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Aim Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). Methods and results The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70–0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88–1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. Conclusion In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients.This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM.Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout.From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and 0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms.Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.

Heart failure with reduced ejection fraction (HFrEF) is a highly morbid condition for which exercise intolerance is a major manifestation. However, methods to assess exercise capacity in HFrEF vary widely in clinical practice and in trials. We describe advances in exercise capacity assessment in HFrEF and a comparative analysis of how various therapies available for HFrEF impact exercise capacity. Current guideline-directed medical therapy has indirect effects on cardiac performance with minimal impact on measured functional capacity. Omecamtiv mecarbil is a novel selective cardiac myosin activator that directly increases cardiac contractility and in a phase 3 cardiovascular outcomes study significantly reduced the primary composite end point of time to first heart failure event or cardiovascular death in patients with HFrEF. The objective of the METEORIC-HF trial (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure) is to assess the effect of omecamtiv mecarbil versus placebo on multiple components of functional capacity in HFrEF. The primary end point is to test the effect of omecamtiv mecarbil compared with placebo on peak oxygen uptake as measured by cardiopulmonary exercise testing after 20 weeks of treatment. METEORIC-HF will provide state-of-the-art assessment of functional capacity by measuring ventilatory efficiency, circulatory power, ventilatory anaerobic threshold, oxygen uptake recovery kinetics, daily activity, and quality-of-life assessment. Thus, the METEORIC-HF trial will evaluate the potential impact of increased myocardial contractility with omecamtiv mecarbil on multiple important measures of functional capacity in ambulatory patients with symptomatic HFrEF. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT03759392.

Aims In GALACTIC-HF, the cardiac myosin activator omecamtiv mecarbil compared with placebo reduced the risk of heart failure events or cardiovascular death in patients with heart failure with reduced ejection fraction. We explored the influence of atrial fibrillation or flutter (AFF) on the effectiveness of omecamtiv mecarbil. Methods and results GALACTIC-HF enrolled patients with New York Heart Association (NYHA) Class II–IV heart failure, left ventricular ejection fraction ≤35%, and elevated natriuretic peptides. We assessed whether the presence or absence of AFF, a pre-specified subgroup, modified the treatment effect for the primary and secondary outcomes, and additionally explored effect modification in patients who were or were not receiving digoxin. Patients with AFF (n = 2245, 27%) were older, more likely to be randomized as an inpatient, less likely to have a history of ischaemic aetiology or myocardial infarction, had a worse NYHA class, worse quality of life, lower estimated glomerular filtration rate, and higher N-terminal pro-B-type natriuretic peptide. The treatment effect of omecamtiv mecarbil was modified by baseline AFF (interaction P = 0.012), with patients without AFF at baseline deriving greater benefit. The worsening of the treatment effect by baseline AFF was significantly more pronounced in digoxin users than in non-users (interaction P = 0.007); there was minimal evidence of effect modification in those patients not using digoxin (P = 0.47) or in digoxin users not in AFF. Conclusion Patients in AFF at baseline were less likely to benefit from omecamtiv mecarbil than patients without AFF, although the attenuation of the treatment effect was disproportionally concentrated in patients with AFF who were also receiving digoxin. Clinical Trial Registration: NCT02929329

Background: \ud In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) (n = 8,256), the cardiac myosin activator, omecamtiv mecarbil, significantly reduced the primary composite endpoint (PCE) of time-to-first heart failure event or cardiovascular death in patients with heart failure and reduced ejection fraction (EF) (≤35%).\ud \ud Objectives: \ud The purpose of this study was to evaluate the influence of baseline EF on the therapeutic effect of omecamtiv mecarbil.\ud \ud Methods: \ud Outcomes in patients treated with omecamtiv mecarbil were compared with placebo according to EF.\ud \ud Results: \ud The risk of the PCE in the placebo group was nearly 1.8-fold greater in the lowest EF (≤22%) compared with the highest EF (≥33%) quartile. Amongst the pre-specified subgroups, EF was the strongest modifier of the treatment effect of omecamtiv mecarbil on the PCE (interaction as continuous variable, p = 0.004). Patients receiving omecamtiv mecarbil had a progressively greater relative and absolute treatment effect as baseline EF decreased, with a 17% relative risk reduction for the PCE in patients with baseline EF ≤22% (n = 2,246; hazard ratio: 0.83; 95% confidence interval: 0.73 to 0.95) compared with patients with EF ≥33% (n = 1,750; hazard ratio: 0.99; 95% confidence interval: 0.84 to 1.16; interaction as EF by quartiles, p = 0.013). The absolute reduction in the PCE increased with decreasing EF (EF ≤22%; absolute risk reduction, 7.4 events per 100 patient-years; number needed to treat for 3 years = 11.8), compared with no reduction in the highest EF quartile.\ud \ud Conclusions: \ud In heart failure patients with reduced EF, omecamtiv mecarbil produced greater therapeutic benefit as baseline EF decreased. These findings are consistent with the drug’s mechanism of selectively improving systolic function and presents an important opportunity to improve the outcomes in a group of patients at greatest risk. (Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329)

Importance Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients’ condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies. Objective To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial. Design, Setting, and Participants The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months. Interventions Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo. Main Outcomes and Measures The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability. Results Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08;P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25];P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo. Conclusions and Relevance In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited. Trial Registration ClinicalTrials.gov Identifier:NCT02929329

Patients with grade 2‐3 essential hypertension and postplacebo mean clinic systolic blood pressure (SBP) 160‐190 mm Hg and 24‐hour SBP 140‐175 mm Hg by ambulatory blood pressure monitoring (ABPM) received 40 mg azilsartan medoxomil (AZL‐M) monotherapy for 4 weeks. “Nonresponders” were then randomized to 8 weeks of double‐blind treatment with AZL‐M 40 mg, AZL‐M/chlortalidone (CLD) 40/25, or AZL‐M/CLD 40/12.5 mg. After 8 weeks, mean clinic SBP change was −21.1 (±1.04) mm Hg for AZL‐M/CLD 40/25 mg, −15.8 (±1.08) mm Hg for AZL‐M/CLD 40/12.5 mg, and −6.4 (±1.05) mm Hg for AZL‐M 40 mg (P

Background: Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD). Objective/methods: We compared FDCs of AZL-M/CTD 20/12.5 mg once daily titrated to 40/25 mg if needed or AZL-M/CTD 40/12.5 mg once daily titrated to 80/25 mg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5 mg FDC once daily titrated to 40/25 mg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160–190 mmHg and DBP 119 mmHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90 mmHg (≥130/80 mmHg if diabetes or chronic kidney disease). The primary endpoint was change from baseline in clinic SBP; 24-h ambulatory BP monitoring was also measured. Results: Greater reductions in clinic SBP from a baseline of 165 mmHg were observed (P

Background: We aimed to describe the relationship between changes in high-sensitivity cardiac troponin I (hsTnI) and cardiovascular outcomes. Methods: The EXAMINE trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) was a phase IIIb clinical outcomes trial designed to evaluate the cardiovascular safety of alogliptin, a nonselective dipeptidyl peptidase 4 inhibitor. Patients with type 2 diabetes mellitus, glycohemoglobin between 6.5% and 11% (or between 7% and 11% if they were on insulin), and a recent acute coronary syndrome (between 15 and 90 days before randomization) were eligible for the trial. hsTnI was measured using the Abbott ARCHITECT assay at baseline and 6 months in patients randomized in the EXAMINE trial. This analysis was restricted to patients randomized ≥30 days after qualifying acute coronary syndrome to mitigate the potential for persistent hsTnI elevation after acute coronary syndrome (n=3808). The primary end point of the trial was cardiovascular death, myocardial infarction, or stroke. Cardiovascular death or heart failure was a prespecified, adjudicated secondary end point. Results: At baseline, hsTnI was detectable (≥1.9 ng/L) in 93% of patients and >99 th percentile upper reference limit in 16%. There was a strong relationship between increasing hsTnI, both at baseline and 6 months, and the incidence of cardiovascular events through 24 months ( P P P P =0.44). Conclusions: Serial assessment of hsTnI revealed a substantial proportion of patients with type 2 diabetes mellitus without clinically recognized events had dynamic or persistently elevated values and were at high risk of recurrent events. hsTnI may have a role in personalizing preventive strategies in patients with diabetes mellitus based on risk. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00968708.

The efficacy and safety of azilsartan medoxomil (AZL-M) were evaluated in African-American patients with hypertension in a 6-week, double-blind, randomized, placebo-controlled trial, for which the primary end point was change from baseline in 24-hour mean systolic blood pressure (BP). There were 413 patients, with a mean age of 52 years, 57% women, and baseline 24-hour BP of 146/91 mm Hg. Treatment differences in 24-hour systolic BP between AZL-M 40 mg and placebo (-5.0 mm Hg; 95% confidence interval, -8.0 to -2.0) and AZL-M 80 mg and placebo (-7.8 mm Hg; 95% confidence interval, -10.7 to -4.9) were significant (P≤.001 vs placebo for both comparisons). Changes in the clinic BPs were similar to the ambulatory BP results. Incidence rates of adverse events were comparable among the treatment groups, including those of a serious nature. In African-American patients with hypertension, AZL-M significantly reduced ambulatory and clinic BPs in a dose-dependent manner and was well tolerated.

Aims To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE). Methods The EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double-blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events. Results Patients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (Pinteraction = 0.971) or HbA1c category at 1 month. Patients in the combined treatment groups (n = 5380) who experienced serious hypoglycaemia (n = 34) had higher MACE rates than those who did not (35.3% vs 11.4%, adjusted hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.27–4.60; P = .007), although the association was less strong when analysing only events after the hypoglycaemic event (adjusted HR 1.60, 95% CI 0.80, 3.20). Conclusions There were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed.

Background Concerns raised regarding adverse cardiovascular (CV) outcomes with new therapies for type 2 diabetes mellitus (T2DM) have led to several large-scale CV outcome trials. The EXAMINE trial confirmed noninferiority of the dipeptidyl dipeptidase 4 inhibitor alogliptin to placebo on major adverse cardiac event rates in a post–acute coronary syndrome (ACS) T2DM population. We present data on additional ischemic cardiac events and CV hospitalizations in EXAMINE. Methods Patients with T2DM and an ACS event in the previous 15 to 90 days were randomly assigned to alogliptin or placebo on a background of standard treatment for diabetes. The incident rates of a 5-component composite end point of CV death, stroke, myocardial infarction, unstable angina, and coronary revascularization as well as CV hospitalization were calculated in all participants and according to macrovascular disease at baseline. Results There were no significant differences between alogliptin (n = 2,701) and placebo (n = 2,679) in the event rate of the 5-component composite endpoint with median follow-up 533 days (21.0% vs 21.5%, hazard ratio [HR] 0.98 [0.87-1.10], P = .72). No differences were observed in terms of CV hospitalization (25.0% vs 25.4%, HR 0.98 [0.88-1.09], P = .70) or coronary revascularization (10.6% vs 10.2%, HR 1.05 [0.88-1.09], P = .60). No interactions were observed for treatment and prior macrovascular disease. Conclusions EXAMINE demonstrates that there was no increase in the risk of cardiac ischemic events and CV hospitalizations with alogliptin in a high-risk post-ACS patient population. Because these are major driver of overall health care costs, these data suggest that there would be no adverse impact on health care resource utilization.

Population pharmacokinetic and exposure-response models for azilsartan medoxomil (AZL-M) and chlorthalidone (CLD) were developed using data from an 8-week placebo-controlled phase 3, factorial study of 20, 40, and 80 mg AZL-M every day (QD) and 12.5 and 25 mg CLD QD in fixed-dose combination (FDC) in subjects with moderate to severe essential hypertension. A 2-compartment model with first-order absorption and elimination was developed to describe pharmacokinetics. An Emax model for exposure-response analysis evaluated AZL-M/CLD effects on ambulatory systolic blood pressure (SBP). Estimated oral clearance and apparent volume of distribution (central compartment) were 1.47 L/h and 3.98 L for AZL, and 4.13 L/h and 62.1 L for CLD. Age as a covariate had the largest effect on AZL and CLD exposure (±20% change). Predicted maximal SBP responses (Emax ) were -15.6 and -23.9 mm Hg for AZL and CLD. Subgroup analysis identified statistically significant Emax differences for black vs nonblack subjects, whereby the reduced AZL response in black subjects was offset by greater response to CLD. The estimated Emax for AZL and CLD was generally greater in subjects with higher baseline BP. In conclusion, no dose adjustments to AZL-M or CLD are warranted based on identified covariates, and antihypertensive efficacy of AZL-M/CLD combination therapy is comparable in black and nonblack subjects.

Background: Angiotensin receptor blockers (ARBs) are preferred antihypertensive therapies in patients with type 2 diabetes mellitus (T2DM). Azilsartan medoxomil (AZL-M) is a potent ARB for the treatment of stages 1-2 hypertension. We compared the efficacy, safety, and metabolic effects of AZL-M to both valsartan (VAL) and olmesartan (OLM), separately in patients with impaired fasting glucose (prediabetes mellitus) and T2DM. Methods: A pooled analysis of 3821 patients from three separate randomized placebo-controlled trials comparing the effects of AZL-M (40 and 80 mg), OLM (40 mg), VAL (320 mg), and placebo on changes in ambulatory and clinic blood pressure (BP) among patients with hypertension and prediabetes mellitus or T2DM was performed. Two analysis pools were created to facilitate comparisons: Pool A included patients who received placebo, AZL-M or OLM and Pool B included those who received AZL-M or VAL. Within each pool, patients were stratified by glycemic subgroups (normoglycemic, prediabetes mellitus, or T2DM) based on hemoglobin A1c values. Changes from baseline in both 24-h and clinic SBP were the primary efficacy assessments. Results: Baseline 24-h mean SBPs were approximately 145 and 146 mmHg in the prediabetes mellitus and T2DM subgroups, respectively; corresponding clinic SBPs were approximately 158 and 159 mmHg. Baseline hemoglobin A1c values for each subgroup (both pools) were normoglycemic, 5.3%; prediabetes mellitus, 6.0%; and T2DM, 6.9%. Changes from baseline in 24-h or clinic SBP were significantly greater with AZL-M, 80 mg compared with either OLM 40 mg or VAL 320 mg in all subgroups in each pool. Safety and tolerability were similar among the active treatment and placebo subgroups. Conclusion: These analyses indicate that AZL-M, 80 mg/day lowers SBP by a greater magnitude than OLM or VAL at maximally approved doses in patients with prediabetes mellitus and T2DM. These findings have important clinical implications for this high-risk patient group.

BACKGROUND AND OBJECTIVES: Biomarkers may improve identification of individuals at risk of eGFR decline who may benefit from intervention or dialysis planning. However, available biomarkers remain incompletely validated for risk stratification and prediction modeling. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined serum cystatin C, urinary kidney injury molecule–1 (uKIM-1), and urinary neutrophil gelatinase-associated lipocalin (UNGAL) in 5367 individuals with type 2 diabetes mellitus and recent acute coronary syndromes enrolled in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial. Baseline concentrations and 6-month changes in biomarkers were also evaluated. Cox proportional regression was used to assess associations with a 50% decrease in eGFR, stage 5 CKD (eGFR

Advances in medical therapies leading to improved patient outcomes are in large part related to successful conduct of clinical trials that offer critical information regarding the efficacy and safety of novel interventions. The conduct of clinical trials in the United States, however, continues to face increasing challenges with recruitment and retention. These trends are paralleled by an increasing shift toward more multinational trials where most participants are enrolled in countries outside the United States, bringing into question the generalizability of the results to the American population. This manuscript presents the perspectives and recommendations from clinicians, researchers, sponsors, and regulators who attended a meeting facilitated by the Food and Drug Administration to improve upon the current clinical trial trends in the United States.

An open-label, long-term study evaluated safety and tolerability of azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs olmesartan/hydrochlorothiazide (OLM/HCTZ) in hypertensive participants with stage 3 chronic kidney disease. Initial therapy was AZL-M/CLD 20/12.5 mg (n = 77) or OLM/HCTZ 20/12.5 mg (n = 76), but could be up-titrated (AZL-M/CLD to 40/25 mg; OLM/HCTZ to 40/25 mg [US] or 20/25 mg [Europe]) with other agents added during weeks 4-52. Primary endpoint was proportion of participants with ≥ 1 adverse event (AE) through week 52. Baseline demographics were similar. AEs did not differ between groups (88.3%, AZL-M/CLD vs 76.3%, OLM/HCTZ; P = .058). AZL-M/CLD showed greater systolic BP reductions after initial dosing (P = .037) but not during long-term follow-up (P = .588). A greater proportion of participants up-titrated to the highest dose with OLM/HCTZ (48.7%) vs AZL-M/CLD (29.9%) (P = .021) and were taking additional antihypertensive medications (26.3% vs 16.9%). Both AZL-M/CLD and OLM/HCTZ showed similar efficacy and tolerability.

Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g., all-cause and cause-specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12-13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group's recommendations for achieving common views on heart failure endpoints in clinical trials.

Hospitalized heart failure (HHF) is associated with unacceptably high postdischarge mortality and rehospitalization rates. This heterogeneous group of patients, however, is still treated with standard, homogenous therapies that are not preventing their rapid deterioration. The costs associated with HHF have added demands from society, government, and payers to improve outcomes. With coordinated and committed efforts in the development of new therapies, improvements may be seen in outcomes for patients with HHF. This article summarizes concepts in developing therapies for HHF discussed during a multidisciplinary panel at the Heart Failure Society of America's Annual Scientific Meeting, September 2012.

Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79–1.19; P =0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73–1.21; P =0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72–1.2; P =0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors.

The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus.

This study compared the efficacy and safety of fixed-dose combinations (FDCs) of the angiotensin II receptor blocker azilsartan medoxomil (AZL-M) and the thiazide-like diuretic chlorthalidone (CLD) with the individual monotherapies in a double-blind factorial study. A total of 1714 patients with clinic systolic blood pressure (SBP) 160 mm Hg to 190 mm Hg inclusive were randomized to AZL-M 0 mg, 20 mg, 40 mg, or 80 mg and/or chlorthalidone 0 mg, 12.5 mg, or 25 mg. The primary efficacy end point was change from baseline to 8 weeks in trough (hour 22-24) SBP by ambulatory blood pressure (BP) monitoring (ABPM). Patients' mean age was 57 years; 47% were men and 20% were black. Baseline trough BP was approximately 165/95 mm Hg and 151/91 mm Hg by clinic and ABPM measurements, respectively. For the pooled AZL-M/CLD 40/25-mg and 80/25-mg FDC groups, SBP reduction by ABPM at trough was 28.9 mm Hg and exceeded AZL-M 80 mg and CLD 25 mg monotherapies by 13.8 mm Hg and 13 mm Hg, respectively (P

Azilsartan medoxomil (AZL-M) is a unique angiotensin II receptor blocker (ARB) under development for the treatment of hypertension. To compare this ARB with another in the class, the authors studied the effects of AZL-M and valsartan (VAL) in 984 patients with primary hypertension in a randomized, double-blind, multicenter study using ambulatory and clinic blood pressure (BP) measurements. The primary end point was change from baseline in 24-hour mean ambulatory systolic BP following 24 weeks of treatment. Hierarchical analysis testing for noninferiority was followed by superiority testing of AZL-M (80 mg then 40 mg) vs VAL. The mean age of participants was 58 years, 52% were men, and 15% were black. Baseline 24-hour mean systolic BP was similar (approximately 145.6 mm Hg) in each group. AZL-M 40 mg and 80 mg lowered 24-hour mean systolic BP (-14.9 mm Hg and -15.3 mm Hg, respectively) more than VAL 320 mg (-11.3 mm Hg; P

The current study assesses the antihypertensive efficacy and safety of the investigational angiotensin receptor blocker (ARB), azilsartan medoxomil (AZL‐M), compared with placebo and the ARB olmesartan medoxomil (OLM‐M). This randomized, double‐blind, placebo‐controlled, multicenter study assessed change from baseline in mean 24‐hour ambulatory systolic blood pressure (SBP) following 6 weeks of treatment. Patients with primary hypertension (n=1275) and baseline 24‐hour mean ambulatory systolic pressure ≥130 mm Hg and ≤170 mm Hg were studied; 142 received placebo and the remainder received 20 mg, 40 mg, or 80 mg AZL‐M or 40 mg OLM‐M. Mean age of participants was 58±11 years, baseline mean 24‐hour SBP was 146 mm Hg. Dose‐dependent reductions in 24‐hour mean SBP at study end occurred in all AZL‐M groups. Reduction in 24‐hour mean SBP was greater with AZL‐M 80 mg than OLM‐M 40 mg by 2.1 mm Hg (95% confidence interval, −4.0 to −0.1; P=.038), while AZL‐M 40 mg was noninferior to OLM‐M 40 mg. The side effect profiles of both ARBs were similar to placebo. AZL‐M is well tolerated and more efficacious at its maximal dose than the highest dose of OLM‐M. J Clin Hypertens (Greenwich). 2011;13:81–88. © 2011 Wiley Periodicals, Inc.

Objectives The purpose of this study was to determine the factors associated with the favorable effect of pioglitazone on atheroma progression. Background Diabetes mellitus is associated with accelerated coronary atheroma progression. Pioglitazone slowed progression compared with glimepiride in this population. Methods In all, 360 diabetic patients with coronary artery disease were treated with pioglitazone or glimepiride for 18 months in the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) study. Coronary atheroma progression was evaluated by serial intravascular ultrasound. The relationship between changes in biochemical parameters, percent atheroma volume, and total atheroma volume was investigated. Results Pioglitazone-treated patients demonstrated greater increases in high-density lipoprotein cholesterol (HDL-C) and reductions in glycated hemoglobin, triglycerides, and C-reactive protein. Significant correlations were observed between changes in percent atheroma volume and triglycerides (r = 0.15, p = 0.04), triglyceride/HDL-C ratio (r = 0.16, p = 0.03), and glycated hemoglobin (r = 0.16, p = 0.03) with pioglitazone, and changes in low-density lipoprotein cholesterol (r = −0.15, p = 0.05), apolipoprotein B (r = −0.16, p = 0.04), and apolipoprotein A-I (r = −0.20, p = 0.01) with glimepiride. Substantial atheroma regression, compared to progression, was associated with greater relative increases in HDL-C (14.2% vs. 7.8%, p = 0.04), relative decreases in triglycerides (−13.3% vs. −1.9%, p = 0.045), triglyceride/HDL-C ratio (−22.5 vs. −9.9%, p = 0.05), and decrease in glycated hemoglobin (−0.6% vs. −0.3%, p = 0.01). Multivariable analysis revealed that pioglitazone-induced effects on triglyceride/HDL-C were associated with changes in percent atheroma volume (p = 0.03) and total atheroma volume (p = 0.02). Conclusions Favorable effects of pioglitazone on the triglyceride/HDL-C ratio correlated with delayed atheroma progression in diabetic patients. This finding highlights the potential importance of targeting atherogenic dyslipidemia in diabetic patients with coronary artery disease.

SummaryThis multicentre dose-finding study compared TAK-442, an oral factor Xa inhibitor, with enoxaparin for thromboprophylaxis after knee arthroplasty. In this parallel group study, patients were randomised to oral TAK-442 (40 or 80 mg once-daily [QD] or 10, 20, 40, or 80 mg twice-daily [BID] started 6–8 hours postoperatively), which was blinded as to dose, or to open-label subcutaneous enoxaparin (30 mg BID starting 12–24 hours postoperatively) for 10 days. Treatments were continued until bilateral venography was performed (maximum of 14 days). The primary efficacy endpoint was the composite of any deep-vein thrombosis, non-fatal pulmonary embolism or all-cause mortality, while the primary safety endpoint was major bleeding. Of 1,038 patients randomised who received at least one dose of study drug, 949 completed the study and 730 (76.9%) were evaluable for the primary efficacy analysis. Recruitment into the 10 and 20 mg BID dose groups was stopped early because the incidences of the primary efficacy endpoint were significantly higher than that with enoxaparin. The primary efficacy endpoint occurred in 22.0% of patients given enoxaparin and in 39.0%, 38.4%, 23.5%, 21.4%, 26.8%, and 14.3% of those receiving TAK-442 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, and 80 mg BID, respectively. The incidences of major and clinically relevant non-major bleeding with TAK-442 were not dose-dependent or different from that with enoxaparin. All TAK-442 doses except 10 and 20 mg BID displayed similar efficacy and safety profiles to enoxaparin.

Background and Purpose— Diabetes is an important risk factor for stroke. We conducted analyses in patients who had entered the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) with a history of stroke or without stroke. Methods— The prospective, double-blind PROactive (mean duration, 34.5 months) randomized 5238 patients with type 2 diabetes and a history of macrovascular disease to pioglitazone (titrated to 45 mg) or placebo, in addition to current diabetes and cardiovascular medications. Cardiovascular end-point events were independently adjudicated. This analysis evaluated the risk of stroke and other cardiovascular outcomes in patients with (n=984) and without (n=4254) prior stroke. Results— In patients with previous stroke (n=486 in the pioglitazone group and n=498 in the placebo group), there was a trend of benefit with pioglitazone for the primary end point of all-cause death, nonfatal myocardial infarction, acute coronary syndrome, and cardiac intervention (including coronary artery bypass graft or percutaneous coronary intervention), stroke, major leg amputation, or bypass surgery or leg revascularization (hazard ratio[HR]=0.78, event rate=20.2% pioglitazone vs 25.3% placebo; 95% CI=0.60–1.02; P =0.0670) and for the main secondary end point of all-cause death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.78, event rate=15.6% pioglitazone vs 19.7% placebo; 95% CI=0.58–1.06; P =0.1095). Pioglitazone reduced fatal or nonfatal stroke (HR=0.53, event rate=5.6% pioglitazone vs 10.2% placebo; 95% CI=0.34–0.85; P =0.0085) and cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.72, event rate=13.0% pioglitazone vs 17.7% placebo; 95% CI=0.52–1.00; P =0.0467). Higher event rates were observed in patients with prior stroke compared with those without prior stroke. In patients without prior stroke, no treatment effect was observed for a first stroke. Conclusions— In a subgroup analysis from PROactive, pioglitazone reduced the risk of recurrent stroke significantly in high-risk patients with type 2 diabetes.

Background Recent studies have raised concerns about potential increased cardiovascular (CV) risk in type 2 diabetes patients treated with some peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists. Objective To ascertain the risk of hospitalization for acute myocardial infarction (AMI) in type 2 diabetes patients treated with pioglitazone relative to rosiglitazone. Methodology Using data covering 2003–2006 from a large health care insurer in the US, a retrospective cohort study was conducted in patients who initiated treatment with pioglitazone or rosiglitazone. The hazard ratio (HR) of incident hospitalization for AMI after initiation of treatment with these drugs was estimated from multivariate Cox's proportional hazards survival analysis; similarly, the HR was ascertained for hospitalization for the composite endpoint of AMI or coronary revascularization (CR). Results A total of 29 911 eligible patients were identified in the database; 14 807 in the pioglitazone and 15 104 in the rosiglitazone group. Baseline demographics, medical history, and dispensed medications were generally well balanced between groups. The unadjusted HR for hospitalization for AMI was 0.82, 95%CI: 0.67–1.01. After adjustment for baseline covariates the HR was 0.78, 95%CI: 0.63–0.96. The adjusted HR for the composite of AMI or CR was 0.85, 95%CI: 0.75–0.98. Conclusion This retrospective cohort study showed that pioglitazone, in comparison with rosiglitazone, is associated with a 22% relative risk reduction of hospitalization for AMI in patients with type 2 diabetes. Copyright © 2007 John Wiley & Sons, Ltd.

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Population pharmacokinetic and exposure-response models for azilsartan medoxomil (AZL-M) and chlorthalidone (CLD) were developed using data from an 8-week placebo-controlled phase 3, factorial study of 20, 40, and 80 mg AZL-M every day (QD) and 12.5 and 25 mg CLD QD in fixed-dose combination (FDC) in subjects with moderate to severe essential hypertension. A 2-compartment model with first-order absorption and elimination was developed to describe pharmacokinetics. An Emax model for exposure-response analysis evaluated AZL-M/CLD effects on ambulatory systolic blood pressure (SBP). Estimated oral clearance and apparent volume of distribution (central compartment) were 1.47 L/h and 3.98 L for AZL, and 4.13 L/h and 62.1 L for CLD. Age as a covariate had the largest effect on AZL and CLD exposure (±20% change). Predicted maximal SBP responses (Emax ) were -15.6 and -23.9 mm Hg for AZL and CLD. Subgroup analysis identified statistically significant Emax differences for black vs nonblack subjects, whereby the reduced AZL response in black subjects was offset by greater response to CLD. The estimated Emax for AZL and CLD was generally greater in subjects with higher baseline BP. In conclusion, no dose adjustments to AZL-M or CLD are warranted based on identified covariates, and antihypertensive efficacy of AZL-M/CLD combination therapy is comparable in black and nonblack subjects.

Summary Background The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial. Methods Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15–90 days were randomly assigned alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov, number NCT00968708. Findings 5380 patients were assigned to alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280–751). The exploratory extended MACE endpoint was seen in 433 (16·0%) patients assigned to alogliptin and in 441 (16·5%) assigned to placebo (hazard ratio [HR] 0·98, 95% CI 0·86–1·12). Hospital admission for heart failure was the first event in 85 (3·1%) patients taking alogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79–1·46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1·00, 95% CI 0·82–1·21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups. Interpretation In patients with type 2 diabetes and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure outcomes. Funding Takeda Development Center Americas.

With one possible exception, the last decade of clinical trials in hospitalized heart failure (HHF) patients has failed to demonstrate improvement in long-term clinical outcomes. This trend necessitates a need to evaluate optimal drug development strategies and standards of trial conduct. It has become increasingly important to recognize the heterogeneity among HHF patients and the differential characterization of novel drug candidates. Targeting these agents to specific subpopulations may afford optimal net response related to the particular mode of action of the drug. Analyses of previous trials demonstrate profound differences in the baseline characteristics of patients enrolled across global regions and participating sites. Such differences may influence risks for events and interpretation of results. Therefore, the actual execution of trials and the epidemiology of HHF populations at the investigative sites must be taken into consideration. Collaboration among participating sites including the provision of registry data tailored to the planned development program will optimize trial conduct. Observational data prior to study initiation may enable sites to feedback and engage in protocol development to allow for feasible and valid clinical trial conduct. This site-centered, epidemiology-based network environment may facilitate studies in specific patient populations and promote optimal data collection and clear interpretation of drug safety and efficacy. This review summarizes the roundtable discussion held by a multidisciplinary team of representatives from academia, National Institutes of Health, industry, regulatory agencies, payers, and contract and academic research organizations to answer the question: Who should be targeted for novel therapies in HHF?

Study Objective. To evaluate the long-term safety and efficacy of glyburide versus pioglitazone in patients with a recent diagnosis of type 2 diabetes mellitus. Design. Prospective, randomized, multicenter, double-blind trial with a 16-week titration period and a 40-week maintenance period. Setting. Sixty-five investigative sites in the United States and Puerto Rico. Patients. Five hundred two subjects with a recent diagnosis of type 2 diabetes that was unsuccessfully treated with diet and exercise were randomly assigned to study treatment. Of the 251 patients in each treatment group, 128 (51.0%) glyburide-treated patients and 134 (53.4%) pioglitazone-treated patients completed the study. Interventions. Dosages of randomly assigned glyburide and pioglitazone were titrated every 4 weeks for 16 weeks in 5-mg/day and 15-mg/day increments, respectively, until a fasting plasma glucose level between 69 and 141 mg/dl was achieved. The optimized regimen was maintained during the subsequent 40-week double-blind phase. Measurements and Main Results. At week 56, glyburide and pioglitazone improved glucose control comparably (change in hemoglobin A1c −2.02% and −2.07%, respectively, p=0.669). Withdrawal due to lack of efficacy or adverse events occurred more frequently with glyburide (20.8%) than pioglitazone (12.8%, p

BACKGROUND: Thorough evaluation of the cardiovascular (CV) safety of new drugs for diabetes mellitus (DM) is now mandated by the US FDA. Alogliptin, a dipeptidyl-peptidase 4 inhibitor, is one of a new drug class for treatment of DM. CV biomarkers may provide useful insight with respect to CV safety of new treatments for DM. We evaluated the predictive value of baseline biomarkers for CV outcomes in a high risk population of DM patients (pts) in a large CV safety trial. METHODS: EXAMINE was a randomized, double-blind, placebo-controlled, multinational trial of alogliptin in pts with DM enrolled 15 to 90 days after an acute coronary syndrome (ACS). We measured B-type natriuretic peptide (BNP) and high sensitivity troponin I (hsTnI) at baseline (Abbott ARCHITECT). The primary endpoint was major adverse CV events (MACE) defined as CV death (CVD), myocardial infarction, or stroke. The composite of CV death or heart failure (HF) was also assessed as an exploratory endpoint. RESULTS: A total of 5230 pts with baseline biomarkers were followed for 18 mo (median). Baseline BNP and hsTnI showed a significant graded relationship with CV outcomes at 18 mo (Figure bars). BNP and hsTnI remained strongly and independently related to CV outcomes through the pts’ final visit after adjusting for age, sex, type of qualifying ACS, eGFR, & history of HF (Figure, adjusted HRs). The rates of MACE were similar with alogliptin vs. placebo in the highest risk pts identified by BNP (Group 4: 19.9 vs. 22.2%) or hsTnI (Group 4: 18.3 vs. 20.6%). Similar results were observed for CV death/HF based on BNP (17.5 vs. 19.4%) or hsTnI (14.3 vs. 14.9%). There was no evidence for heterogeneity in the effect of alogliptin on CV death/HF across BNP strata (p-interaction=0.71). CONCLUSIONS: Among pts with DM who were stable after a recent ACS, BNP & hsTnI identified pts at high risk of poor CV outcomes. In this study, the rates of MACE, including CV death or HF, were not increased with alogliptin vs. placebo even in these high risk pts.

BACKGROUND The International Verapamil/Trandolapril Study (INVEST) demonstrated comparable efficacy between verapamil SR and atenolol antihypertensive treatment strategies for clinical outcomes and blood pressure (BP) control in hypertensive patients with coronary artery disease (N = 22,576). Effects of these antihypertension strategies on mood-related issues are not well understood. OBJECTIVES The objectives of this study were 1) to compare depressive symptoms by strategy and 2) to identify predictors of depressive symptoms in INVEST patients after 1 year of follow up. DESIGN, SETTING, AND PATIENTS Depressive symptoms were assessed in a subset (N = 2317) of consecutively randomized U.S. patients enrolled between April 1, 1999, and October 31, 1999. Patients were mailed surveys after randomization and after 1 year of treatment. INTERVENTION Patients were assigned to either a verapamil SR or atenolol strategy to achieve Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure BP goals. Trandolapril and/or hydrochlorothiazide were recommended as add-on agents. MAIN OUTCOME MEASURE Depressive symptoms were measured by the Center for Epidemiologic Studies-Depression (CES-D) scale. RESULTS CES-D scores improved 1.45 points (p < .001) after 1 year in patients assigned to the verapamil SR strategy, whereas a nonsignificant improvement was observed in patients assigned to the atenolol strategy (0.27 points, p = .44). Predictors of higher depressive symptoms were higher baseline CES-D score (p < .001), history of depression diagnosis (p = .03), history of stroke (p < .001), and assignment to the atenolol strategy (p < .001). CONCLUSIONS A verapamil SR strategy is a viable alternative to beta-blocker therapy for hypertensive patients with coronary artery disease, especially those at risk of depression.

SummaryThrombocytopenic episodes occurring in 18,845 patients treated with the GPIIb/IIIa inhibitors xemilofiban and orbofiban (“fibans”) were analyzed by a blinded review panel and 73 patients were classified as having “possible fiban-induced thrombocytopenia”. When the treatment codes were broken, a significant association between drug exposure and assignment to this group was found (p

The EXAMINE trial showed no increases in cardiovascular (CV) event rates for the DPP-4 inhibitor alogliptin compared to placebo. As concerns have been recently raised regarding increased rates of hospitalized heart failure for other DPP-4 inhibitors, we evaluated pre-specified and post hoc analyses

Objective The aim of the study was to measure the effects on blood pressure (BP) of the angiotensin receptor blocker azilsartan medoxomil, in 40 and 80 mg doses, combined with 5 mg of the calcium channel blocker amlodipine and to compare these effects with placebo plus amlodipine 5 mg. Methods This was a randomized, controlled, double-blind study of 6 weeks’ duration in 566 patients with stage 2 hypertension. The primary endpoint was 24-h systolic BP by ambulatory monitoring. Results The mean age of the participants was 58 years; men and women were equally represented, and baseline 24-h BP (153–154/93 mmHg) and clinic BP (165–166/94–95 mmHg) were similar across the three treatment groups. After 6 weeks, 24-h BP decreased by 25/15 mmHg in both the azilsartan medoxomil/amlodipine 40/5 and 80/5 mg groups. These reductions were each greater than the 14/8 mmHg decrease with placebo plus amlodipine 5 mg (P≤0.001 for both comparisons). All treatments were well tolerated, and adverse events did not increase with the azilsartan medoxomil doses. Edema or fluid retention was less common in both combination groups (2.6 and 2.7%) than with placebo plus amlodipine (7.6%). Conclusion Coadministration of azilsartan medoxomil with amlodipine was well tolerated and led to meaningful additional BP reductions compared with placebo plus amlodipine.

Background: Concerns have been raised regarding adverse cardiovascular outcomes with new therapies for type 2 diabetes (T2DM). The EXAMINE trial studied the effect of the DPP-4 inhibitor alogliptin on major CV events in patients with T2DM and recent acute coronary syndromes. Herein we present data on all cardiac ischemic events and cardiovascular hospitalizations (CVHs) in EXAMINE. Methods: Data from all 5380 patients randomized in EXAMINE were used. The incident rates of MI and unstable angina, coronary revascularization, CVH, and composites of these ischemic endpoints were calculated.

A preponderance of small, dense low-density lipoprotein (LDL) particles may promote the accelerated plaque progression seen on intravascular ultrasound (IVUS) imaging in patients with diabetes, even when LDL cholesterol appears to be well controlled [(1)][1]. The PERISCOPE (Pioglitazone Effect on