Cohort Study Showed a Large Number of Patients Receiving Anticancer Therapy Demonstrate Myocardial Injury or Left Ventricular Dysfunction, With Only Few Showing Severe Cardiotoxicity

A recent study by Dr. Lopez-Sendon, published in European Heart Journal, showed that cardiotoxicity in the form of left ventricular dysfunction or myocardial injury affects a large portion of patients receiving high-risk anticancer therapy with only severe form strongly associated with all-cause mortality.

Cardiotoxicity has been known as one of the major side effects of anti-cancer therapy that may present with left ventricular dysfunction and heart failure. Given that the early recognition and treatment of these side effects have been associated with a higher recovery rate, a united diagnostic and management guideline seems necessary.

The CARDIOTOX (CARDIOvascular TOXicity induced by cancer-related therapies) registry has been established to determine the prevalence of cardiotoxicity markers as well as their association with guideline-based heart failure criteria and treatment in patients receiving chemotherapeutic agents. To achieve this purpose, a total of 865 patients receiving anticancer regimens associated with moderate to high cardiotoxicity were selected and followed for a median of 24 months. Clinical data, blood samples, and echocardiographic features were collected before the initiation of anticancer therapy and then at 3 weeks, 3 months, 6 months, 1 year, 1.5 years, and 2 years afterward. Patients with past or current history of heart failure or reduced left ventricular ejection fraction (< 40%) and those with a history of previous cancer therapy including chemotherapy and radiation therapy were excluded from the study. Cardiotoxicity was defined as any new deterioration from the baseline of myocardial/ventricular function during follow-up periods. Cardiotoxicity was also sub-classified into four stages depending on the worst myocardial dysfunction/injury observed in the follow-up period. Myocardial dysfunction/injury stages include the following: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥ 50%; moderate, LVD with LVEF 40–49%; and severe, LVD with LVEF ≤ 40% or symptomatic heart failure.

The study indicated a high incidence (37.5%) of ventricular dysfunction among the patients, of whom only 3.1% were classified as having severe dysfunction and the majority have been classified as mild (31.6%). All-cause mortality was also observed to be higher among those with severe cardiotoxicity than other groups. According to the author, the relatively low prevalence of severe cardiotoxicity in the study population was due to the exclusion of patients with a previous history of cardiac dysfunction and the improvement in the follow-up of the cancer patients in the context of cardio-oncology service. Severe cardiotoxicity has also been associated with a 10-fold increase in total mortality compared to a less severe form of cardiotoxicity. A classification of cardiotoxicity using current heart failure guidelines is also proposed by the authors for future studies. This study acknowledged the critical role of comprehensive monitoring and follow-up for the development of cardiovascular symptoms and left ventricular dysfunction in patients receiving chemotherapeutic agents with potential cardiotoxicity.

Limitations that are worthy of mentioning include the inclusion of patients with some degree of abnormality in biomarkers and echocardiographic findings at baseline. Secondly, the prevalence of myocardial damage may be underestimated due to a number of missing visits or incomplete data collection during the follow-up period. Future research is warranted to approve the relationship of different stages of cardiotoxicity with clinical outcomes.

Findings From a Randomized Controlled Trial May Usher the Adoption of Angiotensin–Neprilysin Inhibition to the Heart-Failure Armamentarium Presented At the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA.

The results of a trial presented by Dr. Adam DeVore at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, reflected that among patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure, the initiation of sacubitril–valsartan therapy led to a greater reduction in the NT-proBNP concentration as compared with enalapril therapy. In addition to this, the rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two arms. Continue reading

NT-ProBNP-Guided Medical Therapy Failed To Show Superiority Compared To Usual Care In HFrEF Results from the GUIDE-IT trial

Results of a multi-center, randomized clinical trial which enrolled 894 patients with heart failure (HF) with reduced ejection fraction (EF ≤40%) published in the most recent issue of the Journal of the American College of Cardiology (JACC) have shown that management, using NT-ProBNP-guided optimal medical therapy, has higher total costs and fails to show superior efficacy in improving quality of life (QoL) outcomes compared to usual care (titration of guideline-recommended therapy to doses established in pivotal clinical trials).

The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial planned to prospectively enroll 1100 patients from 45 clinical sites in the United States and Canada. After a scheduled review by the DSMB, the study was stopped for lack of efficacy of the biomarker-guided strategy. The patients included in the study presented with chronic HF and an EF of ≤40%; these subjects were randomly assigned in a 1:1 fashion to an NT-proBNP-guided treatment strategy (n=446) or usual care (n=448). Patients in the NT-proBNP- guided strategy received medical therapy with a goal of achieving a NT-proBNP level <1000 pg/ml. Structured evaluations performed at baseline and 3, 6, 12, and 24 months post-randomization were employed to collect and compare data on quality of life (QoL). The Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and the Duke Activity Status Index (DASI) were used to stratify pre-specified QoL measures. In addition, researchers examined the costs associated with either treatment strategy in 735 US patients. The results showed that both the KCCQ and the DASI improved over the first 6 months ( 11-point improvement in the 4 KCCQ composite scales which included physical limitations, total symptoms, QoL, and social limitations), but no evidence was found for a strategy-related difference (mean difference [biomarker-guided usual care] at 24 months of follow-up, 2.0 for DASI [95% confidence interval (CI): 1.3 to 5.3] and 1.1 for KCCQ [95% CI: 3.7 to 5.9]). Albeit the lack of strategy-related difference, both treatment arms did show improvements in KCCQ and DASI scores overall. Total winsorized costs (to reduce the effect of possibly false outliers) averaged $5,919 higher in the biomarker-guided strategy (95% CI: $1,795 + $13,602) over 15-month median follow-up.

“The big message from GUIDE-IT, or a big message from GUIDE-IT, is that, regardless of which arm you ran patients on or who got treated more aggressively, when we were able to get their NT-proBNP levels down, the lower did better regardless of which treatment arm they were in.” – G. Michael Felker, MD, MHS (Duke University Medical Center)

Previous trials have revealed various effective management strategies for HF patients that lead to symptomatic relief (primarily dyspnea) and improve prognosis but other major symptoms such as fatigue and exercise intolerance have not been well correlated with either central measures of cardiac performance or measures of patient-reported QoL. Indeed, most of the clinical trials of effective medical therapies in HF that included QoL measurement showed small or no changes in QoL. NT‐proBNP has emerged as a powerful biomarker in various cardiovascular diseases and serves to provide strong and independent prognostic information in patients with heart failure. The investigators of the GUIDE-IT trial aimed to study whether the attempt to achieve a sufficiently low NT-proBNP level would affect QoL either beneficially or adversely. The investigators concluded that they found no evidence of a QoL effect associated with randomization to the strategy of NT-proBNP– guided therapy. In 735 patients enrolled in the United States, medical costs were increased in the biomarker-guided arm, primarily due to extra hospital-based care.

The limitations of the study included early termination with less follow-up time than was planned for in the trial design, secondly the unblinded nature of the analyses may have contributed to the lack of benefit seen in the biomarker-guided arm. Thirdly, both groups had more frequent medical contacts related to study participation compared to standard of care.