Sirolimus versus paclitaxel coronary stents in clinical practice

Objectives: We aimed at comparing the long term clinical outcome of SES and PES in routine clinical practice. Background: Although sirolimus-eluting stents (SES) more effectively reduce neointimal hyperplasia than paclitaxel-eluting stents (PES), uncertainty prevails whether this difference translates into differences in clinical outcomes outside randomized controlled trials with selected patient populations and protocol-mandated angiographic follow-up. Methods: Nine hundred and four consecutive patients who underwent implantation of a drug-eluting stent between May 2004 and February 2005: 467 patients with 646 lesions received SES, 437 patients with 600 lesions received PES. Clinical follow-up was obtained at 2 years without intervening routine angiographic follow-up. The primary endpoint was a composite of death, myocardial infarction (MI), or target vessel revascularization (TVR). Results: At 2 years, the primary endpoint was less frequent with SES (12.9%) than PES (17.6%, HR = 0.70, 95% CI 0.50–0.98, P = 0.04). The difference in favor of SES was largely driven by a lower rate of target lesion revascularisation (TLR; 4.1% vs. 6.9%, P = 0.05), whereas rates of death (6.4% vs. 7.6%, P = 0.49), MI (1.9% vs. 3.2%, P = 0.21), or definite stent thrombosis (0.6% vs. 1.4%, P = 0.27) were similar for both stent types. The benefit regarding reduced rates of TLR was significant in nondiabetic (3.6% vs. 7.1%, P = 0.04) but not in diabetic patients (5.6% vs. 6.1%, P = 0.80). Conclusions: SES more effectively reduced the need for repeat revascularization procedures than PES when used in routine clinical practice. The beneficial effect is maintained up to 2 years and may be less pronounced in diabetic patients.

Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism

Cytochrome P450 3A4 (CYP3A4), the major P450 present in human liver metabolizes approximately half the drugs in clinical use and requires electrons supplied from NADPH through NADPH-P450 reductase (POR, CPR). Mutations in human POR cause a rare form of congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. In this study we examined the effect of mutations in POR on CYP3A4 activity. We used purified preparations of wild type and mutant human POR and in vitro reconstitution with purified CYP3A4 to perform kinetic studies. We are reporting that mutations in POR identified in patients with disordered steroidogenesis/Antley-Bixler syndrome (ABS) may reduce CYP3A4 activity, potentially affecting drug metabolism in individuals carrying mutant POR alleles. POR mutants Y181D, A457H, Y459H, V492E and R616X had more than 99% loss of CYP3A4 activity, while POR mutations A287P, C569Y and V608F lost 60-85% activity. Loss of CYP3A4 activity may result in increased risk of drug toxicities and adverse drug reactions in patients with POR mutations.