Dapagliflozin and cardiovascular outcomes in type 2 diabetes

BACKGROUND The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium– glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined. METHODS We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause. RESULTS We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001). CONCLUSIONS In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE–TIMI 58 ClinicalTrials.gov number, NCT01730534.

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Background Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. Methods Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. Results A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). Conclusions Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Відновлення показників вегетативної рівноваги та гармонізація функції церебральних і підкоркових структур шляхом модуляції системи ГАМК у хворих з артеріальною гіпертензією

The problem of arterial hypertension is getting more relevant because of the increasing of it prevalence both all over the world and inUkraine.Aim of the work was the investigation of psychoemotional disorders and vegetative homeostasis in patients with non-complicated forms of AH and their correction with the application of Passiflora incarnata extract as a part of the complex antihypertensive therapy.Materials and Methods. 73 patients of both sexes in active working age with AH stage II were examined. All patients were divided into 2 groups. Group 1 consisted of 35 patients with hypertension, who on the background of standard antihypertensive treatment were prescribed a plant remedy containing Passiflora incarnata extract – Alora® syrup (Nobelpharma Ilach Sanayi Wei Tidjaret A. Sh., Turkey) at a dose of 10 ml 3 times a day for 4 weeks. The 2nd group was a control; it included 38 patients with hypertension treated only with antihypertensive therapy.Arterial pressure was measured with a manual mechanical tonometer at rest, according to the Unified clinical protocol of medical care "Arterial hypertension". The psychoemotional state was investigated with the help of test questionnaire using the PHQ-90 Health Scale (maximum 27 points). To assess the state of autonomic regulation we used analysis of heart rate variability (HRV) values obtained with the IPEC-6-CARDIOPLUS FASAGRAF® device. Statistical processing was carried out using the Student's variation method.Results. The clinical study proves that using the medicine of Passiflora incarnata extract for patients with uncomplicated forms of hypertension during 4 weeks provides possibility to obtain an additional hypotensive effect against the background of using standard antihypertensive therapy as a demonstration of a wide range of Passiflora incarnata pharmacological activity.Conclusions. The implementation of the Рassiflora drug complex application are sympatholytic and vascular tone modifying effects, expressed positive dynamics in the psychoemotional state, manifested as anxiolytic and sedative actions, and optimization of the emotional state and degree of psychological tension in patients with AH.Проблема артериальной гипертензии становится всё более актуальной в связи с ростом её распространённости как в мире, так и в Украине.Цель работы – исследование состояния нарушений психоэмоциональной сферы и вегетативного гомеостаза у больных с неосложнёнными формами АГ и их коррекция применением экстракта Passiflora incarnata в комплексной гипотензивной терапии.Материалы и методы. Обследовано 73 больных обоих полов в активном трудоспособном возрасте со ІІ стадией АГ. Пациенты были разделены на 2 группы. Первую группу составили 35 больных АГ, которым на фоне стандартного гипотензивного лечения назначали растительное средство, содержащее экстракт Passiflora incarnata – сироп Алора® («Нобелфарма Илач Санаи Ве Тиджарет А. Ш.», Турция) по 10 мл 3 раза в день в течение 4 недель. Вторая группа была контрольной, в неё вошло 38 больных с АГ, принимавших только гипотензивную терапию.Артериальное давление измерялось с помощью ручного механического тонометра в состоянии покоя согласно Унифицированному клиническому протоколу медицинской помощи «Артериальная гипертензия». Психоэмоциональное состояние исследовалось с помощью тестового опросника по Шкале состояния здоровья PHQ-90 (максимум 27 баллов). Для оценки состояния вегетативной регуляции применялся анализ показателей вариабельности сердечного ритма (ВСР), полученных с помощью прибора ИПЕК-6-КАРДИОПЛЮС ФАЗАГРАФ®. Статистическая обработка проводилась с использованием вариационного метода Стьюдента.Результаты. Клиническое исследование доказывает, что при использовании лекарственного препарата экстракта Passiflora incarnata у больных с неосложнёнными формами АГ в течение 4 недель удаётся получить дополнительный гипотензивный эффект на фоне использования стандартной гипотензивной терапии как проявление широкого спектра фармакологической активности Passiflora incarnata.Выводы. Реализацией комплексного применения препарата пассифлоры является симпатолитический и модифицирующий сосудистый тонус эффекты, выраженная положительная динамика в психоэмоциональной сфере, проявившаяся в анксиолитическом и седативном действиях, и оптимизация эмоционального состояния и степени психологического напряжения больных с АГ.Проблема артеріальної гіпертензії стає все актуальнішою у зв'язку з ростом її поширеності як в світі, так і в Україні.Мета роботи – дослідження стану порушень психоемоційної сфери та вегетативного гомеостазу у хворих із неускладненими формами АГ та їх корекції застосуванням екстракту Passiflora incarnata в комплексній гіпотензивній терапії.Матеріали та методи. Обстежили 73 особи обох статей в активному працездатному віці з ІІ стадією АГ. Пацієнтів поділили на 2 групи. Першу групу становили 35 хворих на АГ, яким на тлі стандартного гіпотензивного лікування призначали рослинний засіб, що містить екстракт Passiflora incarnata – сироп Алора® («Нобелфарма Ілач Санаї Ве Тиджарет А. Ш.», Туреччина) по 10 мл тричі на день протягом 4 тижнів. Друга група – контрольна, до неї ввійшли 38 хворих на АГ, які мали тільки гіпотензивну терапію. Артеріальний тиск вимірювали за допомогою ручного механічного тонометра у стані спокою згідно з Уніфікованим клінічним протоколом медичної допомоги «Артеріальна гіпертензія». Психоемоційний стан досліджували за допомогою тестового опитувальника за шкалою стану здоров’я PHQ-90 (максимум – 27 балів). Для оцінювання стану вегетативної регуляції застосовували аналіз показників варіабельності серцевого ритму (ВСР), що отримали за допомогою приладу ІПЕК-6-КАРДІОПЛЮС ФАЗАГРАФ®. Статистичне опрацювання здійснили з використанням варіаційного методу Стьюдента. Результати. Використовуючи лікарський препарат екстракту Passiflora incarnata, у хворих на АГ протягом 4 тижнів вдалось отримати додатковий гіпотензивний ефект на тлі використання стандартної гіпотензивної терапії як прояв широкого спектра фармакологічної активності екстракту Passiflora incarnata, як-от: симпатолітичної та такої, що модифікує судинний тонус, анксіолітичної та седативної, оптимізуючої емоційний стан і ступені психологічного напруження хворих з АГ.Висновки. Клінічне дослідження показує: при використанні лікарського препарату екстракту Passiflora incarnata у хворих із неускладненими формами АГ протягом 4 тижнів вдається отримати додатковий гіпотензивний ефект на тлі використання стандартної гіпотензивної терапії як прояв широкого спектра фармакологічної активності Passiflora incarnata. Реалізацією комплексного застосування препарату пасифлори є симпатолітичний і такий, що модифікує судинний тонус, ефекти, виражена позитивна динаміка у психоемоційній сфері, котра проявилась в анксіолітичній і седативній дії, та оптимізація емоційного стану й ступенів психологічного напруження хворих з АГ

Restoration of autonomic balance and cortical and cerebral structures functions harmonization indicators by means of gamma-aminobutyric acid system modulation in patients with primary hypertension

The problem of arterial hypertension is getting more relevant because of the increasing of it prevalence both all over the world and inUkraine. Aim of the work was the investigation of psychoemotional disorders and vegetative homeostasis in patients with non-complicated forms of AH and their correction with the application of Passiflora incarnata extract as a part of the complex antihypertensive therapy. Materials and Methods. 73 patients of both sexes in active working age with AH stage II were examined. All patients were divided into 2 groups. Group 1 consisted of 35 patients with hypertension, who on the background of standard antihypertensive treatment were prescribed a plant remedy containing Passiflora incarnata extract – Alora® syrup (Nobelpharma Ilach Sanayi Wei Tidjaret A. Sh., Turkey) at a dose of 10 ml 3 times a day for 4 weeks. The 2nd group was a control; it included 38 patients with hypertension treated only with antihypertensive therapy. Arterial pressure was measured with a manual mechanical tonometer at rest, according to the Unified clinical protocol of medical care "Arterial hypertension". The psychoemotional state was investigated with the help of test questionnaire using the PHQ-90 Health Scale (maximum 27 points). To assess the state of autonomic regulation we used analysis of heart rate variability (HRV) values obtained with the IPEC-6-CARDIOPLUS FASAGRAF® device. Statistical processing was carried out using the Student's variation method. Results. The clinical study proves that using the medicine of Passiflora incarnata extract for patients with uncomplicated forms of hypertension during 4 weeks provides possibility to obtain an additional hypotensive effect against the background of using standard antihypertensive therapy as a demonstration of a wide range of Passiflora incarnata pharmacological activity. Conclusions. The implementation of the Рassiflora drug complex application are sympatholytic and vascular tone modifying effects, expressed positive dynamics in the psychoemotional state, manifested as anxiolytic and sedative actions, and optimization of the emotional state and degree of psychological tension in patients with A

Comparison of Fatal or Irreversible Events With Extended-Duration Betrixaban Versus Standard Dose Enoxaparin in Acutely III Medical Patients: An APEX Trial Substudy

BACKGROUND: Extended-duration betrixaban showed a significant reduction in venous thromboembolism in the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study). Given the variable clinical impact of different efficacy and safety events, one approach to assess net clinical outcomes is to include only those events that are either fatal or cause irreversible harm. METHODS AND RESULTS: This was a post hoc analysis of the APEX trial-a multicenter, double-blind, randomized controlled trial comparing extended-duration betrixaban versus standard-of-care enoxaparin. A composite of all fatal or irreversible safety (fatal bleeding or intracranial hemorrhage) and efficacy events (cardiopulmonary death, myocardial infarction, pulmonary embolism, and ischemic stroke) was evaluated in a time-to-first event analysis. In patients with positive D-dimer results, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.80% versus 3.54%; hazard ratio, 0.73; absolute risk reduction, 1.26%; number needed to treat, 79 [P=0.033]) and at study end at 77 days (6.27% versus 4.36%; hazard ratio, 0.70; absolute risk reduction, 1.91%; number needed to treat, 52 [P=0.005]) versus enoxaparin. In all patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% versus 2.90%; hazard ratio, 0.71; absolute risk reduction, 1.18%; number needed to treat, 86 [P=0.006]) and 77 days (5.17% versus 3.64%; hazard ratio, 0.70; absolute risk reduction, 1.53%; number needed to treat, 65 [P=0.002]). CONCLUSIONS: Among hospitalized medically ill patients, extended-duration betrixaban demonstrated an ≈30% reduction in fatal or irreversible ischemic or bleeding events compared with standard-duration enoxaparin. A total of 65 patients would require treatment with betrixaban to prevent 1 fatal or irreversible event versus enoxaparin. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01583218.status: publishe

Comparison of fatal or irreversible events with extended-duration betrixaban versus standard dose enoxaparin in acutely Ill medical patients: An APEX trial substudy

Background-Extended-duration betrixaban showed a significant reduction in venous thromboembolism in the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study). Given the variable clinical impact of different efficacy and safety events, one approach to assess net clinical outcomes is to include only those events that are either fatal or cause irreversible harm. Methods and Results-This was a post hoc analysis of the APEX trial-a multicenter, double-blind, randomized controlled trial comparing extended-duration betrixaban versus standard-of-care enoxaparin. A composite of all fatal or irreversible safety (fatal bleeding or intracranial hemorrhage) and efficacy events (cardiopulmonary death, myocardial infarction, pulmonary embolism, and ischemic stroke) was evaluated in a time-to-first event analysis. In patients with positive D-dimer results, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.80% versus 3.54%; hazard ratio, 0.73; absolute risk reduction, 1.26%; number needed to treat, 79 [P=0.033]) and at study end at 77 days (6.27% versus 4.36%; hazard ratio, 0.70; absolute risk reduction, 1.91%; number needed to treat, 52 [P=0.005]) versus enoxaparin. In all patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% versus 2.90%; hazard ratio, 0.71; absolute risk reduction, 1.18%; number needed to treat, 86 [P=0.006]) and 77 days (5.17% versus 3.64%; hazard ratio, 0.70; absolute risk reduction, 1.53%; number needed to treat, 65 [P=0.002]). Conclusions-Among hospitalized medically ill patients, extended-duration betrixaban demonstrated an 48 30% reduction in fatal or irreversible ischemic or bleeding events compared with standard-duration enoxaparin. A total of 65 patients would require treatment with betrixaban to prevent 1 fatal or irreversible event versus enoxaparin