One year after the presentation of the 2016 ESC heart failure guidelines: new studies with implications for everyday clinical practice
It was last year in May 2016, during the annual meeting of the ESC Heart Failure Association, when we presented the new 2016 ESC HF guidelines.1 In these guidelines, we proposed the following new aspects related to the comprehensive management of chronic and acute HF:
1. A new algorithm for the diagnosis of HF in the nonacute setting based on three elements: (i) an initial evaluation of the clinical probability of the disease, including a history of coronary artery disease, arterial hypertension, exposure to cardiotoxic drugs, use of diuretics, symptoms of orthopnea/paroxysmal nocturnal dyspnea; (ii) a careful physical examination; and (iii) a resting ECG. In cases where any of the three criteria are abnormal, plasma levels of natriuretic peptide should be assessed (if available) to identify patients who need a transthoracic echocardiography; however, if natriuretic peptide levels cannot be assessed, a direct echocardiography assessment is indicated.
2. A new classification of HF across the whole spectrum of LVEF, with the introduction of a new term—HFMEF—to identify patients with HF and an LVEF between 40% and 49%. We believe that identifying HFMEF as a separate group will stimulate research into the underlying characteristics, pathophysiology, and treatment of this patient population.
3. A new therapeutic algorithm for HF patients with reduced LVEF (HFREF) that contains indications for the use of the sacubitril/valsartan combination, the first ARNi combination (based on the results of the PARADIGM-HF trial2), and modified indications for cardiac resynchronization therapy (based on the results of the EchoCRT trial3).
4. Updated recommendations on the management of comorbidities that often complicate the natural course of the disease, with new data on diabetes mellitus, iron deficiency, sleep disordered breathing, and hyperkalemia.
5. A modified approach to the management of acute HF including: (i) a concept to shorten all diagnostic and therapeutic decisions in the initial phase; (ii) the need to identify coexisting, life-threatening, clinical conditions and/or precipitants immediately (according to the CHAMP criteria) to introduce a specific guideline-recommended management; (iii) a therapeutic algorithm based on clinical profiles to evaluate the presence and/or absence of congestion and peripheral hypoperfusion.
Since the presentation of the 2016 ESC HF guidelines, additional evidence has become available, which may affect everyday practice and possibly form a background for new recommendations and guidelines in the near future. Some of these studies will be summarized below.
IMPORTANCE OF ADHERing TO THE GUIDELINES: RESULTS FROM THE QUALIFY REGISTRY
Although it is taken for granted that good adherence to the HF treatment guidelines would translate into better outcomes; surprisingly, only a few studies have properly addressed this problem. It is particularly important in the context of guideline-recommended disease-modifying treatments that these treatments be applied at optimal target doses. The aim of QUALIFY, a recent international, prospective, longitudinal survey, was to evaluate adherence to five classes of medications recommended by the ESC guidelines as standard disease-modifying therapies for HFREF: ACE inhibitors (or ARBs), β-blockers, MRAs, and ivabradine.4 A global adherence to the guidelines score was developed for the prescription of these drugs and their dosages. From September 2013 to December 2014, 6669 outpatients with HFREF were recruited between 1 and 15 months after HF hospitalization in 36 countries and followed-up at 6 months. The baseline global adherence score was good in 23%, moderate in 55%, and poor in 22% of the patients. At the 6-month follow-up, both poor and moderate adherence were associated with significantly higher overall cardiovascular and HF mortality vs good adherence. There was also a strong trend between poor adherence and a higher risk of HF hospitalizations. The results of the study confirm the necessity for a global use of educational initiatives and disease management programs to facilitate the implementation of guideline-recommended disease-modifying HF therapies (at evidence-based target doses) into everyday clinical practice.
BETTER CHARACTERISTICS OF CONTEMPORARY PATIENTS WITH HFMEF/HFREF: AN ANALYSIS OF THE ESC HEART FAILURE LONG-TERM REGISTRY
The ESC HF Long-Term (ESC-HF-LT) registry is the largest pan-European cohort, which provides a detailed description of the real-world population of patients with chronic HF from all regions of Europe and the Mediterranean countries. As mentioned previously, the new 2016 ESC guidelines proposed a new HF classification, introducing the term HFMEF. There are neither evidence-based characteristics nor any specific therapeutic recommendations for this group of patients. The recent analysis from ESC-HF-LT provides a unique piece of information on the clinical epidemiology, treatment patterns, and long-term outcomes in HFMEF vs the remaining HF patients.5 Among 9 134 ambulatory HF patients with information on LVEF available, 59.8% were classified as HFREF, 24.2% as HFMEF, and 16% as HFPEF (ie, LVEF >50%). HFMEF was the most prevalent in North African countries (45.5% of all HF patients) and resembled the HFREF group in features, such as age, sex, and ischemic etiology, but had less left ventricular and atrial dilation. The use of guideline-directed medical therapies was similar in the HFMEF and HFREF groups; however, ACE inhibitors/ARBs and β-blockers were used in more than 90% of HFREF/HFMEF patients, whereas MRAs were used in less than 70% and ivabradine in less than 10% of these patients.
Devices were implanted at much lower rates in HFMEF vs HFREF patients: CRT in 8.4% (vs 18.1%) and ICD in 13.4% (vs 34.8%). Mortality rates at 1 year were 8.8% in patients with HFREF, 7.6% in patients with HFMEF, and 6.4% in patients with HFPEF. By pairwise comparison, all-cause mortality in HFMEF did not differ significantly from mortality in HFREF or HFPEF. Interestingly, the percentage of patients hospitalized for HF was 8.7% in HFMEF, which was lower than in HFREF (14.6%), but similar to HFPEF (9.7%). The authors concluded that HF patients stratified according to different LVEF categories represent diverse phenotypes of demography, clinical presentation, etiology, and outcomes. Further studies are urgently needed to explore the effects of treatments, which are commonly applied in clinical practice, on the outcomes of patients with HFMEF.
TREATING COMORBIDITIES IN HF: THE WAY TO IMPROVE THE OUTCOMES?
Iron deficiency frequently occurs with HF, and it is associated with poor exercise capacity, impaired quality of life, and a high risk of mortality and morbidity. The 2016 HF guidelines recommended that all HF patients be screened for iron deficiency (based on the assessment of serum ferritin and transferrin) and that patients with HFREF who have an iron deficiency receive intravenous ferric carboxymaltose to alleviate symptoms and improve exercise capacity and quality of life. However, it remains unknown whether correcting iron deficiencies with intravenous iron would improve the outcomes. Anker et al6 presented the individual patient data meta-analysis from four randomized clinical trials comparing ferric carboxymaltose with placebo in patients with HFREF and an iron deficiency on recurrent hospitalizations and mortality. Patients randomized to ferric carboxymaltose had lower rates of recurrent cardiovascular/HF hospitalizations and cardiovascular/all-cause mortality (vs placebo), and these effects were independent of the baseline hemoglobin levels. Clinical trials are now set-up to confirm these findings.
In the EMPA-REG OUTCOME trial, treatment with empagliflozin (an SGLT2 inhibitor), added to the standard of care in patients with type 2 diabetes and a high cardiovascular risk, reduced the risk of the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke and the overall risk of mortality. Fitchett et al7 recently reported the results of additional analyses of the EMPA-REG OUTCOME trial with respect to HF outcomes, where they found that HF hospitalization or cardiovascular death occurred in a significantly lower percentage of patients treated with empagliflozin vs placebo (HR, -0.66). Consistent benefits of empagliflozin were observed across subgroups defined by baseline characteristics, including patients with or without HF. Empagliflozin improved other HF outcomes, including hospitalization for or death from HF, and it was associated with a reduction in all-cause hospitalizations. There are still uncertainties concerning the mechanisms underlying the favorable effect of this drug in terms of early prevention of cardiovascular death and HF hospitalizations.
ICD IMPLANTATION FOR ALL HFREF PATIENTS? NEW EVIDENCE FROM THE DANISH TRIAL
The guidelines recommend using an ICD to reduce the risk of sudden cardiac death and all-cause mortality in patients with symptomatic HF (NYHA class II-III) and an LVEF ≤35% despite optimal medical therapy. However, the evidence on the benefits of an ICD is much stronger for patients with ischemic cardiomyopathy than for those with HF from other etiologies. Given the limited evidence of a benefit from the implantation of an ICD in patients with chronic, nonischemic HF, the DANISH trial recruited patients with symptomatic HFREF (LVEF ≤35%) not caused by coronary artery disease, who were then assigned either an ICD or usual clinical care (control group).8 The primary outcome of the trial was death from any cause. After a median follow-up period of 67.6 months, the primary outcome had occurred in 21.6% in the ICD group vs 23.4% in the control group (HR, -0.87; P=0.28). However, there was a significant 50% reduction in the risk of sudden cardiac death in the ICD group (4.3% vs 8.2% in the ICD vs controls, respectively; P=0.005). The authors concluded that the use of an ICD for primary prevention in patients with HFREF (not caused by coronary artery disease) did not reduce the rate of long-term all-cause mortality. The results raised an interest and started a widespread discussion in the context of both guidelines recommendations and clinical practice.
The interpretation of these findings is still a matter of debate, but this may be because contemporary pharmacological and nonpharmacological treatments for patients with nonischemic HFREF result in a much better outcome, particularly the relatively low rate of sudden cardiac death (which is favorably affected by an ICD). On the other hand, as ICDs do not reduce the risk of death due to pump failure or death due to noncardiovascular causes, it explains the lack of effect on all-cause mortality. The results of the DANISH trial justify the need for a careful and optimal selection of candidates who would benefit from an ICD.
OPTIMIZATION OF LONG-TERM THERAPY FOR PATIENTS HOSPITALIZED FOR ACUTE HF: NEW ANALYSIS FROM THE SHIFT TRIAL
Patients discharged from the hospital after an episode of acute HF decompensation are at a very high risk of death and/or readmission in the first weeks following hospital discharge. Within this vulnerable period, the ESC guidelines recommend setting up a plan for a careful patient follow-up, optimally with the first visit occurring 1 to 2 weeks after discharge as well as enrollment in a disease management program. Although reducing the burden of rehospitalization during the vulnerable phase is of critical clinical importance, in practice, there is a lack of evidence-based protocols for the optimization of pharmacological, disease-modifying therapies. In this context, there is an interesting, recent analysis from the SHIFT trial that evaluated the effects of chronic exposure to ivabradine vs placebo on hospital readmissions occurring up to 3 months after a hospitalization for worsening HF.9 Among patients who experienced hospitalization due to acute HF during the study, 28% were rehospitalized within 3 months after discharge, mostly for cardiovascular causes (86%), including HF (61%). The use of ivabradine was associated with fewer all-cause hospitalizations at 1, 2, and 3 months (incidence rate ratios, 0.70-0.79), and, additionally, a trend for a reduction in cardiovascular and HF hospitalizations was observed in ivabradine-treated patients. The results form a background for future studies to investigate whether in-hospital or early postdischarge initiation of ivabradine could be useful to improve early outcomes in hospitalized HF patients.
We stated in the HF guidelines that “in the year 2016,… by applying all evidence-based discoveries, heart failure is becoming a preventable and treatable disease.”1 We are all eagerly awaiting new data from ongoing studies, which will form the background of the new ESC guidelines.
- Ponikowski P. Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37:2129-2200.
- McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004.
- Ruschitzka F, Abraham WT, Singh JP, et al; EchoCRT Study Group. Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med. 2013;369(15):1395-1405.
- Komajda M, Cowie MR, Tavazzi L, Ponikowski P, Anker SD, Filippatos GS; QUALIFY Investigators. Physicians’ guideline adherence is associated with better prognosis in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry. Eur J Heart Fail. 2017 Apr 30. doi: 10.1002/ejhf.887.
- Chioncel O, Lainscak M, Seferovic PM, et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2017 Apr 6. doi: 10.1002/ejhf.813.
- Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail. 2017 Apr 24. doi: 10.1002/ejhf.823.
- Fitchett D, Zinman B, Wanner C, et al; EMPA-REG OUTCOME Trial Investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37(19):1526-1534.
- Køber L, Thune JJ, Nielsen JC, et al; DANISH Investigators. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med. 2016;375:1221-1230.
- Komajda M, Tavazzi L, Swedberg K, et al; SHIFT Investigators. Chronic exposure to ivabradine reduces readmissions in the vulnerable phase after hospitalization for worsening systolic heart failure: a post-hoc analysis of SHIFT. Eur J Heart Fail. 2016;18(9):1182-1189.