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Spironolactone and Resistant Hypertension in Heart Failure With Preserved Ejection Fraction.

ABSTRACT: BACKGROUND:Recent evidence suggests that the mineralocorticoid receptor antagonist spironolactone should be the preferred fourth-line antihypertensive treatment in resistant hypertension (RHTN). Whether spironolactone improves blood pressure (BP) control in heart failure with preserved ejection fraction (HFpEF) and RHTN is unknown. METHODS:We identified patients with RHTN, defined as baseline systolic blood pressure (SBP) between 140 and 160 mm Hg on 3 or more medications, in the Americas cohort of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial, in which patients with HFpEF were randomized to spironolactone vs. placebo. We evaluated the effects of spironolactone vs. placebo on BP reduction in this group and related this to the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure. RESULTS:We identified 403 participants in the Americas with RHTN. Compared to people without RHTN, those with RHTN were more frequently women, non-White, diabetics, with a higher left ventricular ejection fraction and body mass index, and a lower hemoglobin concentration. In the RHTN group, spironolactone resulted in a decrease of SBP: -6.1 (-8.9, -3.3); P < 0.001 and diastolic BP: -2.9 (-4.6, -1.2); P = 0.001 mm Hg during the first 8 months. BP became controlled after 4 weeks in 63% of patients receiving spironolactone vs. 46% receiving placebo (P = 0.003), with similar responses at 8 weeks, 4 and 8 months. Patients with RHTN derived similar overall benefit from spironolactone on the primary outcomes as those without. CONCLUSIONS:In HFpEF patients with RHTN, spironolactone lowered BP substantially and was associated with similar benefit as those without RHTN. CLINICAL TRIALS REGISTRATION:Trial Number NCT00094302 (ClinicalTrials.gov identifier).

SUBMITTER: Rossignol P

PROVIDER: S-EPMC5861580 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Spironolactone and Resistant Hypertension in Heart Failure With Preserved Ejection Fraction.

Rossignol Patrick P Claggett Brian Lee BL Liu Jiankang J Vardeny Orly O Pitt Bertram B Zannad Faiez F Solomon Scott S

American journal of hypertension 20180301 4

<h4>Background</h4>Recent evidence suggests that the mineralocorticoid receptor antagonist spironolactone should be the preferred fourth-line antihypertensive treatment in resistant hypertension (RHTN). Whether spironolactone improves blood pressure (BP) control in heart failure with preserved ejection fraction (HFpEF) and RHTN is unknown.<h4>Methods</h4>We identified patients with RHTN, defined as baseline systolic blood pressure (SBP) between 140 and 160 mm Hg on 3 or more medications, in the ...[more]

PMID: 29228101

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Project description:Background Resistant hypertension is a salt-retaining condition possibly attributable to inappropriate aldosterone secretion. Methods and Results This study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Patients with heart failure with preserved ejection fraction (HFpEF) with (n=1004) and without (n=2437) resistant hypertension were included. Resistant hypertension was defined as systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥80 mm Hg in a patient with hypertension, despite the concurrent use of a renin-angiotensin system blocker (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker), a calcium channel blocker, and a diuretic; or as those patients using ≥4 classes of antihypertensive medication. The primary outcome was a composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization. We analyzed hazard ratios (HRs) for outcomes with 95% CIs in the spironolactone group and compared them with the placebo group using Cox proportional hazard models. The risk of primary outcome events in patients with HFpEF with resistant hypertension was significantly lower in the spironolactone group than in the placebo group (HR, 0.70; 95% CI, 0.53-0.91; P=0.009), whereas the risk of primary outcome events in patients with HFpEF without resistant hypertension was not significantly different between the 2 groups (HR, 1.00; 95% CI, 0.83-1.20; P=0.97). There was a significant interaction between spironolactone use and resistant hypertension (P=0.03). Similar associations were also observed in patients with HFpEF from the Americas (United States, Canada, Brazil, and Argentina) only. Conclusions Spironolactone may be an effective add-on medication for patients with HFpEF with resistant hypertension taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers, and diuretics.

Project description:BACKGROUND:Albuminuria predicts adverse events in heart failure with preserved ejection fraction. No therapies to date have reduced albuminuria in heart failure with preserved ejection fraction. METHODS AND RESULTS:We analyzed 1175 participants from the Americas from the TOPCAT study (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) with urinary albumin:creatinine ratio (UACR) measurements at baseline. We examined the association of UACR with the primary outcome (cardiovascular death, aborted cardiac arrest, or heart failure hospitalization) and its individual components, all-cause mortality, and several safety end points using multivariable-adjusted Cox regression. We evaluated whether spironolactone reduced albuminuria at the 1-year visit in a subpopulation (N=744). Thirty-five percent had microalbuminuria, 13% had macroalbuminuria, and 80% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Increasing UACR was associated with male sex, higher systolic blood pressure, diabetes mellitus, and renal dysfunction. Macroalbuminuria (hazard ratio, 1.67; 95% CI, 1.22-2.28) and microalbuminuria (hazard ratio, 1.47; 95% CI, 1.15-1.86) were independently associated with the TOPCAT primary end point (compared with normoalbuminuria). Adjusting for placebo response, spironolactone reduced albuminuria by 39% in all participants at the 1-year visit compared with baseline (geometric mean ratio, 0.61; 95% CI, 0.49-0.77) and by 76% (geometric mean ratio, 0.24; 95% CI, 0.10-0.56) among those with macroalbuminuria. Reducing UACR by 50% was independently associated with a reduction in heart failure hospitalization (hazard ratio, 0.90; P=0.017) and all-cause mortality (hazard ratio, 0.91; P=0.019). The change in UACR was significantly associated with change in systolic blood pressure ( P=0.001). CONCLUSIONS:In TOPCAT, albuminuria was independently associated with worse cardiovascular outcomes. Spironolactone significantly reduced albuminuria compared with placebo. Reducing albuminuria was independently associated with improved outcomes. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT00094302.

Project description:ObjectivesThis study sought to assess if clinical phenogroups differ in comprehensive biomarker profiles, cardiac and arterial structure/function, and responses to spironolactone therapy.BackgroundPrevious studies identified distinct subgroups (phenogroups) of patients with heart failure with preserved ejection fraction (HFpEF).MethodsAmong TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) participants, we performed latent-class analysis to identify HFpEF phenogroups based on standard clinical features and assessed differences in multiple biomarkers measured from frozen plasma; cardiac and arterial structure/function measured with echocardiography and arterial tonometry; prognosis; and response to spironolactone.ResultsThree HFpEF phenogroups were identified. Phenogroup 1 (n = 1,214) exhibited younger age, higher prevalence of smoking, preserved functional class, and the least evidence of left ventricular (LV) hypertrophy and arterial stiffness. Phenogroup 2 (n = 1,329) was older, with normotrophic concentric LV remodeling, atrial fibrillation, left atrial enlargement, large-artery stiffening, and biomarkers of innate immunity and vascular calcification. Phenogroup 3 (n = 899) demonstrated more functional impairment, obesity, diabetes, chronic kidney disease, concentric LV hypertrophy, high renin, and biomarkers of tumor necrosis factor-alpha-mediated inflammation, liver fibrosis, and tissue remodeling. Compared with phenogroup 1, phenogroup 3 exhibited the highest risk of the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest (hazard ratio [HR]: 3.44; 95% confidence interval [CI]: 2.79 to 4.24); phenogroups 2 and 3 demonstrated similar all-cause mortality (phenotype 2 HR: 2.36; 95% CI: 1.89 to 2.95; phenotype 3 HR: 2.26, 95% CI: 1.77 to 2.87). Spironolactone randomized therapy was associated with a more pronounced reduction in the risk of the primary endpoint in phenogroup 3 (HR: 0.75; 95% CI: 0.59 to 0.95; p for interaction = 0.016). Results were similar after excluding participants from Eastern Europe.ConclusionsWe identified important differences in circulating biomarkers, cardiac/arterial characteristics, prognosis, and response to spironolactone across clinical HFpEF phenogroups. These findings suggest distinct underlying mechanisms across clinically identifiable phenogroups of HFpEF that may benefit from different targeted interventions.

Project description:BackgroundThe prognostic value of physical examination, its relation to quality of life, and influence of therapy in heart failure with preserved ejection fraction is not well known.Methods and resultsWe studied participants from the Americas with available physical examination (jugular venous distention, rales, and edema) at baseline in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). The association of the number of signs of congestion with the primary outcome (cardiovascular death or heart failure hospitalization), its individual components, and all-cause mortality was assessed using time-updated, multivariable-adjusted Cox regression analyses. We evaluated whether spironolactone improved congestion at 4 months and whether improvement in congestion was related to quality of life as assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores and to outcomes. Among 1644 participants, 22%, 54%, 20%, and 4% had 0, 1, 2, and 3 signs of congestion, respectively, at baseline. After multivariable adjustment, each additional increase in sign of congestion was associated with a 30% to 60% increased risk of each outcome ( P<0.001). Spironolactone reduced the total number of signs of congestion by -0.10 ( P=0.005) signs, jugular venous distention (odds ratio, 0.60; P=0.01), and edema (odds ratio, 0.74; P=0.006) at 4 months compared with placebo. Each reduction in sign of congestion was independently associated with a 4.0 (95% CI, 2.4-5.6) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score. When assessed simultaneously, time-updated, but not baseline congestion, predicted outcomes.ConclusionsIn heart failure with preserved ejection fraction, the physical exam provides independent prognostic value for adverse outcomes. Spironolactone improved congestion compared with placebo. Reducing congestion was independently associated with improved quality of life and outcomes and is a modifiable risk factor.Clinical trial registrationURL: https://www.clinicaltrials.gov . Unique identifier: NCT00094302.

Project description:AimsPatients with heart failure and preserved ejection fraction (HFpEF) frequently have difficult-to-control hypertension. We examined the effect of neprilysin inhibition on 'apparent resistant hypertension' in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril-valsartan with valsartan.Methods and resultsIn this post hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n = 4795). 'Apparent resistant hypertension' was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. 'Apparent mineralocorticoid receptor antagonist (MRA)-resistant' hypertension was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. We examined clinical endpoints and the safety of sacubitril-valsartan according to the hypertension category. We also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension. The rate of the primary outcome was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6-19.1 per 100 person-years] compared to those with a controlled systolic blood pressure (13.4; 12.7-14.3 per 100 person-years), with an adjusted rate ratio of 1.28 (95% CI 1.05-1.57). The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril-valsartan vs. valsartan in patients with apparent resistant hypertension [-4.8 (-7.0 to -2.5) and 3.9 (-6.6 to -1.3) mmHg] and apparent MRA-resistant hypertension [-8.8 (-14.0 to -3.5) and -6.3 (-12.5 to -0.1) mmHg]. The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril-valsartan group and 34.3% in the valsartan group [adjusted odds ratio (OR) 1.78, 95% CI 1.30-2.43]. In patients with apparent MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted OR 2.63, 95% CI 1.18-5.89).ConclusionSacubitril-valsartan may be useful in treating apparent resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA.Clinical trial registrationPARAGON-HF: ClinicalTrials.gov Identifier NCT01920711.

Dataset Information

Spironolactone and Resistant Hypertension in Heart Failure With Preserved Ejection Fraction.

Publications

Spironolactone and Resistant Hypertension in Heart Failure With Preserved Ejection Fraction.

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