A Comparative Analysis of Three Randomised Controlled Trials

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1016/S0140-6736(20)30748-0

Keywords

CHF patients

heart failure

pharmacologic management

PMID (1):

32446323

MeSH

Humans

Angiotensin Receptor Antagonists

Mineralocorticoid Receptor Antagonists

Angiotensin-Converting Enzyme Inhibitors

Sodium-Glucose Transporter 2 Inhibitors

Peptidyl-Dipeptidase A

Neprilysin

heart failure

SLC5A2 protein, human

sodium-glucose transporter 2

Stroke Volume

Control Groups

Receptors, Drug

Progression-Free Survival

Receptors, Angiotensin

NR3C2 protein, human

For those of you who still initiate and manage CHF with reduced LV ejection fraction, this meta-analysis appears to support using combinations of the following five agents: 1) an ACEI or ARB, 2) a beta-blocker, 3) a mineralocorticoid receptor antagonist [MRA], 4) an angiotensin receptor–neprilysin inhibitor [ARNI], and 5) a sodium/glucose cotransporter 2 [SGLT2] inhibitor. They estimate that combined therapy could increase life expectancy for an 80-year-old 1.4 years and for a 55-year-old 6.3 years. If we are going to continue to manage these patients, it looks like we are going to have to develop specific CHF visits and protocols like those used in CHF clinics run by cardiology teams. James W. Mold, MD, MPH

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Background: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF.

Methods: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker).

Findings: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy.

Interpretation: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.

Funding: None.

Author/s:

Vaduganathan, M., Claggett, BL, Jhund, PS, Cunningham, JW, Ferreira, JP, Zannad, F, Packer, M, Fonarow, GC, McMurray, JJV, Solomon, S.D.

Meta-Analysis Evaluating the Effects of Renin-Angiotensin-Aldosterone System Blockade on Outcomes of Heart Failure With Preserved Ejection Fraction

John Bayhi — Sat, 14 Mar 2020 20:03:18 +0000

Date Added:

March 14, 2020

Journal/Publication:

The American Journal of Cardiology

Publisher:

Elsevier Inc.

Publication Date:

January 30, 2020

URL:

Meta-Analysis Evaluating the Effects of Renin-Angiotensin-Aldosterone System Blockade on Outcomes of Heart Failure With Preserved Ejection Fraction

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1016/j.amjcard.2020.01.009

Keywords

RAAS Anatgonists

heart failure

PMID (1):

32081366

ACEIs, ARBs, and spironolactone do not appear to reduce mortality or CHF hospitalizations in patients with CHF with preserved LV function. However, the combination of sacubitril (a neprilysin inhibitor) and valsartan may reduce CHF hospitalizations in those patients. James W. Mold, MD, MPH

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Clinical trials of renin-angiotensin-aldosterone system (RAAS) antagonists in heart failure with preserved ejection fraction (HFpEF) have suggested neutral results and treatment is focused on associated symptoms and comorbidities. MEDLINE and EMBASE were searched through October 2019 for randomized controlled studies investigating the effects of different RAAS antagonists in patients with HFpEF. The main outcomes were all-cause mortality, trial defined cardiovascular mortality, and heart failure (HF) hospitalizations. To compare different RAAS antagonists, a random-effects restricted-maximum-likelihood network meta-analysis based on a frequentist framework for indirect and mixed comparisons was used. We used p scores to rank best treatments per outcome. Our search identified 5 eligible clinical trials (PEP-CHF, perindopril; CHARM-preserved, candesartan; I-PRESERVE, irbesartan; TOPCAT, spironolactone; PARAGON-HF, sacubitril-valsartan and valsartan) enrolling a total 10,523 on RAAS antagonists and 6,259 controls. We did not identify any statistical difference in all-cause and cardiovascular mortality among RAAS antagonists and placebo. The combination of sacubitril-valsartan was associated with significantly decreased HF hospitalization risk compared with controls (odds ratio 0.73, 95% confidence interval 0.61 to 0.87) and angiotensin II receptor blockers (odds ratio 0.80, 95% confidence interval 0.71 to 0.91), without heterogeneity among studies (I2 = 0). Angiotensin receptor neprilysin inhibitor (ARNI) ranked better than other RAAS antagonists for HF hospitalizations (p value 0.9). In conclusion, RAAS antagonists do not affect mortality but the combination of sacubitril-valsartan is associated with lower HF hospitalizations in HFpEF patients.

Author/s:

Kuno, T, Ueyama, H, Fujisaki, T, Briasouli, A, Takagi, H, Briasoulis, A

Management of Heart Failure in 2019-2020, Part 1

Brian Desmarais — Fri, 03 Jan 2020 21:01:21 +0000

Date Added:

January 3, 2020

Journal/Publication:

JN Learning

Publisher:

JAMA

Publication Date:

September 1, 2016

URL:

Management of Heart Failure in 2019-2020, Part 1

Type:

Clinical Research Results

Format:

Video

Keywords

MeSH

Ventricular Remodeling

Aminobutyrates

Tetrazoles

Valsartan

This 16 min audiotape reviews the results of recent studies indicating that systolic CHF patients benefit from blocking an additional compensatory pathway, the neprilysin pathway, with the combination agent, sacubitril-valsartin if they remain symptomatic on an ACEI or ARB. James W. Mold, MD, MPH

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Educational Objective
To understand the effects of sacubitril-valsartan vs enalapril on proximal aortic stiffness, cardiac remodeling, and cardiac contractile function among patients with heart failure with reduced ejection fraction (HFrEF).

Author/s:

Desai, A.

Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study

Brian Desmarais — Sat, 24 Aug 2019 19:20:10 +0000

Date Added:

August 24, 2019

Journal/Publication:

The Lancet

Publication Date:

August 22, 2019

URL:

Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study

Type:

Clinical Research Results

Format:

Article

DOI (1):

https://doi.org/10.1016/S0140-6736(19)31792-1

Keywords

Cardiology

Vascular medicine

MeSH

ventricular dysfunction, left

Peptidyl-Dipeptidase A

Angiotensin-Converting Enzyme Inhibitors

Angiotensin Receptor Antagonists

It appears, from this analysis of a large clinical trial, that women with CHF need only half the doses of ACEs, ARBs, and beta blockers that men do to achieve the same benefits. James W. Mold, MD, MPH

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Summary

Background

Guideline-recommended doses of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), and β blockers are similar for men and women with heart failure with reduced ejection fraction (HFrEF), even though there are known sex differences in pharmacokinetics of these drugs. We hypothesised that there might be sex differences in the optimal dose of ACE inhibitors or ARBs and β blockers in patients with HFrEF.

Methods

We did a post-hoc analysis of BIOSTAT-CHF, a prospective study in 11 European countries of patients with heart failure in whom initiation and up-titration of ACE inhibitors or ARBs and β blockers was encouraged by protocol. We included only patients with left ventricular ejection fraction less than 40%, and excluded those who died within the first 3 months. Primary outcome was a composite of time to all-cause mortality or hospitalisation for heart failure. Findings were validated in ASIAN-HF, an independent cohort of 3539 men and 961 women with HFrEF.

Findings

Among 1308 men and 402 women with HFrEF from BIOSTAT-CHF, women were older (74 [12] years vs 70 [12] years, p<0·0001) and had lower bodyweights (72 [16] kg vs 85 [18] kg, p<0·0001) and heights (162 [7] cm vs 174 [8] cm, p<0·0001) than did men, although body-mass index did not differ significantly. A similar number of men and women reached guideline-recommended target doses of ACE inhibitors or ARBs (99 [25%] vs 304 [23%], p=0·61) and β blockers (57 [14%] vs 168 [13%], p=0·54). In men, the lowest hazards of death or hospitalisation for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and β blockers, but women showed approximately 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels. These sex differences were still present after adjusting for clinical covariates, including age and body surface area. In the ASIAN-HF registry, similar patterns were observed for both ACE inhibitors or ARBs and β blockers, with women having approximately 30% lower risk at 50% of the recommended doses, with no further benefit at higher dose levels.

Interpretation

This study suggests that women with HFrEF might need lower doses of ACE inhibitors or ARBs and β blockers than men, and brings into question what the true optimal medical therapy is for women versus men.

Funding

European Commission.

Author/s:

Santema, B.T., Ouwerkerk, W., Tromp, J., Sama, I.E., Ravera, A., Regitz-Zagrosek, V.

Primary Prevention of Sudden Cardiac Death

Brian Desmarais — Wed, 19 Jun 2019 00:11:44 +0000

Date Added:

June 18, 2019

Journal/Publication:

Journal of the American Medical Association

Publisher:

Journal of the American Medical Association

Publication Date:

June 13, 2019

URL:

Primary Prevention of Sudden Cardiac Death

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2019.7662

Keywords

MeSH

Angiotensin-Converting Enzyme Inhibitors

Mineralocorticoid Receptor Antagonists

myocardial infarction

Receptors, Angiotensin

Death, Sudden, Cardiac

Angiotensin Receptor Antagonists

This is the most recent AHA/ACC guideline regarding how to reduce the risk of sudden cardiac death in those at risk.

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In patients with heart failure with reduced ejection fraction (<40%), guideline-directed medical therapy (GDMT) is recommended to reduce sudden cardiac death and all-cause mortality; GDMT includes β-blockers; mineralocorticoid receptor antagonists; and angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor–neprilysin inhibitors (class I, level A recommendation).
In patients with left ventricular ejection fraction (LVEF) of 35% or less due to ischemic heart disease at least 40 days after myocardial infarction, at least 90 days after revascularization, and with New York Heart Association (NYHA) class II or III heart failure despite GDMT, an ICD is recommended if expected survival is greater than 1 year (class I, level A recommendation).
In patients with LVEF of 30% or less due to ischemic heart disease at least 40 days after myocardial infarction, at least 90 days after revascularization, and with NYHA class I heart failure symptoms despite GDMT, an ICD is recommended if expected survival is greater than 1 year (class I, level A recommendation).
In patients with nonischemic cardiomyopathy, NYHA class II to III symptoms, and LVEF of 35% or less despite GDMT, an ICD is recommended if expected survival is greater than 1 year (class I, level A recommendation).

Author/s:

Beaser, A.D., Cifu, A.S.