Han Naung Tun
Heart and Vascular Centre, Victoria Hospital, Yangon, Myanmar
Correspondence to [email protected]
Disclosure: The author has declared no conflicts of interest.
THE European Society of Cardiology (ESC) Congress 2020 presented several promising clinical trials that may potentially change our practice in heart failure management. Among the trials and studies reported on, I am going to evaluate the most important heart failure studies that may change our practice. What does the future look like for heart failure management?
EMPEROR-Reduced Trial
In the EMPEROR-Reduced trial, outcomes of empagliflozin treatment in patients with chronic heart failure with reduced ejection fraction (HFrEF) were observed. A total of 3,730 patients with HFrEF were randomised to receive empagliflozin (1,863 patients) or placebo (1,867 patients), as well as appropriate background medical therapy with diuretics, inhibitors of the renin–angiotensin system and neprilysin, β-blockers, mineralocorticoid receptor antagonists, and cardiac devices (when indicated). The trial included an equal number of patients with and without diabetes.
About 73% of patients had left ventricular ejection fraction ≤30% and had N-terminal pro B-type natriuretic peptide (NT-proBNP) levels of ≥1,000 pg/mL, compared to 79% in the DAPA-HF trial. The primary composite outcome of death from cardiovascular causes or hospitalisation for heart failure occurred in 361 patients (19.4%) in the empagliflozin group, compared to 462 (24.7%) in the placebo group (hazard ratio [HR]: 0.75). The rate of the decline in the estimated glomerular filtration rate over the duration of the double-blind treatment period was slower in the empagliflozin group than in the placebo group.1
In DAPA-HF, there were also a relatively small number of renal events over 18 months of follow-up; dapagliflozin had no significant impact on worsening renal function compared to placebo, whereas use of empagliflozin yielded significant renal protection.2 In terms of the bigger picture, in EMPEROR-Reduced renal death was reduced by 50% by empagliflozin (statistically significant), but no such benefit with dapagliflozin in DAPA-HF was observed (29%, not statistically significant). Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalisation for heart failure than those in the placebo group, regardless of the presence or absence of diabetes.1,2
Explorer-HCM
In the clinical study to evaluate mavacamten (MYK-461) in adults with symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM), a total of 251 patients received once daily mavacamten or placebo for 30 weeks.3 Mavacamten is a first-in-class cardiac myosin inhibitor for treatment of symptomatic obstructive hypertrophic cardiomyopathy. The primary composite endpoint of mavacamten at Week 30 was assessed relative to placebo on both symptoms and cardiac function. Results showed a ≥1.5 mL/kg/min improvement in peak oxygen consumption and ≥1 New York Heart Association (NYHA) class reduction, or a ≥3.0 mL/kg/min improvement in peak oxygen consumption and no worsening of NYHA class. The assessed secondary endpoints were the change from baseline to Week 30 in post-exercise left ventricular outflow tract gradient, and patient-reported outcomes such as the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and the HCM Symptom Questionnaire-Shortness-of-Breath (HCMSQ-SoB) subscore.
Results showed 45 (36.6%) patients on mavacamten met the primary composite endpoint at Week 30 compared to 22 (17.2%) patients on placebo (p=0.0005). All secondary endpoints, including post-exercise left ventricular outflow tract gradient and patient-reported outcomes, also demonstrated statistically significant improvements for mavacamten compared to placebo (all p<0.0006). No significant differences in safety and tolerability were observed with mavacamten versus placebo.4 EXPLORER-HCM concluded that mavacamten treatment may represent a new era of targeted drug development in hypertrophic obstructive cardiomyopathy.
PARALLAX Trial
PARALLAX was a large randomised, double-blind, controlled study, comparing sacubitril/valsartan to medical therapy for comorbidities in patients with heart failure with preserved ejection fraction (HFpEF). It was designed to compare the action of sacubitril/valsartan with individualised medical therapy (IMT), e.g., the angiotensin-converting-enzyme inhibitor enalapril, the angiotensin II receptor blocker valsartan, or placebo, for reducing NT-proBNP and improving exercise capacity and heart failure symptoms in patients with HFpEF. In this multicentre trial, the mean left ventricular ejection fraction at baseline was 56%. The primary trial endpoints were assigned to the change from baseline to 12 weeks in plasma NT-proBNP, and to the change in 6-minute walk distance from baseline to 24 weeks.5
Overall results found that patients treated with sacubitril/valsartan showed a significant 16.4% greater reduction in NT-proBNP compared to patients treated with optimal IMT, after 12 weeks (p<0.0001). However, there was no significant difference between groups in terms of improvement in the 6-minute walk distance at 24 weeks. Both groups saw improvements compared to baseline (mean change: 9.7 m in the sacubitril/valsartan group and 12.2 m in the IMT group). It was concluded that the combination therapy had no additional benefits on NYHA class from baseline to Week 24 (odds ratio: 1.01 for study drug versus IMT; 95% confidence interval [CI]: 0.75–1.37; p=0.93).5
Secondary endpoints included NYHA functional class and change from baseline to 24 weeks in quality of life (measured by the KCCQ). PARALLAX showed that quality of life improved in both groups but was higher with sacubitril/valsartan compared to the comparator at Week 4. Patients in the sacubitril/valsartan group also had a significantly lower decline in renal function (estimated glomerular filtration rate) at 24 weeks. However, there was no difference between groups in NYHA class at Week 24.
Because of the complexity and heterogeneity of HFpEF, sacubitril/valsartan could potentially be useful in select groups, such as females, patients who are not tolerating other diuretics, and those with recurrent heart failure admissions.
DAPA-CKD Trial
In this positive outcome study on dapagliflozin, patients were randomly allocated to dapagliflozin 10 mg once daily or placebo once daily, alongside standard of care (ACE inhibitor or ARB). Average age was 61.8 years, 66.9% were male, and 67.5% had Type 2 diabetes mellitus. Patient check-ins were set at 2 weeks, 2 months, and 4 months, and then every 4 months until the study ended; a 6-week checkout process concluded the study. The primary composite endpoint was worsening kidney function, onset of end-stage kidney disease, or death caused by kidney disease or cardiovascular disease.6
During a median follow-up of 2.4 years, there were 197 primary endpoint events with dapagliflozin and 312 with placebo. The HR for the primary endpoint was 0.61 (95% CI: 0.51–0.72; p=0.000000028). The benefit of dapagliflozin on the primary endpoint was consistent in patients with and without Type 2 diabetes mellitus. Dapagliflozin reduced all three secondary endpoints, compared to placebo, for first hospitalisation caused by heart failure (HR: 0.49; 95% CI: 0.30–0.81; p=0.005) and composite of time to death caused by cardiac or heart failure, or hospitalisation (HR: 0.64; 95% CI: 0.42–0.97; p=0.034). Secondary endpoints included worsening kidney function or death from kidney failure, heart failure hospitalisation or cardiovascular death, and all-cause mortality. Median follow-up was 2.4 years.6 DAPA-CKD showed that dapagliflozin reduced the risk of worsening kidney function or death from cardiovascular or kidney disease in patients with chronic kidney disease, with or without Type 2 diabetes mellitus.
In summary, heart failure trials presented at the ESC Congress 2020 (Table 1) brought a lot of promise to changes in clinical practice of heart failure management. I do hope that these studies of sodium-glucose cotransporter-2 (SGLT2) inhibitors support it to become one of the standard-of-care therapies, on top of appropriate background medical therapies in patients with HFrEF and HFpEF.
Table 1: Summary of heart failure trials.
| Trial | Topics of Focus | Result |
| EMPORER-Reduced | Heart failure, empagliflozin | Empagliflozin reduced risk of CV death or hospitalisation in patients with HFrEF, whether or not they had DM |
| EXPLORER-HCM | Obstrcutive HCM | Mavacamtem, a first-class cardiac myosin activator, improved heart function and symptoms in patients with HOCM |
| PARALLAX | HFpEF | In patients with HFpEF, sacubitril/valsartan (ARNI) lowered NT-proBNP and decline in renal function, but did not improve functional capacity compare to OMT |
| DAPA-CKD | Dapagliflozin in CKD | In patients with CKD, dapagliflozin significantly reduced kidney failure risk, death from CV causes, HF hospitalisations, and all-cause mortality |
ARNI: angiotensin receptor neprilysin inhibitor; CV: cardiovascular; CKD: chronic kidney disease; DM: diabetes mellitus; HCM: hypertrophic cardiomyopathy; HF: heart failure; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; HOCM: hypertrophic obstructive cardiomyopathy; NT-proBNP: N-terminal pro B-type natriuretic peptide; OMT: optimal medical therapy.
References
1.Packer M et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;DOI:10.1056/NEJMoa2022190.
2.John JV et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995-2008.
3.Ho C et al. Study design and rationale of EXPLORER-HCM, evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. Circulation. 2020;13(6):DOI:10.1161/CIRCHEARTFAILURE.120.006853.
4.Olivotto I et al. EXPLORER-HCM: Efficacy and safety of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. Session at ESC Congress 2020, 29 August, 2020.
5.PieskeB et al. Hotline PARALLAX. Session at ESC Congress 2020, 30 August, 2020.
6.Heerspink HJL et al. Hot Line DAPA-CKD. Session at ESC Congress 2020, 30 August, 2020.
