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Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events [Original Research Article]

2018-01-22T10:40:37-08:00

Background:Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation.Methods:The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo. The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death).Results:Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%). The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P<0.001). In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75–0.97; P<0.001 for noninferiority, P=0.02 for superiority) with no statistical evidence of heterogeneity (interaction P value=0.18) between the primary (HR, 0.98; 95% CI, 0.74–1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72–0.95) cohorts. Renal outcomes (HR, 0.59; 95% CI, 0.44–0.79 versus HR, 0.63; 95% CI, 0.39–1.02; interaction P value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51–0.90 versus HR, 0.64; 95% CI, 0.35–1.15; interaction P value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively. Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43–3.00 versus HR, 1.52; 95% CI, 0.70–3.29; interaction P value=0.63).Conclusions:Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients. Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups. Additional studies will provide further insights into the effects of canagliflozin in these patient populations.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.



Canagliflozin [Editorials]

2018-01-22T10:40:37-08:00




Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease [Original Research Article]

2018-01-22T10:40:37-08:00

Background:The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events.Methods:FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia.Results:Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66–0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80–0.93; P=0.0003; Pinteraction=0.40). For the key secondary end point, the HRs were 0.73 (0.59–0.91; P=0.0040) for those with PAD and 0.81 (0.73–0.90; P<0.0001) for those without PAD (Pinteraction=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38–0.88; P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL.Conclusions:Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.






ICare-ACS (Improving Care Processes for Patients With Suspected Acute Coronary Syndrome) [Original Research Article]

2018-01-22T10:40:38-08:00

Background:Efforts to safely reduce length of stay for emergency department patients with symptoms suggestive of acute coronary syndrome (ACS) have had mixed success. Few system-wide efforts affecting multiple hospital emergency departments have ever been evaluated. We evaluated the effectiveness of a nationwide implementation of clinical pathways for potential ACS in disparate hospitals.Methods:This was a multicenter pragmatic stepped-wedge before-and-after trial in 7 New Zealand acute care hospitals with 31 332 patients investigated for suspected ACS with serial troponin measurements. The implementation was a clinical pathway for the assessment of patients with suspected ACS that included a clinical pathway document in paper or electronic format, structured risk stratification, specified time points for electrocardiographic and serial troponin testing within 3 hours of arrival, and directions for combining risk stratification and electrocardiographic and troponin testing in an accelerated diagnostic protocol. Implementation was monitored for >4 months and compared with usual care over the preceding 6 months. The main outcome measure was the odds of discharge within 6 hours of presentationResults:There were 11 529 participants in the preimplementation phase (range, 284–3465) and 19 803 in the postimplementation phase (range, 395–5039). Overall, the mean 6-hour discharge rate increased from 8.3% (range, 2.7%–37.7%) to 18.4% (6.8%–43.8%). The odds of being discharged within 6 hours increased after clinical pathway implementation. The odds ratio was 2.4 (95% confidence interval, 2.3–2.6). In patients without ACS, the median length of hospital stays decreased by 2.9 hours (95% confidence interval, 2.4–3.4). For patients discharged within 6 hours, there was no change in 30-day major adverse cardiac event rates (0.52% versus 0.44%; P=0.96). In these patients, no adverse event occurred when clinical pathways were correctly followed.Conclusions:Implementation of clinical pathways for suspected ACS reduced the length of stay and increased the proportions of patients safely discharged within 6 hours.Clinical Trial Registration:URL: https://www.anzctr.org.au/ (Australian and New Zealand Clinical Trials Registry). Unique identifier: ACTRN12617000381381.



Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]) [Original Research Article]

2018-01-22T10:40:38-08:00

Background:In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%.Methods:REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise.Results:A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group (P=0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group (P=1.0).Conclusions:In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation.Clinical Trial Registration:URL: https://clinicaltrials.gov. Unique identifier: NCT02600234.



Impact of Regionalization of ST-Segment-Elevation Myocardial Infarction Care on Treatment Times and Outcomes for Emergency Medical Services-Transported Patients Presenting to Hospitals With Percutaneous Coronary Intervention [Original Research Article]

2018-01-22T10:40:38-08:00

Background:Regional variations in reperfusion times and mortality in patients with ST-segment–elevation myocardial infarction are influenced by differences in coordinating care between emergency medical services (EMS) and hospitals. Building on the Accelerator-1 Project, we hypothesized that time to reperfusion could be further reduced with enhanced regional efforts.Methods:Between April 2015 and March 2017, we worked with 12 metropolitan regions across the United States with 132 percutaneous coronary intervention–capable hospitals and 946 EMS agencies. Data were collected in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network)-Get With The Guidelines Registry for quarterly Mission: Lifeline reports. The primary end point was the change in the proportion of EMS-transported patients with first medical contact to device time ≤90 minutes from baseline to final quarter. We also compared treatment times and mortality with patients treated in hospitals not participating in the project during the corresponding time period.Results:During the study period, 10 730 patients were transported to percutaneous coronary intervention–capable hospitals, including 974 in the baseline quarter and 972 in the final quarter who met inclusion criteria. Median age was 61 years; 27% were women, 6% had cardiac arrest, and 6% had shock on admission; 10% were black, 12% were Latino, and 10% were uninsured. By the end of the intervention, all process measures reflecting coordination between EMS and hospitals had improved, including the proportion of patients with a first medical contact to device time of ≤90 minutes (67%–74%; P<0.002), a first medical contact to device time to catheterization laboratory activation of ≤20 minutes (38%–56%; P<0.0001), and emergency department dwell time of ≤20 minutes (33%–43%; P<0.0001). Of the 12 regions, 9 regions reduced first medical contact to device time, and 8 met or exceeded the national goal of 75% of patients treated in ≤90 minutes. Improvements in treatment times corresponded with a significant reduction in mortality (in-hospital death, 4.4%–2.3%; P=0.001) that was not apparent in hospitals not participating in the project during the same time period.Conclusions:Organization of care among EMS and hospitals in 12 regions was associated with significant reductions in time to reperfusion in patients with ST-segment–elevation myocardial infarction as well as in in-hospital mortality. These findings support a more intensive regional approach to emergency care for patients with ST-segment–elevation myocardial infarction.



Standardized Definition of Structural Valve Degeneration for Surgical and Transcatheter Bioprosthetic Aortic Valves [White Paper]

2018-01-22T10:40:38-08:00

Bioprostheses are prone to structural valve degeneration, resulting in limited long-term durability. A significant challenge when comparing the durability of different types of bioprostheses is the lack of a standardized terminology for the definition of a degenerated valve. This issue becomes especially important when we try to compare the degeneration rate of surgically inserted and transcatheter bioprosthetic valves. This document, by the VIVID (Valve-in-Valve International Data), proposes practical and standardized definitions of valve degeneration and provides recommendations for the timing of clinical and imaging follow-up assessments accordingly. Its goal is to improve the quality of research and clinical care for patients with deteriorated bioprostheses by providing objective and strict criteria that can be utilized in future clinical trials. We hope that the adoption of these criteria by both the cardiological and surgical communities will lead to improved comparability and interpretation of durability analyses.



From the Literature [Cardiology News]

2018-01-22T10:40:38-08:00