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Atorvastatin Has a Dose-Dependent Beneficial Effect on Kidney Function and Associated Cardiovascular Outcomes: Post Hoc Analysis of 6 Double-Blind Randomized Controlled Trials.

ABSTRACT: Background Kidney function decreases during the lifetime, and this decline is a powerful predictor of both kidney and cardiovascular outcomes. Statins lower cardiovascular risk, which may relate to beneficial effects on kidney function. We studied whether atorvastatin influences kidney function decline and assessed the association between individual kidney function slopes and cardiovascular outcome. Methods and Results Data were collected from 6 large atorvastatin cardiovascular outcome trials conducted in patients not selected for having kidney disease. Slopes of serum creatinine reciprocals representing measures of kidney function change ([mg/dL]-1/y), were analyzed in 30 621 patients. Based on treatment arms, patients were categorized into 3 groups: placebo (n=10 057), atorvastatin 10 mg daily (n=12 763), and 80 mg daily (n=7801). To assess slopes, mixed-model analyses were performed for each treatment separately, including time in years and adjustment for study. These slopes displayed linear improvement over time in all 3 groups. Slope estimates for patients randomized to placebo or atorvastatin 10 mg and 80 mg were 0.009 (0.0008), 0.011 (0.0006), and 0.014 (0.0006) (mg/dL)-1/y, respectively. A head-to-head comparison of atorvastatin 10 and 80 mg based on data from 1 study ( TNT [Treating to New Targets]; n=10 001) showed a statistically significant difference in slope between the 2 doses ( P=0.0009). From a Cox proportional hazards model using slope as a predictor, a significant ( P<0.0001) negative association between kidney function and cardiovascular outcomes was found. Conclusions In patients at risk of or with cardiovascular disease, atorvastatin improved kidney function over time in a dose-dependent manner. In the 3 treatment groups, kidney function improvement was strongly associated with lower cardiovascular risk. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT00327418; NCT00147602; NCT00327691.

SUBMITTER: Vogt L

PROVIDER: S-EPMC6512126 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Atorvastatin Has a Dose-Dependent Beneficial Effect on Kidney Function and Associated Cardiovascular Outcomes: Post Hoc Analysis of 6 Double-Blind Randomized Controlled Trials.

Vogt Liffert L Bangalore Sripal S Fayyad Rana R Melamed Shari S Hovingh G Kees GK DeMicco David A DA Waters David D DD

Journal of the American Heart Association 20190501 9

Background Kidney function decreases during the lifetime, and this decline is a powerful predictor of both kidney and cardiovascular outcomes. Statins lower cardiovascular risk, which may relate to beneficial effects on kidney function. We studied whether atorvastatin influences kidney function decline and assessed the association between individual kidney function slopes and cardiovascular outcome. Methods and Results Data were collected from 6 large atorvastatin cardiovascular outcome trials c ...[more]

PMID: 31020900

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Project description:ObjectivesThis study aimed to evaluate the efficacy and safety of finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, on cardiovascular and kidney outcomes by age and/or sex.DesignFIDELITY post hoc analysis; median follow-up of 3 years.SettingFIDELITY: a prespecified analysis of the FIDELIO-DKD and FIGARO-DKD trials.ParticipantsAdults with type 2 diabetes and chronic kidney disease receiving optimised renin-angiotensin system inhibitors (N=13 026).InterventionsRandomised 1:1; finerenone or placebo.Primary and secondary outcome measuresCardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure (HHF)) and kidney (kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline or renal death) composite outcomes.ResultsMean age was 64.8 years; 45.2%, 40.1% and 14.7% were aged <65, 65-74 and ≥75 years, respectively; 69.8% were male. Cardiovascular benefits of finerenone versus placebo were consistent across age (HR 0.94 (95% CI 0.81 to 1.10) (<65 years), HR 0.84 (95% CI 0.73 to 0.98) (65-74 years), HR 0.80 (95% CI 0.65 to 0.99) (≥75 years); Pinteraction=0.42) and sex categories (HR 0.86 (95% CI 0.77 to 0.96) (male), HR 0.89 (95% CI 0.35 to 2.27) (premenopausal female), HR 0.87 (95% CI 0.73 to 1.05) (postmenopausal female); Pinteraction=0.99). Effects on HHF reduction were not modified by age (Pinteraction=0.70) but appeared more pronounced in males (Pinteraction=0.02). Kidney events were reduced with finerenone versus placebo in age groups <65 and 65-74 but not ≥75; no heterogeneity in treatment effect was observed (Pinteraction=0.51). In sex subgroups, finerenone consistently reduced kidney events (Pinteraction=0.85). Finerenone reduced albuminuria and eGFR decline regardless of age and sex. Hyperkalaemia increased with finerenone, but discontinuation rates were <3% across subgroups. Gynaecomastia in males was uncommon across age subgroups and identical between treatment groups.ConclusionsFinerenone improved cardiovascular and kidney composite outcomes with no significant heterogeneity between age and sex subgroups; however, the effect on HHF appeared more pronounced in males. Finerenone demonstrated a similar safety profile across age and sex subgroups.Trial registration numbersNCT02540993, NCT02545049.

Project description:Background and objectivesIn the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG Outcome), empagliflozin, in addition to standard of care, significantly reduced risk of cardiovascular death by 38%, hospitalization for heart failure by 35%, and incident or worsening nephropathy by 39% compared with placebo in patients with type 2 diabetes and established cardiovascular disease. Using EMPA-REG Outcome data, we assessed whether the Kidney Disease Improving Global Outcomes (KDIGO) CKD classification had an influence on the treatment effect of empagliflozin.Design, setting, participants, & measurementsPatients with type 2 diabetes, established atherosclerotic cardiovascular disease, and eGFR≥30 ml/min per 1.73 m2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. Post hoc, we analyzed cardiovascular and kidney outcomes, and safety, using the two-dimensional KDIGO classification framework.ResultsOf 6952 patients with baseline eGFR and urinary albumin-creatinine ratio values, 47%, 29%, 15%, and 8% were classified into low, moderately increased, high, and very high KDIGO risk categories, respectively. Empagliflozin showed consistent risk reductions across KDIGO categories for cardiovascular outcomes (P values for treatment by subgroup interactions ranged from 0.26 to 0.85) and kidney outcomes (P values for treatment by subgroup interactions ranged from 0.16 to 0.60). In all KDIGO risk categories, placebo and empagliflozin had similar adverse event rates, the notable exception being genital infection events, which were more common with empagliflozin for each category.ConclusionsThe observed effects of empagliflozin versus placebo on cardiovascular and kidney outcomes were consistent across the KDIGO risk categories, indicating that the effect of treatment benefit of empagliflozin was unaffected by baseline CKD status.Clinical trial registry name and registration numberEMPA-REG OUTCOME, NCT01131676.

Project description:INTRODUCTION:Duloxetine has demonstrated efficacy in chronic low back pain (CLBP). We examined the predictors of response to duloxetine for CLBP. PATIENTS AND METHODS:This was a post hoc analysis of pooled data from 4 double-blind, ran-domized, placebo-controlled trials of duloxetine (60 mg/day for 12-14 weeks) in adult patients with CLBP. Primary outcome was proportion of patients with ?30% reduction in Brief Pain Inventory (BPI) average pain ("pain reduction") at 12-14 weeks. The proportion of patients with ?30% and ?50% (secondary outcome) pain reduction in duloxetine and placebo groups was compared. Variables for responder analyses were early improvement (?15% pain reduction at Week 2), sex, age, baseline BPI average pain score, duration of CLBP, and number of painful body sites according to the Michigan Body Map (?2 vs 1 [isolated CLBP]; 1 trial); relative risk (RR) and 95% confidence interval (CI) were calculated. RESULTS:Compared with placebo (n = 653), a greater proportion of duloxetine-treated patients (n = 642) achieved ?30% (59.7% vs 47.8%; P < 0.001) and ?50% pain reduction (48.6% vs 35.1%; P < 0.001). Among duloxetine-treated patients, early improvement was associated with greater likelihood of ?30% (RR [95% CI], 2.91 [2.30-3.67]) or ?50% (3.24 [2.44-4.31]) pain reduction. Women were slightly more likely than men to achieve ?30% (RR [95% CI], 1.14 [1.00-1.30]) or ?50% (1.17 [0.99-1.38]) pain reduction. Response rates were similar between age, CLBP duration, and baseline BPI average pain score subgroups. Patients with ?2 painful sites were more likely to respond to duloxetine 60 mg relative to placebo than patients with isolated CLBP (RR, duloxetine vs placebo [95% CI]: ?30% reduction, ?2 painful sites 1.40 [1.18-1.66], isolated CLBP 1.07 [0.78-1.48]; ?50% reduction, ?2 painful sites 1.51 [1.20-1.89], isolated CLBP 1.23 [0.81-1.88]). CONCLUSION:Early pain reduction was indicative of overall response. Patients with multiple painful sites had more benefit from duloxetine than patients with isolated CLBP.

Project description:BACKGROUND:In addition to the increased risk for cardiovascular (CV) disease and CV events associated with migraine, patients with migraine can also present with a number of CV risk factors (CVRFs). Existing treatment options can be limited due to contraindications, increased burden associated with monitoring, or patient avoidance of side effects. Safe and effective migraine treatment options are needed for patients with migraine and a history of CV or cerebrovascular disease or with increased risk for CV events. This analysis was designed to evaluate the safety and efficacy of oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor agonist, in acute treatment of migraine attacks in patients with CVRFs. METHODS:SAMURAI and SPARTAN were similarly designed, Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50, 100, or 200?mg. Both studies included patients with CVRFs, and SPARTAN allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Efficacy and safety of lasmiditan in subgroups of patients with differing levels of CVRFs are reported. For efficacy analyses, logistic regression was used to assess treatment-by-subgroup interactions. For safety analyses, Cochran-Mantel-Haenszel test of general association evaluated treatment comparisons; Mantel-Haenszel odds ratio assessed significant treatment effects. RESULTS:In this pooled analysis, a total of 4439 patients received ?1 dose of study drug. A total of 3500 patients (78.8%) had ?1 CVRF, and 1833 patients (41.3%) had ?2 CVRFs at baseline. Both trials met the primary endpoints of headache pain freedom and most bothersome symptom freedom at 2?h. The presence of CVRFs did not affect efficacy results. There was a low frequency of likely CV treatment-emergent adverse events (TEAEs) overall (lasmiditan, 30 [0.9%]; placebo, 5 [0.4%]). There was no statistical difference in the frequency of likely CV TEAEs in either the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ?1, ? 2, ? 3, or???4 CVRFs was palpitations. CONCLUSIONS:When analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Despite the analysis being limited by a single-migraine-attack design, the lack of differences in efficacy and safety with increasing numbers of CVRFs indicates that lasmiditan might be considered in the treatment algorithm for patients with CVRFs. Future studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION:ClinicalTrials.gov NCT02439320 (SAMURAI), registered 18 March 2015 and ClinicalTrials.gov NCT02605174 (SPARTAN), registered 11 November 2015.

Dataset Information

Atorvastatin Has a Dose-Dependent Beneficial Effect on Kidney Function and Associated Cardiovascular Outcomes: Post Hoc Analysis of 6 Double-Blind Randomized Controlled Trials.

Publications

Atorvastatin Has a Dose-Dependent Beneficial Effect on Kidney Function and Associated Cardiovascular Outcomes: Post Hoc Analysis of 6 Double-Blind Randomized Controlled Trials.

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