Clinical factors related to successful or unsuccessful cardioversion in the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) randomized trial.

BACKGROUND: EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation evaluated use of nonvitamin K antagonist oral anticoagulant edoxaban vs enoxaparin-warfarin in patients with nonvalvular atrial fibrillation undergoing electrical cardioversion. HYPOTHESIS: To assess clinical factors related to successful or unsuccessful cardioversion. To evaluate whether differences in adverse events based on anticoagulation strategy may exist. METHODS: In this multicenter prospective randomized open-label blinded end-point evaluation trial, 2199 patients were randomized to edoxaban 60 mg once daily (30 mg for creatinine clearance 15-50 mL/min, weight ≤ 60 kg, and/or concomitant use of P-glycoprotein inhibitor) or enoxaparin-warfarin. Successful cardioversion was confirmed by 12-lead electrocardiography-documented sinus rhythm. RESULTS: Cardioversion was successful in 1578 patients; in 355 patients, cardioversion was unsuccessful. Male, high body weight, high body mass index (BMI), coronary artery disease, concomitant aspirin, or prior statins use were more common in patients with unsuccessful cardioversion; international normalized ratio control did not differ by cardioversion success. On multivariate analysis, gender (P < .05), body weight (P = .0196) and BMI (P = .0377) emerged as independent predictors of successful cardioversion. There were no significant differences in primary efficacy (a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular death during overall study period) regardless of cardioversion success. There were no significant differences in bleeding rates, regardless of cardioversion outcome; notwithstanding low numbers, edoxaban and enoxaparin-warfarin did not differ. CONCLUSIONS: Male gender, higher mean weight and higher mean BMI were associated with unsuccessful cardioversion. Efficacy and safety outcomes were low and did not differ by cardioversion success.

Comparing TEE- vs Non-TEE-guided cardioversion of atrial fibrillation: The ENSURE-AF trial.

BACKGROUND: ENSURE-AF (NCT02072434) assessed therapy with edoxaban vs enoxaparin-warfarin in patients with nonvalvular atrial fibrillation (AF) undergoing elective electrical cardioversion (ECV). OBJECTIVES: To evaluate clinical features and primary efficacy (composite of stroke, systemic embolic events, myocardial infarction and cardiovascular mortality during study period) and safety endpoints (composite of major and clinically relevant nonmajor bleeding during on-treatment period) in patients awaiting ECV of AF with a transesophageal echocardiography (TEE)-guided vs a non-TEE-guided strategy. METHODS: In this prospective, randomized, open-label, blinded endpoint study, 2199 patients were randomized to edoxaban 60 mg once-daily (30 mg for creatinine clearance 15-50 mL/min, weight ≤60 kg and/or concomitant use of P-glycoprotein inhibitor) or enoxaparin-warfarin. Primary efficacy endpoint and safety endpoint were reported. Associates of TEE use, efficacy endpoint and safety endpoint were explored using multivariable logistic regression. RESULTS: In total, 589 patients from the edoxaban stratum and 594 from the enoxaparin-warfarin stratum were allocated to the TEE-guided strategy. Primary efficacy was similar regardless of TEE approach (P = .575). There were no significant differences in bleeding rates, regardless of TEE approach (P = .677). Independent predictors of TEE use were as follows: history of ischaemic stroke/ transient ischaemic attack, hypertension and valvular heart disease. Mean CHA2 DS2 VASc and HAS-BLED score were independent predictors of the efficacy endpoint whilst mean age was an independent predictor of the safety endpoint. CONCLUSIONS: Thromboembolic and bleeding events were not different between patients undergoing TEE-guided strategy and in those undergoing an optimized conventional anticoagulation approach for ECV of AF.

Edoxaban versus warfarin in vitamin K antagonist experienced and naïve patients from the edoxaban versus warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF) randomised trial.

BACKGROUND: In ENSURE-AF study, edoxaban had similar efficacy and safety profile versus enoxaparin-warfarin (enox-warf) in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. OBJECTIVES: To evaluate the efficacy and safety of edoxaban versus enox-warf in patients who were vitamin K antagonists (VKA) naïve or experienced at time of randomisation into ENSURE-AF trial. METHODS: The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular death during the overall study period, 28 days on study drug after cardioversion and 30 days follow-up. The primary safety endpoint was the composite of major and clinically relevant nonmajor bleeding during the on-medication period from time of first dose to last dose of study drug taken + 3 days. RESULTS: Of 2199 patients enrolled in ENSURE-AF, 1095 were randomised to edoxaban and 1104 to enox-warf. There were numerically fewer primary efficacy endpoint events with edoxaban than enox-warf irrespective of whether VKA experienced or naïve (0.5% vs. 0.9%, 0.3% vs. 1.4%, respectively). There were no significant differences in the primary safety endpoint [odds ratio (OR) 2.09, 95% confidence interval (CI) 0.72-6.81 in anticoagulant experienced patients, OR 0.77, 95% CI 0.15-3.60 in anticoagulant naïve patients] and in major bleeding rates regardless of treatment or VKA experience (OR 0.69, 95%CI 0.06-6.04, OR 0.48, 95% CI 0.01-9.25, respectively). CONCLUSIONS: Edoxaban had comparable efficacy and safety to optimized anticoagulation with enox-warf. The primary efficacy and safety endpoint outcomes were broadly similar between VKA experienced or naïve patients.

Determinants of left atrium thrombi in scheduled cardioversion: an ENSURE-AF study analysis.

AIMS: ENSURE-AF (NCT02072434) was the largest prospective randomized clinical trial of anticoagulation for cardioversion in atrial fibrillation (AF), which also provides the largest prospective dataset for transoesophageal echocardiography (TOE) prior to cardioversion. This ancillary analysis investigated determinants of TOE-detected left atrium thrombi (LAT) in patients scheduled for electrical cardioversion (ECV). METHODS AND RESULTS: The ENSURE-AF multicentre PROBE evaluation trial compared edoxaban 60 mg once daily (QD) with enoxaparin/warfarin in 2199 subjects undergoing ECV of non-valvular AF. Patients were stratified by the use of TOE, anticoagulant experience, and selected edoxaban dose. Electrical cardioversion was cancelled or deferred when TOEdetected LAT. In total, 1183 subjects were stratified to the TOE arm and LAT was reported in 91 (8.2%). In univariate analysis, age ≥75 years (26.4% vs. 16.9%, P = 0.0308), lower weight (86.5 ± 15.0 vs. 90.7 ± 18.0 kg, P = 0.0309), lower creatinine clearance (80.1 ± 30.6 vs. 93.2 ± 33.9 mL/min, P = 0.0007), heart failure (59.3% vs. 43.0%, P = 0.0029), and diuretic treatment (53.9% vs. 40.1%, P = 0.0141) were more prevalent in the LAT group. Non-significant trends were seen for higher mean CHA2DS2-VASc score (3.0 ± 1.41 vs. 2.7 ± 1.48, P = 0.0571) and more prevalent anticoagulation use prior to enrolment (60.4% vs. 50.3%, P = 0.0795) in the LAT group. In logistic regression analysis, age (P = 0.0202) and heart failure (P = 0.0064) were independently associated with LAT. CONCLUSION: Elective ECV is commonly cancelled or deferred due to TOE-detected LAT in patients with non-valvular AF. Age ≥75 years and heart failure were associated with the presence of LAT.

Impact of Body Mass Index on Outcomes in the Edoxaban Versus Warfarin Therapy Groups in Patients Underwent Cardioversion of Atrial Fibrillation (from ENSURE-AF).

In the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation study (NCT 02072434), edoxaban showed similar efficacy and safety versus enoxaparin-warfarin in patients underwent electrical cardioversion of nonvalvular atrial fibrillation. In this ancillary analysis, we compared the primary efficacy (composite of stroke, systemic embolic event, myocardial infarction, cardiovascular death, and overall study period) and safety (composite of major and clinically relevant nonmajor bleeding, on-treatment) end points in relation to body mass index (BMI; <30 vs ≥30 kg/m2). We also compared cardioversion outcomes in relation to BMI. Of 2,199 patients enrolled, 1,095 were randomized to edoxaban and 1,104 to enoxaparin-warfarin. Mean age was 64 ± 10 and 64 ± 11 years and mean BMI 30.6 and 30.7 kg/m2, respectively. Cardiovascular and metabolic diseases were more prevalent in obese (n = 1067) than nonobese patients. Overall ischemic event rates were low; rates in the BMI <30 kg/m2 subgroup were numerically lower than the ≥30 kg/m2 subgroup, but not significantly different (odds ratio [OR], 0.74 [95% confidence interval 0.23, 2.24]). Composite major + clinically relevant nonmajor bleeding rates were low and numerically lower, but not significantly different (OR 0.88 [0.38, 2.04]), between the edoxaban and enoxaparin-warfarin arms and across weight categories. Successful cardioversion rate was higher in the BMI <30 versus ≥30 kg/m2 subgroup (73.9% vs 69.9%; OR 1.22 [1.01 to 1.48]). In EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation, BMI did not significantly impact the relative efficacy and safety of edoxaban versus enoxaparin-warfarin. Nevertheless, the nonobese group had a higher rate of cardioversion success than the obese group.

Relation of Stroke and Bleeding Risk Profiles to Efficacy and Safety of Edoxaban for Cardioversion of Atrial Fibrillation (from the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation [ENSURE-AF] Study).

In the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) study, edoxaban was compared with enoxaparin-warfarin in patients who underwent electrical cardioversion of nonvalvular atrial fibrillation, showing comparable low rates of bleeding and thromboembolism. The present study is an ancillary analysis investigating differences in relation to stroke and bleeding risk profiles. It also determined the relation of patients' clinical risk profiles to the quality of anticoagulation control in the warfarin arm. Primary efficacy (composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular death) and safety (composite of major and clinically relevant nonmajor bleeding) outcomes and time to therapeutic range (TtTR) and time in therapeutic range (TiTR) were analyzed in relation to CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years (2 points), diabetes mellitus, stroke (2 points), vascular disease, age 65-74 years, sex category) and HAS-BLED (hypertension, age, stroke, bleeding tendency/predisposition, labile INRs, elderly age/frailty, drugs such as concomitant aspirin/nonsteroidal anti-inflammatory drugs or alcohol excess) scores. A total of 1,095 patients were randomized to edoxaban and 1,104 received enoxaparin-warfarin. Mean age was 64.3 ± 10 and 64.2 ± 11 years, respectively. Mean CHA2DS2-VASc score was 2.6 (standard deviation [SD] 1.5 and 1.4, respectively) and mean HAS-BLED score was 0.9 (SD 0.8) in both arms. There were nonsignificant trends toward lower odds ratios (ORs) for the efficacy end point in patients with CHA2DS2-VASc scores >2 and higher ORs with HAS-BLED score ≥3. Mean TiTR was >67%, with no differences between stroke or bleeding risk strata. The correlation between CHA2DS2-VASc and TtTR (p = 0.0286) and HAS-BLED and TiTR (p = 0.0286) were statistically significant. In patients who were at high risk of stroke, edoxaban had numerically lower primary efficacy end-point events and showed a trend for higher ORs, with HAS-BLED scores ≥3 compared with enoxaparin-warfarin. TtTR was shorter with higher CHA2DS2-VASc scores, whereas bleeding risk was inversely correlated with quality of anticoagulation control.

Anticoagulation Control in Warfarin-Treated Patients Undergoing Cardioversion of Atrial Fibrillation (from the Edoxaban Versus Enoxaparin-Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation Trial).

In the Edoxaban Versus Enoxaparin-Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation (ENSURE-AF) study (NCT 02072434), edoxaban was compared with enoxaparin-warfarin in 2,199 patients undergoing electrical cardioversion of nonvalvular atrial fibrillation (AF). In this multicenter prospective randomized open blinded end-point trial, we analyzed patients randomized to enoxaparin-warfarin. We determined time to achieve therapeutic range (TtTR); time in therapeutic range (TiTR); their clinical determinants; relation to sex, age, medical history, treatment, tobacco use, race risk (SAMe-TT2R2) score; and impact on primary end points (composite of stroke, systemic embolic event[SEE], myocardial infarction [MI], and cardiovascular death [CVD] and composite of major + clinically relevant nonmajor bleeding). Among 1,104 patients randomized to enoxaparin-warfarin, 27% were naïve to oral anticoagulants. Mean age was 64.2 ± 11 years and mean congestive heart failure, hypertension, age ≥75 (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65-74, female (CHA2DS2-VASc) score was 2.6. Mean TtTR was 7.7 days (median 7 days) and mean TiTR after reaching an international normalized ratio of 2.0 to 3.0 was 71%. In 695 patients who had an INR <2.0 before the first dose and who reached an INR ≥2.0, 436 had a SAMe-TT2R2 score ≤2 and 259 had a score >2. On multivariate regression, an independent predictor of extended TtTR was creatinine clearance (p = 0.02). TtTR was marginally related to stroke/SEE/MI/CVD (p = 0.06; odds ratio 0.23, 95% confidence interval 0.02 to 1.17) but not to any bleeding. Independent predictors of TiTR were previous vitamin K antagonist experience (p<0.01) and low hypertension, abnormal renal or liver function, stroke, bleeding, labile INRs, age >65, concomitant drugs or alcohol (HAS-BLED) score (p = 0.02). TiTR was related to any bleeding (p = 0.02; odds ratio 0.39, 95% confidence interval 0.16 to 0.88), but not stroke/SEE/MI/CVD. In this cohort of warfarin users with a high TiTR no difference was seen between TtTR and TiTR in relation to SAMe-TT2R2 score. In conclusion, even in this short-term study, TiTR was significantly related to bleeding events.

Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.

BACKGROUND: Edoxaban, an oral factor Xa inhibitor, is non-inferior for prevention of stroke and systemic embolism in patients with atrial fibrillation and is associated with less bleeding than well controlled warfarin therapy. Few safety data about edoxaban in patients undergoing electrical cardioversion are available. METHODS: We did a multicentre, prospective, randomised, open-label, blinded-endpoint evaluation trial in 19 countries with 239 sites comparing edoxaban 60 mg per day with enoxaparin-warfarin in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. The dose of edoxaban was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, low bodyweight [≤60 kg], or concomitant use of P-glycoprotein inhibitors) were present. Block randomisation (block size four)-stratified by cardioversion approach (transoesophageal echocardiography [TEE] or not), anticoagulant experience, selected edoxaban dose, and region-was done through a voice-web system. The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, analysed by intention to treat. The primary safety endpoint was major and clinically relevant non-major (CRNM) bleeding in patients who received at least one dose of study drug. Follow-up was 28 days on study drug after cardioversion plus 30 days to assess safety. This trial is registered with ClinicalTrials.gov, number NCT02072434. FINDINGS: Between March 25, 2014, and Oct 28, 2015, 2199 patients were enrolled and randomly assigned to receive edoxaban (n=1095) or enoxaparin-warfarin (n=1104). The mean age was 64 years (SD 10·54) and mean CHA2DS2-VASc score was 2·6 (SD 1·4). Mean time in therapeutic range on warfarin was 70·8% (SD 27·4). The primary efficacy endpoint occurred in five (<1%) patients in the edoxaban group versus 11 (1%) in the enoxaparin-warfarin group (odds ratio [OR] 0·46, 95% CI 0·12-1·43). The primary safety endpoint occurred in 16 (1%) of 1067 patients given edoxaban versus 11 (1%) of 1082 patients given enoxaparin-warfarin (OR 1·48, 95% CI 0·64-3·55). The results were independent of the TEE-guided strategy and anticoagulation status. INTERPRETATION: ENSURE-AF is the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation. Rates of major and CRNM bleeding and thromboembolism were low in the two treatment groups. FUNDING: Daiichi Sankyo provided financial support for the study.

Triple-combination treatment with olmesartan medoxomil/amlodipine/ hydrochlorothiazide in Hispanic/Latino patients with hypertension: the TRINITY study.

OBJECTIVE(S): Evaluate efficacy/safety of olmesartan medoxomil (OM)/amlodipine (AML)/ hydrochlorothiazide (HCTZ) in Hispanic/Latino adults with hypertension. DESIGN: Randomized, double-blind, 12-week, parallel-group study followed by a 40-week open-label extension phase. SETTING: Clinical sites (317) in the United States and Puerto Rico. PATIENTS OR PARTICIPANTS: Individuals > or =18 years of age with mean seated blood pressure (BP) > or =140/100 or > or =160/90 mm Hg divided into Hispanic/Latino (369) and non-Hispanic/Latino (2122) subgroups. INTERVENTIONS: Participants were randomized to OM 40/AML 10 mg, OM 40/HCTZ 25 mg, AML 10/HCTZ 25 mg, or OM 40/AML 10/HCTZ 25 mg during the double-blind phase. During the open-label extension, all participants received OM 40/AML 5/HCTZ 12.5 mg; participants not reaching BP goal within 2 weeks were randomly titrated to OM 40/AML 10/HCTZ 12.5 mg or OM 40/AML 5/HCTZ 25 mg, then to OM 40/AML 10/ HCTZ 25 mg after another 2 weeks. MAIN OUTCOME MEASURE: Change in mean seated diastolic BP (SeDBP) from baseline (double-blind phase). RESULTS: Triple-drug therapy vs the dual therapies resulted in greater mean reduction in SeBP (Hispanic/Latino: 35.0/20.9 mm Hg vs 27.8-30.9/15.3-17.7 mm Hg; non-Hispanic/Latino: 39.0/21.7 mm Hg vs 28.9-31.5/14.6-17.8 mm Hg) and enabled more participants to reach BP goal (Hispanic/Latino: 56.8% vs 40.6%-51.2%; non-Hispanic/Latino: 65.7% vs 33.8%-46.6%) irrespective of ethnicity. The efficacy of triple-drug therapy in achieving BP goal was sustained long-term (40-week open-label extension period) in Hispanic/Latino (63.3%) and non-Hispanic/ Latino (64.2%) participants. Triple-drug therapy was well tolerated in Hispanic/Latino and non-Hispanic/Latino participants. CONCLUSIONS: In this study, OM/AML/HCTZ was an effective treatment option in Hispanic/ Latino patients with hypertension.

The TRINITY Study: distribution of systolic blood pressure reductions.

BACKGROUND: Elevated systolic blood pressure is more difficult to control than elevated diastolic blood pressure. The objective of this prespecified analysis of the Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY) was to compare the efficacy of olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment with the component dual-combination treatments in reducing elevated seated systolic blood pressure (SeSBP). METHODS: The 12-week TRINITY study randomized participants to either one of the three component dual-combination treatments (OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg) or the triple-combination treatment. The primary outcome of this analysis was the categorical distribution of SeSBP reductions at week 12 from baseline with OM 40 mg/AML 10 mg/HCTZ 25 mg versus the dual-combination treatments. RESULTS: SeSBP reductions >50 mmHg were seen in 24.4% of participants receiving triple-combination treatment versus 8.1%-15.8% receiving dual-combination treatment. More participants receiving triple-combination treatment achieved the SeSBP target of <140 mmHg (73.6% versus 51.3%-58.8%; P < 0.001) and the seated blood pressure target of <140/90 mmHg (69.9% versus 41.1%-53.4%; P < 0.001). Prevalence and severity of adverse events were similar in all treatment groups. CONCLUSION: Treatment with OM 40 mg/AML 10 mg/HCTZ 25 mg was well tolerated and more effective in reducing SeSBP than the dual-combination treatments.

Olmesartan/amlodipine/hydrochlorothiazide in obese participants with hypertension: a TRINITY subanalysis.

The objective of this prespecified TRINITY study subgroup analysis was to assess the efficacy and safety of triple-combination treatment with olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg vs the component dual-combination treatments in obese (body mass index [BMI] ≥30 kg/m(2) ) and nonobese (BMI <30 kg/m(2) ) hypertensive participants. The double-blind treatment period primary end point was the least-squares (LS) mean reduction in seated diastolic BP (SeDBP) at week 12 (end of the double-blind period). Of the 2492 randomized participants, 1555 (62.4%) had BMI ≥30 kg/m(2) . Irrespective of BMI, triple-combination treatment resulted in greater LS mean reductions in seated BP (SeBP) (≥30 kg/m(2) , 6.7-10.5/4.5-7.3 mm Hg; <30 kg/m(2) , 5.1-8.6/2.5-6.0 mm Hg [P<.005] vs dual-combination treatments for both subgroups) at week 12. Furthermore, triple-combination treatment enabled a greater proportion of participants to reach BP goal vs the dual-combination treatments (≥30 kg/m(2) , 62% vs 31%-46% [P<.0001]; <30 kg/m(2) , 69% vs 41%-55% [P<.005]) at week 12. SeBP reduction and goal attainment (≥30 kg/m(2) , 63%; <30 kg/m(2) , 67%) was maintained through week 52/early termination. Triple-combination treatment was well tolerated in both BMI subgroups.

Combined olmesartan, amlodipine, and hydrochlorothiazide therapy in randomized patients with hypertension: a subgroup analysis of the TRINITY study by age.

BACKGROUND: Hypertension is often inadequately controlled in older people. OBJECTIVE: This prespecified subgroup analysis assessed the efficacy and safety of an olmesartan medoxomil (OM) 40 mg/amlodipine besylate (AML) 10 mg/hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment compared with the 3 components as dual-combination treatments in participants with hypertension who were <65 and ≥ 65 years of age. Within the ≥ 65 years of age subgroup, efficacy and safety were also summarized for participants ≥ 75 years of age. STUDY DESIGN: 12-week, multicenter, double-blind, randomized, parallel-group study. SETTING: 317 ambulatory care sites in the US and Puerto Rico. PARTICIPANTS: Individuals ≥ 18 years of age with mean seated blood pressure (SeBP) ≥ 140/100 or ≥ 160/90 mmHg off antihypertensive medication on 2 consecutive clinic visits with no recent history of significant cerebrovascular disease, coronary artery disease, heart failure (New York Heart Association class III or IV), severe renal insufficiency, or uncontrolled diabetes (HbA1c >9 %). INTERVENTION: Participants were randomized, stratified by age, diabetes status, and race to one of four treatment assignments: OM 40/AML 10/HCTZ 25 mg, OM 40/AML 10 mg, OM 40/HCTZ 25 mg, or AML 10/HCTZ 25 mg. MAIN OUTCOME MEASURE: Least squares (LS) mean change from baseline in seated diastolic blood pressure (SeDBP) at week 12 (last observation carried forward) in each age subgroup (prespecified analysis). RESULTS: Of the 2492 randomized participants in the study (total cohort), 2021 (81.1 %) were <65 and 471 (18.9 %) were ≥ 65 years of age, including 79 (3.2 %) who were ≥ 75 years of age. OM 40/AML 10/HCTZ 25 mg triple-combination treatment resulted in a significantly greater reduction in LS mean SeDBP at week 12 than dual-combination component treatments in participants in both cohorts: <65 years (21.0 vs. 14.2-17.2 mmHg; p < 0.0001) and ≥ 65 years (23.7 vs. 17.3-20.0 mmHg; p ≤ 0.002). Similarly, triple-combination treatment resulted in a greater reduction in LS mean seated systolic blood pressure (SeSBP) at week 12 than dual-combination component treatments: <65 years (38.2 vs. 28.3-31.4 mmHg; p < 0.0001) and ≥ 65 years (39.2 vs. 29.3-31.1 mmHg; p < 0.0001). Triple-combination treatment was more effective than dual-combination treatments in enabling participants to reach SeBP goal (<140/90 mmHg [<130/80 mmHg in participants with diabetes, chronic kidney disease, or chronic cardiovascular disease]) in both age subgroups (<65 years: 65 vs. 34-50 %, respectively, p < 0.0001 and ≥ 65 years: 63 vs. 32-39 %; p ≤ 0.0004). All 4 treatments were safe and well tolerated with low discontinuation rates in both age subgroups. There were no clinically relevant differences in the incidence of treatment-emergent adverse events between participants <65 and ≥ 65 years of age receiving triple-combination treatment. CONCLUSION: Triple-combination treatment with OM 40/AML 10/HCTZ 25 mg was well tolerated and more effective in lowering BP than the component dual-combination treatments in elderly and non-elderly subgroups.

Model-Supported Development of CS-8635: A Fixed-Dose Combination of Olmesartan, Amlodipine, and Hydrochlorothiazide.

CS-8635, a fixed-dose triple combination of olmesartan, amlodipine, and hydrochlorothiazide, was developed to address the growing need for additional blood pressure (BP) reduction in patients not controlled with dual-combination therapies. Prior to Phase III, modeling and simulation (M&S) was conducted to estimate the additional BP lowering effect of CS-8635 compared to the respective dual combinations. The Phase III study evaluated CS-8635 BP lowering effects only at the highest dose strength among the five dose strengths to be developed. Post-trial M&S was performed using an integrated dataset from three Phase III programs; CS-8635 plus two prior dual combinations. M&S robustly estimated and described the BP lowering effects of CS-8635 evaluated in a clinical setting. Furthermore, M&S evaluated BP lowering effects of the additional four dose strengths not studied. In summary, M&S aided the development of the clinical study and full characterization of the BP lowering effects of CS-8635 across intermediate doses.

Olmesartan/amlodipine/hydrochlorothiazide in participants with hypertension and diabetes, chronic kidney disease, or chronic cardiovascular disease: a subanalysis of the multicenter, randomized, double-blind, parallel-group TRINITY study.

BACKGROUND: Patients with hypertension and cardiovascular disease (CVD), diabetes, or chronic kidney disease (CKD) usually require two or more antihypertensive agents to achieve blood pressure (BP) goals. METHODS: The efficacy/safety of olmesartan (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg versus the component dual-combinations (OM 40/AML 10 mg, OM 40/HCTZ 25 mg, and AML 10/HCTZ 25 mg) was evaluated in participants with diabetes, CKD, or chronic CVD in the Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY). The primary efficacy end point was least squares (LS) mean reduction from baseline in seated diastolic BP (SeDBP) at week 12. Secondary end points included LS mean reduction in SeSBP and proportion of participants achieving BP goal (<130/80 mm Hg) at week 12 (double-blind randomized period), and LS mean reduction in SeBP and BP goal achievement at week 52/early termination (open-label period). RESULTS: At week 12, OM 40/AML 10/HCTZ 25 mg resulted in significantly greater SeBP reductions in participants with diabetes (-37.9/22.0 mm Hg vs -28.0/17.6 mm Hg for OM 40/AML 10 mg, -26.4/14.7 mm Hg for OM 40/HCTZ 25 mg, and -27.6/14.8 mm Hg for AML 10/HCTZ 25 mg), CKD (-44.3/25.5 mm Hg vs -39.5/23.8 mm Hg for OM 40/AML 10 mg, -25.3/17.0 mm Hg for OM 40/HCTZ 25 mg, and -33.4/20.6 mm Hg for AML 10/HCTZ 25 mg), and chronic CVD (-37.8/20.6 mm Hg vs -31.7/18.2 mm Hg for OM 40/AML 10 mg, -30.9/17.1 mm Hg for OM 40/HCTZ 25 mg, and -27.5/16.1 mm Hg for AML 10/HCTZ 25 mg) (P<0.05 for all subgroups vs dual-component treatments). BP goal achievement was greater for participants receiving triple-combination treatment compared with the dual-combination treatments, and was achieved in 41.1%, 55.0%, and 38.9% of participants with diabetes, CKD, and chronic CVD on OM 40/AML 10/HCTZ 25 mg, respectively. At week 52, there was sustained BP lowering with the OM/AML/HCTZ regimen. Overall, the triple combination was well tolerated. CONCLUSIONS: In patients with diabetes, CKD, or chronic CVD, short-term (12 weeks) and long-term treatment with OM 40/AML 10/HCTZ 25 mg was well tolerated, lowered BP more effectively, and enabled more participants to reach BP goal than the corresponding 2-component regimens. TRIAL IDENTIFICATION NUMBER: NCT00649389.

Triple-Combination therapy with olmesartan, amlodipine, and hydrochlorothiazide in black and non-black study participants with hypertension: the TRINITY randomized, double-blind, 12-week, parallel-group study.

BACKGROUND: Although awareness of hypertension in Black patients has increased, blood pressure (BP) is frequently inadequately controlled. OBJECTIVE: This prespecified subgroup analysis of the TRINITY study evaluated the efficacy and safety of olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment compared with the component dual-combination treatments in Black and non-Black study participants. STUDY DESIGN: TRINITY was a 12-week, randomized, double-blind, parallel-group evaluation. The first patient was enrolled in May 2008 and the last patient completed the study in February 2009. The study consisted of a 3-week washout period for participants receiving antihypertensive therapy and a 12-week double-blind treatment period. For the treatment phase, all study participants were stratified by age, race, and diabetes mellitus status and randomized to a treatment sequence that led to their final treatment assignment, which they received from weeks 4 to 12 (OM 40 mg/AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg). In the first 2 weeks of the double-blind treatment period, all participants received either dual-combination treatment or placebo. Participants assigned to dual-combination treatment continued treatment until week 4, and participants receiving placebo were switched at week 2 to receive one of the dual-combination treatments until week 4. At week 4, participants either continued dual-combination treatment or randomly received triple-combination treatment until week 12. SETTING: 317 clinical sites in the USA and Puerto Rico were included in the study. PATIENTS: Study participants eligible for randomization (N = 2492) were ≥18 years of age with mean seated blood pressure (SeBP) ≥140/100 mmHg or ≥160/90 mmHg (off antihypertensive medication). INTERVENTION: The intervention was with dual- or triple-combination antihypertensive treatment: OM 40 mg/AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg. MAIN OUTCOME MEASURE: The primary efficacy variable was the change in least squares (LS) mean seated diastolic BP (SeDBP) from baseline to week 12. Secondary efficacy variables included the LS mean change in seated systolic BP (SeSBP), percentage of study participants reaching BP goal, and safety parameters. RESULTS: In both Black and non-Black participants, triple-combination treatment resulted in significant and similar mean reductions in SeDBP and SeSBP (p ≤ 0.0001 vs each dual-combination treatment) with a greater proportion of participants reaching BP goal compared with dual-combination treatments, regardless of race. Most treatment-emergent adverse events were mild or moderate in severity and no new safety concerns were identified. CONCLUSION: Triple-combination treatment provided greater BP reductions than dual-combination treatments regardless of race. CLINICAL TRIAL REGISTRATION: Registered at ClinicalTrials.gov as NCT00649389.

Long-term efficacy and safety of triple-combination therapy with olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide for hypertension.

J Clin Hypertens (Greenwich). 2012;14:149-157. ©2012 Wiley Periodicals, Inc. Most patients with hypertension require combination therapy in order to achieve blood pressure (BP) goals. This 40-week open-label extension of the 12-week double-blind Triple Therapy With Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY) evaluated the efficacy and safety of triple-combination treatments with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide (OM/AML/HCTZ) in 2112 participants with moderate to severe hypertension. Following 2 weeks of initial treatment with OM 40/AML 5/HCTZ 12.5 mg, participants not achieving BP goal were titrated to OM 40/AML 5/HCTZ 25 mg or OM 40/AML 10/HCTZ 12.5 mg on a randomized basis. At week 16, participants who did not achieve BP goal were further titrated to OM 40/AML 10/HCTZ 25 mg. At the end of the study, 44.5% to 79.8% of participants reached BP goal and the mean BP decreased from 168.6/100.7 mm Hg (baseline BP at randomization) to 125.0 to 136.8 mm Hg/77.8 to 82.5 mm Hg, depending on treatment. Long-term treatment with OM/AML/HCTZ was well tolerated and effective with no new safety concerns.

Efficacy and safety of triple-combination therapy with olmesartan, amlodipine, and hydrochlorothiazide in study participants with hypertension and diabetes: a subpopulation analysis of the TRINITY study.

BACKGROUND: Most patients with hypertension and diabetes require two or more antihypertensive agents to achieve the recommended blood pressure (BP) goal of <130/80 mm Hg. This prespecified subgroup analysis from the TRIple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in HyperteNsIve PatienTs StudY assessed the efficacy and safety of triple-combination treatment (olmesartan medoxomil 40/amlodipine besylate 10/hydrochlorothiazide 25 mg) versus the component dual-combination treatments according to diabetes status (diabetes; non-diabetes). METHODS: Participants received dual-combination treatment for 4 weeks or placebo for 2 weeks. Participants receiving placebo switched to dual-combination treatment from week 2 to week 4. At week 4, participants switched to triple-combination treatment or continued on dual-combination treatment until week 12. RESULTS: The prespecified changes in BP from baseline for the diabetes subgroup receiving triple-combination treatment were greater than the respective dual-combination treatments (P ≤ .0013). Also, more participants with diabetes receiving triple-combination treatment reached BP goal (<130/80 mm Hg) versus those receiving dual-combination treatments (P ≤ .0092). In a post hoc analysis, significantly greater proportions of study participants with diabetes achieved BP targets with triple-combination treatment compared with each dual-combination treatment. Most treatment-emergent adverse events were mild to moderate in severity. CONCLUSIONS: In participants with hypertension and diabetes, triple-combination treatment led to greater BP reductions and enabled greater proportions of participants to reach BP goal versus the dual-combination treatments. Triple-combination treatment was well tolerated in both diabetes and non-diabetes subgroups.

24-hour efficacy and safety of Triple-Combination Therapy With Olmesartan, Amlodipine, and Hydrochlorothiazide: the TRINITY ambulatory blood pressure substudy.

This 12-week, multicenter, randomized, double-blinded, 4-arm study in 440 patients with moderate to severe hypertension compared ambulatory blood pressure (ABP) responses with a triple-combination regimen (olmesartan medoxomil [OM] 40 mg, amlodipine besylate [AML] 10 mg, and hydrochlorothiazide [HCTZ] 25 mg) and its component dual-combination regimens at similar doses. At week 12, the triple combination resulted in a greater reduction in mean 24-hour systolic and diastolic blood pressure (-30.3/-18.0 mm Hg) compared with the 3 dual-combination regimens (OM 40 mg/AML 10 mg: -23.5/-13.9, OM 40 mg/HCTZ 25 mg: -23.9/-14.5, and AML 10 mg/HCTZ 25 mg: -18.5 mm Hg/-10.7 mm Hg; P<.0001 each). Greater efficacy was also found during daytime and nighttime hours and during the last 6, 4, or 2 hours of the dosing interval. The authors conclude that the triple combination of OM 40 mg/AML 10 mg/HCTZ 25 mg demonstrated superior efficacy and sustained reductions in ABP compared with its dual-combination components.

Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: The TRINITY multicenter, randomized, double-blind, 12-week, parallel-group study.

BACKGROUND: Patients with hypertension may require a combination of > or =2 antihypertensive agents to achieve blood pressure (BP) control. OBJECTIVE: The aim of this study was to determine whether a triple combination of olmesartan medoxomil (OM), amlodipine besylate (AML), and hydrochlorothiazide (HCTZ) had a clinically significant benefit compared with dual combinations of the individual components in patients with moderate to severe hypertension. METHODS: This was a multicenter, randomized, doubleblind, parallel-group study in which triple combination treatment with OM 40 mg + AML 10 mg + HCTZ 25 mg was compared with dual combinations of the individual components-OM 40 mg/AML 10 mg in fixed-dose combination, OM 40 mg/HCTZ 25 mg in fixed-dose combination, and AML 10 mg + HCTZ 25 mg-in patients aged > or =18 years who had a mean seated BP > or =140/100 mm Hg or > or =160/90 mm Hg. The study consisted of a 3-week washout period with no study medication and a 12-week double-blind treatment period. In the first 2 weeks of the double-blind treatment period, all patients were randomized to receive dual combination treatment or placebo. All patients assigned to a dual combination treatment group continued the assigned treatment until week 4, and all patients assigned to placebo were switched at week 2 to receive 1 of the dual combination treatments until week 4. At week 4, patients either continued dual combination treatment or switched to triple combination treatment until week 12. The primary end point was the change in seated diastolic BP (SeDBP) from baseline to week 12; SeDBP reduction of > or =2 mm Hg was considered a clinically significant benefit. Secondary efficacy end points included the change in seated systolic BP (SeSBP) at week 12 and the percentages of patients achieving BP targets of <140/90 mm Hg, <120/80 mm Hg, SeSBP <140 mm Hg, and SeDBP <90 mm Hg at week 12. The tolerability of the treatments was also evaluated based on adverse events (AEs), clinical laboratory evaluations (chemistry, hematology, and urinalysis), physical examinations, and 12-lead ECGs. RESULTS: The 2492 randomized patients (52.9% male, 66.8% white, 30.4% black) had a mean (SD) age of 55.1 (10.9) years and a mean weight of 96.0 (22.9) kg. Diabetes was present in 15.5% of the population, chronic cardiovascular disease in 9.1%, and chronic kidney disease in 4.1%. At baseline, the mean SeBP was 168.5/100.9 mm Hg. At week 12, triple combination treatment was associated with significantly greater least squares mean reductions in SeBP compared with the dual combinations (SeDBP: -21.8 vs -15.1 to -18.0 mm Hg, respectively [P < 0.001]; SeSBP: -37.1 vs -27.5 to -30.0 mm Hg [P < 0.001]). A significantly higher proportion of patients receiving triple combination treatment reached BP targets compared with the dual combinations at week 12 (P < 0.001). The proportions of patients reaching the BP target of <140/90 mm Hg at week 12 was 69.9% in the triple combination treatment group and 52.9%, 53.4%, and 41.1% in the treatment groups receiving OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, and AML 10 mg + HCTZ 25 mg, respectively (P < 0.001, triple combination vs each dual combination). The incidence of treatment-emergent AEs (TEAEs) was 58.4% for triple combination treatment and 51.7% to 58.9% for the dual combinations; most TEAEs were mild or moderate in severity. The most common TEAEs in the triple combination treatment group were dizziness (9.9%), peripheral edema (7.7%), and headache (6.4%). In total, 52 patients (2.3%) discontinued the study due to TEAEs-6 (1.0%) in the OM 40 mg/AML 10 mg group, 12 (2.1%) in the OM 40 mg/HCTZ 25 mg group, 11 (2.0%) in the AML 10 mg + HCTZ 25 mg group, and 23 (4.0%) in the OM 40 mg + AML 10 mg + HCTZ 25 mg group. Thirty-two patients (1.4%)-4 (0.7%), 5 (0.9%), 5 (0.9%), and 18 (3.1%) in the respective treatment groups-discontinued the study due to drug-related TEAEs. CONCLUSIONS: In these adult patients with moderate to severe hypertension, triple combination treatment with OM 40 mg + AML 10 mg + HCTZ 25 mg was associated with significant BP reductions compared with dual combinations of the individual components. All treatments were generally well tolerated. ClinicalTrials. gov identifier: NCT00649389.