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Aim In patients with prior myocardial infarction (MI) on aspirin, the addition of ticagrelor reduces ischaemic risk but increases bleeding risk. The simultaneous assessment of baseline ischaemic and bleeding risk may assist clinicians in selecting patients who are most likely to have a favourable risk/benefit profile with long-term ticagrelor. Methods and results PEGASUS-TIMI 54 randomized 21 162 prior MI patients, 13 956 of which to the approved 60 mg dose or placebo and who had all necessary data. The primary efficacy endpoint was cardiovascular death, MI, or stroke, and the primary safety outcome was TIMI major bleeding; differences in Kaplan–Meier event rates at 3 years are presented. Post-hoc subgroups based on predictors of bleeding and ischaemic risk were merged into a selection algorithm. Patients were divided into four groups: those with a bleeding predictor (n = 2721, 19%) and then those without a bleeding predictor and either 0–1 ischaemic risk factor (IRF; n = 3004, 22%), 2 IRF (n = 4903, 35%), or ≥3 IRF (n = 3328, 24%). In patients at high bleeding risk, ticagrelor increased bleeding [absolute risk difference (ARD) +2.3%, 95% confidence interval (CI) 0.6, 3.9] and did not reduce the primary efficacy endpoint (ARD +0.08%, 95% CI −2.4 to 2.5). In patients at low bleeding risk, the ARDs in the primary efficacy endpoint with ticagrelor were −0.5% (−2.2, 1.3), −1.5% (−3.1, 0.02), and −2.6% (−5.0, −0.24, P = 0.03) in those with ≤1, 2, and 3 risk factors, respectively (P = 0.076 for trend across groups). There were significant trends for greater absolute risk reductions for cardiovascular death (P -trend 0.018), all-cause mortality (P -trend 0.027), and net outcomes (P -trend 0.037) with ticagrelor across these risk groups. Conclusion In a post-hoc exploratory analysis of patients with prior MI, long-term ticagrelor therapy appears to be best suited for those with prior MI with multiple IRFs at low bleeding risk. Clinical Trial Registration NCT01225562 ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the cardiovascular (CV) safety of sitagliptin versus placebo on CV outcomes in patients with type 2 diabetes and CV disease and found sitagliptin noninferior to placebo. Subsequently, based on feedback from FDA, the Sponsor of the trial, Merck & Co., Inc., engaged a separate academic research organization, the TIMI Study Group, to re‐adjudicate a prespecified set of originally adjudicated events. Methods: TIMI adjudicated in a blinded fashion all potential hospitalization for heart failure (HHF) events, all potential MACE+ events previously adjudicated as not an endpoint event, and a random subset (~10%) of MACE+ events previously adjudicated as an endpoint event. An updated study‐level meta‐analysis of four randomized, placebo‐controlled, CV outcomes trials with dipeptidyl peptidase 4 (DPP‐4) inhibitors was then performed. Results: After re‐adjudication of potential HHF events in the intent‐to‐treat population, there were 224 patients with a confirmed event in the sitagliptin arm (1.05/100 person‐years) and 239 patients in the placebo arm (1.13/100 person‐years), corresponding to a hazard ratio (HR) of 0.94 (95% confidence interval [95% CI]: 0.78–1.13, p =.49). Concordance between the outcome of the original adjudication and the re‐adjudication for HHF events was 82.7%. The meta‐analysis of CV outcomes trials with DPP‐4 inhibitors with placebo and involving 43 522 patients yielded an HR of 1.07 (95% CI: 0.83–1.39), with moderate heterogeneity (p =.45, I2 = 62.07%). Conclusion: The results of this independent re‐adjudication process and analyses of CV outcomes from TECOS were consistent with the original adjudication results and overall study findings. An updated study‐level meta‐analysis showed no overall significant risk for HHF with DPP‐4 inhibitors, but with statistical heterogeneity. [ABSTRACT FROM AUTHOR]

Aims PEGASUS-TIMI 54 demonstrated that long-term dual antiplatelet therapy (DAPT) with aspirin and ticagrelor reduced the risk of major adverse cardiovascular events (MACE), with an acceptable increase in bleeding, in patients with prior myocardial infarction (MI). While much of the discussion around prolonged DAPT has been focused on stented patients, patients with prior MI without prior coronary stenting comprise a clinically important subgroup. Methods and results This was a pre-specified analysis from PEGASUS-TIMI 54, which randomized 21 162 patients with prior MI (1–3 years) and additional high-risk features to ticagrelor 60 mg, 90 mg, or placebo twice daily in addition to aspirin. A total of 4199 patients had no history of coronary stenting at baseline. The primary efficacy outcome (MACE) was the composite of cardiovascular death, MI, or stroke. Patients without history of coronary stenting had higher baseline risk of MACE [13.2% vs. 8.0%, adjusted hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.15–1.73, in the placebo arm]. The relative risk reduction in MACE with ticagrelor (pooled doses) was similar in patients without (HR 0.82, 95% CI 0.68–0.99) and with prior stenting (HR 0.85, 95% CI 0.75–0.96; P for interaction = 0.76). Conclusion Long-term ticagrelor reduces thrombotic events in patients with prior MI regardless of whether they had prior coronary stenting. These data highlight the benefits of DAPT in prevention of spontaneous atherothrombotic events and indicate that long-term ticagrelor may be considered in high-risk patients with prior MI even if they have not been treated with stenting. ClinicalTrials.gov Identifier NCT01225562. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Aims Although presenting features and early sequelae of non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are well described, less is known about longer-term risks and modes of death. The purpose of this study was to characterize modes of death following NSTE-ACS in clinical trial populations. Methods and results We evaluated 66 252 patients with NSTE-ACS enrolled in 14 Thrombolysis in Myocardial Infarction (TIMI) trials, examining baseline characteristics and modes and timing of death. Of the 66 252 patients followed for a median of 372 (interquartile range 218–521) days, 3147 (4.8%) died by the time of last follow-up. Of the 2606 patients (82.8%) with known modes of death, 75.1% were related to a cardiovascular (CV) event, 3.0% were related to a bleeding event (including intracranial haemorrhage), and 21.8% were related to a non-CV/non-bleeding event. The most common modes of CV death were sudden death (SD) and recurrent myocardial infarction (MI) (36.4% and 23.4%, respectively, of CV deaths). The proportion of CV deaths related to recurrent MI was higher in the first 30 days than it was after 30 days following NSTE-ACS (30.6% vs. 18.7%), whereas the proportion of SD was lower in the first 30 days than after 30 days (21.6% vs. 46.2%). Conclusion Sudden death represents the largest proportion of CV deaths after 30 days among patients enrolled in CV clinical trials with NSTE-ACS. Further investigations aimed at defining the epidemiology of SD and developing specific therapies and management approaches to reduce SD following NSTE-ACS may be critical to reducing late mortality. View large Download slide View large Download slide [ABSTRACT FROM AUTHOR]

Introduction: Optimal antithrombotic therapy after transcatheter aortic valve replacement (TAVR) remains unclear. We evaluated the association between antithrombotic regimens and outcomes in TAVR patients.Methods: We retrospectively analyzed consecutive patients who underwent TAVR at a single academic center from April 2009 to March 2014. Antithrombotic regimens were classified as single or dual antiplatelet therapy (AP), single antiplatelet plus anticoagulant (SAC), or triple therapy (TT). The primary endpoint was a composite of death, myocardial infarction (MI), stroke, and major bleeding. Adjusted hazard ratios (HRs) were obtained with best subset variable selection methods using bootstrap resampling.Results: Of 246 patients who underwent TAVR, 241 were eligible for analysis with 133, 88, and 20 patients in the AP, SAC, and TT groups, respectively. During a median 2.1-year follow-up, 53.5% had at least one endpoint—the most common was death (68%), followed by major bleeding (23%), stroke (6%), and MI (3%). At 2 years, the composite outcome occurred in 70% of TT, 42% of SAC, and 31% of AP patients. Compared to AP, adjusted HRs for the composite outcome were 2.88 [95% Confidence intervals (CI) (1.61-5.16); p = 0.0004] and 1.66 (95% CI [1.13-2.42]; p = 0.009) in the TT and SAC groups, respectively. Mortality rates at 2 years were 61% in the TT, 32% in the SAC, and 26% in the AP groups (p = 0.005).Conclusions: The risk of the composite outcome of death, MI, stroke, or major bleeding at 2-year follow-up was significantly higher in TAVR patients treated with TT or SAC versus AP, even after multivariate adjustment. [ABSTRACT FROM AUTHOR]

Hypoglycaemia is a well-known risk associated with the use of sulphonylureas and insulin, often limiting achievement of glycaemic goals. Recognizing the precipitants and recurrence patterns of hypoglycaemic events, particularly major events, is therefore clinically important. The SAVOR-TIMI-53 trial was a cardiovascular outcome study of 16 492 patients allocated to saxagliptin vs placebo added to conventional care for a median of 2.1 years. Hypoglycaemic events were a prespecified outcome in the study and were defined as a symptomatic episode that recovered with carbohydrates or any recorded blood glucose <3.0 mmol/l (<54 mg/ dL). A major event was defined as one that required third-party assistance. Analysis of the features of the first hypoglycaemic event for each patient showed that a precipitant for the event was recognized by fewer than half of the patients, with the precipitant most often being a missed meal. In 40% of patients reporting major hypoglycaemic events, no precipitating factor was recognized, and in >60%, no previous hypoglycaemic event was reported during the timespan of the study, underscoring the lack of predictability of such an event. [ABSTRACT FROM AUTHOR]

Objective: Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy.Research Design and Methods: We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial.Results: At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g), 4,426 (26.8%) had microalbuminuria (ACR 30-300 mg/g), and 1,638 (9.9%) had macroalbuminuria (ACR >300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was -19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m2 (BSA), -105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and -245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA. Analyzing ACR as a continuous variable showed reduction in ACR with saxagliptin (1 year, P < 0.0001; 2 years, P = 0.0143; and EOT, P = 0.0158). The change in ACR did not correlate with that in HbA1c (r = 0.041, 0.052, and 0.036; 1 year, 2 years, and EOT, respectively). The change in eGFR was similar in the saxagliptin and placebo groups. Safety renal outcomes, including doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar as well.Conclusions: Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control. [ABSTRACT FROM AUTHOR]

Importance: The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain.Objective: To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies.Data Sources and Study Selection: The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included.Data Extraction and Synthesis: Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression.Main Outcomes and Measures: The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level.Results: A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P < .001) for statins and 0.75 (95% CI, 0.66-0.86; P = .002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P = .72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P < .001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P = .24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P = .002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11 301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%-2.6%] per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%-6.4%] per each 1-mmol/L lower LDL-C level; P < .001).Conclusions and Relevance: In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events. [ABSTRACT FROM AUTHOR]

Objective: To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study.Research Design and Methods: Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied.Results: At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia.Conclusions: The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy. [ABSTRACT FROM AUTHOR]

Importance: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme.Objective: To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event.Design, Setting, and Participants: SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries.Interventions: Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013.Main Outcomes and Measures: The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years.Results: During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%).Conclusions and Relevance: In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events.Trial Registration: clinicaltrials.gov Identifier: NCT01000727. [ABSTRACT FROM AUTHOR]

Objectives: (1) To estimate caregiver support required by patients 2 months after prolonged (at least 48 h) mechanical ventilation (MV) in an ICU; (2) to describe caregiver burden, caregiver depressive symptomatology, and caregiver limitations in activities; and (3) to investigate factors related to depressive symptoms at 2 months in caregivers.Design: Prospective cohort study.Study Participants: Caregivers of 115 patients who received prolonged MV in an ICU.Measurements: Sociodemographics, employment status, hours spent providing care, help from paid caregiving sources, caregiver burden, and caregiver depressive symptoms.Results: The proportion of patients who survived at least 2 months and required caregiver support was 74.8%. The average age of caregivers was 52.9 years (SD, 14.2), 76.5% were women, and more than half were spouses (52.2%). Only 33 of the caregivers (28.7%) were working, and 30.3% had to reduce their time spent at work to provide care to the patient. The prevalence of risk of clinical depression (defined as Center for Epidemiological Studies depression scale [CES-D] score > or =16) among caregivers was 33.9%. The mean caregiver CES-D score was 13.2 (SD, 11; median, 10). Multiple linear regression analysis showed that higher CES-D score was associated with more hours per day helping with patients' activities of daily living and instrumental activities of daily living (p = 0.003).Conclusions: Two months after being placed on MV for at least 48 h, a high proportion of patients need caregiver support. Approximately 34% of caregivers are at risk of clinical depression. Many caregivers report lifestyle changes and burden when providing care for the patients. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article on moderate-intensity statin therapy.

A letter to the editor is presented discussing liver transplantation in HIV-infected individuals.