Jen-Fue Maa

Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex Concentrate

Background— The oral factor Xa inhibitor edoxaban has demonstrated safety and efficacy in stroke prevention in patients with atrial fibrillation and in the treatment and secondary prevention of venous thromboembolism. This study investigated the reversal of edoxaban’s effects on bleeding measures and biomarkers by using a 4-factor prothrombin complex concentrate (4F-PCC). Methods and Results— This was a phase 1 study conducted at a single site. This was a double-blind, randomized, placebo-controlled, 2-way crossover study to determine the reversal effect of descending doses of 4F-PCC on bleeding duration and bleeding volume following edoxaban treatment. A total of 110 subjects (17 in part 1, 93 in part 2) were treated. Intravenous administration of 4F-PCC 50, 25, or 10 IU/kg following administration of edoxaban (60 mg) dose-dependently reversed edoxaban’s effects on bleeding duration and endogenous thrombin potential, with complete reversal at 50 IU/kg. Effects on prothrombin time were partially reversed at 50 IU/kg. A similar trend was seen for bleeding volume. Conclusions— The 4F-PCC dose-dependently reversed the effects of edoxaban (60 mg), with complete reversal of bleeding duration and endogenous thrombin potential and partial reversal of prothrombin time following 50 IU/kg. Edoxaban alone and in combination with 4F-PCC was safe and well tolerated in these healthy subjects. A dose of 50 IU/kg 4F-PCC may be suitable for reversing edoxaban anticoagulation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02047565.

Efficacy of amlodipine and olmesartan medoxomil in patients with hypertension: the AZOR Trial Evaluating Blood Pressure Reductions and Control (AZTEC) study:

The aim of the present study was to use ambulatory blood pressure (BP) monitoring (ABPM) to determine the efficacy of a fixed-dose combination of amlodipine (AML) and olmesartan medoxomil (OM) over the 24-hour dosing interval. This 12-week, titrate-to-goal study was conducted in 185 patients with hypertension. Patients were initially treated with AML 5 mg/ day and uptitrated to AML/OM 5/20, 5/40, and 10/40 mg/day every 3 weeks if mean seated BP (SeBP) was ≥120/80 mmHg. The primary efficacy endpoint was the change from baseline in mean 24-hour systolic BP at week 12 as assessed by ABPM. At baseline, the mean 24-hour ambulatory BP (±standard deviation [SD]) was 144.8±11.1/85.7±7.9 mmHg. At week 12, the change from baseline in mean 24-hour ambulatory BP (±standard error of the mean [SEM]) was -21.4±0.8/-12.7±0.5 mmHg (p < 0.0001 versus baseline). At baseline, the mean SeBP (±SD) was 158.2±12.6/92.8±8.6 mmHg and at week 12, the mean SeBP change (±SEM) from baseline (last observation carried forward) was -24.1±1.1/-12.1±0.7 mmHg (p < 0.0001 versus baseline). Proportions of patients achieving mean 24-hour ambulatory BP prespecified study targets were 70.9% (<130/80 mmHg), 48.3% (<125/75 mmHg), and 40.7% (<120/80 mmHg). Cumulatively, 76.8% of patients uptitrated to AML/OM 10/40 mg/day attained an SeBP goal of <140/90 mmHg. The study drug was well tolerated with few adverse events (peripheral edema, 2.2%; dizziness, 1.1%). An AML/OM-based titration regimen effectively reduces BP in patients with hypertension.

Efficacy of Amlodipine and Olmesartan Medoxomil in Hypertensive Patients With Diabetes and Obesity

A subgroup analysis of a prospective, open‐label, single‐arm titration study in patients with hypertension and type 2 diabetes or obesity is reported. The primary end point was the change from baseline in mean 24‐hour ambulatory systolic blood pressure (BP) after 12 weeks. Patients received amlodipine 5 mg/d and were uptitrated (if seated [Se] BP was ≥120/80 mm Hg) at 3‐week intervals to amlodipine/olmesartan medoxomil 5/20 mg/d, 5/40 mg/d, and 10/40 mg/d. In patients with diabetes and obesity, baseline 24‐hour ambulatory BP (±standard deviation) was 145.6±10.4/83.1±9.0 mm Hg and 143.7±9.8/84.9±8.2 mm Hg, respectively, and baseline SeBP was 159.1±11.3/90.3±9.2 mm Hg and 158.2±12.5/94.2±8.5 mm Hg, respectively. Changes from baseline in mean 24‐hour ambulatory BP (±standard error of the mean) were −21.5±1.8/−12.6±1.1 mm Hg and 21.6±1.1/13.4±0.8 mm Hg in patients with diabetes and obesity, respectively. Prespecified 24‐hour ambulatory BP targets of <130/80 mm Hg, <125/75 mm Hg, and <120/80 mm Hg were achieved by 79.1%, 53.5%, and 39.5% of patients with diabetes and 75.3%, 58.4%, and 43.8% of obese patients, respectively. The SeBP goal of <130/80 mm Hg was achieved by 26.1% of patients with diabetes and <140/90 mm Hg was achieved by 78.1% of obese patients. J Clin Hypertens (Greenwich). 2011;13:422–430. ©2011 Wiley Periodicals, Inc.

Efficacy of an amlodipine/olmesartan treatment algorithm in patients with or without type 2 diabetes and hypertension (a secondary analysis of the BP-CRUSH study)

A prespecified subgroup analysis of an open-label, multicenter, single-arm, dose-titration study is presented. The efficacy and safety of 20-week treatment with an amlodipine (AML)/olmesartan medoxomil (OM)±hydrochlorothiazide (HCTZ) algorithm were assessed in patients with hypertension and type 2 diabetes mellitus (T2DM) who were uncontrolled by antihypertensive monotherapy. Eligible patients received AML/OM 5/20 mg for 4 weeks, followed by stepwise uptitration to AML/OM 5/40 mg, AML/OM 10/40 mg, AML/OM 10/40 mg+HCTZ 12.5 mg and AML/OM 10/40 mg+HCTZ 25 mg at 4-week intervals if blood pressure (BP) remained uncontrolled. The primary end point was the achievement of the seated cuff systolic BP (SeSBP) goal (<140 mm Hg, or <130 mm Hg for patients with T2DM) at week 12. Seated cuff BP was significantly reduced from baseline at all titration dose periods. At week 12, the cumulative SeSBP goal was achieved by 57.9% and 80.1% of patients in the T2DM and non-T2DM subgroups, respectively. Treatment was well tolerated, with low rates of peripheral edema. In summary, switching to a treatment algorithm based on AML/OM±HCTZ after failed monotherapy was safe and improved BP control in patients with hypertension and T2DM.

Efficacy of amlodipine/olmesartan medoxomil ± HCTZ in obese patients uncontrolled on antihypertensive monotherapy.

Abstract Objective: BP-CRUSH (Blood Pressure Control in All Subgroups With Hypertension) was a phase IV, prospective, open-label, multicenter, single-arm, dose-titration study (N = 999). The present subgroup analysis reports the efficacy/safety of up to 20 weeks of treatment with amlodipine (AML)/olmesartan medoxomil (OM) ± hydrochlorothiazide (HCTZ) in obese and non-obese patients with hypertension uncontrolled on antihypertensive monotherapy. Research design and methods: Eligible obese (body mass index ≥30 kg/m2; n = 505) and non-obese (<30 kg/m2; n = 494) patients were switched to AML/OM 5/20 mg and uptitrated at 4-week intervals to AML/OM 5/40 mg, AML/OM 10/40 mg, AML/OM 10/40 mg + HCTZ 12.5 mg, and AML/OM 10/40 mg + HCTZ 25 mg. Uptitration to higher doses of AML/OM was permitted if mean seated systolic BP (SeSBP) was ≥120 mmHg, or mean seated diastolic BP (SeDBP) was ≥70 mmHg. HCTZ was added if mean SeSBP was ≥125 mmHg, or mean SeDBP was ≥75 mmHg. Clinical trial registration: ClinicalTrials.gov identifier: NCT00791258. Main outcome measures: The primary efficacy endpoint was the cumulative proportion of patients achieving SeSBP <140 mmHg (<130 mmHg for patients with diabetes mellitus) at 12 weeks. Secondary endpoints included seated cuff BP (SeBP) goal rates, ambulatory BP target rates, and mean change from baseline in SeBP and ambulatory BP at weeks 12 and 20. Results: At 12 weeks, 71.6% of obese patients (80.2% non-obese) achieved the primary endpoint of cumulative SeSBP <140 mmHg (<130 mmHg for patients with diabetes). The cumulative SeBP goal of <140/90 mmHg (<130/80 mmHg if diabetes) was achieved by 64.8% and 81.2% of obese patients by weeks 12 and 20, respectively (vs. 77.9% and 88.5% of non-obese patients, respectively). Treatment was well-tolerated, with 26.1% of obese patients (24.9% non-obese) experiencing drug-related treatment-emergent adverse events (TEAEs). There were no serious drug-related TEAEs. Conclusion: An AML/OM ± HCTZ treatment regimen provided effective and safe BP control in obese patients with hypertension uncontrolled on monotherapy.

Efficacy of Olmesartan Medoxomil and Hydrochlorothiazide Fixed-Dose Combination Therapy in Patients Aged 65 Years and Older with Stage 1 and 2 Hypertension or Isolated Systolic Hypertension

AbstractBackground: The incidence of hypertension, particularly isolated systolic hypertension, increases with in-creasing age, as does the risk of fatal cardiovascular disease. A combination antihypertensive therapy regimen may be required to reach recommended BP goals in older patients. Objectives: This study set out to report blood pressure (BP) data in elderly patients across the subgroups of stage 1 and stage 2 hypertension (prespecified subgroup) and isolated systolic hypertension (ISH) [post hoc]. Design and Setting: This was a subgroup analysis of a prospective, open-label study carried out in a multicenter, outpatient setting (e.g. the BeniSILVER [Benicar Efficacy: New Investigation Shows OM Treatment Increasingly Leads to Various Elderly Populations to Safe BP Reductions; ClinicalTrials.gov identifier: NCT00412932] study). The study included 176 patients with a mean age of approximately 72 years; stage 1 hypertension, 60, stage 2 hypertension, 116, and ISH, 98. Intervention: After a 2- to 3-week placebo run-in period, patients were uptitrated every 3 weeks from olmesartan medoxomil (OM) 20 mg daily to OM 40 mg, OM/hydrochlorothiazide (HCTZ) 40 mg/12.5 mg, and OM/HCTZ 40 mg/25 mg, if seated cuff BP (SeBP) was ≥120/70 mmHg. Measurements: Measurements included change from baseline in mean 24-hour ambulatory BP and SeBP after 12 weeks of treatment, percentage of patients achieving a cumulative SeBP goal of <140/90mmHg (stage 1 and stage 2 cohorts) or seated cuff systolic BP (SeSBP) goal of <140 mmHg (ISH cohort), and the incidence of adverse events (AEs). Results: Combination therapy was required by 159 patients. Changes from baseline in mean 24-hour ambulatory BP (±standard deviation [SD]) were −24.2 (± 11.8)/−11.8 (± 6.9) mmHg, −26.5 (± 11.8)/−12.6 (± 6.7) mmHg, and −24.7 (− 12.5)/−11.2 (± 6.4) mmHg in the stage 1, stage 2, and ISH cohorts, respectively (all p< 0.001 vs baseline). Mean SeBP changes (± SD) from baseline in patients titrated to OM/HCTZ 40 mg/25 mg were −24.6 (± 11.4)/−10.5 (± 7.3) mmHg in the stage 1 cohort, −26.4 (± 17.2)/−11.3 (±9.7) mmHg in the stage 2 cohort, and −21.5 (± 15.6)/−6.8 (± 7.8) mmHg in the ISH cohort (all p <0.001). The cumulative proportions of patients achieving an SeBP goal of <140/90mmHg by week 12 were 88.3%, 56.0%, and 72.4% in the stage 1, stage 2, and ISH cohorts, respectively, while 72.4% of patients achieved an SeSBP of <140 mmHg in the ISH cohort. Treatment-emergent AEs ranged from 32.3% to 32.8%, with <3% of patients reporting drug-related hypotension. Conclusion: An OM/HCTZ-based titration regimen enabled elderly patients with hypertension to safely reduce BP throughout the 24-hour dosing interval and allowed the majority of these patients to achieve a BP target of <140/90 mmHg or <140 mmHg.

Efficacy of Amlodipine/Olmesartan ± Hydrochlorothiazide in Patients Uncontrolled on Prior Calcium Channel Blocker or Angiotensin II Receptor Blocker Monotherapy

IntroductionWhile monotherapy is often recommended as initial treatment, most patients require dose escalation and add-on agents to achieve their blood pressure (BP) goal. This secondary analysis evaluated the efficacy and safety of initiating patients on a regimen of fixed-dose amlodipine (AML)/olmesartan medoxomil (OM) ± hydrochlorothiazide (HCTZ) who were uncontrolled on prior monotherapy with a calcium channel blocker (CCB) or angiotensin II receptor blocker (ARB).MethodsPatients uncontrolled on prior monotherapy with CCB or ARB therapy were initiated on AML/OM 5/20 mg and up-titrated every 4 weeks to AML/OM 5/40 mg, AML/OM 10/40 mg, AML/OM 10/40 + HCTZ 12.5 mg, and AML/OM 10/40 + HCTZ 25 mg. Patients were up-titrated to a higher AML/OM dose if mean seated cuff BP (SeBP) was ≥120/70 mmHg, and up-titrated to any HCTZ dose if mean SeBP was ≥125/75 mmHg. The primary efficacy endpoint was the cumulative proportion of patients achieving a seated cuff systolic BP (SeSBP) goal of <140 mmHg (<130 mmHg for patients with diabetes) after 12 weeks. Secondary endpoints included mean change from baseline in SeBP and ambulatory BP, ambulatory BP target achievement, and safety.ResultsFor the prior CCB (n = 118; baseline SeBP: 153.4/91.5 mmHg) and ARB (n = 237; 154.6/92.6 mmHg) groups, SeSBP goal achievement after 12 weeks was 72.7% and 76.9%, respectively. Mean changes (± SE) from baseline in SeBP were dose proportional for prior CCB and ARB patients, ranging from −9.9 (± 1.25)/−5.8 (± 0.83) mmHg and −13.9 (± 0.79)/−7.6 (± 0.47) mmHg at the AML/OM 5/20 mg dose, respectively, to −21.8 (± 1.68)/−11.6 (±.12) mmHg and −26.2 (± 1.31)/−15.0 (± 0.86) mmHg at the AML/OM 10/40 mg + HCTZ 25 mg dose (P < 0.0001 for all).ConclusionAn AML/OM-based titration regimen was efficacious in achieving BP goal in patients uncontrolled on prior monotherapy with a CCB or ARB.

Blood pressure-lowering efficacy of an olmesartan medoxomil/hydrochlorothiazide-based treatment algorithm in elderly patients (age ≥65 years) stratified by age, sex and race: subgroup analysis of a 12-week, open-label, single-arm, dose-titration study.

AbstractIntroduction: Hypertension is a leading risk factor for development of heart failure, stroke and renal disease in the elderly. Objective: The objective of this study was to evaluate, by means of a prespecified secondary analysis of a 12-week, open-label, single-arm, dose-titration study, the blood pressure (BP)-lowering efficacy and safety of an olmesartan medoxomil (OM)/hydrochlorothiazide (HCTZ)-based titration regimen in patients aged ≥65 years with hypertension. Subgroups were stratified by age (≥65 to ≤75 or >75 years), sex (male or female) and race (Black or non-Black). Methods: Following a 2- to 3-week placebo run-in phase, patients received OM 20 mg, uptitrated to OM 40 mg, followed by addition of HCTZ 12.5–25 mg step-wise at 3-week intervals if seated cuff BP (SeBP) was ≥ 120/70 mmHg. Patients below this target SeBP were maintained at their current dose but uptitrated to the next consecutive dose if mean seated cuff systolic BP (SBP) was ≥140 mmHg and/or mean seated cuff diastolic BP was ≥90 mmHg at follow-up visits. Efficacy was assessed by 24-hour ambulatory BP monitoring (ABPM) and SeBP measurements. The primary efficacy variable was the change from baseline in mean 24-hour ambulatory SBP after 12 weeks. Secondary efficacy endpoints included the change from baseline in mean 24-hour ambulatory SBP; change from baseline in ambulatory BP during the daytime (8:00 am–4:00 pm), nighttime (10:00 pm–6:00 am) and the last 6, 4 and 2 hours of the dosing interval; change from baseline in SeBP at each titration step and at study end; and the proportion of patients achieving mean 24-hour ambulatory BP targets and SeBP goals at week 12. The frequency and severity of treatment-emergent adverse events (TEAEs) were also documented. Results: Baseline and week 12 ABPM data were available for 150 out of 178 patients who entered the active treatment phase. Changes from baseline in mean 24-hour ambulatory BP were −26.0/−12.5 mmHg and −24.9/−12.0 mmHg in patients aged ≥65 to ≤75 years (n = 128) and >75 years (n = 48), respectively (all p < 0.0001 vs baseline). Changes from baseline in mean 24-hour ambulatory BP were −26.0/−13.0 mmHg and −25.4/−11.5 mmHg in male (n = 92) and female (n = 84) patients, respectively (all p < 0.0001 vs baseline) and −26.7/−11.8 mmHg and −25.6/−12.4 mmHg in Black (n = 28) and non-Black (n = 148) patients, respectively (all p < 0.0001 vs baseline). Clinically significant ambulatory BP reductions were observed during the daytime, nighttime and the last 6, 4 and 2 hours of the dosing interval in all subgroups. Changes from baseline at week 12 in mean SeBP were similar to 24-hour ambulatory BP changes reported previously. At week 12, the proportion of patients achieving the 24-hour ambulatory BP target of <30/80 mmHg ranged from 67.5% to 77.4% and achieving the SeBP goal of <140/90mmHg ranged from 60.7% to 68.8% across the subgroups. Most TEAEs and drug-related TEAEs were mild or moderate in severity, and there were no trends across subgroups. Conclusions: In a subgroup analysis based upon age, sex and race in patients aged ≥65 years with hypertension, an OM/HCTZ-based algorithm was efficacious and well tolerated. ClinicalTrials.gov Identifier: NCT00412932

Efficacy of amlodipine/olmesartan medoxomil ± hydrochlorothiazide in patients aged ≥ 65 or < 65 years with uncontrolled hypertension on prior monotherapy.

Abstract Our subanalysis evaluated the efficacy of an amlodipine/olmesartan medoxomil (AML/OM)-based titration regimen to achieve blood pressure (BP) goals among patients aged ≥ 65 years. In this dose-titration study, 999 patients (228 of whom were aged ≥ 65 years) with uncontrolled BP after ≥ 1 month of monotherapy were switched to fixed-dose AML/OM 5/20 mg and uptitrated every 4 weeks to AML/OM 5/40 and 10/40 mg to achieve BP < 120/70 mm Hg. Patients were subsequently uptitrated every 4 weeks to AML/OM 10/40 mg + hydrochlorothiazide (HCTZ) 12.5 mg and AML/OM 10/40 mg + HCTZ 25 mg to achieve BP < 125/75 mm Hg. The primary efficacy endpoint (ie, the cumulative percentage of patients achieving the seated cuff systolic BP goal of < 140 mm Hg [or < 130 mm Hg for patients with type 2 diabetes mellitus] during first 12 weeks of treatment) was achieved by 76.7% and 75.6% of patients aged ≥ 65 (ie, 65−80) years and < 65 (ie, 18−64) years, respectively. For patients aged ≥ 65 and < 65 years, mean seated cuff BP changes from baseline during the titration periods ranged from −14.5/−7.8 mm Hg and −14.1/−7.7 mm Hg, respectively, for AML/OM 5/20 mg, to −28.5/−12.4 and −24.5/−14.0 mm Hg for AML/OM 10/40 mg + HCTZ 25 mg (all P < 0.0001). By week 20, the cumulative BP threshold of < 140/90 mm Hg was achieved by 86.8% and 84.2% of patients aged ≥ 65 and < 65 years, respectively. Among patients aged ≥ 65 years who underwent ambulatory BP monitoring, mean 24-hour, daytime, and nighttime ambulatory BP all decreased from baseline at weeks 12 and 20 (all P < 0.0001). At weeks 12 and 20, the mean 24-hour American Heart Association-recommended ambulatory BP target of < 130/80 mm Hg was achieved in 80.4% and 97.4% of patients aged ≥ 65 years, respectively, and in 71.3% and 88.8% of patients aged < 65 years, respectively. The majority of adverse events were mild to moderate in intensity and the incidence of treatment-emergent adverse events determined by clinical laboratory evaluation was low. The incidence of drug-related hypotension and orthostatic hypotension in patients aged ≥ 65 years was 2.2% and 0.0%, respectively, and in patients aged < 65 years, was 2.3% and 0.3%, respectively. Fixed-dose AML/OM + HCTZ combination therapy effectively lowered BP and achieved BP goals in patients aged ≥ 65 and < 65 years with hypertension previously uncontrolled on monotherapy. The treatment regimen was well tolerated irrespective of patient age.

Efficacy and tolerability of fixed-dose amlodipine/olmesartan medoxomil with or without hydrochlorothiazide in Hispanic and non-Hispanic patients whose blood pressure is uncontrolled on antihypertensive monotherapy.

Objectives: This is a prespecified subgroup analysis in Hispanic and non-Hispanic patients of a study that evaluated blood pressure (BP) control with fixed-dose amlodipine/olmesartan medoxomil (AML/OM)-based therapy in patients whose condition was uncontrolled on prior monotherapy. Methods: In this prospective, open-label, dose-titration study, patients with uncontrolled BP after at least 1 month of antihypertensive monotherapy were switched to fixed-dose AML/OM 5/20 mg. Patients were uptitrated to AML/OM 5/40 and 10/40 mg, with uptitration to AML/OM + hydrochlorothiazide 10/40 + 12.5 mg and 10/40 + 25 mg to achieve target BP. The primary efficacy endpoint was the cumulative proportion of patients achieving seated cuff systolic BP (SeSBP) less than 140 mmHg (<130 mmHg in patients with diabetes mellitus) at 12 weeks. Secondary endpoints included SeBP goal rates, ambulatory BP (ABP) target rates, and mean change from baseline in seated cuff BP (SeBP) and ABP at weeks 12 and 20. Results: Mean baseline BP was similar in Hispanics (153.6/92.8 mmHg; n = 105) and non-Hispanics (153.7/91.8 mmHg; n = 894). At 12 weeks, 72.0% of Hispanics and 76.3% of non-Hispanics achieved the primary endpoint. At week 12, goal rates for cumulative SeBP (<140/90 mmHg or <130/80 mmHg in patients with diabetes) were 69.0% and 71.5% in Hispanic and non-Hispanic patients, respectively. Mean change in SeBP in Hispanics ranged from −15.3/−7.3 mmHg for AML/OM 5/20 mg to −23.2/−13.8 mmHg for AML/OM 10/40 mg + hydrochlorothiazide 25 mg, and in non-Hispanics from −14.1/−7.8 mmHg to −25.4/−13.7 mmHg (all p < 0.0001 versus baseline). A majority of patients achieved mean 24 h, daytime, and nighttime ABP targets in both subgroups. Greater proportions of Hispanics achieved ABP targets versus non-Hispanics at week 12; however, this trend was reversed at week 20. Treatment was well tolerated. Conclusions: Switching to a fixed-dose combination of AML/OM ± hydrochlorothiazide provided significant BP lowering and effectively controlled BP in a large proportion of Hispanic and non-Hispanic patients with hypertension uncontrolled on previous monotherapy.