Medication Influence on Cardiovascular Outcomes

Jamie McCarrell, Pharm.D., BCPS, CGPAssistant Professor, TTUHSC SOP/SOM

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.

http://www.cardiachealth.org/

Torsade de Pointes

• Complication of prolonged QTc interval

http://www.bmj.com/content/324/7340/776

Known Risk

–Amiodarone–Azithromycin–Chlorpromazine–Cilostazole–Ciprofloxacin–Citalopram–Donepezil

– ERY– Escitalopram– Fluconazole–Haloperidol– Levofloxacin–Ondansetron– Sotalol

Possible Risk

– Alfuzosin– Aripiprazole– Clozapine– Famotidine– Gemifloxacin– Granisetron– Lithium– Mirabegron– Mirtazapine– Nicardipine– Olanzapine

– Paliperidone– Promethazine– Quetiapine– Ranolazine– Risperidone– Tacrolimus– Tizanidine– Tolterodine– Vardenafil– Venlafaxine– Ziprasidone

Conditional Risk

– Amitriptyline– Desipramine– Diphenhydramine– Doxepin– Fluoxetine– Furosemide– Galantamine– HCTZ– Hydroxyzine– Itraconazole– Ketoconazole

– Metoclopramide– Metronidazole– Pantoprazole– Paroxetine– Sertraline– Solifenacin– Torsemide– Trazodone– Voriconazole

Confounders

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

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

NEW CONCERNS – SUDDEN CARDIAC DEATH

Journal Club

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.

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

Azithromycin

NEJM, 2012

Azithromycin

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

ORAL ANTICOAGULANTSStroke Prevention

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)

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

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

Renal Adjustments of New Agents

>50 ml/min 30-49 ml/min 15-29 ml/min <15 ml/min

Dabigatran 150 mg BID 150 mg BID 75 mg BID Contraindicated

Rivaroxaban 20 mg daily 15 mg daily 15 mg daily Contraindicated

Apixaban If 2 of these are present, 2.5 mg BID:1. Age 80 or older2. SCr 1.5 or higher3. Weight 60 kg or less

Guidelines

• CHEST– Minimal mention– May favor apixaban

• FDA Approved Indications

Acute DVT Acute PE Non-valve Afib Prophylaxis

Dabigatran X X X

Rivaroxaban X X X 2nd Prev, postop knee/hip

Apixaban X X X Postop knee/hip

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?

CV OUTCOMES WITH ANTIPSYCHOTICS

A Quick Look

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The BadAripiprazole Olanzapine Quetiapine Risperidone

QTc prolongation Unk ✓ ✓ ✓Weight gain Unk ✓✓✓ ✓✓ ✓✓Diabetes Unk ✓✓✓ ✓✓ ✓✓ Triglycerides 0 ✓ 0 Unk Prolactin Unk Unk Unk ✓✓✓N/V/Const 0 0 ✓ UnkEPS ✓✓ ✓ ✓ ✓✓✓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.

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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

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

16. Chatterjee S, et al. Drugs Aging. 2012. Epub 9.27.12.

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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

17. Huybrechts KF, et al. BMJ. 2012;344:e977.

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????

National/Texas Data

11Q2 11Q3 11Q4 12Q1 12Q2 12Q3 12Q4 13Q1 13Q2 13Q3 13Q414%

16%

18%

20%

22%

24%

26%

28%

30%

32%

NationalTexasCalifornia

Fiscal Quarter

NH

Anti

psyc

hotic

Use

10.9% Reduction

Texas Ranking:51/51

20.4% Reduction

18.3% Reduction

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

Patient Case

• Divide into small groups (4-5) of different disciplines if possible

• Take a few minutes to read and discuss the simple case

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?

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?

Medication Influence on Cardiovascular Outcomes

Jamie McCarrell, Pharm.D., BCPS, CGPAssistant Professor, TTUHSC SOP/SOM