Background
We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes.
...Methods
We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure.
Results
Improvement in renal function was more frequently observed with serelaxin when compared with placebo OR 1.88 (95% CI 1.64–2.15,
p
< 0.0001), but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin OR 0.70 (95% CI 0.60–0.83,
p
< 0.0001) and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin CVD HR 1.01 (0.99–1.04), ACM HR 1.01 (0.99–1.03), HF/renal failure hospitalization HR 0.99 (0.97–1.00).
Conclusions
Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF.
Graphical abstract
Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.
Renal transplant recipients (RTR) have shortened life expectancy, primarily due to premature cardiovascular disease (CVD). Traditional CVD risk factors are highly prevalent. In addition, several ...non‐traditional risk factors may contribute to the high risk. The aim of the study was to evaluate the effects of renal dysfunction on mortality and cardiovascular complications in 1052 placebo‐treated patients of the Assessment of LEscol in Renal Transplantation (ALERT) trial. Follow‐up was 5–6 years and endpoints included cardiac death, non‐cardiovascular death, all‐cause mortality, major adverse cardiac event (MACE), non‐fatal myocardial infarction (MI) and stroke. The effects of serum creatinine at baseline on these endpoints were evaluated. Elevated serum creatinine in RTR was a strong and independent risk factor for MACE, cardiac, non‐cardiovascular, and all‐cause mortality, but not for stroke or non‐fatal MI alone. Serum creatinine was associated with increased mortality and MACE, independent of established CVD risk factors. Graft loss resulted in increased incidences of non‐cardiovascular death, all‐cause mortality, MACE and non‐fatal MI. In conclusion, elevated serum creatinine is a strong risk factor for all‐cause, non‐cardiovascular and cardiac mortality, and MACE, independent of traditional risk factors, but not for stroke or non‐fatal MI alone.
Background. Renal transplant recipients have a significantly reduced life expectancy, largely due to premature cardiovascular disease. The aim of the current analysis was to investigate the ...importance of time of initiation of therapy after transplantation, on the benefits of statin therapy. Methods. 2102 renal transplant recipients with total cholesterol levels of 4.0–9.0 mmol/l were randomly assigned to treatment with fluvastatin (n = 1050) or placebo (n = 1052) and followed for a mean time of 5.1 years. The end-points were major cardiac events. The average median time from transplantation to randomization was 4.5 years (range: 0.5–29 years). Results. In patients starting treatment with fluvastatin <4.5 years after renal transplantation, the incidence of cardiac events was 4.6% over 5.1 years vs 9.2% in those on placebo (P = 0.007). Fluvastatin significantly reduced the risk of cardiac death and non-fatal myocardial infarction by 56% risk ratio (RR): 0.44; 95% confidence interval (95% CI): 0.26–0.74; P = 0.002. In a more detailed analysis patients were grouped into 2-year intervals (since the last transplantation). The frequency of cardiac death and non-fatal myocardial infarction was reduced by 3.2%, 5.1%, 9.6% and 8.2% with fluvastatin treatment as compared to 6%, 10.4%, 13.4% and 9.6% with placebo when treatment was initiated at 0–2, 2–4, 4–6 and >6 years, respectively. The risk reduction for patients initiating therapy with fluvastatin at years 0–2 (compared with >6 years) following transplantation was 59% (RR: 0.41; 95% CI: 0.18–0.92; P = 0.0328). This is also reflected in total time on renal replacement therapy: in patients in the first quartile (<47 months) fluvastatin use was associated with a risk reduction of 64% compared with 19% for patients in the fourth quartile (>120 months) (P = 0.033). Conclusions. Our data support an early introduction of fluvastatin therapy in a population of transplant recipients at high risk of premature coronary heart disease.
Summary
Concerns regarding a potential link between statin treatment and increased risk of cancer were raised following the increased cancer incidence observed in patients treated with pravastatin in ...the Cholesterol and Recurrent Events and Pravastatin in Elderly Individuals at Risk of Vascular Disease studies. The aim of the present study was to investigate the risk of cancer associated with fluvastatin treatment in clinical trials. A pooled analysis of all available, randomised, placebo‐controlled trials with fluvastatin with a minimum treatment period of 24 weeks was performed. The cancer incidences were compared in 3512 patients receiving fluvastatin, 20–80 mg/day, and 3289 patients receiving placebo. Overall, fewer patients were diagnosed with cancer in the fluvastatin group compared with the placebo group 220/3512 (6.3%) vs. 263/3289 (8.0%) respectively; p = 0.0309. Cox regression analysis, adjusted for baseline covariates and stratified by study, revealed a hazard ratio for first cancer diagnosis of 0.812 95% confidence interval (CI) 0.667–0.989; p = 0.037 for fluvastatin compared with placebo. No significant differences were observed in the incidence of cancers by site, with the exception of non‐melanoma skin cancer (103 vs. 125 cases in the fluvastatin and placebo groups respectively; p = 0.047). Cox regression analysis showed that there was no association between baseline low‐density lipoprotein cholesterol levels and the risk of developing cancer (hazard ratio 0.998, 95% CI 0.995–1.000; p = 0.107). In conclusion, fluvastatin treatment is not associated with an increased risk of cancer compared with placebo in clinical trials, independent of patient age, treatment duration and baseline cholesterol levels.
Renal-transplant recipients have shortened life expectancy primarily because of premature cardiovascular disease. Traditional and nontraditional risk factors for cardiovascular disease are prevalent ...in renal patients. In renal-transplant recipients, immunosuppressive therapy can be nephrotoxic and aggravate cardiovascular disease risk factors. Renal dysfunction has been established as a risk factor for cardiovascular disease and mortality in different populations. We evaluated the effects of baseline renal-transplant function on mortality and cardiovascular and renal endpoints in 1,052 placebo-treated patients of the Assessment of Lescol in Renal Transplantation trial.
All renal-transplant recipients were on cyclosporine-based immunosuppressive therapy. Follow-up was 5 to 6 years, and endpoints included cardiac death, noncardiovascular death, all-cause mortality, major adverse cardiac event (MACE), stroke, nonfatal myocardial infarction, and graft loss.
Baseline serum creatinine was strongly and independently associated with increased cardiac, noncardiovascular, and all-cause mortality, as well as MACE and graft loss. Serum creatinine was not a risk factor for stroke or nonfatal myocardial infarction.
Elevated baseline serum creatinine in renal-transplant recipients is a strong and independent risk factor for all-cause, noncardiovascular and cardiac mortality, MACE, and graft loss.
Chagas' disease is an important cause of cardiomyopathy in Latin America. We aimed to compare clinical characteristics and outcomes in patients with heart failure (HF) with reduced ejection fraction ...caused by Chagas' disease, with other etiologies, in the era of modern HF therapies.
This study included 2552 Latin American patients randomized in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure) trials. The investigator-reported etiology was categorized as Chagasic, other nonischemic, or ischemic cardiomyopathy. The outcomes of interest included the composite of cardiovascular death or HF hospitalization and its components and death from any cause. Unadjusted and adjusted Cox proportional hazards models were performed to compare outcomes by pathogenesis. There were 195 patients with Chagasic HF with reduced ejection fraction, 1300 with other nonischemic cardiomyopathy, and 1057 with ischemic cardiomyopathy. Compared with other etiologies, Chagasic patients were more often female, younger, and had lower prevalence of hypertension, diabetes mellitus, and renal impairment (but had higher prevalence of stroke and pacemaker implantation) and had worse health-related quality of life. The rates of the composite outcome were 17.2, 12.5, and 11.4 per 100 person-years for Chagasic, other nonischemic, and ischemic patients, respectively-adjusted hazard ratio for Chagasic versus other nonischemic: 1.49 (95% confidence interval, 1.15-1.94;
=0.003) and Chagasic versus ischemic: 1.55 (1.18-2.04;
=0.002). The rates of all-cause mortality were also higher.
Despite younger age, less comorbidity, and comprehensive use of conventional HF therapies, patients with Chagasic HF with reduced ejection fraction continue to have worse quality of life and higher hospitalization and mortality rates compared with other etiologies.
PARADIGM-HF: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255; ATMOSPHERE: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.
Heart failure (HF) guidelines recommend initiation and optimization of guideline directed medical therapy (GDMT), including mineralocorticoid receptor antagonists (MRAs), before hospital discharge. ...However, scientific evidence for this recommendation is lacking. Our objective was to determine whether initiation of MRA prior to hospital discharge is associated with improved outcomes.
We performed a secondary analysis of 6197 patients enrolled in the RELAXin in AHF-2 (acute HF) study. Patients were divided into 4 groups according to MRA therapy at baseline and discharge. At baseline 30% of patients received MRA therapy, which increased to 50% of patients at discharge. In-hospital initiation of an MRA was observed in 1690 (27%) patients, 1438 (23%) patients remained on MRA therapy, 418 (7%) patients discontinued MRA treatment, and 2651 (42%) patients did not receive an MRA during hospital stay. Compared with patients who did not receive MRA therapy, in-hospital initiation of a MRA was independently associated with lower risks of mortality (multivariable hazard ratio (HR) 0.76 (0.60-0.96), p = 0.02), cardiovascular (CV) death (HR 0.77 (0.59-1.01), p = 0.06), hospitalization for HF or renal failure (HR 0.72 (0.60-0.86), p = 0.0003) and the composite endpoint of CV death and/or rehospitalization for HF or renal failure (HR 0.71 (0.61-0.83), p < 0.0001) at 180 days. These results were independent of baseline left ventricular ejection fraction.
In patients hospitalized for acute HF, in-hospital initiation of an MRA was associated with improved post-discharge outcomes, independent of LVEF and other potential confounders. This article is protected by copyright. All rights reserved.
Although left ventricular ejection fraction (LVEF) is routinely used to categorize heart failure (HF) patients, whether this variable predicts outcomes across the full spectrum of patients with acute ...heart failure (AHF) is uncertain. We assessed the relationship between LVEF and cardiovascular outcomes in a large cohort of patients hospitalized with AHF.
6128 AHF patients from the RELAX-AHF-2 trial who had LVEF measured during AHF hospitalization were separated into quartiles: Q1, LVEF 7-29%; Q2, LVEF >29-38%; Q3, LVEF >38-50% and Q4, LVEF >50-87% in order to determine the relationship between LVEF and a composite of cardiovascular (CV) mortality and rehospitalization for HF or renal failure (RF) through 180 days, the individual components of this composite and all-cause mortality.
Patients in the lowest LVEF quartile had the highest risk for the composite of CV mortality and HF or RF hospitalization. When LVEF was assessed as a continuous variable, risk for the composite outcome, its components and all-cause mortality became progressively lower as EF increased (HR 0.95, 95% CI 0.93-0.98 per 5% LVEF increase for composite endpoint, P<0.001). The smooth HR spline modeling showed a U-shaped relationship with significantly increased risk for the outcomes only in reduced LVEF range (Figure 1). Similar trends were seen for each of the components of the composite and for all-cause mortality. Although the association between LVEF and risk was reduced in multivariate analysis, it remained significant for Q2 and Q3 compared to Q1. (adjusted HR 0.73, 95%CI 0.6-0.88, P=0.001 and adjusted HR 0.74, 95%CI 0.6-0.91, P=0.004 respectively). Differences between the quartiles and the composite outcome were highly significant in patients with an ischemic etiology and in those with decompensated existing HF but less in patients with non-ischemic etiology and insignificant in de novo HF (Figure 2).
In patients hospitalized with AHF, cardiovascular events occurred more frequently at 180 days in patients in the lowest LVEF quartile, especially in patients with an ischemic etiology and pre-existing HF.
Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in ...life expectancy, a progressive decline in health‐related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two‐day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run‐in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.
The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with ...hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM).
ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction).
This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM.
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