Copyright by Teresa A. Mann 2012 The Dissertation Committee for Teresa A. Mann Certifies that this is the approved version of the following dissertation: The Cost-Effectiveness of Cardiac Monitoring in Breast Cancer Patients Who Have Received Cardiotoxic Therapies Committee: Karen L. Rascati, Supervisor Grant H. Skrepnek Kenneth A. Lawson James P. Wilson Scott A. Strassels The Cost-Effectiveness of Cardiac Monitoring in Breast Patients Who Have Received Cardiotoxic Therapies by Teresa A. Mann, B.S., PharmD Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin May 2012 Acknowledgements I would like to thank my dissertation committee members for their contributions to this project. I would especially like to thank my major professor, Dr. Karen Rascati, for her continued guidance and support throughout this process. I would also like to acknowledge the rest of my dissertation committee Dr. Grant Skrepnek, Dr. Ken Lawson, Dr. James Wilson, and Dr. Scott Strassels for their participation and valuable feedback. I am also grateful to Dr. JoLaine Draugalis for her mentorship and encouragement throughout graduate school. iv The Cost-Effectiveness of Cardiac Monitoring in Breast Cancer Patients Who Received Cardiotoxic Therapies Teresa A. Mann, PhD The University of Texas at Austin, 2012 Supervisor: Karen L. Rascati It has been known that anthracycline-based chemotherapy has the potential to cause cardiac dysfunction in breast cancer patients; however, recently evidence has shown that the addition of trastuzumab increases this risk. The study objective was to compare the cost-effectiveness of monitoring for cardiotoxicity with B-type natriuretic peptide (BNP), multi-gated acquisition scanning (MUGA), echocardiography (ECHO) or no monitoring from a payer’s prospective. Cost-effectiveness was compared between alternatives using an incremental cost-effectiveness ratio with outcomes of 1) quality- adjusted life-years and 2) percentage of patients diagnosed with each monitoring strategy. Costs estimates (in 2010 U.S. Dollars) of each strategy (obtained from the Center for Medicare and Medicaid Services website [www.cms.gov]) included the cost of the test, cost of treating heart failure once discovered (which includes medications, routine office visits, medication management) and the cost of potential acute care (which includes emergency department visits and hospitalizations). Estimates for the probabilities of heart failure development, disease progression, need for acute care, and mortality, as well as utility estimates for all disease stages were obtained from published literature. A 15-year time-frame was used with a 3% discount rate for both costs and QALYs. v In the base-case analysis, the average costs and QALYs for monitoring patients were $10,062/ 6.92 QALY, $13,627/4.22 QALY, $14,739/ 6.61 QALY and $15,656/ 6.49 QALY for BNP, No Monitoring, ECHO and MUGA respectively. When comparing all alternatives to BNP, the ICER values were negative, indicating that BNP was the dominant monitoring strategy. Percent detection was similar between the three monitoring methods [21-22 % for HER-2(-) and 30-31% for HER-2(+) patients]. Again BNP was dominant over the other monitoring strategies. Sensitivity analyses were robust to changes in discount rate, probability of patients testing HER-2 (+), probability of patients being diagnosed in an asymptomatic stage, incidence of cardiac dysfunction in patients receiving anthracycline therapy ± trastuzumab and estimate of disutility associated with additional testing. A probabilistic sensitivity analysis conducted via Monte Carlo simulation led to the same conclusion as the base-case analysis; BNP was the dominant strategy over all monitoring alternatives. vi TABLE OF CONTENTS List of Tables ....................................................................................................... xiii List of Figures .................................................................................................... xviii List of Abbreviations .............................................................................................xx Chapter One: Background........................................................................................1 1.1 Introduction .....................................................................................................1 1.2 Overview .........................................................................................................3 1.3 Breast Cancer ..................................................................................................5 1.3.1 Disease Process/Epidemiology ..............................................................6 1.3.2 Risk Factors ...........................................................................................7 1.3.3 Risk-Reduction Strategies ....................................................................16 1.3.4 Screening..............................................................................................17 1.3.5 Staging/Classification ..........................................................................26 1.3.6 Treatment Options ...............................................................................33 1.3.6.1 Surgery ...............................................................................34 1.3.6.2 Radiation ............................................................................35 1.3.6.3 Chemotherapy ....................................................................37 1.3.6.4 Hormone Therapy ..............................................................40 1.3.6.5 Trastuzumab .......................................................................40 1.3.7 Response to Therapy ............................................................................41 1.3.8 Surveillance/Follow-Up .......................................................................47 1.3.9 Disease Recurrence ..............................................................................49 1.3.10 Non-Cardiac Consequences of Therapy .....................................51 1.3.11 Outcomes/Mortality/ Prognosis ..................................................59 1.4 Heart Failure .................................................................................................63 1.4.1 Disease Process ....................................................................................63 1.4.2 Classification........................................................................................66 1.4.3 Treatment .............................................................................................68 vii 1.4.4 Outcomes/ Assessment of Therapy ......................................................73 1.4.5 Prognosis ..............................................................................................75 1.4.6 Mortality ..............................................................................................79 1.5 Summary of Chapter One .............................................................................82 Chapter Two: Cardiovascular Complications of Breast Cancer Therapy ..............83 2.1 Introduction ...................................................................................................83 2.2 Mechanism of Cardiotoxicity .......................................................................84 2.3 Cardiotoxicity of Specific Agents.................................................................85 2.3.1 Anthracyclines .....................................................................................85 2.3.2 Other Chemotherapy Agents................................................................88 2.3.3 Trastuzumab .........................................................................................89 2.4 Toxicity Criteria ............................................................................................92 2.5 Heart Failure in Breast Cancer ......................................................................96 2.5.1 Incidence/Prevalence ...........................................................................97 2.5.2 Risk Factors .........................................................................................98 2.5.2.1 Combination Therapy ......................................................101 2.5.2.2 Dose-Dependence ............................................................104 2.5.3 Preventive Strategies ..........................................................................108 2.5.3.1 Pegylated/Liposomal Anthracycline Formulations..........110 2.5.3.2 Anthracycline Analogs.....................................................113 2.5.3.3 Protective Agents .............................................................117 2.5.4 Management of Cardiotoxicity ..........................................................119 2.5.4.1 Medications ......................................................................121 2.5.4.2 Surgical Options...............................................................124 2.5.5 Outcomes/Prognosis ..........................................................................126 2.5.6 Economic Implications ......................................................................128 viii 2.6 Summary of Chapter Two...........................................................................130 Chapter Three: Detection of Cardiotoxicity ........................................................132