Presentation is loading. Please wait.

Presentation is loading. Please wait.

Cardiotoxic Medications Echocardiography Conference January 2, 2008 Michael Chuang.

Similar presentations


Presentation on theme: "Cardiotoxic Medications Echocardiography Conference January 2, 2008 Michael Chuang."— Presentation transcript:

1 Cardiotoxic Medications Echocardiography Conference January 2, 2008 Michael Chuang

2 Cardiotoxicity Impairment of function Impairment of function Valvular disorders Valvular disorders Infarction Infarction Arrhythmias Arrhythmias Thrombophilia Thrombophilia

3 Cardiotoxic Drugs Anthracyclines Anthracyclines Tyrosine kinase inhibitors Tyrosine kinase inhibitors Dopamine agonists Dopamine agonists Appetite suppressants Appetite suppressants Glucocorticoids Glucocorticoids Antifungals Antifungals Herbals Herbals Thiazolidinediones NSAIDs – COX2 inhibitors Alkylating drugs Interferons TNF antagonists Antidepressants Antipsychotics

4

5 Cardiotoxic Drugs Anthracyclines Anthracyclines Tyrosine kinase inhibitors Tyrosine kinase inhibitors Dopamine agonists (anti-Parkinsonians) Dopamine agonists (anti-Parkinsonians) Appetite suppressants Appetite suppressants Thiazolidinediones NSAIDs – COX2 inhibitors Alkylating drugs Interferons TNF antagonists Antidepressants Antipsychotics Glucocorticoids Antifungals Herbals

6 Anthracyclines: Background Purpose: anti-cancer, chemotherapy Purpose: anti-cancer, chemotherapy breast, soft tissue sarcoma, leukemia, lymphoma, childhood tumors breast, soft tissue sarcoma, leukemia, lymphoma, childhood tumors Therapeutic mechanism: insertion into DNA of replicating cells, → DNA fragmentation, decreased DNA, RNA and protein synthesis Therapeutic mechanism: insertion into DNA of replicating cells, → DNA fragmentation, decreased DNA, RNA and protein synthesis Toxicity via: free radicals, ↑ oxidative stress Toxicity via: free radicals, ↑ oxidative stress Toxicity probably NOT via therapeutic mechanism Toxicity probably NOT via therapeutic mechanism Examples: doxorubicin ( Adriamycin® ), danorubicin ( Cerubidine® ), epirubicin ( Pharmorubicin® ), mitoxantrone ( Novantrone® [anthracendione] ) Examples: doxorubicin ( Adriamycin® ), danorubicin ( Cerubidine® ), epirubicin ( Pharmorubicin® ), mitoxantrone ( Novantrone® [anthracendione] )

7 Anthracyclines: Clinical Manifestations Acute Toxicity: BNP elevation, ventricular dysfunction, EKG abnormalities, pericarditis- myocarditis syndrome Acute Toxicity: BNP elevation, ventricular dysfunction, EKG abnormalities, pericarditis- myocarditis syndrome days to weeks days to weeks transient, not dose related transient, not dose related Early Toxicity: ventricular dysfunction, heart failure Early Toxicity: ventricular dysfunction, heart failure weeks to months weeks to months dose-related dose-related Late Toxicity: ventricular dysfunction, heart failure Late Toxicity: ventricular dysfunction, heart failure years years dose-related dose-related

8 Anthracyclines: Incidence [1] Retrospective study: 3941 patients given doxorubicin Retrospective study: 3941 patients given doxorubicin Overall incidence of heart failure 2.2% Overall incidence of heart failure 2.2% strongly dose related strongly dose related Cumulative Dose Heart Failure <400 mg/m 2 0.14% ~400 mg/m 2 3% ~550 mg/m 2 7% ~700 mg/m 2 18% Von Hoff et al, Ann Intern Med 1979

9 Anthracyclines: Incidence [2] 630 patients receiving FAC (fluorouracil, doxorubicin, cyclophosphamide) and dexrazoxane for advanced breast cancer. Swain et al, Cancer 2003 Dose%CHF ≤400 mg/m 2 5% ~500 mg/m 2 16% ~550 mg/m 2 26% ~700 mg/m 2 48%

10 Anthracyclines: Risk Factors and Modifiers Risk factors: cumulative dose, age, combination chemotherapy (e.g. cyclophosphamide, taxanes, trastuzumab), prior cardiac disease, mediastinal radiation, hypertension, female sex (pediatric patients only) 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, β- blockers, CCBs, ARBs Risk reduction via: dose minimization, continuous (vs. bolus) administration, liposomal formulation of anthracycline, dexrazaxone, β- blockers, CCBs, ARBs

11 Anthracyclines: Maximum “Safe” Doses DrugDose doxorubicin 550 mg/m 2 danorubicin 600 mg/m 2 epirubicin 1000 mg/m 2 idarubicin 100 mg/m 2 Mitoxantrone 160 mg/m 2

12 Anthracyclines: Assessment Biomarkers Biomarkers natriuretic peptides: ANP, BNP natriuretic peptides: ANP, BNP Troponin Troponin ECG: QRS duration, QTc, T-wave changes ECG: QRS duration, QTc, T-wave changes Endomyocardial biopsy Endomyocardial biopsy Ejection Fraction Ejection Fraction

13 Ventriculography

14 Imaging Assessment of Cardiac Function Accuracy versus Reproducibility Accuracy versus Reproducibility Modalities Modalities Radionuclide ventriculography (RVG, MUGA) Radionuclide ventriculography (RVG, MUGA) Echocardiography Echocardiography Cardiovascular Magnetic Resonance (CMR) Cardiovascular Magnetic Resonance (CMR) Computed Tomography (CT) Computed Tomography (CT)

15 Radionuclide Ventriculography Widely used in oncology trials Widely used in oncology trials Reproducibility good Reproducibility good Injection of tagging agent Injection of tagging agent Radiation expousre (~8 mSv) Radiation expousre (~8 mSv)

16 Computed Tomography Very fast Very fast Accurate* and reproducible Accurate* and reproducible Iodinated contrast agent Iodinated contrast agent Radiation exposure Radiation exposure *Limited temporal resolution *Limited temporal resolution

17 Echocardiography Noninvasive, generally well tolerated Noninvasive, generally well tolerated Patient-associated image quality limitations Patient-associated image quality limitations Assessement of valves, hemodynamics in addition to function Assessement of valves, hemodynamics in addition to function Reproducibility of 2D echo limited compared with volumetric techniques Reproducibility of 2D echo limited compared with volumetric techniques 3D echo markedly improves reproducibility 3D echo markedly improves reproducibility

18 Improved Reproducibility of 3DE Otterstad et al, Eur Heart J 1997 Hibberd et al, AHA 1996

19 CMR Very accurate (probably) Very accurate (probably) Reproducible Reproducible Contraindications Contraindications Local availablity and expertise Local availablity and expertise Chuang et al, JACC 2000

20 Reproducibility Beware systematic differences between imaging methods and modalities Beware systematic differences between imaging methods and modalities Lack of mean bias does not guarantee detection of small changes Lack of mean bias does not guarantee detection of small changes Chuang et al, JACC 2000

21 Tyrosine Kinase Inhibitors: Background Purpose: anti-cancer, chemotherapy Purpose: anti-cancer, chemotherapy hematologic cancers, breast cancer, gastrointestinal stromal tumor (GIST) hematologic cancers, breast cancer, gastrointestinal stromal tumor (GIST) Therapeutic Mechanism: inhibition of dysregulated TKs causal/contributory to tumorigenesis Therapeutic Mechanism: inhibition of dysregulated TKs causal/contributory to tumorigenesis Humanized monoclonal antibodies Humanized monoclonal antibodies Small-molecule TKIs Small-molecule TKIs Cardiotoxicity: asymptomatic LV dysfunction, CHF Cardiotoxicity: asymptomatic LV dysfunction, CHF Examples: trastuzumab ( Herceptin® ), sunitinib ( Sutent® ), imatinib ( Gleevec®, Glivec® ) Examples: trastuzumab ( Herceptin® ), sunitinib ( Sutent® ), imatinib ( Gleevec®, Glivec® )

22 Trastuzumab (Herceptin ® ) [1] Human epidermal growth factor (HER2, ERBB2) overexpressed in ~25% breast cancers, marker of poor prognosis 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 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 Multiple randomized trials show trastuzumab benefit in ERBB2+ breast cancers, 80% of trials show cardiotoxicity Viani et al, BMC Cancer 2007

23 Trastuzumab (Herceptin ® ) [2] 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 agents Interaction with other chemotherapeutic agents Antibody-dependent cell-mediated cytotoxicity Antibody-dependent cell-mediated cytotoxicity Downregulation/inhibition of ERBB2 signalling Downregulation/inhibition of ERBB2 signalling

24 Trastuzumab (Herceptin ® ) [2.1] ERBB2 signalling mandatory for embryonic cardiomyocyte proliferation (germline deletion of ERBB2 fatal in mice) 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 Late ERBB2 deletion → age-related DCM, impaired response to pressure overload

25 Trastuzumab (Herceptin ® ) [2.2] ERBB2-binding triggers intracellular signalling ERBB2-binding triggers intracellular signalling Breast CA: inhibits autophosphorylation of ERBB2- ERBB3 heterodimers Breast CA: inhibits autophosphorylation of ERBB2- ERBB3 heterodimers Cardiomyocytes (rat): Cardiomyocytes (rat): ↓ ERBB2 activatio n, ↓ BCL-X L, ↑ BCL-X S ↓ ERBB2 activatio n, ↓ BCL-X L, ↑ BCL-X S Release of cytochrome c, caspase activation Release of cytochrome c, caspase activation Loss of mitochondrial membrane potential Loss of mitochondrial membrane potential Reduction in ATP levels Reduction in ATP levels Contractile dysfunction Contractile dysfunction Grazette et al, JACC 2004

26 Trastuzumab (Herceptin ® ) [2.3] Force et al, Nature Rev: Cancer 2007

27 Trastuzumab (Herceptin ® ) [2.2] ERBB2-binding triggers intracellular signalling ERBB2-binding triggers intracellular signalling Breast CA: inhibits autophosphorylation of ERBB2- ERBB3 heterodimers Breast CA: inhibits autophosphorylation of ERBB2- ERBB3 heterodimers Cardiomyocytes (rat): Cardiomyocytes (rat): ↓ ERBB2 activation, ↓ BCL-X L, ↑ BCL-X S ↓ ERBB2 activation, ↓ BCL-X L, ↑ BCL-X S Release of cytochrome c, caspase activation Release of cytochrome c, caspase activation Loss of mitochondrial membrane potential Loss of mitochondrial membrane potential Reduction in ATP levels Reduction in ATP levels Contractile dysfunction Contractile dysfunction Grazette, JACC 2004

28 Trastuzumab (Herceptin ® ) [2.4] Force et al, Nature Rev: Cancer 2007

29 Trastuzumab (Herceptin ® ) [2] 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 agents Interaction with other chemotherapeutic agents Antibody-dependent cell-mediated cytotoxicity Antibody-dependent cell-mediated cytotoxicity Downregulation/inhibition of ERBB2 signalling Downregulation/inhibition of ERBB2 signalling Toxicity at least partially reversible Toxicity at least partially reversible Reversal after drug discontinuation Reversal after drug discontinuation Response to CHF medications Response to CHF medications

30 Trastuzumab (Herceptin ® ) [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, risk with prior anthracycline exposure 6-fold that of anthracycline-naïve Decrease in EF ≥ 15%: ~5% of subjects, risk with prior anthracycline exposure 6-fold that of anthracycline-naïve Symptomatic dysfunction: Symptomatic dysfunction: 78% improved off drug 78% improved off drug 12% progressive HF 12% progressive HF Risk factors: prior/concommitant anthracycline exposure, pretreatment NYHA class Risk factors: prior/concommitant anthracycline exposure, pretreatment NYHA class Suter et al, Breast, 2004

31 Sunitinib (Sutent ® ) Small-molecule multi targeted TKI Small-molecule multi targeted TKI VEGFR 1-3, PDGFR , KIT, CSF-1, RET VEGFR 1-3, PDGFR , KIT, CSF-1, RET Inhibition of angiogenesis Inhibition of angiogenesis FDA and EU approved for GIST, renal-cell carcinoma FDA and EU approved for GIST, renal-cell carcinoma Cardiotoxicity: Cardiotoxicity: GIST: no change in EF after 8 weeks [Demetri, Lancet 2006] 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] 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% Pfizer insert: 11% of patients have decrease in EF to less than 50%

32

33

34 Sunitinib: Study Design 75 adults with imatinib-resistant GIST 75 adults with imatinib-resistant GIST Open-label Phase I/II trial of sunitinib at DFCI Open-label Phase I/II trial of sunitinib at DFCI Cycle: 50 mg daily. 4 weeks on, 2 weeks off Cycle: 50 mg daily. 4 weeks on, 2 weeks off 4 cycles 4 cycles Serial EKG, biomarkers, radionuclide ventriculography (baseline EF > 50%) Serial EKG, biomarkers, radionuclide ventriculography (baseline EF > 50%) Interstudy reproducibility: 2-3% Interstudy reproducibility: 2-3%

35 Sunitinib: CV Events - Definitions CHF: documented signs and symptoms, reduction in EF to < 50%, typical CXR and relief with CHF therapy 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 MI: TnI>0.10 and clinical symptoms, EKG changes Death: cardiovascular vs. noncardiovascular, adjucated by cardiologists and oncologists; CV death only if concordance Death: cardiovascular vs. noncardiovascular, adjucated by cardiologists and oncologists; CV death only if concordance

36 Sunitinib: CV Events

37 Sunitinib: Maximum Decline in EF

38 Sunitinib: Predicted Decrease in EF

39 Sunitinib: Mitochondrial Abnormalities (rodent models)

40 Sunitinib: Hypertension [1]

41 Sunitinib: Hypertension [2]

42 Sunitinib: Study Summary 11% of 75 patients had CV event 11% of 75 patients had CV event 8% had NYHA Class III or IV HF 8% had NYHA Class III or IV HF ~50% developed hypertension ~50% developed hypertension EF declined after each cycle of treatment EF declined after each cycle of treatment In mice: In mice: Increased mitochondrial damage Increased mitochondrial damage No increase in cardiomyocyte apoptosis No increase in cardiomyocyte apoptosis Sunitinib + phenylephrine (inducing HTN) increased apoptosis 7-fold vs phenylephrine alone Sunitinib + phenylephrine (inducing HTN) increased apoptosis 7-fold vs phenylephrine alone

43 Dopamine Agonists: Background [1] Purpose: anti-Parkinsonian, restless leg syndrome, hyperprolactinemia, Tourette’s syndrome Purpose: anti-Parkinsonian, restless leg syndrome, hyperprolactinemia, Tourette’s syndrome Therapeutic mechanisms: stimulation of dopamine receptors Therapeutic mechanisms: stimulation of dopamine receptors Toxicity via: agonism of 5-HT 2B receptors on cardiac valves → fibrosis, regurgitation Toxicity via: agonism of 5-HT 2B receptors on cardiac valves → fibrosis, regurgitation Examples: pergolide (Permax®), cabergoline (Dostinex ®) Examples: pergolide (Permax®), cabergoline (Dostinex ®)

44 Dopamine Agonists: Background [2] Ergot derivatives vs. non-ergot Ergot derivatives vs. non-ergot Ergot: pergolide, cabergoline Ergot: pergolide, cabergoline Non-ergot: pramipexole, ropinrole Non-ergot: pramipexole, ropinrole Non-cardiac side effects: retroperitoneal and pleuropulmonary fibrosis Non-cardiac side effects: retroperitoneal and pleuropulmonary fibrosis

45 Ergot Claviceps fungus, parasitic on many grains Claviceps fungus, parasitic on many grains Overwinters as a sclerotium which contains alkaloids, e.g. ergotamine Overwinters as a sclerotium which contains alkaloids, e.g. ergotamine Effects include: Effects include: Vasoconstriction – St. Anthony’s fire Vasoconstriction – St. Anthony’s fire Uterine contractions Uterine contractions Hallucinations Hallucinations Convulsions Convulsions Death Death

46 Ergot-Derived Dopamine Agonists [3] 155 patients on dopamine-agonist anti- Parkinsonians, 90 controls 155 patients on dopamine-agonist anti- Parkinsonians, 90 controls On treatment ≥ 12 months, no prior valve disease, no other drugs likely to cause valvulopathy On treatment ≥ 12 months, no prior valve disease, no other drugs likely to cause valvulopathy Pergolide (n=64), cabergoline (49), nonergot (42) Pergolide (n=64), cabergoline (49), nonergot (42) Transthoracic echo (Sequoia) Transthoracic echo (Sequoia) Per-valve regurgitation graded 0-4 Per-valve regurgitation graded 0-4 Composite valve score 0-12 Composite valve score 0-12 Thickening defined as >5mm Thickening defined as >5mm Mitral-valve tenting area Mitral-valve tenting area Zanettini et al, NEJM 2007

47 Ergot-Derived Dopamine Agonists [4] Valvular abnormalities more prevalent in pergolide and cabergolide groups vs. controls and vs. non-ergot dopamine agonist treated Valvular abnormalities more prevalent in pergolide and cabergolide groups vs. controls and vs. non-ergot dopamine agonist treated Grade III and IV regurgitation Grade 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

48 Ergot-Derived Dopamine Agonists [5] Cumulative doses correlated with severity of regurgitation 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 Relative Risk MRARTR Pergolide 6.3 [1.4-28.3] 4.2 [1.2-15] 5.6 [0.7-49] Cabergoline 4.6 [0.9-22.8] 7.3 [2.2-24.8] 5.5 [0.6-51.6]

49 Ergot-Derived Dopamine Agonists [6] Case-control (1:25) study UK GPRD data Case-control (1:25) study UK GPRD data Aged 40-80 with ≥ 2 prescriptions btwn 1988-2005 Aged 40-80 with ≥ 2 prescriptions btwn 1988-2005 No prior valve disease, murmurs, CHF, MI, carcinoid, other drugs assoc. with valve dz, IVDU No prior valve disease, murmurs, CHF, MI, carcinoid, other drugs assoc. with valve dz, IVDU 31 patients with new valve regurgitation 31 patients with new valve regurgitation Only 16 cases confirned by echo or cath Only 16 cases confirned by echo or cath Relative risk Relative 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 dose/duration Risk increased with cumulative dose/duration Schade et al, NEJM 2007

50 Ergot-derived dopamine agonists: Summary [7] Results consistent across multiple studies Results consistent across multiple studies Risk of valve disease increases ~5-6 fold with pergolide or cabergoline Risk of valve disease increases ~5-6 fold with pergolide or cabergoline Risk increases with dose, duration of exposure Risk increases with dose, duration of exposure Susceptibility depends on individual factors Susceptibility depends on individual factors Reversibility after drug discontinuation unknown Reversibility after drug discontinuation unknown Serial monitoring by echocardiography ? Serial monitoring by echocardiography ?

51 Anorectic Agents/Fenfluramine: Background Purpose: appetite suppression Purpose: appetite suppression Therapeutic mechanisms: activation of serotonin release, inhibition of serotonin breakdown Therapeutic mechanisms: activation of serotonin release, inhibition of serotonin breakdown Toxicity via: increased serotonin levels, likely in combination with activation of 5-HT 2B receptors Toxicity via: increased serotonin levels, likely in combination with activation of 5-HT 2B receptors Examples: fenfluramine (dexfenfluramine), phentermine Examples: fenfluramine (dexfenfluramine), phentermine

52 Fenfluramine: Cardiac Effects Clinically-significant valvular regurgitation Clinically-significant valvular regurgitation Mitral valve abnormalities Mitral valve abnormalities Decreased posterior-leaflet mobility Decreased posterior-leaflet mobility Anterior-leaflet thickening and diastolic doming Anterior-leaflet thickening and diastolic doming Subvalvular disease (chordal shortening/thickening) Subvalvular disease (chordal shortening/thickening) Aortic regurgitation, leaflet thickening and retraction Aortic regurgitation, leaflet thickening and retraction Pulmonary hypertension Pulmonary hypertension

53 Fenfluramine [3] 24 women (44±8 years), 12±7 months after fenfluramine-phentermine therapy 24 women (44±8 years), 12±7 months after fenfluramine-phentermine therapy No history of CV disease No history of CV disease Right and left-sided valvular lesions Right and left-sided valvular lesions 5 went to surgery at press time 5 went to surgery at press time 8 new cases of pulmonary hypertension 8 new cases of pulmonary hypertension Connolly et al, NEJM 1997

54 Fenfluramine: MV Gross Specimen [4] Connolly et al, NEJM 1997

55 Fenfluramine: Mitral Valve [5] Connolly et al, NEJM 1997

56 Fenfluramine: [6] Multisite reader-blinded controlled study Multisite reader-blinded controlled study 30 days of drug therapy within 14 months of enrollment 30 days of drug therapy within 14 months of enrollment 1473 patients, mean BMI 35±7 kg/m 2 1473 patients, mean BMI 35±7 kg/m 2 2D Echo on HP Sonos 2000 or 2500 systems 2D Echo on HP Sonos 2000 or 2500 systems Valvular regurgitation Valvular regurgitation Valve leaflet thickness and mobility Valve leaflet thickness and mobility Gardin et al, JAMA 2000

57 Fenfluramine: [6] Treated patients had higher prevalence of AR Treated patients had higher prevalence of AR No difference in prevalence of MR (4.9, 5.1, 3.2%) No difference in prevalence of MR (4.9, 5.1, 3.2%) No difference in valve mobility No difference in valve mobility No difference in MI, CHF or serious arrhythmia No difference in MI, CHF or serious arrhythmia Prevalence Relative Risk dexfenfluramine8.9% 2.18 [1.32-3.59] dexfenfluramine / phentermine 13.7% 3.34 [2.09-5.35] control4.1%- Gardin et al, JAMA 2000

58 Fenfluramine: [7] 1-year follow up in 78% of subjects 1-year follow up in 78% of subjects Interreader agreement for change in grade Interreader agreement for change in grade AR: 87.4%,  =0.63 AR: 87.4%,  =0.63 MR: 57.1%,  =0.32 MR: 57.1%,  =0.32 Intrareader agreement for change in grade Intrareader agreement for change in grade AR: 96.5%,  =0.32 AR: 96.5%,  =0.32 MR: 86.8%,  =0.30 MR: 86.8%,  =0.30 Gardin et al, JAMA 2001

59 Fenfluramine: [8] Gardin et al, JAMA 2001

60 Fenfluramine: [9] Multiple studies suggest that after drug discontinuation: Multiple studies suggest that after drug discontinuation: Progression of valve disease is rare Progression of valve disease is rare Regression of disease is possible Regression 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


Download ppt "Cardiotoxic Medications Echocardiography Conference January 2, 2008 Michael Chuang."

Similar presentations


Ads by Google