The Year in Cardiology: Heart Failure 2014
The Year in Cardiology: Heart Failure 2014
During the last decades, treatment of patients with heart failure with reduced ejection fraction (HFrEF) has improved dramatically with the introduction of ACE-inhibitors, β-blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. This caused a stepwise reduction in mortality and heart failure hospitalization. However, residual mortality and morbidity is still too high. Therefore, there is a continuous need for better therapies.
The biggest heart failure news of 2014 in heart failure was the presentation and publication of the PARADIGM trial. The trial reported the effects of LCZ696, a first in class angiotensin receptor neprilysin inhibitor. LCZ696 comprises the molecular moieties of the angiotensin II AT1 receptor antagonist valsartan and the neprilysin inhibitor prodrug AHU377. In PARADIGM, the effect of LCZ696 on a composite of death from cardiovascular causes or hospitalization for heart failure was compared with enalapril in 8442 patients with HFrEF. The trial was stopped prematurely due to an overwhelming benefit of LCZ696. Compared with enalapril, LCZ696 significantly reduced the primary endpoint by 20% and all-cause mortality by 16%. The drug was well tolerated, with no increase in angioedema, which was a concern with the combined ACE-inhibitor/neprilysin inhibitor omapatrilat. There were more cases of symptomatic hypotension in the LCZ696 group and less cases of worsening of renal function. The major question is to which extent should LCZ696 replace ACE inhibitors in patients with HFrEF, for whom these agents are a mainstay. Although the trial was well conducted, the run-in period is of concern. More than 1200 patients were excluded because of adverse events or abnormal laboratory test results. So, patients who tolerated enalapril but became hypotensive on LCZ696 in the second run-in phase were not included in this study, which might have biased the results in favour of LCZ696. Nevertheless, since the CONSENSUS trial was published in 1987, this is the first drug that proved to be superior over enalapril, and therefore this trial will probably be the end of an era. The drug now needs to be approved and reimbursed, so it will unfortunately take some time before the drug will be readily available, but this will provide physicians and policy-makers time to get more insights in the study.
The second important trial that was presented and published during the scientific sessions of the European Society of Cardiology in Barcelona, September 2014, was the CONFIRM-HF trial. This trial confirmed beneficial effects of intravenous iron on symptoms, functional capacity, and quality of life in patients with HFrEF, with and without anaemia. Iron deficiency (ferritin level <100 μg per L or between 100 and 299 μg per L, if the transferrin saturation is <20%) is found in >40% of patients with HFrEF, and is related to severity of symptoms and a poor clinical outcome. CONFIRM-HF was a double-blind, placebo-controlled trial in 304 HFrEF patients with iron deficiency. Patients were randomized 1 : 1 to treatment with i.v. iron, as ferric carboxymaltose or placebo for 52 weeks. Ferric carboxymaltose improved functional capacity, symptoms, and quality of life and was associated with a reduction in the risk of hospitalization for worsening heart failure (Figure 1). CONFIRM-HF confirmed the results of FAIR-HF that were nearly identical. However, blinding of these patients in both studies remained difficult, which is important due to the soft endpoints that were used. Also, both FAIR-HF and CONFIRM-HF were too small to show effects (both beneficial and/or deleterious) on mortality.
(Enlarge Image)
Figure 1.
Patient global assessment and NYHA functional class over time (full-analysis set). The data presented are odds ratios for patient global assessment (A) and NYHA functional class (B) for the ferric carboxymaltose group when compared with the placebo, of being in a better category of patient global assessment (A) and NYHA functional class (B). In those panels, the P-values are for the comparison between the two study groups, and the I bars denote the 95% confidence intervals.
A third study that received a lot of attention in 2014 was related to the efficacy of β-blockers in patients with HFrEF and atrial fibrillation. A pooled analysis was performed using individual patient data from 10 randomized controlled trials that compared β-blockers and placebo in HFrEF. Overall, 18 254 patients were included (13 946 in sinus rhythm and 3066 with atrial fibrillation). β-Blockers were associated with a 27% reduction in all-cause death among HFrEF patients in sinus rhythm, but among patients with AF, no mortality reduction was seen. The authors conclude that β-blockers should not be regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation. However, we have to be careful with sub-group analyses, even when performed in such a well-performed meta-analysis, and prospective studies in HFrEF patients with AF should be performed to establish the value of β-blockers in HFrEF patients with atrial fibrillation.
Finally, in May 2014, long-term follow-up data of the MADIT-cardiac resynchronization therapy (CRT) trial were published in the New England Journal of Medicine. The original study enrolled 1820 patients to either CRT-D or ICD in patients with mild HFrEF (NYHA classes I–II; LVEF ≤30%) and a QRS duration of 130 ms or more. After a follow-up of 2.4 years, CRT-D was associated with a significant reduction in death from any cause or a heart-failure event. However, the outcome was mainly driven by heart-failure events. After a median follow-up of 5.6 years, a 41% mortality reduction was shown in patients with left bundle branch block, while no benefit was found in patients without a left bundle branch block.
ACE Inhibitors in Heart Failure With Reduced Ejection Fraction: The End of an Era?
During the last decades, treatment of patients with heart failure with reduced ejection fraction (HFrEF) has improved dramatically with the introduction of ACE-inhibitors, β-blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. This caused a stepwise reduction in mortality and heart failure hospitalization. However, residual mortality and morbidity is still too high. Therefore, there is a continuous need for better therapies.
The biggest heart failure news of 2014 in heart failure was the presentation and publication of the PARADIGM trial. The trial reported the effects of LCZ696, a first in class angiotensin receptor neprilysin inhibitor. LCZ696 comprises the molecular moieties of the angiotensin II AT1 receptor antagonist valsartan and the neprilysin inhibitor prodrug AHU377. In PARADIGM, the effect of LCZ696 on a composite of death from cardiovascular causes or hospitalization for heart failure was compared with enalapril in 8442 patients with HFrEF. The trial was stopped prematurely due to an overwhelming benefit of LCZ696. Compared with enalapril, LCZ696 significantly reduced the primary endpoint by 20% and all-cause mortality by 16%. The drug was well tolerated, with no increase in angioedema, which was a concern with the combined ACE-inhibitor/neprilysin inhibitor omapatrilat. There were more cases of symptomatic hypotension in the LCZ696 group and less cases of worsening of renal function. The major question is to which extent should LCZ696 replace ACE inhibitors in patients with HFrEF, for whom these agents are a mainstay. Although the trial was well conducted, the run-in period is of concern. More than 1200 patients were excluded because of adverse events or abnormal laboratory test results. So, patients who tolerated enalapril but became hypotensive on LCZ696 in the second run-in phase were not included in this study, which might have biased the results in favour of LCZ696. Nevertheless, since the CONSENSUS trial was published in 1987, this is the first drug that proved to be superior over enalapril, and therefore this trial will probably be the end of an era. The drug now needs to be approved and reimbursed, so it will unfortunately take some time before the drug will be readily available, but this will provide physicians and policy-makers time to get more insights in the study.
The second important trial that was presented and published during the scientific sessions of the European Society of Cardiology in Barcelona, September 2014, was the CONFIRM-HF trial. This trial confirmed beneficial effects of intravenous iron on symptoms, functional capacity, and quality of life in patients with HFrEF, with and without anaemia. Iron deficiency (ferritin level <100 μg per L or between 100 and 299 μg per L, if the transferrin saturation is <20%) is found in >40% of patients with HFrEF, and is related to severity of symptoms and a poor clinical outcome. CONFIRM-HF was a double-blind, placebo-controlled trial in 304 HFrEF patients with iron deficiency. Patients were randomized 1 : 1 to treatment with i.v. iron, as ferric carboxymaltose or placebo for 52 weeks. Ferric carboxymaltose improved functional capacity, symptoms, and quality of life and was associated with a reduction in the risk of hospitalization for worsening heart failure (Figure 1). CONFIRM-HF confirmed the results of FAIR-HF that were nearly identical. However, blinding of these patients in both studies remained difficult, which is important due to the soft endpoints that were used. Also, both FAIR-HF and CONFIRM-HF were too small to show effects (both beneficial and/or deleterious) on mortality.
(Enlarge Image)
Figure 1.
Patient global assessment and NYHA functional class over time (full-analysis set). The data presented are odds ratios for patient global assessment (A) and NYHA functional class (B) for the ferric carboxymaltose group when compared with the placebo, of being in a better category of patient global assessment (A) and NYHA functional class (B). In those panels, the P-values are for the comparison between the two study groups, and the I bars denote the 95% confidence intervals.
A third study that received a lot of attention in 2014 was related to the efficacy of β-blockers in patients with HFrEF and atrial fibrillation. A pooled analysis was performed using individual patient data from 10 randomized controlled trials that compared β-blockers and placebo in HFrEF. Overall, 18 254 patients were included (13 946 in sinus rhythm and 3066 with atrial fibrillation). β-Blockers were associated with a 27% reduction in all-cause death among HFrEF patients in sinus rhythm, but among patients with AF, no mortality reduction was seen. The authors conclude that β-blockers should not be regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation. However, we have to be careful with sub-group analyses, even when performed in such a well-performed meta-analysis, and prospective studies in HFrEF patients with AF should be performed to establish the value of β-blockers in HFrEF patients with atrial fibrillation.
Finally, in May 2014, long-term follow-up data of the MADIT-cardiac resynchronization therapy (CRT) trial were published in the New England Journal of Medicine. The original study enrolled 1820 patients to either CRT-D or ICD in patients with mild HFrEF (NYHA classes I–II; LVEF ≤30%) and a QRS duration of 130 ms or more. After a follow-up of 2.4 years, CRT-D was associated with a significant reduction in death from any cause or a heart-failure event. However, the outcome was mainly driven by heart-failure events. After a median follow-up of 5.6 years, a 41% mortality reduction was shown in patients with left bundle branch block, while no benefit was found in patients without a left bundle branch block.