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Background The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density l...

In 1984, the National Heart, Lung, and Blood Institute (NHLBI) decided to study the efficacy and safety of the treatment of acute myocardial infarction with an emerging therapy, coronary thrombolysis, and thus the TIMI (Thrombolysis In Myocardial Infarction) Study Group was born. Following completion of 3 clinical trials of thrombolytic therapy supported by the NHLBI, TIMI became an academic research organization headquartered at Brigham and Women's Hospital and subsequently branched out to study a wide range of patients, including those with stable coronary, cerebrovascular, and peripheral arterial disease; dyslipidemia; heart failure; atrial fibrillation; diabetes; and obesity. TIMI also began to study a wide range of interventions including thrombolytic, antithrombotic, lipid-modifying, anti-inflammatory, heart failure, glucose-lowering, and weight loss agents. TIMI, now in its 37th year, has completed >70 trials. This review describes the origins of the TIMI Study Group, summarizes several of its completed trials and the major lessons learned from them, and discusses ongoing trials and future directions.

Supplemental Digital Content is available in the text., Background: Female sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men. Methods: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS2 score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis–defined major bleeding (safety). Results: In comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, P

Background: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease. Methods: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. Results: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke ( P trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98–1.36) and 1.24 (95% CI 1.05–1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04–1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81–1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA 2 DS 2 -VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA 2 DS 2 -VASc score of 3. Conclusions: Across a broad spectrum of subjects with cardiometabolic disease, a 32–single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA 2 DS 2 -VASc scores, the GRS identified patients with risk comparable to those with higher CHA 2 DS 2 -VASc scores.

Background: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease. Methods: We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trials (history of a major atherosclerotic cardiovascular event, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE genetic risk score based on 297 single nucleotide polymorphisms with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared with available clinical risk factors (age, obesity, smoking, history of heart failure, and diabetes) and common monogenic mutations. Results: A total of 29 663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles ( P -trend P =0.004) and 2.70-fold (95% CI, 1.81–4.06; P P Conclusions: In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia.

AimsCeramide (Cer) and phosphatidylcholine (PC) lipids are associated with pathophysiological processes in cardiovascular (CV) diseases. A previously derived and validated plasma Cer-PC risk score (CERT2) was associated with CV death risk in patients with stable disease, but its prognostic value has not been evaluated in patients early post-acute coronary syndrome (ACS).Methods and resultsPrespecified plasma Cer and PC species in the CERT2 risk score were measured in 4871 subjects from SOLID-TIMI 52, which enrolled patients ≤30 days after ACS (median follow-up 2.5 years). The CERT2 score (scale 0–12 points) was calculated as previously defined. The primary outcome was CV death; Coronary heart disease death, all-cause death, hospitalization for heart failure (HF), myocardial infarction (MI) and stroke were also analyzed. Poisson models included baseline characteristics and established biomarkers. Patients with higher CERT2 risk scores were more likely to be older, female, current smokers, presenting with STEMI, and to have impaired renal function and higher LDL-C. After multivariable adjustment, patients in the highest risk score category remained at a nearly two-fold higher risk of CV death (adj relative risk [RR] 1.92, 95% CI 1.01–3.66, P = 0.047). Patients in the highest risk score category were also at higher risk of all-cause death (adj RR 2.01, 95% CI 1.21–3.35, P = 0.007), whereas the relationships with HF, MI, and stroke were attenuated with multivariable adjustment.ConclusionsA plasma ceramide and phospholipid-based risk score is associated with the risk of CV death independent of established clinical risk factors and biomarkers in patients after ACS.

Summary Background The clinical benefit of LDL cholesterol lowering treatment in older patients remains debated. We aimed to summarise the evidence of LDL cholesterol lowering therapies in older patients. Methods In this systematic review and meta-analysis, we searched MEDLINE and Embase for articles published between March 1, 2015, and Aug 14, 2020, without any language restrictions. We included randomised controlled trials of cardiovascular outcomes of an LDL cholesterol-lowering drug recommended by the 2018 American College of Cardiology and American Heart Association guidelines, with a median follow-up of at least 2 years and data on older patients (aged ≥75 years). We excluded trials that exclusively enrolled participants with heart failure or on dialysis because guidelines do not recommend lipid-lowering therapy in such patients who do not have another indication. We extracted data for older patients using a standardised data form for aggregated study-level data. We meta-analysed the risk ratio (RR) for major vascular events (a composite of cardiovascular death, myocardial infarction or other acute coronary syndrome, stroke, or coronary revascularisation) per 1 mmol/L reduction in LDL cholesterol. Findings Data from six articles were included in the systematic review and meta-analysis, which included 24 trials from the Cholesterol Treatment Trialists' Collaboration meta-analysis plus five individual trials. Among 244 090 patients from 29 trials, 21 492 (8·8%) were aged at least 75 years, of whom 11 750 (54·7%) were from statin trials, 6209 (28·9%) from ezetimibe trials, and 3533 (16·4%) from PCSK9 inhibitor trials. Median follow-up ranged from 2·2 years to 6·0 years. LDL cholesterol lowering significantly reduced the risk of major vascular events (n=3519) in older patients by 26% per 1 mmol/L reduction in LDL cholesterol (RR 0·74 [95% CI 0·61–0·89]; p=0·0019), with no statistically significant difference with the risk reduction in patients younger than 75 years (0·85 [0·78–0·92]; pinteraction=0·37). Among older patients, RRs were not statistically different for statin (0·82 [0·73–0·91]) and non-statin treatment (0·67 [0·47–0·95]; pinteraction=0·64). The benefit of LDL cholesterol lowering in older patients was observed for each component of the composite, including cardiovascular death (0·85 [0·74–0·98]), myocardial infarction (0·80 [0·71–0·90]), stroke (0·73 [0·61–0·87]), and coronary revascularisation (0·80 [0·66–0·96]). Interpretation In patients aged 75 years and older, lipid lowering was as effective in reducing cardiovascular events as it was in patients younger than 75 years. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin treatment, in older patients. Funding None.

Objectives This study compared the efficacy and safety of sacubitril/valsartan to enalapril in Black and non-Black Americans with acute decompensated heart failure (ADHF). Background Black patients have a different response to treatment with angiotensin-converting enzyme inhibitors compared with other racial and ethnic groups. How Black patients with ADHF respond to sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, is unclear. PIONEER-HF was a double-blind randomized clinical trial of sacubitril/valsartan versus enalapril in hospitalized patients with ADHF following hemodynamic stabilization. Methods In a pre-specified subgroup analysis, we examined changes in N-terminal pro–B-type natriuretic peptide, clinical outcomes, and safety according to race. Results The study population, all enrolled in the United States, included 316 (36%) Black participants, 515 (58%) White participants, and 50 (5.7%) participants of other racial groups. The reduction in N-terminal pro–B-type natriuretic peptide concentration at weeks 4 and 8 was significantly greater with sacubitril/valsartan than enalapril in both Black (ratio of change with sacubitril/valsartan vs. enalapril: 0.71; 95% confidence interval [CI]: 0.58 to 0.88) and non-Black patients (ratio of change: 0.71; 95% CI: 0.61 to 0.83; interaction p = 1.00). Compared with enalapril, sacubitril/valsartan also reduced the pre-specified exploratory composite of cardiovascular death or HF rehospitalization in both Black (hazard ratio: 0.47; 95% CI: 0.24 to 0.93) and non-Black patients (hazard ratio: 0.65; 95% CI: 0.40 to 1.06; interaction p = 0.44). Conclusions Among Black patients admitted with ADHF in the United States, the in-hospital initiation of sacubitril/valsartan was more effective than enalapril in reducing natriuretic peptide levels and the composite of cardiovascular death or HF rehospitalization. The effect of sacubitril/valsartan did not differ by race. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890)

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Mor...

Objectives This study sought to evaluate the efficacy and safety of sacubitril/valsartan according to dose level achieved in the PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode) trial. Background In patients hospitalized for acute decompensated heart failure (ADHF), in-hospital initiation and continuation of sacubitril/valsartan as compared with enalapril is well tolerated, achieves a greater reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP), and reduces the risk of cardiovascular death or rehospitalization for HF through 8 weeks. However, not all patients achieve the target dose of sacubitril/valsartan, and its efficacy and safety in such patients are of interest. Methods PIONEER-HF was a randomized, double-blind, active-controlled trial of sacubitril/valsartan versus enalapril in 881 patients stabilized during hospitalization for ADHF. Blinded study medication was administered for 8 weeks, with initial dosing selected based on the systolic blood pressure at randomization and titrated toward a target of sacubitril/valsartan 97/103 mg twice daily, or enalapril 10 mg twice daily, with an algorithm based on systolic blood pressure and the investigator’s assessment of tolerability. Results At 4 weeks, 199 (55%) patients allocated to sacubitril/valsartan and 211 (60%) patients allocated to enalapril were dispensed the target dose. Baseline characteristics were similar in the 2 treatment groups within each dose level. There was no heterogeneity across dose levels in the effect of sacubitril/valsartan on the reduction in NT-proBNP (pinteraction = 0.69), the reduction in cardiovascular death or rehospitalization for heart failure (pinteraction = 0.42), or the pre-specified adverse events of special interest through 8 weeks. Conclusions In hemodynamically stabilized patients with ADHF, the efficacy and safety of sacubitril/valsartan are generally consistent across dose levels. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890)

The PIONEER-HF (comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode) trial demonstrated the efficacy and safety of sacubitril/valsartan (S/V) in stabilized patients with acute decompensated heart failure (HF) and reduced ejection fraction.The study sought to determine whether and how prior HF history and treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) affected the results.The PIONEER-HF trial was a prospective, multicenter, double-blind, randomized clinical trial enrolling 881 patients with an ejection fraction ≤40%. Patients were randomly assigned 1:1 to in-hospital initiation of S/V (n = 440) versus enalapril (n = 441). Pre-specified subgroup analyses were performed based on prior HF history (i.e., de novo HF vs. worsening chronic HF) and treatment with an ACE inhibitor or ARB (i.e., ACE inhibitor or ARB-yes vs. ACE inhibitor or ARB-no) at admission.At enrollment, 303 (34%) patients presented with de novo HF and 576 (66%) patients with worsening chronic HF. A total of 421 (48%) patients had been treated with an ACE inhibitor or ARB, while 458 (52%) had not been treated with an ACE inhibitor or ARB. N-terminal pro-B-type natriuretic peptide declined significantly in all 4 subgroups (p 0.001), with greater decreases in the S/V versus the enalapril arm (p 0.001). There was no interaction between prior HF history (p = 0.350) or ACE inhibitor or ARB treatment (p = 0.880) and the effect of S/V versus enalapril on cardiovascular death or rehospitalization for HF. The incidences of adverse events were comparable between S/V and enalapril across all 4 subgroups.Among patients admitted for acute decompensated HF, S/V was safe and well tolerated, led to a significantly greater reduction in N-terminal pro-B-type natriuretic peptide, and improved clinical outcomes compared with enalapril irrespective of previous HF history or ACE inhibitor or ARB treatment. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).

Background An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial. Objectives The purpose of this study was to clarify this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Methods Within IMPROVE-IT, 17,708 patients post–acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took ≥1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy. Results In this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68). Conclusions Among 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878), Central Illustration

Author(s): Anker, Stefan D; Butler, Javed; Khan, Muhammad Shahzeb; Abraham, William T; Bauersachs, Johann; Bocchi, Edimar; Bozkurt, Biykem; Braunwald, Eugene; Chopra, Vijay K; Cleland, John G; Ezekowitz, Justin; Filippatos, Gerasimos; Friede, Tim; Hernandez, Adrian F; Lam, Carolyn SP; Lindenfeld, JoAnn; McMurray, John JV; Mehra, Mandeep; Metra, Marco; Packer, Milton; Pieske, Burkert; Pocock, Stuart J; Ponikowski, Piotr; Rosano, Giuseppe MC; Teerlink, John R; Tsutsui, Hiroyuki; Van Veldhuisen, Dirk J; Verma, Subodh; Voors, Adriaan A; Wittes, Janet; Zannad, Faiez; Zhang, Jian; Seferovic, Petar; Coats, Andrew JS | Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.

Background Diabetes mellitus is an independent risk factor for stroke and atrial fibrillation. Therefore, the risk/benefit profile of the oral factor Xa inhibitor edoxaban stratified by diabetes is of clinical interest. Methods 21,105 patients enrolled in ENGAGE AF-TIMI 48 were stratified into 2 pre-specified groups: without (N = 13,481) and with diabetes (N = 7,624). Results On average, patients with diabetes were younger, and had a higher body mass index, CHA2DS2-VASc score and baseline endogenous Factor Xa activity. After multivariate adjustments, patients with diabetes had a similar rate of stroke and systemic embolism compared to those without diabetes (adjusted hazard ratio (HRadj) 1.08; 95% confidence interval (CI) 0.94–1.24; p = 0.28). However, the risk of major bleeding was significantly higher in patients with diabetes (HRadj 1.28; 95% CI 1.14–1.44; p 0.05), a finding supported by the preserved edoxaban concentrations and inhibition of Factor Xa regardless of diabetes. The HRs of stroke and systemic embolism in patients receiving the higher-dose edoxaban regimen vs warfarin were 0.93 and 0.84 (p-interaction = 0.54) in those with and without diabetes respectively. The higher-dose edoxaban regimen reduced major bleeding (by 19–21%) and cardiovascular death (by 7–17%) regardless of diabetes (p-interactions = 0.81 and 0.33 respectively). Conclusion Patients with diabetes in ENGAGE AF-TIMI 48 had higher bleeding risk, but after adjustment similar stroke risk, compared to those without diabetes. The higher-dose edoxaban regimen had similar efficacy compared to warfarin, while reducing bleeding and cardiovascular mortality, irrespective of diabetes.

An elevated white blood cell (WBC) count is associated with an increased risk of ischemic events among acute coronary syndrome (ACS) patients, but the association between WBC count and bleeding in ACS patients is not well established. The aim of this analysis was to assess and compare the association between WBC count and the occurrence of short- and long-term bleeding and ischemic events. This was a post hoc analysis of the ATLAS ACS2-TIMI 51 trial. A subset of patients had a WBC count measurement at baseline (n = 14,231, 91.6%). Univariate and multivariable Cox proportional hazard models were constructed to determine if there is an association between WBC count at baseline and a composite outcome of Thrombolysis in Myocardial Infarction (TIMI) major and minor bleeds at 30 days and 1 year. Variables with a p0.2 in the univariate analysis were included as potential parameters in the backward selection process A similar multivariable model was constructed to assess the association between WBC count and a composite ischemic endpoint of cardiovascular death, myocardial infarction and stroke. An increased risk of bleeding per a 1 × 10

Changes in the regulatory guidelines by the U.S. Food and Drug Administration and the European Medical Agency requiring large-scale trials that study the cardiovascular safety of new glucose-lowering drugs have improved our understanding of type 2 diabetes mellitus. Unexpectedly, these trials demonstrated that sodium-glucose cotransporter 2 inhibitors reduce adverse cardiovascular outcomes. This second part of this 2-part review summarizes the findings of recent clinical trials and their clinical implications and describes ongoing trials and future areas of research.

Highlights •T2DM, HF, and CKD are closely intertwined. •SGLT2i exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects. •SGLT2i reduce inflammation, oxidative stress, fibrosis, intraglomerular hypertension, and sympathetic nervous system activation, and may improve mitochondrial function and myocardial efficiency. •Cardiologists, diabetologists, nephrologists, and primary care physicians should be familiar with this drug class.

Atrial dysfunction has been widely considered a marker or consequence of other cardiac conditions rather than the cause itself. Here, we propose the term atrial failure as a clinically relevant entity, defined as any atrial dysfunction causing impaired heart performance, symptoms, and worsening quality of life or life expectancy. Aspects of the etiology, mechanisms, and consequences of atrial failure are discussed. Recent advances in cardiac electrophysiology and imaging have improved our understanding of the highly complex atrial anatomy and function, underlying the paramount importance of the atria in optimal heart performance. It is time to reappraise the concept of the failing atrium as a primary cause or aggravating factor of the symptoms in many of our patients. The concept of atrial failure may foster basic and translational research to gain a better understanding of how to identify and manage atrial dysfunction.

Ovo istraživačko pismo prikazuje detaljniju analizu kliničkih ishoda u kliničkom ispitivanju PARADISE- MI.

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.

BACKGROUND: The optimal revascularisation strategy for patients with left main coronary artery disease is uncertain. We therefore aimed to evaluate long-term outcomes for patients treated with percutaneous coronary intervention (PCI) with drug-eluting stents versus coronary artery bypass grafting (CABG).METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane database using the search terms "left main", "percutaneous coronary intervention" or "stent", and "coronary artery bypass graft*" to identify randomised controlled trials (RCTs) published in English between database inception and Aug 31, 2021, comparing PCI with drug-eluting stents with CABG in patients with left main coronary artery disease that had at least 5 years of patient follow-up for all-cause mortality. Two authors (MSS and BAB) identified studies meeting the criteria. The primary endpoint was 5-year all-cause mortality. Secondary endpoints were cardiovascular death, spontaneous myocardial infarction, procedural myocardial infarction, stroke, and repeat revascularisation. We used a one-stage approach; event rates were calculated by use of the Kaplan-Meier method and treatment group comparisons were made by use of a Cox frailty model, with trial as a random effect. In Bayesian analyses, the probabilities of absolute risk differences in the primary endpoint between PCI and CABG being more than 0·0%, and at least 1·0%, 2·5%, or 5·0%, were calculated.FINDINGS: Our literature search yielded 1599 results, of which four RCTs-SYNTAX, PRECOMBAT, NOBLE, and EXCEL-meeting our inclusion criteria were included in our meta-analysis. 4394 patients, with a median SYNTAX score of 25·0 (IQR 18·0-31·0), were randomly assigned to PCI (n=2197) or CABG (n=2197). The Kaplan-Meier estimate of 5-year all-cause death was 11·2% (95% CI 9·9-12·6) with PCI and 10·2% (9·0-11·6) with CABG (hazard ratio 1·10, 95% CI 0·91-1·32; p=0·33), resulting in a non-statistically significant absolute risk difference of 0·9% (95% CI -0·9 to 2·8). In Bayesian analyses, there was an 85·7% probability that death at 5 years was greater with PCI than with CABG; this difference was more likely than not less than 1·0% (INTERPRETATION: Among patients with left main coronary artery disease and, largely, low or intermediate coronary anatomical complexity, there was no statistically significant difference in 5-year all-cause death between PCI and CABG, although a Bayesian approach suggested a difference probably exists (more likely than not FUNDING: No external funding.

Importance: Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. Objective: To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins. Design, Setting, and Participants: This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40430 patients with established atherosclerosis who were receiving statin treatment. Exposures: ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. Main Outcome and Measures: The primary study outcome was incident myocardial infarction (MI). Results: Of the 389529 individuals in the primary prevention group, 224097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P

Importance The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. Objective To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. Design, Setting, and Participants A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. Intervention Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. Main Outcomes and Measures The area under the curve (AUC) for the ratio of N-terminal pro–brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. Results Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08;P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non–life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%];P = .04), there were no observed safety concerns. Conclusions and Relevance The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. Trial Registration ClinicalTrials.gov Identifier:NCT02816736

OBJECTIVE Heart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM. RESEARCH DESIGN AND METHODS We derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events–Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58. RESULTS The strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each P < 0.001). A risk score using these three variables identified a gradient of HHF risk (P-trend CONCLUSIONS We developed and validated a risk score for HHF in T2DM that incorporated NT-proBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin.

Background Coronary stent type and risk of stent thrombosis remain important factors affecting recommended duration of dual antiplatelet therapy. We investigated the efficacy and safety of long‐term ticagrelor in patients with prior coronary stenting enrolled in the PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) trial. Methods and Results Patients in PEGASUS‐TIMI 54 had a myocardial infarction 1 to 3 year prior and were randomized 1:1:1 to ticagrelor 60 or 90 mg BID or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events). Stent thrombosis was prospectively adjudicated (Academic Research Consortium definition). Baseline characteristics were compared by most recent stent type (bare metal versus drug‐eluting stent and first‐ versus later‐generation drug‐eluting stent). Treatment arms were compared using Cox proportional hazards models. Of 21 162 patients randomized, 80% (n=16 891) had prior coronary stenting. Following randomization, myocardial infarction was the most frequent ischemic event in patients with prior stenting in the placebo arm, occurring in 5.2% of patients (Type 1: 4.1%), followed by cardiovascular death (2.3%), stroke (1.7%), and stent thrombosis (0.9%). Ticagrelor pooled reduced major adverse cardiovascular events (7.0% versus 8.0%; hazard ratio [HR], 0.85; 95% CI, 0.75–96) regardless of stent type (bare metal stent versus drug‐eluting stent: p interaction =0.767; first versus later generation: p interaction =0.940). The rate of any stent thrombosis was numerically lower with ticagrelor pooled (0.7% versus 0.9%; HR, 0.73; 95% CI, 0.50–1.05) and Thrombolysis in Myocardial Infarction major bleeding was increased (HR, 2.65; 95% CI, 1.90–3.68). Conclusions Long‐term ticagrelor reduces major adverse cardiovascular events in patients with prior myocardial infarction and coronary stenting regardless of stent type, with the benefit driven predominantly by reduction in de novo events. Nonfatal major bleeding is increased with ticagrelor. Registration Information clinicaltrials.gov. Identifier: NCT01225562.

The preferred contemporary approach to the management of stable ischemic heart disease, also referred to as chronic coronary syndrome,1 is not well defined. Two strategies are commonly used.2 The c...

Background: Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing heart failure. Sodium-glucose cotransporter-2 inhibitors reduce the risk of hospitalization for heart failure (HHF) in patients with T2DM. We aimed to develop and validate a practical clinical risk score for HHF in patients with T2DM and assess whether this score can identify high-risk patients with T2DM who have the greatest reduction in risk for HHF with a sodium-glucose cotransporter-2 inhibitor. Methods: We developed a clinical risk score for HHF in 8212 patients with T2DM in the placebo arm of SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using multivariable Cox regression, and independent clinical risk indicators achieving statistical significance of P Results: Five clinical variables were independent risk predictors of HHF: prior heart failure, history of atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. A simple integer-based score (0–7 points) using these predictors identified a >20-fold gradient of HHF risk ( P for trend P for trend=0.04), with high-risk (2 points) and very-high-risk (≥3 points) patients having 1.5% and 2.7% absolute reductions in Kaplan-Meier estimates of HHF risk at 4 years, respectively. Conclusions: Risk stratification using a novel clinical risk score for HHF in patients with T2DM identifies patients at higher risk for HHF who derive greater absolute benefit from sodium-glucose cotransporter-2 inhibition. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01107886 and NCT01730534.

Background: Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved. Methods: In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) with baseline biomarker samples (n=12 156) were classified as ever versus never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models. Results: Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min −1 ·1.73 m −2 ). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76–1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59–0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease. Conclusions: In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01107886.

Hypertension is a risk factor for both stroke and bleeding in patients with atrial fibrillation. Data are sparse regarding the interaction between blood pressure and the efficacy and safety of direct oral anticoagulants. In the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48), 19,679 patients with atrial fibrillation and hypertension were categorized according to average systolic blood pressure (SBP) and diastolic blood pressure (DBP). The primary efficacy and safety end points were the time to the first stroke or systemic embolic event and the time to the first International Society of Thrombosis and Hemostasis major bleeding event, respectively. Risk was calculated using Cox proportional hazards models based on average SBP and DBP and adjusting for 18 clinical characteristics. The efficacy and safety of a higher dose edoxaban regimen (60/30 mg) versus warfarin were evaluated with stratification by average SBP and DBP. Stroke/systemic embolic event occurred significantly more frequently in patients with elevated average SBP (hazard ratio, 2.01; 95% CI, 1.50–2.70 for SBP ≥150 mm Hg relative to 130–139 mm Hg) or DBP (hazard ratio, 2.36; 95% CI, 1.76–3.16 for DBP ≥90 mm Hg relative to 75–P interaction =0.55) and DBP ( P interaction =0.44) compared with warfarin. The higher dose edoxaban regimen reduced the risk of major bleeding events, including intracranial hemorrhage, without modification by average SBP ( P interaction =0.29). The relative safety of edoxaban was most pronounced in patients with elevated DBP ( P interaction =0.007). The efficacy and safety of edoxaban were consistent across the full range of SBP, while the superior safety of edoxaban was most pronounced among patients with elevated DBP.

Background Addition of ezetimibe to statin therapy reduces the risk of recurrent cardiovascular (CV) events in patients with prior acute coronary syndrome (ACS). The role of biomarkers in identifying subsets of patients who may derive greater clinical benefit with ezetimibe is unknown. Objectives This study sought to evaluate the role of established CV biomarkers in assessing likely benefit with ezetimibe added to statin therapy in post-ACS patients. Methods In a pre-specified nested analysis within a randomized, double-blind trial of ezetimibe/simvastatin versus placebo/simvastatin (IMPROVE-IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), high-sensitivity troponin T, N-terminal pro–B-type natriuretic peptide, growth-differentiation factor-15, and high-sensitivity C-reactive protein was measured in 7,195 patients stabilized (1 month post-randomization) after ACS. A multimarker approach based on biomarker values was used to examine the risk of recurrent CV events and clinical benefit with ezetimibe. Results Elevated levels of each biomarker were independently associated with higher risks of CV death/myocardial infarction/stroke and CV death/heart failure (ptrend Conclusions A biomarker-based strategy identifies a gradient of risk among patients post-ACS, offering the potential to identify higher-risk patients with a correspondingly high absolute benefit from the addition of ezetimibe to statin therapy.

In the Cardiology Masters section of European Cardiology Review, we bring you an insight into the career of a key contributor to the field of cardiology. In this issue, we feature Professor Eugene Braunwald, cardiovascular medicine specialist at Brigham and Women’s Hospital and distinguished Hersey Professor of Medicine at Harvard University, Boston, Massachusetts, US.

The prevalence of Type 2 diabetes mellitus (T2DM) has reached pandemic proportions. T2DM frequently causes macrovascular and/or microvascular pathologic changes and thereby increases the risks for the development of myocardial infarction, heart failure, stroke, renal failure, and reduced survival. This article describes the important interactions between T2DM, heart failure, and renal dysfunction, forming vicious circles. The interruption of these circles represents important therapeutic goals.

Background Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents. Objectives This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease. Methods ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration. Results Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HRadj]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj: 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups. Conclusions Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin.

Aims Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3′5′ monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF). Methods and results PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P Conclusion Biomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1–4 weeks. Clinical trials registration NCT 02554890 clinical.trials.gov

Acute decompensated heart failure accounts for more than 1 million hospitalizations in the United States annually. Whether the initiation of sacubitril-valsartan therapy is safe and effective among patients who are hospitalized for acute decompensated heart failure is unknown.We enrolled patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure at 129 sites in the United States. After hemodynamic stabilization, patients were randomly assigned to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or enalapril (target dose, 10 mg twice daily). The primary efficacy outcome was the time-averaged proportional change in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration from baseline through weeks 4 and 8. Key safety outcomes were the rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema.Of the 881 patients who underwent randomization, 440 were assigned to receive sacubitril-valsartan and 441 to receive enalapril. The time-averaged reduction in the NT-proBNP concentration was significantly greater in the sacubitril-valsartan group than in the enalapril group; the ratio of the geometric mean of values obtained at weeks 4 and 8 to the baseline value was 0.53 in the sacubitril-valsartan group as compared with 0.75 in the enalapril group (percent change, -46.7% vs. -25.3%; ratio of change with sacubitril-valsartan vs. enalapril, 0.71; 95% confidence interval [CI], 0.63 to 0.81; P0.001). The greater reduction in the NT-proBNP concentration with sacubitril-valsartan than with enalapril was evident as early as week 1 (ratio of change, 0.76; 95% CI, 0.69 to 0.85). The rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups.Among patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure, the initiation of sacubitril-valsartan therapy led to a greater reduction in the NT-proBNP concentration than enalapril therapy. Rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups. (Funded by Novartis; PIONEER-HF ClinicalTrials.gov number, NCT02554890 .).

Patients with type 2 diabetes are at increased risk of developing heart failure, cardiovascular death and renal failure. The recent results of three large sodium-glucose cotransporter 2 inhibitor cardiovascular outcomes trials have demonstrated a reduction in heart failure hospitalisation and progressive renal failure. One trial also showed a fall in cardiovascular and total death. A broad spectrum of patients with diabetes benefit from these salutary effects in cardiac and renal function and so these trials have important implications for the management of patients with type 2 diabetes. Selected glucagon-like peptide 1 receptor agonists have also been shown to reduce adverse cardiovascular outcomes.

Background: Numerous scales exist for the classification of major bleeding events. Limited data compare the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. Here, we analyze bleeding outcomes according to the ISTH (International Society on Thrombosis and Hemostasis), TIMI (Thrombolysis in Myocardial Infarction), GUSTO (Global Usage of Strategies to Open Occluded Arteries), and BARC (Bleeding Academic Research Consortium) bleeding scales in the ENGAGE AF (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation)–TIMI 48 trial (NCT00781391) of edoxaban versus warfarin. Methods: A total of 21 105 patients with atrial fibrillation at risk for stroke (CHADS 2 score ≥2) were enrolled in the ENGAGE AF-TIMI 48 trial comparing warfarin with a higher- (60/30 mg daily) or lower- (30/15 mg daily) dose edoxaban regimen. Median follow-up was 2.8 years. Bleeding events occurring among on-treatment patients were examined. Annualized event rates were calculated by the ISTH, TIMI, GUSTO, and BARC scales and compared across treatment arms. Cox proportional hazards for a first bleeding event of each type were calculated for higher-dose edoxaban regimen vs warfarin and lower-dose edoxaban regimen versus warfarin. Results: A total of 10 311 bleeding events were reported. In a comparison of the most severe events in each scale, ISTH major bleeding was the most common (n=1289), followed by TIMI major (n=548), GUSTO severe/life-threatening (n=347), and BARC 3c+5 (n=276) bleeding. Lower bleeding risk with edoxaban compared with warfarin was seen regardless of bleeding scale (higher-dose edoxaban regimen range: hazard ratio [HR], 0.47 [95% CI, 0.35–0.62] for BARC 3c+5 versus HR, 0.80 [95% CI, 0.71–0.91] for ISTH major; lower-dose edoxaban regimen range: HR, 0.32 [95% CI, 0.23–0.45] for BARC 3c+5 versus HR, 0.47 [95% CI, 0.41–0.55] for ISTH major). Furthermore, a gradient of more pronounced risk reduction with edoxaban was observed with greater severity of first bleeding event (higher-dose edoxaban regimen: HR, 0.47 [95% CI, 0.35–0.62] for BARC 3c+5 bleeds versus HR, 0.86 [95% CI, 0.81–0.91] for any BARC bleed; lower-dose edoxaban regimen: HR, 0.32 [95% CI, 0.23–0.45] for BARC 3c+5 bleeds versus HR, 0.68 [95% CI, 0.63–0.72] for any BARC bleed). The direction of this trend was consistent for both gastrointestinal bleeding and nongastrointestinal bleeding. Conclusions: Among patients with atrial fibrillation at risk for stroke, there was a >4-fold difference in the frequency of the most severe bleeding events across commonly used bleeding scales. Furthermore, the relative safety of edoxaban compared with warfarin tended to increase with greater severity of bleeding. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

We sought to assess the prevalence of polyvascular disease in patients with type 2 diabetes mellitus (T2DM) and its impact on ischemic events. Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53, a large contemporary, randomized trial, evaluated the effect of saxagliptin versus placebo in 16,492 patients with T2DM and a history of or at risk for cardiovascular (CV) events. Polyvascular disease was defined as a history of clinical events involving 2 or more vascular beds (coronary, peripheral, or cerebrovascular system) at the time of randomization. The primary composite endpoint of CV death, myocardial infarction, or ischemic stroke was compared according to the number of diseased arterial beds. At the time of randomization, 3,667 (22.2%) patients had risk factors for CV events; 11,423 (69.3%) had established 1 arterial bed disease; 1,298 (7.9%) had 2 bed disease; and 104 (0.6%) had 3 bed disease. Compared with diabetic patients with no established atherosclerosis, the adjusted hazard ratio for the composite primary end point in 1, 2, or 3 diseased beds was 1.95, 3.54, and 4.64, respectively (trend p < 0.0001). The adjusted risk for overall mortality increased in a similar stepwise fashion from 1.47 to 2.33 to 3.12, respectively (trend p = 0.0001) with each additional diseased arterial territory. In conclusion, in patients with confirmed atherosclerosis enrolled in SAVOR-TIMI 53, 11% had polyvascular disease; and compared with diabetic patients with single bed disease, the risk of ischemic events and overall mortality was substantially higher in patients with T2DM and polyvascular disease.

Polyvascular disease and type 2 diabetes are each associated with increased cardiovascular risk, but whether these risks are additive is unknown. In this exploratory analysis of a randomised trial, we explored the long-term cardiovascular risk associated with polyvascular disease, type 2 diabetes, and their combination in patients with acute coronary syndrome, and assessed the effect of ezetimibe given on top of statin therapy in patients with these concomitant conditions.IMPROVE-IT was a multicentre, double-blind, randomised, placebo-controlled trial assessing the effect of ezetimibe added to statin therapy after acute coronary syndrome. Recruitment was from Oct 26, 2005, to July 8, 2010, and the trial was done at 1158 sites in 39 countries. 18 144 patients aged 50 years and older who had been stabilised after an acute coronary syndrome were randomly assigned to 40 mg per day simvastatin plus either 10 mg per day ezetimibe or matched placebo, for a median duration of 6 years. In this post-hoc exploratory analysis, we assessed the prespecified endpoints of the trial, including the primary composite endpoint (cardiovascular death, a major coronary event [non-fatal myocardial infarction, documented unstable angina requiring hospital admission, or coronary revascularisation occurring at least 30 days after randomisation], or stroke [ischaemic or haemorrhagic]) by concomitant polyvascular disease at baseline (peripheral artery disease or previous stroke or transient ischaemic attack) and stratified by concomitant type 2 diabetes. Efficacy analyses were done according to intention to treat and event rates. IMPROVE-IT is registered with ClinicalTrials.gov, number NCT00202878.1005 patients (6%) had peripheral artery disease and 1071 (6%) had stroke or transient ischaemic attack at baseline. Of these, 388 (39%) and 409 (38%) also had concomitant type 2 diabetes, respectively. At 7 years, patients with either polyvascular disease or type 2 diabetes had similar rates of the primary endpoint (39·8% and 39·9%, respectively), which were higher than patients without polyvascular disease or diabetes (29·6%). Polyvascular disease with concomitant type 2 diabetes was associated with further heightened risk (60·0% 7-year Kaplan-Meier rate, adjusted hazard ratio versus those with polyvascular disease 1·60, 95% CI 1·38-1·85; p0·0001). Ezetimibe reduced cardiovascular risk consistently across groups with greater numerical absolute risk reductions in the highest-risk subgroups.In patients with coronary artery disease, concomitant polyvascular disease or type 2 diabetes are associated with increased long-term cardiovascular risk. The combination of polyvascular disease and diabetes is additive, resulting in very high risk. The benefit of ezetimibe is consistent in patients with and without polyvascular disease and type 2 diabetes; however, by nature of their higher risk patients with one, or especially both, of these diseases might derive the greatest absolute benefits.Merck.

AIMS Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven angiotensin-converting enzyme (ACE) inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial. METHODS AND RESULTS PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, estimated glomerular filtration rate