Clyde Yancey (US) presented the 2016 focused update of the ACC/AHA practice guidelines for heart failure, which included new epidemiological data. The prevalence of heart failure was 6.5 million between 2011 and 2014, which was a 14% increase from the data obtained between 2009 and 2012. However, the age and sex-adjusted incidence decreased by 37.5%. The 5-year survival from heart failure post-Ml improved by 7% in the 2001 to 2010 interval versus the 1990 to 2000 interval (61% from 54%). While the lifetime risk of heart failure has diminished, hospitalizations have increased (34%), although these hospitalizations were due predominantly to noncardiac causes (63%). The risk of cardiovascular death was lower for HFPEF than for HFREF, but it was the same as the risk of noncardiovascular death. 

The updated guidelines emphasize the need to respond with evidence-based therapies for natural history improvement. These therapies all are supported by RCTs and now include an ACE inhibitor or ARB, which can be replaced with an ARNI in appropriate patients, supplemented by an MRA, a B-blocker, and, in appropriately selected patients in whom the heart rate is not adequately controlled with a B-blocker alone, by the addition of ivabradine. In addition, in African-American patients who remain symptomatic on these therapies (despite an adjunctive diuretic), a combination of hydralazine and isosorbide dinitrate is valuable. Evidence indicates that, at recommended doses, treating between 7 and 26 patients (depending on the drug) can be expected to reduce mortality and/or heart failure hospitalizations by one event. Finally, in patients with HFREF, a biomarker response (specifically BNP) may predict the best outcomes, although this has not yet been rigorously demonstrated.

The changes in recommended therapies since the last update to the guidelines all relate to chronic stable HFREF, and, inappropriately defined patients, including replacing the ACE inhibitor or ARB with an ARNI, administering ARNI in conjunction with B-blockers and adding ivabradine to ACE inhibitors or ARBs plus a B-blocker.

Tracy E. Macaulay (US) discussed dose selection, responding to the question, "how much is too much?" She illustrated her concerns with the effects of therapy on BP, where the issues are the clearest. Macauley cited three trials (MOCHA, HF-ACTION, and CIBIS-ELD) that demonstrated dose-related improvements in outcomes to support slow titration of B-blockers to the peak doses achieved in the trials. Support for a similar strategy with ACE inhibitors/ARBS/ARNIs was inferred from the results of the ATLAS, HEAAL, NETWORK, and PARADIGM-HF trials, but these can be interpreted as supporting preferential titration of B-blocker therapy first. However, the potential downside of dose titration to the maximal targets includes adverse drug effects; thus, this strategy requires more frequent patient monitoring. Hypotension, hyperkalemia, and fluid imbalance are among the most prominent adverse effects. In addition, polypharmacy, defined as taking six or more concurrent medications, makes it likely that at least one of the drugs is inappropriate, though selecting the inappropriate drug might be insolubly challenging. Finally, complicated regimens that involve high pill burden and costs can decrease adherence to the prescribed, evidence-based regimen, resulting in sub-optimal outcomes. Indeed, patients receiving two drugs or less are twice as likely to be adherent than are patients on six or more.

The potential for an overdose and achieving less than optimal outcomes is best illustrated with relation to the effects of drugs on BP. In large RCTs for heart failure, patients with severe heart failure, low BP, and a low heart rate were largely excluded from evaluation and many dose combinations were not studied. Nonetheless, several trials suggest that outcomes can be adversely affected if the BP is reduced below a certain level. In the LIFE trial, among patients with hypertension and left ventricular hypertrophy, a systolic BP <130 mm Hg increased the risk of and left ventricular hypertrophy, a systolic BP <130 mm Hg increased the risk of death (HR, 1.29) compared with subjects with a systolic BP ≥130 mm Hg. Similarly, among patients with HFREF in the DIG trial, an LVEF <30% increased cardiovascular and heart failure mortality as the BP decreased (HR, 1.15 and 1.30, respectively). Consistent with these observations, the BEST study showed that, in patients with severe HFREF, a systolic BP <120 mm Hg was an independent predictor of poor outcomes (HR. 1.33). To minimize the adverse effects, Macauley suggested: first. assembling a complete medication list (over-the-counter and herbal medications, inhalers, etc); second, assessing adherence to the prescribed regimen (eg, the Morisky scale for drug adherence); third, identifying and remedying adherence barriers (eg, using relatively longer acting-drugs to reduce daily pill burden); and fourth, engaging the patient in their treatment through education. The resulting Comprehensive Medication Management Plan must include the patient's primary physician and other specialists to ensure that there is an agreement on minimal therapy, individualized therapy, and monitoring based on the patient's goals, preferences, and other disease states, and to provide patients and caregivers with an updated medication list after each visit. Macauley suggests using slow and diligent dose titration, increasing monitoring frequency in high-risk patients, and recognizing that not all patients will tolerate maximum or target doses. The best results are likely to be obtained if the clinician discusses the possible adverse drug effects and titration schedules that may be expected. 

Finn Gustafsson (DK) discussed the therapeutic role of lowering heart rate, focusing on data from studies using ivabradine, a pure heart rate-lowering drug with no direct effects on vascular tone, inotropy, or electrolyte and fluid metabolism. The pharmacological effect of ivabradine involves blocking the hyperpolarization-activated cyclic nucleotide-gated channels in the sinoatrial node. Ivabradine was approved in the US in 2015 specifically to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic, chronic heart failure with an LVEF ≤35%, who are in sinus rhythm with a resting heart rate ≥70 bpm while taking maximally tolerated doses of B-blockers or for whom B-blockers are contraindicated. The drug had been approved previously in Europe and elsewhere for patients with heart failure to reduce mortality or heart failure hospitalizations.

After discussing the pharmacological effect of ivabradine, Gustafsson presented the results of the BEAUTIFUL trial (which included patients with chronic, stable, coronary artery disease, many of whom had symptoms suggesting heart failure, usually mild, and an LVEF <40%) and the SHIFT study (which included patients with NYHA class II to IV heart failure, ischemic or nonischemic etiology, with an LVEF <35%, and a heart rate 270 bpm in sinus rhythm, with a documented hospitalization for worsening heart failure <12 months prior to inclusion). Although one analysis of the SHIFT trial supported the European labeling for reducing mortality and/or heart failure hospitalizations, this analysis only included the subset of patients with a heart rate of 275 bpm at study entry. He emphasized that the ivabra- ivabradine-associated benefits in SHIFT were obtained from the population who were already receiving B-blockers; therefore, he concluded that ivabradine should be used when B-blockers alone cannot lower heart rate below <70 bpm.

Matthew Konerman (US) discussed in whom, when, and how a transition should be made from ACE inhibitors or ARBs to sacubitril/valsartan. First, he noted that sacubitril/valsartan was studied in stable patients with mild-to-moderate HFREF who were tolerating ACE inhibitor/ARB therapy. Their systolic BP was ≥100 mm Hg, renal dysfunction, if present, was no more than moderate (GFR ≥30), hyperkale- mía was not present (K $5.2 mmol/L), and there was no history of angioedema. Applying the drug to patients outside of this patient population may introduce unforeseen hazards and may limit the benefits. Indeed, during the run-in phase of PARADIGM-HF. 977 patients on sacubitril/valsartan (approximately 10% of the patients screened for the study) were discontinued from therapy because of symptomatic hypotension, unacceptable renal dysfunction, or hyperkalemia. Thus, little experience was compiled among patients outside the stated population. For context, after the publication of the RALES trial and the consequent widespread application of spironolactone for heart failure, the rate of hyperkalemia more than doubled compared with pre-RALES values in patients treated with the new preferred drug combination, suggesting that trial-related inclusion and exclusion criteria were not being rigorously followed after the release of the data. Next, he suggested that initiation should occur before patients deteriorate; the PARADIGM-HF data indicate that the reduction in mortality and heart failure hospitalizations occurred throughout the study population, including those with a relatively low risk of heart failure sequelae. Therefore, the combination should be applied as soon as possible. Nonetheless, data on the results of inpatient initiation are largely lacking. Therefore, initiation should occur in stable outpatients, never in decompensated patients and always after a 36-hour washout from ACE inhibition. Further, noting the titration schedule used in PARADIGM-HF, Konerman suggested that there should be a "low and slow" dose titration.

In summary, in 2017, several issues were clarified with new data, leading, it is hoped, to therapies that are more effective for patients with heart failure.