Effect of Dapagliflozin Versus Placebo on Symptoms and 6-Minute Walk Distance in Patients With Heart Failure: The DETERMINE Randomized Clinical Trials.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of worsening heart failure (HF) and cardiovascular death in patients with HF irrespective of left ventricular ejection fraction. It is important to determine whether therapies for HF improve symptoms and functional capacity. METHODS: The DETERMINE (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure) double-blind, placebo-controlled, multicenter trials assessed the efficacy of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on the Total Symptom Score (TSS) and Physical Limitation Scale (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance (6MWD) in 313 patients with HF with reduced ejection fraction (DETERMINE-Reduced) and in 504 patients with HF with preserved ejection fraction (DETERMINE-Preserved) with New York Heart Association class II or III symptoms and elevated natriuretic peptide levels. The primary outcomes were changes in the KCCQ-TSS, KCCQ-PLS, and 6MWD after 16 weeks of treatment. RESULTS: Among the 313 randomized patients with HF with reduced ejection fraction, the median placebo-corrected difference in KCCQ-TSS from baseline at 16 weeks was 4.2 (95% CI, 1.0, 8.2; P=0.022) in favor of dapagliflozin. The median placebo-corrected difference in KCCQ-PLS was 4.2 (95% CI, 0.0, 8.3; P=0.058). The median placebo-corrected difference in 6MWD from baseline at 16 weeks was 3.2 meters (95% CI, -6.5, 13.0; P=0.69). In the 504 patients with HF with preserved ejection fraction, the median placebo-corrected 16-week difference in KCCQ-TSS and KCCQ-PLS was 3.2 (95% CI, 0.4, 6.0; P=0.079) and 3.1 (-0.1, 5.4; P=0.23), respectively. The median 16-week difference in 6MWD was 1.6 meters (95% CI, -5.9, 9.0; P=0.67). In an exploratory post hoc analysis of both trials combined (DETERMINE-Pooled), the median placebo-corrected difference from baseline at 16 weeks was 3.7 (1.5, 5.9; P=0.005) for KCCQ-TSS, 4.0 (0.3, 4.9; P=0.036) for KCCQ-PLS, and 2.5 meters (-3.5, 8.4; P=0.50) for 6MWD. CONCLUSIONS: Dapagliflozin improved the KCCQ-TSS in patients with HF with reduced ejection fraction but did not improve KCCQ-PLS or 6MWD. Dapagliflozin did not improve these outcomes in patients with HF with preserved ejection fraction. In a post hoc analysis including all patients across the full spectrum of ejection fraction, there was a beneficial effect of dapagliflozin on KCCQ-TSS and KCCQ-PLS but not 6MWD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03877237 and NCT03877224.

Effect of Once-Weekly Exenatide in Patients With Type 2 Diabetes Mellitus With and Without Heart Failure and Heart Failure-Related Outcomes: Insights From the EXSCEL Trial.

BACKGROUND: Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW's effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events. METHODS: The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed. RESULTS: Of 14 752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, and more likely to be male and white, with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (hazard ratio [HR], 0.86 [95% CI, 0.77-0.97]) and the composite outcome of all-cause death or HHF (HR, 0.89 [95% CI, 0.80-0.99]). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR, 1.05 [95% CI, 0.85-1.29]), while the risk of mortality was reduced with EQW in the no-HF group (HR, 0.79 [95% CI, 0.68-0.92]) with an interaction P value of 0.031. The reduction in all-cause death or HHF seen with EQW in patients without baseline HF (HR, 0.81 [95% CI, 0.71-0.93]) was not seen in patients with baseline HF (HR, 1.07 [95% CI, 0.89-1.29]; interaction P=0.015). First, plus recurrent, HHF was reduced in the exenatide group versus placebo (HR, 0.82 [95% CI, 0.68-0.99]; P=0.038). CONCLUSIONS: In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

Totally endoscopic coronary artery bypass grafting is feasible in morbidly obese patients.

Development of robotic technology has enabled totally endoscopic coronary artery bypass grafting (TECAB) procedures. With complete preservation of sternal and thoracic stability, this operation would be an interesting option for obese patients, who are known to be at higher risk for deep sternal wound infection. We describe a case of successful totally endoscopic left internal mammary artery to left anterior descending artery bypass grafting using the da Vinci telemanipulation system in a patient who was morbidly obese. The patient underwent a so called staged hybrid coronary intervention with percutaneous angioplasty and placement of a stent to the right coronary artery.

Comparison of economic and patient outcomes with minimally invasive versus traditional off-pump coronary artery bypass grafting techniques.

BACKGROUND: Minimally invasive coronary artery bypass grafting (miniCABG) decreases in-hospital morbidity versus traditional sternotomy CABG. We performed a prospective cohort study (NCT00481806) to assess the impact of miniCABG on costs and metrics that influence quality of life after hospital discharge. METHODS: One hundred consecutive miniCABG cases performed using internal mammary artery (IMA) grafting +/- coronary stenting were compared with a matched group of 100 sternotomy CABG patients using IMA and saphenous veins, both treating equivalent number of target coronaries (2.7 vs. 2.9), off-pump. We compared perioperative costs, time to return to work/normal activity, and risk of major adverse cardiac/cerebrovascular events (MACCE) at 1 year: myocardial infarction (elevated troponin or EKG changes), target vessel occlusion (CT angiography at 1 year), stroke, or death. RESULTS: For miniCABG, robotic instruments and stents increased intraoperative costs; postoperative costs were decreased from significantly less intubation time (4.80 +/- 6.35 vs. 12.24 +/- 6.24 hours), hospital stay (3.77 +/- 1.51 vs. 6.38 +/- 2.23 days), and transfusion (0.16 +/- 0.37 vs. 1.37 +/- 1.35 U) leading to no significant differences in total costs. Undergoing miniCABG independently predicted earlier return to work after adjusting for confounders (t = -2.15; P = 0.04), whereas sternotomy CABG increased MACCE (HR, 3.9; 95% CI, 1.4-7.6), largely from lower target-vessel patency. CONCLUSIONS: MiniCABG shortens patient recovery time, minimizes MACCE risk at 1 year, and showed superior quality and outcome metrics versus standard-of-care CABG. These findings occurred without increasing costs and with superior target vessel graft patency.

Simultaneous "hybrid" percutaneous coronary intervention and minimally invasive surgical bypass grafting: feasibility, safety, and clinical outcomes.

Surgical and percutaneous coronary artery intervention revascularization are traditionally considered isolated options. A simultaneous hybrid approach may allow an opportunity to match the best strategy for a particular anatomic lesion. Concerns regarding safety and feasibility of such an approach exist. We examined the safety, feasibility, and early outcomes of a simultaneous hybrid revascularization strategy (minimally invasive direct coronary bypass grafting of the left anterior descending [LAD] artery and drug-eluting stent [DES] to non-LAD lesions) in 13 patients with multivessel coronary artery disease that underwent left internal mammary artery to LAD minimally invasive direct coronary bypass performed through a lateral thoracotomy, followed by stenting of non-LAD lesions, in a fluoroscopy-equipped operating room. Assessment of coagulation parameters was also undertaken. Inhospital and postdischarge outcomes of these patients were compared to a group of 26 propensity score matched parallel controls that underwent standard off-pump coronary artery bypass. Baseline characteristics were similar in both groups. All hybrid patients were successfully treated with DES and no inhospital mortality occurred in either group. Hybrid patients had a shorter length of stay (3.6 +/- 1.5 vs 6.3 +/- 2.3 days, P < .0001) and intubation times (0.5 +/- 1.3 vs 11.7 +/- 9.6 hours, P < .02). Despite aggressive anticoagulation and confirmed platelet inhibition, hybrid patients had less blood loss (581 +/- 402 vs 1242 +/- 941 mL, P < .05) and decreased transfusions (0.33 +/- 0.49 vs 1.47 +/- 1.53 U, P < .01). Six-month angiographic vessel patency and major adverse cardiac events were similar in the hybrid and off-pump coronary artery bypass groups. A simultaneous hybrid approach consisting of minimally invasive coronary artery bypass grafting with left internal mammary artery to LAD combined with revascularization of the remaining coronary targets using percutaneous coronary artery intervention with DES is a feasible option accomplished with acceptable clinical outcomes without increased bleeding risk.

Effect of Once-Weekly Exenatide on Clinical Outcomes According to Baseline Risk in Patients With Type 2 Diabetes Mellitus: Insights From the EXSCEL Trial.

Background In the EXSCEL (Exenatide Study of Cardiovascular Event Lowering), exenatide once-weekly resulted in a nonsignificant reduction in major adverse cardiovascular events ( MACEs ) and a nominal 14% reduction in all-cause mortality in 14 752 patients with type 2 diabetes mellitus (T2 DM ) with and without cardiovascular disease. Whether patients at increased risk for events experienced a comparatively greater treatment benefit with exenatide is unknown. Methods and Results In the EXSCEL population, we created risk scores for MACEs and all-cause mortality using step-wise selection of baseline characteristics. A risk score was calculated for each patient, and a time-to-event model for each end point was developed including the risk score, treatment assignment, and risk-treatment interaction. Interaction P values evaluating for a differential treatment effect by baseline risk were reported. Over a median follow-up of 3.2 years (interquartile range, 2.2, 4.4), 1091 (7.4%) patients died and 1744 (11.8%) experienced a MACE . Independent predictors of MACEs and all-cause mortality included age, sex, comorbidities (eg, previous cardiovascular event), body mass index, blood pressure, hemoglobin A1c, and estimated glomerular filtration rate. The all-cause mortality and MACE risk models had modest discrimination with optimism-corrected c-indices of 0.73 and 0.71, respectively. No interaction was observed between treatment effect and risk profile for either end point (both interactions, P>0.1). Conclusions Baseline characteristics (eg, age, previous cardiovascular events) and routine laboratory values (eg, hemoglobin A1c, estimated glomerular filtration rate) provided modest prognostic value for mortality and MACEs in a broad population of patients with type 2 diabetes mellitus. Exenatide's effects on mortality and MACEs were consistent across the spectrum of baseline risk. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 01144338.

Simultaneous hybrid coronary revascularization reduces postoperative morbidity compared with results from conventional off-pump coronary artery bypass.

OBJECTIVES: Less-invasive options are available for surgical treatment of multivessel coronary artery disease. We hypothesized that stenting combined with grafting of the left anterior descending artery with the left internal thoracic artery through a minithoracotomy (hybrid procedure) would provide the best outcome. METHODS: Patients with equivalent numbers of coronary lesions (2.8 +/- 0.4) underwent either hybrid (n = 15) or off-pump coronary artery bypass through a sternotomy (n = 30). Early and 1-year outcomes were compared. Blood drawn from the aorta and coronary sinus immediately postoperatively was analyzed for activation of coagulation (prothrombin fragment 1.2 and activated Factor XII), myocardial injury (myoglobin), and inflammation (interleukin 8) by using an enzyme-linked immunosorbent assay. Target-vessel patency was determined by means of computed tomographic angiographic analysis. RESULTS: The hybrid procedure was associated with significantly shorter lengths of intubation and stays in the intensive care unit and hospital and perioperative morbidity (P < .05). Intraoperative costs were increased but postoperative costs were reduced for the hybrid procedure compared with off-pump coronary artery bypass through a sternotomy. As a result, overall total costs were not significantly different between the groups. After adjusting for potential confounders, assignment to the hybrid group was an independent predictor of shortened time to return to work (t = -2.12, P = .04). Patient satisfaction after the hybrid procedure, as judged on a 6-point scale, was greater versus that after off-pump coronary artery bypass through a sternotomy. Finally, the hybrid procedure showed significantly reduced transcardiac gradients of markers of coagulation, myocardial injury, and inflammation and a trend toward significant improvement in target-vessel patency. CONCLUSIONS: Perhaps because of reduced myocardial injury, inflammation, and activation of coagulation, patients undergoing the hybrid procedure had better perioperative outcomes and satisfaction, with excellent patency at 1 year's follow-up. These promising preliminary findings warrant further investigation of this procedure.

A hybrid alternative for high risk left main disease.

Percutaneous revascularization strategies for bifurcation disease of the left main are complex and carry significant risk. These risks are magnified in the setting of a left main which trifurcates. In a patient with complex ostial disease of two of the three limbs of a left main trifurcation, turned down for conventional bypass surgery, we report on a hybrid approach for complete revascularization, consisting of minimally invasive bypass grafting of the LAD combined with simultaneous drug eluting stent placement.