Showing papers by "Marc A. Pfeffer published in 2016"

Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction

Abstract: Aims While mineralocorticoid receptor antagonists (MRAs) have been shown to benefit patients with reduced left ventricular ejection fraction (LVEF), spironolactone did not reduce the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT trial, which enrolled patients with LVEF of 45% or greater. We utilized data from TOPCAT to assess the relationship between LVEF as well as outcomes and efficacy of spironolactone. Methods and results We assessed differences in baseline characteristics and outcomes across LVEF categories in 3444 patients with HFpEF, and determined whether LVEF modified the treatment effect of spironolactone. Ejection fraction ranged from 44 to 85%. Patients with higher ejection fraction were older, more likely to be female, less likely to have a history of myocardial infarction, and more likely to have a history of hypertension and diabetes. The incidence of the primary endpoint and cardiovascular death was highest in patients at the lower end of the ejection fraction spectrum. Ejection fraction modified the spironolactone treatment effect, particularly in the patients enrolled in the Americas, for the primary outcome ( P = 0.046) and for heart failure hospitalization ( P = 0.039), with stronger estimated benefits of spironolactone at the lower end of the ejection fraction spectrum with respect to the primary endpoint (LVEF <50%: HR 0.72, 95% CI 0.50, 1.05; LVEF ≥60%: HR 0.97, 95% CI 0.76, 1.23) and heart failure hospitalization (LVEF <50%: HR 0.76, 95% CI 0.46, 1.27; LVEF ≥60%: HR 0.98, 95% CI 0.74, 1.30). Conclusion In patients with HFpEF enrolled in TOPCAT, patient characteristics and outcomes varied substantially by LVEF. The potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum. ClinicalTrials.gov number NCT00094302.

On the restricted mean survival time curve in survival analysis.

Abstract: For a study with an event time as the endpoint, its survival function contains all the information regarding the temporal, stochastic profile of this outcome variable. The survival probability at a specific time point, say t, however, does not transparently capture the temporal profile of this endpoint up to t. An alternative is to use the restricted mean survival time (RMST) at time t to summarize the profile. The RMST is the mean survival time of all subjects in the study population followed up to t, and is simply the area under the survival curve up to t. The advantages of using such a quantification over the survival rate have been discussed in the setting of a fixed-time analysis. In this article, we generalize this approach by considering a curve based on the RMST over time as an alternative summary to the survival function. Inference, for instance, based on simultaneous confidence bands for a single RMST curve and also the difference between two RMST curves are proposed. The latter is informative for evaluating two groups under an equivalence or noninferiority setting, and quantifies the difference of two groups in a time scale. The proposal is illustrated with the data from two clinical trials, one from oncology and the other from cardiology.

Impact of Spironolactone on Longitudinal Changes in Health-Related Quality of Life in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial

Abstract: Background—Heart failure (HF) with preserved ejection fraction patients have equally impaired health-related quality of life (HRQL) compared with those with HF with reduced ejection fraction, but limited studies have evaluated the impact of therapies on changes in HRQL. Methods and Results—Patients ≥50 years of age, with symptomatic HF and left ventricular ejection fraction ≥45%, were enrolled in Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) and randomized to spironolactone or placebo. Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), which was the primary HRQL instrument, and EQ5D visual analog scale at baseline, 4 months, 12 months, and annually thereafter. McMaster Overall Treatment Evaluation was assessed at 4 and 12 months to assess global change scores. Change scores (+SD) were calculated to determine between-group differences, and multivariable repeated-measures models were created to identify other factors associated with change...

Is a reduction in albuminuria associated with renal and cardiovascular protection? : A post-hoc analysis of the ALTITUDE trial

Abstract: Aims: In the ALTITUDE trial, direct renin inhibition with aliskiren on top of ACEi_or_ARB therapy decreased albuminuria by 14% while this did not lead to cardiorenal protection. Prior studies have demonstrated that the renoprotective effect of single RAAS blockade is associated with approximately 30% albuminuria reduction. . We therefore firstly investigated whether the degree of albuminuria reduction is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria in ALTITUDE was too small to afford clinical benefit. Methods: In a post-hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of month-6 albuminuria changes on renal and cardiovascular outcomes by Cox proportional_hazard_regression. Results: The median change in albuminuria in the first 6 months in the aliskiren group was -12%( 25th to 75th Percentile: -48.7_to_+41.9%) and 0.0[-40.2_to_55%] in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: >30% reduction in albuminuria in the first 6 months was associated with 62% renal and 25% cardiovascular risk reduction compared to an increase in albuminuria. The association between month-6 changes in albuminuria and renal or cardiovascular endpoints was similar in both treatment groups (p for interaction >0.1 for both endpoints). Conclusions: Addition of aliskiren to ACEi/ARB therapy shows albuminuria changes that are associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection since the overall albuminuria reduction in the aliskiren arm was too small and nearly similar to placebo.

Worsening renal function and outcome in heart failure patients with reduced and preserved ejection fraction and the impact of angiotensin receptor blocker treatment: data from the CHARM-study programme

Abstract: Aims We investigated the association between worsening renal function (WRF) that occurs during renin–angiotensin–aldosterone system inhibition initation and outcome in heart failure (HF) patients with preserved ejection fraction (HFPEF) and compared this with HF patients with reduced ejection fraction (HFREF). Methods and results We examined changes in estimated glomerular filtration rate (GFR) and the relationship between WRF (defined as ≥26.5 µmol/L and ≥25% increase in serum creatinine from baseline to 6 weeks) and outcome, according to randomized treatment, in patients with HFREF (EF <45%; n = 1569) and HFPEF (EF ≥45%; n = 836) in the CHARM programme. The primary outcome was cardiovascular death or HF hospitalization. Estimated GFR decreased 9.0 ± 21 vs. 4.0 ± 21 mL/min/1.73 m2 with candesartan and placebo, respectively, and this was similar in HFREF and HFPEF. WRF developed more frequently with candesartan, 16% vs. 7%, P < 0.001, with similar findings in patients with HFREF and HFPEF. WRF was associated with a higher risk of the primary outcome: multivariable hazard ratio (HR) 1.26, 95% confidence interval 1.03–1.54, P = 0.022, in both treatment groups, and in both HFREF and HFPEF (P for interaction 0.98). In HFREF, WRF was mostly related to HF hospitalization, while in HFPEF, WRF seemed more associated with mortality. Conclusions GFR decreased more and WRF was more common with candesartan compared with placebo, and this was similar in HFREF and HFPEF. WRF was associated with worse outcomes in HFREF and HFPEF. Although no formal interaction was present, the association between candesartan treatment, WRF, and type of clinical outcome was slightly different between HFREF and HFPEF.

Renal function estimation and Cockroft-Gault formulas for predicting cardiovascular mortality in population-based, cardiovascular risk, heart failure and post-myocardial infarction cohorts: The Heart 'OMics' in AGEing (HOMAGE) and the high-risk myocardial infarction database initiatives.

Abstract: Renal impairment is a major risk factor for mortality in various populations. Three formulas are frequently used to assess both glomerular filtration rate (eGFR) or creatinine clearance (CrCl) and mortality prediction: body surface area adjusted-Cockcroft–Gault (CG-BSA), Modification of Diet in Renal Disease Study (MDRD4), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The CKD-EPI is the most accurate eGFR estimator as compared to a “gold-standard”; however, which of the latter is the best formula to assess prognosis remains to be clarified. This study aimed to compare the prognostic value of these formulas in predicting the risk of cardiovascular mortality (CVM) in population-based, cardiovascular risk, heart failure (HF) and post-myocardial infarction (MI) cohorts. Two previously published cohorts of pooled patient data derived from the partners involved in the HOMAGE-consortium and from four clinical trials – CAPRICORN, EPHESUS, OPTIMAAL and VALIANT – the high risk MI initiative, were used. A total of 54,111 patients were included in the present analysis: 2644 from population-based cohorts; 20,895 from cardiovascular risk cohorts; 1801 from heart failure cohorts; and 28,771 from post-myocardial infarction cohorts. Participants were patients enrolled in the respective cohorts and trials. The primary outcome was CVM. All formulas were strongly and independently associated with CVM. Lower eGFR/CrCl was associated with increasing CVM rates for values below 60 mL/min/m2. Categorical renal function stages diverged in a more pronounced manner with the CG-BSA formula in all populations (higher χ2 values), with lower stages showing stronger associations. The discriminative improvement driven by the CG-BSA formula was superior to that of MDRD4 and CKD-EPI, but remained low overall (increase in C-index ranging from 0.5 to 2%) while not statistically significant in population-based cohorts. The integrated discrimination improvement and net reclassification improvement were higher (P < 0.05) for the CG-BSA formula compared to MDRD4 and CKD-EPI in CV risk, HF and post-MI cohorts, but not in population-based cohorts. The CKD-EPI formula was superior overall to MDRD4. The CG-BSA formula was slightly more accurate in predicting CVM in CV risk, HF, and post-MI cohorts (but not in population-based cohorts). However, the CG-BSA discriminative improvement was globally low compared to MDRD4 and especially CKD-EPI, the latter offering the best compromise between renal function estimation and CVM prediction.

Risk of stroke in chronic heart failure patients with preserved ejection fraction, but without atrial fibrillation: analysis of the CHARM-Preserved and I-Preserve trials.

Abstract: Aims: The incidence and predictors of stroke in patients with heart failure and preserved ejection fraction (HF-PEF), but without atrial fibrillation (AF), are unknown. We described the incidence of stroke in HF-PEF patients with and without AF and predictors of stroke in those without AF. Methods and results: We pooled data from the CHARM-Preserved and I-Preserve trials. Using Cox regression, we derived a model for stroke in patients without AF in this cohort and compared its performance with a published model in heart failure patients with reduced ejection fraction (HF-REF)—predictive variables: age, body mass index, New York Heart Association class, history of stroke, and insulin-treated diabetes. The two stroke models were compared and Kaplan–Meier curves for stroke estimated. The risk model was validated in a third HF-PEF trial. Of the 6701 patients, 4676 did not have AF. Stroke occurred in 124 (6.1%) with AF and in 171 (3.7%) without AF (rates 1.80 and 1.00 per 100 patient-years, respectively). There was no difference in performance of the stroke model derived in the HF-PEF cohort and the published HF-REF model (c-index 0.71, 95% confidence interval 0.57–0.84 vs. 0.73, 0.59–0.85, respectively) as the predictive variables overlapped. The model performed well in the validation cohort (0.86, 0.62–0.99). The rate of stroke in patients in the upper third of risk approximated to that in patients with AF (1.60 and 1.80 per 100 patient-years, respectively). Conclusions: A small number of clinical variables identify a subset of patients with HF-PEF, but without AF, at elevated risk of stroke.

QRS Duration Is a Predictor of Adverse Outcomes in Heart Failure With Preserved Ejection Fraction.

Abstract: Objectives This study examined the relationship between baseline QRS duration and clinical outcomes in subjects enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Background Heart failure with preserved ejection fraction (HFPEF) is a heterogeneous clinical syndrome. Whether QRS duration identifies HFPEF subjects at an increased risk of adverse outcomes has not been well studied. Methods QRS duration was analyzed as a dichotomous variable (≥120 ms or Results The QRS duration of ≥120 ms was independently associated with an increased risk of the primary outcome (p = 0.009) and HFH (p = 0.003) in the entire study cohort and in the subset enrolled in the Americas. There was a linear relation of QRS duration with risk of the primary outcome and HFH. No interaction was observed between treatment with spironolactone and QRS duration. The risk of adverse outcomes was increased independently of the type of conduction abnormality underlying prolonged QRS duration. Conclusions This post hoc analysis demonstrated that prolonged QRS duration identifies HFPEF subjects at a higher risk of adverse clinical outcomes and that spironolactone had a similar effect on outcomes independent of QRS duration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302)

The Future of Clinical Trials in Cardiovascular Medicine.

Abstract: Few medical disciplines have been as influenced by the results of randomized controlled trials as cardiovascular medicine. Whether for the treatment of hypertension, acute myocardial infarction, use of specific interventional techniques, devices, or primary prevention, the randomized trial has emerged as the principal method by which new therapies are evaluated. Results of clinical trials have transformed cardiovascular practice from one that was anecdote based to one that is evidence based. Before the first outcomes trial in cardiovascular disease, the VA Cooperative trial1,2 in the late 1960s, clinicians based their practice on tradition, often steeped in unjustified beliefs about untested therapies, or hopelessly confounded observational studies. The switch from empirical therapy to therapies based on the results of well-performed and informative clinical trials ushered in the evidenced-based era in cardiovascular medicine. Today, the introduction of a new therapy would be unheard of without the justifying results from a randomized clinical outcome trial. Yet clinical trials in cardiovascular medicine have grown in size, scope, and complexity. As therapeutic approaches in cardiovascular medicine have become more effective, the level of evidence required to support incremental new advances has increased substantially. This fact, in conjunction with real and perceived increases in regulatory requirements, and the mandate for better estimation of cardiovascular safety for noncardiovascular therapies, have resulted in bloated and prohibitively expensive trials. Thus, despite the success of clinical trials in cardiovascular medicine over the past 25 years, the ability to bring new cardiovascular therapies to patients will require new approaches to curtail cost and maintain quality of future trials. A clinical trial, defined as “a prospective study evaluating the effect and value of intervention(s) against a control in human beings,”3 is generally designed for 1 of 2 purposes: hypothesis generation or hypothesis testing. The former requires careful, detailed testing …

Coronary Artery Disease Is a Predictor of Progression to Dialysis in Patients With Chronic Kidney Disease, Type 2 Diabetes Mellitus, and Anemia: An Analysis of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)

Abstract: Background Although clear evidence shows that chronic kidney disease is a predictor of cardiovascular events, death, and accelerated coronary artery disease (CAD) progression, it remains unknown whether CAD is a predictor of progression of chronic kidney disease to end‐stage renal disease. We sought to assess whether CAD adds prognostic information to established predictors of progression to dialysis in patients with chronic kidney disease, diabetes, and anemia. Methods and Results Using the previously described Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) population, we compared baseline characteristics of patients with and without CAD. Cox proportional hazards models were used to assess the association between CAD and the outcomes of end‐stage renal disease and the composite of death or end‐stage renal disease. Of the 4038 patients, 1791 had a history of known CAD. These patients were older (mean age 70 versus 65 years, P P P =0.04) and to have the composite of death or end‐stage renal disease (adjusted hazard ratio 1.15 [95% CI 1.01–1.30], P =0.03). Conclusions In patients with chronic kidney disease, diabetes, and anemia, a history of CAD is an independent predictor of progression to dialysis. In patients with diabetic nephropathy, a history of CAD contributes important prognostic information to traditional risk factors for worsening renal disease.

Severity of renal impairment in patients with heart failure and atrial fibrillation: implications for non-vitamin K antagonist oral anticoagulant dose adjustment

Abstract: Aims The non-vitamin K antagonist oral anticoagulants (NOACs) have varying degrees of renal elimination which may be challenging in patients with heart failure (HF) and atrial fibrillation (AF). We examined the severity and variation in renal impairment, and the proportion of patients requiring NOAC cessation or dose reduction. Methods and results A retrospective analysis of patients with HF and AF in the Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity programme was carried out. Trends in renal impairment over 26 months were defined using Cockcroft–Gault (CG), simplified Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Mean estimated glomerular filtration rate (eGFR) was worse at every time point in patients with AF compared with those without AF, the difference being ∼11 mL/min (CG), 9 mL/min (CKD-EPI), and 7 mL/min (MDRD). As renal function declined, CG classified a greater proportion of patients as having moderate or severe CKD and agreement with MDRD/CKD-EPI declined. At least moderate renal impairment was present in a quarter of patients with AF at baseline, a third by study completion, and approaching a half at least once during follow-up. The projected need for NOAC dose reduction was accordingly high, though it varied between individual NOACs due to different criteria for adjustment. Conclusions Renal impairment in patients with HF and AF is common, fluctuates, progresses, and frequently mandates NOAC dose reduction, though the need for cessation is rare. Baseline renal function, the method of estimating GFR, and intensity of monitoring should be considered when commencing oral anticoagulation.

Urine Injury Biomarkers and Risk of Adverse Outcomes in Recipients of Prevalent Kidney Transplants: The Folic Acid for Vascular Outcome Reduction in Transplantation Trial

Abstract: Recipients of kidney transplants (KTR) are at increased risk for cardiovascular events, graft failure, and death. It is unknown whether urine kidney injury biomarkers are associated with poor outcomes among KTRs. We conducted a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial using a case-cohort study design, selecting participants with adjudicated cardiovascular events, graft failure, or death. Urine neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver-type fatty acid binding protein (L-FABP) were measured in spot urine samples and standardized to urine creatinine concentration. We adjusted for demographics, cardiovascular risk factors, eGFR, and urine albumin-to-creatinine ratio. Patients had 291 cardiovascular events, 257 graft failure events, and 359 deaths. Each log increase in urine NGAL/creatinine independently associated with a 24% greater risk of cardiovascular events (adjusted hazard ratio [aHR], 1.24; 95% confidence interval [95% CI], 1.06 to 1.45), a 40% greater risk of graft failure (aHR, 1.40; 95% CI, 1.16 to 1.68), and a 44% greater risk of death (aHR, 1.44; 95% CI, 1.26 to 1.65). Urine KIM-1/creatinine and IL-18/creatinine independently associated with greater risk of death (aHR, 1.29; 95% CI, 1.03 to 1.61 and aHR, 1.25; 95% CI, 1.04 to 1.49 per log increase, respectively) but not with risk of cardiovascular events or graft failure. Urine L-FABP did not associate with any study outcomes. In conclusion, among prevalent KTRs, higher urine NGAL, KIM-1, and IL-18 levels independently and differentially associated with greater risk of adverse outcomes.

Lessons in Uncertainty and Humility — Clinical Trials Involving Hypertension

Abstract: Ethical issues can arise in the design and conduct of clinical trials. Using the trials that set the stage for our current treatment of hypertension, the authors show how the changing treatment landscape raised ethical problems as these trials were undertaken.

Pulse pressure is not an independent predictor of outcome in type 2 diabetes patients with chronic kidney disease and anemia--the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT)

Abstract: Pulse pressure (PP) remains an elusive cardiovascular risk factor with inconsistent findings. We clarified the prognostic value in patients with type 2 diabetes, chronic kidney disease (CKD) and anemia in the Trial to Reduce cardiovascular Events with Aranesp (darbepoetin alfa) Therapy. In 4038 type 2 diabetes patients, darbepoetin alfa treatment did not affect the primary outcome. Risk related to PP at randomization was evaluated in a multivariable model including age, gender, kidney function, cardiovascular disease (CVD) and other conventional risk factors. End points were myocardial infarction (MI), stroke, end stage renal disease (ESRD) and the composite of cardiovascular death, MI or hospitalization for myocardial ischemia, heart failure or stroke (CVD composite). Median (interquartile range) age, gender, eGFR and PP was 68 (60-75) years, 57.3% women, 33 (27-42) ml min(-1) per 1.73 m2 and 60 (50-74) mm Hg. During 29.1 months (median) follow-up, the number of events for composite CVD, MI, stroke and ESRD was 1010, 253, 154 and 668. In unadjusted analyses, higher quartiles of PP were associated with higher rates per 100 years of follow-up of all end points (P⩽0.04), except stroke (P=0.52). Adjusted hazard ratios (95% confidence interval) per one quartile increase in PP were 1.06 (0.99-1.26) for MI, 0.96 (0.83-1.11) for stroke, 1.01 (0.94-1.09) for ESRD and 1.01 (0.96-1.07) for CVD composite. Results were similar in continuous analyses of PP (per 10 mm Hg). In patients with type 2 diabetes, CKD and anemia, PP did not independently predict cardiovascular events or ESRD. This may reflect confounding by aggressive antihypertensive treatment, or PP may be too rough a risk marker in these high-risk patients.

Predicting Outcomes Over Time in Patients With Heart Failure, Left Ventricular Systolic Dysfunction, or Both Following Acute Myocardial Infarction

Abstract: Background Most studies of risk assessment or stratification in patients with myocardial infarction (MI) have been static and fail to account for the evolving nature of clinical events and care processes. We sought to identify predictors of mortality, cardiovascular death or nonfatal MI, and cardiovascular death or nonfatal heart failure (HF) over time in patients with HF, left ventricular systolic dysfunction, or both post‐MI. Methods and Results Using data from the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial, we developed models to estimate the association between patient characteristics and the likelihood of experiencing an event from the time of a follow‐up visit until the next visit. The intervals are: hospital arrival to discharge or 14 days, whichever occurs first; hospital discharge to 30 days; 30 days to 6 months; and 6 months to 3 years. Models were also developed to predict the entire 3‐year follow‐up period using baseline information. Multivariable Cox proportional hazards modeling was used throughout with Wald chi‐squares as the comparator of strength for each predictor. For the baseline model of overall mortality, the 3 strongest predictors were age (adjusted hazard ratio [HR], 1.35; 95% CI, 1.28–1.42; P <0.0001), baseline heart rate (adjusted HR, 1.17; 95% CI, 1.14–1.21; P <0.0001), and creatinine clearance (≤100 mL/min; adjusted HR, 0.86; 95% CI, 0.84–0.89; P <0.0001). According to the integrated discrimination improvement (IDI) and net reclassification improvement (NRI) indices, the updated model had significant improvement over the model with baseline covariates only in all follow‐up periods and with all outcomes. Conclusions Patient information assessed closest to the time of the outcome was more valuable in predicting death when compared with information obtained at the time of the index hospitalization. Using updated patient information improves prognosis over using only the information available at the time of the index event.

Abstract 17827: Impact of Spironolactone on Profibrotic Markers in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT)

Abstract: Introduction: The balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) reflects myocardial collagen turnover. Increases in collagen and Galectin-3 (Gal-3) are associated with cardiac fibrosis, a critical element in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Mineralocorticoid receptor antagonists (MRAs) reduce myocardial fibrosis in HF with reduced EF, however their role in HFpEF remains uncertain. Hypothesis: Several biomarkers associated with myocardial fibrosis are activated in HFpEF and the MRA spironolactone modifies their levels. Methods: Biomarkers were measured at baseline (n=443) and 1-year (n=367) in serum samples obtained for TOPCAT. Changes in Gal-3, procollagen type III amino-terminal propeptide (PIIINP), procollagen type I carboxy-terminal peptide (PICP), carboxy-terminal telopeptide of collagen type I (CITP), MMPs 2 and 9, TIMP-1 and MMP-2, 9/TIMP-1 ratios were analyzed using ANCOVA models adjusted for baseline biomarker levels and relevant clinical characteristics (Table). All biomarker levels were log transformed (non-normal distributions). We also explored regional variations in the effect of spironolactone on biomarker levels. Results: Use of spironolactone was associated with reductions in MMP-2 and increases in MMP-9, while TIMP-1 remained unchanged. MMP-9/TIMP-1 ratio and aldosterone increased significantly in all patients (Table). In North America, PICP levels were also significantly decreased (adjusted treatment effect -15%, P=0.015), but not in Russia. Gal-3, PIIINP and CITP levels were not affected by treatment in either region. Conclusions: The use of spironolactone in HFpEF is associated with significant changes in biomarkers that favor the degradation of collagen. Collagen type I (PICP, North America) appears most affected while collagen type III is unchanged (PIIINP); findings in agreement with a pressure overload model of HFpEF.

Effect of single and dual renin-angiotensin blockade on stroke in patients with and without diabetes in VALIANT

Abstract: Introduction Concern has been raised about a possible increase in risk of stroke in patients with diabetes treated with the combination of the renin-inhibitor aliskiren and an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. We compared the rate of stroke in patients with and without diabetes treated with single or dual renin-angiotensin system blockade after acute myocardial infarction.Patients and methods We performed a post hoc analysis of the Valsartan in Acute Myocardial Infarction trial in which 14,703 patients with heart failure, left ventricular systolic dysfunction or both, were randomised to captopril (C), valsartan (V) or both (C + V) after 0.5–10 days after acute myocardial infarction and followed for a median of 2.1 years. We used Cox proportional-hazard regression to estimate the hazard ratios [HR (95% CI)] of stroke in each treatment group.Results Among patients with diabetes, 60/1303 (4.6%) receiving captopril, 60/1337 (4.5%) valsartan and 41/1340 (3.1%) valsartan p...