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.

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.

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.

Implications of variability in definition and reporting of major bleeding in randomized trials of oral P2Y12 inhibitors for acute coronary syndromes.

AIMS: Various definitions of major bleeding have been used to evaluate safety in randomized controlled trials of antiplatelet therapy. We compared the definitions and rates of major bleeding in phase III randomized controlled trials of oral P2Y(12) inhibitors in the management of patients with acute coronary syndromes (ACS). METHODS AND RESULTS: Electronic searches identified six phase III randomized controlled oral P2Y(12) inhibitor trials published between 2001 and 2010 involving 119 020 patients with ACS. The trials compared clopidogrel standard-dose (300-mg loading dose, 75-mg daily thereafter) vs. placebo (CURE, CLARITY-TIMI 28, COMMIT), clopidogrel standard-dose vs. prasugrel (TRITON-TIMI 38) or ticagrelor (PLATO) and clopidogrel standard-dose vs. clopidogrel double-dose (600-mg loading dose, 150-mg daily for 6-days, 75-mg daily thereafter) (CURRENT-OASIS 7). Using the trial definition, major bleeding rates in patients treated with standard-dose clopidogrel ranged from 0.6% in COMMIT to 11.2% in PLATO. The contrast in bleeding rates of standard-dose clopidogrel among the trials was attenuated when using the thrombolysis in myocardial infarction (TIMI) definition for major bleeding (range 1.1-7.7%) and bleeding rates in all the trials were less than 2% when comparing 30 day rates of non-coronary artery bypass graft surgery-related TIMI major bleeding (range 0.3-1.9%). CONCLUSION: Differences in major bleeding rates between trials of P2Y(12) inhibitors in patients with ACS are minimized after standardization of bleeding definitions, timing of reporting of bleeding outcomes, and procedure rates. Interpretation of the risk of bleeding associated with different P2Y(12) inhibitors would be facilitated by a consistent approach to the definition and reporting of bleeding.

Relationship between risk stratification at admission and treatment effects of early invasive management following fibrinolysis: insights from the Trial of Routine ANgioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI).

AIMS: We sought to determine the effectiveness of early routine percutaneous coronary intervention (PCI) post-fibrinolysis for ST-elevation myocardial infarction (STEMI) in relation to baseline risk status. METHODS AND RESULTS: In this post hoc subgroup analysis of Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI), we stratified 1059 STEMI patients receiving tenecteplase into low-intermediate [Global Registry of Acute Coronary Events (GRACE) risk score<155; n=889] vs. high-risk (GRACE risk score ≥155; n=170) groups, based on the GRACE risk score for in-hospital mortality. There was a significant interaction between treatment assignment and risk status for the composite endpoint of death/re-MI at 30 days (P for interaction<0.001). Compared with the standard treatment, pharmacoinvasive therapy (early routine PCI) was associated with a lower rate of death/re-MI at 30 days in the low-intermediate risk stratum (8.1 vs. 2.9%, P<0.001), but a higher rate of death/re-MI in the high-risk group (13.8 vs. 27.8%, P=0.025). We found similar heterogeneity in the treatment effects on 30-day mortality and death/re-MI at 1 year (P for interaction=0.008 and 0.001, respectively), when the GRACE risk score was analysed as a continuous variable (P for interaction<0.001) and when patients were stratified by the Thrombolysis In Myocardial Infarction (TIMI) risk score (P for interaction=0.001). CONCLUSION: We observed a strong heterogeneity in the treatment effects of a pharmacoinvasive strategy after fibrinolysis for STEMI, which is associated with improved outcomes only among patients with a low-intermediate GRACE risk score. Conversely, the early invasive strategy is associated with worse outcomes in high-risk patients. These novel findings should be considered exploratory only and require confirmation in other trials and meta-analyses. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov/ct2/show/NCT00164190 ClinicalTrials.gov number, NCT00164190.

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.

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.

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.

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.

Applying the evidence: do patients with stroke, coronary artery disease, or both achieve similar treatment goals?

BACKGROUND AND PURPOSE: The importance of early and aggressive initiation of secondary prevention strategies for patients with both coronary artery disease (CAD) and cerebrovascular disease (CVD) is emphasized by multiple guidelines. However, limited information is available on cardiovascular protection and stroke prevention in an outpatient setting from community-based populations. We sought to evaluate and compare differences in treatment patterns and the attainment of current guideline-recommended targets in unselected high-risk ambulatory patients with CAD, CVD, or both. METHODS: This multicenter, prospective, cohort study was conducted from December 2001 to December 2004 among ambulatory patients in a primary care setting. The prospective Vascular Protection and Guidelines-Oriented Approach to Lipid-Lowering Registries recruited 4933 outpatients with established CAD, CVD, or both. All patients had a complete fasting lipid profile measured within 6 months before enrollment. The primary outcome measure was the achievement of blood pressure (BP) <140/90 mm Hg (or <130/80 mm Hg for patients with diabetes) and LDL cholesterol <2.5 mmol/L (<97 mg/dL) according to the Canadian guidelines in place at that time (similar to the National Cholesterol Education Program's value of 100 mg/dL). Secondary outcomes include use of antithrombotic, antihypertensive, and lipid-modifying therapies. RESULTS: Of the 4933 patients, 3817 (77%) had CAD only; 647 (13%) had CVD only; and 469 (10%) had both CAD and CVD. Mean+/-SD age was 67+/-10 years, and 3466 (71%) were male. Mean systolic and diastolic BPs were 130+/-16 and 75+/-9 mm Hg, respectively. Minor but significant differences were observed on baseline BP, total cholesterol, and LDL cholesterol measurements among the 3 groups. Overall, 83% of patients were taking a statin and 93% were receiving antithrombotic therapy (antiplatelet and/or anticoagulant agents). Compared with patients with CAD, those with CVD only were less likely to achieve the recommended BP (45.3% vs 57.3%, respectively; P<0.001) and lipid (19.4% vs 30.5%, respectively; P<0.001) targets. Among patients with CVD only, women were less likely to achieve the recommended BP and lipid targets compared with their male counterparts (for LDL cholesterol <2.5 mmol/L, 18.7% vs 23.8%, respectively; P=0.048). In multivariable analysis, patients with CVD alone were less likely to achieve treatment success (BP or lipid targets) after adjusting for age, sex, diabetes, and use of pharmacologic therapy. CONCLUSIONS: Despite the proven benefits of available antihypertensive and lipid-lowering therapies, current management of hypertension and dyslipidemia continues to be suboptimal. A considerable proportion of patients failed to achieve guideline-recommended targets, and this apparent treatment gap was more pronounced among patients with CVD and women. Quality improvement strategies should target these patient subgroups.

Quantitative troponin elevation does not provide incremental prognostic value beyond comprehensive risk stratification in patients with non-ST-segment elevation acute coronary syndromes.

BACKGROUND: The aim of this study was to evaluate whether quantitative cardiac troponin (cTn) assessment can improve risk stratification in a spectrum of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) using the validated Global Registry of Acute Cardiac Events (GRACE) risk model. METHODS: The Canadian ACS Registry II is a prospective, multicenter study that enrolled patients admitted to hospital with a suspected NSTE ACS within 24 hours of symptom onset. Of the total 2297 patients, those with elevated cTn (n = 1013) were further stratified into tertiles of cTn ranges. Our primary end point was death and our secondary end point was a composite of death or/and recurrent myocardial infarction at 1-year follow-up. RESULTS: Multivariable analysis adjusting for validated predictors of death confirmed the independent prognostic value of any abnormal cTn (vs normal) for death (adjusted odds ratio 2.28, 95% CI 1.49-3.49, P < .001) and for the composite outcome (adjusted odds ratio 2.18, 95% CI 1.61-2.95, P < .001) at 1 year. With quantitative assessment, the gradient of mortality risk with increasing cTn level was not evident after adjusting for other prognosticators. Quantitative (compared to qualitative) assessment of cTn level did not improve either the GRACE risk model discrimination for 1-year death. CONCLUSIONS: Any cTn elevation is associated with higher rate of death at 1 year, but its quantitative assessment did not prove as important as its mere presence as an independent long-term prognosticator in a nonclinical trial, "real-world" NSTE ACS population.

Bleeding and outcome in acute coronary syndrome: insights from continuous electrocardiogram monitoring in the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) Trial.

BACKGROUND: Bleeding is associated with adverse outcome in acute coronary syndromes. However, the precise pathophysiologic mechanisms have not been elucidated. We sought to determine the relationship between bleeding and myocardial ischemia detected by concurrent continuous electrocardiogram (ECG) monitoring and their independent long-term prognostic significance. METHODS: The INTERACT trial was a randomized controlled trial of enoxaparin versus unfractionated heparin in patients with high-risk non-ST-elevation acute coronary syndromes. Continuous ECG monitoring, performed after enrollment up to 96 hours, was analyzed by an automated algorithm and reviewed by a blinded cardiologist. We centrally adjudicated all bleeding and clinical events in a blinded fashion and calculated the Global Registry of Acute Coronary Events risk score (a validated predictor of mortality) for each patient. RESULTS: Of the 746 patients enrolled, 34 (4.6%) developed major bleeding within 96 hours. After a median follow-up of 2.4 years, patients with bleeding had a higher risk of death (28.4% vs 7.3%, P < .001) and death/myocardial infarction (38.0% vs 12.9%, P < .001) compared with those without bleeding. Overall, 619 patients survived the first 96 hours with complete data on continuous ECG monitoring. Bleeding was associated with the simultaneous presence of ST-segment shifts on continuous ECG monitoring (P = .03). After adjusting for Global Registry of Acute Coronary Events risk score and myocardial ischemia detected by continuous ECG monitoring, major bleeding remained an independent predictor of death (adjusted hazard ratio = 3.48, 95% confidence interval 1.51-8.03, P = .003) and death/myocardial infarction (adjusted hazard ratio = 2.85, 95% confidence interval 1.40-5.78, P = .004). CONCLUSIONS: Bleeding is a powerful independent predictor of poor long-term outcome, even after adjusting for other associated prognostic factors such as advanced age and renal dysfunction. Although bleeding is associated with concurrent myocardial ischemia, its adverse prognostic impact may be mediated by complex pathophysiologic mechanisms rather than myocardial ischemia alone. Our findings suggest that future investigations should focus on other biologically plausible mechanisms.

Impact of delayed presentation on management and outcome of non-ST-elevation acute coronary syndromes.

BACKGROUND: The impact of delayed presentation on the management and outcomes of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) has not been well studied. Furthermore, the prognostic value of initial biomarker level in relation to the time of presentation has not been determined. METHODS: The Canadian ACS II registry was a national, multicenter, prospective observational study of 1,956 patients with NSTE-ACS (October 2002-December 2003). We compared the baseline characteristics, treatment, and outcomes in early (within 6 hours of symptom onset) versus late presenters (>6 hours). A logistic regression model was developed to examine the independent association of late presentation with 1-year mortality. We also evaluated the prognostic value of initial biomarker level in relation to early versus late presentation. RESULTS: A total of 1,219 (62.3%) patients presented early, whereas 727 (37.7%) presented late; their rates of in-hospital revascularization were similar (40.5% vs 42.5%, respectively, P = .39). There was also no significant difference in hospital mortality (1.6% vs 2.2%, P = .30) or 1-year mortality (7.6% vs 5.7%, P = .13) between early and late presenters. After adjusting for other prognosticators, late presentation was not an independent predictor of 1-year mortality (adjusted odds ratio 0.78, 95% confidence interval 0.48-1.26, P = .3). Elevated initial biomarker was independently associated with higher 1-year mortality (adjusted odds ratio 2.17, 95% CI 1.31-3.58, P = .002) regardless of whether hospital presentation was early or late (P for interaction = .74). CONCLUSIONS: There is still considerable delay between symptom onset of NSTE-ACS and hospital presentation in the contemporary era. In contrast to studies of ST-elevation myocardial infarction, we found no significant differences in the management and outcome of early presenters as compared with late presenters with NSTE-ACS. Nevertheless, measures to reduce patient delay time should continue to be implemented. Initial biomarker status is a useful prognosticator irrespective of the delay time.

Management patterns in relation to risk stratification among patients with non-ST elevation acute coronary syndromes.

BACKGROUND: Randomized clinical trials have established the efficacy of an early invasive management strategy for high-risk non-ST elevation acute coronary syndromes (ACSs). We examined the use of in-hospital cardiac catheterization and medications in relation to risk across the broad spectrum of non-ST elevation ACSs. METHODS: We evaluated 4414 patients with non-ST elevation ACSs in the prospective, multicenter, Canadian ACS 1 (September 1, 1999-June 30, 2001) and ACS 2 (October 1, 2002-December 31, 2003) Registries. Patients were stratified into low-, intermediate-, and high-risk groups based on tertiles of the calculated Global Registry of Acute Coronary Events risk score (a validated predictor of in-hospital mortality). RESULTS: Although in-hospital mortality rates were similar, the in-hospital use of cardiac catheterization increased significantly over time (38.8% in the ACS 1 Registry vs 63.5% in the ACS 2 Registry; P<.001). The rates of cardiac catheterization in the low-, intermediate-, and high-risk groups were 48.0%, 41.1%, and 27.3% in the ACS 1 Registry, and 73.8%, 66.9%, and 49.7% in the ACS 2 Registry, respectively (P<.001 for trend for both). After adjusting for other confounders, intermediate-risk (adjusted odds ratio, 0.75; 95% confidence interval, 0.63-0.90; P<.001) and high-risk (adjusted odds ratio, 0.35; 95% confidence interval, 0.28-0.45; P<.001) patients remained less likely to undergo cardiac catheterization compared with low-risk patients. Furthermore, there existed a similar inverse relationship between risk and the use of in-hospital revascularization and medications. CONCLUSIONS: Despite temporal increases in the use of cardiac catheterization and revascularization in the management of non-ST elevation ACSs, evidence-based invasive and pharmacological therapies remain paradoxically targeted toward low-risk patients. Strategies to eliminate this treatment-risk paradox must be implemented to fully realize the benefits and optimize the cost-effectiveness of invasive management.

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.

Long-term prognostic value and therapeutic implications of continuous ST-segment monitoring in acute coronary syndrome.

BACKGROUND: In patients with acute coronary syndromes (ACS), recurrent ischemia detected by continuous electrocardiographic monitoring portends a poor outcome. We sought to investigate (1) the additional long-term prognostic value of ST-segment monitoring beyond the validated Global Registry of Acute Coronary Events (GRACE) risk score in ACS and (2) whether ST-segment monitoring can identify patients who benefit from early revascularization. METHODS: We determined the GRACE risk score (a validated predictor of inhospital mortality) in 681 non-ST-elevation ACS patients enrolled in the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment trial. Continuous ST-segment monitoring in the first 48 hours was analyzed by an automated algorithm and reviewed by a blinded cardiologist. Clinical outcomes were centrally adjudicated in a blinded fashion. RESULTS: ST-segment shifts were present in 19.1% of 681 patients. After a median follow-up of 30 months, patients with ST-segment shifts had a higher risk of death (17.7% vs 5.8%, log-rank P < .001) and death or myocardial infarction (MI) (24.6% vs 11.1%, log-rank P < .001). In multivariable analysis adjusting for GRACE risk score, the presence of ST-segment shifts remained an independent predictor of death (adjusted hazard ratio = 2.37, 95% CI 1.38-4.09, P = .002) and death/MI (adjusted hazard ratio = 1.93, 95% CI 1.25-3.00, P = .003). Inhospital revascularization was independently associated with a lower risk of death/MI among patients with ST-segment shifts but not among those without (P for interaction = .02). CONCLUSIONS: Continuous ST-segment monitoring provides incremental prognostic information beyond the validated GRACE risk score determined on presentation and identifies high-risk patients who benefit from early revascularization. This simple and valuable clinical tool may be useful in the routine management of ACS.

Optimal medical therapy at discharge in patients with acute coronary syndromes: temporal changes, characteristics, and 1-year outcome.

BACKGROUND: There are limited data on the recent trend in the use of optimal evidence-based medical therapies after acute coronary syndromes (ACSs). We sought to evaluate (1) the temporal changes in medical management of patients discharged after an ACS; (2) patient and practice characteristics associated with optimal medical therapy at discharge; and (3) the association between discharge medication use and 1-year outcome. METHODS: The Canadian ACS I (September 1999-June 2001) and ACS II (October 2002-December 2003) Registries were prospective, multicenter, observational studies of 6853 patients admitted for ACS. We examined the discharge use of medications among 5833 hospital survivors who did not have any contraindications to antiplatelet/anticoagulant, beta-blocker, angiotensin-converting enzyme inhibitor, or lipid-modifying therapies. Optimal medical therapy was defined as the use of all indicated medications. Follow-up data at 1 year were collected by telephone interview. We performed hierarchical logistic regression to identify patient characteristics and care patterns associated with optimal medical treatment and to examine its relationship with 1-year mortality. RESULTS: There were significant increases in the discharge use of all 4 classes of medications over time; 28.9% and 51.8% of patients in ACS I and ACS II Registries, respectively, were prescribed optimal medical therapy (P < .001). Advanced age, female sex, prior heart failure, renal dysfunction, and coronary bypass surgery during hospitalization were negative independent predictors of optimal medical therapy. Conversely, enrollment in ACS II Registry, history of dyslipidemia, presence of ST elevation and abnormal cardiac biomarker, previous myocardial infarction, and previous coronary revascularization were independently associated with the use of combination therapy. After adjusting for other validated prognosticators, patients receiving optimal medical therapy had significantly lower 1-year mortality (adjusted odds ratio 0.54, 95% confidence interval 0.36-0.81, P = .003) compared with those given 0 or 1 drug at discharge. Over the 1-year follow-up period, substantial numbers of patients discontinued therapies, whereas others were initiated on treatment. CONCLUSIONS: Despite the temporal increases in the combined use of evidence-based pharmacologic therapies, which is associated with improved outcome, medical management of ACS remains suboptimal. Quality improvement strategies are needed to enhance the appropriate use of effective therapies, targeting specifically the high-risk but undertreated patients who may derive the greatest therapeutic benefit.

Missed opportunities for the secondary prevention of cardiovascular disease in Canada.

BACKGROUND: Strong evidence supports the use of antithrombotic agents (antiplatelets or oral anticoagulants), statins and angiotensin-converting enzyme inhibitors in patients with atherosclerotic cardiovascular disease; beta-blockers are additionally indicated in patients with coronary artery disease. OBJECTIVES: The investigators sought to determine the extent to which guideline-recommended treatments and target goals are adopted in ambulatory patients with cardiovascular disease in Canada. METHODS: Two large, prospective, community-based registries (the Vascular Protection Registry and the Guideline Oriented Approach to Lipid Lowering Registry) enrolled 9809 outpatients with coronary artery disease, cerebrovascular disease, peripheral vascular disease or multiple cardiovascular risk factors from primary care settings in nine provinces across Canada between 2001 and 2004. This analysis focused primarily on patients with cardiovascular disease (n=6296). RESULTS: At baseline, antithrombotics, statins and angiotensin-converting enzyme inhibitors were used in 92%, 80% and 57% of patients, respectively; beta-blockers were used in 59% of patients with coronary artery disease. The dosing of most drug therapies was suboptimal compared with guideline-recommended dosing derived from clinical trials. Treatment goals for cardiovascular risk factors were suboptimally attained: low-density lipoprotein cholesterol in 50% of patients, total to high-density lipoprotein cholesterol ratio in 51% of patients, systolic and diastolic blood pressure in 58% and 78% of patients, respectively, and waist circumference and body mass index in 45% and 19%, respectively. CONCLUSIONS: These data suggest specific opportunities for improving the care of patients with cardiovascular disease in Canada. The focus must now shift from awareness of treatment gaps to implementation of effective solutions.