New treatments for heart failure and exercise capacity

This article refers to ‘A randomized clinical trial on the short-term effects of 12-week sacubitril/valsartan vs. enalapril on peak oxygen consumption in patients with heart failure with reduced ejection fraction: results from the ACTIVITY-HF study’ by M. Halle et al., published in this issue on pages 2073–2082. New heart failure drugs have proven to be remarkably effective in recent years in improving prognosis (mortality and rehospitalizations) but also symptoms and quality of life of patients with heart failure. Improving quality of life and exercise capacity is now recognized as an important criterion by health authorities, in addition to improving prognosis, and is often requested for registration of a drug or a device in heart failure. Sacubitril/valsartan is one of these new drugs that markedly improves prognosis, symptoms and quality of life in patients. In this issue of the Journal, Halle et al.1 evaluated if sacubitril/valsartan also improved, as one could imagine, maximal exercise capacity, measured by cardiorespiratory exercise testing, compared to enalapril, an angiotensin-converting enzyme inhibitor (ACEi). ACTIVITY-HF is the first randomized study to evaluate the effects of sacubitril/valsartan on maximal exercise capacity in New York Heart Association class III patients with heart failure with reduced ejection fraction (HFrEF). At the end of a well-conducted, randomized, double-blind, parallel-group study in 201 HFrEF patients, sacubitril/valsartan did not significantly improve maximal oxygen uptake (VO2) after 3 months of treatment compared to enalapril. Absolute increase in mean peak VO2 was very low (+0.5 and +0.1 ml/min/kg only in the sacubitril/valsartan and the valsartan group, respectively). The authors also found no benefit on submaximal exercise parameters [supposed to better reflect the ability to perform submaximal efforts during daily life, such as the minute ventilation to carbon dioxide production (VE/VCO2) slope or the ventilatory threshold]. There was also no improvement in the 6-min walk test. Quality of life, assessed by questionnaires, daily physical activity assessed by actigraphy, were no more, apparently surprisingly, improved by sacubitril/valsartan compared to enalapril. First of all, the study methodology appears satisfactory.2 The exercise parameters were centrally evaluated by a corelab. It is possible that the population was not severe enough to benefit from sacubitril/valsartan: this was not the case, patients seem to have severe heart failure with a peak VO2 only around 13 ml/min/kg only; unfortunately, baseline natriuretic peptide values were not reported. The achieved doses of sacubitril/valsartan and enalapril were close to those expected. Contrary to what is often thought, in many drug studies, improvement in symptoms and quality of life has not always been associated with an improvement in maximum exercise capacity assessed by peak VO2.3 The results of studies with beta-blockers, ACEi, phosphodiesterase 5 inhibitors have often been contradictory. However, other studies4 had appeared to show a beneficial effect of sacubitril/valsartan after switching from ARBs or ACEi on peak VO2, but this was an open-label study with a small number of patients. In OUTSTEP-HF,5 sacubitril/valsartan did not improve the 6-min walk distance any more than enalapril. Dos Santos et al.,6 on the contrary, found an increase in peak VO2 and 6-min walk distance with sacubitril/valsartan compared to enalapril at 12 and 24 weeks. The duration of the German study may also be a bit short, i.e. 3 months. While haemodynamic improvement can be rapid, it may take time for the entire cardio-circulatory and muscular system to improve. In many studies with cardiorespiratory exercise testing, the follow-up time is 6 months. What is surprising, however, and seems to confirm the results of exercise tests, is that there was no benefit on either quality of life or daily physical activity assessed by an actigraf; or even on the 6-min walk distance. One of the explanations that can then be retained is that haemodynamic and symptomatic improvement did not translate into an expected increase in the daily physical activity of patients with normalization of the vascular and peripheral muscular abnormalities of HFrEF and therefore did not lead to improvement in peak VO2. We could also have expected an improvement in the sub-maximum parameters such as a delay in the ventilatory threshold appearance or a reduction in the VE/VCO2 slope, which generally reflects – among other things – the pulmonary pressures. This was not the case either. In summary, these results should not deter us from the use of sacubitril/valsartan. Similar results have been found with other drug classes that are hardly questionable. No improvement in peak VO2 does not mean no improvement in symptoms. Heart failure drugs thus differ from physical activity programmes that improve peak VO2, peak, sub-maximal parameters, quality of life and symptoms much more and should be offered much more often in these patients. It is likely that our patients should be encouraged to be more active once they feel better with drugs for maximizing the potential benefit of our drugs. Conflict of interest: A.C.S. received fees for consulting or grants from Vifor, AstraZeneca, Novartis, Pfizer, Merck, Sanofi, Leo, Boehringer Ingelheim. F.B. has nothing to disclose.