Φαρμακευτικές ουσίες που μπορούν να προκαλέσουν ή να επιδεινώσουν την καρδιακή ανεπάρκεια ΒΑΣΙΛΙΚΗ ΜΠΙΣΤΟΛΑ ΚΑΡΔΙΟΛΟΓΟΣ

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1 Φαρμακευτικές ουσίες που μπορούν να προκαλέσουν ή να επιδεινώσουν την καρδιακή ανεπάρκεια ΒΑΣΙΛΙΚΗ ΜΠΙΣΤΟΛΑ ΚΑΡΔΙΟΛΟΓΟΣ

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3 Φάρμακα που προκαλούν ΚΑ Χημειοθεραπεία Ανοσοτροποποιητικοί παράγοντες

4 Φάρμακα που προκαλούν ΚΑ Χημειοθεραπεία Ανοσοτροποποιητικοί παράγοντες mab TNF-α (ρευματικής αρχής αρθρίτιδες, φλεγμονώδεις παθήσεις εντέρου) Αντιμυκητιασικά Ιτρακοναζόλη (μετεγκριτικές περιπτώσεις νέας εμφάνισης ΚΑ) Φάρμακα υπερπλασίας προστάτη Dutasteride (νέα εμφάνιση ΚΑ) Αντιψυχωσικά Clozapine (μυοκαρδιοπάθεια, μυοκαρδίτιδα)

5 Καρδιοτοξικότητα από ΧΜΘ «Κλασική» ΧΜΘ Ανθρακυκλίνες (doxorubicin): μυοκαρδιοπάθεια Στοχευμένες θεραπείες Anti-HER2 (trastuzumab, lapatinib): μυοκαρδιοπάθεια

6 Incidence of left ventricular dysfunction and heart failure with specific chemotherapeutic agents Class Drug Incidence Anthacyclines Doxorubicin 3-48% Alkylating agents Cyclophosphamide 7-28% Antimicrotubule agents Docetaxel 2-13% Monoclonal Ab Trastuzumab 1-20% Tyrosine kinase inhibitors Sunitinib 3-19% Proteasome inhibitors Carfilzomib 11-15% Modified from ESC 2016

7 Anthracyclines induce cardiomyocyte apoptosis/necrosis through inhibition of topoisomerase-2β Vejpongsa & Yeh, J Am Coll Cardiol 2014 Zhang et al, Nat Med 2012 Top2β roles: protects cardiomyocytes from DNA damage and transcriptome changes responsible for defective mitochondrial biogenesis and ROS formation In experimental models protects mice from heart failure

8 Trastuzumab-related cardiotoxicity: inhibition of the HER2:HER4 heterodimer limits repair mechanisms during myocyte stress Wells & Lenihan, Prog Cardiovasc Dis 2010

9 Anthracycline-trastuzumab interaction Ewer and Ewer, Nat Rev Cardiol 2015

10 55 RCTs, anthracycline vs non-anthracycline regimens (OR 5.43) * Dexrazoxane Smith et al, BMJ Cancer 2010

11 ESC 2016 Anthracycline cardiotoxicity is dosedependent

12 CREC: Cardiac Review and Evaluation Committee LV dysfunction: Trastuzumab: 3-7% Trastuzumab+doxorubicin: 27% (16% HF ΝΥΗΑ ΙΙΙ/ΙV) Trastuzumab+paclitaxel: 13% (vs 1% paclitaxel) Seidman et al, J Clin Oncol 2002

13 Is anthracycline-induced cardiotoxicity reversible? Wells & Lenihan, Prog Cardiovasc Dis 2010

14 201 pts, LVEF <45% due to anthracycline chemotherapy Enalapril +/- carvedilol mean follow-up 36 months The percentage of responders progressively decreased as the time to the start of HF treatment increased; no complete recovery of LVEF was observed after 6 months. Cardinale et al, JACC 2010

15 Φάρμακα που προκαλούν ΚΑ Χημειοθεραπεία «Κλασικά» χημειοθεραπευτικά Βιολογικοί παράγοντες (στοχευμένες θεραπείες) Ανοσοτροποποιητικοί παράγοντες mab TNF-α (ρευματικής αρχής αρθρίτιδες, φλεγμονώδεις παθήσεις εντέρου) Αντιμυκητιασικά Ιτρακοναζόλη (μετεγκριτικές περιπτώσεις νέας εμφάνισης ΚΑ) Φάρμακα υπερπλασίας προστάτη Dutasteride (νέα εμφάνιση ΚΑ) Αντιψυχωσικά Clozapine (μυοκαρδιοπάθεια, μυοκαρδίτιδα)

16 RCTs of anti-tnf-α in HF Etanercept vs placebo Death or HF hospitalization Infliximab vs placebo Death or HF hospitalization ATTACH trial In RENAISSANCE there were higher rates of HF hospitalization in the etanercept arm In ATTACH there were higher rates of death/hf hospitalization in the high-dose infliximab arm Anker SD, Coats A. Int J Cardiol 2002

17 2757 patients on infliximab/etanercept vs 1491 pts on conventional DMARDs HR for new-onset HF: 1.66 (p=ns) Arthritis Rheum. 2008; 58:667-77

18 2121 patients with RA and 1897 with Crohn s disease, age <50 years Not statistically significant increase of risk for newonset HF by anti-tnf-α treatment in RA patients: RR 4.3 Lower RR in Crohn s disease patients: RR 1.2 Rheumatology 2007;46:

19 Anti-TNF-α EMA summary product characteristics Infliximab: Is contraindicated in patients with moderate or severe heart failure (NYHA class III/IV) Should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored and infliximab must not be continued in patients who develop new or worsening symptoms of heart failure Etanercept: Physicians should use caution when using Enbrel in patients who have congestive heart failure.

20 Φάρμακα που επιδεινώνουν την καρδιακή ανεπάρκεια

21 Multicenter Diltiazem Postinfarction Trial (MDPIT) Post-MI, with LVEF <40%, Diltiazem vs placebo Goldstein R, et al. Circulation 1991

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23 24335 patients with arterial hypertension plus 1 CV risk factor Doxazosin vs chlorthalidone Doxazosin increased risk for CHF, angina, coronary revascularization JAMA 2000;283:

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25 Kober L. N Engl J Med 2008;358:

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27 Rosiglitazone: HR for Heart Failure= 2.10 (95% CI, )

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29 16,492 patients with DM type 2, and a history of, or at risk for cardiovascular events 12% had HF history

30 TECOS: Sitagliptin in patients with established CV disease Sitagliptin n=7332 Placebo n=7339 All-cause mortality 547 (7.5%) 537 (7.3%) 2.48 per 100 pyrs 2.45 per 100 pyrs ITT HR=1.01 (0.90, 1.14), p=0.88 Non-cardiovascular 167 (2.3%) 171 (2.3%) Unknown* 109 (1.5%) 107 (1.5%) 18% had HF history Cardiovascular Sudden cardiac death 72 (1.0%) 73 (1.0%) Acute myocardial infarction 21 (0.3%) 27(0.4%) Heart failure 28 (0.4%) 35 (0.5%) Stroke 29 (0.4%) 36 (0.5%) Other cardiovascular 8 (0.1%) 5 (0.1%) * Counted as cardiovascular for the primary analysis Presumed cardiovascular 113 (1.5%) 83 (1.1%) Adapted from Green JB et al. NEJM 2015; DOI: /NEJMoa

31 Hospitalisations for heart failure, DPP-4i class effect? Combined analysis Analysis DPP-4i s Placebo HR (95%CI) P value SAVOR TIMI SAXAGLIPTIN (n=16,492) EXAMINE ALOGLIPTIN (n=5380) TECOS SITAGLIPTIN (n=14,671) COMBINED ANALYSIS 289 (3.5%) 228 (2.8%) 1.27 (1.07,1.51) (3.9%) 89 (3.3%) 1.19 (0.89, 1.58) (3.1%) 229 (3.1%) 1.00 (0.83, 1.20) (3.4%) 546 (3.0%) Test for heterogeneity for 3 trials: p=0.178, I 2 = 42% 1.14 (0.97, 1.34) Presented at ADA2015 on June 8 th, unpublished data

32 Hospitalisations for heart failure, DPP-4i class effect? Meta-analysis, n=85224 pts with DM, DPP4i vs placebo Int J Cardiol 2015;181:

33 NSAIDs and COX-2 inhibitors increase the risk of worsening HF pts (arthritis/nonrheumatic disorders), NSAIDs vs placebo 62,653 pts NSAIDs vs COX-2 inhibitors Scott PA, et al. Eur J Heart Fail 2008;10:

34 2016 ESC guidelines Management of heart failure

35 2016 ESC guidelines Management of heart failure

36 DRUG NEW-ONSET HF CLINICAL USE CHEMOTHERAPY YES INDIVIDUALIZE CARDIO-ONCOLOGY TEAM BIOLOGICAL RESPONSE MODIFIERS POSSIBLE CAUTION/INDIVIDUALIZE DRUG WORSENING HF CLINICAL USE DILTIAZEM/VERAPAMIL YES CONTRAINDICATED MOXONIDINE YES CONTRAINDICATED ANTIARRYTHMICS (CLASS I, DRONEDARONE) Exception: Amiodarone, dofetilide YES CONTRAINDICATED GLITAZONES YES CONTRAINDICATED DPP4Is UNCERTAIN CAUTION/INDIVIDUALIZE NSAIDs/COX-2-i YES CONTRAINDICATED