Which drugs for which patients?

The new guidelines for the diagnosis and treatment of heart failure were presented at this year’s congress of the European Society of Cardiology at the end of May. The new guidelines introduce heart failure with mid-range ejection fraction (HFmrEF; LVEF 40-49%). The new therapeutic concept of angiotensin receptor neprilysin inhibitors (ARNI) has significantly expanded drug therapy options. Newly, cardiac resynchronization therapy should be used in patients with an LVEF ≤35% and a QRS duration of ≥130 msec. be evaluated.

Heart failure is now defined as a clinical syndrome in which patients suffer from typical symptoms such as dyspnea and decreased exercise capacity and in which clinical signs exist (e.g., congested jugular veins, pulmonary rales, peripheral edema) caused by impaired cardiac function [1]. The development and therapeutic use of neurohumoral inhibitors can slow disease progression, avoid hospitalizations, and reduce mortality [1].

The field of heart failure diagnosis and therapy is undergoing constant change, so the new treatment guidelines from the European Society of Cardiology were urgently awaited. These guidelines were presented at this year’s congress of the Heart Failure Association of the European Society of Cardiology in Florence at the end of May 2016. This article presents the major changes regarding the therapy of chronic heart failure and a selection of common comorbidities, taking into account the needs of general practice.

Revised terminology

The common terminology of heart failure has evolved historically and is essentially based on left ventricular ejection fraction (LVEF) [1]. Previous guidelines distinguished heart failure with preserved ejection fraction (HFpEF; LVEF ≥50%) from heart failure with reduced ejection fraction (HFrEF; LVEF <40%) [2]. The new guidelines additionally introduce heart failure with mid-range ejection fraction (HFmrEF; LVEF 40-49%). Additional diagnostic criteria for HFpEF and HFmrEF were symptoms and signs of heart failure and elevated natriuretic peptides and at least one of the following:

Relevant structural heart disease (left ventricular hypertrophy and/or enlarged left atrium) or
Diastolic dysfunction.

It is well known that the data regarding the therapy of heart failure is dependent on systolic LV function, with data being particularly sparse in the range of LVEF of 40-50%. The introduction of the HFmrEF is therefore intended to stimulate research in this area in particular [1].

Diagnosis of heart failure

In the non-acute clinical setting, the suspected diagnosis of heart failure is based on the following basic factors: Medical history, physical examination, and ECG. For example, if typical anamnestic clues are found, such as known coronary artery disease, known arterial hypertension, orthopnea, paroxysmal nocturnal dyspnea, use of diuretics or cardiotoxic drugs, or radiation in the past, heart failure becomes likely. This is further supported by appropriate clinical signs: rales over the lungs, ankle edema, heart murmurs, congested neck veins, etc. Additionally indicative is an abnormal ECG.

Natriuretic peptides are useful for ruling out heart failure. If the values are below the respective threshold (BNP <35 pg/ml or NT-proBNP <125 pg/ml), heart failure is very unlikely.

Because echocardiography plays a central role in diagnosis, transthoracic echocardiography should be ordered if the limits are exceeded or if natriuretic peptide determination is not routinely performed. If the diagnosis of heart failure is confirmed, further investigation of the etiology is indicated.

Therapy of chronic heart failure

In addition to treating symptoms with diuretics, ACE inhibitors, beta-blockers, and mineral corticoid receptor antagonists (ARBs) remain the first-line drugs in the treatment of HFrEF. These medications should be given at maximum tolerated dosages.

The introduction of a new therapeutic concept, namely angiotensin receptor neprilysin inhibitors (ARNI), has significantly expanded drug therapy options. The first compound, LCZ 696, combines the pharmacological properties of the angiotensin receptor blocker (ARB) valsartan with those of a neprilysin inhibitor. Inhibition of neprilysin delays the degradation of natriuretic peptides (ANP, BNP, bradykinin, etc.), resulting in increased diuresis, natriuresis, myocardial relaxation, and desirable reversal of myocardial remodeling. Selective AT-1 receptor blockade also prevents vasoconstriction, myocardial hypertrophy, and sodium and water retention [3,4]. The superiority of this new substance over the ACE inhibitor enalapril was impressively demonstrated in the PARADIGM-HF trial [5]. The position of the new compound within the treatment regimen of heart failure with reduced pump function was therefore awaited with particular interest. In particular, if patients can tolerate the maximally tolerated up-dose ACE inhibitor or ARB, they should be switched to an ARNI (Class I, Level of Evidence B). ARBs continue to be substitutes, as in the 2012 guidelines, if ACE inhibitors are not tolerated.

Another agent that affects the renin-angiotensin-aldosterone system is the renin inhibitor aliskiren, which was tested against enalapril in patients with HFrEF in the recently published ATMOSPHERE trial [6]. Unfortunately, the authors were unable to show any benefit for patients treated with the renin inhibitor.
The use of ivabradine should still be considered to reduce the risk of hospitalization for heart failure and cardiovascular death if patients fail to achieve a resting heart rate <70/min despite extended beta-blocker therapy [7,8].

In clinical practice, the question of the place of digoxin arises in individual patients. Although there are no studies that tested the effect of digoxin during concomitant therapy with beta-blockers, digoxin may be considered to re-duce hospitalizations for heart failure in symptomatic HFrEF patients in sinus rhythm (Class IIb, Level of Evidence B) [1].

While implantable cardioverter/defibrillators (ICDs) continue to be indicated in patients with LVEF ≤35% despite extended medical therapy or known symptomatic episodes of ventricular flutter/ventricular fibrillation, cardiac resynchronization therapy (CRT) should be newly indicated in patients with LVEF ≤35% and a QRS duration of ≥130 msec. be evaluated. The EchoCRT study initiated and led from the University Hospital Zurich was crucial for the elevation of QRS duration and the omission of echocardiographic signs of dyssynchrony for indication. This study demonstrated that CRT was effective in patients with narrow QRS complex <130 msec. does not improve prognosis and increases all-cause mortality [9].

Arterial hypertension

Arterial hypertension is a major risk factor for heart failure. Therefore, aggressive therapy of arterial hypertension is an essential component of prevention. The SPRINT trial published last year showed that treatment significantly reduced the risk of cardiovascular death or hospitalization for heart failure in terms of lower target blood pressure (systolic blood pressure <120 mmHg versus <140 mmHg) in patients ≥75 years of age or at high cardiovascular risk [10].

Dyslipidemia

Dyslipidemia is also a common concomitant cardiovascular disease, which is why the question of the place of statins in patients with heart failure regularly arises in clinical practice. Most trials of statins have excluded patients with heart failure, but there are two trials that showed no benefit in this patient population [11,12]. Statins should therefore not be restarted in patients with heart failure. However, if heart failure patients are already receiving a statin, e.g., because of known coronary artery disease or dyslipidemia, statin treatment can be continued.

Anticoagulation

In family practice, questions about anticoagulation of patients with impaired LVEF also arise frequently. Whereas it was previously thought that patients with HFrEF should receive oral anticoagulation (OAC), more recent studies have found no evidence that patients with HFrEF without atrial fibrillation benefit from OAC or OAC. Acetylsalicylic acid compared to placebo benefit [13]. Studies with the new oral anticoagulants (NOAKs) have not yet been completed. However, heart failure patients receiving OAK for another established indication may continue OAK.

Osteoarthritis

Osteoarthritis is also a common concomitant disease and regularly leads to the use of non-steroidal anti-inflammatory drugs (NSAID, e.g. ibuprofen or diclofenac) or COX-2 inhibitors (celecoxib), which can damage kidney function. The drugs also increase the risk for worsening heart failure and increased hospitalizations and should be avoided.

Diabetes mellitus

Another class of drugs that should be avoided in heart failure are the thiazolidinediones (glitazones), which are used to treat type 2 diabetes mellitus (DM) [14,15]. For the first time, an oral antidiabetic drug has been shown to improve mortality in high-risk cardiovascular patients. Treatment with the sodium-glucose cotransporter inhibitor 2 (SGLT-2 inhibitor) empagliflozin significantly reduced all-cause mortality and also the rate of hospitalizations for heart failure (Class: IIa, Level of Evidence B).

Iron deficit

In recent years, it has been shown that patients with heart failure are more frequently iron deficient, leading to anemia and/or musculo-skeletal weakness and associated with a worse prognosis [16–18]. Although no definitive outcome study has been completed, based on the available data from two studies, intravenous iron supplementation should be considered in patients with HFrEF and a serum ferritin <100 µg/l or a serum ferritin of 100-299 µg/l and a transferrin saturation <20% to improve heart failure symptoms and enhance exercise capacity and quality of life.

Conclusion

The treatment of HFrEF and its comorbidities remains challenging despite new, improved treatment options. Collaboration between general practitioners and heart failure specialists is therefore of particular importance.

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