Trial Of Spironolactone Research Articles

Bilateral, tender axillary nodules

Bilateral, tender axillary nodules

Systolic blood pressure visit-to-visit variability and clinical outcomes of heart failure with preserved ejection fraction

Abstract Background Previous studies have shown that increased systolic blood pressure visit-to-visit variability (SBP-VVV) is associated with higher risk for cardiovascular events in patients with hypertension, atrial fibrillation, and heart failure with reduced ejection fraction, However, no studies have reported the relationship between SBP-VVV and adverse outcomes in heart failure with preserved ejection fraction (HFpEF). Methods This was a post-hoc analysis of the TOPCAT trial, a multicentered, randomized, placebo-controlled trial of spironolactone in patients with HFpEF. SBP-VVV was assessed during the first year of the trial and clinical outcomes were analysed from the end of the first year to the end of the follow-up period. SBP-VVV was primarily assessed by SBP-SD, the standard deviation (SD) of the mean SBP across these six visits of every patient. The primary study outcome was the composite outcomes of cardiovascular death, hospitalization for heart failure or aborted cardiac arrest occurring after the first 12 months after randomization. The secondary outcomes included cardiovascular mortality, first HF hospitalization event, and all-cause mortality occurring beyond the first 12 months following randomization. Results Of the 2907 patients from the TOPACT trial, SBP-VVV was categorized into quartiles (1st, <6.05; 2nd, 6.06–8.94; 3rd, 8.95–12.81; and 4th, ≥12.82 mmHg) and as a continuous variable. During the subsequent median follow-up of 2.48 years, 373 (12.8%) patients met the primary outcome. On multiple Cox regression, patients in the 4th quartile were at higher risk for a primary outcome (hazard ratio for 4th vs. 1st quartile, 1.79;, 95% CI, 1.28–2.49; P<0.001). Patients in the 4th quartile were also at higher risk of HF hospitalization (hazard ratio for 4th vs. 1st quartile, 2.49; 95% CI, 1.54–4.02; P<0.001) and all-cause mortality (hazard ratio for 4th vs. 1st quartile, 1.52; 95% CI, 1.08–2.15; P=0.017). SBP-SD as a continuous variable was also associated with an increased risk of all outcomes. Conclusions In patients with HFpEF, high SBP-VVV was associated with an increased risk of adverse outcomes, independent of baseline and on-treatment SBP. Funding Acknowledgement Type of funding sources: None. Relationship between SBP-SD and HR

Homage Proof of Concept Trial of Spironolactone for the Prevention of Heart Failure

Introduction In patients at risk of developing heart failure (HF), targeting cardiac fibrosis might be a major determinant of slowing the progression HF. Hypothesis HOMAGE (Heart OMics in AGEing) investigated whether a 9-month exposure to spironolactone can favourably alter markers of progression to HF. Methods In this proof-of-concept, multi-centre, randomized, open-label with blinded evaluation design (PROBE) trial, we compared the effect of spironolactone 25-50 mg/day to standard care in patients aged 60 or more, at risk of developing HF (coronary artery disease and/or diabetes and/or hypertension, and NT-pro BNP 125 to 1,000 ng/L or BNP 35 to 280 ng/L, and no HF history, signs or symptoms. Patients were assessed at baseline, 1, 3 and 9 months for changes in peptides Procollagen Type III N-Terminal Peptide (PIIINP) and Carboxy-Terminal Propeptide of Type 1 Procollagen (P1CP) (primary endpoint). Secondary end-points include changes in cardiac dimensions and function, functional capacity, NTproBNP and multi-omics biomarker profiles (Olink proteomics, miRNA, MS metabolomics and transcriptomics). Whether the effect can be predicted by the baseline bioprofiles was assessed using interaction analysis. Results A total of 527 patients were randomised, 265 to spironolactone and 262 to usual care. The treatment groups were well balanced (aged 73 years, 26% female, 40% diabetes 71% history of myocardial infarction, blood pressure 140/78 mmHg, eGFR 72 ml/min, LVEF 63%, the left atrial volume (LAV) 60 ml, LV mass 180g, median PIIINP 4 (3-5) ng/mL, PICP 80 (65-97) ng/mL, and Galectin-3 16 (13-20) ng/mL. Spironolactone did not significantly affect the PIIINP levels: -0.15 (-0.44, 0.15), p=0.32 but PICP was significantly reduced by spironolactone: -8.1 (-11.9, -4.3), p=0.001, increased LVEF +1.2 (0.2, 2.2), p=0.022, reduced LAV -2.5 (-4.5, -0.6), p=0.010, and tended to reduce LVM -4.1 (-8.6, 0.4), p=0.076. Detailed analyses of the other endpoints, and of prediction of changes using baseline bioprofiles, will be presented at the time of the meeting. Conclusions In patients at risk of developing HF, mineralocorticoid receptor antagonist therapy produces changes in circulating levels of PICP and in echocardiographic parameters, potentially contributing to preventing progression to HF. Other results, including whether multi-omics bioprofiles may predict response and could help selecting patients in a future MRA HF-prevention trial will be presented. (NCT02556450, EUFP7 HOMAGE ID: 305507).

Abstract 11159: Prolonged QRS Duration Predicts Outcomes in Heart Failure With Preserved Ejection Fraction

Introduction: QRS widening on the surface electrocardiogram (ECG) is a marker of disease progression in heart failure (HF) with reduced ejection fraction. We hypothesized that prolonged QRS duration would similarly identify patients with HF with preserved ejection fraction (HFPEF) at high risk for cardiovascular (CV) events. Methods: We examined the relationship of baseline QRS duration to primary outcome [composite of CV death, aborted cardiac arrest, or HF hospitalization (HFH)] and HFH alone in TOPCAT, a multicenter, randomized, placebo-controlled trial of spironolactone in HFPEF. QRS duration was analyzed as a dichotomous variable (≥ 120 ms or < 120 ms). Multivariable analyses were conducted including variables that were significantly associated with QRS duration ≥ 120 ms (Table 1). Analyses were conducted in the entire study cohort as well as in separate analyses for only subjects enrolled from the Americas or from Russia/Georgia independently. Results: QRS duration was known in 3426 of 3445 TOPCAT patients. Compared to those with QRS duration < 120ms, 613 (17.9%) subjects had a QRS duration ≥ 120 ms and were older (72.9 years vs. 67.8 years; p < 0.0001) and more likely to be men (62% vs. 45%; p<0.0001). A QRS duration ≥ 120 ms was independently associated with an increased risk of primary outcome and HFH in the entire study cohort and in the subset of patients enrolled in the Americas but was of borderline statistical significance in Russia/Georgia (Table 1). No statistical interaction was observed between treatment with spironolactone and QRS duration (p value for interaction= 0.33). Conclusions: QRS duration identifies HFPEF subjects at a higher risk of adverse clinical outcomes; spironolactone had a similar effect on outcomes independent of QRS duration. This easily obtainable marker may be an important component of risk stratification in this syndrome.

Spironolactone for Management of Heart Failure with Preserved Ejection Fraction: Whither to After TOPCAT?

Mineralocorticoid receptor antagonists (MRAs) represent an attractive class of drugs for the treatment of heart failure with preserved ejection fraction (HFpEF) because of the deleterious cardiovascular effects of aldosterone and because MRAs combat myocardial fibrosis and improve cardiac structure/function and vascular health. Recently, the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study, a randomized, double-blind clinical trial of spironolactone versus placebo, was conducted in 3445 patients with symptomatic HFpEF. Although considered by some to be a negative trial, TOPCAT demonstrated that spironolactone decreases heart failure hospitalizations in patients with HFpEF. Furthermore, a pre-specified subgroup analysis of TOPCAT by geographic region uncovered concerning findings from Russia/Georgia, questioning (1) whether the correct patients were enrolled in this region and (2) whether enrolled patients actually received the study drug. In the Americas, spironolactone was clearly superior to placebo in reducing cardiovascular events. Given these data from TOPCAT, basic science evidence for the role of aldosterone in HFpEF, and results from other MRA clinical trials in HFpEF, we advocate using spironolactone in HFpEF with close monitoring of potassium and renal function.

A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness of aldosterone antagonists for postmyocardial infarction heart failure

Two aldosterone inhibitors are currently licensed for heart failure (HF) in the UK: spironolactone and eplerenone. Recent clinical guidelines recommend eplerenone after an acute myocardial infarction (MI) for patients with symptoms and/or signs of HF and left ventricular dysfunction. The primary objective was to evaluate relative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone in patients with postMI HF and explore the possibility of conducting an indirect comparison of spironolactone and eplerenone. A second objective was to undertake value-of-information (VOI) analyses to determine the need for further research to identify research questions critical to decision-making and to help inform the design of future studies. Relevant databases including MEDLINE, EMBASE and CENTRAL were searched between September and December 2008. Randomised controlled trials (RCTs) of spironolactone, eplerenone, canrenone or potassium canrenoate were included if conducted in a postMI HF population. Trials of general HF patients with a subgroup of postMI HF patients were considered if they had at least 100 ischaemic participants per arm and the authors provided subgroup data when contacted. Adverse events summary data were sought from recognised reference sources and RCTs or observational studies in any population that recruited more than 100 participants. The comparative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone was derived using Bayesian meta-regression drawing on a wider 'network' of aldosterone trials to those considered in the main clinical effectiveness review. An alternative scenario was also considered assuming a 'class effect' for the aldosterone antagonists in terms of major clinical events, but allowing for potential differences in side effect profiles. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) where appropriate. Uncertainty in cost-effectiveness results was also presented and used to inform future research priorities using VOI analyses based on expected value of perfect information (EVPI). A probabilistic decision analytic model was developed to estimate cost-effectiveness of spironolactone, eplerenone and standard care for management of postMI HF, provide estimates relevant to the NHS and explore alternative approaches to an indirect comparison between spironolactone and eplerenone. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life-years (QALYs) and costs from the NHS persepctive. In the base-case analysis, 2-year treatment duration was assumed, consistent with the follow-up in the main RCTs. Other scenarios were explored to examine the robustness of alternative assumptions including impact of different treatment durations. Searches yielded five RCTs: two spironolactone trials of poor methodological quality and three trials of which only one (of eplerenone) specifically examined postMI HF (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, EPHESUS). One trial of spironolactone (Randomised Aldactone Evaluation Study, RALES) and one of canrenone (Antiremodelling Effect of Aldosterone receptors blockade with canrenone In mild Chronic Heart Failure, AREA IN-CHF) comprised general HF, but data were available for an ischaemic subgroup. Structural similarity of spironolactone and eplerenone suggests that they may be interchangeable, but formal indirect comparison between the three trials was severely limited by trial differences. Relative safety data were limited from RCTs and observational sources. Hyperkalaemia rates varied, but were generally higher than for placebo; data were insufficient to assess discontinuation because of hyperkalaemia.Gynaecomastia rates were higher with spironolactone. Adverse event data were sparse. Systematic review of economic evidence identified three main published studies but none used a UK perspective or attempted to compare cost-effectiveness in postMI HF. The new decision model indicated that eplerenone was the most cost-effective strategy for postMI HF (ICER of eplerenone compared with standard care was 4457 pounds per QALY, increasing to 7893 pounds per QALY if treatment continued over the patient's lifetime); in neither scenario did spironolactone appear cost-effective. The ICER of eplerenone was consistently under the 20,000-30,000 pounds per QALY threshold used to establish value for money in the NHS. Uncertainty resulted in EVPI estimates between 820M pounds (base-case) and 1265M pounds (lifetime treatment duration scenario). When class effect for mortality and hospitalisations was assumed spironolactone emerged as the most cost-effective treatment and EVPI estimates were negligible. If class effect is considered more plausible than the results of the evidence synthesis model then there would be limited value in additional research. Exchangeability between trials was poor and there was a lack of robust data in RCTs. Only two good-quality trials of aldosterone inhibitors in the postMI HF population were found, but lack of exchangeability with respect to study populations, meant that a comparison between these drugs could not be done. It consistently emerged that, compared with usual care, use of an aldosterone antagonist appears to be a highly cost-effective strategy for the management of postMI HF patients in the NHS. An adequately powered, well-conducted RCT that directly compares spironolactone and eplerenone is required to provide more robust evidence on the optimal management of postMI HF patients.

Management of hypertension in the elderly patient

Hypertension in the elderly is associated with increased occurrence rates of sodium sensitivity, isolated systolic hypertension, and 'white coat effect'. Arterial stiffness and endothelial dysfunction also increase with age. These factors should be considered in selecting antihypertensive therapy. The prime objective of this therapy is to prevent stroke. The findings of controlled trials show that there should be no cut-off age for treatment. A holistic program for controlling cardiovascular risks should be fully discussed with the patient, including evaluation to exclude underlying causes of secondary hypertension, and implementation of lifestyle measures. The choice of antihypertensive drug therapy is influenced by concomitant disease and previous medication history, but will typically include a thiazide diuretic as the first-line agent; to this will be added an angiotensin inhibitor and/or a calcium channel blocker. Beta blockers are not generally recommended, in part because they do not combat the effects of increased arterial stiffness. The hypertension-hypotension syndrome requires case-specific management. Drug-resistant hypertension is important to differentiate from faulty compliance with medication. Patients resistant to third-line drug therapy may benefit from treatment with extended-release isosorbide mononitrate. A trial of spironolactone may also be worthwhile.

The spironolactone renaissance

Until recently, spironolactone was considered only as an antagonist at the aldosterone receptors of the epithelial cells of the kidney and was used clinically in the treatment of hyperaldosteronism and, occasionally, as a K+-sparing diuretic. The spironolactone renaissance started with the experimental finding that spironolactone reversed aldosterone-induced cardiac fibrosis by a cardiac action. Experimentally, spironolactone also has direct effects on blood vessels. Spironolactone reduces vascular fibrosis and injury, inhibits angiogenesis, reduces vascular tone and reduces portal hypertension. The rationale for the Randomized Aldactone Evaluation Study (RALES) of spironolactone in heart failure was that ‘aldosterone escape’ occurred through non-angiotensin II mechanisms. The RALES clinical trial was stopped early when it was shown that there was a 30% reduction in risk of death among the spironolactone patients. In RALES, spironolactone also reduced hospitalisation for worsening heart failure and improved the symptoms of heart failure. Other recent clinical trials have shown that spironolactone reduces cardiac and vascular collagen turnover, improves heart variability, reduces ventricular arrhythmias, improves endothelial dysfunction and dilates blood vessels in human heart failure and these effects probably all contribute to the increased survival in heart failure. Spironolactone may also be useful in the treatment of left ventricular hypertrophy, portal hypertension and cirrhosis. There have also been some recent small clinical trials of spironolactone as an anti-androgen showing potential in acne, hirsutism and precocious puberty.

Clinical trial of spironolactone or sclerotherapy for prevention of recurrent esophageal variceal bleeding

Clinical trial of spironolactone or sclerotherapy for prevention of recurrent esophageal variceal bleeding