This study sought to assess the effects of neurohormonal therapies in preventing cardiotoxicity in patients receiving chemotherapy.
Various cardioprotective approaches have been evaluated to prevent ...chemotherapy-related cardiotoxicity; however, their overall utility remains uncertain.
This meta-analysis included randomized clinical trials of adult patients that underwent chemotherapy and neurohormonal therapies (β-blockers, mineralocorticoid receptor antagonists, or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) versus placebo with follow-up ≥4 weeks. The primary outcome was change in left ventricular ejection fraction (LVEF) from baseline to the end of the trial. Other outcomes of interest were measures of LV size, strain, and diastolic function. Pooled estimates for each outcome were reported as standardized mean difference and weighted mean difference between the neurohormonal therapy and placebo groups using random effects models.
We included 17 trials, collectively enrolling 1,984 participants. In pooled analysis, neurohormonal therapy (vs. placebo) was associated with significantly higher LVEF on follow-up (standardized mean difference: +1.04 95% confidence interval (CI): 0.57 to 1.50) but with significant heterogeneity in the pooled estimate (I2 = 96%). Compared with placebo-treated patients, those randomized to neurohormonal therapies experienced a 3.96% (95% CI: 2.90 to 5.02) less decline in LVEF estimated by weighted mean difference, but with significant heterogeneity (I2 = 98%). There was a trend toward lower adverse clinical events with neurohormonal therapy (vs. placebo) that did not meet statistical significance (risk ratio: 0.80 95% CI: 0.53 to 1.20; I2 = 71%).
Neurohormonal therapies are associated with higher LVEF in follow-up among cancer patients receiving chemotherapy, although absolute changes in LVEF are small and may be within inter-test variability. Furthermore, significant heterogeneity is observed in the treatment effects across studies highlighting the need for larger trials of cardioprotective strategies.
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Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.
To determine whether the QT interval, a marker ...of ventricular repolarization, could be used to predict incident AF.
We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas.
Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio HR 2.05; 95% confidence interval CI 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts.
A prolonged QT interval is associated with an increased risk of incident AF.
Several clinical prediction schemes for right ventricular failure (RVF) risk after left ventricular assist device (LVAD) implantation have been developed in both the pulsatile- and continuous-flow ...LVAD eras. The performance of these models has not been evaluated systematically in a continuous-flow LVAD cohort.
We evaluated 6 clinical RVF prediction models (Michigan, Penn, Utah, Kormos et al, CRITT, Pittsburgh Decision Tree) in 116 patients (age 51 ± 13 years; 41.4% white and 56.0% black; 66.4% men; 56.0% bridge to transplant, 37.1% destination therapy, 17.4% bridge to decision) who received a continuous-flow LVAD (HeartMate II: 79 patients, HeartWare: 37 patients) between 2008 and 2013.
Overall, 37 patients (31.9%) developed RVF, defined: as pulmonary vasodilator use for ≥48 hours or inotrope use for ≥14 days post-operatively; re-institution of inotropes; multi-organ failure due to RVF; or need for mechanical RV support. Median (Quartile 1 to Quartile 3) time to initial discontinuation of inotropes was 6 (range 4 to 8) days. Among scores, the Michigan score reached significance for RVF prediction but discrimination was modest (C = 0.62 95% CI 0.52 to 0.72, p = 0.021; positive predictive value PPV 60.0%; negative predictive value NPV 75.8%), followed by CRITT (C = 0.60 95% CI 0.50 to 0.71, p = 0.059; PPV 40.5%; NPV 72.2%). Other models did not significantly discriminate RVF. The newer, INTERMACS 3.0 definition for RVF, which includes inotropic support beyond 7 days, was reached by 57 patients (49.1%). The Kormos model performed best with this definition (C = 0.62 95% CI 0.54 to 0.71, p = 0.005; PPV 64.3%; NPV 59.5%), followed by Penn (C = 0.61), Michigan (C = 0.60) and CRITT (C = 0.60), but overall score performance was modest.
Current schemes for post-LVAD RVF risk prediction perform only modestly when applied to external populations.
Background Efficient conduct of clinical trials is essential for the timely generation of critical medical knowledge. Methods We systematically assessed size, duration, enrollment rates, and ...geographic distribution of randomized cardiovascular trials published between 2001 and 2012 in the 8 highest-impact journals in general medicine and cardiology. Results Of the 1,224 trials, 27.0% were conducted in North America, 36.5% in Western Europe, and 7.7% in other countries, and 28.8% were multiregional. Trials enrolled a median of 452 patients (interquartile range 167-1,530) in 20 sites (2-76). Median duration was 2.1 (1.3-3.3) years, with an estimated enrollment rate of 1.1 (0.5-3.5) patients/site per month. Between 2001-2003 and 2009-2012, the proportion of North American trials decreased from 34.5% to 25.7% ( P = .006), whereas that of multiregional trials (from 26.0% to 30.3%; P = .046) and trials conducted in other countries (from 4.6% to 10.3%; P = .012) increased. Over time, trials involved more patients (from 400 to 500 median; P = .032) and sites (from 20 to 22; P = .049), multiregional trials involved more countries (from 12 to 18; P = .031), and enrollment rate declined from 1.2 to 0.9 patients/site per month ( P = .017). The proportion of trials meeting their primary end point (“positive”) decreased from 69% to 57% ( P < .001). Trials with higher enrollment rates were more likely to be positive (odds ratio 1.20 per doubling, 95% CI 1.12-1.29), as were industry-sponsored compared with government-sponsored trials (odds ratio 2.62, 95% CI 1.67-4.12). Conclusions From 2001 to 2012, cardiovascular clinical trials have become larger, more global, and less likely to meet their primary end point. Enrollment rates have declined, requiring more sites and regions.
Introduction Data on the association between exercise capacity and risk for heart failure (HF) in older adults are limited. Methods This study examined the association of exercise capacity, and its ...change over time, with 10-year mortality and incident HF in 2,935 participants of the Health, Aging, and Body Composition Study without HF at baseline (age, 73.6 SD=2.9 years; 52.1% women; 41.4% black; 58.6% white). This cohort was initiated in 1997–1998 and exercise capacity was evaluated with a long-distance corridor walk test (LDCW) at baseline and Year 4. Outcomes were collected in 2007–2008 and initial analysis performed in 2014. Results Ten-year incident HF for completers ( n =2,245); non-completers ( n =331); and those excluded from LDCW for safety reasons ( n =359) was 11.4%, 19.2%, and 23.0%, respectively. The corresponding 10-year mortality was 27.9%, 41.1%, and 42.4%. In models accounting for competing mortality, the adjusted subhazard ratio for HF was 1.37 (95% CI=1.00, 1.88; p =0.049) in non-completers and 1.41 (95% CI=1.06, 1.89; p =0.020) in those excluded versus completers. Non-completers (adjusted hazard ratio, 1.49; 95% CI=1.21, 1.84; p <0.001) and those excluded (hazard ratio, 1.27; 95% CI=1.04, 1.55; p =0.016) had elevated mortality. In adjusted models, LDCW performance variables were associated mainly with mortality. Only 20-meter walking speed and resting heart rate retained prognostic value for HF. Longitudinal changes in LDCW did not predict subsequent incident HF or mortality. Conclusions Completing an LDCW is strongly associated with lower 10-year mortality and HF risk in older adults. Therefore, walking capacity may serve as an early risk marker.
Abstract Background A systematic assessment of the temporal trends in heart failure (HF) clinical trials is lacking. Methods and Results A total of 154 phase II–IV HF trials including 162,725 ...patients published from 2001 to 2012 in 8 high-impact-factor journals were reviewed. The median number of participants and sites per trial were 367 (interquartile range IQR 133-1450) and 38 (5–101), respectively. Median enrollment duration was 2.2 (1.5–3.3) years. The majority of studies investigated treatment for chronic HF (82.5%) and investigated HF with reduced ejection fraction (EF) (71.4%), whereas 27 trials (17.5%) enrolled patients with mixed EF and 9 (5.8%) enrolled HF with preserved EF patients alone. Enrollment rates did not significantly change over time (median 0.49 patients site−1 month−1 , IQR 0.34–0.98; P = .53). Trials meeting their primary end point decreased over time from 73.5% in 2001–2003 to 52.5% in 2010–2012 ( P = .08) and were more often smaller and used nonmortality end points. Industry trials were larger with shorter enrollment duration, more concentrated in North America, and more likely to be positive. Trials conducted exclusively outside North America and Western Europe had the highest enrollment rates (median 1.95 patients site−1 month−1 , IQR 1.34–4.11). Conclusions Contemporary HF clinical trials display slow enrollment rates and decreased rates of positive outcomes over time. Positive trials tended to be smaller size with a higher proportion of surrogate end points.
Abstract Little is known about specific modes of death in patients with heart failure with preserved ejection fraction (HFpEF). Herein, the authors critically appraise the current state of data and ...offer potential future directions. They conducted a systematic review of 1,608 published HFpEF papers from January 1, 1985, to December 31, 2015, which yielded 8 randomized clinical trials and 24 epidemiological studies with mode-of-death data. Noncardiovascular modes of death represent an important competing risk in HFpEF. Although sudden death accounted for ∼25% to 30% of deaths in trials, its definition is nonspecific; it is unclear what proportion represents arrhythmic deaths. Moving forward, reporting and definitions of modes of death must be standardized and tailored to the HFpEF population. Broad-scale systematic autopsies and long-term rhythm monitoring may clarify the underlying pathology and mechanisms driving mortal events. There is an unmet need for a longitudinal multicenter, global registry of patients with HFpEF to map its natural history.
Highlights • Enrollment criteria used in advanced heart failure clinical trials vary widely. • New York Heart Association class and left ventricular ejection fraction are the most frequent criteria. ...• Cutoff points for quantitative criteria vary considerably. • Average left ventricular ejection fraction among participants increased over time.
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