Background
Despite a significant improvement in therapeutic management, heart failure (HF) remains a major health problem. In France, recent publications clearly show that mortality and rehospitalization rates for HF remain high .
The new European Society of Cardiology (ESC) guidelines for the management of patients with HF were presented and published in May 2016 . Concomitantly, an update of the 2013 American College of Cardiology (ACC) Foundation/American Heart Association (AHA) guidelines , focused on the pharmacological treatment, was published by the ACC/AHA/Heart Failure Society of America (HFSA) . We are obliged to follow these guidelines as closely as possible. However, as always, some statements raise questions. We will comment on some of these, focusing on the change in HF definition, diagnostic algorithm, and preventive and curative treatments in patients with chronic HF.
As always, guidelines are based on classes of recommendations (class I: recommended; IIa: should be considered; IIB: may be considered; III: not recommended) and level of evidence (A: multiple randomized studies or meta-analyses; B: single randomized study or large non-randomized studies; C: expert opinion or small, retrospective studies or registries) .
A new classification of chronic heart failure
The most important parameter used to classify HF is left ventricular ejection fraction (LVEF). Previous 2012 ESC guidelines used the threshold of 50% for LVEF to divide patients with HF into two groups: those with a LVEF ≤ 50% had HF with reduced ejection fraction (HFrEF) while those with LVEF > 50% were classified as HF with preserved ejection fraction (HFpEF) ( Table 1 ). Most of the major HFrEF clinical trials included patients with LVEF ≤ 35%. Therefore, the subgroup of HFrEF patients with LVEF 36–50% were individualized as patients with mild systolic dysfunction without clear therapeutic recommendations. In clinical practice, most of these patients received the same treatment as patients with LVEF ≤ 35%. The new ESC guidelines propose a new subgroup of HF, namely HF with mid-range ejection fraction (HFmrEF), defined as LVEF 40–49% ( Table 1 ). Consequently, the two other subgroups are HFpEF when LVEF ≥ 50% and HFrEF when LVEF < 40%. Patients with either HFmrEF or HFpEF must have structural cardiac abnormalities (left ventricular hypertrophy, left atrial dilatation or diastolic dysfunction) and an increase in natriuretic peptides (NPs). Echocardiography plays a key role in patients with HF, depending on the mode of presentation, for diagnosis, aetiology determination, treatment planning and follow-up. Appropriateness criteria have been reported and compared to available guidelines, highlighting difficulties or uncertainties in clinical practice . This new classification has the advantage of clearly defining different cut-off values of LVEF for HFpEF (≥ 50%) and for the “grey zone”, HFmrEF. This classification will also stimulate new research into the pathophysiology and treatment of HFmrEF and HFpEF.
| ESC 2012 | ESC 2016 | ACC/AHA/HFSA 2013 | |
|---|---|---|---|
| HFrEF | LVEF ≤ 35% | LVEF < 40% | LVEF ≤ 40% |
| HF with mild systolic dysfunction | LVEF 36–50% | ||
| HFmrEF | LVEF 40–49% | ||
| HFpEF | LVEF > 50% | LVEF ≥ 50% | LVEF ≥ 50% |
| HFpEF, borderline | LVEF 41–49% | ||
| HFpEF, improved | LVEF ≤ 40% but > 40% after optimal therapy |
In clinical practice, there are several limitations to the use of this new definition. First is the measurement of LVEF itself, although this limitation is true for all LVEF cut-off values. LVEF measurement is subject to high inter- and intra-observer variability when using one technique, but also varies when different techniques are used to measure it (echocardiography, radionuclide angiography and magnetic resonance imaging). In clinical practice, the method of choice is echocardiography, and most cardiologists generally determine LVEF by a combination of different methods (visual estimation, four-cavity Simpson method or biplane method) and consequently, use increments of 5% (i.e. 30%, 35%, 40%, 45%) . Second, most HFrEF treatments are indicated for patients with LVEF ≤ 35%. Therefore, this new definition creates a subgroup of HFrEF with LVEF 36–39% without clear recommended treatments. Third, patients in the five major clinical trials in HFpEF (DIG , PEP-CHF , CHARM-Preserved , I-PRESERVE , TOPCAT ) had LVEF > 40%. Thus, why are patients only considered to have HFpEF when their LVEF is ≥ 50%? Finally, patients with LVEF of 40% are now classified as HFmrEF and not HFrEF patients, contrasting with USA guidelines ( Table 1 ).
Guidelines are lacking for patients with an initial reduced LVEF (≤ 40%) who had a significant LVEF increase (LVEF > 40%) after appropriate treatment (either medications or resynchronization therapy). Should they be included in the HFmrEF or HFpEF subgroups? Recent publications show that recovered HF patients do not have the same clinical presentation as HFpEF patients and do not have the same prognosis as those who do not recover . In contrast with ESC guidelines, such patients have been individualized in USA guidelines as “patients with recovered EF” or “improved HFpEF” ( Table 1 ). As for HFmrEF, we need to improve our knowledge of the pathophysiology and treatment of this subgroup of patients.
Diagnostic algorithm in chronic heart failure
In patients with chronic (i.e. not acute) HF, a clear algorithm is presented in the new ESC guidelines . This algorithm is firstly based on clinical history, signs and symptoms, and electrocardiogram findings. NP measurement and/or echocardiography is to be performed after this first step rather than immediately in patients with symptoms. Compared with the 2012 version of the ESC guidelines , we do appreciate that the clinical evaluation has been integrated. In most cases, general practitioners are the first contact of the patient. Although HF is unlikely in a patient with a normal electrocardiogram, its interest is limited in France because few general practitioners performed electrocardiograms. The diagnostic algorithm recommends that all patients with symptoms suggestive of HF should be seen by a cardiologist, but this is not realistic in clinical practice. However, this algorithm is appropriate to be able to exclude HF in symptomatic patients. HF is also unlikely in patients with low NP levels, but the thresholds for NP (which are similar to those presented in the 2012 ESC guidelines ), appear to be surprisingly low (≥ 35 pg/mL for B-type natriuretic peptide [BNP] or ≥ 125 pg/mL for N-terminal pro-B type natriuretic peptide [NT-proBNP] ), particularly for HFpEF, with mainly affects elderly patients. In contrast, echocardiography should be performed in patients with increased NP levels to confirm the presence of cardiac structural abnormalities. Echocardiography should also be performed when NP determination is not available. Finally, in France, HF is likely to be diagnosed after clinical evaluation and NP measurement, but before evaluation by a cardiologist.
Diagnostic tests are only recommended if their results imply “a meaningful clinical consequence” . Echocardiography remains the technique of choice for the diagnosis and management of patients with HF (level of recommendation: I – C). However, new techniques have been added to the new ESC guidelines : tissue Doppler imaging and strain (IIa – C), cardiac magnetic resonance imaging with late gadolinium enhancement (IIa – C), cardiac computed tomography for the analysis of coronary arteries (IIb – C) and bone scintigraphy (3,3-diphosphono-1,2-propanodicarboxylicacid) for the diagnosis of transthyretin cardiac amyloidosis (no level of recommendation), an underestimated cause of heart failure . The level of recommendation has been changed for non-invasive stress imaging, from IIa – C to IIb – B .
Delay or prevention of chronic heart failure
A new chapter has been included in the new ESC guidelines , focused on delaying or preventing clinical HF. The authors summarize important recommendations for the management of hypertension, dyslipidaemia, control of other cardiac risk factors with counselling and drugs (e.g. angiotensin converting enzyme inhibitors [ACEIs], beta-blockers) (levels of recommendation from I – A to IIa – C), but also empagliflozin for patients with diabetes mellitus (IIa – B) .
Treatment of chronic heart failure
The most keenly awaited chapter was the one detailing the recommendations on the treatment of chronic HF. The cornerstone of the treatment of left ventricular systolic dysfunction remains the combination of ACEI and beta-blockers, up-titrated to maximal tolerated doses (I – A) . Mineralocorticoid receptor antagonists (MRAs) are recommended for symptomatic patients with LVEF ≤ 35% and either a recent hospitalization for HF (< 6 months) or elevated NP (BNP > 250 pg/mL or NT-proBNP > 500 pg/mL in men or > 750 pg/mL in women) (I – A). The up-titration to maximal tolerated doses is an extremely important step that will have a significant impact on the second step. If the position of MRA in the chart cannot be discussed in general, we must keep in mind that the mean age of French patients with HF is close to 80 years. In elderly patients, it might be dangerous to choose this option systematically due to the risk of renal failure and/or hyperkalemia.
Three options are available for patients who remain symptomatic with LVEF ≤ 35% . In case of QRS ≥ 130 ms, cardiac resynchronization therapy (CRT) must be considered (the various levels of recommendation are shown in Table 2 ). If the heart rate is ≥ 70 bpm and the patient is in sinus rhythm, ivabradine should be added (IIa – B). If the patient is tolerant to ACEI (or angiotensin receptor blockers [ARBs]) at maximal dosage (i.e. “doses equivalent to enalapril 10 mg b.i.d.” ) but still have increased NP levels (BNP ≥ 150 pg/mL or NT-proBNP ≥ 600 pg/mL or, in case of HF hospitalization within 12 months, BNP ≥ 100 pg/mL or NT-proBNP ≥ 400 pg/mL), the replacement of these drugs by an angiotensin receptor neprilysin inhibitor (ARNI), namely LCZ696 (valsartan/sacubitril), must be considered (I – B). This switch requires the ACEI to be stopped 36 hours before starting the ARNI due to the potential risk of angioedema. This recommendation follows the results of the PARADIGM-HF trial , which demonstrated, for the first time since the SOLVD trial , that a new drug, LCZ696, significantly reduced total mortality compared with enalapril, an ACEI.
