Showing papers by "Marc A. Pfeffer published in 2012"

Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes

Abstract: Results The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P = 0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pres sures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). Conclusions The addition of aliskiren to standard therapy with renin–angiotensin system block ade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.)

Evaluation of Multiple Biomarkers of Cardiovascular Stress for Risk Prediction and Guiding Medical Therapy in Patients With Stable Coronary Disease

Abstract: Background—Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy. Methods and Results—We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin, in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker...

Mortality Rates in Trials of Subjects With Type 2 Diabetes

Abstract: Background— In randomized controlled trials (RCTs) of subjects with type 2 diabetes mellitus, mortality rates vary substantially. We sought to examine the inclusion and exclusion criteria of these RCTs to explore relationships with mortality. Methods and Results— MEDLINE database was searched from August 1980 through March 2011. Selection criterion included published RCTs of adults with type 2 diabetes mellitus of at least 1000 patients, reporting all-cause mortality and having follow-up duration of at least 1 year. Twenty-two trials were eligible. Annualized mortality rates were derived. Inclusion and exclusion criteria were tabulated for each trial. Trials were categorized in 4 groups according to annual mortality rates: <1, ≥1 to <2, ≥2 to <4, and ≥4 per 100 patient-years. The analysis cohort included 91842 patients and 6837 deaths. Mortality rates ranged from 0.28 to 8.24 per 100 patient-years. Patients enrolled in the highest mortality category were more likely to be older and had longer diabetes duration and higher blood pressure. The selection for hypertension was common in the low- as well as high-mortality trials. Although the mortality rates were higher in RCTs with prior cardiovascular morbidity, the selection for chronic kidney disease—defined by either higher serum creatinine or lower estimated glomerular filtration rate and/or the presence of proteinuria—was associated with the highest mortality rates. Conclusions— In this analysis of RCTs of type 2 diabetes mellitus, a 29-fold difference in annualized mortality was observed. In these RCTs, selection for renal disease, defined by either decline in renal function or presence of proteinuria, portends important mortality risk.

Utilizing the integrated difference of two survival functions to quantify the treatment contrast for designing, monitoring, and analyzing a comparative clinical study.

Abstract: Background Consider a comparative, randomized clinical study with a specific event time as the primary end point. In the presence of censoring, standard methods of summarizing the treatment difference are based on Kaplan-Meier curves, the logrank test, and the point and interval estimates via Cox's procedure. Moreover, for designing and monitoring the study, one usually utilizes an event-driven scheme to determine the sample sizes and interim analysis time points. Purpose When the proportional hazards (PHs) assumption is violated, the logrank test may not have sufficient power to detect the difference between two event time distributions. The resulting hazard ratio estimate is difficult, if not impossible, to interpret as a treatment contrast. When the event rates are low, the corresponding interval estimate for the 'hazard ratio' can be quite large due to the fact that the interval length depends on the observed numbers of events. This may indicate that there is not enough information for making inferences about the treatment comparison even when there is no difference between two groups. This situation is quite common for a postmarketing safety study. We need an alternative way to quantify the group difference. Methods Instead of quantifying the treatment group difference using the hazard ratio, we consider an easily interpretable and model-free parameter, the integrated survival rate difference over a prespecified time interval, as an alternative. We present the inference procedures for such a treatment contrast. This approach is purely nonparametric and does not need any model assumption such as the PHs. Moreover, when we deal with equivalence or noninferiority studies and the event rates are low, our procedure would provide more information about the treatment difference. We used a cardiovascular trial data set to illustrate our approach. Results The results using the integrated event rate differences have a heuristic interpretation for the treatment difference even when the PHs assumption is not valid. When the event rates are low, for example, for the cardiovascular study discussed in this article, the procedure for the integrated event rate difference provides tight interval estimates in contrast to those based on the event-driven inference method. Limitations The design of a trial with the integrated event rate difference may be more complicated than that using the event-driven procedure. One may use simulation to determine the sample size and the estimated duration of the study. Conclusions The procedure discussed in this article can be a useful alternative to the standard PHs method in the survival analysis.

The many faces of heart failure with preserved ejection fraction.

Abstract: By definition, patients with heart failure and preserved ejection fraction are characterized by a normal or near-normal left ventricular ejection fraction, but marked heterogeneity in the extent of other cardiac structural and functional abnormalities exists. Improved appreciation of this diversity might provide insights into prognosis and therapeutic interventions.

Baseline characteristics in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE):

Abstract: Introduction: Patients with type 2 diabetes are at enhanced risk for macro- and microvascular complications. Albuminuria and/or reduced kidney function further enhances the vascular risk. We initiated the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). Aliskiren, a novel direct renin inhibitor, which lowers plasma renin activity, may thereby provide greater cardio-renal protection compared with angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) alone. Materials and methods: ALTITUDE is a randomized, double-blind, placebo-controlled study in high risk type 2 diabetic patients receiving aliskiren 300 mg once daily or placebo added to recommended cardio-renal protective treatment including ACEi or ARB, but not both. The number of patients randomized was 8606. Results: Baseline characteristics (median, IQR) are: age 65 (58, 72) years, male 68%, BMI 29.1 (25.7, 32.2) kg/m 2 , cardiovascular disease 47.9%, blood pressure 134.7 (126, 150)/74.3 (67, 81) mmHg, HbA1c 7.5 (6.6, 8.6)%, LDL-cholesterol 2.4 (1.9, 3.0) mmol/L, haemoglobin 130 (119, 143) g/L, serum creatinine 115 (91, 137) µmol/L, eGFR 51.7 (42, 65) ml/min per 1.73 m 2 , geometric mean UACR 198.9 (52, 2886) mg/g and frequency of micro/macroalbuminuria 25.7% and 58.2%. ALTITUDE is an event-driven trial to continue until 1628 patients experience a primary cardiovascular-renal event. Conclusions: ALTITUDE will determine the potential cardio-renal benefit and safety of aliskiren in combination with ACEi or ARB in high risk patients with type 2 diabetes.

Left ventricular systolic and diastolic function, remodelling, and clinical outcomes among patients with diabetes following myocardial infarction and the influence of direct renin inhibition with aliskiren

Abstract: Aims We assessed the relationship between diabetes and cardiac structure and function following myocardial infarction (MI) and whether diabetes influences the effect of direct renin inhibition on change in left ventricular (LV) size. Methods and results The ASPIRE trial enrolled 820 patients 2–8 weeks after MI with ejection fraction ≤45% and randomized them to the direct renin inhibitor aliskiren (n= 423) or placebo (n = 397) added to standard medical therapy. Echocardiography was performed at baseline and after 36 weeks in 672 patients with evaluable paired studies. Compared with non-diabetic patients, diabetic patients (n = 214) were at higher risk for a composite of cardiovascular (CV) death, heart failure hospitalization, recurrent MI, stroke, or aborted sudden death (14 vs. 7%; adjusted hazard ratio 1.63, 95% confidence interval 1.01–2.64, P= 0.045), despite similar left ventricular ejection fraction (37.9 ± 5.3 vs. 37.6 ± 5.2%, P= 0.48) and end-systolic volume (ESV) (84 ± 25 vs. 82 ± 28 mL, P= 0.46). Diabetic patients demonstrated greater concentric remodelling (relative wall thickness 0.38 ± 0.07 vs. 0.36 ± 0.07, P= 0.0002) and evidence of higher LV filling pressure (E/E′ 11.1 ± 5.3 vs. 9.1 ± 4.3, P= 0.0011). At 36 weeks, diabetic patients experienced similar per cent reduction in ESV overall (−4.9 ± 17.9 vs. −5.5 ± 16.9, P= 0.67) but tended to experience greater reduction in ESV than non-diabetic patients when treated with aliskiren (interaction P = 0.08). Conclusions Compared with non-diabetic patients, diabetic patients are at increased risk of CV events post-MI despite no greater LV enlargement or reduction in systolic function. Diabetic patients demonstrate greater concentric remodelling and evidence of higher LV filling pressure, suggesting diastolic dysfunction as a potential mechanism for the higher risk observed among these patients.

Mechanisms and predictors of mitral regurgitation after high-risk myocardial infarction.

Abstract: Background Mitral regurgitation (MR) has been associated with adverse outcomes after myocardial infarction (MI). Without structural valve disease, functional MR has been related to left ventricular (LV) remodeling and geometric deformation of the mitral apparatus. The aims of this study were to elucidate the mechanistic components of MR after high-risk MI and to identify predictors of MR progression during follow-up. Methods The Valsartan in Acute Myocardial Infarction Echo substudy prospectively enrolled 610 patients with LV dysfunction, heart failure, or both after MI. MR at baseline, 1 month, and 20 months was quantified by mapping jet expansion in the left atrium in 341 patients with good-quality echocardiograms. Indices of LV remodeling, left atrial size, and diastolic function and parameters of mitral valve deformation, including tenting area, coaptation depth, anterior leaflet concavity, annular diameters, and contractility, were assessed and related to baseline MR. The progression of MR was further analyzed, and predictors of worsening among the baseline characteristics were identified. Results Tenting area, coaptation depth, annular dilatation, and left atrial size were all associated with the degree of baseline MR. Tenting area was the only significant and independent predictor of worsening MR; a tenting area of 4 cm 2 was a useful cutoff to identify worsening of MR after MI and moderate to severe MR after 20 months. Conclusions Increased mitral tenting and larger mitral annular area are determinants of MR degree at baseline, and tenting area is an independent predictor of progression of MR after MI. Although LV remodeling itself contributes to ischemic MR, this influence is directly dependent on alterations in mitral geometry.