Empagliflozin in patients with type 2 diabetes mellitus and chronic obstructive pulmonary disease.

AIMS: Type 2 diabetes mellitus (T2DM) and chronic obstructive pulmonary disease (COPD) often co-exist, yielding increased risk of cardiovascular (CV) complications including heart failure (HF). We assessed risk of cardiorenal outcomes, mortality and safety in patients with versus without COPD in the EMPA-REG OUTCOME trial. METHODS: Patients (n = 7,020) with T2DM and CV disease (CVD) were treated with empagliflozin (10 mg or 25 mg) or placebo. Cox regression was used to assess COPD subgroup (placebo only) associations with, and treatment effects of empagliflozin versus placebo on first hospitalization for HF (HHF), CV death, all-cause mortality, incident/worsening nephropathy, and all-cause hospitalization. RESULTS: At baseline, patients with COPD (n = 707) had more HF and used insulin more frequently than those without COPD. During follow-up in the placebo group, those with baseline COPD had increased risk of HHF (HR 2.15 [95% CI 1.32, 3.49]), HHF/CV death (1.60 [1.10, 2.33]), incident/worsening nephropathy (1.68 [1.26, 2.24]), all-cause hospitalization (1.44 [1.19, 1.74]) and all-cause death (1.60 [1.09, 2.35]) compared to those without COPD. Empagliflozin consistently reduced all clinical outcomes, irrespective of COPD status (interaction p-values 0.14 to 0.96), with a confirmed safety profile. CONCLUSIONS: In patients with T2DM and CVD, COPD increased the risk of mortality and cardiorenal outcomes, including HF. Empagliflozin consistently reduced these outcomes versus placebo regardless of COPD, suggesting that empagliflozin's benefits in patients with T2DM and CVD are not mitigated by the presence of COPD.

Effects of empagliflozin on insulin initiation or intensification in patients with type 2 diabetes and cardiovascular disease: Findings from the EMPA-REG OUTCOME trial.

AIM: To evaluate the effects of empagliflozin versus placebo on subsequent insulin initiation or dosing changes in a large cardiovascular outcomes trial. MATERIALS AND METHODS: In EMPA-REG OUTCOME, 7020 patients with type 2 diabetes and cardiovascular disease received empagliflozin 10 mg, 25 mg, or placebo. Median follow-up was 3.1 years. After 12 weeks of treatment, changes in background antihyperglycaemic therapy were permitted. Among insulin-naïve patients, we assessed the effects of pooled empagliflozin arms versus placebo on time to initiation of insulin. Among insulin-treated patients, we assessed effects on time to an increase or decrease in insulin dose of more than 20%. RESULTS: In 3633 (52%) participants not treated with insulin at baseline, empagliflozin reduced new use of insulin versus placebo by 60% (7.1% vs. 16.4%; adjusted HR 0.40 [95% CI 0.32-0.49]; P < .0001). In 3387 (48%) patients using insulin at baseline, empagliflozin reduced the need for a greater than 20% insulin dose increase by 58% (14.4% vs. 29.3%; adjusted HR 0.42 [95% CI 0.36-0.49]; P < .0001) and increased the proportion achieving sustained greater than 20% insulin dose reductions without subsequent increases in HbA1c compared with placebo (9.2% vs. 4.9%; adjusted HR 1.87 [95% CI: 1.39-2.51]; P < .0001). Sensitivity analyses confirmed consistent findings when insulin dose changes of more than 10% or more than 30% were considered. CONCLUSIONS: In patients with type 2 diabetes and cardiovascular disease, empagliflozin markedly and durably delays insulin initiation and substantial increases in insulin dose, while facilitating sustained reductions in insulin requirements over time.

Cardio/Kidney Composite End Points: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial.

Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time-to-first-event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49-0.64]; WR, 1.76 [95% CI, 1.53-2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%-20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time-to-first-event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01131676.

Update to Evidence-Based Secondary Prevention Strategies After Acute Coronary Syndrome.

A recent acute coronary syndrome provides an opportunity to optimise secondary prevention strategies to reduce the risk of future cardiovascular events. This review provides an updated synopsis of current evidence-based approaches. New clinical trial data on the use of antiplatelet and anticoagulants allow choices of the selection and duration of treatment. Lipid lowering after an acute coronary syndrome is now enhanced, with proprotein convertase subtilisin-kexin type 9 inhibitors providing added benefit on top of statin and ezetimibe treatment in high-risk patients. In addition, a recent trial of icosapent ethyl, a highly purified ethyl ester of eicosapentaenoic acid, addresses residual risk in patients with elevated triglycerides already treated with statins. The use of both sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes reduces cardiovascular events independently of glucose lowering.

La survenue récente d'un syndrome coronarien aigu offre l'occasion d'optimiser les stratégies de prévention secondaire en vue de réduire le risque d'événements cardiovasculaires futurs. Le présent article de synthèse offre une vue d'ensemble actualisée des approches contemporaines fondées sur des données probantes. Les nouvelles données d'essais cliniques sur l'utilisation d'antiplaquettaires et d'anticoagulants permettent de choisir un traitement et sa durée. La réduction des lipides après la survenue d'un syndrome coronarien aigu se trouve maintenant améliorée, les bienfaits des inhibiteurs de la proprotéine convertase subtilisine/kexine de type 9 s'ajoutant à ceux du traitement par des statines et l'ézétimibe chez les patients à haut risque. En outre, un essai récent portant sur l'icosapent éthyl, un ester éthylique hautement purifié de l'acide eicosapentaénoïque, aborde le risque résiduel chez les patients présentant une hypertriglycéridémie déjà traités par des statines. L'utilisation d'inhibiteurs du cotransporteur sodium-glucose de type 2 et d'agonistes des récepteurs du peptide-1 apparenté au glucagon chez les patients atteints de diabète de type 2 limite les événements cardiovasculaires indépendamment de la diminution de la glycémie.

Cardiovascular Benefit of Empagliflozin Across the Spectrum of Cardiovascular Risk Factor Control in the EMPA-REG OUTCOME Trial.

CONTEXT: Control of multiple cardiovascular (CV) risk factors reduces CV events in individuals with type 2 diabetes. OBJECTIVE: To investigate this association in a contemporary clinical trial population, including how CV risk factor control affects the CV benefits of empagliflozin, a sodium-glucose cotransporter-2 inhibitor. DESIGN: Post hoc analysis. SETTING: Randomized CV outcome trial (EMPA-REG OUTCOME). PARTICIPANTS: Type 2 diabetes patients with established CV disease. INTERVENTION: Empagliflozin or placebo. MAIN OUTCOME MEASURES: Risk of CV outcomes-including the treatment effect of empagliflozin-by achieving 7 goals for CV risk factor control at baseline: (1) glycated hemoglobin <7.5%, (2) low-density lipoprotein cholesterol <100 mg/dL or statin use, (3) systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg, (4) pharmacological renin-angiotensin-aldosterone system blockade, (5) normoalbuminuria, (6) aspirin use, (7) nonsmoking. RESULTS: In the placebo group, the hazard ratio (HR) for CV death was 4.00 (95% CI, 2.26-7.11) and 2.48 (95% CI, 1.52-4.06) for patients achieving only 0-3 or 4-5 risk factor goals at baseline, respectively, compared with those achieving 6-7 goals. Participants achieving 0-3 or 4-5 goals also had increased risk for the composite outcome of hospitalization for heart failure or CV death (excluding fatal stroke) (HR 2.89 [1.82-4.57] and 1.90 [1.31-2.78], respectively) and 3-point major adverse CV events (HR 2.21 [1.53-3.19] and 1.42 [1.06-1.89]). Empagliflozin significantly reduced these outcomes across all risk factor control categories (P > 0.05 for treatment-by-subgroup interactions). CONCLUSIONS: Cardiovascular risk in EMPA-REG OUTCOME was inversely associated with baseline CV risk factor control. Empagliflozin's cardioprotective effect was consistent regardless of multiple baseline risk factor control.

Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial.

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease. METHODS: Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m2. The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide). RESULTS: Among the 97 participants (90 men [93%], mean [standard deviation] age 62.8 [9.0] years, type 2 diabetes mellitus duration 11.0 [8.2] years, estimated glomerular filtration rate 88.4 [16.9] mL/min/1.73m2, LV mass indexed to body surface area 60.7 [11.9] g/m2), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m2 and 0.01 g/m2 for those assigned empagliflozin and placebo, respectively (adjusted difference -3.35 g/m2; 95% CI, -5.9 to -0.81g/m2, P=0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference -6.8mmHg, 95% CI -11.2 to -2.3mmHg, P=0.003), diastolic blood pressure (adjusted difference -3.2mmHg; 95% CI, -5.8 to -0.6mmHg, P=0.02) and elevation of hematocrit (P=0.0003). CONCLUSIONS: Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02998970.

Empagliflozin and Cardio-renal Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease - Implications for Clinical Practice.

In patients with type 2 diabetes (T2D), the excretion of glucose by the kidney with sodium-glucose cotransporter 2 (SGLT2) inhibitors lowers glycosylated haemoglobin (HbA1c) levels, decreases body weight and visceral adiposity, as well as improving cardio-renal haemodynamics. Currently, four SGLT2 inhibitors are approved in the US and Europe to improve glycaemic control - empagliflozin, dapagliflozin, canagliflozin, and ertuglifozin. Recently, the SGLT2 inhibitor empagliflozin was approved by the FDA for the reduction of cardiovascular (CV) death in adults with T2D and CV disease (CVD). This approval was based on the findings of the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) study, which was the first study to show a significant reduction of a primary CV endpoint with a glucose-lowering agent. In this study, the primary outcome (CV mortality, non-fatal myocardial infarction [MI] and non-fatal stroke) was reduced by empagliflozin (10.5%; 490/4,687) compared with placebo (12.1%; 282/2,333); hazard ratio (HR), 0.86 (95% confidence interval [CI]: 0.74, 0.99). The primary outcome was driven by a large reduction of CV mortality (relative risk reduction [RRR], 38%). Empagliflozin also reduced all-cause mortality (RRR, 32%). Furthermore, empagliflozin reduced the adjudicated outcome of heart failure (HF) hospitalisation by 35% (HR, 0.65; 95% CI: 0.50, 0.85). Other non-adjudicated measures of HF outcomes were similarly reduced including investigator reported HF, the introduction of loop diuretics and death from HF. In the analysis of renal outcomes, incident or worsening nephropathy was reduced for empagliflozin (12.7%) compared with placebo (18.8%); HR, 0.61 (95% CI: 0.53, 0.70). Empagliflozin significantly reduced the risk of progression to macroalbuminuria (38%) and doubling of creatinine (44%), as well as the need of starting renal-replacement therapy (55%). The benefits of empagliflozin for the reduction of CV death, all-cause death and hospitalisation for HF were observed across a range of baseline subgroups such as HbA1c level and renal function (down to estimated glomerular filtration rate [eGFR] 30 ml/min/1.73 m2). The rapid reduction of HF outcomes with empagliflozin is observed across the spectrum of CVD and HF risk and represents a therapeutic advance in the prevention and perhaps also in the treatment of HF, an often poorly recognised complication of T2D. This review discusses the EMPA-REG OUTCOME study and the implications for treating patients with T2D and CVD.

Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes.

Diabetes is a major risk factor for heart failure (HF). Patients with diabetes have a high incidence of both clinical HF and subclinical LV dysfunction. Although intensive glucose lowering does not appear to impact on HF outcomes, the choice of glucose-lowering agents plays an important role in the development of HF and related cardiovascular outcomes. Whilst metformin and insulin appear to have little impact on HF progression, the role of sulphonylurea agents in this patient population remains uncertain. Thiazolidinediones (TZDs) are associated with a significant risk of HF progression and are best avoided in patients at risk. The incretin-based therapies (GLP agonists and DPP-4 inhibitors) are generally not associated with any HF interaction. However, a small increase in HF admissions was observed with the DPP-4 inhibitor saxagliptin. The GLP-1 agonist liraglutide was recently shown to reduce cardiovascular and all-cause mortality, yet hospitalization for HF was not significantly reduced. The SGLT2 inhibitor empagliflozin was shown to reduce HF admissions and cardiovascular mortality in patients with prior cardiovascular disease including HF. These recent data showing improved outcomes with a glucose-lowering category provide a novel strategy to improve survival and reduce morbidity in diabetic patients at high cardiovascular disease risk.

Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate <60 mL·min(-1)·1.73 m(-2)). In contrast, blood pressure lowering, estimated glomerular filtration rate, and albuminuric effects are preserved, and perhaps exaggerated in chronic kidney disease. With regard to long-term clinical outcomes, the EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) in patients with type 2 diabetes mellitus and established cardiovascular disease randomly assigned to empagliflozin versus placebo reported a 14% reduction in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and >30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.

Secondary Prevention Beyond Hospital Discharge for Acute Coronary Syndrome: Evidence-Based Recommendations.

In the past 3 decades, a better understanding of the pathophysiology of cardiovascular disease has resulted in innovations in the treatment and prevention of its clinical manifestations such as death, myocardial infarction, or stroke. After an acute coronary syndrome there are short- and long-term risks of subsequent cardiovascular events. This leads to opportunities to initiate strategies to reduce complications resulting from myocardial injury (cardiac protection) and to prevent recurrent acute coronary events (vascular protection). The results from clinical trials inform best practice and guidelines for patient management. Despite clear and consistent guidelines, an important number of patients are not receiving these treatments. Moreover, many others do not receive treatment that follows the strategy proven in the clinical trial and this is associated with a significant loss of opportunities to improve outcomes. The Canadian Heart Research Centre has therefore assembled a panel of experts to provide a review of available data and distill it to specific evidence-based recommendations that can be used by specialists and primary care physicians as a platform for secondary prevention. The therapeutic recommendations are conveniently divided into vascular protection (dual antiplatelet therapy, lipid-lowering, and renin angiotensin system inhibition) which should be considered in all patients; cardiac protection (addition of ß-blocker therapy) in patients with left ventricular dysfunction including consideration for management of heart failure; and continuing management of risk factors and comorbid conditions on the basis of the specific patient profile. These recommendations are intended as a decision support tool and a quick reference for Canadian physicians.

Risk stratification and selection for statin therapy: going beyond Framingham.

Decisions for statin therapy in the primary prevention of atherosclerotic cardiovascular disease are generally made using the 10-year Framingham Risk Score (FRS). Even when a family history of premature cardiovascular disease is taken into account, there is often ambiguity about the need for statin therapy for patients with a 10-year FRS of 5%-19% and low-density lipoprotein cholesterol <3.5 mmol/L. Current Canadian dyslipidemia guidelines recommend consideration of a diversity of other factors, including biochemical measurements and imaging studies to help determine whether the calculated FRS might be misleadingly low and whether statin therapy might, therefore, be prudent. However, efficient use of the plethora of secondary factors makes this decision process itself potentially ambiguous. This brief summary provides a practical approach for using clinical information, basic biochemical tests, and more specialized tests, such as carotid ultrasound and coronary artery calcium scoring, to identify groups of patients at greater risk for atherosclerotic cardiovascular disease than suggested by the FRS.

Identification and management of patients at elevated cardiometabolic risk in canadian primary care: how well are we doing?

BACKGROUND: We evaluated the risk assessment and management patterns employed by primary care physicians in patients at elevated cardiometabolic risk. METHODS: Between April 2011 and March 2012, multiple physicians from 9 Primary Care Teams (PCTs) and 88 physicians from traditional nonteam (Solo) practices completed a practice assessment on the management of 2461 patients > 40 years old with no clinical evidence of cardiovascular disease and diagnosed with at least 1 of the following: dyslipidemia, type 2 diabetes mellitus (T2DM), or hypertension. RESULTS: Individuals with dyslipidemia, T2DM, or hypertension tended to have a body mass index ≥ 25 kg/m(2). Waist circumference measurements, obtained for only 392/829 (47.0%) Solo patients, revealed that 88.9% of these individuals were abdominally obese and that at least 52.2% of Solo patients had metabolic syndrome. Cardiovascular risk, determined by the physicians for 83.5% of all patients without T2DM and typically performed using traditional risk engines, was often miscalculated (43.2% PCTs, 58.8% Solo; P = 0.0007). Healthy behavioural modifications were infrequently recommended (< 50%). Pharmacotherapy was widely used (> 70%) but treatment targets were infrequently met. The composite outcome of guideline-recommended low-density lipoprotein cholesterol, glycemic, and blood pressure targets was met by 9.0% and 8.1% of patients managed by PCT and Solo physicians respectively. CONCLUSIONS: Obesity and cardiovascular risk were underassessed and the latter often underestimated. Patients were infrequently counselled on the benefits of healthy behavioural changes. A paradigm change in assessing and managing obesity and cardiovascular risk via aggressive lifestyle interventions is warranted in individuals at elevated cardiometabolic risk.

Comparison of coronary artery bypass surgery and percutaneous coronary intervention in patients with diabetes: a meta-analysis of randomised controlled trials.

BACKGROUND: The choice between coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI) for revascularisation in patients with diabetes and multivessel coronary artery disease, who account for 25% of revascularisation procedures, is much debated. We aimed to assess whether all-cause mortality differed between patients with diabetes who had CABG or PCI by doing a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing CABG with PCI in the modern stent era. METHODS: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from Jan 1, 1980, to March 12, 2013, for studies reported in English. Eligible studies were those in which investigators enrolled adult patients with diabetes and multivessel coronary artery disease, randomised them to CABG (with arterial conduits in at least 80% of participants) or PCI (with stents in at least 80% of participants), and reported outcomes separately in patients with diabetes, with a minimum of 12 months of follow-up. We used random-effects models to calculate risk ratios (RR) and 95% CIs for pooled data. We assessed heterogeneity using I(2). The primary outcome was all-cause mortality in patients with diabetes who had CABG compared with those who had PCI at 5-year (or longest) follow-up. FINDINGS: The initial search strategy identified 3414 citations, of which eight trials were eligible. These eight trials included 7468 participants, of whom 3612 had diabetes. Four of the RCTs used bare metal stents (BMS; ERACI II, ARTS, SoS, MASS II) and four used drug-eluting stents (DES; FREEDOM, SYNTAX, VA CARDS, CARDia). At mean or median 5-year (or longest) follow-up, individuals with diabetes allocated to CABG had lower all-cause mortality than did those allocated to PCI (RR 0.67, 95% CI 0.52-0.86; p=0.002; I(2)=25%; 3131 patients, eight trials). Treatment effects in individuals without diabetes showed no mortality benefit (1.03, 0.77-1.37; p=0.78; I(2)=46%; 3790 patients, five trials; p interaction=0.03). We identified no differences in outcome whether PCI was done with BMS or DES. When present, we identified no clear causes of heterogeneity. INTERPRETATION: In the modern era of stenting and optimum medical therapy, revascularisation of patients with diabetes and multivessel disease by CABG decreases long-term mortality by about a third compared with PCI using either BMS or DES. CABG should be strongly considered for these patients.

Potential role of rivaroxaban in patients with acute coronary syndrome.

Patients with acute coronary syndrome (ACS) continue to be at risk for recurrent ischemic events, despite an early invasive strategy and the use of dual antiplatelet therapy. The anticoagulant pathway remains activated for a prolonged period after ACS and, consequently, has been a target for treatment. Early studies with warfarin indicated its benefit, but the risk of bleeding and the complexities of warfarin anticoagulation resulted in little use of this strategy. Rivaroxaban, apixaban, and dabigatran are new specific inhibitors of anticoagulant factors (Xa or IIa) currently available for the prevention of thrombosis and/or thromboembolism. Thus far, studies with dabigatran and apixaban in ACS have shown no clinical benefit and bleeding has been increased. The ATLAS ACS 2-TIMI 51 trial observed the impact of rivaroxaban 2.5 mg and 5 mg twice daily in patients with recent ACS receiving current management (both early invasive strategy and dual antiplatelet therapy with aspirin and clopidogrel) over a follow-up period of over 1 year. Rivaroxaban 2.5 mg twice daily reduced cardiovascular death, myocardial infarction, or stroke by 16%, and both cardiovascular and all-cause mortality by approximately 20%. Although major bleeding increased from 0.6% to 2.1% and intracranial hemorrhage from 0.2% to 0.6%, there was no increase in fatal bleeding. The role of rivaroxaban in the management of ACS is discussed in this review. The reduction in mortality is the main finding that could lead to the use of rivaroxaban in the management of ACS in high-risk individuals with a low bleeding risk.