Kenneth L. McCall

Effect of Angiotensin‐Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Blockers on the Rate of New‐Onset Diabetes Mellitus: A Review and Pooled Analysis

The rising prevalence and health burden of diabetes mellitus require that new approaches for prevention among high‐risk populations be evaluated. Emerging evidence from the prospective evaluations of secondary and tertiary outcomes and from retrospective evaluations in randomized controlled trials suggests that angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs) may reduce the occurrence of new‐onset diabetes. Therefore, we each independently searched MEDLINE for randomized controlled trials from January 1966–October 2005 that used an ACE inhibitor or ARB as a primary intervention versus a control group not receiving an ACE inhibitor or ARB and that reported the occurrence of diabetes. Thirteen trials were identified. In each of the 13 studies, the frequency of diabetes in the ACE inhibitor or ARB groups was lower than that in the control groups. In addition, it was consistent in that no study significantly excluded any benefit from ACE inhibitors or ARBs on the rate of new‐onset diabetes. The combined occurrence of new‐onset diabetes in all 13 studies was 2249 cases among 31,283 patients (7.2%) in the ACE inhibitor or ARB group versus 3230 cases among 35,988 patients (9.0%) in the control group. The combined relative risk of diabetes was 0.80, with a 95% confidence interval of 0.76–0.84, based on a two‐sided α of 0.05, in favor of ACE inhibitors and ARBs. This observation needs to be confirmed by randomized controlled trials with the frequency of diabetes as the primary prospective end point.

Retrospective Evaluation of a Possible Interaction Between Warfarin and Levofloxacin

Study Objectives. In order to clarify the clinical significance of a suspected drug interaction, we sought to determine if the international normalized ratio (INR) is affected when levofloxacin is administered in patients receiving long‐term warfarin therapy.

Determination of the Lack of a Drug Interaction Between Azithromycin and Warfarin

Study Objective. To determine the effect on the international normalized ratio (INR) of adding azithromycin to patients receiving stable dosages of warfarin.

Ximelagatran: A New Era in Oral Anticoagulation

Objective: To review the pharmacology, pharmacokinetics, and clinical trials of the oral direct thrombin inhibitor ximelagatran. Data Sources: All primary articles involving ximelagatran or its active form, melagatran, and indexed on MEDLINE or International Pharmaceutical Abstracts databases (1966–December 2002) were evaluated. Recent ximelagatran and melagatran abstracts were also obtained online from the American Society of Hematology at www.hematology.org/meeting/abstracts.cfm (2001 and 2002). Data Synthesis: Ximelagatran is an orally bioavailable prodrug of melagatran that directly blocks unbound thrombin and fibrin-bound thrombin. Ximelagatran displays predictable pharmacodynamic and pharmacokinetic properties with a linear dose–response relationship and low interpatient variability. These parameters allow fixed dosing of ximelagatran without routine coagulation monitoring. Ximelagatran has yet to be approved by the FDA; however, several major clinical trials have been completed. These clinical trials have revealed that an easier-to-manage ximelagatran regimen is at least as effective and has a similar safety profile as conventional therapy for prevention of venous thromboembolism (VTE). The results of studies with ximelagatran for treatment of VTE and prevention of thrombosis associated with atrial fibrillation are promising, but need further investigation. Conclusions: Ximelagatran possesses several advantages over warfarin including fixed dosing and the lack of coagulation monitoring, the absence of known diet or drug interactions, and a faster onset of action. Ximelagatran appears to be at least as effective as warfarin for prevention of VTE. Further research is needed with ximelagatran in the treatment of VTE and atrial fibrillation.