cardiotoxic medications echocardiography conference january 2, 2008 michael chuang

Cardiotoxic Cardiotoxic MedicationsMedications

Echocardiography Echocardiography ConferenceConference

January 2, 2008January 2, 2008

Michael ChuangMichael Chuang

CardiotoxicityCardiotoxicity

Impairment of functionImpairment of function Valvular disordersValvular disorders InfarctionInfarction ArrhythmiasArrhythmias ThrombophiliaThrombophilia

Cardiotoxic DrugsCardiotoxic Drugs

AnthracyclinesAnthracyclines Tyrosine kinase Tyrosine kinase

inhibitorsinhibitors Dopamine agonists Dopamine agonists Appetite Appetite

suppressantssuppressants GlucocorticoidsGlucocorticoids AntifungalsAntifungals HerbalsHerbals

ThiazolidinedionesThiazolidinediones NSAIDs – COX2 NSAIDs – COX2

inhibitorsinhibitors Alkylating drugsAlkylating drugs InterferonsInterferons TNF antagonistsTNF antagonists AntidepressantsAntidepressants AntipsychoticsAntipsychotics

Cardiotoxic DrugsCardiotoxic Drugs

AnthracyclinesAnthracyclines Tyrosine kinase Tyrosine kinase

inhibitorsinhibitors Dopamine Dopamine

agonists agonists (anti-(anti-Parkinsonians)Parkinsonians)

Appetite Appetite suppressantssuppressants

ThiazolidinedionesThiazolidinediones NSAIDs – COX2 NSAIDs – COX2

inhibitorsinhibitors Alkylating drugsAlkylating drugs InterferonsInterferons TNF antagonistsTNF antagonists AntidepressantsAntidepressants AntipsychoticsAntipsychotics GlucocorticoidsGlucocorticoids AntifungalsAntifungals HerbalsHerbals

Anthracyclines: Anthracyclines: BackgroundBackground

Purpose:Purpose: anti-cancer, chemotherapy anti-cancer, chemotherapy breast, soft tissue sarcoma, leukemia, breast, soft tissue sarcoma, leukemia,

lymphoma, childhood tumorslymphoma, childhood tumors Therapeutic mechanism:Therapeutic mechanism: insertion into DNA insertion into DNA

of replicating cells, → DNA fragmentation, of replicating cells, → DNA fragmentation, decreased DNA, RNA and protein synthesisdecreased DNA, RNA and protein synthesis

Toxicity via:Toxicity via: free radicals, ↑ oxidative free radicals, ↑ oxidative stressstress Toxicity probably NOT via therapeutic Toxicity probably NOT via therapeutic

mechanismmechanism Examples:Examples: doxorubicin ( doxorubicin (Adriamycin®Adriamycin®), ),

danorubicin (danorubicin (Cerubidine®Cerubidine®), epirubicin ), epirubicin ((Pharmorubicin®Pharmorubicin®), mitoxantrone (), mitoxantrone (Novantrone® Novantrone®

[anthracendione][anthracendione]))

Anthracyclines: Clinical Anthracyclines: Clinical ManifestationsManifestations

Acute Toxicity: BNP elevation, ventricular Acute Toxicity: BNP elevation, ventricular dysfunction, EKG abnormalities, dysfunction, EKG abnormalities, pericarditis-myocarditis syndrome pericarditis-myocarditis syndrome days to weeksdays to weeks transient, not dose relatedtransient, not dose related

Early Toxicity: ventricular dysfunction, Early Toxicity: ventricular dysfunction, heart failureheart failure weeks to monthsweeks to months dose-relateddose-related

Late Toxicity: ventricular dysfunction, Late Toxicity: ventricular dysfunction, heart failureheart failure yearsyears dose-relateddose-related

Anthracyclines: Anthracyclines: Incidence Incidence [1][1] Retrospective study: 3941 patients Retrospective study: 3941 patients

given doxorubicingiven doxorubicin Overall incidence of heart failure 2.2%Overall incidence of heart failure 2.2%

strongly dose relatedstrongly dose relatedCumulative DoseCumulative Dose Heart FailureHeart Failure

<400 mg/m<400 mg/m22 0.14%0.14%

~400 mg/m~400 mg/m22 3%3%

~550 mg/m~550 mg/m22 7%7%

~700 mg/m~700 mg/m22 18%18%

Von Hoff et al, Ann Intern Med 1979

Anthracyclines: Anthracyclines: Incidence Incidence [2][2]

630 patients receiving FAC 630 patients receiving FAC (fluorouracil, doxorubicin, (fluorouracil, doxorubicin, cyclophosphamide) and dexrazoxane cyclophosphamide) and dexrazoxane for advanced breast cancer.for advanced breast cancer.

Swain et al, Cancer 2003

DoseDose %CHF%CHF

≤≤400 400 mg/mmg/m22

5%5%

~500 ~500 mg/mmg/m22

16%16%

~550 ~550 mg/mmg/m22

26%26%

~700 ~700 mg/mmg/m22

48%48%

Anthracyclines: Anthracyclines: Risk Factors and ModifiersRisk Factors and Modifiers

Risk factors:Risk factors: cumulative dose, age, cumulative dose, age, combination chemotherapy (e.g. combination chemotherapy (e.g. cyclophosphamide, taxanes, cyclophosphamide, taxanes, trastuzumab), prior cardiac disease, trastuzumab), prior cardiac disease, mediastinal radiation, hypertension, mediastinal radiation, hypertension, female sex (pediatric patients only)female sex (pediatric patients only)

Risk reduction via:Risk reduction via: dose minimization, dose minimization, continuous (vs. bolus) administration, continuous (vs. bolus) administration, liposomal formulation of anthracycline, liposomal formulation of anthracycline, dexrazaxone, dexrazaxone, ββ-blockers, CCBs, ARBs-blockers, CCBs, ARBs

Anthracyclines: Anthracyclines: Maximum “Safe” DosesMaximum “Safe” Doses

DrugDrug DoseDose

doxorubicindoxorubicin 550 mg/m550 mg/m22

danorubicindanorubicin 600 mg/m600 mg/m22

epirubicinepirubicin 1000 mg/m1000 mg/m22

idarubicinidarubicin 100 mg/m100 mg/m22

MitoxantroneMitoxantrone 160 mg/m160 mg/m22

Anthracyclines: Anthracyclines: AssessmentAssessment

BiomarkersBiomarkers natriuretic peptides: ANP, BNPnatriuretic peptides: ANP, BNP TroponinTroponin

ECG: QRS duration, QTc, T-wave ECG: QRS duration, QTc, T-wave changeschanges

Endomyocardial biopsyEndomyocardial biopsy Ejection FractionEjection Fraction

VentriculographyVentriculography

Imaging Assessment of Imaging Assessment of Cardiac FunctionCardiac Function

Accuracy versus ReproducibilityAccuracy versus Reproducibility ModalitiesModalities

Radionuclide ventriculography (RVG, Radionuclide ventriculography (RVG, MUGA)MUGA)

EchocardiographyEchocardiography Cardiovascular Magnetic Resonance Cardiovascular Magnetic Resonance

(CMR)(CMR) Computed Tomography (CT)Computed Tomography (CT)

Radionuclide Radionuclide VentriculographyVentriculography

Widely used in oncology trialsWidely used in oncology trials Reproducibility goodReproducibility good Injection of tagging agentInjection of tagging agent Radiation expousre (~8 mSv)Radiation expousre (~8 mSv)

Computed TomographyComputed Tomography

Very fastVery fast Accurate* and reproducibleAccurate* and reproducible Iodinated contrast agentIodinated contrast agent Radiation exposureRadiation exposure *Limited temporal resolution*Limited temporal resolution

EchocardiographyEchocardiography

Noninvasive, generally well toleratedNoninvasive, generally well tolerated Patient-associated image quality Patient-associated image quality

limitationslimitations Assessement of valves, hemodynamics Assessement of valves, hemodynamics

in addition to functionin addition to function Reproducibility of 2D echo limited Reproducibility of 2D echo limited

compared with volumetric techniquescompared with volumetric techniques 3D echo markedly improves 3D echo markedly improves

reproducibilityreproducibility

Improved Reproducibility Improved Reproducibility of 3DEof 3DE

Otterstad et al, Eur Heart J 1997Hibberd et al, AHA 1996

EDV ESV SV EF0

5

10

15

20

25

Coe

ffici

ent o

f Var

iatio

n, %

3D Intra

3D Inter

2D Intra

2D Inter

CMRCMR

Very accurate (probably)Very accurate (probably) ReproducibleReproducible ContraindicationsContraindications Local availablity and expertiseLocal availablity and expertise

Chuang et al, JACC 2000

ReproducibilityReproducibility Beware systematic differences between Beware systematic differences between

imaging methods and modalitiesimaging methods and modalities Lack of mean bias does not guarantee Lack of mean bias does not guarantee

detection of small changesdetection of small changes

Chuang et al, JACC 2000

Tyrosine Kinase Inhibitors: Tyrosine Kinase Inhibitors: BackgroundBackground

Purpose:Purpose: anti-cancer, chemotherapy anti-cancer, chemotherapy hematologic cancers, breast cancer, hematologic cancers, breast cancer,

gastrointestinal stromal tumor (GIST)gastrointestinal stromal tumor (GIST) Therapeutic Mechanism:Therapeutic Mechanism: inhibition of inhibition of

dysregulated TKs causal/contributory to dysregulated TKs causal/contributory to tumorigenesistumorigenesis Humanized monoclonal antibodiesHumanized monoclonal antibodies Small-molecule TKIsSmall-molecule TKIs

Cardiotoxicity:Cardiotoxicity: asymptomatic LV asymptomatic LV dysfunction, CHFdysfunction, CHF

Examples:Examples: trastuzumab ( trastuzumab (Herceptin®Herceptin®), sunitinib ), sunitinib ((Sutent®Sutent®), imatinib (), imatinib (Gleevec®, Glivec®Gleevec®, Glivec®))

Trastuzumab Trastuzumab (Herceptin(Herceptin®®) ) [1][1]

Human epidermal growth factor (HER2, Human epidermal growth factor (HER2, ERBB2) overexpressed in ~25% breast ERBB2) overexpressed in ~25% breast cancers, marker of poor prognosiscancers, marker of poor prognosis

Trastuzumab: humanized monoclonal Trastuzumab: humanized monoclonal antibody targeting ERBB2, often used in antibody targeting ERBB2, often used in combination with taxanescombination with taxanes

Multiple randomized trials show Multiple randomized trials show trastuzumab benefit in ERBB2+ breast trastuzumab benefit in ERBB2+ breast cancers, 80% of trials show cancers, 80% of trials show cardiotoxicitycardiotoxicity

Viani et al, BMC Cancer 2007


Aysmptomatic LV dysfunction: 4-17%Aysmptomatic LV dysfunction: 4-17% Symptomatic CHF: up to 4.5%Symptomatic CHF: up to 4.5% Mechanism unknown, but may include: Mechanism unknown, but may include:

Interaction with other chemotherapeutic Interaction with other chemotherapeutic agentsagents

Antibody-dependent cell-mediated Antibody-dependent cell-mediated cytotoxicitycytotoxicity

Downregulation/inhibition of ERBB2 Downregulation/inhibition of ERBB2 signallingsignalling

Trastuzumab Trastuzumab (Herceptin(Herceptin®®) ) [2.1][2.1]

ERBB2 signalling mandatory for ERBB2 signalling mandatory for embryonic cardiomyocyte embryonic cardiomyocyte proliferation (germline deletion of proliferation (germline deletion of ERBB2 fatal in mice)ERBB2 fatal in mice)

Late ERBB2 deletion → age-related Late ERBB2 deletion → age-related DCM, impaired response to DCM, impaired response to pressure overloadpressure overload


ERBB2-binding triggers intracellular ERBB2-binding triggers intracellular signallingsignalling Breast CA: inhibits autophosphorylation of Breast CA: inhibits autophosphorylation of

ERBB2-ERBB3 heterodimersERBB2-ERBB3 heterodimers Cardiomyocytes (rat):Cardiomyocytes (rat):

↓ ↓ ERBB2 activatio n, ↓ BCL-XERBB2 activatio n, ↓ BCL-XLL , ↑ BCL-X , ↑ BCL-XSS

Release of cytochrome Release of cytochrome cc, caspase activation, caspase activation Loss of mitochondrial membrane potentialLoss of mitochondrial membrane potential Reduction in ATP levelsReduction in ATP levels Contractile dysfunctionContractile dysfunction

Grazette et al, JACC 2004


Force et al, Nature Rev: Cancer 2007


ERBB2-binding triggers intracellular ERBB2-binding triggers intracellular signallingsignalling Breast CA: inhibits autophosphorylation of Breast CA: inhibits autophosphorylation of

ERBB2-ERBB3 heterodimersERBB2-ERBB3 heterodimers Cardiomyocytes (rat):Cardiomyocytes (rat):

↓ ↓ ERBB2 activation, ↓ BCL-XERBB2 activation, ↓ BCL-XLL , ↑ BCL-X , ↑ BCL-XSS

Release of cytochrome Release of cytochrome cc, caspase activation, caspase activation Loss of mitochondrial membrane potentialLoss of mitochondrial membrane potential Reduction in ATP levelsReduction in ATP levels Contractile dysfunctionContractile dysfunction

Grazette, JACC 2004


Force et al, Nature Rev: Cancer 2007


Aysmptomatic LV dysfunction: 4-17%Aysmptomatic LV dysfunction: 4-17% Symptomatic CHF: 1-3%Symptomatic CHF: 1-3% Mechanism unknown: Mechanism unknown:

Interaction with other chemotherapeutic Interaction with other chemotherapeutic agentsagents

Antibody-dependent cell-mediated cytotoxicityAntibody-dependent cell-mediated cytotoxicity Downregulation/inhibition of ERBB2 signallingDownregulation/inhibition of ERBB2 signalling

Toxicity at least partially reversibleToxicity at least partially reversible Reversal after drug discontinuationReversal after drug discontinuation Response to CHF medicationsResponse to CHF medications

Trastuzumab Trastuzumab (Herceptin(Herceptin®®) ) [3][3] Combination therapy and risk of CHF:Combination therapy and risk of CHF:

Paclitaxel: 4.2%Paclitaxel: 4.2% Paxlitaxel + trastuzumab: 8.8%Paxlitaxel + trastuzumab: 8.8% Anthracycline: 9.6%Anthracycline: 9.6% Anthracycline + trastuzumab: 28%Anthracycline + trastuzumab: 28%

Decrease in EF ≥ 15%: ~5% of subjects, Decrease in EF ≥ 15%: ~5% of subjects, risk with prior anthracycline exposure 6-risk with prior anthracycline exposure 6-fold that of anthracycline-naïvefold that of anthracycline-naïve

Symptomatic dysfunction: Symptomatic dysfunction: 78% improved off drug78% improved off drug 12% progressive HF12% progressive HF

Risk factors: prior/concommitant Risk factors: prior/concommitant anthracycline exposure, pretreatment anthracycline exposure, pretreatment NYHA classNYHA class Suter et al, Breast, 2004

Sunitinib (Sutent Sunitinib (Sutent ®®)) Small-molecule multi targeted TKISmall-molecule multi targeted TKI

VEGFR 1-3, PDGFRVEGFR 1-3, PDGFR, KIT, CSF-1, RET, KIT, CSF-1, RET Inhibition of angiogenesisInhibition of angiogenesis

FDA and EU approved for GIST, FDA and EU approved for GIST, renal-cell carcinomarenal-cell carcinoma

Cardiotoxicity:Cardiotoxicity: GIST: no change in EF after 8 weeks GIST: no change in EF after 8 weeks

[Demetri, Lancet 2006][Demetri, Lancet 2006] Metastatic RCC: 10% had decrease in Metastatic RCC: 10% had decrease in

EF after 6 months, no clinical sequelae EF after 6 months, no clinical sequelae [Motzer, NEJM 2007][Motzer, NEJM 2007]

Pfizer insert: 11% of patients have Pfizer insert: 11% of patients have decrease in EF to less than 50%decrease in EF to less than 50%

Sunitinib: Study DesignSunitinib: Study Design

75 adults with imatinib-resistant GIST75 adults with imatinib-resistant GIST Open-label Phase I/II trial of sunitinib Open-label Phase I/II trial of sunitinib

at DFCIat DFCI Cycle: 50 mg daily. 4 weeks on, 2 weeks offCycle: 50 mg daily. 4 weeks on, 2 weeks off 4 cycles4 cycles

Serial EKG, biomarkers, radionuclide Serial EKG, biomarkers, radionuclide ventriculography (baseline EF > 50%)ventriculography (baseline EF > 50%) Interstudy reproducibility: 2-3%Interstudy reproducibility: 2-3%

Sunitinib: CV Events - Sunitinib: CV Events - DefinitionsDefinitions

CHF: documented signs and symptoms, CHF: documented signs and symptoms, reduction in EF to < 50%, typical CXR reduction in EF to < 50%, typical CXR and relief with CHF therapyand relief with CHF therapy

MI: TnI>0.10 MI: TnI>0.10 andand clinical symptoms, clinical symptoms, EKG changesEKG changes

Death: cardiovascular vs. Death: cardiovascular vs. noncardiovascular, adjucated by noncardiovascular, adjucated by cardiologists and oncologists; CV death cardiologists and oncologists; CV death only if concordanceonly if concordance

Sunitinib: CV EventsSunitinib: CV Events

Sunitinib: Maximum Sunitinib: Maximum Decline in EFDecline in EF

Sunitinib: Predicted Sunitinib: Predicted Decrease in EFDecrease in EF

Sunitinib: Mitochondrial Sunitinib: Mitochondrial AbnormalitiesAbnormalities

(rodent models)

Sunitinib: Hypertension Sunitinib: Hypertension [1][1]

Sunitinib: Hypertension Sunitinib: Hypertension [2][2]

Sunitinib: Study Sunitinib: Study SummarySummary

11% of 75 patients had CV event11% of 75 patients had CV event 8% had NYHA Class III or IV HF8% had NYHA Class III or IV HF ~50% developed hypertension~50% developed hypertension EF declined after each cycle of EF declined after each cycle of

treatmenttreatment

In mice:In mice: Increased mitochondrial damageIncreased mitochondrial damage No increase in cardiomyocyte apoptosisNo increase in cardiomyocyte apoptosis Sunitinib + phenylephrine (inducing HTN) Sunitinib + phenylephrine (inducing HTN)

increased apoptosis 7-fold vs phenylephrine increased apoptosis 7-fold vs phenylephrine alonealone

Dopamine Agonists: Dopamine Agonists: Background Background [1][1]

Purpose:Purpose: anti-Parkinsonian, restless anti-Parkinsonian, restless leg syndrome, hyperprolactinemia, leg syndrome, hyperprolactinemia, Tourette’s syndromeTourette’s syndrome

Therapeutic mechanisms:Therapeutic mechanisms: stimulation of dopamine receptorsstimulation of dopamine receptors

Toxicity via:Toxicity via: agonism of 5-HT agonism of 5-HT2B2B receptors on cardiac valves → receptors on cardiac valves → fibrosis, regurgitationfibrosis, regurgitation

Examples: Examples: pergolide (Permax®), pergolide (Permax®), cabergoline (Dostinex ®)cabergoline (Dostinex ®)

Dopamine Agonists: Dopamine Agonists: Background Background [2][2]

Ergot derivatives vs. non-ergot Ergot derivatives vs. non-ergot Ergot: pergolide, cabergolineErgot: pergolide, cabergoline Non-ergot: pramipexole, ropinroleNon-ergot: pramipexole, ropinrole

Non-cardiac side effects: Non-cardiac side effects: retroperitoneal and pleuropulmonary retroperitoneal and pleuropulmonary fibrosisfibrosis

ErgotErgot Claviceps fungus, parasitic on many Claviceps fungus, parasitic on many

grainsgrains Overwinters as a sclerotium which Overwinters as a sclerotium which

contains alkaloids, e.g. ergotaminecontains alkaloids, e.g. ergotamine Effects include:Effects include:

Vasoconstriction – St. Anthony’s fireVasoconstriction – St. Anthony’s fire Uterine contractionsUterine contractions HallucinationsHallucinations ConvulsionsConvulsions DeathDeath

Ergot-Derived Dopamine Ergot-Derived Dopamine Agonists Agonists [3][3]

155 patients on dopamine-agonist anti-155 patients on dopamine-agonist anti-Parkinsonians, 90 controlsParkinsonians, 90 controls On treatment ≥ 12 months, no prior valve On treatment ≥ 12 months, no prior valve

disease, no other drugs likely to cause disease, no other drugs likely to cause valvulopathyvalvulopathy

Pergolide (n=64), cabergoline (49), nonergot Pergolide (n=64), cabergoline (49), nonergot (42)(42)

Transthoracic echo (Sequoia)Transthoracic echo (Sequoia) Per-valve regurgitation graded 0-4Per-valve regurgitation graded 0-4 Composite valve score 0-12Composite valve score 0-12 Thickening defined as >5mmThickening defined as >5mm Mitral-valve tenting areaMitral-valve tenting area

Zanettini et al, NEJM 2007


Valvular abnormalities more prevalent Valvular abnormalities more prevalent in pergolide and cabergolide groups vs. in pergolide and cabergolide groups vs. controls and vs. non-ergot dopamine controls and vs. non-ergot dopamine agonist treatedagonist treated

Grade III and IV regurgitationGrade III and IV regurgitation Pergolide (23.4%)Pergolide (23.4%) Cabergoline (28.6%)Cabergoline (28.6%) Controls (5.6%), non-ergot (0%)Controls (5.6%), non-ergot (0%)

Valve thickening:Valve thickening: Pergolide (n=17, 27%)Pergolide (n=17, 27%) Cabergoline (n=8, 16%)Cabergoline (n=8, 16%) Control and non-ergot (0%)Control and non-ergot (0%) Zanettini et al, NEJM 2007


Cumulative doses correlated with severity of Cumulative doses correlated with severity of regurgitationregurgitation Pergolide: r=0.34, p=0.005Pergolide: r=0.34, p=0.005 Cabergoline: r=0.26, r=0.06Cabergoline: r=0.26, r=0.06

Mitral-valve tenting > in treatment vs Mitral-valve tenting > in treatment vs controlscontrols

Tenting correlated with MR severity, p=0.001Tenting correlated with MR severity, p=0.001

Zanettini et al, NEJM 2007

Relative Relative RiskRisk

MRMR ARAR TRTR

PergolidePergolide 6.3 [1.4-6.3 [1.4-28.3]28.3]

4.2 [1.2-4.2 [1.2-15]15]

5.6 [0.7-5.6 [0.7-49]49]

CabergoliCabergolinene

4.6 [0.9-4.6 [0.9-22.8]22.8]

7.3 [2.2-7.3 [2.2-24.8]24.8]

5.5 [0.6-5.5 [0.6-51.6]51.6]


Case-control (1:25) study UK GPRD dataCase-control (1:25) study UK GPRD data Aged 40-80 with ≥ 2 prescriptions btwn 1988-Aged 40-80 with ≥ 2 prescriptions btwn 1988-

20052005 No prior valve disease, murmurs, CHF, MI, No prior valve disease, murmurs, CHF, MI,

carcinoid, other drugs assoc. with valve dz, carcinoid, other drugs assoc. with valve dz, IVDUIVDU

31 patients with new valve regurgitation31 patients with new valve regurgitation Only 16 cases confirned by echo or cathOnly 16 cases confirned by echo or cath

Relative riskRelative risk Pergolide 4.9 [1.5-15.6]Pergolide 4.9 [1.5-15.6] Cabergoline 7.1 [2.3-22.3]Cabergoline 7.1 [2.3-22.3]

Risk increased with cumulative Risk increased with cumulative dose/durationdose/duration

Schade et al, NEJM 2007

Ergot-derived dopamine Ergot-derived dopamine agonists: Summary agonists: Summary [7][7]

Results consistent across multiple studiesResults consistent across multiple studies Risk of valve disease increases ~5-6 fold Risk of valve disease increases ~5-6 fold

with pergolide or cabergolinewith pergolide or cabergoline Risk increases with dose, duration of Risk increases with dose, duration of

exposureexposure Susceptibility depends on individual factorsSusceptibility depends on individual factors Reversibility after drug discontinuation Reversibility after drug discontinuation

unknownunknown Serial monitoring by echocardiography ?Serial monitoring by echocardiography ?

Anorectic Anorectic Agents/Fenfluramine: Agents/Fenfluramine:

BackgroundBackground Purpose:Purpose: appetite suppression appetite suppression Therapeutic mechanisms:Therapeutic mechanisms: activation of activation of

serotonin release, inhibition of serotonin release, inhibition of serotonin breakdownserotonin breakdown

Toxicity via:Toxicity via: increased serotonin increased serotonin levels, likely in combination with levels, likely in combination with activation of 5-HTactivation of 5-HT2B2B receptors receptors

Examples:Examples: fenfluramine fenfluramine (dexfenfluramine), phentermine(dexfenfluramine), phentermine

Fenfluramine: Cardiac Fenfluramine: Cardiac EffectsEffects

Clinically-significant valvular regurgitationClinically-significant valvular regurgitation Mitral valve abnormalitiesMitral valve abnormalities

Decreased posterior-leaflet mobilityDecreased posterior-leaflet mobility Anterior-leaflet thickening and diastolic domingAnterior-leaflet thickening and diastolic doming Subvalvular disease (chordal Subvalvular disease (chordal

shortening/thickening)shortening/thickening) Aortic regurgitation, leaflet thickening and Aortic regurgitation, leaflet thickening and

retractionretraction Pulmonary hypertensionPulmonary hypertension

Fenfluramine Fenfluramine [3][3]

24 women (44±8 years), 12±7 24 women (44±8 years), 12±7 months after fenfluramine-months after fenfluramine-phentermine therapyphentermine therapy

No history of CV diseaseNo history of CV disease Right and left-sided valvular lesionsRight and left-sided valvular lesions 5 went to surgery at press time5 went to surgery at press time 8 new cases of pulmonary 8 new cases of pulmonary

hypertensionhypertension

Connolly et al, NEJM 1997

Fenfluramine: MV Gross Fenfluramine: MV Gross Specimen Specimen [4][4]


Fenfluramine: Mitral Fenfluramine: Mitral Valve Valve [5][5]


Fenfluramine: Fenfluramine: [6][6]

Multisite reader-blinded controlled Multisite reader-blinded controlled studystudy

30 days of drug therapy within 14 30 days of drug therapy within 14 months of enrollmentmonths of enrollment

1473 patients, mean BMI 35±7 kg/m1473 patients, mean BMI 35±7 kg/m22

2D Echo on HP Sonos 2000 or 2500 2D Echo on HP Sonos 2000 or 2500 systemssystems Valvular regurgitationValvular regurgitation Valve leaflet thickness and mobilityValve leaflet thickness and mobility

Gardin et al, JAMA 2000

Fenfluramine: Fenfluramine: [6][6] Treated patients had higher prevalence of ARTreated patients had higher prevalence of AR

No difference in prevalence of MR (4.9, 5.1, No difference in prevalence of MR (4.9, 5.1, 3.2%)3.2%)

No difference in valve mobilityNo difference in valve mobility No difference in MI, CHF or serious No difference in MI, CHF or serious

arrhythmiaarrhythmia

PrevalencePrevalence Relative RiskRelative Risk

dexfenfluradexfenfluraminemine

8.9%8.9% 2.18 [1.32-2.18 [1.32-3.59]3.59]

dexfenfluradexfenfluramine/ mine/ phenterminephentermine

13.7%13.7% 3.34 [2.09-3.34 [2.09-5.35]5.35]

controlcontrol 4.1%4.1% --



1-year follow up in 78% of subjects1-year follow up in 78% of subjects Interreader agreement for change in Interreader agreement for change in

gradegrade AR: 87.4%, AR: 87.4%, =0.63=0.63 MR: 57.1%, MR: 57.1%, =0.32=0.32

Intrareader agreement for change in Intrareader agreement for change in gradegrade AR: 96.5%, AR: 96.5%, =0.32=0.32 MR: 86.8%, MR: 86.8%, =0.30=0.30



Multiple studies suggest that after Multiple studies suggest that after drug discontinuation:drug discontinuation: Progression of valve disease is rareProgression of valve disease is rare Regression of disease is possibleRegression of disease is possible

Davidoff et al, Arch Intern Med 2001

Mast et al, Ann Intern Med 2001

Weissman et al, Ann Intern Med 2001

cardiotoxic medications echocardiography conference january 2, 2008 michael chuang

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