Jennifer Ng

The effect of finasteride in men with benign prostatic hyperplasia

Background Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5 alpha-reductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. Methods In a double-blind study, we evaluated the effect of two doses of finasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 men with prostatic hyperplasia. Urinary symptoms, urinary flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the treatment period. Results As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P less than 0.001), an increase of 1.6 ml per second (22 percent, P less than 0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P less than 0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. Conclusions The treatment of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction.

Off-Pump or On-Pump Coronary-Artery Bypass Grafting at 30 Days

BACKGROUND The relative benefits and risks of performing coronary-artery bypass grafting (CABG) with a beating-heart technique (off-pump CABG), as compared with cardiopulmonary bypass (on-pump CABG), are not clearly established. METHODS At 79 centers in 19 countries, we randomly assigned 4752 patients in whom CABG was planned to undergo the procedure off-pump or on-pump. The first coprimary outcome was a composite of death, nonfatal stroke, nonfatal myocardial infarction, or new renal failure requiring dialysis at 30 days after randomization. RESULTS There was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (9.8% vs. 10.3%; hazard ratio for the off-pump group, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P=0.59) or in any of its individual components. The use of off-pump CABG, as compared with on-pump CABG, significantly reduced the rates of blood-product transfusion (50.7% vs. 63.3%; relative risk, 0.80; 95% CI, 0.75 to 0.85; P<0.001), reoperation for perioperative bleeding (1.4% vs. 2.4%; relative risk, 0.61; 95% CI, 0.40 to 0.93; P=0.02), acute kidney injury (28.0% vs. 32.1%; relative risk, 0.87; 95% CI, 0.80 to 0.96; P=0.01), and respiratory complications (5.9% vs. 7.5%; relative risk, 0.79; 95% CI, 0.63 to 0.98; P=0.03) but increased the rate of early repeat revascularizations (0.7% vs. 0.2%; hazard ratio, 4.01; 95% CI, 1.34 to 12.0; P=0.01). CONCLUSIONS There was no significant difference between off-pump and on-pump CABG with respect to the 30-day rate of death, myocardial infarction, stroke, or renal failure requiring dialysis. The use of off-pump CABG resulted in reduced rates of transfusion, reoperation for perioperative bleeding, respiratory complications, and acute kidney injury but also resulted in an increased risk of early revascularization. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294.).

The Effect of Finasteride in Men with Benign Prostatic Hyperplasia

BACKGROUND Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5 alpha-reductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. METHODS In a double-blind study, we evaluated the effect of two doses of finasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 men with prostatic hyperplasia. Urinary symptoms, urinary flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the treatment period. RESULTS As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P less than 0.001), an increase of 1.6 ml per second (22 percent, P less than 0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P less than 0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. CONCLUSIONS The treatment of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction.

Multicenter, randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer.

A total of 28 untreated patients with asymptomatic, stage D prostate cancer was randomized in a double-blinded fashion to receive finasteride (10 mg. per day), a 5 alpha-reductase inhibitor or placebo. Patients were evaluated at 3-week intervals by rectal examination, and serum prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) levels, and at 6-week intervals by bone scan and transrectal ultrasound determinations of prostatic volume. Patients stopped the medication at week 6 at the discretion of the investigator when PSA levels increased from baseline. After 12 weeks all patients were reevaluated. Of the patients 13 received finasteride and 15 received placebo. The 2 groups did not differ statistically with respect to patient age, initial PSA and PAP level, or the extent of metastases on initial bone scan. A statistically significant decrease in the median percentage change from baseline in PSA at weeks 3 and 6 occurred in the finasteride group compared to the placebo group (-22.9% versus -2.9% and -15.1% versus +11.7%, respectively, p less than 0.05). Finasteride had no effect upon PAP, serum testosterone, prostatic volume or appearance of bone scans. A decrease in serum PSA in the finasteride treatment group suggests that finasteride exerts a minor effect in patients with prostate cancer. This effect does not approach that seen with medical or surgical castration yet because of the potency preserving feature and the lack of toxicity finasteride may warrant further study in the treatment of prostate cancer.

Efficacy and Tolerability Profile of Etoricoxib in Patients with Osteoarthritis: A Randomized, Double-blind, Placebo and Active- comparator Controlled 12-Week Efficacy Trial

Summary Objective: To evaluate the efficacy of 12 weeks of treatment with etoricoxib, a selective COX-2 inhibitor, in patients with osteoarthritis (OA) of the knee or hip. Methods: In the 12-week placebo- and active comparator-controlled period of a randomized, double-blind study, eligible patients were treated with etoricoxib 60 mg once daily (n = 224), naproxen 500 mg twice daily (n = 221), or placebo (n = 56). Western Ontario McMasters Osteoarthritis Index (WOMAC) pain and physical function subscales and patients global assessment of disease status were primary end points. Key secondary and other end points were patients and investigators global assessment of response to therapy, WOMAC stiffness subscale, investigators global assessment of disease status, rescue paracetamol use, proportion of patients discontinuing due to lack of efficacy, and study joint tenderness. Results: Etoricoxib 60 mg demonstrated efficacy significantly superior to placebo (p ≤ 0.005) and comparable to naproxen 500mg twice daily as assessed by the primary efficacy end points. Secondary and other end points confirmed these results. Treatment effects were evident by day 2, maximal by week 2, and sustained over the entire 12 weeks. Etoricoxib was well tolerated for 12 weeks. Conclusions: Etoricoxib showed rapid and durable treatment effects in patients with OA of the knee or hip. Etoricoxib was generally well tolerated.

Net clinical benefit of adding clopidogrel to aspirin therapy in patients with atrial fibrillation for whom vitamin K antagonists are unsuitable.

BACKGROUND Adding clopidogrel to aspirin therapy reduces stroke in patients with atrial fibrillation (AF) but increases hemorrhage. OBJECTIVE To quantify the net benefit of adding clopidogrel to aspirin therapy, accounting for differences in clinical significance between ischemic and hemorrhagic events. DESIGN Observational cohort study to assign the relative weighting of events and post hoc analysis of randomized trial data to assess net benefit of dual antiplatelet therapy in the ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) clinical trials. SETTING Global randomized clinical trial. PATIENTS 10,041 patients with AF, 7554 of whom were not candidates for warfarin therapy. MEASUREMENTS Ischemic events (ischemic stroke or myocardial infarction) and hemorrhagic events (hemorrhagic stroke or subdural or extracranial bleeding), weighted by the hazard ratio for death (or death or disability) after an event relative to death (or death or disability) after ischemic stroke. The net clinical benefit of dual antiplatelet therapy in the ACTIVE A trial participants was defined as the sum of weighted event incidence with dual antiplatelet therapy subtracted from the sum of weighted event incidence on control treatment, expressed as ischemic stroke equivalents prevented per 100 patients years. RESULTS Adding clopidogrel to aspirin therapy prevented 0.57 ischemic stroke equivalent (95% CI, -0.12 to 1.24) per 100 patient-years of treatment when weighted by hazard for death after ischemia or hemorrhage and 0.67 ischemic stroke equivalent (CI, -0.03 to 1.18) when weighted by death or disability after ischemia or hemorrhage. LIMITATION No attempt was made to relate deaths used for weighting to events; disability data were missing for more than one half of patients. CONCLUSION Adding clopidogrel to aspirin therapy resulted in a modest net benefit among patients with AF for whom warfarin was unsuitable. The benefit would probably be clinically relevant for some patients, but estimates could not exclude the possibility of either no benefit or very small harm in this population. PRIMARY FUNDING SOURCE Bristol-Myers Squibb and sanofi-aventis.

Renal effects of etoricoxib and comparator nonsteroidal anti-inflammatory drugs in controlled clinical trials

BACKGROUND Based on the experience with selective cyclooxygenase (COX)-2 inhibitors, including rofecoxib, valdecoxib, and celecoxib, it was anticipated that etoricoxib, a new selective COX-2 inhibitor, would display mechanism-based, dose-dependent renal adverse effects (AEs) similar to those observed with nonselective non-steroidal anti-inflammatory drugs (NSAIDs) in long-term treatment. OBJECTIVE The present analysis examined pooled safety data from the etoricoxib clinical development program with the aim of comparing the renal AE profiles of etoricoxib 60, 90, and 120 mg/d with those of approved therapeutic dosages of the comparator nonselective NSAIDs, naproxen 1000 mg/d and ibuprofen 2400 mg/d, and with that of placebo. METHODS The etoricoxib program database included data from 8 placebo-controlled Phase III studies of osteoarthritis, rheumatoid arthritis, and chronic low back pain. As part of the program-wide assessment of etoricoxib, the investigator-reported incidence of and discontinuations due to renal AEs, including hypertension, lower-extremity edema (LEE), elevated serum creatinine concentration (SCC), and congestive heart failure (CHF) were examined. RESULTS Data from 4770 patients were included in the analysis. Most patients were women (69.0%-80.3%), and most were white (68.0%-83.3%). The mean (SD) age at baseline ranged from 53.6 (12.1) to 62.2 (8.4) years. Overall, the incidence of renal AEs was low and generally similar between the active-treatment groups. In the placebo; etoricoxib 60-, 90-, and 120-mg; naproxen, and ibuprofen groups, the incidences of hypertension were 2.0%, 4.0%, 3.4%, 4.7%, 2.9%, and 6.6%, respectively, and the incidences of LEE were 1.9%, 3.2%, 1.5%, 1.3%, 2.3%, and 1.8%, respectively. The only significant difference found was the incidence of hypertension with etoricoxib 90 mg/d versus that with placebo (P=0.001); however, the rates of hypertension observed with etoricoxib at any dosage were not clinically meaningfully different versus comparator NSAIDs. Also, LEE was rarely of clinical significance with etoricoxib or comparator NSAIDs; related discontinuations were infrequent in all treatment groups. In addition, the incidences of elevated SCC and CHF were low among active-treatment groups (0.0% to 0.8% and 0.0% to 0.2%, respectively). CONCLUSIONS Based on this combined data review, the risks for renal AEs (i.e., hypertension, LEE, elevated SCC changes, and CHF) with etoricoxib 60, 90, and 120 mg/d were low, with a shallow dose response, and were generally similar to those found with the comparator NSAIDs naproxen 1000 mg/d and ibuprofen 2400 mg/d.