The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared outcomes in patients receiving ARNI therapy to those receiving enalapril.26 The authors stopped the trial early due to the overwhelming benefit seen in the ARNI arm.
After a median follow-up of 27 months, the researchers found a reduction in the primary outcomes of either cardiovascular death or first hospitalization for HF (26.5% in the enalapril-treated group vs 21.8% in the ARNI-treated group; NNT=21).26 There were slightly more cases of angioedema in the ARNI arm than in the enalapril arm (0.5% vs 0.2%), although there were no patients in the trial who required endotracheal intubation.26
Because of this increased risk, do not prescribe ARNI therapy for any patient with a history of angioedema.6 Hypotension was more common in the ARNI-treated group than in the enalapril group (14% vs 9.2%), but there were lower rates of hyperkalemia, elevated serum creatinine, and cough in the ARNI-treated group than in the enalapril group.26
Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker. Do not administer ARNI therapy concomitantly with an ACE inhibitor or ARB. When switching, do not start ARNI therapy for at least 36 hours after the last dose of an ACE inhibitor or ARB.6
Ivabradine is a sinoatrial node modulator that provides additional heart rate reduction. It does not affect ventricular repolarization or myocardial contractility.27 Early trials with this medication have shown reduced cardiac mortality and an NNT to prevent one first HF hospitalization within one year of 27.28 Adverse effects include symptomatic and asymptomatic bradycardia and luminous phenomena.28
Recommend ivabradine as add-on therapy to all patients with an EF ≤35%, normal sinus rhythm, and resting heart rate ≥70 bpm who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.6 The dose is adjusted to achieve a resting heart rate of 50 to 60 bpm.27
Nonpharmacologic options
Implantable cardioverter defibrillators (ICDs) are recommended as primary prevention in select HFrEF patients to reduce the risk of sudden cardiac death and all-cause mortality. The 2013 American College of Cardiology Foundation/AHA Guideline for the Management of Heart Failure recommends an ICD for primary prevention for: 1) patients with symptomatic HF and an LVEF ≤35% despite ≥3 months of optimal medical therapy, and 2) patients at least 40 days post-MI with an LVEF of ≤30%.5,29 ICDs are not recommended for patients who have a life expectancy of less than one year, and the devices are of unclear benefit for patients ≥75 years of age.5
Cardiac resynchronization therapy (CRT), although not new to the field of cardiology, is new to the treatment of heart failure. A number of patients with HFrEF have QRS prolongation and in particular, left bundle branch block (LBBB).5 CRT uses biventricular pacing to restore synchronous contraction of the left and right ventricles.30 It is strongly recommended for patients with an EF ≤35%, sinus rhythm, LBBB, QRS ≥150 ms, and a life expectancy of at least one year.5,7 It is weakly recommended for patients with an EF ≤35% and a QRS ≥150 ms but without LBBB. It’s also weakly recommended for patients with an EF ≤35% and LBBB with a QRS of 120 to 150 ms.5,31
Left ventricular assist devices (LVADs) and cardiac transplantation are considerations for patients with severe symptoms refractory to all other interventions.5 LVADs may be used either while awaiting cardiac transplantation (bridge therapy) or as definitive treatment (destination therapy). Appropriate patient selection for such therapies requires a team of experts that ideally includes HF and transplantation cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians.5
Treatment of HFpEF: Evidence is lacking
While HFpEF is common—affecting about half of all patients with HF—ideal treatment remains unclear.32 Some trials have shown promise, but to date no unequivocal evidence exists that any standard therapy reduces mortality in patients with HFpEF.33-37 Underlying mechanisms of action of HFpEF include cardiac rate and rhythm abnormalities, atrial dysfunction, and stiffening of the ventricles. In a sense, it represents an exaggerated expression of the pathophysiology seen with the normal aging of the heart and can be conceptualized as “presbycardia.”37 Indeed, HFpEF is more common in the elderly, but it is also more common in patients of African descent.38,39 Common contributing causes (which we’ll get to in a bit) include HTN, CAD, atrial fibrillation (AF), obesity, and obstructive sleep apnea (OSA).
Trials have failed to show clear benefit for ACE inhibitors, ARBs, or beta-blockers.7,33 The evidence for MRAs is somewhat unclear; however, they have recently been recommended as an option for patients who have been hospitalized in the last year to reduce the risk of subsequent hospitalizations.40 Digoxin is used primarily for rate control in the setting of AF, but otherwise is of unclear benefit.7 A low-sodium diet (ie, ≤2 g/d) may be useful in those patients who are prone to fluid overload.5,7 The cornerstone of treatment of HFpEF is the relief of volume overload with diuretics and the treatment of coexisting conditions.33