Hottest developments in the field of cardiology in 2020. Section 3: Heart failure

Interesting developments have shown promise to improve the management of heart failure in 2020. From introducing the arrival of myosin inhibitors in cardiomyopathies to strengthening the role of SGLT inhibitors in heart failure patients, 2020 witnessed exciting results through these trials:

1. EXPLORER-HCM (Mavacamten for Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy) trial

New drug option for obstructive hypertrophic cardiomyopathy.

This Phase III study administered mavacamten, a cardiac myosin inhibitor, or a placebo, to 251 patients with symptomatic obstructive hypertrophic cardiomyopathy for 30 weeks.

Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient, greater increase in pVO2, and improved symptom scores. More patients in the mavacamten group improved by at least one NYHA symptom class.

"The results of this pivotal trial support a role for disease-specific therapy for obstructive hypertrophic cardiomyopathy (HCM) which treats the cause instead of just managing symptoms," said principal investigator Professor Iacopo Olivotto of Careggi University Hospital, Florence, Italy.

Professor Olivotto adds,  "The totality and consistency of the results showed benefit of mavacamten treatment compared to placebo in patients on background HCM therapy. Mavacamten improved functional capacity, LVOT gradient, symptoms, and key aspects of quality of life in patients with obstructive HCM and was generally well tolerated." 

Source: Lancet cardiology: Olivotto I, Oreziak A, et al Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): Lancet. 2020 Sep 12;396(10253):759-769. doi: 10.1016/S0140-6736(20)31792-X. 2020

2. The EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction) trial

Empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFrEF (EF ≤40%) on excellent baseline guideline-directed medical therapy(GDMT), irrespective of diabetes status.

Patients were randomized in a 1:1 fashion to either empagliflozin 10 mg (n = 1,863) or matching placebo (n = 1,867). All the patients were receiving appropriate treatments for heart failure.

The primary outcome, cardiovascular death or HF hospitalization, for empagliflozin vs. placebo, was 19.4% vs. 24.7%  p < 0.001.

Cardiovascular death: 10% vs. 10.8% (HR 0.92, 95% CI 0.75-1.12)

HF hospitalization: 13.2% vs. 18.3% (HR 0.69, 95% CI 0.59-0.81)

The results of this trial indicate that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFrEF (EF ≤40%) on excellent baseline guideline-directed medical therapy (GDMT), irrespective of diabetes status.

a) Benefit is primarily driven by a reduction in HF hospitalizations, not mortality.

b) There was an early and sustained benefit on Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS). There was also a benefit in renal outcomes.

c) This trial mirrors similar findings from the DAPA-HF trial for dapagliflozin.

d) Even patients with severe LV dysfunction appeared to benefit.

Principal investigator Dr. Milton Packer of Baylor University Medical Centre, Dallas, Texas said: "Empagliflozin reduced the risk of serious heart failure events by 30% and decreased the risk of serious adverse renal outcomes by 50%. This trial extends the benefits of SGLT2 inhibitors to higher-risk patients and shows a meaningful benefit on renal outcomes in patients with heart failure for the first time."

Dr. Packer said: "Based on the combined results of our trial (together with the earlier trial with dapagliflozin), we believe that SGLT2 inhibition with empagliflozin and dapagliflozin will now become a new standard of care for patients with heart failure and a reduced ejection fraction."

Source: NEJM: N Engl J Med 2020; 383:1413-1424 DOI: 10.1056/NEJMoa2022190

3. DAPA-CKD (Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease) trial

Dapagliflozin reduces the risk of kidney failure, death from cardiovascular causes or heart failure hospitalization and all-cause mortality in chronic kidney disease patients with or without type 2 diabetes.

Eligible patients were randomized in a 1:1 fashion to either dapagliflozin 10 mg daily (n = 2,152) or placebo (n = 2,152). 

The primary endpoint, decline in eGFR ≥50%, end-stage kidney disease, death from renal causes, or cardiovascular (CV) death for dapagliflozin vs. placebo, was 9.2% vs. 14.5%, hazard ratio (HR) 0.61 (95% confidence interval [CI] 0.51-0.72; p < 0.01).

The benefit of dapagliflozin on the primary endpoint was consistent in patients with and without type 2 DM.

Study author Professor Hiddo J.L. Heerspink of University Medical Centre Groningen, the Netherlands, said: 'DAPACKD showed that dapagliflozin reduced the risk of worsening kidney function or death from cardiovascular or kidney disease in patients with chronic kidney disease with and without type 2 diabetes. The results highlight the medicine's potential to benefit patients with chronic kidney disease who are in need of improved treatment options'.

Source: journal: NEJM: Wheeler DC, Stefansson BV et al The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial Nephrol Dial Transplant. 2020 Oct 1;35(10):1700-1711. doi: 10.1093/ndt/gfaa234.

4. PARALLAX (Angiotensin Receptor Neprilysin Inhibition Compared With Individualized Medical Therapy for Comorbidities in Patients With Heart Failure and Preserved Ejection Fraction) trial

Sacubitril/valsartan reduces NTproBNP, a biomarker predictive of long-term clinical outcomes in heart failure (HF) but does not improve functional capacity compared to individualized background therapy in patients with heart failure with preserved ejection fraction (HFpEF).

Eligible patients were randomized to sacubitril/valsartan (n = 1,286) versus individualized medical therapy (n = 1,286). Patients were assigned to one of three strata: 1) sacubitril/valsartan 93/103 mg twice daily versus enalapril 10 mg twice daily, 2) sacubitril/valsartan 93/103 mg twice daily versus valsartan 160 mg twice daily, or 3) sacubitril/valsartan 93/103 mg twice daily versus placebo.

The primary co-outcome, NT-proBNP change from baseline to week 12, favored sacubitril/valsartan vs. individualized medical therapy (adjusted geometric mean ratio 0.84, p < 0.0001).

The primary co-outcome, 6-minute walk distance change from baseline to week 24, was similar between sacubitril/valsartan vs. individualized medical therapy (adjusted mean difference -2.5, p = 0.24).

Among patients with heart failure due to preserved or mid-range ejection fraction, angiotensin receptor neprilysin inhibition compared with individualized medical therapy was associated with a reduction in NT-proBNP.

However, angiotensin receptor neprilysin inhibition was not associated with improvements in 6-minute walk distance, KCCQ-CSS, or NYHA class. Sacubitril/valsartan compared with individualized medical therapy was associated with a reduction in death or heart failure hospitalization and slowed decline in renal function.

Overall, with these mixed results, sacubitril/valsartan deserves further study in this patient population.

Source: European heart journal: Wachter R, Shah SJ, et al. Angiotensin receptor neprilysin inhibition versus individualized RAAS blockade. ESC Heart Fail. 2020 Jun;7(3):856-864. doi: 10.1002/ehf2.12694.

5. VICTORIA(Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial:

 Vericiguat was superior to placebo at improving heart failure outcomes.

Vericiguat increases soluble guanylate cyclase activity. By stimulating the production of cyclic guanosine monophosphate, may help to improve myocardial and vascular function.

a) In this phase 3, randomized, double-blind, placebo-controlled trial, patients with CHF were randomized to vericiguat (n = 2,526) versus placebo (n = 2,524). Vericiguat started at 2.5 mg daily, increased to 5 mg daily, then 10 mg daily.

Vericiguat compared with placebo was effective at reducing cardiovascular death or hospitalization for heart failure.

b) There was a possible enhanced benefit among patients <75 years of age.

c) There was no apparent reduction in all-cause mortality with vericiguat compared with placebo.

d) Vericiguat was safe and well-tolerated and did not require monitoring of renal function or electrolytes.Vericiguat may represent a novel treatment among patients with recent heart failure decompensation.

Source: NEJM: Armstrong PW, Pieske B, Anstrom KJ, et al., on behalf of the VICTORIA Study Group. Vericiguat in Patients With Heart Failure and Reduced Ejection Fraction. N Engl J Med 2020; 382:1883-93

6. GALACTIC HF (Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure) trial

a) When added to standard therapies, omecamtiv mecarbil—a novel cardiac myosin activator, or myotrope—significantly reduces the combined risk of first heart failure events or CV death in patients with chronic heart failure and reduced ejection fraction (HFrEF).

A total of 781 patients with acute heart failure were randomized to early intensive and sustained vasodilatation (nitrates, hydralazine, angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker, sacubitril/valsartan) vs. standard of care. Both groups received loop diuretics, beta-blockers, aldosterone antagonists, cardiac devices, and routine follow-up.

b)The primary outcome, death or acute heart failure rehospitalization at 180 days, occurred at a similar frequency between groups (hazard ratio 1.07, p = 0.59). The benefit was modest, with an absolute reduction of 2.1% and a relative reduction of 8% over a median follow-up of about 22 months.

c) Also, there was no significant benefit of omecamtiv on either of the components of the primary composite endpoint when considered individually.

d) Nevertheless, "for the first time, these results confirm the hypothesis that selectively increasing cardiac function with a cardiac myosin activator such as omecamtiv mecarbil can improve clinical outcomes in patients with heart failure and reduced ejection fraction," John Teerlink, MD (University of California, San Francisco), chair of the trial's executive committee, reported during the virtual American Heart Association (AHA) 2020 Scientific Sessions.

Source: NEJM: DOI: 10.1056/NEJMoa2025797