Effect of disease duration and prior disease-modifying antirheumatic drug use on treatment outcomes in patients with rheumatoid arthritis.

OBJECTIVES: To determine if disease duration and number of prior disease-modifying antirheumatic drugs (DMARDs) affect response to therapy in patients with established rheumatoid arthritis (RA). METHODS: Associations between disease duration or number of prior DMARDs and response to therapy were assessed using data from two randomised controlled trials in patients with established RA (mean duration, 11 years) receiving adalimumab+methotrexate. Response to therapy was assessed at week 24 using disease activity outcomes, including 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)), Simplified Disease Activity Index (SDAI) and Health Assessment Questionnaire Disability Index (HAQ-DI), and proportions of patients with 20%/50%/70% improvement in American College of Rheumatology (ACR) responses. RESULTS: In the larger study (N=207), a greater number of prior DMARDs (>2 vs 0-1) was associated with smaller improvements in DAS28(CRP) (-1.8 vs -2.2), SDAI (-22.1 vs -26.9) and HAQ-DI (-0.43 vs -0.64) from baseline to week 24. RA duration of >10 years versus <1 year was associated with higher HAQ-DI scores (1.1 vs 0.7) at week 24, but results on DAS28(CRP) and SDAI were mixed. A greater number of prior DMARDs and longer RA duration were associated with lower ACR response rates at week 24. Data from the second trial (N=67) generally confirmed these findings. CONCLUSIONS: Number of prior DMARDs and disease duration affect responses to therapy in patients with established RA. Furthermore, number of prior DMARDs, regardless of disease duration, has a limiting effect on the potential response to adalimumab therapy.

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.

Treatment with adenosine diphosphate receptor inhibitors-longitudinal assessment of treatment patterns and events after acute coronary syndrome (TRANSLATE-ACS) study design: expanding the paradigm of longitudinal observational research.

BACKGROUND: Platelet inhibition is critical in reducing both short- and long-term atherothrombotic risks after acute myocardial infarction (MI), especially among patients managed with percutaneous coronary intervention (PCI). Currently available antiplatelet medications, including adenosine diphosphate (ADP) receptor inhibitors, have demonstrated variability in efficacy and safety in clinical trials, yet few studies have examined contemporary "real-world" approaches to platelet inhibition and associated outcomes. METHODS: TRANSLATE-ACS is a prospective observational study that will track up to 17,000 MI patients managed with PCI, from the inhospital to outpatient settings for up to 12 months postdischarge to provide a comprehensive picture of current treatment patterns and outcomes in routine clinical practice. TRANSLATE-ACS exemplifies a collaborative study design that efficiently builds upon a well-established PCI registry platform, and yet, through a systematic telephone interview follow-up process, provides important longitudinal clinical and economic follow-up capacity through 15 months after initial MI hospitalization. Furthermore, TRANSLATE-ACS incorporates a hospital-level, clustered, randomized substudy to investigate the impact of point-of-care platelet inhibition testing on subsequent patient management. Finally, TRANSLATE-ACS provides feedback through quarterly reports to participating sites on their care practices benchmarked to peer performance to support and promote longitudinal quality of cardiovascular care delivery. CONCLUSION: TRANSLATE-ACS not only addresses important clinical and scientific questions but also includes pioneering design features that will assist in the evolution of clinical registries.

Effect of an olmesartan medoxomil-based treatment algorithm on systolic blood pressure in patients with stage 1 or 2 hypertension: a randomized, double-blind, placebo-controlled study.

BACKGROUND AND OBJECTIVE: Elevated systolic BP (SBP) is a major contributor to cardiovascular disease. SBP control reduces the occurrence of stroke, heart failure, and cardiovascular and total mortality. The aim of this study was to analyze the magnitude of SBP reductions and the achievement of individual SBP targets in the original BENIFORCE study. METHODS: An olmesartan medoxomil-based treatment algorithm was evaluated in a double-blind, placebo-controlled titration study in 276 patients with stage 1 (47.1%) or 2 (52.9%) hypertension. After placebo run-in, patients were randomized to placebo (12 weeks) or olmesartan medoxomil 20 mg/day (weeks 1-3). Olmesartan medoxomil was uptitrated to 40 mg/day (weeks 4-6), then olmesartan medoxomil/hydrochlorothiazide (HCTZ) 40/12.5 mg per day (weeks 7-9), and olmesartan medoxomil/HCTZ 40/25 mg per day (weeks 10-12) if BP remained ≥120/80 mmHg at any time interval. SETTING: The BENIFORCE study was a multicenter (29 sites) study conducted between January and October 2007 in the US. RESULTS: In patients receiving olmesartan medoxomil-based therapy, 81.0%, 67.2%, and 46.6% of patients with stage 1 hypertension and 70.4%, 49.4%, and 23.5% of patients with stage 2 hypertension achieved SBP targets of <140, <130, and <120 mmHg, respectively (all p < 0.01 vs placebo). The proportions of patients achieving SBP targets increased with escalating doses of olmesartan medoxomil and HCTZ, administered alone or in combination, and was highest for combination therapy. Similarly, escalating doses of olmesartan medoxomil or olmesartan medoxomil/HCTZ increased the proportion of patients achieving SBP reductions of >15 but ≤30, >30 but ≤45, and >45 mmHg compared with placebo. CONCLUSION: An olmesartan medoxomil-based treatment algorithm effectively reduced SBP and achieved SBP targets in patients with stage 1 or 2 hypertension. This regimen resulted in >80% of patients achieving SBP reductions of ≥15 mmHg while 44% achieved SBP reductions of >30 mmHg.

Efficacy and Safety of Adalimumab by Disease Duration: Analysis of Pooled Data From Crohn's Disease Studies.

BACKGROUND AND AIMS: Analyses of Crohn's Disease [CD] studies of anti-TNF agents, including adalimumab, have reported higher remission rates among patients with shorter disease duration. To further explore the relationship between disease duration and clinical efficacy, we analysed a larger patient cohort. METHODS: Data were pooled from 10 clinical trials in patients with moderately to severely active CD who received treatment with either adalimumab or placebo. Analyses of efficacy using Crohn's Disease Activity Index [CDAI] endpoints [remission, clinical response [CR]-70, CR-100, patient-reported outcome [PRO] remission] or Harvey-Bradshaw Index [HBI] endpoints [remission/response] were conducted for induction and maintenance treatment periods. Logistic regression was used for comparisons between adalimumab and placebo treatment. Cochran-Armitage trend tests were used for comparisons between disease-duration subgroups [<1 year, ≥1-<2 years, 2-≤5 years, and >5 years]. RESULTS: During induction, the proportion of patients achieving CDAI remission was higher in adalimumab- versus placebo-treated patients [p <0.001] and was highest [adalimumab: 45.8%] in the <1 year subgroup compared with longer disease-duration subgroups [≥1-<2 years: 31.0%; 2-≤5 years: 23.1%; >5 years: 23.6%, Cochran-Armitage p = 0.026]. In the majority of maintenance treatment analyses, patients with <1 year disease duration had the highest efficacy responses, with statistically significant differences in remission rates across disease-duration subgroups. CONCLUSIONS: This analysis demonstrates that earlier initiation of adalimumab treatment shortly after diagnosis in patients with moderately to severely active CD leads to improved long-term clinical outcomes.

The effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in paediatric patients with Crohn's disease: a post hoc analysis.

BACKGROUND: In the IMAgINE 1 study, adalimumab induced and maintained remission of moderate-to-severe Crohn's disease in children. AIM: To assess the efficacy, pharmacokinetics, immunogenicity and safety of immunomodulator and adalimumab combination therapy vs adalimumab monotherapy in paediatric patients with Crohn's disease. METHODS: Patients 6-17 years old with moderate-to-severe Crohn's disease (n = 192) received weight-based adalimumab induction at baseline and week 2. At week 4, 188 patients were randomised to high-dose or low-dose adalimumab. Patients receiving immunomodulators (investigator's decision) at baseline maintained a stable dose until week 26; patients could then discontinue immunomodulators. Adalimumab serum concentrations were measured at weeks 4, 26 and 52. Safety was evaluated at each study visit. Data were analysed using non-responder imputation (NRI; week 4) or modified NRI (weeks 26; 52). RESULTS: At week 4, patients with (n = 117) and without (n = 71) baseline immunomodulator use had similar response (79%; 87%; P = 0.235) and remission (26%; 30%; P = 0.737) rates. At week 26, patients with and without baseline immunomodulators had no significant difference in response (68%; 55%; P = 0.086) or remission (41%; 30%; P = 0.122). At week 52, patients with (n = 82) and without (n = 106) immunomodulator use had no significant difference in response (56%; 46%; P = 0.189) or remission (38%; 33%; P = 0.539). Adalimumab serum trough concentrations and serious infection rates (7%; 6%) were not significantly different between groups. CONCLUSIONS: Analyses found no statistically significant difference in response or remission between patients receiving adalimumab monotherapy vs immunomodulator and adalimumab combination therapy. Serious and infectious adverse event rates were similar between groups.

Randomization to once-daily stavudine extended release/lamivudine/efavirenz versus a more frequent regimen improves adherence while maintaining viral suppression.

BACKGROUND: In antiretroviral (ARV) therapy, pill burden, dosing frequency, and regimen complexity adversely affect adherence. We sought to evaluate the effect of regimen simplification on maintenance of virologic suppression and treatment adherence. METHOD: In this 48-week, open-label, randomized study, 320 HIV-1-infected adult patients with a viral load of <50 copies/mL on a twice-daily or more frequent ARV regimen were either switched to a once-daily regimen of efavirenz, extended-release stavudine, and lamivudine (QD arm) or continued on existing therapy (BID+ arm). Medication Event Monitoring System (MEMS) caps, AIDS Clinical Trials Group (ACTG)-validated questionnaire, and pill counts were used to evaluate adherence. Treatment satisfaction and preference were also evaluated. RESULTS: The QD arm was noninferior to the BID+ arm in the primary efficacy measure (proportion of patients who maintained virologic suppression at Week 48; QD arm, 80.0% vs. BID+ arm, 75.8%). Adherence and treatment satisfaction significantly favored the QD arm, in which 91.0% of patients preferred the simpler regimen. Overall, the majority of adverse events were mild to moderate in severity and resulted in a low rate of treatment discontinuations. CONCLUSIONS: Simplifying twice-daily or more frequent ARV therapy to a once-daily efavirenz-containing regimen in virologically suppressed HIV-1-infected patients maintains virologic suppression while improving adherence and patient satisfaction.

Efficacy of Adalimumab for Treatment of Perianal Fistula in Children with Moderately to Severely Active Crohn's Disease: Results from IMAgINE 1 and IMAgINE 2.

BACKGROUND AND AIMS: Adalimumab has been shown to be more effective than placebo in healing fistulae in adults with moderately to severely active Crohn's disease. The efficacy and safety of adalimumab in healing fistulae in children/adolescents with Crohn's disease from the 52-week IMAgINE 1 clinical trial, and its open-label extension IMAgINE 2, are reported. METHODS: Children/adolescents with perianal fistulae at baseline of IMAgINE 1 were assessed for fistula closure and improvement during IMAgINE 1 [Weeks 0-52] and from Week 0 of IMAgINE 2 [Week 52 of IMAgINE 1] through to Week 240 of IMAgINE 2 using non-responder imputation. RESULTS: A total of 36 children/adolescents had fistulae at baseline of IMAgINE 1 and were included in the analysis. Fistula closure and improvement were observed in 44.4% and 52.8%, respectively, at Week 12. Rates of closure and improvement were maintained throughout the analysis period to Week 292. No new safety signals were identified. CONCLUSIONS: In children/adolescents with moderately to severely active, fistulizing Crohn's disease, adalimumab induced perianal fistula closure and improvement within 12 weeks of treatment, with rates that were sustained for more than 5 years. The safety profile of adalimumab in patients with fistulae at baseline was similar to that of the overall population in IMAgINE 1/2. ClinicalTrials.gov identifiers: IMAgINE 1 (NCT00409682); IMAgINE 2 (NCT00686374).

Performance of Crohn's disease Clinical Trial Endpoints based upon Different Cutoffs for Patient Reported Outcomes or Endoscopic Activity: Analysis of EXTEND Data.

Background: Clinical trial endpoints for Crohn's disease (CD) activity correlate poorly with mucosal inflammation; to assess treatment efficacy, patient-reported outcomes and endoscopic assessments are preferred. This study assessed the impact on treatment efficacy estimations of using different definitions of clinical and endoscopic remission and endoscopic response, and of using site- or central-based endoscopy evaluation. Methods: This post hoc analysis of data fromEXTEND (extend the safety and efficacy of adalimumab through endoscopic healing), a placebo (PBO)-controlled, randomized trial of adalimumab (ADA) for mucosal healing, included adults with moderate-to-severe CD. Subsets of patients meeting specified Simplified Endoscopic Score for CD (SES-CD) inclusion criteria, according to site or central reading, and baseline stool frequency (SF) and/or abdominal pain score (AP) thresholds were evaluated. Various endpoint definitions based on the Crohn's Disease Activity Index (CDAI), its SF and AP components, SES-CD, and composite endpoints were compared between treatment groups. Results: Increased stringency of Week 12 clinical endpoints compared to CDAI<150 to SF≤3.0/1.5&AP≤1.0 reduced PBO response rates by ≥12% and increased treatment effects by ≤10%. Amending the SES-CD endpoint from ≤4 to ≤2 reduced the treatment effect from 24% to 8%. Composite endpoints further diminished response rates and effect sizes. Site-based evaluation was associated with lower remission rates versus central reading in the PBO group and, thus, greater ADA-related treatment effects. Conclusions: This analysis is the first to demonstrate that increasing the stringency of clinical and endoscopic endpoint definitions in CD trials, especially lowering SF or SES-CD definitions, reduces the ability to detect treatment-related change in CD activity; focus on endpoints that reflect clinical change is warranted.

Clinical Benefit of Long-Term Adalimumab Treatment in Patients With Crohn's Disease Following Loss of Response or Intolerance to Infliximab: 96-Week Efficacy Data From GAIN/ADHERE Trials.

BACKGROUND AND AIMS: In the 4-week GAIN clinical trial, adalimumab was efficacious in inducing remission in patients with moderate-to-severe Crohn's disease [CD] who had prior loss of response/intolerance to infliximab. The efficacy and safety of adalimumab in these patients are reported here for up to 96 weeks or for 3 years, respectively, in the ADHERE open-label extension study. METHODS: Patients who completed GAIN could enrol in ADHERE and receive open-label adalimumab 40 mg every other week. Efficacy variables included clinical response (Crohn's Disease Activity Index [CDAI] decrease from baseline ≥70/≥100 points [CR-70/CR-100]) and remission [CDAI<150], steroid discontinuation and fistula remission [absence of drainage]. Data were reported using hybrid non-responder imputation [hNRI], last observation carried forward and as-observed analysis. Subgroup analyses were performed by randomized group in GAIN and by Week 4 efficacy in GAIN. Safety was also assessed. RESULTS: A total of 310 patients from GAIN enrolled in ADHERE. CR-70, CR-100 and remission rates at Week 96 were 39.0%, 35.5%, and 26.5% [hNRI], respectively. Of the patients with CR-70 response or remission at Week 4 of GAIN, 45.5% and 44.4% [hNRI], respectively, maintained the effect at Week 96. Steroid discontinuation and steroid-free remission rates increased from Week 12 to 96 in patients using corticosteroids at GAIN baseline. CONCLUSIONS: Long-term adalimumab maintenance therapy led to sustained clinical remission and response, and steroid discontinuation in a considerable proportion of patients with CD previously treated with infliximab. No new safety signals were observed in this patient population.

Adalimumab Reduces Extraintestinal Manifestations in Patients with Crohn's Disease: A Pooled Analysis of 11 Clinical Studies.

INTRODUCTION: Extraintestinal manifestations (EIMs) in patients with Crohn's disease (CD) are common and associated with additional morbidity. This study aimed to evaluate the effect of adalimumab therapy on EIM resolution and identify potential predictors of EIM resolution in adult and pediatric patients with moderate to severe CD. METHODS: EIM data were pooled from 11 induction, maintenance, and open-label extension studies of adalimumab. Resolution of EIMs was evaluated at approximately 6 months and 1 year. Median time to initial EIM resolution and first EIM recurrence (reflecting durable resolution) of any EIM and specific categories of EIMs (arthritis/arthralgia, ocular, cutaneous) were calculated. A Cox model was used to determine predictors of initial and durable EIM resolution. RESULTS: At baseline, 54% (1137/2094) of patients receiving adalimumab and 51% (297/586) receiving placebo had EIMs. EIM resolution occurred in a significantly greater proportion of adalimumab versus placebo patients at 6 months (54% vs 31%; P < .001) and 1 year (60% vs 42%; P = .008). Median time to initial resolution of any EIM, arthritis/arthralgia, and cutaneous EIMs was significantly shorter in patients receiving adalimumab versus placebo. Durable resolution of any EIM and arthritis/arthralgia was significantly longer for patients receiving adalimumab versus placebo. Clinically meaningful predictors of EIM resolution included adalimumab treatment, male sex, and moderate (versus severe) disease activity at baseline. CONCLUSION: Adalimumab is effective for achieving initial and durable resolution of any EIM and, in particular, arthritis/arthralgia in patients with moderate to severe CD. Predictors of EIM resolution included adalimumab treatment and moderate disease severity. FUNDING: AbbVie.

Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro and clinically.

BACKGROUND: The HIV protease inhibitor (PI) atazanavir does not impair insulin sensitivity acutely but ritonavir and lopinavir induce insulin resistance at therapeutic concentrations. OBJECTIVE: To test the hypothesis that atazanavir combined with a lower dose of ritonavir would have significantly less effect on glucose metabolism than lopinavir/ritonavir in vitro and clinically. METHODS: Glucose uptake was measured following insulin stimulation in differentiated human adipocytes in the presence of ritonavir (2 micromol/l) combined with either atazanavir or lopinavir (3-30 micromol/l). These data were examined clinically using the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing (OGTT) in 26 healthy HIV-negative men treated with atazanavir/ritonavir (300/100 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) for 10 days in a randomized cross-over study. RESULTS: Atazanavir inhibited glucose uptake in vitro significantly less than lopinavir and ritonavir at all concentrations. Ritonavir (2 micromol/l) combined with either atazanavir or lopinavir (3-30 micromol/l) did not further inhibit glucose uptake. During euglycemic clamp, there was no significant change from baseline insulin sensitivity with atazanavir/ritonavir (P = 0.132), while insulin sensitivity significantly decreased with lopinavir/ritonavir from the baseline (-25%; P < 0.001) and from that seen with atazanavir/ritonavir (-18%; P = 0.023). During OGTT, the HOMA insulin resistance index significantly increased from baseline at 120 min with atazanavir/ritonavir and at 150 min with lopinavir/ritonavir. The area under the curve of glucose increased significantly with lopinavir/ritonavir but not with atazanavir/ritonavir. CONCLUSIONS: Both glucose uptake in vitro and clinical insulin sensitivity in healthy volunteers demonstrate differential effects on glucose metabolism by the combination PI atazanavir/ritonavir and lopinavir/ritonavir.

Pharmacokinetics and Pharmacodynamics of the Nonvitamin K Antagonist Oral Anticoagulant Edoxaban When Administered Alone or After Switching from Rivaroxaban or Dabigatran Etexilate in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Edoxaban is an oral, once-daily direct factor Xa inhibitor. To support the possibility that patients may choose to switch treatment from another nonvitamin K antagonist oral anticoagulant to edoxaban, this clinical study was conducted to evaluate the pharmacokinetic and pharmacodynamic effects of edoxaban after switching from rivaroxaban or dabigatran etexilate to edoxaban. METHODS: In this open-label, three-period, crossover study, healthy subjects received 3 days of edoxaban 60 mg daily, rivaroxaban 20 mg daily, or dabigatran etexilate 150 mg twice daily, followed by edoxaban 60 mg on day 4. RESULTS: Day 4 edoxaban pharmacokinetic parameters were similar for all treatments. The peak effect of edoxaban on prothrombin time (PT) after 4 days of edoxaban only was 21.8 ± 2.46 s; after switching from rivaroxaban to edoxaban, peak effect on PT was similar at 21.8 ± 2.88 s. After switching from dabigatran etexilate to edoxaban, least squares mean activated partial thromboplastin time (aPTT) at 2 h after administration was 47.6 vs 35.0 s for edoxaban alone. The treatment difference was 12.8 s (95% confidence interval 10.5-15.1; p < 0.0001). Post hoc analysis revealed that predose aPTT was elevated on day 3 of dabigatran etexilate administration, and on day 4, indicating a carryover effect from dabigatran. All treatments were well tolerated and there were no safety concerns upon switching, with no increased risk of bleeding. CONCLUSIONS: The study results suggest that switching to edoxaban from either rivaroxaban or dabigatran etexilate at the time of the next dose is well tolerated and maintains coagulation status.

Host factors may be more important than choice of antiretrovirals in the development of lipoatrophy.

Peripheral fat loss, or lipoatrophy, has been reported as an emerging complication of long-term antiretroviral regimens, mainly when nucleoside analogues are included. However, lipoatrophy does not develop in the majority of nucleoside inhibitor-treated patients, leading to the investigation of factors other than drug effects alone as potential contributors to this complication. We conducted a retrospective cohort study study and analysis of repository plasma samples taken from HIV-infected patients being treated with their initial antiretroviral regimen. CD4 cell count and plasma tumor necrosis factor (TNF), soluble TNF receptors, and leptin levels were assessed and correlated with the development of lipoatrophy. The most significant treatment-related factor in this study of patients on their first drug regimen was duration of antiretroviral therapy, rather than type of nucleoside inhibitor treatment. No association was found between lipoatrophy and specific nucleoside inhibitors, including zidovudine and stavudine. A significant association between lipoatrophy was found for 2 nondrug risk factors: older age and lower pretherapy body mass index. Our results emphasize the need for keeping in mind the role of host factors in the generation of lipoatrophy.

Efficacy/safety of a fixed-dose amlodipine/olmesartan medoxomil-based treatment regimen in hypertensive blacks and non-blacks with uncontrolled BP on prior antihypertensive monotherapy.

In this secondary analysis of a dose-titration study of patients with hypertension uncontrolled on prior monotherapy, blacks (n=234) and non-blacks (n=765) were switched to amlodipine (AML)/olmesartan medoxomil (OM) 5/20 mg, with uptitration every 4 weeks to AML/OM 5/40 mg and then AML/OM 10/40 mg to achieve a seated cuff blood pressure (SeBP) of <120/70 mm Hg. Hydrochlorothiazide 12.5 and 25 mg could be added if SeBP was ≥125/75 mm Hg. The cumulative proportions of patients achieving systolic SeBP <140 mm Hg (<130 mm Hg if diabetic) at 12 weeks were 71.6% for blacks and 77.2% for non-blacks. Mean SeBP change from baseline in blacks (mean baseline BP: 153.0/93.7 mm Hg) ranged from -11.7/-6.1 mm Hg for AML/OM 5/20 mg to -23.6/-12.9 mm Hg for AML/OM 10/40 mg +hydrochlorothiazide 25 mg (all P<.0001). Antihypertensive efficacy was maintained throughout the 24-hour dosing interval. An AML/OM-based regimen was effective in blacks with hypertension uncontrolled on prior monotherapy.

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

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.

The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study.

OBJECTIVES: The goal of this study was to evaluate the effect of smoking on the pharmacokinetics and pharmacodynamics (PD) of clopidogrel and prasugrel therapy. BACKGROUND: Major randomized trial data demonstrated that nonsmokers experience less or no benefit from clopidogrel treatment compared with smokers (i.e., the "smokers' paradox"). METHODS: PARADOX was a prospective, randomized, double-blind, double-dummy, placebo-controlled, crossover study of objectively assessed nonsmokers (n = 56) and smokers (n = 54) with stable coronary artery disease receiving aspirin therapy. Patients were randomized to receive clopidogrel (75 mg daily) or prasugrel (10 mg daily) for 10 days and crossed over after a 14-day washout. PD was assessed by using VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein phosphorylation assays. Clopidogrel and prasugrel metabolite levels, cytochrome P450 1A2 activity, CYP2C19 genotype, and safety parameters were determined. RESULTS: During clopidogrel therapy, device-reported inhibition of platelet aggregation (IPA) trended lower in nonsmokers than smokers (least squares mean treatment difference ± SE: 7.7 ± 4.1%; p = 0.062). Device-reported IPA was significantly lower in clopidogrel-treated smokers than prasugrel-treated smokers (least squares mean treatment difference: 31.8 ± 3.4%; p < 0.0001). During clopidogrel therapy, calculated IPA was lower and P2Y12 reaction units and vasodilator-stimulated phosphoprotein phosphorylation and platelet reactivity index were higher in nonsmokers than in smokers (p = 0.043, p = 0.005, and p = 0.042, respectively). Greater antiplatelet effects were present after prasugrel treatment regardless of smoking status (p < 0.001 for all comparisons). CONCLUSIONS: PARADOX demonstrated lower clopidogrel active metabolite exposure and PD effects of clopidogrel in nonsmokers relative to smokers. Prasugrel was associated with greater active metabolite exposure and PD effects than clopidogrel regardless of smoking status. The poorer antiplatelet response in clopidogrel-treated nonsmokers may provide an explanation for the smokers' paradox. (The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease; NCT01260584).

Efficacy of amlodipine/olmesartan ± hydrochlorothiazide in patients uncontrolled on prior calcium channel blocker or angiotensin II receptor blocker monotherapy.

INTRODUCTION: While 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). METHODS: Patients 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. RESULTS: For 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). CONCLUSION: An AML/OM-based titration regimen was efficacious in achieving BP goal in patients uncontrolled on prior monotherapy with a CCB or ARB.

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.

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

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/m(2); n = 505) and non-obese (<30 kg/m(2); 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.