Evidence generation methods & evidence requirements
Biomarkers and assessment of drug efficacy in cardiovascular disease
This thesis develops a multiple risk parameter response efficacy (PRE) score that integrates the effect of a pharmaceutical on multiple risk parameters and which performs much better in predicting disease outcomes than any score based on changes in single on-target or off-target risk markers.
The test of a pharmaceutical's efficacy is usually its ability to decrease long-term disease outcomes, or to induce effect in so-called on target risk markers, like blood pressure and cholesterol for cardiovascular disease. Recent studies however indicate that a pharmaceutical's long-term effects are mediated by off-target risk markers, which should thus (also) be measured to predict long-term disease outcomes. In this thesis I demonstrate that antihypertensive pharmaceuticals that intervene in the renin-angiotensin-aldosterone-system and that affect long-term renal or cardiovascular outcome influence multiple risk parameters. I develop and show the benefit of a score that integrates effects on both on- and off-target risk markers to predict long-term outcomes. This score may help regulators evaluate a pharmaceutical's efficacy when long-term data are lacking and guide physicians and their patients in making therapeutic choices.
Results
- Smink PA, Miao Y, De Zeeuw D, Lambers Heerspink HJ. Drug-induced changes in risk/biomarkers and their relationship with renal and cardiovascular long-term outcome in patients with diabetes. In: Clin Chem, 2011; 57(2): 186-95. (journal publication)
- Smink PA, Bakker SJ, Laverman GD, Berl T, Cooper ME, De Zeeuw D, et al. An initial reduction in serum uric acid during angiotensin receptor blocker treatment is associated with cardiovascular protection: a post-hoc analysis of the RENAAL and IDNT trials. In: J Hypertens, 2012; 30(5): 1022-8. (journal publication)
- Smink PA, Hoekman J, Grobbee DE, Eijkemans MJC, Parving H-H, Persson F, et al. A prediction of the renal and cardiovascular efficacy of aliskiren in ALTITUDE using short-term changes in multiple risk markers. In: European Journal of Preventive Cardiology, 2013. (journal publication)
- Smink PA, Lambers Heerspink HJ, Gansevoort RT, de Jong PE, Hillege HL, Bakker SJ, et al. Albuminuria, estimated GFR, traditional risk factors, and incident cardiovascular disease: The PREVEND (Prevention of Renal and Vascular Endstage Disease) Study. In: Am J Kidney Dis, 2012; 60(5): 804-11. (journal publication)