MADIT-CHIC: Cardiac Resynchronization Therapy in the Treatment of Chemotherapy-Induced Cardiomyopathy

According to the National Cancer Institute, approximately 14 million Americans with a history of cancer were alive in 2012. Survival from cancer has improved significantly over the last several decades due in large part to advances in therapy. In 2013, approximately 1.7 million new patients were expected to be diagnosed with cancer.¹ Many of these patients will have their cancer treated with chemotherapies that have the potential for cardiotoxicity. These treatments include anthracyclines such as doxorubicin, as well as newer targeted therapies including trastuzumab and vascular endothelial growth factor (VEGF) signaling pathway inhibitors.

These newer agents target cellular pathways that are implicated in a variety of cancers, but these pathways also have important roles in cardiovascular biology and set the stage for potential toxicity. 

With improved survival from cancer, many patients will face increased risks of chemotherapy- and radiotherapy-associated cardiovascular disease. In addition to cardiomyopathy, there is a broad range of potential cardiovascular complications from chemotherapy and radiotherapy, including hypertension, QT prolongation, ischemic complications, arterial and venous thrombosis, pericardial disease, and valvular disease. 

Cardio-oncology is the discipline which focuses on the intersection of cancer and cardiovascular disease. A better understanding of the incidence, mechanism, and risk factors for developing cardiotoxicity will lead to more effective screening programs and preventive strategies, including the use of cardioprotective interventions. As a new field, cardio-oncology represents a multidisciplinary collaboration between cardiologists and oncologists working together to optimize the long-term health of cancer patients. From the cardiovascular perspective, cancer patients can present with a broad spectrum of conditions. Collaboration amongst clinical cardiologists, cardiac imagers, interventional cardiologists, heart failure specialists, electrophysiologists, vascular specialists, and cardiothoracic surgeons is necessary to manage the broad spectrum of cardiovascular disease in these patients. 

Patients with chemotherapy-induced cardiomyopathy can present with a rather advanced NYHA classification with less left ventricular (LV) dilatation compared to other populations with non-ischemic cardiomyopathy. In the case of anthracyclines, it is a dose-dependent cardiomyopathy, which can present several years after exposure to chemotherapeutic agents and has been associated with significant mortality. The overall incidence of chemotherapy-induced cardiomyopathy is significantly underestimated, as within the U.S. alone, greater than 60,000 patients receive anthracyclines every year.² Patients with chemotherapy-induced cardiomyopathy with advanced heart failure have a worse prognosis when compared to other types of heart failure.³ A new research study will now be available for these patients with the hopes of improving outcomes in this unique population. 

The Multicenter Automatic Defibrillator Implantation Trial – Chemotherapy-Induced Cardiomyopathy (MADIT-CHIC) was conceived through collaboration between Dr. Arthur Moss of the University of Rochester Medical Center and members of the Resynchronization and Advanced Cardiac Therapeutics and Cardio-Oncology Programs at Massachusetts General Hospital. Dr. Moss has previously led several landmark studies demonstrating the benefits of ICD and CRT-D therapies in patients with congestive heart failure, which in turn have led to improvements in patient outcomes and major advancements in practice guidelines in the field of electrophysiology. There have previously been only a few single-center, small observational studies showing a significant beneficial effect of cardiac resynchronization therapy in patients with chemotherapy-induced cardiomyopathy.^4,5

Led by Dr. Moss as well as Dr. Jagmeet Singh of Massachusetts General Hospital, MADIT-CHIC will be the first prospective study of the cardiac resynchronization therapy defibrillator (CRT-D) in chemotherapy-induced cardiomyopathy. The study will seek to enroll 100 patients, and will include approximately 12 institutions across the United States.

The primary objective of the trial is to determine if CRT-D in high-risk patients with chemotherapy-induced cardiomyopathy will significantly improve the left ventricular ejection fraction (LVEF), as determined by echocardiography within six months of initiating CRT, without adversely affecting mortality.

 The secondary objectives are to determine the effects of CRT on all-cause mortality, left ventricular volumes (at end systole and end diastole), and on NYHA functional class when compared to baseline. Additionally, during the six-month observational period, the effects of CRT on standard heart failure endpoints (hospital admissions, changes in diuretic therapy, etc.) will be analyzed.

The inclusion criteria for the MADIT-CHIC trial are male or female patients over the age of 18 with sinus rhythm, an LVEF ≤35%, and either (1) left bundle branch block with a QRS duration >120 ms, and NYHA class II, III, or ambulatory IV symptoms, on stable guideline-directed medical therapy, or (2) non-left bundle branch block with a QRS duration ≥150 ms, and NYHA class III or ambulatory IV symptoms, on stable guideline-directed medical therapy. Additionally, two calendar years must have passed since the patient’s last chemotherapy treatment. 

A unique aspect of this trial is its emphasis on the growing field of cardio-oncology. As survival from cancer continues to improve, it is imperative that we focus on the cardiovascular risk of this population to ensure long-term health. Heart failure due to cancer therapy includes traditional chemotherapies like anthracyclines as well as the expanding arsenal of targeted therapies. The care of cancer survivors with congestive heart failure is multidisciplinary and includes internists, oncologists, cardio-oncologists, heart failure specialists, and electrophysiologists. Cardio-oncology programs like the one at Massachusetts General Hospital are being formed at institutions worldwide in response to this expanding patient population. This clinical trial will further develop these collaborations and set the stage for future investigations to improve the cardiovascular health of cancer survivors.

Disclosures:  The authors have no conflicts of interest to report regarding the article herein. Outside the submitted work, Dr. Francis reports he is a consultant for Clovis, and has received honorarium from Medtronic for an educational symposium.

References

1. Cancer Facts & Figures 2013. American Cancer Society. Available online at https://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed June 3, 2014.
2. Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracyline therapy. JAMA. 1991;266:1672-1677.
3. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342(15):1077-1084.
4. Rickard J, Kumbhani DK, Baranowski B, et al. Usefulness of cardiac resynchronization therapy in patients with Adriamycin-induced cardiomyopathy. Am J Cardiol. 2010;105:522-526.
5. Ajijola OA, Nandigam KV, Chabner BA, et al. Usefulness of cardiac resynchronization therapy in the management of Doxorubicin-induced cardiomyopathy. Am J Cardiol. 2008;101:1371-1372.