Medication Influence on
Cardiovascular Outcomes
Jamie McCarrell, Pharm.D., BCPS, CGP
Assistant 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
Journal Club
NEW CONCERNS – SUDDEN
CARDIAC DEATH
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
Stroke Prevention
ORAL ANTICOAGULANTS
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 older
2. SCr 1.5 or higher
3. Weight 60 kg or less
Guidelines
• CHEST
– Minimal mention
– May favor apixaban
• FDA Approved Indications
Dabigatran
Acute DVT
Acute PE
Non-valve Afib
X
X
X
Prophylaxis
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?
A Quick Look
CV OUTCOMES WITH
ANTIPSYCHOTICS
The Bad
Aripiprazole
Olanzapine
Quetiapine
Risperidone
QTc prolongation
Unk
✓
✓
✓
Weight gain
Unk
✓✓✓
✓✓
✓✓
Diabetes
Unk
✓✓✓
✓✓
✓✓
0
✓
0
Unk
Unk
Unk
Unk
✓✓✓
0
0
✓
Unk
✓✓
✓
✓
✓✓✓
0
✓✓
✓
0
 Triglycerides
 Prolactin
N/V/Const
EPS
Anticholinergic
Adapted from Table 2. Am Geri Society. A guide to the management of psychotic disorders and neuropsychiatric symptoms of
dementia in older adults. 2011.
26
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
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.
28
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.
29
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
32%
Texas Ranking:
51/51
30%
NH Antipsychotic Use
28%
26%
10.9%
Reduction
24%
National
22%
Texas
California
20%
18.3%
Reduction
18%
20.4%
Reduction
16%
14%
11Q2
11Q3
11Q4
12Q1
12Q2
12Q3
12Q4
Fiscal Quarter
13Q1
13Q2
13Q3
13Q4
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, CGP
Assistant Professor, TTUHSC SOP/SOM