Late Breaking Trials in Clinical Science: Highlights from the Heart Failure Meeting, Paris 2017
FOCUS ON ACUTE HEART FAILURE
Bromocriptine for the treatment of peripartum cardiomyopathy – multicenter proof-of-concept study
PPCM is a poorly understood, rare disorder in which LV systolic dysfunction and symptoms of HF occur between the last month of pregnancy and the first 5 months postpartum. Recent data suggest that uncontrolled oxidative stress leads to the activation of the prolactin cleaving enzyme cathepsin D, which, in turn, leads to an increase in a cleaved 16 kDa prolactin, which is angiostatic and proapoptotic and appears to drive PPCM by adversely impacting the endothelium and cardiomyocytes. Bromocriptine reduces prolactin production by dopamine agonists, which may improve outcomes in PPCM patients, by eliminating the cleaved form of prolactin. In a small, multicenter trial, presented by Denise Hilfiker-Kleiner (DE), bromocriptine associated with prophylactic anticoagulation using LMWH was associated with better outcomes in morbidity, mortality, and functional recovery and less VAD or heart transplantation. A total of 63 PPCM patients with a LVEF <35% were randomly assigned to short-term (2.5 mg for 7 days) or long-term (8 weeks, 5 mg for 2 weeks followed by 2.5 mg for 6 weeks) bromocriptine treatment, in addition to standard HF therapy. This is the largest RCT so far in PPCM. Safety and efficacy of low-dose intracoronary IGF-1 to prevent HF following PCI for acute MI (RESUS-AMI)
In an MI, there is blockage of a coronary artery supplying oxygen to the heart muscle, which may weaken, causing HF. The body naturally makes a protein called IGF-1, which may prevent the cardiomyocyte death and HF, or lessen the damage. In this study, MI patients were given either a dose of mecasermin (a recombinant IGF-1) or a placebo (inactive treatment) after stenting of their coronary artery. This therapy was assessed in terms of safety and its capacity to prevent or lessen HF using a cardiac MRI one day and eight weeks after the MI. Of the 473 patients originally screened, 47 were randomized to low- or high-dose IGF-1 or placebo. Noel Caplice (IE) reported that there were no safety issues, but there were no differences between the treatment arms and the placebo arms, and only the low-dose IGF-1 treatment improved LV remodeling.
Relationship between baseline SBP and long-term outcomes in patients with acute HF treated with TRV027: an exploratory subgroup analysis of the BLAST-AHF trial
TRV027 is a novel “biased” ligand of the angiotensin-2 type 1 receptor that antagonizes angiotensin-stimulated G-protein activation while stimulating β-arrestin. In animal models, these effects reduce afterload while increasing cardiac performance and maintaining stroke volume. In the initial human studies, TRV027 appeared to be hemodynamically active primarily in patients with activation of the RAAS, a potentially attractive profile in acute HF therapy. BLAST-AHF is an international, prospective, randomized, phase 2b, dose-ranging study in over 600 patients with acute HF and SBP values between 120 and 200 mm Hg within 24 hours of the initial presentation. Patients were randomized to 1 of 3 doses of intravenous TRV027 (1, 5, or 25 mg/hour) or matching placebo (1:1:1:1) for at least 48 hours and up to 96 hours. The primary end point was a composite of five clinical end points (dyspnea, worsening HF, length of hospital stay, 30-day rehospitalization, and 30-day mortality). Gadi Cotter (US) reported no effect on the clinical end points and identified two typical scenarios in acute HF: a 60-year-old with low LVEF and BP, in contrast to 70 to 80 year old patients with high LVEF and BP. He highlighted the inefficacy of a standardized approach and the need for a more tailored therapy.
Deep-dive results of the TRUE-AHF trial
TRUE-AHF is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that evaluated the efficacy and safety of ularitide as an IV infusion in addition to conventional therapy in patients with acute HF.1 In the presentation at the last AHA meeting, early IV treatment with a synthetic natriuretic peptide decongested patients with acute decompensated HF and made them feel better in the first 48 hours, but did nothing to improve long-term survival or protect the myocardium from damage, as measured by troponin levels, which was an important prospective end point. Milton Parker (US) reported that a short-term infusion of ularitide reduced SBP, BNP, and cardiac decompression, but not troponin levels, hospitalization, or death. However, there was an issue with eligibility: 17% of the recruited patients did not meet the prespecified enrollment criteria (such as stability, prohibition of confounding drugs, or BP instability). In the 1799 eligible patients, ularitide did better, but this did not affect mortality. Therefore, in the “deep-dive” analysis, the 48-hour infusion may benefit eligible patients, but it is associated with adverse outcomes in ineligible patients. This result may have led to the “neutral” finding of the overall TRUE-AHF trial (relating to the hierarchical clinical composite end point). There was also a geographical issue: the majority of the ineligible patients were recruited in some specific areas and countries.
RELAX-AHF-2: serelaxin in acute HF
Serelaxin, the first-in-class recombinant form of human hormone relaxin 2, improved symptoms and outcomes in the RELAX-AHF trial. However, it failed to meet its primary end points in acute HF in RELAX-AHF-2. An update of the phase 3 data presented by John R. Teerlink (US) and Marco Metra (IT) confirmed that serelaxin did not significantly reduce the rate of CV death through day 180 or worsening HF through day 5 in patients with acute HF when added to standard therapy.2 The RELAX-AHF-2 study involved >6600 patients from >550 sites in 34 countries: 3298 patients were allocated to serelaxin and 3271 to placebo. There was no safety issues or effect of serelaxin on CV death.
FOCUS ON CHRONIC HEART FAILURE
Which HF intervention is most cost-effective in reducing the length of the hospital stay?
The WHICH study is investigating the cost-effective application of chronic HF management programs to reduce the negative impact on individuals and the wider community. Simon Stewart (AU) presented the WHICH II trial, which compared two interventions. The first was a standard, postdischarge chronic HF management program, incorporating a combination of at least one home visit and hospital outpatient clinics for metropolitan-dwelling patients and structured telephone support for patients in remote areas. The second was a more intensive program of management targeting those most at risk of recurrent and costly hospital stays. The two programs were compared in a population of 809 patients (mean age, 74; two-thirds had HFREF, mainly NYHA class II). There were no differences between the two interventions in health care cost or clinical end points, such as CV events or mortality.
HFMEF in CHARM: characteristics, outcomes, and effects of candesartan across the entire EF spectrum.
An LVEF of 40% to 49% was recently defined as HFMEF by the 2016 ESC guidelines. In the CHARM program, a unimodal, bell-shaped distribution was observed across the range of EFs, indicating a substantial proportion of patients (17%) in the “middle band” of EFs (40% to 50%). Among patients with chronic stable HFMEF, Lars Lund (SE) reported a graded relationship between a lower EF and a higher risk of events, with increased risk beginning at an EF <50%. Above an EF of ≈45%, all-cause mortality, CV death, and all components of CV death remained relatively stable with increasing EF values. These data suggest that, in terms of outcomes, chronic stable HFMEF has characteristics intermediate between HFPEF and HFREF. The beneficial treatment effect of candesartan was significant and similar in HFMEF and HFREF. A limitation of the CHARM program is that it was published in 2003, and it used a patient population with a low-percentage use of β-blockade (55%) and MRAs (17%). Empagliflozin decreases the risk of kidney function decline in patients with type 2 diabetes
EMPA-REG OUTCOME, the first type 2 diabetes trial to demonstrate improved CV outcomes in high-risk patients, involved 7020 patients with type 2 diabetes, established CVD (but not necessarily HF), and an eGFR of at least 30 mL/min/1.73m2, randomized to receive empagliflozin 10 mg or 25 mg or equivalent placebo.3 The SGLT2 inhibitor empagliflozin significantly reduced deaths among individuals with type 2 diabetes and established CVD when compared with placebo. In patients with type 1 diabetes, short-term treatment with empagliflozin attenuated renal hyperfiltration, likely by affecting tubular-glomerular feedback mechanisms. Alfred Cheung (US) reported that empagliflozin caused an initial acute reduction in eGFR, followed by a long-term stabilization of eGFR in patients with type 2 diabetes, independently of the concomitant presence of HF.
Targeting heart rate to improve mortality in patients with HFREF: a comparison of sinus rhythm and AF
AF and HF often coexist, causing substantial CV morbidity and mortality. Although β-blockers are indicated in patients with symptomatic HFREF, their efficacy in patients with concomitant AF is uncertain. John Cleland (UK) reported the individual patient data meta-analysis of the efficacy of β blockers in 8254 patients with HF in sinus rhythm (13 946; 76%) vs those with AF (3066; 17%).4 β-Blocker therapy significantly reduced all-cause mortality in patients in sinus rhythm (HR, 0.73), but not in patients with AF (HR, 0.97), with a significant P value (0.002) for interaction of baseline rhythm. In patients in sinus rhythm, β-blockers reduced heart rate and mortality, but, in patients with AF, this heart rate reduction did not affect mortality.
Does the duration of chronic HF affect patient outcomes?
The SHIFT trial showed that, in patients with chronic systolic HF and in sinus rhythm, ivabradine reduces the composite of CV death and HF hospitalization; however, it is unknown whether the duration of HF affects the outcomes. Therefore, Michael Böhm et al (DE) examined the outcomes and treatment effects of ivabradine vs placebo in patients with systolic HF, who had a short (<1.5 years), medium (1.5 to <4 years), or long (≥4 years) HF duration before randomization.5 Patients with a longer duration of HF were older, had greater disease severity (NYHA III/IV), and had more comorbidities compared with patients with a more recent diagnosis of HF. The longer duration of HF was also associated with poorer outcomes. Böhm et al showed that the heart rate reduction achieved with ivabradine improved clinical outcomes in chronic systolic HF independent of HF duration, including patients with recent-onset HF. Therefore, ivabradine treatment should be initiated early. Physicians’ guideline adherence is associated with better prognosis in outpatients with HFREF: the QUALIFY international registry
QUALIFY, an international, prospective, observational, longitudinal survey, recruited 6669 outpatients with HFREF between 1 and 15 months after HF hospitalization in 36 countries. In the Registry Hotline session, Michel Komajda et al (FR) reported the results from their evaluation of the impact of physicians’ adherence to guideline-recommended medications for HFREF on clinical outcomes at a 6-month follow-up visit.6 The authors showed that good adherence to the pharmacologic treatment guidelines, as determined by the prescription of ACE inhibitors, ARBs, β-blockers, MRAs, and ivabradine, in dosages that are at least 50% of those recommended, is associated with better clinical outcomes.
FOCUS ON INNOVATIVE AND DEVICE THERAPIES
Do the patients with acute HF who secrete relaxin-2 at pregnancy concentrations have longer survival rates?
Oscar Miro et al (ES) enrolled around 500 patients with acute HF, of whom 10 fulfilled the criteria for elevated relaxin-2 secretion (>1000 pg/dL, ie, at pregnancy concentrations). This group did not differ from the remaining population or show differences in outcomes.
The HeartLogic multisensor algorithm as an automatic predictor of HF events: results from the MultiSENSE trial
Roy S. Gardner (UK) reported that, in the MultiSENSE trial in around 900 CRT-D patients, the HeartLogic alert had an observed sensitivity of 70% and a low unexplained alert rate (alerts not followed by an HF event) of 1.47 per patient per year. The HeartLogic alert successfully notified clinicians of an associated HF event – defined as hospitalization with HF as the primary diagnosis and HF outpatient treatment with intravenous therapy – with a 34-day median alert window. This algorithm, which mimics the activity and analysis of a clinician by combining multiple measurements evaluating different aspects of heart physiology, may be a better predictor of HF events than natriuretic peptide concentration.
Cardiopoietic stem cell therapy improved LV remodeling: longitudinal results from the CHART-1 study
John R. Teerlink (US) reported that therapy using bone marrow–derived stem cells to promote heart repair did not significantly improve the primary outcome over a sham procedure among patients with congestive HF. Cardiopoietic stem cell therapy involves isolating mesenchymal stem cells from a patient’s own bone marrow, exposing these cells to a “cardiogenic cocktail” that turns them into cardiopoietic cells, and injecting these cardiopoietic cells into damaged heart tissue. The CHART-1 study randomized patients with symptomatic ischemic HF to either a sham procedure (n=151) or cardiopoietic cells (n=120). At 39 weeks, there were no significant between-group differences in the primary efficacy end point, which was a composite of all-cause mortality, worsening HF events, Minnesota Living with Heart Failure Questionnaire total score, 6-minute walk distance, LVESV, and ejection fraction. However, a subgroup analysis of patients with severe heart enlargement at baseline (LVEDV between 200 and 370 mL) suggested a positive effect of the cell treatment over sham. Data at 1 year showed reductions in LVESV and LVEDV, but these reductions may have been influenced by treatment modification. The benefit was related to the number of injections.
CRT survey: a comparison of CRT survey I and II
Camilla Normand (NO) reported that a comparison between 13 Western European countries involved in 2 surveys showed that a substantial percentage of patients underwent CRT implantation in the absence of evidence-based medicine data (ie, 23% with AF, 2% with NYHA class I, 31% older than 75).
Two-year follow-up results from the AUGMENT-HF trial
AUGMENT-HF, an international, multicenter, prospective, open-label, randomized, controlled evaluation, tested the hypothesis that Algisyl (an injectable calcium alginate hydrogel) is superior to standard medical therapy for improving functional capacity and clinical outcomes in patients with advanced HF. Andrew Coats (UK) reported that, after a 12-month follow-up, there was a significant improvement in exercise tolerance and quality of life indices in 78 patients with advanced HF;7 patients were randomized 1:1 to Algisyl plus standard medical therapy or standard medical therapy alone as previously reported.5 The patient inclusion criteria were an LVEF ≤35%, a peak VO2 between 9.0 and 14.5 mL/min/kg, and an LVEDD index between 30 and 40 mm/m2. During a 12-month follow-up, there were 4 deaths (10.5%) in the control group and 9 in the Algisyl group (22.5%). The 2-year extended follow-up data confirmed the benefit on quality of life. However, exercise tolerance data are missing and the lack of evidence concerning cardiac hemodynamics requires further investigation.
- Packer M, O’Connor C, McMurray JJ, et al; TRUE-AHF Investigators. Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med. 2017 Apr 12. doi: 10.1056/NEJMoa1601895.
- Metra M, Teerlink J. Serelaxin in acute heart failure. Late Breaking trials I during the HFA congress 2017.
- Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOMES Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;37(22):2117-2128.
- Kotecha D, Flather MD, Altman DG, et al; Beta-blockers in heart failure collaborative group. heart rate, heart rhythm, and prognostic benefits of beta-blockers in heart failure: individual patient-data meta-analysis. J Am Coll Cardiol. 2017 Apr 5. doi: 10.1016/j.jacc.2017.04.001.
- Bohm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Ivabradine effect on outcomes in patients with systolic heart failure according to the duration of their disease: analysis from SHIFT. Eur J Heart Fail. 2017;19(suppl S1):225.
- Komajda M, Cowie MR, Tavazzi L, Ponikowski P, Anker SD, Filippatos GS; QUALIFY Investigators. Physicians’ guideline adherence is associated with better prognosis in outpatients with HFREF: the QUALIFY international registry. Eur J Heart Fail. 2017 April 30. doi: 10.1002/ejhf.887.
- Mann DL, Lee RJ, Coats AJ, et al. One-year follow-up results from AUGMENT-HF: a multicentre randomized controlled clinical trial of the efficacy of left ventricular augmentation with Algisyl in the treatment of heart failure. Eur J Heart Fail. 2016;18(3):314-325.