Utility of the SENIORS elderly heart failure risk model applied to the RICA registry of acute heart failure

Background: Heart failure (HF) is predominantly a disease of the elderly. Reliable risk stratification would help in the management of this population, but no model has been well evaluated in elderly HF patients in both acute and chronic settings and not being restricted by ejection fraction. To evaluate the utility of the SENIORS risk model, developed from a clinical trial of elderly patients with chronic HF, in an independent cohort (National Spanish Registry: RICA) of elderly acute HF patients. Methods: We applied the SENIORS risk model to 926 patients in RICA to estimate risk at one year of a) composite outcome of all-cause mortality or cardiovascular hospital admission and b) all-cause mortality. Results: In the RICA registry mean age was 78 years, mean ejection fraction 51% and 87% were in NYHA II and III. At one year death/CV hospitalization occurred in 31.9% and all-cause mortality in 19.5%. The risk model provided good separation of Kaplan Meier curves stratified by tertile for death/CV hospitalization and all-cause mortality. The observed versus expected rates of death/CV hospitalization in the lowest, middle and highest risk tertiles were (%) 34/24, 45/41 and 57/67, and for death 13/16, 32/38 and 44/70 respectively. C-statistic for all-cause mortality or CV hospitalization was 0.60 and for all-cause mortality 0.66. Conclusion: The SENIORS risk model was a reliable tool for relative risk stratification among acute heart failure patients in a “real world” registry, but predicted versus observed risk showed some variability. The model provides a useful basis for clinical risk prediction

Cardiovascular Magnetic Resonance and prognosis in cardiac amyloidosis

Background: Cardiac involvement is common in amyloidosis and associated with a variably adverse outcome. We have previously shown that cardiovascular magnetic resonance (CMR) can assess deposition of amyloid protein in the myocardial interstitium. In this study we assessed the prognostic value of late gadolinium enhancement (LGE) and gadolinium kinetics in cardiac amyloidosis in a prospective longitudinal study.Materials and methods: The pre-defined study end point was all-cause mortality. We prospectively followed a cohort of 29 patients with proven cardiac amyloidosis. All patients underwent biopsy, 2D-echocardiography and Doppler studies, I-123-SAP scintigraphy, serum NT pro BNP assay, and CMR with a T-1 mapping method and late gadolinium enhancement (LGE).Results: Patients with were followed for a median of 623 days (IQ range 221, 1436), during which 17 (58%) patients died. The presence of myocardial LGE by itself was not a significant predictor of mortality. However, death was predicted by gadolinium kinetics, with the 2 minute post-gadolinium intramyocardial T1 difference between subepicardium and subendocardium predicting mortality with 85% accuracy at a threshold value of 23 ms (the lower the difference the worse the prognosis). Intramyocardial T1 gradient was a better predictor of survival than FLC response to chemotherapy (Kaplan Meier analysis P = 0.049) or diastolic function (Kaplan-Meier analysis P = 0.205).Conclusion: In cardiac amyloidosis, CMR provides unique information relating to risk of mortality based on gadolinium kinetics which reflects the severity of the cardiac amyloid burden

Dabrafenib, alone or in combination with trametinib, in BRAF V600–mutated pediatric Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare, heterogenous, neoplastic disorder primarily affecting children. BRAF mutations have been reported in >50% of patients with LCH. The selective BRAF inhibitor, dabrafenib, in combination with the MEK1/2 inhibitor, trametinib, has been approved in select BRAF V600–mutant solid tumors. Two open-label phase 1/2 studies were conducted in pediatric patients with BRAF V600–mutant, recurrent/refractory malignancies treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772). The primary objectives of both studies were to determine safe and tolerable doses that achieve similar exposure to the approved doses for adults. Secondary objectives included safety, tolerability, and preliminary antitumor activity. Thirteen and 12 patients with BRAF V600–mutant LCH received dabrafenib monotherapy and in combination with trametinib, respectively. Investigator-assessed objective response rates per Histiocyte Society criteria were 76.9% (95% confidence interval [CI], 46.2-95.0) and 58.3% (95% CI, 27.7-84.8) in the monotherapy and combination studies, respectively. More than 90% of responses were ongoing at study completion. The most common treatment-related adverse events (AEs) were vomiting and increased blood creatinine with monotherapy and pyrexia, diarrhea, dry skin, decreased neutrophil count, and vomiting with combination therapy. Two patients each discontinued treatment with monotherapy and combination therapy because of AEs. Overall, dabrafenib monotherapy or in combination with trametinib demonstrated clinical efficacy and manageable toxicity in relapsed/refractory BRAF V600–mutant pediatric LCH, with most responses ongoing. Safety was consistent with that reported in other pediatric and adult conditions treated with dabrafenib plus trametinib

Total anomalous pulmonary venous connection: Outcome of postoperative pulmonary venous obstruction

ObjectivePulmonary venous obstruction (PVO) is an important cause of late mortality in total anomalous pulmonary venous connection (TAPVC). We aimed to describe current practices for the management of postoperative PVO and the efficacy of the different interventional procedures.MethodsWe conducted a retrospective international collaborative population-based study involving 19 pediatric cardiac centers in the United Kingdom, Ireland, and Sweden. Patients with TAPVC born between January 1, 1998, and December 31, 2004, were identified. Patients with functionally univentricular circulation or atrial isomerism were excluded. All available data and images were reviewed.ResultsOf 406 patients undergoing repair of TAPVC, 71 (17.5%) had postoperative PVO. The diagnosis was made within 6 months of surgery in 59 (83%) of the 71 patients. In 12, serial imaging documented change in appearance of the pulmonary veins. Good-sized pulmonary veins can progress to diffusely small veins and rarely atresia. Patients presenting after 6 months had less severe disease; all are alive at most recent follow-up. Fifty-six (13.8%) of 406 patients underwent intervention for postoperative PVO: 44 had surgical treatment and 12 had an initial catheter intervention. One half underwent 1 or more reinterventions. Three-year survival for patients with postoperative PVO was 58.7% (95% confidence intervals, 46.2%-69.2%) with a trend that those having a surgical strategy did better (P = .083). Risk factors for death included earlier presentation after TAPVC repair, diffusely small pulmonary veins at presentation of postoperative PVO, and an increased number of lung segments affected by obstruction.ConclusionsPostoperative PVO tends to appear in the first 6 months after TAPVC repair and can be progressive. Early intervention for PVO may be indicated before irreversible secondary changes occur

Six-minute walk test: prognostic value and effects of nebivolol versus placebo in elderly patients with heart failure from the SENIORS trial

Background: There is limited information about the 6-min walk test (6MWT) in elderly patients with heart failure. We evaluated 6MWT and the effect of nebivolol on 6MWT from the SENIORS trial. Methods and results: The SENIORS trial evaluated nebivolol versus placebo on death and hospitalisation in patients aged ≥ 70 years with heart failure. A total of 1982 patients undertook a 6MWT at baseline and 1716 patients at 6 months. Patients were divided into tertiles (≤ 200 m, 201 to ≤ 300 m and > 300 m) and to change in distance walked between baseline and 6 months (< 0 m, 0 to < 30 m and ≥ 30 m). The primary outcome was all-cause mortality and cardiovascular hospital admission. Secondary endpoint was all-cause mortality. Baseline walk distance of ≤ 200 m incurred a greater risk of the primary and secondary outcomes (HR 1.41, CI 95% 1.17–1.69, p < 0.001) and (HR 1.37, CI 95% 1.05–1.78, p = 0.019). A decline in walk distance over 6 months was associated with increased risk of clinical events. Nebivolol had no influence on change in walk distance over 6 months. Conclusions: The 6MWT has prognostic utility in elderly patients. Those who walked less than 200 m were at highest risk. Nebivolol had no effect on 6MWT

Effect of deferiprone or deferoxamine on right ventricular function in thalassemia major patients with myocardial iron overload

<p>Abstract</p> <p>Background</p> <p>Thalassaemia major (TM) patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular (LV) function but little is known of their relative effects on the right ventricle (RV), which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT) comparing these chelators was retrospectively analysed to assess the RV responses to these drugs.</p> <p>Methods</p> <p>In the RCT, 61 TM patients were randomised to receive either deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment.</p> <p>Results</p> <p>From baseline to 12 months, deferiprone reduced RV end systolic volume (ESV) from 37.7 to 34.2 mL (p = 0.008), whilst RV ejection fraction (EF) increased from 69.6 to 72.2% (p = 0.001). This was associated with a 27% increase in T2* (p < 0.001) and 3.1% increase in LVEF (p < 0.001). By contrast, deferoxamine showed no change in RVESV (38.1 to 39.1 mL, p = 0.38), or RVEF (70.0 to 69.9%, p = 0.93) whereas the T2* increased by 13% (p < 0.001), but with no change in LVEF (0.32%; p = 0.66). Analysis of between drugs treatment effects, showed significant improvements favouring deferiprone with a mean effect on RVESV of -1.82 mL (p = 0.014) and 1.16% for RVEF (p = 0.009). Using regression analysis the improvement in RVEF at 12 months was shown to be greater in patients with lower baseline EF values (p < 0.001), with a significant difference in RVEF of 3.5% favouring deferiprone over deferoxamine (p = 0.012).</p> <p>Conclusion</p> <p>In this retrospective analysis of a prospective RCT, deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with deferiprone.</p