1. Medication Influence on Cardiovascular Outcomes Jamie McCarrell, Pharm.D., BCPS, CGP Assistant Professor, TTUHSC SOP/SOM

2. Objectives Identify high-risk medications known to influence cardiac electrical activity. Describe recent literature regarding potential drug interactions that lead to adverse cardiac outcomes. Review new oral anticoagulant medications regarding efficacy, safety, and place in therapy. Given a patient case, optimize pharmacotherapy to improve patient outcomes and minimize adverse effects.

3. http://www.cardiachealth.org/

4. Torsade de Pointes Complication of prolonged QTc interval http://www.bmj.com/content/324/7340/776

5. Known Risk – Amiodarone – Azithromycin – Chlorpromazine – Cilostazole – Ciprofloxacin – Citalopram – Donepezil – ERY – Escitalopram – Fluconazole – Haloperidol – Levofloxacin – Ondansetron – Sotalol

6. Possible Risk – Alfuzosin – Aripiprazole – Clozapine – Famotidine – Gemifloxacin – Granisetron – Lithium – Mirabegron – Mirtazapine – Nicardipine – Olanzapine – Paliperidone – Promethazine – Quetiapine – Ranolazine – Risperidone – Tacrolimus – Tizanidine – Tolterodine – Vardenafil – Venlafaxine – Ziprasidone

7. Conditional Risk – Amitriptyline – Desipramine – Diphenhydramine – Doxepin – Fluoxetine – Furosemide – Galantamine – HCTZ – Hydroxyzine – Itraconazole – Ketoconazole – Metoclopramide – Metronidazole – Pantoprazole – Paroxetine – Sertraline – Solifenacin – Torsemide – Trazodone – Voriconazole

8. Confounders Metabolism: CYP 3A4 especially Existing LQTS Electrolyte abnormalities Female gender Baseline rhythm disorders Bradycardia High dosing (dose dependent)

9. Safety in Numbers Know the numbers! – EKG at baseline if possible for high-risk or multiple medications – If available, know the potential increase in QTc for the medication you are using – Flag these patients somehow…all PRN medications, new starts, etc should be considered in light of prolonged QTc potential

10. NEW CONCERNS – SUDDEN CARDIAC DEATH Journal Club

11. Bactrim® + ACE/ARBs Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients receiving ingibitors of renen-angiotensin system: population based study. BMJ. 2014;349:g6196. doi:10.1136/bmj.g6196.

12. Bactrim® + ACE/ARBs Evaluated over 39,000 sudden deaths – Exposure to outpatient Abx = 1,027 – Matched with 3733 controls Compared to amoxicillin + ACE/ARB… – Bactrim + ACE/ARB had OR = 1.54 (1.29 – 1.84) at 14 days. – 3 sudden deaths per 1,000 Bactrim Rxs – Cipro also has risk with OR 1.29 (1.03 – 1.62) Thought to be due to acute hyperkalemia

13. Azithromycin NEJM, 2012

14. Azithromycin Nearly 350,000 azithromycin Rxs – Compared CV death outcomes to: No antibiotic use Amoxicillin Ciprofloxacin Levofloxacin

18. ORAL ANTICOAGULANTS Stroke Prevention

19. Dabigatran (Pradaxa®) Direct thrombin inhibitor RE-LY trial – 150 mg PO BID – CrCl < 30 was excluded from trial – Canadian labeling: CrCl < 30 is contraindicated Major bleed = warfarin for >75 y.o. cohort – No antidote – Intracranial bleed better for dabigatran Australia/New Zealand audit (postmarket 2012) – 2 months, 78 cases of bleeding with dabigatran FDA Review – rates similar to RE-LY trial (11/2012)

20. Rivaroxaban (Xarelto®) Oral factor Xa inhibitor ROCKET-AF trial – Non-inferiority study – Mean age 73, 14000 pts, 45 countries – More GI bleeds, less brain bleeds (vs warfarin) – Moderate renal insuff = higher rates of strokes and bleeding 20 mg PO once daily if normal renal fxn No antidote

21. Apixaban (Eliquis®) Oral factor Xa inhibitor ARISTOTLE trial – 5 mg PO BID – 1.6% vs 1.27% (p=0.01 for superiority) for stroke or systemic embolism – 3.09% vs 2.13% (p<0.001) for major bleeding – Cohort evaluation determined that these hold true for all age groups No antidote

22. Renal Adjustments of New Agents >50 ml/min30-49 ml/min15-29 ml/min<15 ml/min Dabigatran150 mg BID 75 mg BID Contraindicated Rivaroxaban20 mg daily15 mg daily Contraindicated ApixabanIf 2 of these are present, 2.5 mg BID: 1.Age 80 or older 2.SCr 1.5 or higher 3.Weight 60 kg or less

23. Guidelines CHEST – Minimal mention – May favor apixaban FDA Approved Indications

24. Common Questions Warfarin – Management of INR out of range High INR without bleeding Low INR When to use vitamin K? – Initiation Loading dose? When to monitor INR? Bridging?

25. CV OUTCOMES WITH ANTIPSYCHOTICS A Quick Look

26. The Bad 26 AripiprazoleOlanzapineQuetiapineRisperidone QTc prolongation Unk ✓✓✓ Weight gain Unk ✓✓✓✓✓ Diabetes Unk ✓✓✓✓✓  Triglycerides 0 ✓ 0Unk  Prolactin Unk ✓✓✓ N/V/Const 00 ✓ Unk EPS ✓✓✓✓✓✓✓ Anticholinergic 0 ✓✓✓ 0 Adapted from Table 2. Am Geri Society. A guide to the management of psychotic disorders and neuropsychiatric symptoms of dementia in older adults. 2011.

27. The Ugly BBW – Based on 17 placebo-controlled trials – Relative risk of death = 1.6 – 1.7 – Absolute risk difference Placebo = 2.6% Atypical antipsychotic = 4.5% Absolute risk increase = 1.9% Number needed to harm (NNH) = 53 27

28. Are All Antipsychotics Created Equally? NO. Typical antipsychotics have no better efficacy with more adverse effects. Chatterjee S, et al. 14 – Age > 50, NOT specific for dementia, studied CV events – Compared quetiapine and risperidone to olanzapine – Quetiapine HR = 0.88 (0.78 – 0.99) – Risperidone HR = 1.05 (0.95 – 1.16) – Quetiapine may be better for CV events 28 16. Chatterjee S, et al. Drugs Aging. 2012. Epub 9.27.12.

29. Are All Antipsychotics Created Equally? Huybrechts KF, et al. 15 – Age > 65, NH patients, studied mortality – Compared many antipsychotics to risperidone – Haloperidol HR = 2.07 (1.89 – 2.26) – Quetiapine HR = 0.81 (0.75 – 0.88) – All other medications equal to risperidone Author’s conclusions: – Haloperidol = most risk – Quetiapine = least risk – Risk higher with higher doses 29 17. Huybrechts KF, et al. BMJ. 2012;344:e977.

30. CMS Initial Goals 2011 – CMS initiative announced 12% reduction in antipsychotic use across the board nationally Reasons: – Poor data for efficacy – Good data for adverse effects – Cost – $7.6 BILLION for part D (8.4% of total 2011 part D budget) How did we do????

31. National/Texas Data 10.9% Reduction Texas Ranking: 51/51 20.4% Reduction 18.3% Reduction

32. CMS New Goals 25% reduction by end of 2015* 30% reduction by end of 2016* Will be checking to make sure that the meds aren’t just replaced with anxiolytics and other sedatives *Measured as reduction from 11Q4

33. Patient Case Divide into small groups (4-5) of different disciplines if possible Take a few minutes to read and discuss the simple case

34. Patient Case Question 1 – What drug regimen would you use to treat HH’s Afib? Question 2 – Is HH a low, moderate, or high stroke risk? Question 3 – Based on risk, what drug regimen would you start for stroke prevention?

35. Patient Case Question 4 – The decision is made to start Apixaban. What dose? 6 months later, HH decides that he can’t live with taking a blood thinner with no antidote. He wants warfarin now. How do you convert to warfarin?

36. Medication Influence on Cardiovascular Outcomes Jamie McCarrell, Pharm.D., BCPS, CGP Assistant Professor, TTUHSC SOP/SOM