Long-Term Cardiovascular Risk in Women Prescribed Fertility Therapy

ObjectivesThe purpose of the study was to investigate whether fertility therapy might contribute to subsequent cardiovascular disease.BackgroundFertility medications are used for 1% of births yet may also lead to endothelial injury with long-term adverse consequences for the mother.MethodsA population-based cohort analysis was performed of women who gave birth in Ontario, Canada, between July 1, 1993, and March 31, 2010, distinguishing those who did and did not receive fertility therapy in the 2 years before delivery. Cox proportional models were derived to estimate hazard ratios with and without adjustment for baseline characteristics. The primary outcome was a composite cardiovascular endpoint of death, nonfatal coronary ischemia, stroke, transient ischemic attack, thromboembolism, or heart failure.ResultsAmong 1,186,753 women who delivered during the study period, 6,979 gave birth after fertility therapy. After 9.7 years of median follow-up, women who delivered after fertility therapy had fewer cardiovascular events than controls (103 vs. 117 events per 100,000 person-years), equivalent to an unadjusted hazard ratio of 0.96 (95% confidence interval: 0.72 to 1.29, p = 0.79) and an adjusted hazard ratio of 0.55 (95% confidence interval: 0.41 to 0.74, p < 0.0001). An apparent relative lower risk was observed across all age and income groups. Women who received fertility therapy also had lower risk-adjusted all-cause mortality, thromboembolic events, subsequent depression, alcoholism, and self-harm (p < 0.01 for each).ConclusionsSuccessful fertility therapy was not associated with an increased risk of cardiovascular disease later in life

Prasugrel Versus Clopidogrel in Patients With ST-Segment Elevation Myocardial Infarction According to Timing of Percutaneous Coronary Intervention A TRITON–TIMI 38 Subgroup Analysis (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38)

ObjectivesThis study sought to evaluate the efficacy of prasugrel versus clopidogrel in ST-segment elevation myocardial infarction (STEMI) by the timing of percutaneous coronary intervention (PCI).BackgroundTreatment strategies and outcomes for patients with STEMI may differ when treated with primary compared with secondary PCI.MethodsSTEMI patients in the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) were randomized to prasugrel or clopidogrel on presentation if primary PCI was intended or later during secondary PCI. Primary PCI was defined as within 12 h of symptom onset. The primary endpoint was cardiovascular death, myocardial infarction (MI), or stroke. Because periprocedural MI is difficult to assess in the setting of STEMI, we performed analyses excluding these events.ResultsReductions in the primary endpoint with prasugrel versus clopidogrel (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.65 to 0.97; p = 0.022) were consistent between primary and secondary PCI patients at 15 months (HR: 0.89; 95% CI: 0.69 to 1.13 vs. HR: 0.65; 95% CI: 0.46 to 0.93; p interaction = 0.15). However, a tendency toward a difference in treatment effect at 30 days (HR: 0.68; 95% CI: 0.54 to 0.87; p = 0.002) was observed between primary and secondary PCI patients (HR: 0.81; 95% CI: 0.60 to 1.09 vs. HR: 0.51; 95% CI: 0.34 to 0.76; p interaction = 0.06). When periprocedural MI was excluded, the efficacy of prasugrel remained consistent among primary and secondary PCI patients at 30 days (HR: 0.53; 95% CI: 0.34 to 0.81 vs. HR: 0.44; 95% CI: 0.22 to 0.88; p interaction = 0.68) and 15 months (HR: 0.76; 95% CI: 0.56 to 1.03 vs. HR: 0.75; 95% CI: 0.46 to 1.21; p interaction = 0.96).ConclusionsThe efficacy of prasugrel versus clopidogrel was consistent irrespective of the timing of PCI, particularly in preventing nonprocedural events. (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38; NCT00097591

Use of the CANHEART ‘big data’ registry to conduct a large randomized registry clinical trial to improve lipid management in Ontario, Canada

Introduction Creation of registries using linked population-based databases could potentially be used to conduct large registry-based clinical trials. As part of the CANHEART-Strategy for Patient-Oriented Research (SPOR) innovative clinical trials initiative, we explored the practicality of using the linked CANHEART registry to conduct a cluster-randomized trial aimed at improving lipid management. Objectives and Approach The CANHEART registry (www.canheart.ca) was created through the linkage of 19 population-based health databases in Ontario, Canada, providing individual-level socio-demographic, geographic, hospitalization, disease testing/screening, mortality, prescription medication, and behavior/lifestyle information. Using CANHEART defined eligibility criterion, small and medium-sized, high cardiovascular-risk health regions (defined as having acute myocardial infarction, stroke or cardiovascular death rates greater than the Ontario average) are being randomly allocated to receive either the intervention (availability of a lipid management ‘toolbox’) or standard care. Cohort linkages to additional years of data will occur regularly over the 3-year trial to ascertain the primary outcome of appropriate statin prescribing rates.   \section*{Results} Record linkage enabled us to determine baseline characteristics of 835,345 patients aged 40-75 as of January 2016, being treated in the 28 study-eligible regions by 2,012 family physicians. Preceding the study, the baseline statin use rate was 35.7\% (in 66-75 year olds) across these regions and the cardiovascular event rate ranged from 3.78-5.64 events/1000 person-years. A randomization procedure yielded 14 regions in both the intervention and control arms which did not differ significantly in socio-demographic characteristics, traditional cardiovascular risk factors, disease history, prevalence of statin use, or access to healthcare indicators. Working groups have been established to operationalize the lipid management tools that will be made available in the intervention regions. Analysis of newly linked participant data will permit outcome ascertainment at trial completion.   \section*{Conclusion/Implications} Our work demonstrates the feasibility of using the CANHEART ‘big data’ registry to conduct a large, cluster-randomized clinical trial aimed at improving lipid management, without requiring any primary data collection. Broader use of this methodology has the potential to change the existing paradigm for conducting pragmatic clinical trial research

Linking big data for cardiovascular health surveillance – opportunities and challenges using the CANHEART cohort

Introduction Our increasing ability to link large population-based health administrative datasets to create ‘big data’ cohorts offers unique opportunities to conduct health and health services surveillance at lower costs than traditional methods using surveys or primary data collection. However, comparability of findings from big data with traditional methods is unknown. Objectives and Approach In the CArdiovascular HEalth in Ambulatory Care Research Team (CANHEART) ‘big data’ initiative, we linked 19 population-based health databases to obtain baseline and 5-year follow-up health information on a cohort of 9.8 million adult residents of Ontario, Canada as of January 2008. We compared cardiovascular risk factor prevalence with results from 3500 participants in the 2007-09 Canadian Health Measures Survey (CHMS), a traditional population health surveillance survey. Additionally, we determined cardiovascular preventative care use and clinical event rates by sex and age. Planned linkages to new data sources will enable continued cohort surveillance of population health-related and care indicators. Results Cholesterol and glucose levels determined from the CANHEART cohort were comparable to the CHMS, whereas blood pressure values and obesity rates were substantially higher. Overall, receipt of cardiovascular preventive care in the CANHEART cohort was high, with 85.7% of males and 91.8% of females having blood pressure assessments, and 67.8% of males and 79.4% of females having weight assessments. Cholesterol and diabetes screening rates among those recommended for screening were over 75%. Incidence of myocardial infarction, stroke or cardiovascular death was 51% higher among males than females (3.8 and 2.5 events per 1000 person-years, respectively). Challenges encountered in analyzing data included treatment of repeated and time-varying measures, selection of valid diagnostic and physician billing codes, changing coding practices and handling of missing and outlying data. Conclusion/Implications Comparability of cardiovascular risk factor prevalence using linked administrative data with survey methods varies by indicator. Selection biases amongst survey participants and different measurement methods could explain discrepancies. The added ability to examine health care indicators longitudinally and by subgroup supports use of linked population-based data to enhance health surveillance

A Feasibility Study for CODE-MI: High-Sensitivity Cardiac Troponin - Optimizing the Diagnosis of Acute Myocardial Infarction/Injury in Women.

Objectives This feasibility study was conducted to inform the design and power evaluation of CODE-MI, a pan-Canadian trial evaluating the impact of using the female-specific 99th-percentile threshold for high-sensitivity cardiac troponin (hs-cTn) on the diagnosis, treatment and outcomes of women presenting to the emergency department with symptoms suggestive for myocardial ischemia. Approach CODE-MI is a multi-center, stepped-wedge cluster randomized trial. The cohort and outcomes will be obtained from routinely collected administrative data. Using linked administrative data from 11 hospitals in Ontario from 2014/10 to 2017/09, this feasibility study obtained the following estimates: number of eligible patients, i.e., women presenting to the emergency department with symptoms suggestive of myocardial ischemia and a 24-hour peak hs-cTn value within the female-specific and overall thresholds (i.e. primary cohort); the rate of the 1-year composite outcome of all-cause mortality, re-admission for non-fatal myocardial infarction, incident heart failure, or emergent/urgent coronary revascularization. Study power was evaluated via simulations. Results Overall, 2,073,849 emergency department visits were assessed. Among women, chest pain (with or without cardiac features) and shortness of breath were the most common complaints associated with a diagnosis of acute coronary syndrome. An estimated 7.7% of women with these complaints are eligible for inclusion in the primary cohort. The rate of the 1-year outcome in the primary cohort varied significantly across hospitals with a median rate of 12.2% (95%CI: 7.9%-17.7%). With 30 hospitals, randomized at 5-month intervals in 5 steps, approximately 19,600 women are expected to be included in CODE-MI, resulting in >82% power to detect a 20% decrease in the odds of the primary outcome at a 0.05 significance level. Conclusion Routinely collected administrative health data serve as a rich and essential resource for conducting pragmatic trials assessing process change, such as CODE-MI. We demonstrated the strength of using linked administrative health data to guide the design of pragmatic clinical trials and accurately evaluate the study power

Effects of canagliflozin on myocardial infarction:a post hoc analysis of the CANVAS Program and CREDENCE trial

AIMS: Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post-hoc analysis of CANVAS Program and CREDENCE trial.METHODS AND RESULTS: Individuals with type 2 diabetes and history or high risk of cardiovascular disease (CANVAS Program) or type 2 diabetes and chronic kidney disease (CREDENCE) were included. The intervention was Canagliflozin 100 or 300 mg (combined in the analysis) or placebo. MI events were adjudicated as ST-elevation myocardial infarction (STEMI), non-STEMI as well as type 1 MI or type 2 MI. 421 first MI events in the CANVAS Program and 178 first MI events in the CREDENCE trial were recorded (83 fatal, 128 STEMI, 431 non-STEMI, and 40 unknown). No benefit of canagliflozin compared with placebo on time to first MI event was observed (HR 0.89; 95% CI 0.75, 1.05). Canagliflozin was associated with lower risk for non-STEMI (HR 0.78; 95% CI 0.65, 0.95) but suggested a possible increase in STEMI (HR 1.55; 95% CI 1.06, 2.27), with no difference in risk of type 1 or type 2 MI. There was no change in fatal MI (HR 1.22, 95% CI 0.78, 1.93).CONCLUSIONS: Canagliflozin was not associated with a reduction in overall MI in the pooled CANVAS Program and CREDENCE trial population. The possible differential effect on STEMI and Non-STEMI observed in the CANVAS cohort warrants further investigation.</p

Empagliflozin in patients post myocardial infarction rationale and design of the EMPACT-MI trial

Background : Patients with acute myocardial infarction (MI) are at risk for developing heart failure (HF) and subsequently are at an increased risk of mortality. Sodium-glucose cotransporter-2 inhibitors have been proven to improve outcomes in patients with HF with reduced ejection fraction, and, in the case of empagliflozin, in HF with preserved ejection fraction even without diabetes, but their efficacy and safety in the post-MI population has not yet been evaluated. Methods : The EMPACT-MI trial will evaluate the safety and efficacy of empagliflozin compared with placebo in patients hospitalized for MI with or at high risk of new onset HF, in addition to standard care. EMPACT-MI is a streamlined, multinational, randomized, double-blind, placebo-controlled trial randomizing 5,000 participants at approximately 480 centers in 22 countries. Eligible patients presenting with spontaneous MI must have new signs or symptoms of pulmonary congestion requiring treatment or new left ventricular dysfunction (LVEF&lt;45%), and at least one additional risk factor for development of future HF. Eligible and consenting patients are randomized to empagliflozin 10mg or placebo daily in addition to standard of care within 14 days of hospital admission for MI. The primary composite endpoint is time to first hospitalization for HF or all-cause mortality. Conclusions : EMPACT-MI will inform clinical practice regarding the role of empagliflozin in patients after an MI with high risk for the development of future HF and mortality

Baseline characteristics of patients enrolled in the EMPACT‐MI trial

Aims: Empagliflozin has been shown to reduce the risk of adverse cardiovascular outcomes in patients with type 2 diabetes and in those with heart failure. The impact of empagliflozin in post-acute myocardial infarction (AMI) patients is unknown. Methods and results: The Study to Test the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction (EMPACT-MI) trial screened 6610 participants with AMI and randomized 6522 to empagliflozin or placebo in addition to standard of care. The median (interquartile) age was 64 (56–71) years and 75.1% of patients were male. Major comorbidities included hypertension (69.1%), type 2 diabetes (31.7%), prior myocardial infarction (13.0%), and atrial fibrillation (10.9%). The majority (74.3%) of patients presented with an ST-elevation myocardial infarction. Overall, 56.9% of patients had acute signs or symptoms of congestion requiring treatment and 78.3% had left ventricular systolic dysfunction with ejection fraction &lt;45%. Clinical characteristics, including baseline demographics, rates of revascularization, and cardiovascular medications at discharge were largely comparable to recent trials of the post-AMI population. Conclusion: The EMPACT-MI trial will establish the benefit and risks of empagliflozin treatment in patients with AMI

Sotagliflozin in patients with diabetes and chronic kidney disease

BACKGROUND: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. METHODS: We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m 2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. RESULTS: Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo. CONCLUSIONS: In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.)

Left ventricular function, congestion, and effect of empagliflozin on heart failure risk after myocardial infarction

Background Empagliflozin reduces the risk of heart failure (HF) hospitalizations but not all-cause mortality when started within 14 days of acute myocardial infarction (AMI). Objective To evaluate the association between left ventricular ejection fraction (LVEF), congestion, or both on outcomes and the impact of empagliflozin in reducing HF risk post-MI. Methods In the EMPACT-MI trial, patients were randomized within 14 days of an AMI complicated by either newly reduced LVEF&lt;45%, congestion, or both to empagliflozin 10 mg daily or placebo and followed for a median of 17.9 months. Results Among 6522 patients, the mean baseline LVEF was 41%+9%; 2648 patients (40.6%) presented with LVEF&lt;45% alone, 1483 (22.7%) presented with congestion alone, and 2181 (33.4%) presented with both. Among patients in the placebo arm, multivariable adjusted risk for each 10-point reduction in LVEF included all-cause death or HF hospitalization (hazard ratio [HR] 1.49; 95%CI, 1.31-1.69; P&lt;0.0001), first HF hospitalization (HR, 1.64; 95%CI, 1.37-1.96; P&lt;0.0001), and total HF hospitalizations (rate ratio [RR], 1.89; 95%CI, 1.51-2.36; P&lt;0.0001). Presence of congestion was also associated with a significantly higher risk for each of these outcomes (HR 1.52, 1.94, and RR 2.03, respectively). Empagliflozin reduced the risk for first (HR 0.77, 95%CI 0.60-0.98) and total (RR 0.67, 95%CI 0.50-0.89) HF hospitalization, irrespective of LVEF or congestion or both. The safety profile of empagliflozin was consistent across baseline LVEF and irrespective of congestion status. Conclusions In patients with AMI, severity of LV dysfunction and the presence of congestion was associated with worse outcomes. Empagliflozin reduced first and total HF hospitalizations across the range of LVEF with and without congestion