Is lower and lower better and better? A re-evaluation of the evidence from the Cholesterol Treatment Trialists' Collaboration meta-analysis for low-density lipoprotein lowering.
ABSTRACT Researchers from the Cholesterol Treatment Trialists' (CTT) Collaboration have argued for maximal lowering of low-density lipoprotein cholesterol (LDL-C) by the use of pharmacologic agents, with the strongest evidence coming from the five comparison statin studies in their second meta-analysis. The CTT meta-analysis has many strengths but also a number of limitations, which have not been discussed and which, given the clinical implications, require consideration. Among these are: (1) the impact and validity of including revascularizations within a composite primary end point; (2) the inclusion of the A-Z study, whose design does not allow for valid comparisons of two statin regimens; (3) the fact that baseline LDL-C levels in the comparison studies were not low enough to test whether statin therapy reduces risk significantly in groups with an initial low LDL-C; and, most important, (4) authors of the five studies compared doses at the extremes of statin regimens. However, the clinical choice is not between the lowest and the greatest dose of a statin statin regimens, for example, between 10 and 80 mg atorvastatin, but, more realistically, between intermediate and high dose, that is, between 40 and 80 mg atorvastatin. On the basis of the CTT meta-analysis, we calculate that any potential gain from increasing the dose from 40 to 80 mg atorvastatin would be very small, at best a further 2% further reduction in clinical events. The increase in dose, unfortunately, would likely be associated with increased side effects and decreased compliance. Accordingly, whether net benefit would be demonstrable cannot be assumed. It follows that definitive evidence supporting maximal lowering of LDL-C or maximal dose of statins is still lacking and guidelines, if they are to be evidence-based, should acknowledge this uncertainty.
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ABSTRACT: Unfortunately, abundant examples could be given of pitfalls in the current drug development paradigm-including in the design, conduct and evaluation of phase III clinical trials. This article discusses issues of particular relevance to clinical trials in nephrology, including the inappropriate use of placebo, publication of reports that emphasize potential treatment benefits over adverse reactions, the sometimes dubious impartiality of independent guidelines, and inadequate recruitment of elderly patients. This Perspectives article aims to highlight and summarize the flaws in the current drug development process, while suggesting a way forward that equally satisfies the requirements of academia, patients and the pharmaceutical industry. We suggest improvements to the drug development process and related legislation that intend to balance public needs with commercial aims and ensure effective drug evaluation by regulatory authorities.Nature Reviews Nephrology 08/2014; · 8.37 Impact Factor
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ABSTRACT: The phase 3 ODYSSEY OPTIONS studies (OPTIONS I, NCT01730040; OPTIONS II, NCT01730053) are multicenter, multinational, randomized, double-blind, active-comparator, 24-week studies evaluating the efficacy and safety of alirocumab, a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, as add-on therapy in ∼ 650 high-cardiovascular (CV)-risk patients whose low-density lipoprotein cholesterol (LDL-C) levels are ≥100 mg/dL or ≥70 mg/dL according to the CV-risk category, high and very high CV risk, respectively, with atorvastatin (20–40 mg/d) or rosuvastatin (10–20 mg/d). Patients are randomized to receive alirocumab 75 mg via a single, subcutaneous, 1-mL injection by prefilled pen every 2 weeks (Q2W) as add-on therapy to atorvastatin (20–40 mg) or rosuvastatin (10–20 mg); or to receive ezetimibe 10 mg/d as add-on therapy to statin; or to receive statin up-titration; or to switch from atorvastatin to rosuvastatin (OPTIONS I only). At week 12, based on week 8 LDL-C levels, the alirocumab dose may be increased from 75 mg to 150 mg Q2W if LDL-C levels remain ≥100 mg/dL or ≥70 mg/dL in patients with high or very high CV risk, respectively. The primary efficacy endpoint in both studies is difference in percent change in calculated LDL-C from baseline to week 24 in the alirocumab vs control arms. The studies may provide guidance to inform clinical decision-making when patients with CV risk require additional lipid-lowering therapy to further reduce LDL-C levels. The flexibility of the alirocumab dosing regimen allows for individualized therapy based on the degree of LDL-C reduction required to achieve the desired LDL-C level.Clinical Cardiology 09/2014; · 1.83 Impact Factor
- European Heart Journal 06/2014; · 14.72 Impact Factor