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Chronic heart failure treatment: what lies ahead

ESC Congress Report

  • Serum aldosterone level is an important predictor of a poor outcome for hospitalized HF patients.
  • Elevated plasma renin activity (PRA) has been found to be an independent marker of adverse prognostic outcomes in CHF patients.
  • PDE5 inhibition (sildenafil) significantly improved LV ejection fraction, diastolic function, cardiac geometry, and clinical status at 1 year.
  • The use of low molecular weight heparin in hospitalized HF patients reduces the incidence of VTE, PE and sudden death.
  • The first angiotensin receptor neprilysin inhibitor (ARNI) to be tested on patients, LCZ696, was highly statistically significant against enalapril in HF-REF patients and is clinically important.

Mihai Gheorghiade (Chicago,US) began his discussion on rennin inhibitors by noting  the significantly higher admission rate for heart failure (HF) and a high mortality in-hospital and post discharge, despite great advances in pharmacological and devices treatments. Because the event rate in patients, hospitalized for HF, hasn’t change in the last decade, Prof. Gheorghiade said it is important to recognize hospitalized HF as a problem that needs to be addressed and that new treatments must be created to improve patient outcomes. One of the most important predictors of a poor prognosis for hospitalized HF patients is serum aldosterone level.
In the EVEREST trial, high levels of serum aldosterone were associated with high mortality during the first weeks after discharge from a HF hospitalization, unless the patients were treated with optimal medical therapy (OMT): renin– angiotensin–aldosterone system (RAAS) inhibitors and betablockers. Based on this pathophysiological concept of RAAS escape, one such alternative strategy in the blockade of the RAAS is inhibition of renin, the rate-limiting enzyme in the formation of Angiotensin I. Elevated plasma renin activity (PRA) has been found to be an independent marker of adverse prognostic outcomes in CHF patients.
Unlike angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), direct renin inhibitors (DRIs) reduce rather than increased circulating levels of PRA and Ang I. Aliskiren is the first orally active DRI. In this clinical scenario, the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was designed. The investigators hypothesized that the addition of a DRI to OMT may improve long-term outcomes. ASTRONAUT was a double-blinded, placebo-controlled study that randomized hemodynamically stable hospitalized HF patients a median 5 days after admission. Eligible patients were 18 years or older with left ventricular ejection fraction (LVEF) 40% or less, elevated natriuretic peptides (brain natriuretic peptide [BNP] ≥400 pg/mL or N -terminal pro-BNP [NT-proBNP] ≥1600 pg/mL), and signs and symptoms of fluid overload. All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy.
In total, 1615 patients were included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). 24.9% of patients received aliskiren (77 CV deaths, 153 HF rehospitalizations) and 26.5% of patients received placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point at 6 months (hazard ratio [HR], 0.92; 95% CI, 0.76-1.12; P = .41). At 12 months, the event rates were 35.0% for the aliskiren group and 37.3% for the placebo group (HR, 0.93; 95% CI, 0.79-1.09; P = .36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group than the placebo.
Recently a pre-specified subgroup analysis from the ASTRONAUT was published showing that the addition of aliskiren to standard hospitalized HF therapy in non-diabetic patients is generally well-tolerated and significantly improves  post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes and more adverse events, such as hyperkalemia and hypotension.
Finally, and in reference to the future of the DRIs, we have to wait for the results of the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). This study evaluates the effect of both aliskiren and enalapril monotherapy and aliskiren/enalapril combination therapy on cardiovascular death and HF hospitalization in patients with chronic systolic HF, NYHA functional class II–IV symptoms, and elevated plasma levels of BNP.

Marco Guazzi (Milan, IT) discussed the role of phosphodiesterase-5 (PDE5) inhibitors in chronic HF. PD5 is express in different tissues and vascular beds (penis and lungs) and the inhibition of the isoenzyme that breaks down cyclic guanosin-monofosphate (cGMP) to its inactive form, may be an effective and well-tolerated tool for targeting the pulmonary vasculature and unloading the RV in left-sided PH. In failing hearts of animal models, PDE5 inhibition has also shown the attractive therapeutic property of reversing left ventricular (LV) chamber remodeling by preventing and reversing LV hypertrophy and fibrosis. In humans, PDE5 inhibition increase protein kinase-G (PKG) inducing a reduction in cardiomyocite stiffness and myocardial hypertrophy. Based on this, Guazzi investigated in a cohort of systolic HF patients, the effects of PDE5 inhibition (sildenafil) observing a significant improvement of LV ejection fraction, diastolic function, cardiac geometry, and clinical status at 1 year.
The next step was to evaluate the use of sildenafil in HF with preserved ejection fraction (HFPEF) in the RELAX trial: randomized, double-blinded, placebo-controlled, parallel-group, clinical trial. 216 stable outpatients with HFPEF were included to sildenafil or placebo administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. The administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status.
So after these disappointing results the ideal field for these drugs is the use in patients with HF and pulmonary hypertension (PH). The use of sildenafil reduces mean pulmonary pressure and pulmonary vascular resistance (PVR) and increase levels of cGMP in patients with PH and is safe in terms of systemic vascular effect or important hypotension. Several studies have tested the use of sildenafil in chronic and acute HF with PH and the overall results are positive in terms of reducing pulmonary pressures. Prof. Guazzi also discussed his article regarding HFPEF and PH treated with sildenafil 50 mg/BID.
In this setting there was an improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism. Actually, there are several studies ongoing on this field but, unfortunately, the most important trial (PITCH trial) was stopped because the lack of fundings. So, the future for the use of PDE5 inhibitors remains on better knowledge in molecular physiopathology and to define the right clinical responders.

Hiroshi Hito (Okayama,JN) focussed his presentation on the use of antithrombotics in HF. Throboembolism is the third cause of death for patients with HF. The incidence of thromboembolics events in HF patients is ranged between 1,4 – 12,5% and the majority of then were on sinus rhythm. Also, HF is associated with major risk of venous thromboembolism (VTE) that consists of two related conditions: deep vein thrombosis (DVT) that commonly occurs in leg veins, and pulmonary embolism (PE).
Furthermore the mortality of VTE is increase when is associated with HF (15,6% vs 6,4%; p < .0001) and the results for PE are similar. The relation between HF and thrombus depends on several factors, mainly on the presence of endothelial injury, circulatory stasis and hipercoagulability. He stressed the importance of an early diagnosis of VTE in patients with HF using D-dimer, ultrasounds and venography using a CT scan. The use of antithrombotics in acute phase of HF is established but in the chronic phase is controversial.
The risk of stroke or thromboembolism is higher in patients with the novo HF or hospitalized. The use of low molecular weight heparin in hospitalized HF patients reduces the incidence of VTE, PE and sudden death. There is an under-utilisation of anticoagulation in hospitalized HF patients; only 31% of the eligible patients receive anticoagulants. In the analysis of different registries and trials, there is no proven efficacy of universal use of warfarin in chronic HF patients. Patients with HF and sinus rhythm were studied in the WARCEF trial. In 2305 patients with ejection fraction ≤ 35%, warfarin was not superior to aspirin on the primary endpoint (ischemic stroke, intracerebral hemorrhage and death from any cause). Throughout the study, warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke, however the benefit of warfarin in reducing the rate of ischemic stroke was offset by a significant increase in the rate of major bleeding (1.78 events per 100 patient-years vs 0.87 in the aspirin group; p<0.001). So, the guidelines recommend anticoagulation in patients with HF, if the present atrial fibrillation, previous episodes of thromboembolism and in patients with a large anterior myocardial infarction or LV thrombus.
Prof. Hito continued by evaluating the role of new oral anticoagulants (NOACs) in patients with VTE in comparison with warfarin. There were no clinical differences in outcomes, but there was more major bleeding with warfarin. In a meta-analysis of three NOACs trials (ARISTOTLE, RE-LY and ROCKET-AF), in HF subpopulations there were no efficacy reducing systemic embolism in compare with warfarin. Finally, to establish the role of NOACs in patients with sinus rhythm and HF we have to wait until the results of clinical trials (COMMANDER-HF).

Milton Packer (Dallas, US) discussed firstly the role of different treatments for patients with HF with reduced ejection fraction (HFREF). ACE inhibitors and ARBs are the cornerstone of the therapy for HFREF but betablockers or mineralocorticoid receptor antagonists has been show superior results in survival. Although the focus of therapeutic intervention has been on blocking RASS thought to be harmful in heart failure, potentially beneficial counter-regulatory systems are also activated in heart failure. These pathways variously promote vasodilatation, natriuresis, and suppress the RAAS and SNS. The best understood mediators exerting these actions are the natriuretic peptides (NP). The blockade of NP breakdown, by inhibition of neprilysin, has been developed as an alternative approach to increasing NP.
Oral neprilysin inhibitors, used in combination with ACE inhibitor, omapatrilat, was studied in heart failure (OVERTURE trial), but its development was terminated because omapratilat was not superior to placebo and for an unacceptable incidence of angioedema. Angiotensin receptor neprilysin inhibitors (ARNIs) are a new class of drugs developed both to block the RAAS and augment NP.
LCZ696 is the first ARNI to be tested in patients, and Prof. Packer described the design of the Prospective comparison of ARNI with ACE inhibitor to Determine Impact on Global Mortalilty and morbidity in Heart Failure trial (PARADIGM-HF). The magnitude of benefit with LCZ696 against enalapril in HF-REF patients was highly statistically significant and clinically important. In the study, the benefit of LCZ696 was seen early, was sustained and was consistent across subgroups. LCZ696: reduced the risk of death from cardiovascular causes by 20% (p=0.00004); reduced heart failure hospitalizations by 21% (p=0.00004); reduced the risk of all-cause mortality by 16% (p=0.0005).
Overall there was a 20% risk reduction on the primary endpoint, a composite measure of CV death or heart failure hospitalization (p=0.0000002). The LCZ696 group had more hypotension and non-serious angioedema but less renal impairment, hyperkalemia and cough than the enalapril group. There are several and important clinical considerations: this study is one of the largest trials in HF-REF ever performed, the mean dose of enalapril used in this trial (18,9 mg daily) was higher than in any other trial of this ACE inhibitor in HF, and the finding that LCZ696 has an 20% greater effect on cardiovascular mortality than ACE inhibitors strongly support the conclusion that LCZ696 should replace current use of ACE inhibitors or ARBs in the management of HFREF.




Chronic heart failure treatment: what lies ahead

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.