NEWS & VIEWS DECADE IN REVIEW—HEART FAILURE
10 Years of progress in HF research—what have we learned? Henry Krum
In this Decade in Review article, I highlight the top 10 advances in heart failure (HF) over the past decade, including new pharmacological therapies and expanded indications for devices in HF with reduced ejection fraction. The poor progress in acute HF and HF with preserved ejection fraction is emphasised. Biomarkers and devices that help prevent, detect, and guide treatment represent the future of HF management. Krum, H. Nat. Rev. Cardiol. advance online publication 2 September 2014; doi:10.1038/nrcardio.2014.127
One of the great advances in cardiovascular therapy during the past 20 years has been the use of cardiac resynchronization therapy (CRT) in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Several studies have indicated major out come benefits in patients with HFrEF and advanced NYHA class III–IV symptoms. Investigators in MADIT‑CRT1 tested the hypothesis that mildly symptomatic patients with HFrEF would also benefit from CRT. In a cohort of >1,000 patients, the primary end point (HF events or death) was reduced to 17.2% with CRT versus 25.3% without CRT, driven primarily by a reduction in HF events.1 These findings were supported by a subsequent trial, in which HF events and mortality were reduced by CRT. CRT is now guideline-recommended for all patients with HFrEF and a prolonged QRS duration (>150 ms). Major drug therapy trials directed towards novel targets have also been conducted in the past decade (Figure 1). Pharmacological inhibition of neprilysin can augment the physiological effects of endogenous natri uretic peptides, which have beneficial vasodilatory, anti-fibrotic, and natriuretic actions. Dual therapy with angiotensinconverting enzyme (ACE) inhibitors was shown to be unsuccessful because of study design flaws and off-target effects; however, combination with an angiotensin-receptor blocker (ARB) seems to overcome this risk and might offer clinical benefits beyond ARB monotherapy. The researchers in the PARADIGM‑HF study 2 aimed to deter mine whether the ARB–neprilysin inhibitor
LCZ696 would be superior to the goldstandard ACE-inhibitor enalapril in patients with HFrEF. Patients received either the ARB–neprilysin inhibitor LCZ696 (200 mg twice daily) or enalapril (10 mg twice daily), with the primary end point of cardiovascular death or HF hospitalization (n = 8,442). Although the final results have not yet been presented, the study was terminated pre maturely for overwhelming efficacy benefit. Given the positive outcome, and assuming that the drug has an acceptable safety profile, LCZ696 should supplant ACE inhibitors as standard therapy for these patients. The clinical benefit of β‑blockers for HF might be partly attributable to their capac ity to lower heart rate. If channel-blocking agents, which are direct sinus node inhibi tors, were used to investigate this heart-ratelowering hypothesis in the SHIfT study 3 (n = 6,558; 89% receiving background β‑blocker therapy), in which the If channel blocker ivabradine was compared with placebo. The primary end point (cardio vascular death or HF hospitalization) was
reached by 24% of patients receiving ivabra dine compared with 29% of patients taking placebo, driven primarily by reduced hos pitalization for HF. The benefits of adding ivabradine were diminished with increasing dose of background β‑blockers, possibly because the additive effect of ivabradine on lowering the heart-rate was abrogated by full-dose β‑blocker therapy. Ivabradine is now approved as an adjunct to background ACE inhibitor, β‑blocker, and mineralo corticoid-receptor antagonists (MRAs) in symptomatic patients with HFrEF and a sinus rhythm heart rate >70 bpm. MRAs increase survival in patients with advanced HFrEF and in those who have experienced a myocardial infarction and have HF. However, until the EMPHASIS‑HF trial,4 patients with mild symptoms of HFrEF had not been formally studied. Researchers in EMPHASIS‑HF4 evaluated the efficacy of eplerenone compared with placebo in 2,737 patients in NYHA class II. The trial was ter minated prematurely (median follow-up 21 months) because only 18.3% of patients receiving eplerenone reached the primary end point (cardiovascular death or hospitali zation for HF) compared with 25.9% in the placebo group.4 Importantly, these benefits were additional to background ACE inhibi tor and β‑blocker therapy. MRAs have, there fore, become mandated therapy for patients with mild HFrEF. In contrast to HFrEF, pharmacological therapy has so far failed to reduce major adverse events in patients with HF and pre served ejection fraction (HFpEF). Given the established benefit of MRAs in patients with HFrEF, researchers in the TOPCAT study 5 evaluated the efficacy of spironolactone (15–45 mg per day) versus placebo in 3,445
Novel drug therapies Improved understanding of pathophysiology
Expanding indications for HF therapeutic devices Advances in HF
HF preventive strategies
Gene-based therapies Plasma biomarker and implantable device-based tracking of patient clinic status
Figure 1 | Key advances in the past 10 years of HF research.
NATURE REVIEWS | CARDIOLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS patients with an ejection fraction >45% in addition to one other HF indicator, in an attempt to recruit a more homogenous pop ulation with ‘true’ HFpEF. The occurrence of the primary end point (cardiovascular death, cardiac arrest, or HF hospitalization) was not significantly different between the two groups. Patients who entered the study because of an elevated plasma B‑type natri uretic peptide (BNP) concentration exhib ited a stand-alone benefit on the primary end point with spironolactone. This result suggests that patients who fulfilled the criteria of ‘HF hospitalization’ rather than elevated BNP might not have had true HFpEF, and in turn did not benefit from MRA therapy. Further efforts to recruit a more homogenous patient population and establish the existence of true HFpEF before study entry are required to evaluate the role of MRAs definitively in this setting. Improving HF outcomes by treat ing comorbidities has become a concept of great therapeutic interest. Two inter related strategies involve the correction of HF‑related anaemia and iron deficiency. Erythropoietin-stimulating agents (ESAs) are frequently used to treat anaemia, but have not reduced major cardiovascular events in HF patients. By contrast, correc tion of iron deficiency has produced more encouraging results. Investigators in the FAIR‑HF study 6 enrolled 459 patients with HFrEF and iron deficiency, based on either serum ferritin or transferrin saturation levels. Patients were randomly allocated to either intravenous ferric carboxymaltose or saline. Fifty percent of the patients who received ferric carboxymaltose showed improvement according to the Patient Global Assessment, compared with only 28% of those receiving placebo. However, an adequately-sized trial to assess the effect of intravenous iron on morbidity and mortality has not yet been performed in patients with HFrEF who are iron-deficient. Treatment of acute HF has not changed for ≥40 years. Numerous proposed agents have demonstrated favourable effects on natriuresis and diuresis, but at the expense of worsened renal function and lack of benefit on prognosis. Relaxin is an endog enous peptide with diuretic, natriuretic, vasodilatory, and anti-fibrotic properties. Investigators in the RELAX‑AHF study 7 evaluated 1,061 patients with acute HF randomly allocated to serelaxin (a recombi nant form of relaxin) or placebo. Serelaxin
improved one of two dyspnoea end points, but had no effect on cardiovascular/renal death or hospital readmission at 60 days in patients with acute HF. However, fewer deaths occurred at 180 days with serelaxin, and evidence existed of reduced in-hospi tal worsening of HF. On the basis of these mixed findings, regulatory authorities did not approve the agent; however, the find ings were sufficiently compelling to warrant a definitive mortality trial, RELAX‑II, which is currently ongoing. Gene-based approaches for HF manage ment are beginning to emerge, after much promise. Insertion of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) gene into the failing heart has been considered a potential therapeutic strategy on the basis of its pivotal role in myocardial contrac tile function. The CUPID study 8 involved 39 patients with HF who received intra coronary adeno-associated virus type 1/ SERCA2a or placebo. Initial findings sug gested that gene transfer might improve relevant surrogate end points and reduce cardiovascular events. The CUPID 2 trial, with an increased cohort of patients, is currently ongoing. The discovery of biomarkers that indi cate the likelihood of risk factors trans itioning to left ventricular (LV) dysfunction might change the future of HF diagnosis. Investigators in the STOP‑HF study 9 trialled a BNP screening programme in which highrisk asymptomatic patients (n = 1374) were randomly assigned to receive care based on knowledge of the plasma BNP level, or usual care. Using this approach, 5.3% of the BNP group developed LV dysfunction (with or without HF) compared with 8.7% receiving usual care, over a 4.2‑year period. Additional biomarkers, including some specific to the LV dysfunction transition phase (such as ST2, galectin‑3), have been proposed and are currently under assessment. Tracking of patient clinical status has underg one substantial technological advance in the past decade. In an individual patient meta-analysis of over 2,000 indi viduals with HFpEF or HFrEF, BNP-guided HF treatment was shown to significantly reduce all-cause mortality and HF hospi talization in those
10 Years of progress in HF research—what have we learned? Henry Krum
In this Decade in Review article, I highlight the top 10 advances in heart failure (HF) over the past decade, including new pharmacological therapies and expanded indications for devices in HF with reduced ejection fraction. The poor progress in acute HF and HF with preserved ejection fraction is emphasised. Biomarkers and devices that help prevent, detect, and guide treatment represent the future of HF management. Krum, H. Nat. Rev. Cardiol. advance online publication 2 September 2014; doi:10.1038/nrcardio.2014.127
One of the great advances in cardiovascular therapy during the past 20 years has been the use of cardiac resynchronization therapy (CRT) in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Several studies have indicated major out come benefits in patients with HFrEF and advanced NYHA class III–IV symptoms. Investigators in MADIT‑CRT1 tested the hypothesis that mildly symptomatic patients with HFrEF would also benefit from CRT. In a cohort of >1,000 patients, the primary end point (HF events or death) was reduced to 17.2% with CRT versus 25.3% without CRT, driven primarily by a reduction in HF events.1 These findings were supported by a subsequent trial, in which HF events and mortality were reduced by CRT. CRT is now guideline-recommended for all patients with HFrEF and a prolonged QRS duration (>150 ms). Major drug therapy trials directed towards novel targets have also been conducted in the past decade (Figure 1). Pharmacological inhibition of neprilysin can augment the physiological effects of endogenous natri uretic peptides, which have beneficial vasodilatory, anti-fibrotic, and natriuretic actions. Dual therapy with angiotensinconverting enzyme (ACE) inhibitors was shown to be unsuccessful because of study design flaws and off-target effects; however, combination with an angiotensin-receptor blocker (ARB) seems to overcome this risk and might offer clinical benefits beyond ARB monotherapy. The researchers in the PARADIGM‑HF study 2 aimed to deter mine whether the ARB–neprilysin inhibitor
LCZ696 would be superior to the goldstandard ACE-inhibitor enalapril in patients with HFrEF. Patients received either the ARB–neprilysin inhibitor LCZ696 (200 mg twice daily) or enalapril (10 mg twice daily), with the primary end point of cardiovascular death or HF hospitalization (n = 8,442). Although the final results have not yet been presented, the study was terminated pre maturely for overwhelming efficacy benefit. Given the positive outcome, and assuming that the drug has an acceptable safety profile, LCZ696 should supplant ACE inhibitors as standard therapy for these patients. The clinical benefit of β‑blockers for HF might be partly attributable to their capac ity to lower heart rate. If channel-blocking agents, which are direct sinus node inhibi tors, were used to investigate this heart-ratelowering hypothesis in the SHIfT study 3 (n = 6,558; 89% receiving background β‑blocker therapy), in which the If channel blocker ivabradine was compared with placebo. The primary end point (cardio vascular death or HF hospitalization) was
reached by 24% of patients receiving ivabra dine compared with 29% of patients taking placebo, driven primarily by reduced hos pitalization for HF. The benefits of adding ivabradine were diminished with increasing dose of background β‑blockers, possibly because the additive effect of ivabradine on lowering the heart-rate was abrogated by full-dose β‑blocker therapy. Ivabradine is now approved as an adjunct to background ACE inhibitor, β‑blocker, and mineralo corticoid-receptor antagonists (MRAs) in symptomatic patients with HFrEF and a sinus rhythm heart rate >70 bpm. MRAs increase survival in patients with advanced HFrEF and in those who have experienced a myocardial infarction and have HF. However, until the EMPHASIS‑HF trial,4 patients with mild symptoms of HFrEF had not been formally studied. Researchers in EMPHASIS‑HF4 evaluated the efficacy of eplerenone compared with placebo in 2,737 patients in NYHA class II. The trial was ter minated prematurely (median follow-up 21 months) because only 18.3% of patients receiving eplerenone reached the primary end point (cardiovascular death or hospitali zation for HF) compared with 25.9% in the placebo group.4 Importantly, these benefits were additional to background ACE inhibi tor and β‑blocker therapy. MRAs have, there fore, become mandated therapy for patients with mild HFrEF. In contrast to HFrEF, pharmacological therapy has so far failed to reduce major adverse events in patients with HF and pre served ejection fraction (HFpEF). Given the established benefit of MRAs in patients with HFrEF, researchers in the TOPCAT study 5 evaluated the efficacy of spironolactone (15–45 mg per day) versus placebo in 3,445
Novel drug therapies Improved understanding of pathophysiology
Expanding indications for HF therapeutic devices Advances in HF
HF preventive strategies
Gene-based therapies Plasma biomarker and implantable device-based tracking of patient clinic status
Figure 1 | Key advances in the past 10 years of HF research.
NATURE REVIEWS | CARDIOLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS patients with an ejection fraction >45% in addition to one other HF indicator, in an attempt to recruit a more homogenous pop ulation with ‘true’ HFpEF. The occurrence of the primary end point (cardiovascular death, cardiac arrest, or HF hospitalization) was not significantly different between the two groups. Patients who entered the study because of an elevated plasma B‑type natri uretic peptide (BNP) concentration exhib ited a stand-alone benefit on the primary end point with spironolactone. This result suggests that patients who fulfilled the criteria of ‘HF hospitalization’ rather than elevated BNP might not have had true HFpEF, and in turn did not benefit from MRA therapy. Further efforts to recruit a more homogenous patient population and establish the existence of true HFpEF before study entry are required to evaluate the role of MRAs definitively in this setting. Improving HF outcomes by treat ing comorbidities has become a concept of great therapeutic interest. Two inter related strategies involve the correction of HF‑related anaemia and iron deficiency. Erythropoietin-stimulating agents (ESAs) are frequently used to treat anaemia, but have not reduced major cardiovascular events in HF patients. By contrast, correc tion of iron deficiency has produced more encouraging results. Investigators in the FAIR‑HF study 6 enrolled 459 patients with HFrEF and iron deficiency, based on either serum ferritin or transferrin saturation levels. Patients were randomly allocated to either intravenous ferric carboxymaltose or saline. Fifty percent of the patients who received ferric carboxymaltose showed improvement according to the Patient Global Assessment, compared with only 28% of those receiving placebo. However, an adequately-sized trial to assess the effect of intravenous iron on morbidity and mortality has not yet been performed in patients with HFrEF who are iron-deficient. Treatment of acute HF has not changed for ≥40 years. Numerous proposed agents have demonstrated favourable effects on natriuresis and diuresis, but at the expense of worsened renal function and lack of benefit on prognosis. Relaxin is an endog enous peptide with diuretic, natriuretic, vasodilatory, and anti-fibrotic properties. Investigators in the RELAX‑AHF study 7 evaluated 1,061 patients with acute HF randomly allocated to serelaxin (a recombi nant form of relaxin) or placebo. Serelaxin
improved one of two dyspnoea end points, but had no effect on cardiovascular/renal death or hospital readmission at 60 days in patients with acute HF. However, fewer deaths occurred at 180 days with serelaxin, and evidence existed of reduced in-hospi tal worsening of HF. On the basis of these mixed findings, regulatory authorities did not approve the agent; however, the find ings were sufficiently compelling to warrant a definitive mortality trial, RELAX‑II, which is currently ongoing. Gene-based approaches for HF manage ment are beginning to emerge, after much promise. Insertion of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) gene into the failing heart has been considered a potential therapeutic strategy on the basis of its pivotal role in myocardial contrac tile function. The CUPID study 8 involved 39 patients with HF who received intra coronary adeno-associated virus type 1/ SERCA2a or placebo. Initial findings sug gested that gene transfer might improve relevant surrogate end points and reduce cardiovascular events. The CUPID 2 trial, with an increased cohort of patients, is currently ongoing. The discovery of biomarkers that indi cate the likelihood of risk factors trans itioning to left ventricular (LV) dysfunction might change the future of HF diagnosis. Investigators in the STOP‑HF study 9 trialled a BNP screening programme in which highrisk asymptomatic patients (n = 1374) were randomly assigned to receive care based on knowledge of the plasma BNP level, or usual care. Using this approach, 5.3% of the BNP group developed LV dysfunction (with or without HF) compared with 8.7% receiving usual care, over a 4.2‑year period. Additional biomarkers, including some specific to the LV dysfunction transition phase (such as ST2, galectin‑3), have been proposed and are currently under assessment. Tracking of patient clinical status has underg one substantial technological advance in the past decade. In an individual patient meta-analysis of over 2,000 indi viduals with HFpEF or HFrEF, BNP-guided HF treatment was shown to significantly reduce all-cause mortality and HF hospi talization in those
