4/5/2017 Chemotherapy‐Related Cardiac Dysfunction &  How a Cardiology‐Oncology Clinic Can Help!

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
Cardiology Team
Canadian Cardio‐Oncology Network (CCON) http://cardiaconcology.ca/
Chemotherapy‐Related Cardiac Dysfunction LVEF
At high risk for HF
No cardiac dysfunction
Occult LV dysfunction
LVEF > 53%, abnormal strain and/or cardiac biomarkers
Overt LV dysfunction
LVEF < 53%
Symptomatic HF, responsive to conventional therapy
LVEF < 53%
Symptomatic HF, LVEF < 53% (usually lower) unresponsive to conventional therapy
Cancer Treatment
Stage Definition
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
• 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
Approach to Care
Risk Assessment
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
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
“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
(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‐
• Positive health‐promoting behaviour
• Cancer treatment considerations JCO 2017; 893‐911
Cancer Treatment
EHJ 2016; 37: 2768‐2801
Cardiac Status
• Cardioprotective medications
– 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
MANTICORE 101‐Breast
RCT, PC, DB, 2 x 2 factorial, ITT, single center in Norway
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
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
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
Perindopril 8 mg (n=33) or bisoprolol 10 mg (n=31)
Initiated within 7 days of trastuzumab & continued during adjuvant period (usually 12 months)
Placebo (n=30)
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
Evidence for Prevention
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)
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
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
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
• 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
Prospective, single centre in Milan between June 1, 1995 and May 31, 2014
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
– 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
Prospective, single centre in Milan between March 1, 2000 and March 1, 2008
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
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
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 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 Patient Cardiac Treatment
Anwar M, Sheppard C. CAPhO Conference 2017 Poster Putting it all together …
SHC Cardio‐Oncology Clinic patients & staff
Christina Sheppard
Gloria Kinsella
Deb Bosley
Dr. Brian Clarke Circ 2012; 2749‐2763