Transcript Slide 1

Cardiotoxic Medications
Echocardiography Conference
January 2, 2008
Michael Chuang
Cardiotoxicity
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Impairment of function
Valvular disorders
Infarction
Arrhythmias
Thrombophilia
Cardiotoxic Drugs
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Anthracyclines
Tyrosine kinase
inhibitors
Dopamine agonists
Appetite suppressants
Glucocorticoids
Antifungals
Herbals
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Thiazolidinediones
NSAIDs – COX2
inhibitors
Alkylating drugs
Interferons
TNF antagonists
Antidepressants
Antipsychotics
Cardiotoxic Drugs
Anthracyclines
 Tyrosine kinase
inhibitors
 Dopamine agonists
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(anti-Parkinsonians)
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Appetite
suppressants
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Thiazolidinediones
NSAIDs – COX2 inhibitors
Alkylating drugs
Interferons
TNF antagonists
Antidepressants
Antipsychotics
Glucocorticoids
Antifungals
Herbals
Anthracyclines: Background
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Purpose: anti-cancer, chemotherapy
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Therapeutic mechanism: insertion into DNA of
replicating cells, → DNA fragmentation,
decreased DNA, RNA and protein synthesis
Toxicity via: free radicals, ↑ oxidative stress
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breast, soft tissue sarcoma, leukemia, lymphoma,
childhood tumors
Toxicity probably NOT via therapeutic mechanism
Examples: doxorubicin (Adriamycin®), danorubicin
(Cerubidine®), epirubicin (Pharmorubicin®), mitoxantrone
(Novantrone® [anthracendione])
Anthracyclines: Clinical Manifestations
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Acute Toxicity: BNP elevation, ventricular
dysfunction, EKG abnormalities, pericarditismyocarditis syndrome
days to weeks
 transient, not dose related
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Early Toxicity: ventricular dysfunction, heart failure
weeks to months
 dose-related
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Late Toxicity: ventricular dysfunction, heart failure
years
 dose-related
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Anthracyclines: Incidence [1]
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Retrospective study: 3941 patients given doxorubicin
Overall incidence of heart failure 2.2%
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strongly dose related
Cumulative Dose
<400 mg/m2
~400 mg/m2
~550 mg/m2
~700 mg/m2
Heart Failure
0.14%
3%
7%
18%
Von Hoff et al, Ann Intern Med 1979
Anthracyclines: Incidence [2]
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630 patients receiving FAC (fluorouracil,
doxorubicin, cyclophosphamide) and
dexrazoxane for advanced breast cancer.
Dose
≤400 mg/m2
~500 mg/m2
~550 mg/m2
~700 mg/m2
%CHF
5%
16%
26%
48%
Swain et al, Cancer 2003
Anthracyclines:
Risk Factors and Modifiers
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Risk factors: cumulative dose, age, combination
chemotherapy (e.g. cyclophosphamide, taxanes,
trastuzumab), prior cardiac disease, mediastinal
radiation, hypertension, female sex (pediatric
patients only)
Risk reduction via: dose minimization,
continuous (vs. bolus) administration, liposomal
formulation of anthracycline, dexrazaxone, βblockers, CCBs, ARBs
Anthracyclines:
Maximum “Safe” Doses
Drug
Dose
doxorubicin
550 mg/m2
danorubicin
600 mg/m2
epirubicin
1000 mg/m2
idarubicin
100 mg/m2
Mitoxantrone
160 mg/m2
Anthracyclines: Assessment
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Biomarkers
natriuretic peptides: ANP, BNP
 Troponin
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ECG: QRS duration, QTc, T-wave changes
Endomyocardial biopsy
Ejection Fraction
Ventriculography
Imaging Assessment of Cardiac
Function
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Accuracy versus Reproducibility
Modalities
Radionuclide ventriculography (RVG, MUGA)
 Echocardiography
 Cardiovascular Magnetic Resonance (CMR)
 Computed Tomography (CT)
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Radionuclide Ventriculography
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Widely used in oncology trials
Reproducibility good
Injection of tagging agent
Radiation expousre (~8 mSv)
Computed Tomography
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Very fast
Accurate* and reproducible
Iodinated contrast agent
Radiation exposure
*Limited temporal resolution
Echocardiography
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Noninvasive, generally well tolerated
Patient-associated image quality limitations
Assessement of valves, hemodynamics in
addition to function
Reproducibility of 2D echo limited compared
with volumetric techniques
3D echo markedly improves reproducibility
Improved Reproducibility of 3DE
Hibberd et al, AHA 1996
Otterstad et al, Eur Heart J 1997
Coefficient of Variation, %
25
3D Intra
3D Inter
20
2D Intra
2D Inter
15
10
5
0
EDV
ESV
SV
EF
CMR
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Very accurate (probably)
Reproducible
Contraindications
Local availablity and expertise
Chuang et al, JACC 2000
Reproducibility
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Beware systematic differences between imaging
methods and modalities
Lack of mean bias does not guarantee detection
of small changes
Chuang et al, JACC 2000
Tyrosine Kinase Inhibitors:
Background
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Purpose: anti-cancer, chemotherapy
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hematologic cancers, breast cancer, gastrointestinal
stromal tumor (GIST)
Therapeutic Mechanism: inhibition of dysregulated
TKs causal/contributory to tumorigenesis
Humanized monoclonal antibodies
 Small-molecule TKIs
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Cardiotoxicity: asymptomatic LV dysfunction, CHF
Examples: trastuzumab (Herceptin®), sunitinib (Sutent®),
imatinib (Gleevec®, Glivec®)
Trastuzumab (Herceptin®) [1]
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Human epidermal growth factor (HER2,
ERBB2) overexpressed in ~25% breast cancers,
marker of poor prognosis
Trastuzumab: humanized monoclonal antibody
targeting ERBB2, often used in combination
with taxanes
Multiple randomized trials show trastuzumab
benefit in ERBB2+ breast cancers, 80% of trials
show cardiotoxicity
Viani et al, BMC Cancer 2007
Trastuzumab (Herceptin®) [2]
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Aysmptomatic LV dysfunction: 4-17%
Symptomatic CHF: up to 4.5%
Mechanism unknown, but may include:
Interaction with other chemotherapeutic agents
 Antibody-dependent cell-mediated cytotoxicity
 Downregulation/inhibition of ERBB2 signalling
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Trastuzumab (Herceptin®) [2.1]
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ERBB2 signalling mandatory for embryonic
cardiomyocyte proliferation (germline deletion
of ERBB2 fatal in mice)
Late ERBB2 deletion → age-related DCM,
impaired response to pressure overload
Trastuzumab (Herceptin®) [2.2]
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ERBB2-binding triggers intracellular signalling
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Breast CA: inhibits autophosphorylation of ERBB2ERBB3 heterodimers
Cardiomyocytes (rat):
↓ ERBB2 activatio n, ↓ BCL-XL , ↑ BCL-XS
 Release of cytochrome c, caspase activation
 Loss of mitochondrial membrane potential
 Reduction in ATP levels
 Contractile dysfunction
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Grazette et al, JACC 2004
Trastuzumab (Herceptin®) [2.3]
Force et al, Nature Rev: Cancer 2007
Trastuzumab (Herceptin®) [2.2]
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ERBB2-binding triggers intracellular signalling
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Breast CA: inhibits autophosphorylation of ERBB2ERBB3 heterodimers
Cardiomyocytes (rat):
↓ ERBB2 activation, ↓ BCL-XL , ↑ BCL-XS
 Release of cytochrome c, caspase activation
 Loss of mitochondrial membrane potential
 Reduction in ATP levels
 Contractile dysfunction
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Grazette, JACC 2004
Trastuzumab (Herceptin®) [2.4]
Force et al, Nature Rev: Cancer 2007
Trastuzumab (Herceptin®) [2]
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Aysmptomatic LV dysfunction: 4-17%
Symptomatic CHF: 1-3%
Mechanism unknown:
Interaction with other chemotherapeutic agents
 Antibody-dependent cell-mediated cytotoxicity
 Downregulation/inhibition of ERBB2 signalling
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Toxicity at least partially reversible
Reversal after drug discontinuation
 Response to CHF medications
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Trastuzumab (Herceptin®) [3]
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Combination therapy and risk of CHF:
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Paclitaxel: 4.2%
Paxlitaxel + trastuzumab: 8.8%
Anthracycline: 9.6%
Anthracycline + trastuzumab: 28%
Decrease in EF ≥ 15%: ~5% of subjects, risk with
prior anthracycline exposure 6-fold that of
anthracycline-naïve
Symptomatic dysfunction:
78% improved off drug
 12% progressive HF
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Risk factors: prior/concommitant anthracycline
exposure, pretreatment NYHA class
Suter et al, Breast, 2004
Sunitinib (Sutent ®)
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Small-molecule multi targeted TKI
VEGFR 1-3, PDGFRa,b, KIT, CSF-1, RET
 Inhibition of angiogenesis
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FDA and EU approved for GIST, renal-cell
carcinoma
Cardiotoxicity:
GIST: no change in EF after 8 weeks [Demetri,
Lancet 2006]
 Metastatic RCC: 10% had decrease in EF after 6
months, no clinical sequelae [Motzer, NEJM 2007]
 Pfizer insert: 11% of patients have decrease in EF to
less than 50%
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Sunitinib: Study Design
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75 adults with imatinib-resistant GIST
Open-label Phase I/II trial of sunitinib at DFCI
Cycle: 50 mg daily. 4 weeks on, 2 weeks off
 4 cycles
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Serial EKG, biomarkers, radionuclide
ventriculography (baseline EF > 50%)
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Interstudy reproducibility: 2-3%
Sunitinib: CV Events - Definitions
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CHF: documented signs and symptoms,
reduction in EF to < 50%, typical CXR and
relief with CHF therapy
MI: TnI>0.10 and clinical symptoms, EKG
changes
Death: cardiovascular vs. noncardiovascular,
adjucated by cardiologists and oncologists; CV
death only if concordance
Sunitinib: CV Events
Sunitinib: Maximum Decline in EF
Sunitinib: Predicted Decrease in EF
Sunitinib: Mitochondrial Abnormalities
(rodent models)
Sunitinib: Hypertension [1]
Sunitinib: Hypertension [2]
Sunitinib: Study Summary
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11% of 75 patients had CV event
8% had NYHA Class III or IV HF
~50% developed hypertension
EF declined after each cycle of treatment
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In mice:
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Increased mitochondrial damage
 No increase in cardiomyocyte apoptosis
 Sunitinib + phenylephrine (inducing HTN)
increased apoptosis 7-fold vs phenylephrine alone
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Dopamine Agonists: Background [1]
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Purpose: anti-Parkinsonian, restless leg
syndrome, hyperprolactinemia, Tourette’s
syndrome
Therapeutic mechanisms: stimulation of
dopamine receptors
Toxicity via: agonism of 5-HT2B receptors on
cardiac valves → fibrosis, regurgitation
Examples: pergolide (Permax®), cabergoline
(Dostinex ®)
Dopamine Agonists: Background [2]
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Ergot derivatives vs. non-ergot
Ergot: pergolide, cabergoline
 Non-ergot: pramipexole, ropinrole
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Non-cardiac side effects: retroperitoneal and
pleuropulmonary fibrosis
Ergot
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Claviceps fungus, parasitic on many grains
Overwinters as a sclerotium which contains
alkaloids, e.g. ergotamine
Effects include:
Vasoconstriction – St. Anthony’s fire
 Uterine contractions
 Hallucinations
 Convulsions
 Death
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Ergot-Derived Dopamine Agonists [3]
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155 patients on dopamine-agonist antiParkinsonians, 90 controls
On treatment ≥ 12 months, no prior valve disease,
no other drugs likely to cause valvulopathy
 Pergolide (n=64), cabergoline (49), nonergot (42)
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Transthoracic echo (Sequoia)
Per-valve regurgitation graded 0-4
 Composite valve score 0-12
 Thickening defined as >5mm
 Mitral-valve tenting area
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Zanettini et al, NEJM 2007
Ergot-Derived Dopamine Agonists [4]
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Valvular abnormalities more prevalent in
pergolide and cabergolide groups vs. controls
and vs. non-ergot dopamine agonist treated
Grade III and IV regurgitation
Pergolide (23.4%)
 Cabergoline (28.6%)
 Controls (5.6%), non-ergot (0%)
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Valve thickening:
Pergolide (n=17, 27%)
 Cabergoline (n=8, 16%)
 Control and non-ergot (0%)
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Zanettini et al, NEJM 2007
Ergot-Derived Dopamine Agonists [5]
Relative Risk MR
AR
TR
Pergolide
6.3 [1.4-28.3] 4.2 [1.2-15]
Cabergoline
4.6 [0.9-22.8] 7.3 [2.2-24.8] 5.5 [0.6-51.6]
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Cumulative doses correlated with severity of
regurgitation
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5.6 [0.7-49]
Pergolide: r=0.34, p=0.005
Cabergoline: r=0.26, r=0.06
Mitral-valve tenting > in treatment vs controls
Tenting correlated with MR severity, p=0.001
Zanettini et al, NEJM 2007
Ergot-Derived Dopamine Agonists [6]
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Case-control (1:25) study UK GPRD data
Aged 40-80 with ≥ 2 prescriptions btwn 1988-2005
 No prior valve disease, murmurs, CHF, MI,
carcinoid, other drugs assoc. with valve dz, IVDU
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31 patients with new valve regurgitation
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Only 16 cases confirned by echo or cath
Relative risk
Pergolide 4.9 [1.5-15.6]
 Cabergoline 7.1 [2.3-22.3]
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Risk increased with cumulative dose/duration
Schade et al, NEJM 2007
Ergot-derived dopamine agonists:
Summary [7]
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Results consistent across multiple studies
Risk of valve disease increases ~5-6 fold with
pergolide or cabergoline
Risk increases with dose, duration of exposure
Susceptibility depends on individual factors
Reversibility after drug discontinuation
unknown
Serial monitoring by echocardiography ?
Anorectic Agents/Fenfluramine:
Background
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Purpose: appetite suppression
Therapeutic mechanisms: activation of
serotonin release, inhibition of serotonin
breakdown
Toxicity via: increased serotonin levels, likely in
combination with activation of 5-HT2B
receptors
Examples: fenfluramine (dexfenfluramine),
phentermine
Fenfluramine: Cardiac Effects
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Clinically-significant valvular regurgitation
Mitral valve abnormalities
Decreased posterior-leaflet mobility
 Anterior-leaflet thickening and diastolic doming
 Subvalvular disease (chordal shortening/thickening)
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Aortic regurgitation, leaflet thickening and
retraction
Pulmonary hypertension
Fenfluramine [3]
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24 women (44±8 years), 12±7 months after
fenfluramine-phentermine therapy
No history of CV disease
Right and left-sided valvular lesions
5 went to surgery at press time
8 new cases of pulmonary hypertension
Connolly et al, NEJM 1997
Fenfluramine: MV Gross Specimen [4]
Connolly et al, NEJM 1997
Fenfluramine: Mitral Valve [5]
Connolly et al, NEJM 1997
Fenfluramine: [6]
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Multisite reader-blinded controlled study
30 days of drug therapy within 14 months of
enrollment
1473 patients, mean BMI 35±7 kg/m2
2D Echo on HP Sonos 2000 or 2500 systems
Valvular regurgitation
 Valve leaflet thickness and mobility
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Gardin et al, JAMA 2000
Fenfluramine: [6]
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Treated patients had higher prevalence of AR
Prevalence
Relative Risk
dexfenfluramine
8.9%
2.18 [1.32-3.59]
dexfenfluramine
/ phentermine
control
13.7%
3.34 [2.09-5.35]
4.1%
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No difference in prevalence of MR (4.9, 5.1, 3.2%)
No difference in valve mobility
No difference in MI, CHF or serious arrhythmia
Gardin et al, JAMA 2000
Fenfluramine: [7]
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1-year follow up in 78% of subjects
Interreader agreement for change in grade
AR: 87.4%, k=0.63
 MR: 57.1%, k=0.32
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Intrareader agreement for change in grade
AR: 96.5%, k=0.32
 MR: 86.8%, k=0.30
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Gardin et al, JAMA 2001
Fenfluramine: [8]
Gardin et al, JAMA 2001
Fenfluramine: [9]
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Multiple studies suggest that after drug
discontinuation:
Progression of valve disease is rare
 Regression of disease is possible
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Davidoff et al, Arch Intern Med 2001
Mast et al, Ann Intern Med 2001
Weissman et al, Ann Intern Med 2001