March 2018 at a Glance: Clinical Trials, Co-Morbidities and Treatment of Mitral Regurgitation

Main results of two trials are shown: the Double-blind, RandOmised, two-arm Parallel group, serum c-terminal Propeptide of Procollagen type I (DROP-PIP) trial and the Heart Failure Outpatient Monitoring Evaluation (HOME HF) study.1, 2 The aim of DROP-PIP was to assess whether torasemide, a diuretic previously shown to reduce collagen type I synthesis, could reduce, compared with furosemide, serum C-terminal propeptide of procollagen type I (PIP), a marker of fibrosis, in patients with heart failure with preserved ejection fraction (HFpEF), diabetes and high PIP levels at baseline. After 9 months of treatment, no difference was found between the two treatment groups with respect to serum PIP levels as well as signs of functional capacity, diastolic function, quality of life, or neuroendocrine activation.1 HOME HF was designed as a randomized clinical trial to test the hypothesis that daily brain natriuretic peptide (BNP) measurements at home could improve outcomes, compared to a home management system without BNP measurements or routine clinical care, in patients with HF and reduced ejection fraction (HFrEF).2 The study was terminated early because of slow enrolment and the need for an algorithm testing serial BNP changes. Changes in BNP values, calculated using a moving average filter to reduce day-to-day fluctuations, were independently related to cardiac events and prediction was improved by adjustment for baseline values.2 Selvaraj et al. analysed 1645 participants from Americas enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study.3 Despite different clinical characteristics, there was no relationship between baseline systolic blood pressure (SBP) and outcomes after multivariable adjustment. Spironolactone reduced SBP by 4.4 ± 0.6 mmHg compared with placebo, with no interaction between treatment effect for all outcomes and baseline or 8-week change in SBP. Thus, the anti-hypertensive effects of spironolactone did not account for its potential benefit in cardiovascular outcomes in the Americas.3 Senni et al. examined the relationship between baseline SBP and achievement of the target dose of sacubitril/valsartan in 498 patients in the TITRATION trial, a study comparing two different titration regimens of sacubitril/valsartan in patients with HFrEF.4, 5 Patients were divided into four groups based on SBP at screening: 100–110 mmHg, 111–120 mmHg, 121–139 mmHg and ≥140 mmHg. Overall, 72.7%, 76.1%, 85.6% and 82.9% of patients, respectively, achieved and maintained the target dose of sacubitril/valsartan without downtitration/dose interruption over 12 weeks with no significant differences among groups. A gradual, slower, uptitration was associated with a higher likelihood of treatment success in the lowest SBP group (∼80% vs. ∼69% with rapid uptitration).5 Wolsk et al. assessed the relative contribution of cardiac and extra-cardiac disease burden and demographic factors to cardiovascular outcomes in patients with HFrEF or HFpEF in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme.6 Extra-cardiac disease burden contributed more than the cardiac one to mortality in HFpEF patients [population attributable risk (PAR) 49% and 15%, respectively, P < 0.05]. The demographic burden was also especially high in HFpEF patients (PAR 62%).6 These data are consistent with previous analyses regarding the role of co-morbidities in HFpEF as well as with the neutral results of clinical trials to date.7-9 Cowie et al. show the results of the pre-planned sub-study of the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnoea by Adaptive Servo-Ventilation (ASV) in Patients With Heart Failure (SERVE-HF) trial, in which 312 randomized patients were assessed by cardiac imaging and biomarker analysis at baseline, 3 and 12 months.10 The primary endpoint of this sub-study, change in echocardiographically determined left ventricular ejection fraction (LVEF) from baseline to 12 months, did not differ significantly between the ASV and the control groups. There were also no significant between-group differences for changes in all the other imaging parameters and in biomarkers.10 Hensen et al. showed a 32% prevalence of impaired global longitudinal strain (GLS) among 200 patients with advanced chronic kidney disease and preserved LVEF.11 Impaired GLS identified patients at higher risk of death and heart failure hospitalizations, consistent with previous data showing its role in detecting subtle left ventricular systolic dysfunction.11, 12 Tarvasmäki et al. assessed the incidence and prognostic significance of acute kidney injury, detected using serum creatinine, urine output and cystatin C plasma levels, in patients with cardiogenic shock.13 The rates of acute kidney injury were 31%, 50% and 33% based on these different measurements. Increases in serum creatinine or cystatin C plasma levels were independent predictors of mortality. Also a stricter cut-off of urine output <0.3 mL/kg/h for 6 h was independently associated with 90-day mortality (odds ratio 3.6, 95% confidence interval 1.4–9.3).13 Two studies from the German TRAnscatheter Mitral valve Interventions (TRAMI) registry assessed the prognostic value of echocardiographically measured systolic pulmonary artery pressure (sPAP) and of LVEF, respectively, in patients undergoing MitraClip therapy.14, 15 In the first study, patients were divided into three groups based on sPAP values (≤36 mmHg, 37–50 mmHg, >50 mmHg). Severity of mitral regurgitation (MR) was similar across groups. Reduction to MR of grade 1 or lower was achieved more often in patients with lower sPAP. In-hospital and 30-day major adverse cardiac and cardiovascular events (MACCEs) were similar across the three groups. At 1 year, MACCE and mortality rates were lower in patients with sPAP ≤36 mmHg (20.3% vs. 33.1% and 34.7% for 1-year mortality; P < 0.01).14 In the second study, patients were divided according to their LVEF. Success rates and in-hospital MACCEs were similar across groups. Mortality rates at 1 year were 24.2% (LVEF <30%), 17.3% (LVEF 30–50%), and 18.9% (LVEF >50%) with also a higher MACCE rate in the lowest LVEF group. Procedural failure was the main predictor of mortality in patients with LVEF <30% (hazard ratio 10.38; 95% confidence interval 3.71–29.02). Improved clinical symptoms were observed in the majority of patients in all groups.15