Antihypertensives and Statin Therapy for Primary Stroke Prevention: A Secondary Analysis of the HOPE-3 Trial

BACKGROUND AND PURPOSE: The HOPE-3 trial (Heart Outcomes Prevention Evaluation­3) found that antihypertensive therapy combined with a statin reduced first stroke among people at intermediate cardiovascular risk. We report secondary analyses of stroke outcomes by stroke subtype, predictors, treatment effects in key subgroups. METHODS: Using a 2-by-2 factorial design, 12 705 participants from 21 countries with vascular risk factors but without overt cardiovascular disease were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily or placebo and to rosuvastatin 10 mg daily or placebo. The effect of the interventions on stroke subtypes was assessed. RESULTS: Participants were 66 years old and 46% were women. Baseline blood pressure (138/82 mm Hg) was reduced by 6.0/3.0 mm Hg and LDL-C (low-density lipoprotein cholesterol; 3.3 mmol/L) was reduced by 0.90 mmol/L on active treatment. During 5.6 years of follow-up, 169 strokes occurred (117 ischemic, 29 hemorrhagic, 23 undetermined). Blood pressure lowering did not significantly reduce stroke (hazard ratio [HR], 0.80 [95% CI, 0.59­1.08]), ischemic stroke (HR, 0.80 [95% CI, 0.55­1.15]), hemorrhagic stroke (HR, 0.71 [95% CI, 0.34­1.48]), or strokes of undetermined origin (HR, 0.92 [95% CI, 0.41­2.08]). Rosuvastatin significantly reduced strokes (HR, 0.70 [95% CI, 0.52­0.95]), with reductions mainly in ischemic stroke (HR, 0.53 [95% CI, 0.37­0.78]) but did not significantly affect hemorrhagic (HR, 1.22 [95% CI, 0.59­2.54]) or strokes of undetermined origin (HR, 1.29 [95% CI, 0.57­2.95]). The combination of both interventions compared with double placebo substantially and significantly reduced strokes (HR, 0.56 [95% CI, 0.36­0.87]) and ischemic strokes (HR, 0.41 [95% CI, 0.23­0.72]). CONCLUSIONS: Among people at intermediate cardiovascular risk but without overt cardiovascular disease, rosuvastatin 10 mg daily significantly reduced first stroke. Blood pressure lowering combined with rosuvastatin reduced ischemic stroke by 59%. Both therapies are safe and generally well tolerated.

Antihypertensives and Statin Therapy for Primary Stroke Prevention: A Secondary Analysis of the HOPE-3 Trial.

Background and Purpose: The HOPE-3 trial (Heart Outcomes Prevention Evaluation­3) found that antihypertensive therapy combined with a statin reduced first stroke among people at intermediate cardiovascular risk. We report secondary analyses of stroke outcomes by stroke subtype, predictors, treatment effects in key subgroups. Methods: Using a 2-by-2 factorial design, 12 705 participants from 21 countries with vascular risk factors but without overt cardiovascular disease were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily or placebo and to rosuvastatin 10 mg daily or placebo. The effect of the interventions on stroke subtypes was assessed. Results: Participants were 66 years old and 46% were women. Baseline blood pressure (138/82 mm Hg) was reduced by 6.0/3.0 mm Hg and LDL-C (low-density lipoprotein cholesterol; 3.3 mmol/L) was reduced by 0.90 mmol/L on active treatment. During 5.6 years of follow-up, 169 strokes occurred (117 ischemic, 29 hemorrhagic, 23 undetermined). Blood pressure lowering did not significantly reduce stroke (hazard ratio [HR], 0.80 [95% CI, 0.59­1.08]), ischemic stroke (HR, 0.80 [95% CI, 0.55­1.15]), hemorrhagic stroke (HR, 0.71 [95% CI, 0.34­1.48]), or strokes of undetermined origin (HR, 0.92 [95% CI, 0.41­2.08]). Rosuvastatin significantly reduced strokes (HR, 0.70 [95% CI, 0.52­0.95]), with reductions mainly in ischemic stroke (HR, 0.53 [95% CI, 0.37­0.78]) but did not significantly affect hemorrhagic (HR, 1.22 [95% CI, 0.59­2.54]) or strokes of undetermined origin (HR, 1.29 [95% CI, 0.57­2.95]). The combination of both interventions compared with double placebo substantially and significantly reduced strokes (HR, 0.56 [95% CI, 0.36­0.87]) and ischemic strokes (HR, 0.41 [95% CI, 0.23­0.72]). Conclusions: Among people at intermediate cardiovascular risk but without overt cardiovascular disease, rosuvastatin 10 mg daily significantly reduced first stroke. Blood pressure lowering combined with rosuvastatin reduced ischemic stroke by 59%. Both therapies are safe and generally well tolerated. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00468923.

An international multicenter observational non-interventional prospective study of the efficacy of azilsartan medoxomil in overweight or obese patients with arterial hypertension (CONSTANT).

BACKGROUND: Control of arterial hypertension in obese or overweight patients is complicated since obesity directly contributes to increased blood pressure, requiring new, highly effective antihypertensive drugs. This study evaluates the efficacy of azilsartan medoxomil in real clinical practice. METHODS: An international multicenter observational non-interventional prospective study of azilsartan medoxomil was conducted in 64 clinical centers in the Russian Federation and 5 centers in the Republic of Kazakhstan. This study included 1945 obese or overweight patients with arterial hypertension. Azilsartan medoxomil was prescribed in accordance with the approved instruction for use. The decision to prescribe the drug, dose adjustment and monitoring target BP achievement belonged to the attending physicians according to their routine clinical practice. The observation period took about 6 months. RESULTS: The average duration of taking the medicine was 26.1 ± 4 weeks. By the fourth visit, the use of azilsartan medoxomil either in a monotherapy regimen or in free combinations resulted in a pronounced decrease in systolic and diastolic blood pressure by 30.5 ± 13.4 and 14 ± 9.4 mmHg, respectively (p < .001 compared to baseline value). A positive response to therapy was observed in 92.6% of cases (95% CI: 91.3-93.7%). Target blood pressure was achieved by 86.4% of cases (95% CI: 84.8-87.9%). During the study period 43 adverse events were recorded, the most common of which were arterial hypotension and dizziness. CONCLUSIONS: Over the study time of 1945 patients, significant changes in blood pressure levels over time were noted, and a high frequency of response to the azilsartan therapy was observed. Adverse events related to the study drug were of mild or moderate intensity and did not require discontinuation of therapy. Thus, azilsartan medoxomil demonstrated a good safety profile and provided effective blood pressure control for overweight or obese patients with hypertension in real clinical practice.

Initial Riociguat Monotherapy and Transition from Sildenafil to Riociguat in Patients with Idiopathic Pulmonary Arterial Hypertension: Influence on Right Heart Remodeling and Right Ventricular-Pulmonary Arterial Coupling.

PURPOSE: To evaluate the influence of riociguat on World Health Organization functional class (WHO FC), 6-min walk distance (6MWD), right heart remodeling, and right ventricular-pulmonary arterial (RV-PA) coupling in patients with idiopathic pulmonary arterial hypertension (IPAH) who are treatment-naïve or who have failed to achieve treatment goals with sildenafil therapy. METHODS: Twenty patients with IPAH were enrolled: 12 had not previously received PAH-targeted therapy (treatment-naïve subgroup) and 8 had been receiving sildenafil therapy but failed to achieve treatment goals; on entering this pilot study these 8 patients were switched from sildenafil to riociguat therapy (treatment-switch subgroup). Patients received riociguat individually dose-adjusted up to a maximum of 2.5 mg three times daily. After 12 weeks, patients were assessed for WHO FC, 6MWD, right heart remodeling, and RV-PA coupling. RESULTS: Riociguat significantly improved WHO FC in treatment-naïve patients (from 0/4/8/0 patients in WHO I/II/III/IV at baseline to 1/6/5/0 at week 12) and in treatment-switch patients (from 0/4/4/0 patients in WHO I/II/III/IV at baseline to 1/4/3/0 at week 12). Additionally, treatment-naïve and treatment-switch patients showed significant improvements at week 12 versus baseline in 6MWD (increases of + 76.8 m and + 71.6 m, respectively), RV systolic function, and RV-PA coupling. CONCLUSION: These results support the proven efficacy of riociguat in patients with IPAH, including treatment-naïve patients and those switching to riociguat following failure to achieve treatment goals with sildenafil, and suggest that it may be possible to delay disease progression in this patient group.

Comparison of single-pill strategies first line in hypertension: perindopril/amlodipine versus valsartan/amlodipine.

OBJECTIVES: An international double-blind, parallel-group, randomized controlled trial was performed to determine the efficacy and safety of a new first-line strategy in mild to moderate hypertension based on a single-pill combination of perindopril/amlodipine versus a validated stepped-care strategy (initiation with valsartan monotherapy, up-titrating to valsartan/amlodipine after 2 months). METHODS: At inclusion, patients received perindopril/amlodipine 3.5/2.5 mg or valsartan 80 mg. At 1, 2, and 3 months, patients were up-titrated if they had uncontrolled hypertension (≥140/90 mmHg). The up-titration steps were: perindopril/amlodipine 7/5 mg, 14/10 mg, and 14/10 mg + indapamide sustained release 1.5 mg; or valsartan 160 mg, valsartan/amlodipine 160/5 mg, and 160/10 mg. The two groups were similar at baseline (55.5 years, 53% men, blood pressure 163.5/100.2 mmHg); 881 perindopril/amlodipine and 876 valsartan/amlodipine patients were analyzed for efficacy. RESULTS: After 1 month, the rate of controlled hypertension was 33% with perindopril/amlodipine versus 27% with valsartan/amlodipine (estimate of difference, +6.1%; P = 0.005); this between-strategy difference remained significant at every visit (P < 0.05). After 3 months, blood pressure was 137.8 ±â€Š12.4/83.3 ±â€Š8.7 and 139.7 ±â€Š13.3/84.8 ±â€Š9.0 mmHg, respectively, with greater reductions from baseline with perindopril/amlodipine (primary endpoint -2.0/-1.5 mmHg; both P < 0.001). Similar results were observed at all other visits (all P ≤ 0.001). The safety of the two strategies was equivalent. CONCLUSIONS: The three-step strategy of initiation with single-pill perindopril/amlodipine produces greater reductions in blood pressure, and better and quicker rates of control of hypertension. This can be expected to be associated with benefits beyond blood pressure control, notably improved compliance and better cardioprotection.

Comparison of single-pill strategies first line inhypertension: perindopril/amlodipine versusvalsartan/amlodipine

An international double-blind, parallel-group,randomized controlled trial was performed to determinethe efficacy and safety of a new first-line strategy in mildto moderate hypertension based on a single-pillcombination of perindopril/amlodipine versus a validatedstepped-care strategy (initiation with valsartanmonotherapy, up-titrating to valsartan/amlodipine after2 months).Methods: At inclusion, patients received perindopril/amlodipine 3.5/2.5mg or valsartan 80 mg. At 1, 2, and3 months, patients were up-titrated if they haduncontrolled hypertension ( 140/90 mmHg). The uptitrationsteps were: perindopril/amlodipine 7/5 mg,14/10 mg, and 14/10mg R indapamide sustained release1.5 mg; or valsartan 160 mg, valsartan/amlodipine160/5 mg, and 160/10 mg. The two groups were similarat baseline (55.5 years, 53% men, blood pressure163.5/100.2 mmHg); 881 perindopril/amlodipine and876 valsartan/amlodipine patients were analyzed forefficacy.Results: After 1 month, the rate of controlledhypertension was 33% with perindopril/amlodipine versus27% with valsartan/amlodipine (estimate of difference,R6.1%; P»0.005); this between-strategy differenceremained significant at every visit (P<0.05). After 3months, blood pressure was 137.8 12.4/83.3 8.7 and139.7 13.3/84.8 9.0 mmHg, respectively, with greaterreductions from baseline with perindopril/amlodipine(primary endpoint 2.0/ 1.5 mmHg; both P<0.001).Similar results were observed at all other visits (allP 0.001). The safety of the two strategies wasequivalent.Conclusions: The three-step strategy of initiation withsingle-pill perindopril/amlodipine produces greaterreductions in blood pressure, and better and quicker ratesof control of hypertension. This can be expected to beassociated with benefits beyond blood pressure control,notably improved compliance and better cardioprotection.Keywords: amlodipine, hypertension, perindopril, singlepillcombination, valsartan...

Real-life safety and effectiveness of amlodipine/valsartan combination in the treatment of hypertension.

INTRODUCTION: The aim of our study was to evaluate the safety and effectiveness of the free combination of amlodipine/valsartan in patients with arterial hypertension in a real-life setting. METHODS: This was a multicenter, open-label, observational, noninterventional, postmarketing surveillance study conducted in 298 centers in China, Malaysia, Pakistan, Bangladesh, Egypt, and Russia. We evaluated changes in heart rate, systolic and diastolic office blood pressure (BP), as well as BP control rate (<140/90 mmHg) overall, and in clinically relevant subgroups of hypertensive patients (BP >140/90 mmHg) after 12 weeks of treatment with 5/10 mg amlodipine and 80/160 mg valsartan combination. RESULTS: Two thousand seven hundred and eighty-five patients with arterial hypertension were enrolled, 52 discontinued (eight due to adverse events), and four patients' data were missing. In total, 2729 patients completed the study: mean age 57.9 years, 54.5% men, 54.2% Asian, 44.6% Caucasian; 86.5% had prior hypertension treatment (which was discontinued), baseline BP was 163.1/96.2 mmHg. The significant reduction in BP (-33.2/-16.9 mmHg, P<0.0001) was achieved with amlodipine/valsartan treatment resulting in a final BP of 129.9/79.3 mmHg. A dose-dependent effect was observed with the least BP reduction for 5/80 mg (-29.2/-15.1 mmHg, P<0.0001) and the greatest for the 10/160 mg dose regimen (-43.6/-22.4 mmHg, P<0.0001). Treatment response increased with increasing initial severity of hypertension with the least BP reduction in patients with baseline grade 1 hypertension BP level (SBP 140-159 mmHg): -20.0/-13.4 mmHg, P<0.0001, and the greatest BP drops observed in grade 3 hypertensive patients with baseline systolic BP over 200 mmHg: -73.1/-26.3 mmHg, P<0.0001. Patients with isolated systolic hypertension had BP reductions of -24.2/-4.8 mmHg, P<0.0001. CONCLUSION: An optimal BP reduction was achieved for all hypertension grades as well as isolated systolic hypertension, providing evidence that most hypertensive patients may benefit from amlodipine/valsartan combination treatment.