Cased Based Approaches to Treatment of Pregnancy and Anthracycline Cardiomyopathy

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1 Cased Based Approaches to Treatment of Pregnancy and Anthracycline Cardiomyopathy JEAN-BERNARD DURAND, M.D., FCCP, FACC,FACP,FHFSA,FAHA PROFESSOR OF MEDICINE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER MEDICAL DIRECTOR CARDIOMYOPATHY SERVICES DIRECTOR CARDIOVASCULAR GENETICS RESEARCH CO-CHAIR IRB HOUSTON, TEXAS

2 Jean-Bernard Durand, M.D. Presenter Disclosure Information I will not discuss off label use and/or investigational use in my presentation. I have the following financial relationships to disclose: Funding-NHLBI,NIH,NCI/American Cancer Society Employee of: University of Texas MD Anderson Cancer Center

3 The Initial Pre-Pregnancy Consult Higher risk of development of LVSD from Prior Anthracycline Cardiomyopathy (2.35 Fold) If concerns of pregnancy, avoid use of Ace-I, Hydralazine/Nitrates/Carvedilol Risk Management Goals for Modifiable risk factors: DM, Blood pressure, Afib and any symptoms of heart failure Fertility counseling Treated as high risk, Monthly History & Physical We have very low threshold for non-invasive Imaging

4 LVEF (EF units) Carvedilol Dose-Response Trial (MOCHA * ): Effect on Ejection Fraction and Mortality Changes in LVEF Placebo 6.25 mg bid 12.5 mg bid 25 mg bid Carvedilol Patients receiving diuretics, ACE inhibitors, ± digoxin; follow-up 6 months; placebo (n=84), carvedilol (n=261). * Multicenter Oral Carvedilol Heart Failure Assessment. Adapted from Bristow MR et al. Circulation. 1996;94: P<.05 vs placebo.

5 Blood. 118(23); Risk Of CHF Increases with CV RF and Anthracycline

6 Mean Biopsy Grade Cardiotoxicity occurs earlier than change in EF Doxorubicin was given IV every 3 to 4 weeks. Biopsy specimens were taken approximately 3 weeks following last therapy. 3 Mackay MDAH n=7 2 Billingham Stanford n=22 n=8 n=3 1 n=8 n=18 5% * 0 *Risk of CHF >500 Cumulative Doxorubicin Dose (mg/m2) Adapted from Ewer et al. J Clin Oncol 1984;2:

7 Lipshultz SE, et al Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation. Oct ;128(17): Application to Onco-Cardiology Female sex and younger age at time of cancer diagnosis are risk factors for anthracycline induced asymptomatic cardiac dysfunction Hypertension Prior cardiomyopathy, Including Familial Anthracycline dose prior to pregnancy Time from Cancer treatment to 1 st Pregnancy

8 Case #1 Patient with history of ALL diagnosed in 1998 at age 17 Treatment with total cumulative anthracycline dose of 233.3mg/m2 Other PMH: neurofibromatosis type 1, osteoporosis, avascular necrosis of bilateral hips, cerebral palsy Pregnancy in 2002 (age 21), delivered prematurely by C-section, child with autism

9 Case #1 Routine echo ordered March 2004, EF was 40-45% Patient had mild SOB and fatigue, NYHA class 2 She was also 10 weeks pregnant

10 Case #1 Started Carvedilol 6.25mg po bid Symptoms resolved and systolic function normalized during the pregnancy Echo in July 2004, in 2 nd trimester, EF 55-60%

11 Case #1 After 2nd trimester, presents with complaints of palpitations occurring once per week. Holter shows, NSR, Repeat Echo shows LVEF unchanged (normal LA Size/Vol index) What are next steps? Increased Coreg to 12.5mg BID & add ASA 81mg Continue with same therapy EP Study Implantable Loop recorder

12 Indications for Reveal Monitor Diagnosis: Syncope Diagnosis of Atrial Fibrillation/Atrial Flutter Management of Arrhythmia Palpitations Cryptogenic Stroke

13 Implantation of Loop Recorder-Cellular Based

Reveal XT Patient Assistant Physician Programmable Query Notifications Eight different physician programmable query notifications via the Patient

14 Reveal XT Patient Assistant Physician Programmable Query Notifications Eight different physician programmable query notifications via the Patient Assistant Programmer interrogation resets all Query notifications Medtronic CareLink System interrogation resets only the Arrhythmia Query notifications

15 Case #1 Monitor revealed short runs of Atrial flutter with RVR, (Aflutter burden 16% Symptomatic/asymptomatic Increased Cardvedilol to 12.5mg BID Follow up one month later she is asymptomatic Aflutter Burden documented to be < 1% per day

16 Case Study #2 31 Y/O Female S/P Allogeneic SCT 11/10. Uncomplicated delivery at 36 weeks (6/2013). Presents with 2 weeks Atypical Chest pain, NYHA Class III symptoms and fevers. H/O GVH disease Electively Intubated 48 Hours after admission BNP=1439 and peak troponin=9.3. Plts=12,000 Pre=SCT LVEF=60%, EKG-Diffuse ST Elevation

17 Abnormal Strain and LVEF with RV Collapse GLPS=-13.1%

18 Case Study #2 Prior to Initiation of therapy, She has several beat runs of NSVT. What is the etiology of his LVSD? Are Viral Titers in this patient population important? Pericarditis/Myocarditis? Once Euvolemic, Carvedilol/Valsartan/IVIG/Steroids/Other? MDACC is to consider Non-invasive vs Invasive approach CMR in high volume centers would be highly considered for diagnosis Invasive approach EMBx in experienced center is also reasonable

19 Etiologic Agents of Myocarditis Viral (Most Common) Adenovirus Coxsackie B, enterovirus ****Cytomegalovirus Parovirus B19 Hepatitis C virus HIV Herpesvirus Epstein-Barr virus *H1N1 Bacterial Myobacterial species Chlamydia pneumoniae Streptococcal species Myoplasma pneumoniae Treponema pallidum Fungal Aspergillus Candida Coccidioides Cryptococcus Histoplasma Protozoal Trypanosoma cruzi Parasitic Schistosomiasis Larva migrans Hypersensitivity Clozapine Sulfonamides Cephalosporins Penicillins Tricyclic antidepressants Autoimmune Activation Smallpox vaccine Giant cell myocarditis Churg-Strauss syndrome Sjogren syndrome Celiac disease Sarcoidosis SLE Takayasu arteritis Wegener granulomatosis

20 EMBx=Myocarditis Normal LHC Pericardiocentesis- No Malignant cells, Mixed Acute/Chronic Inflammatory cells MultiFocal inflammatory Infiltrate. MP,Neut,Eos

21 Improvement of GLPS and LVEF Treated with IVIG for Myocarditis/GVH? GLPS=-18.4%

CMR for Diagnosis of Myocarditis MRI Findings in Patients with Myocarditis Cardiac magnetic resonance imaging (MRI) images of a young patient presenting with acute chest pain syndrome due to acute

22 CMR for Diagnosis of Myocarditis MRI Findings in Patients with Myocarditis Cardiac magnetic resonance imaging (MRI) images of a young patient presenting with acute chest pain syndrome due to acute myocarditis. (A) Long-axis and (B) short axis T2-weighted edema images demonstrating focal myocardial edema in the subepicardium of the left midventricular lateral wall (red arrows). Corresponding (C) long-axis and (D) short-axid T1-weighted late gadolinium enhanced images demonstrate presence of typical gadolinium enchancement in the sbuepicardium of the left midventricular lateral wall and the basal septum (red arrows). Kinderman et al., J Am Coll Cardiol 59(9):

23 Case #3 Patient diagnosed with non-hodgkins lymphoma in 1981 at age 16 Adriamycin 480 mg/m2 Amenorrhea after treatment On OCPs until 1998 Stopped OCPs as she thought she was infertile Pregnancy 3 months later at age 33 Reported normal EF prior to pregnancy

24 Case #3 CHF and toxemia at 22 weeks C-section at 26 weeks, daughter with cerebral palsy Treated with Coreg and Captopril with EF of 50% in 2004 In 2013 in setting of H1N1 influenza, EF decreased to 35% At last f/u in 2015, EF 33% with restrictive LV filling pattern, remains on Carvedilol and Captopril

25 Current Guidelines Dutch Echo in 3 rd trimester International Echo before pregnancy or in 1 st trimester Recommendations have not been formulated for ongoing surveillance in pregnant survivors who have normal EF before or in 1 st trimester Sieswerda E, Ann Oncol 2012 Armenian SH, Lancet Oncol 2015

26 Studies EJ of Cancer-vanDalen 2006 Retrospective 53 women Mean anthracycline dose 267mg/m2 2 with CHF following anthracyclines CHF definition = signs/sx No echocardiograms No CHF Low Incidence of CHF American J of OB & Gyn Bar 2003 Prospective 37 women All with anthracycline dose <500mg/m2, mean 400mg/m2 29 with FS > 30%, none with CHF with pregnancy 8 with FS < 30%, 2 of 8 with CHF at delivery, 1 recovered and 1 did not Low Incidence and recovery

27 Recent Study Retrospective 847 patients, 1554 pregnancies Median anthracycline dose 200mg/m2 CMP = EF < 50%, FS < 28%, tx for CMP 43 with CMP 3 with pregnancy (0.3%) 26 prior to pregnancy 8 deteriorated 3 of 8 had normalized before pregnancy 5 after pregnancy Hines MR, J Cancer Surviv 2015.

28 Comparison Incidence of PPCM is 1 in in US, i.e. about 0.03% Incidence of pregnancy assoc. CMP in CCS was 0.3% in Hines study Patients were identified from self reported cardiac events Our experience at MDA higher, 12% incidence of CMP assoc. with pregnancy in CCS More frequent screening of LV function? Sliwa K, European Journal of Heart Failure, 2010.

29 Conclusions Differential Diagnosis should be considered in young women with PPCM Non-invasive approach is ideal, CMR and invasive approaches should be considered at High Volume Centers Recovery of LV function is common with anthracycline provided diagnosis is made early and treatment is started immediately. Management of Modifiable Comorbid conditions may have an important role in successful outcomes

30 Thank you! Twitter- Jean-Bernard

Myocarditis and Pericarditis

Myocarditis and Pericarditis Elias V. Haddad, M.D., FACC Advances in Cardiovascular Care 2012 Kingston, Jamaica December 7, 2012 Financial Disclosures No disclosures relevant to this presentation Learning