Efficacy of simvastatin therapy in attainment of LDL-C and TG goal levels in patients with type 2 diabetic dyslipidemia.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) has been identified as the primary target of cholesterol-lowering therapy, with the LDL-C goal set at ≤100 mg/dL for patients at high risk, such as those with diabetes. OBJECTIVE: To evaluate the efficacy of simvastatin (S) in achieving LDL-C levels <70 mg/dL in patients with type 2 diabetes mellitus (DM). METHODS: This was a post-hoc analysis of a multicenter, randomized, double-blind, three-way crossover, placebo (PL)-controlled study that evaluated S80 mg or S40 mg versus PL for increasing high-density lipoprotein cholesterol (HDL-C). Patients with type 2 DM (n = 151), LDL-C >100 mg/dL, HDL-C <40 mg/dL, and triglycerides (TG) >150 and <700 mg/dL were randomized to daily S80 mg, S40 mg, or PL for three 6-week periods. The percentage of patients reaching LDL-C <70 mg/dL and the percentage reaching TG <150 mg/dL after 6 weeks was assessed. RESULTS: After 6 weeks, 59% (82 of 140) of patients in the S80 mg group achieved LDL-C <70 mg/dL versus 43% (60 of 139) receiving S40 m, and 0% (0 fo 140) in the PL group (P < 0.001 for S80 mg and S40 mg vs PL, and S80 mg vs S40 mg). In patients with coronary heart disease (CHD) (n = 32), 63% (20 of 32) receiving S80 mg reached LDL-C <70 mg/dL, versus 50% (15 of 30) in the S40 mg and 0% (0 of 32) in the PL group (P <0.001 for S80 mg and S40 mg vs PL, and P = 0.063 for S80 mg vs S40 mg). For TG levels, 27% (35 of 132) of the S80 mg patients and 23% (30 of 130) of the S40 mg patients reached a goal of TG <150 mg/dL. The dual goal of LDL-C level <70 mg/dL and TG level <150 mg/dL was attained by 14.7% of patients in the S80 mg, 7.8% in the S40 mg, and 0% in the PL group. CONCLUSION: S40 mg or S80 mg daily allowed 43% to 59% of patients with type 2 DM at risk of CHD to reach the goal of lowering LDL-C levels to the National Cholesterol Education Program Adult Treatment Panel III optional target level of <70 mg/dL. Reaching TG goals may require additional therapeutic considerations.

The effect of routine, early invasive management on outcome for elderly patients with non-ST-segment elevation acute coronary syndromes.

BACKGROUND: Although increasing age is an important risk factor for adverse outcome among patients with acute coronary syndromes, elderly patients are more often managed conservatively. OBJECTIVE: To examine outcome according to age and management strategy for patients with unstable angina and non-ST-segment elevation myocardial infarction (MI). DESIGN: Randomized, controlled trial conducted from December 1997 to June 2000. SETTING: 169 community and tertiary care hospitals in 9 countries. PATIENTS: 2220 patients hospitalized with unstable angina and non-ST-segment elevation MI who were randomly assigned to an early invasive or conservative management strategy. INTERVENTIONS: Medical therapy and coronary angiography at 4 to 48 hours versus medical therapy and predischarge exercise testing. MEASUREMENTS: Rates of 30-day and 6-month mortality, nonfatal MI, rehospitalization, stroke, and hemorrhagic complications. RESULTS: Among patients 65 years of age and older, the early invasive strategy compared with the conservative strategy yielded an absolute reduction of 4.8 percentage points (8.8% vs. 13.6%; P = 0.018) and a relative reduction of 39% in death or MI at 6 months. Outcomes of the 2 strategies were similar, however, among patients younger than 65 years of age (6.1% vs. 6.5%; P > 0.2). Among patients older than 75 years of age, the early invasive strategy conferred an absolute reduction of 10.8 percentage points (10.8% vs. 21.6%; P = 0.016) and a relative reduction of 56% in death or MI at 6 months. The additional cost per death or MI prevented with the early invasive strategy was lower for elderly patients, but major bleeding rates were higher with this strategy in patients older than 75 years of age (16.6% vs. 6.5%; P = 0.009). LIMITATIONS: Because this study involved patients in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial, its generalizability to elderly patients with excluded comorbid conditions is unknown. CONCLUSION: Despite an increased risk for major bleeding in patients older than 75 years of age, a routine early invasive strategy can significantly improve ischemic outcomes in elderly patients with unstable angina and non-ST-segment elevation MI.

Dorzolamide/Timolol fixed combination versus concomitant administration of brimonidine and timolol in patients with elevated intraocular pressure: a 3-month comparison of efficacy, tolerability, and patient-reported measures.

BACKGROUND: To compare the intraocular pressure (IOP) lowering effect, tolerability, and patient-reported measures of the dorzolamide/timolol fixed combination and the concomitant administration of brimonidine and timolol after 3 months. METHODS: Four hundred ninety-two patients with ocular hypertension, primary open-angle glaucoma, exfoliative glaucoma, or pigmentary glaucoma participated in this randomized, observer-masked, multicenter study. Following 3 weeks of timolol monotherapy, patients with a peak IOP of > or = 2 mm Hg were randomized to receive either fixed combination dorzolamide/timolol twice daily or concomitant brimonidine plus timolol twice daily for 3 months. The IOP-lowering effects at peak and trough, tolerability, and patient-reported convenience and satisfaction were measured at months 1 and 3. RESULTS: At month 3 peak, the dorzolamide/timolol group had an adjusted mean (SE) change from baseline IOP of -4.30 (0.24) mm Hg versus -5.27 (0.23) mm Hg in the brimonidine-plus-timolol group, with a treatment difference of 0.97 mm Hg (95% CI: 0.40, 1.53). At the month 3 trough timepoint and both month 1 timepoints, the 95% CIs of the treatment differences were within the prespecified comparability boundary of +/- 1.5 mm Hg. The incidence of drug-related adverse experiences was similar between treatment groups. Patient-reported assessments of convenience and satisfaction showed no statistically significant differences between treatment groups. CONCLUSIONS: The IOP-lowering effect of the dorzolamide/timolol fixed combination and concomitant brimonidine plus timolol were comparable at 3 of the 4 timepoints measured. Patient-reported measures and the incidence of adverse experiences in both treatment groups were similar.

Greater benefit of early invasive strategy for unstable angina and non-ST elevation myocardial infarction in United States compared with non-United States patients: a TACTICS-TIMI 18 substudy.

BACKGROUND: The TACTICS-TIMI 18 (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy - Thrombolysis in Myocardial Infarction 18) trial compared routine invasive to conservative care for the management of patients with unstable angina and non ST-elevation myocardial infarction, and included the routine use of the platelet glycoprotein IIb/IIIa inhibitor tirofiban in the initial medical stabilization of all patients. METHODS: Because previous trials utilizing IIb/IIIa inhibition for acute coronary syndrome (ACS) patients have demonstrated different outcomes in non-US and US patients, the authors sought to determine whether differences in baseline characteristics and practice patterns between 1844 US and 376 non-US patients and physicians would affect outcomes in the TACTICS-TIMI 18 trial. Event rates were stratified by treatment strategy and adjusted for baseline and treatment differences between cohorts. RESULTS: Although US subjects were more likely women, hypertensive, and diabetic, the US and non-US patients did not differ with respect to low, intermediate, or high TIMI risk scores. For US patients, the primary composite end point of death, myocardial infarction (MI), and rehospitalization for ACS was reduced with an invasive strategy by 40% (95% CI: 0.43-0.83) at 30 days and by 30% (95% CI: 0.55-0.88) at 180 days. Non-US patients managed conservatively had 35% fewer events at 180 days than their invasive counterparts resulting in no benefit for the invasive strategy (P = 0.016 for the interaction term between country and treatment group). Similar results were observed for the additional outcome of death and MI, and in troponin-positive patients. Adjustment for baseline characteristics, medications during the initial hospitalization, and the use of cardiac procedures suggested that a higher cross-over rate from conservative to invasive care in non-US patients (59% versus 49%, P = 0.02) was the most likely explanation for the lower event rate in the conservatively managed patients outside the US. CONCLUSION: US patients treated with tirofiban and early routine cardiac catheterization had a 30% reduction in major cardiac events by 6 months compared with those treated with tirofiban and a conservative (selective invasive) approach. Non-US patients treated conservatively had fewer events than US patients, which appears to be related to a higher rate of cross-over to invasive care. These findings emphasize the importance of both risk stratification and invasive management for ACS patients.

Dorzolamide/timolol combination versus concomitant administration of brimonidine and timolol: six-month comparison of efficacy and tolerability.

PURPOSE: To compare the efficacy and tolerability of the 2% dorzolamide/0.5% timolol combination ophthalmic solution twice daily to the concomitant administration of 0.2% brimonidine ophthalmic solution twice daily and 0.5% timolol ophthalmic solution twice daily. DESIGN: Randomized, multicenter, observer-masked, parallel-group study. PARTICIPANTS: Two hundred ninety-three patients with ocular hypertension or primary open-angle glaucoma participated. INTERVENTION: After an open-label 3-week 0.5% timolol run-in period, patients with an hour 2 intraocular pressure (IOP) of > or = 22 mmHg were randomly assigned to receive either the dorzolamide/timolol combination twice daily or the concomitant use of brimonidine twice daily and timolol twice daily (brimonidine + timolol) for 6 months. MAIN OUTCOME MEASURES: The IOP-lowering effects at hour 0 and hour 2 were collected at 1, 3, and 6 months. We hypothesized that both treatment regimens would have comparable hour 2 IOP-lowering effects at month 3. The treatments were considered comparable if the two-sided 95% confidence interval of the treatment difference was within +/- 1.5 mmHg. Tolerability data were also collected at 1, 3, and 6 months. RESULTS: The primary efficacy analysis was based on the modified intent-to-treat population. At month 3, hour 2, the dorzolamide/timolol group had an adjusted mean (standard error) change in IOP of -5.04 (0.30) mmHg versus -5.41 (0.30) mmHg in the brimonidine + timolol group, with a treatment difference of 0.36 (0.40) mmHg (95% confidence interval [CI] of -0.42-1.14 mmHg). At month 3, hour 0, the dorzolamide/timolol group had a change in IOP of -3.66 (0.29) mmHg versus -4.15 (0.28) mmHg in the brimonidine + timolol group, with a treatment difference of 0.49 (0.39) mmHg (95% CI of -0.27-1.25 mmHg). Likewise, at all other observed time points, the 95% confidence interval of the treatment difference was within +/- 1.5 mmHg. Ninety-three patients (64%) in the dorzolamide/timolol group and 88 patients (60%) in the brimonidine + timolol group had adverse experiences that were deemed drug related by the investigator, for which 7 patients (5%) in the dorzolamide/timolol group and 8 patients (5%) in the brimonidine + timolol group were discontinued from the study. CONCLUSIONS: The efficacy of the dorzolamide/timolol combination and the concomitant administration of brimonidine and timolol were comparable. The incidence of drug-related adverse experiences and the incidence of discontinuations caused by drug-related adverse experiences were similar between groups.