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1.
Clin Pharmacol Ther ; 95(2): 208-15, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24067744

ABSTRACT

Angiotensin receptor blockers (ARBs) have multiple effects that may contribute to their efficacy on renal/cardiovascular outcomes. We developed and validated a risk score that incorporated short-term changes in multiple risk markers to predict the ARB effect on renal/cardiovascular outcomes. The score was used to predict renal/cardiovascular risk at baseline and at month 6 in the ARB treatment arm of the Reduction of Endpoints in NIDDM (noninsulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial. The net risk difference at these time points indicated the estimated long-term renal/cardiovascular treatment effect. Predicted relative risk reductions (RRRs) based on multiple markers were close to observed RRRs for renal (RRR(predicted): 30.1% vs. RRR(observed): 21.8%; P = 0.44) and cardiovascular outcomes (RRR(predicted): 9.4% vs. RRR(observed): 9.2%; P = 0.98), in addition to being markedly more accurate than predicted RRRs based on changes in single markers. The score was validated in an independent ARB trial. Predictions of long-term renal/cardiovascular ARB effects are more accurate when considering short-term changes in multiple risk markers, challenging the use of single markers to establish drug efficacy.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Cardiovascular Diseases/prevention & control , Kidney Diseases/prevention & control , Antihypertensive Agents/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Humans , Losartan/therapeutic use , Risk Reduction Behavior , Time Factors , Treatment Outcome
2.
Eur J Prev Cardiol ; 21(4): 434-41, 2014 Apr.
Article in English | MEDLINE | ID: mdl-23467676

ABSTRACT

INTRODUCTION: We recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted. METHODS: We established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change. RESULTS: Based on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of -7.9% (95% CI -2.5 to -13.4) for the cardio-renal endpoint, a risk change of -5.1% (-1.2 to -9.0) for the CV endpoint and a non-significant risk change of -19.9% (-42.1 to +2.1) for the renal endpoint. CONCLUSIONS: PRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.


Subject(s)
Amides/therapeutic use , Antihypertensive Agents/therapeutic use , Cardiovascular Diseases/prevention & control , Decision Support Techniques , Diabetes Mellitus, Type 2/drug therapy , Diabetic Nephropathies/prevention & control , Fumarates/therapeutic use , Renin-Angiotensin System/drug effects , Aged , Algorithms , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Biomarkers/blood , Cardiovascular Diseases/blood , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/etiology , Cardiovascular Diseases/physiopathology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/physiopathology , Diabetic Nephropathies/blood , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/etiology , Diabetic Nephropathies/physiopathology , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome
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