Gaps in Pharmacological Therapy
Substantial progress has been made in pharmacological therapy for HF with reduced ejection fraction (HFrEF) including angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers and aldosterone antagonists, and novel agents continue to be developed. However, uncertainty remains with some of the oldest class of drugs. The vasodilator combination hydralazine and isosorbide dinitrate (H-ISDN) is the first therapy proven in a RCT to improve outcome in HFrEF. The initial Vasodilator-Heart Failure Trial 1 (V-HeFT I) showed 28 % mortality reduction compared with placebo, although this finding only reached borderline statistical significance (p=0.053).4 The follow-up V-HeFT II actually showed 28.2 % higher mortality with H-ISDN when compared with enalapril (p=0.016).5 Definitive mortality benefit of H-ISDN was finally established with the subsequent African-American Heart Failure Trial (A-HeFT) that enrolled self-identified African Americans with symptomatic HFrEF who were already on modern GDMT.6 The study terminated early as the H-ISDN arm showed 43 % decrease in all-cause mortality (p=0.01) and 33 % reduction in rate of hospitalisation (p=0.001) compared with placebo. However, the role of H-ISDN in non-African American patients with HFrEF in the modern era remains uncertain and warrants further research. The ESC Guideline currently gives H-ISDN an equivocal recommendation of Class IIb/LOE B in patients with HFrEF. The ACC/ AHAF Guideline recognises the differential treatment effect and gives H-ISDN Class I/LOE A in African Americans with HFrEF and Class IIa/ LOE B in other patients with HFrEF who cannot tolerate ACE inhibitor or angiotensin receptor blocker (ARB).
The use of digoxin, the oldest compound in cardiovascular medicine, declined after the disappointing Digitalis Investigation Group (DIG) trial, which showed a 28 % reduction in hospitalisations (p<0.001) but no difference in mortality.7,8 This trial, however, was done in an era where the current GDMT and device therapy were not commonly part of background therapy. Subsequent meta-analysis, retrospective studies and post-hoc analysis of more contemporary clinical databases have yielded conflicting conclusions, suggesting potential benefit as well as harm.9–13 Prospective RCT data would help clarify the role of digoxin in modern clinical practice in HFrEF with and without atrial fibrillation (AF).
The benefit of anticoagulation for stroke prevention in patients with AF is well established. However, in patients with very depressed ejection fraction (EF) who are at risk for intracardiac thrombi, anticoagulation has not been shown to be beneficial. Two RCTs of patients with HFrEF in sinus rhythm showed no clinical benefit and increased bleeding with warfarin when compared with aspirin.14,15 Given the improved safety and efficacy of the new oral anticoagulants (dabigatran, apixaban and rivaroxaban), these agents should be studied in subsets of patients with HFrEF in sinus rhythm that are at highest risk for thromboembolism.
Newer agents, ivabradine, aliskiren and LCZ696, are still establishing their roles in HF. The ESC Guideline gives ivabradine a Class IIa/LOE B recommendation in patients with symptomatic HFrEF and heart rate >70 beats per minute (BPM) based on the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), which showed 26 % decrease in HF hospitalisations (p<0.0001) and a previous trial, which established its safety.16,17 In the US, ivabradine is still awaiting US Food and Drug Administration (FDA) approval and has not received formal recommendation in the ACCF/AHA Guideline. Aliskiren is a novel agent that targets the renin–angiotensin–aldosterone system (RAAS) to reduce blood pressure. The Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) investigated aliskiren in patients with HFrEF and acute decompensated heart failure (ADHF). It showed increased rates of adverse effects, such as hyperkalaemia (relative risk [RR] 1.19 [0.98–1.46]), hypotension (RR 1.36 [1.07–1.72]) and renal failure (RR 1.37 [1.08–1.75]) in the aliskiren arm without benefit in mortality or hospitalisation.18 An ongoing RCT is investigating the role of aliskiren or aliskiren/enalapril combination in patients with chronic HFrEF (NCT00853658). Aliskiren has not received formal recommendation by the ACCF/AHA or ESC guidelines and its role in HF appears uncertain. In contrast to this is LCZ696, a novel dual-acting angiotensin receptor–neprilysin inhibitor (ARNI), which has the potential to shift the foundation of HFrEF therapy. The recent Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial was stopped early with LCZ696 demonstrating significant reduction in all-cause mortality (hazard ratio [HR] 0.84, 95 % confidence interval [CI] 0.76–0.93) and HF hospitalisations (HR 0.79, 95 % CI 0.71–0.89) as well as improvement in quality of life compared with enalapril.19 Based on these findings, we anticipate expedited approval of LCZ696 by both US and European regulatory agencies, and the addition of ARNI in the next ESC and ACCF/AHA Guideline update.