The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial.

Patients with heart failure and preserved ejection fraction (HFpEF) have a high burden of symptoms and functional limitations, and have a poor quality of life. By targeting cardiometabolic abmormalities, sodium glucose cotransporter 2 (SGLT2) inhibitors may improve these impairments. In this multicenter, randomized trial of patients with HFpEF (NCT03030235), we evaluated whether the SGLT2 inhibitor dapagliflozin improves the primary endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS), a measure of heart failure-related health status, at 12 weeks after treatment initiation. Secondary endpoints included the 6-minute walk test (6MWT), KCCQ Overall Summary Score (KCCQ-OS), clinically meaningful changes in KCCQ-CS and -OS, and changes in weight, natriuretic peptides, glycated hemoglobin and systolic blood pressure. In total, 324 patients were randomized to dapagliflozin or placebo. Dapagliflozin improved KCCQ-CS (effect size, 5.8 points (95% confidence interval (CI) 2.3-9.2, P = 0.001), meeting the predefined primary endpoint, due to improvements in both KCCQ total symptom score (KCCQ-TS) (5.8 points (95% CI 2.0-9.6, P = 0.003)) and physical limitations scores (5.3 points (95% CI 0.7-10.0, P = 0.026)). Dapagliflozin also improved 6MWT (mean effect size of 20.1 m (95% CI 5.6-34.7, P = 0.007)), KCCQ-OS (4.5 points (95% CI 1.1-7.8, P = 0.009)), proportion of participants with 5-point or greater improvements in KCCQ-OS (odds ratio (OR) = 1.73 (95% CI 1.05-2.85, P = 0.03)) and reduced weight (mean effect size, 0.72 kg (95% CI 0.01-1.42, P = 0.046)). There were no significant differences in other secondary endpoints. Adverse events were similar between dapagliflozin and placebo (44 (27.2%) versus 38 (23.5%) patients, respectively). These results indicate that 12 weeks of dapagliflozin treatment significantly improved patient-reported symptoms, physical limitations and exercise function and was well tolerated in chronic HFpEF.

The effect of age, diagnosis, and previous surgery in children and adults undergoing heart transplantation for congenital heart disease.

OBJECTIVES: We sought to evaluate the outcomes and identify risk factors for mortality after heart transplantation (HT) for congenital heart disease (CHD) in infants, children, and adults. BACKGROUND: CHD is considered a risk factor for mortality after HT, yet this unique group of patients represents a spectrum of complexity. METHODS: There were 488 patients transplanted for CHD from the combined Pediatric Heart Transplant Study (1993 to 2002, n = 367) and the Cardiac Transplant Registry Database (1990 to 2002, n = 121) who were analyzed. RESULTS: The median age at HT was 12.4 years. Primary diagnosis included single ventricle (36%), d-transposition of the great arteries (12%), right ventricular outflow tract lesions (10%), l-transposition of the great arteries (8%), ventricular/atrial septal defects (8%), left ventricular outflow obstruction (8%), and other (18%). Ninety-three percent of patients had at least 1 operation before HT. Survival at 3 months post-HT was significantly worse in CHD patients versus children with cardiomyopathy, but not adults with cardiomyopathy (86%, 94%, and 91%, respectively). There was no difference in conditional 3-month survival among the 3 groups. Five-year survival was 80%. Risk factors for early mortality were older recipient age, older donors with longer ischemic times, and pre-HT Fontan operations. Predicted survival in Fontan patients was lower (77% and 70% at 1 and 5 years) versus non-Fontan patients (88% and 81% at 1 and 5 years). Risk factors for constant phase mortality included younger recipient age, higher transpulmonary gradient, cytomegalovirus mismatch at HT, and earlier classical Glenn operation. CONCLUSIONS: Patients undergoing transplantation for CHD have a good late survival if they survive the early post-operative period. Risk factors for reduced survival are older age at transplant and a previous Fontan operation.

The case for selective re-issuance of medical certificates to allow pilots who have received a heart transplant to resume flying.

BACKGROUND: Cardiac transplant recipients have been regarded as not medically fit to fly an airplane. Recently, the Federal Aviation Administration decided to re-examine this policy and, in response, this study was undertaken to determine the risk of death from any cause and sudden-onset death in heart transplant recipients during the 12 months after an annual evaluation. METHODS: Of 6,510 patients undergoing primary orthotopic cardiac transplantation enrolled in the Cardiac Transplant Research Database (CTRD), 4,978 patients survived for at least 1 year and formed the basis of this study. Risk factors for death from any causes and sudden-onset death (a composite of causes of death that could conceivably result in a pilot's incapacitation) were determined during the 12-month period after an anniversary evaluation. Patients were re-entered into the analysis at each evaluation, resulting in a total of 23,575 anniversary evaluations. RESULTS: The presence of coronary allograft vasculopathy (CAV), left ventricular systolic dysfunction, history of rejection, malignancy, infection and pre-transplant insulin-dependent diabetes were associated with an increased risk of death from any cause and sudden-onset death during the 12-month period after an evaluation. Based on the absence of these risk factors, a group of heart transplant recipients could be defined with a 12-month risk of death from any cause of 1.0% and of sudden-onset death of 0.3% (which is identical to the mortality rate of a matched population from the U.S. life-table). CONCLUSION: Using these identified risk factors, a group of heart transplant recipients can be defined that are potentially medically certifiable to fly without compromising aviation safety.

Failure of benefit and early hazard of bucindolol for Class IV heart failure.

OBJECTIVES: The risks and benefits of beta-blockade with bucindolol were assessed in heart failure (HF) patients with Class IV symptoms within the Beta-blocker Evaluation of Survival Trial (BEST). BACKGROUND: beta-blockade is accepted therapy for mild to moderate HF, but its safety and efficacy in advanced HF have not been established. METHODS: BEST recruited 2708 HF patients; of these, 226 with Class IV symptoms (n=114 randomized to bucindolol, n=112 to placebo) formed the basis of this study. All-cause death, HF hospitalization, and drug discontinuations occurring early during therapy (< or =6 months) and overall during follow-up were assessed. Compared with Class III, Class IV patients were older and had higher plasma norepinephrine levels, prevalence of coronary disease, S3 gallops, and lower ejection fractions, but characteristics of the 2 Class IV treatment groups were similar. RESULTS: During a mean of 1.6 years, 49% Class IV patients died, and 54% were hospitalized for HF. Bucindolol increased the combined endpoint of death or HF hospitalization within the first 6 months (hazard ratio [HR]=1.7, 95% confidence interval [CI]=1.1-2.7) and did not result in benefit overall (HR=1.2, 95% CI=0.9-1.6). HF hospitalization alone within 6 months was increased by bucindolol (HR=1.7), and an early adverse trend for death was seen (HR=1.6) with no benefit overall (HR=1.1). Bucindolol was discontinued more frequently than placebo for worsening HF (11% versus 4%) and hypotension (3% versus 0%). CONCLUSIONS: Class IV HF patients in BEST were at high risk. Bucindolol did not reduce death or HF hospitalization and was associated with early hazard.

Coronary plaque morphology and frequency of ulceration distant from culprit lesions in patients with unstable and stable presentation.

OBJECTIVE: Intravascular ultrasound studies describe ruptured coronary plaques at sites remote from the culprit lesion in patients with acute myocardial infarction (MI), suggesting multifocal plaque vulnerability. However, the role of intravascular ultrasound in the diagnosis of lesion vulnerability before rupture is unclear. METHODS AND RESULTS: We compared morphology and frequency of ulceration of additional plaques proximal to the culprit lesion in 105 patients treated with emergent stenting during an evolving, acute MI in the CADILLAC study and 92 patients with stable/subacute presentation who underwent elective stenting. Additional plaques proximal to the culprit lesion were found in 52 (50%) and 54 (59%) patients in the acute MI and stable/subacute group, respectively. The prevalence of ulceration was significantly higher in the acute MI than in the stable/subacute group (19% versus 4%; P=0.014). However, there was no significant difference in other morphological lesion characteristics. CONCLUSIONS: Additional plaques are frequently found adjacent to the culprit lesions in patients undergoing percutaneous coronary intervention independent of clinical presentation. The increased prevalence of plaque ulceration but otherwise similar morphology of additional lesions in patients with acute MI versus stable/subacute presentation demonstrates the limitations of imaging in the assessment of plaque vulnerability.