Efficacy and Tolerability of Telmisartan/Amlodipine and Rosuvastatin Coadministration in Hypertensive Patients with Hyperlipidemia: A Phase III, Multicenter, Randomized, Double-blind Study.

PURPOSE: Dyslipidemia and hypertension increase the risk for cardiovascular disease. Combination therapy improves patient compliance. This study was conducted to compare the efficacy and tolerability of the combination therapies telmisartan/amlodipine + rosuvastatin, telmisartan/amlodipine, and telmisartan + rosuvastatin in patients with hypercholesterolemia and hypertension. METHODS: In this Phase III, multicenter, 8-week randomized, double-blind study, participants with hypertension and dyslipidemia (defined as a sitting systolic blood pressure [sitSBP] of ≥140 mm Hg, a low-density lipoprotein-cholesterol [LDL-C] level of ≤250 mg/dL, and a triglyceride level of ≤400 mg/dL) were screened. After a 4-week washout/run-in period involving therapeutic lifestyle changes and telmisartan 80 mg once a day, eligible patients had a sitSBP of ≥140 mm Hg and met the LDL-C level criteria according to the National Cholesterol Education Program Adult Treatment Panel III cardiovascular disease risk category. Patients were randomly assigned to 1 of 3 groups: (1) telmisartan/amlodipine 80/10 mg + rosuvastatin 20 mg (TAR group); (2) telmisartan/amlodipine 80/10 mg (TA group); or (3) telmisartan 80 mg + rosuvastatin 20 mg (TR group). The primary efficacy end points were the percentage changes from baseline in LDL-C in the TAR and TA groups and the mean changes in sitSBP in the TAR and TR groups at week 8 compared to baseline. Continuous variables were compared using the unpaired t test or the Wilcoxon rank sum model, and categorical variables were compared using the χ2 or Fisher exact test. Tolerability was assessed based on adverse events found on physical examination including vital sign measurements, laboratory evaluations, and 12-lead ECG. FINDINGS: A total of 134 patients were enrolled. The least squares mean percentage changes in LDL-C at 8 weeks after administration of the drug compared to baseline were -51.9% (3.0%) in the TAR group and -3.2% (2.9%) in the TA group (P < 0.001). At 8 weeks after baseline, the least squares mean (SE) changes sitSBP were -28.3 (2.4) mm Hg in the TAR group and -10.7 (2.1) mm Hg in the TR group (P < 0.001). The prevalence rates of treatment-emergent adverse events were 15.0%, 25.0%, and 12.2% in the TAR, TA, and TR groups, respectively; those of adverse drug reactions were 15.0%, 22.7%, and 10.2%. None of the differences in rates were significant among 3 groups. IMPLICATIONS: Triple therapy with TAR can be an effective treatment in patients with dyslipidemia and hypertension. The TAR combination has value for hypertensive patients with hyperlipidemia in terms of convenience, tolerability, and efficacy. ClinicalTrials.gov identifier: NCT03566316.

Blood Pressure and Cholesterol-lowering Efficacy of a Fixed-dose Combination With Irbesartan and Atorvastatin in Patients With Hypertension and Hypercholesterolemia: A Randomized, Double-blind, Factorial, Multicenter Phase III Study.

PURPOSE: A fixed-dose combination of a stain and an antihypertensive drug may be useful for the treatment of patients with hypertension and hyperlipidemia. It may also improve patient drug compliance to help control risk factors of cardiovascular disease. This study was designed to evaluate the blood pressure-lowering and cholesterol-lowering effect of a fixed-dose combination of irbesartan-atorvastatin compared with monotherapy by either agent over an 8-week treatment period. METHODS: Patients with comorbid hypertension and hypercholesterolemia were screened for this randomized, double-blind, Phase III study. Eligible study patients were randomly assigned to test groups receiving a combination of irbesartan 300 mg and atorvastatin 40 mg or 80 mg (IRB300 + ATO40 and IRB300 + ATO80). Comparator groups comprised monotherapy groups with irbesartan 300 mg (IRB300) or atorvastatin 40 mg (ATO40) or atorvastatin 80 mg (ATO80), or placebo. Patients who were eligible at screening were subjected to a 4- to 6-week washout period before commencing 8 weeks of therapy per their assigned group. The primary efficacy end points were percent change in LDL-C and sitting diastolic blood pressure (DBP) levels from baseline to end of therapy. Tolerability profiles of combination therapy were compared with other groups. FINDINGS: A total of 733 patients with comorbid hypertension and hypercholesterolemia were screened for this study; 230 eligible patients were randomized to treatment. The mean age of patients was 58.9 (8.5) years, and their mean body mass index was 25.8 (3.2) kg/m2. More than two thirds (70.9%) of the study patients were male. Mean LDL-C and sitting DBP levels at baseline were 149.54 (29.19) mg/dL and 92.32 (6.03) mm Hg, respectively. Percent reductions in LDL-C after 8 weeks were 46.74% (2.06%) in the IRB300 + ATO40 group and 48.98% (2.12%) in the IRB300 + ATO80 group; these values were 47.13% (3.21%) and 48.30% (2.98%) in the ATO40 and ATO80 comparator groups. Similarly, a reduction in sitting DBP after 8 weeks was -8.50 (1.06) mm Hg in the IRB300 + ATO40 group and 10.66 (1.08) mm Hg in the IRB300 + ATO80 group compared with 8.40 (1.65) mm Hg in the IRB300 group. The incidence rate for treatment-emergent adverse events was 22.27% and was similar between the monotherapy and combination groups. IMPLICATIONS: A once-daily combination product of irbesartan and atorvastatin provided an effective, safe, and more compliable treatment for patients with coexisting hypertension and hyperlipidemia. ClinicalTrials.gov identifier: NCT01442987.

Usefulness of combined intravascular ultrasound parameters to predict functional significance of coronary artery stenosis and determinants of mismatch.

AIMS: Efficacy of combined intravascular ultrasound (IVUS) parameters in functional significance prediction and discrepancy between IVUS and fractional flow reserve (FFR) have not been well defined. This study therefore aimed to: 1) evaluate the diagnostic accuracy of combined IVUS parameters, namely minimal lumen area (MLA) and percent plaque burden (%PB), in functional significance prediction of coronary artery stenosis; and 2) define factors that affect the relation between FFR value and IVUS parameters. METHODS AND RESULTS: At 11 international centres, IVUS and FFR measurements were concurrently performed in 945 major epicardial coronary artery lesions (886 patients). Functional significance was defined as FFR ≤0.8. MLA and FFR correlated weakly (r=0.289, p<0.001). Diagnostic accuracy of MLA ≤4.0 mm2, %PB >70% and their combination were 50%, 47% and 51%, respectively, with similar area under the curve (AUC) of 0.561, 0.511 and 0.516, respectively. The best cut-off values (BCV) were MLA ≤3.0 mm2 and %PB >75%, with accuracy of 60% for MLA, 50% for %PB and 56% for their combination, and AUC of 0.618, 0.511 and 0.533, respectively. MLA BCV ≤3.0 mm2 had higher predictive power than %PB BCV >75% or their combination. Independent predictors of functional significance were male gender (odds ratio 1.76 [95% confidence interval: 1.19-2.62]), left ventricular ejection fraction (LVEF, 0.98 [0.96-0.99]), LAD lesion (2.52 [1.73-3.67]), reference vessel diameter (0.60 [0.41-0.86]), lesion length (1.04 [1.02-1.06]) and MLA (0.79 [0.69-0.92]). False negative lesion incidence was 24.4% in association with race (for Asians, 0.391 [0.219-0.698]), LAD lesion (2.677 [1.709-4.191]) and LVEF (0.977 [0.957-0.997]). False positive lesion incidence was 17.0% in association with non-LAD lesion (2.444 [1.620-3.686]). CONCLUSIONS: Combined IVUS parameters did not improve the accuracy of functional significance prediction. Discrepancy between IVUS and FFR, which was not rare, should be taken into account in clinical decision making.

Optimal intravascular ultrasound criteria for defining the functional significance of intermediate coronary stenosis: an international multicenter study.

OBJECTIVE: We aimed to assess the ideal cut-off value of minimal lumen area (MLA) by intravascular ultrasound (IVUS) and its diagnostic performance to predict ischemia, using a large-scale, pooled analysis. METHODS: Eleven centers worldwide were invited to provide their clinical, IVUS and fractional flow reserve (FFR) data. A total of 881 lesions were enrolled. RESULTS: Angiographic % diameter stenosis (r = -0.373, p < 0.0001) and IVUS MLA (r = 0.289, p < 0.0001) correlated with FFR. Best cut-off value (BCV) of IVUS MLA to define the functional significance (FFR <0.8) was 2.75 mm(2) (AUC 0.646, 95% CI 0.609-0.684). When the diagnostic performance of IVUS MLA was tested according to the lesion location, BCV could be found only in lesions in the proximal artery and the mid-left anterior descending artery. Interestingly, Asians (n = 623) and Westerners (n = 258) showed different demographic and lesion characteristics as well as different BCVs to define ischemia. The BCV for the proximal/mid-left anterior descending artery lesions was 2.75 mm(2) (AUC 0.688, 95% CI 0.635-0.742) in Asians and 3.0 mm(2) (AUC 0.695, 95% CI 0.605-0.786) in Westerners. CONCLUSION: In this pooled analysis, an IVUS MLA of 2.75 mm(2) was the BCV to define the functional significance of intermediate coronary stenosis. However, when IVUS MLA is used to determine the functional significance, both the lesion and patient characteristics should be considered.

Efficacy and tolerability of a generic and a branded formulation of atorvastatin 20 mg/d in hypercholesterolemic Korean adults at high risk for cardiovascular disease: a multicenter, prospective, randomized, double-blind, double-dummy clinical trial.

BACKGROUND: The reduction in plasma LDL-C concentrations with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has been reported to reduce cardiovascular risk and mortality in individuals with or without preexisting coronary artery disease and elevated LDL-C concentrations. Atorvastatin is a statin used for lowering LDL-C concentrations. A generic formulation of atorvastatin is being developed in Korea. This study was undertaken for the purposes of marketing the generic formulation. OBJECTIVE: This study was designed to compare the efficacy and tolerability of a generic formulation of atorvastatin 20 mg/d versus a branded formulation at the same dosage in hypercholesterolemic Korean adults at high risk for cardiovascular events. METHODS: This 8-week, multicenter, randomized, double-blind, double-dummy study was conducted at 10 clinical centers in Korea between September 2008 and May 2009. Male and female patients aged 20 to 85 years at high risk for cardiovascular events (defined as an elevated LDL-C concentration [≥100 mg/dL]) were enrolled. Eligible patients were randomly assigned to receive generic or branded atorvastatin 20 mg once daily for 8 weeks. The primary end point was the percentage change from baseline to 8 weeks in LDL-C concentration. Secondary end points were the percentage changes from baseline in total cholesterol (TC), triglycerides (TG), HDL-C, apolipoprotein (apo) A1 and B, and high-sensitivity C-reactive protein concentrations; small, dense LDL (sdLDL) fraction; and tolerability. Tolerability was assessed using physical examination, laboratory testing, and by recording adverse events (AEs) at each visit. An additional secondary end point was the proportion of patients who achieved an LDL-C goal of <100 mg/dL. RESULTS: A total of 244 patients were randomized to treatment, and 33 patients were withdrawn from the study (9 patients did not receive the study medication, 11 patients due to AEs, and 13 patients due to withdrawal of consent). A total of 211 patients completed the study (50.7% male; 100% Asian; mean [SD] age, 61.7 [9.2] years) (106 patients in the group that received Accepted for publication October 5, 2010. the generic formulation and 105 patients in the group that received the branded formulation). LDL-C concentrations were reduced from the baseline by 44% and 46% after 8 weeks of treatment with the generic and branded formulations, respectively (P = NS). The percentage changes from baseline to study end in HDL-C, TC, TG, apo A1, apo B, and hsCRP concentrations and sdLDL fraction the proportions of patients who achieved the LDL-C goal between the 2 groups did not reach statistical significance. The most commonly reported events were hepatobiliary laboratory abnormality (1.7%), general somatic discomfort (1.7%), and epigastric pain (0.8%) in the group that received the generic formulation, and myalgia (1.7%), epigastric pain (0.9%), and elevation of creatinine phosphokinase (0.9%) in the group that received the branded formulation. No serious AEs were reported in either group. CONCLUSIONS: After 8 weeks of treatment, the differences in the LDL-C-lowering effects between the generic and branded formulations of atorvastatin 20 mg/d did not reach statistical significance in these Korean patients at high risk for cardiovascular events. Both formulations were generally well tolerated.