4/5/2017 Chemotherapy‐Related Cardiac Dysfunction & How a Cardiology‐Oncology Clinic Can Help! April 22, 2017 Maria Anwar, BScPharm, ACPR [email protected] Key Learning Objectives • To provide a brief background about cardio‐oncology • To define of chemotherapy‐related cardiac dysfunction and review the incidence, mechanism and risks associated with various agents • To highlight an approach to care and patient risk assessment • To review the Canadian Cardiovascular Society Guidelines for the Evaluation and Management of Cardiovascular Complications of Cancer Therapy and select clinical trials including: strategies for prevention, detection & surveillance and treatment of chemotherapy‐related cardiac dysfunction • To share the South Health Campus (SHC) Cardio‐Oncology Clinic service model • To discuss implications for pharmacists and patients Cardio‐Oncology • Emerging subspecialty that aims to “optimize cardiac care for cancer patients” • Increasing rates of both cancer survival and morbidity & mortality from cardiovascular causes • Shared population & risk factors • Cardiovascular health linked to improved cancer outcomes • Multidisciplinary collaboration • “Cure Cancer, Save Hearts” CJC 2016; 831‐841 Family & Friends Support Services Resources Community Cancer Treatment Cardiac Status Patient Cardiology Team Canadian Cardio‐Oncology Network (CCON) http://cardiaconcology.ca/ Chemotherapy‐Related Cardiac Dysfunction LVEF Symptoms A At high risk for HF No cardiac dysfunction No B1 Occult LV dysfunction LVEF > 53%, abnormal strain and/or cardiac biomarkers No B2 Overt LV dysfunction LVEF < 53% No C Symptomatic HF, responsive to conventional therapy LVEF < 53% Yes Symptomatic HF, LVEF < 53% (usually lower) unresponsive to conventional therapy Anthracyclines Cancer Treatment Stage Definition D Cancer Oncology Team Persistent NYHA IV Adapted from: CJC 2016; 891‐899 • Mechanism: Cancer Treatment • Early (1.6 – 2.1%) – Enter nuclear DNA impaired protein synthesis & production of reactive oxygen species – Bind to DNA and topoisomerase II‐beta in cardiac myocytes myocardial damage & cell death – Cumulative dose related – Within first year of treatment – Can be asymptomatic, continuous progressive decline in LVEF – Usually irreversible good functional recovery if detected and treated early with HF medications • Late (1.6 – 5%) • Acute (< 1%): – Immediately after transfusion – Transient LV dysfunction, supraventricular arrhythmias and ECG changes – Usually reversible myocyte injury can evolve into early or late cardiotoxicity CJC 2016; 831‐841 – After first year of treatment – Decline LVEF followed by clinical decompensation – Usually irreversible EHJ 2016; 37: 2768‐2801 Circ Heart Fail 2016; e002661 1 4/5/2017 HER2‐Inhibitors • Incidence: trastuzumab (1.7‐ 20.1%), pertuzumab (0.7‐1.2%), lapatinib (0.2‐1.5%) • Mechanism (trastuzumab): binds to human epidermal receptor 2 (HER2) protein on cardiac myocyte inhibiting ErbB2‐ErbB4 signaling disables cell growth pathway activated during times of myocardial stress myocardial dysfunction CJC 2016; 831‐841 • Features: – – – – Usually appears during treatment Generally not dose related Likely reversible Concomitant or previous use of anthracyclines or paclitaxel increases risk EHJ 2016; 37: 2768‐2801 Other Agents Cancer Treatment Cancer Treatment Alkylating agents • Incidence: cyclophosphamide (7‐28%), ifosfamide (0.5‐17%) • Mechanism: direct endothelial injury cardiomyocyte damage and edema • Features: usually occurs within 1‐14 days after administration, likely single high‐dose related, may be reversible or irreversible VEGF Inhibitors Incidence: bevacizumab (1.6‐4%), sunitinib (2.7‐19%), sorafenib (4‐8%), dasatinib (2‐ 4%), imatinib (0.2‐2.7%) Mechanism: inhibition of vascular endothelial growth factor receptor mediated angiogenesis mitochondrial damage Features: generally reversible Antimicrotubule agents • Incidence: docetaxel (2.3‐13%), paclitaxel (< 1%) • Mechanism: impair cell division, interfere with metabolism & excretion of anthracyclines (potentiate risk) myocyte damage Proteasome inhibitors Incidence: bortezomib (2‐5%) Mechanism: impaired proteasome mediated maintenance of cardiomyocytes myocardial dysfunction BJC 2009; 684‐692 Circ Heart Fail 2016; e002661 CJC 2016; 831‐841 EHJ 2016; 37: 2768‐2801 Circ Heart Fail 2016; e002661 Cancer Approach to Care Risk Assessment Patient 1. Identify patients at increased risk of developing chemotherapy‐ related cardiac dysfunction 2. Optimize management of cardiovascular risk factors and co‐ morbidities 3. Monitor patients while receiving chemotherapy 4. Monitor patients after completion of chemotherapy (surveillance) 5. Manage patients that experience chemotherapy‐related cardiac dysfunction with medications and lifestyle recommendations CJC 2016; 831‐841 JCO 2017; 893‐911 1. 2. 3. 4. History Physical exam Evaluation of LV function ECHO, CMR, MUGA Cardiac biomarkers troponin, NT‐proBNP Patient Factors: • Advanced or young age • Female (anthracycline) • Hypertension • Diabetes • Dyslipidemia • Obesity • Smoking • Family history • Sedentary CJC 2016; 831‐841 Prevention “We recommend evaluation of traditional cardiovascular risk factors and optimal treatment of cardiovascular disease, as per current CCS guidelines, be part of routine care for all patients before, during, and after receiving cancer therapy (Strong Recommendation, Moderate-Quality Evidence). We recommend that patients who receive potentially cardiotoxic cancer therapy undergo evaluation of LV ejection fraction (LVEF) before initiation of cancer treatments known to cause impairment in LV function (Weak Recommendation, Moderate-Quality Evidence).” CJC 2016; 831‐841 Cardiac Status Cardiac Factors: • Heart failure • Left ventricular dysfunction • Coronary artery disease • Moderate or severe valvular heart disease • Arrhythmias • Cardiomyopathy • Cardiac sarcoidosis involving myocardium Cancer Treatment Factors: • High cumulative dose of anthracycline • Timing of administration of anthracycline and other chemotherapy (ie. trastuzumab, cyclophosphamide, paclitaxel) • Prior anthracycline use • Prior or current radiation therapy involving the heart • Curative vs palliative intent EHJ 2016; 37: 2768‐2801 CCS Guidelines: Risk Assessment Cancer Treatment • Treat risk factors and co‐ morbidities • Positive health‐promoting behaviour • Cancer treatment considerations JCO 2017; 893‐911 Cancer Treatment EHJ 2016; 37: 2768‐2801 Cardiac Status • Cardioprotective medications – ACEI/ARB – BB – Statins – Less cardiotoxic agents – Limit anthracycline cumulative doses – Administration technique & formulation – Minimize cardiac irradiation CJC 2016; 831‐841 JCO 2017; 893‐911 EHJ 2016; 37: 2768‐2801 2 4/5/2017 MANTICORE 101‐Breast PRADA D RCT, PC, DB, 2 x 2 factorial, ITT, single center in Norway D RCT, PC, DB, ITT, 2 centers in Canada P Adult women with early breast cancer receiving adjuvant chemotherapy with 5‐fluorouracil, epirubicin and cyclophosphamide (FEC) LVEF > 50% No prior cardiac disease ~ 22% received trastuzumab and ~ 80% taxanes after FEC P Adult women with HER2‐postive early breast cancer receiving adjuvant trastuzumab therapy ~67‐87% docetaxel, carboplatin and trastuzumab (TCH) ~13‐30% 5‐fluorouracil, epirubicin and cyclophosphamide followed by docetaxel and trastuzumab (FEC‐DH) LVEF > 50% No prior cardiac disease I Candesartan 32 mg daily + metoprolol succinate 100 mg daily (n=30) Candesartan 32 mg daily + placebo (n=32) Metoprolol succinate + placebo (n=32) Placebo + placebo (n=32) Initiated prior to chemotherapy & continued 10 – 61 weeks (during adjuvant treatment period) C O I Perindopril 8 mg (n=33) or bisoprolol 10 mg (n=31) Initiated within 7 days of trastuzumab & continued during adjuvant period (usually 12 months) C Placebo (n=30) O Primary = change in indexed LV end diastolic volume (LVEDVi in ml/m2) from baseline to completion of trastuzumab therapy: + 7 perindopril, + 8 bisoprolol and +4 placebo (P = 0.36) Secondary = change in LVEF from baseline to completion of trastuzumab therapy by CMR: ‐ 1% bisoprolol vs ‐ 3% perindopril or – 3% placebo (P = 0.001) CTRCD = > 10 percentage decline in LVEF to < 53%: 3% perindopril or 3.2% bisoprolol vs 20% placebo (P = 0.02 post‐cycle 4) (NS post‐cycle 17) Clinical cardiotoxicity = > 7 day interruption in trastuzumab due to LV dysfunction 9% perindopril or 9.7% bisoprolol vs 30% placebo (P = 0.03) Change in LVEF from baseline to completion of adjuvant therapy by CMR: ‐ 0.6% candesartan + metoprolol (P = 0.075 compared to placebo‐placebo) ‐ 0.9% candesartan + placebo (P = 0.025 compared to placebo‐placebo) ‐ 2.5% metoprolol + placebo (P = 0.71 compared to placebo‐placebo) ‐ 2.8% placebo + placebo (control) Secondary = No symptomatic HF No significant change in RVEF, LV GLS, diastolic function, troponin or BNP levels EHJ 2016; 1671‐1680 JCO 2017; 870‐878 Atorvastatin Evidence for Prevention D RCT, single centre Follow up: 6 month after chemotherapy P Patients with non‐Hodgkin lymphoma, multiple myeloma, leukemia treated with regimens containing doxorubin or idarubicin No prior cardiac disease Regardless of lipid levels I Atorvastatin 40 mg daily (n=20) Initiated prior to chemo & continued x 6 months C Control (n=20) O Primary = LV systolic impairment defined as LVEF < 50% by ECHO: not statistically significant 1 patient in atorvastatin group, 5 patients in control group Secondary = Mean change LVEF 6 months after chemotherapy: +1.3% atorvastatin vs ‐7.9% control (P < 0.001) Strengths: Limitations: • RCT data • Low to moderate doses of anthrayclines • With or without trastuzumab • Endpoints with imaging data from CMR • Primary prevention of LVEF decline may reduce long‐term risk of cardiac dysfunction • • • • • • • • JACC 2011; 988‐989 Cardiac Status Small sample sizes Heterogeneity Low cardiac risk Variation in combination and duration of cardioprotective medication regimens Different surrogate primary endpoints Extent of clinical benefit? Exposure to potential side effects & dug interactions Cost CJC 2016; 831‐841 CCS Guidelines: Prevention Cancer Treatment JCO 2017; 893‐911 EHJ 2016; 37: 2768‐2801 Detection & Surveillance “We suggest that in patients deemed to be at high risk for cancer treatment-related LV dysfunction, an ACE inhibitor or angiotensin receptor blocker, and/or beta-blocker, and/or statin be considered to reduce the risk of cardiotoxicity.” • Close monitoring & early detection • Serial determination of LV function – Frequency – LVEF • • • • Weak Recommendation Moderate-Quality Evidence CJC 2016; 831‐841 Bottom line Individualized monitoring strategy tailored based on risk assessment, signs & symptoms of HF & results of cardiac imaging and biomarkers Imaging modality Cardiac biomarkers Local institutional protocols Clinical assessment CJC 2016; 831‐841 JCO 2017; 893‐911 EHJ 2016; 37: 2768‐2801 3 4/5/2017 SHC Cardio‐Oncology Protocol CCS Guidelines: Detection Approved May 12, 2016 “We recommend the same imaging modality and method be used to determine LVEF before, during, and after completion of cancer therapy (Suggestion, Low-Quality Evidence). Adjuvant Herceptin or Kadcyla Anthracycline Based Chemotherapy: (Trastuzumab Based) Treatment: Baseline CMR pre chemo Baseline CMR pre chemo Repeat CMR every 3 months during treatment Repeat CMR every 3 months Annual CMR from chemo start date for during treatment 5 years Surveillance ends when treatment completed NT‐proBNP/troponin with imaging unless MD specifies otherwise NT‐proBNP/troponin unless MD specifies otherwise Use strain ECHO or MUGA if CMR contraindicated Use strain ECHO or MUGA if CMR contraindicated Consider Cardiology Consult: Consider Cardiology Consult: LVEF absolute drop >10%, LVEDVi increase of 2 SD, NT‐proBNP > age determined limit, troponin (hs TnT) > 50 ng/L LVEF absolute drop >10%, LVEDVi increase of 2 SD, NT‐proBNP > age determined limit, troponin (hs TnT) 50 ng/L Treatment • Prompt treatment • Risk vs benefit assessment • Cancer treatment considerations – Holding medications – Dose reductions – Switching to less cardiotoxic agents We suggest that myocardial strain imaging be considered a method for early detection of subclinical LV dysfunction in patients treated with potentially cardiotoxic cancer therapy (Suggestion, Low-Quality Evidence). We suggest that serial use of cardiac biomarkers (eg, BNP, troponin) be considered for early detection of cardiotoxicity in cancer patients who receive cardiotoxic therapies implicated in the development of LV dysfunction (Weak Recommendation, Moderate- Quality Evidence).” CJC 2016; 831‐841 Enalapril or Enalapril + Beta‐Blocker Cancer Treatment Cardiac Status D Prospective, single centre in Milan between June 1, 1995 and May 31, 2014 P Adult patients (n=2625) Mainly non‐Hodgkin lymphoma and breast cancer receiving anthracyclines LVEF > 50% No high dose anthracycline or trastuzumab I Enalapril (before 1999) or enalapril + carvedilol/bisoprolol (after 1999) Initiated promptly upon detection, up‐titrated to max tolerated doses Follow up: ECHO at baseline, q3mo during & the first year following treatment, q6mo during the following 4 years then annually (median follow up = 5.2 years) O Primary = time of occurrence of cardiotoxicity reduction in LVEF > 10 points from baseline and < 50% by ECHO: 9% (n=226) developed cardiotoxicity (dose‐dependent) median time = 3.5 months after last dose of anthracycline (98% within the first year) Secondary: 82% (n=185) recovered from cardiotoxicity after the initiation of HF treatment 71% (n=160) partial recovery (LVEF increase > 5 points and > 50%, no HF symptoms) 11% (n=25) full recovery (LVEF increase to the baseline) 18% (n=41) did not recover and were more likely to be in NYHA III‐IV, less tolerant to cardiac medications, lower LVEF before HF therapy and had a higher incidence of adverse cardiac events • Heart failure therapy – ACEI/ARB – BB – MRA – Diuretics/symptom management CJC 2016; 831‐841 JCO 2017; 893‐911 EHJ 2016; 37: 2768‐2801 Circ 2015; 1981‐1988 Enalapril or Enalapril + Carvedilol D Prospective, single centre in Milan between March 1, 2000 and March 1, 2008 P Adult patients who received anthracyclines (n=201) mostly doxorubicin & epirubicin Mainly non‐Hodgkin lymphoma, breast cancer and other tumors LVEF < 45% +/‐ HF symptoms and excluded other causes for cardiac dysfunction I Enalapril (if < 5mg/day) or enalapril + carvedilol Initiated within 4 months (median) and up‐titrated to maximum tolerated doses Follow up: ECHO at baseline, q1mo x 3 months, then q3mo for the first 2 following years then q6mo until the end of study (median follow up = 3 years) O Primary = LVEF response to HF therapy 1. 42% (n=85) full response (LVEF > 50%) – 13% NHYA III or IV, LVEF 41% prior to HF treatment, 75% on ACEI & BB, HF treatment initiated within 2 months, complete reversal within 7 months 2. 13% (n=26) partial response (LVEF increased > 10 points but remained < 50%) 69% NHYA III or IV, LVEF 28% prior to HF treatment, 50% on ACEI & BB, 69% diuretics, HF treatment initiated within 2 month 3. 45% (n=90) non responders (LVEF increased < 10 and remained < 50%) 27% NHYA III or IV, LVEF 38% prior to HF treatment, 54% on ACEI & BB, 50% diuretics, HF treatment initiated within 17 months, more cardiac events JACC 2010;213‐220 CJC 2016; 296‐310 4 4/5/2017 Evidence for Treatment Cancer Treatment Strengths: Limitations: • Prospective trials • Heart failure evidence‐based ACEI and beta blockers • Early detection and prompt treatment may result in recovery of heart function • Blinded RCTs lacking • Various definitions of cardiac dysfunction & response to therapy • Heterogeneity • Mainly patients with anthracycline‐ related cardiac dysfunction • Approach not independently validated • Ideal cardiac medication treatment regimen and initiation of therapy? • Optimal duration of therapy? CJC 2016; 831‐841 JCO 2017; 893‐911 • • We suggest that patients at high risk of cancer therapy-related cardiovascular disease or patients who develop cardiovascular complications during cancer therapy (eg, > 10% decrease in LVEF from baseline or LVEF < 53%) be referred to a cardio-oncology clinic or practitioner skilled in the management of this patient population, for optimization of cardiac function and consideration of primary or secondary prevention strategies (Suggestion, Low-Quality Evidence).” CJC 2016; 831‐841 Cancer Cancer Treatment Mandate: “We recommend that in cancer patients who develop clinical HF or an asymptomatic decline in LVEF (eg, > 10% decrease in LVEF from baseline or LVEF < 53%) during or after treatment, investigations, and management follow current CCS guidelines. Other causes of LV dysfunction should be excluded (Strong Recommendation, High-Quality Evidence). EHJ 2016; 37: 2768‐2801 SHC Cardio‐Oncology Clinic • CCS Guidelines: Treatment Cardiac Status Cardiac Status Implications for Pharmacists Service Delivery Model: Consultative service for adult patients currently under the care of a cancer specialist Aim to help patients remain on their cancer treatment and protect their heart Referral criteria: – Baseline assessment and surveillance prior to initiating chemotherapy – Cardiac surveillance for 5 years after completion of anthracycline‐based chemotherapy treatment – Cardiac symptoms or concerns during or post cancer treatment – Cardiac clearance for stem cell transplant – Cardiac amyloidosis – Cancer survivors > 18 years of age, previously followed by the Alberta Children’s Hospital and treated with anthracycline based chemotherapy or radiation to the chest • • • • • • • Referral triage: – Urgent (within 72 hours) – Semi‐urgent (within 5 business days) – Routine (within 3 weeks) Collaborative practice Patient and family education Risk assessment Surveillance Management of cardiac complications due to cancer treatment Telephone and face to face visits 1. Who do we treat? 2. How do we treat them? 3. What is most important to the patient? 4. Research & evidence is growing 5. Care is evolving Cancer Cancer Patient Cardiac Treatment Status Anwar M, Sheppard C. CAPhO Conference 2017 Poster Putting it all together … Acknowledgments SHC Cardio‐Oncology Clinic patients & staff Christina Sheppard Gloria Kinsella Deb Bosley Dr. Brian Clarke Circ 2012; 2749‐2763 5