Back to BasicsPractical Pharmacology – part 3

Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD

Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team

April 2013rhalil@bruyere.org

Objectives

• List the 4 steps in rationalizing drug therapy choices using evidence based medicine.

• List the important parameters in choosing anti-thrombotic and psychiatric drugs in a clinical setting.

• Identify clinically important differences in the efficacy, toxicity, cost and convenience of these different drugs.

• Recognize the inherent weaknesses of current guidelines.

Topics

• Anti-Thrombotics– Anti-platelets– Anti-coagulants

• Psychiatric Medications– Anti-depressants– Anxiolytics– Anti-psychotics

Oral Anti-Thrombotics

Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD

Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team

April 2013rhalil@bruyere.org

Anti-Thrombotics

From: http://en.wikipedia.org/wiki/Direct_thrombin_inhibitor

Oral Anti-thrombotics

Antiplatelets• ASA• ASA + Dipyridamole MR– (Aggrenox®)

• Thienopyridines:– Clopidogrel– Ticlopidine– Prasugrel

• Ticagrelor

Anticoagulants• Warfarin• Dabigatran• Rivaroxaban• Apixaban

AntiplateletsIndications

• Primary prevention MI– ASA– Clopidogrel – Ticlopidine

• Secondary prevention MI– ASA– Clopidogrel– Ticlopidine– Prasugrel– Ticagrelor

Indications• Primary prevention CVA– ASA– Clopidogrel – Ticlopidine

• Secondary prevention CVA– ASA– Clopidogrel – Ticlopidine– ASA + Dipyridamole MR

Mechanisms of ActionASA

• Irreversible inh of COX-1– (thromboxane reduction)– Platelet lifespan: 7-10 days

Dipyridamole MR• inh the uptake of

adenosine & breakdown of cGMP

Ticagrelor• Reversible inhibition of

ADP platelet receptor subtype P2Y12

Thienopyridines• Clopidogrel & Ticlopidine

– Prodrugs activated by P450-2C19– N.B. 2% - 14% of population are

poor metabolizers

• Prasugrel– Prodrug activated by ester bond

hydrolysis

via:• Irreversible inhibition of

ADP platelet receptor subtype P2Y12

How to Choose?(if only there was a process…)

1. Efficacy2. Toxicity3. Cost4. Convenience

Primary Prevention – MI & CVA1) Efficacy (all ~ equivalent)

– ASA (++ evidence)

• 75mg = 325mg daily• “For older patients with risk

factors”• CHEST’12: >50yrs consider risk vs benefit • CCS’11: not recommended • AHA’10: if 10yr CAD risk ≥10% • USPSTF’09: men 45 79 yrs if low bleed ‐

risk• Diabetes: men≥45yr/women≥50yr; & ≥1

risk factor (smoking,↑BP, ↑ lipids, history of young parenteral MI, albuminuria)

– Clopidogrel & Ticlopidine• Little direct evidence• Only for ASA allergy or

intolerance

2) Toxicity (bleeding ~ same)

• ASA– NNH 125; major bleeds (WHS trial)– Any GI bleed ~ 2.7% (severe 0.7%)– Dyspepsia ~ 5%

• Clopidogrel (C) & Ticlopidine (T)

– Bleed: • Any GI bleed 2% (severe 0.5%) (C)

– Rash: • 6% (C) / 12% (3% severe) (T)

– TTP: • >20/3 million (C) / >1/5000 (T)

– Neutropenia: • <1% (C) / 2.4% (T) !!

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

Primary Prevention – MI & CVA

3) Cost– ASA • Pennies!• 81mg costs > 325mg

– Can cut 325mg in 1/4th

– Clopidogrel• ~ $95/mo

– Ticlopidine• ~ $35/mo

4) Convenience– ASA• 75-325mg once daily

– Clopidogrel• 75mg once daily

– Ticlopidine• 250mg BID po• Requires regular

monitoring of CBC, LFTs

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

Bottom Line – 1o Prevention MI & CVA• ASA.– Most evidence, well tolerated, cheap cheap!, QD– Consider bleed risks, even with “baby” ASA (81mg)

• RISK FACTORS FOR BLEEDING: – Age >75 yrs, DM, elevated INR warfarin, female, ↓ hematocrit, HF/MI, ↑HR, length

of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke noncardioembolic, ↑Scr, ↓ wt.

– Clopidogrel only if ASA allergic / severe intolerance– Ignore ticlopidine: • Little evidence, serious toxicities, BID dosing plus regular

blood work!

– No evidence for Aggrenox® in primary prevention

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

Secondary Prevention – MIEfficacy

Agent Monotherapy Combo w/ ASAASA Excellent evidence for NSTEMI,

STEMI, CABG, PCI (low NNTs) --

Clopidogrel ~ equivalent to ASA (small absolute improvement per CAPRIE trial)

Clopidogrel + ASA > ASA 3-12 mo (CURE trial))(ACS, PCI various durations)

Prasugreluntested

Prasugrel + ASA > Clop + ASA (ACS + PCI) x12 mo (TRITON-TIMI 38 trial)

Ticagreloruntested

Ticagrelor + ASA > Clop + ASA (ACS + PCI +/- CABG) x12mo (PLATO trial)

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.

Secondary Prevention – MIToxicity

Agent Monotherapy Combo w/ ASAASA w/ ASA: rate of hemorrhagic events = 5.58 (95% CI, 5.39-5.77) /

1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, 3.48-3.72) Incidence rate ratio: 1.55; (95% CI, 1.48-1.63)

--

Clopidogrel Less GI bleed - clopidogrel < ASA (1.99% vs 2.66% p < 0.002) (Less severe GI bleed - 0.49 vs 0.71%; p < 0.05)Less GI events - clopidogrel < ASA (27.1 vs 29.8%; p < 0.001) More Diarrhea clopidogrel > ASA (4.46 vs 3.36%; p < 0.001)More Rash – clopidogrel > ASA (6.0% vs 4.6% p < 0.001)No difference in: Early D/C, Neutropenia, Thrombocytopenia & Intracranial bleed. (per CAPRIE)

Major bleeding – clop + ASA > ASA (3.7% vs. 2.7%; RR = 1.38; P=0.001), Life-threatening bleeding - no diff (2.1 percent vs. 1.8 percent, P=0.13) Hemorrhagic strokes – no diff (per CURE trial)

Prasugreluntested

More fatal and life-threatening bleeds vs clopid + ASA

Ticagreloruntested

More major and minor bleeds vs clopid + ASAMore dyspnea, & incr UA

Secondary Prevention – MIToxicity

Agent Monotherapy Combo w/ ASAASA w/ ASA: rate of hemorrhagic events = 5.58 (95%

CI, 5.39-5.77) / 1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, 3.48-3.72)

Incidence rate ratio: 1.55; (95% CI, 1.48-1.63)

--

Clopidogrel ~ equivalent in absolute senseSlightly less GI bleed & GI events except diarrhea; More Rash

More major bleeding vs ASA alone

Prasugreluntested

More fatal and life-threatening bleeds vs Clopid + ASA

Ticagrelor

untested

More major and minor bleeds vs Clopid + ASAMore dyspnea & increased urate

Secondary Prevention – MI3) Cost– ASA • Pennies! (only 325mg covered)

– Clopidogrel• ~ $95/mo• LU code for MI

– Prasugrel• ~ $95/mo; not covered

– Ticagrelor• ~ $105/mo; not covered

4) Convenience– ASA• 75-325mg once daily

– Clopidogrel• 75mg once daily

– Prasugrel• 10mg once daily

– Tigagrelor• 90mg BID po

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

Bottom Line: 2o Prevention MI

• ASA + Clopidogrel x 3- 12 mo, then ASA alone– Clopidogrel alone if ASA allergy– Prasugrel only in cardiac centres post ACS + PCI &

if no excess bleed risks

Secondary Prevention – CVAEfficacy

Agent Monotherapy Combo w/ ASAASA ASA ~23% RRR > placebo

NNT ~ 50-100 x1 year to prevent any vascular event. (50-325mg)(CAST, IST, SALT, Dutch-TIA trials)

--

Ticlopidine Superior to ASA (CATS & TASS trials) unknown

Clopidogrel Equivalent to ASA (extremely small absolute improvement per CAPRIE trial)

Possible improvement for 1st 21 days post CVA (CHANCE trial)No benefit long term (CHARISMA, MATCH trials)

Aggrenox® Superior to ASA (ESPRIT & ESPS2 trials), but Equivalent to Clopidogrel (PRoFESS trial) whaa?

--

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.

Secondary Prevention – CVAToxicity

Agent Monotherapy Combo w/ ASAASA Low, but look at additive bleeding risk factors:

(Age >75 yrs, DM, elevated INR warfarin, female, ↓ hematocrit, HF/MI, ↑HR, length of antithrombotic tx,

liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed

or stroke noncardioembolic, ↑Scr, ↓ wt.)

--

Clopidogrel ~ equivalent in absolute senseSlightly less GI bleed & GI events except diarrhea; More Rash

More bleeding vs ASA alone(CHARISMA & MATCH trials)

Aggrenox® More headache, diarrhea, GI upset, dizziness, & early D/C vs ASA or Clopidogrel

More intracranial bleed vs Clopidogrel--

Secondary Prevention – CVA

3) Cost– ASA • Pennies!

– Clopidogrel• ~ $95/mo• LU code for ASA

intolerance only

– Aggrenox®• ~ $61/mo• LU code for CVA

4) Convenience– ASA• 75-325mg once daily

– Clopidogrel• 75mg once daily

– Aggrenox®• 200/25mg BID po

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

Bottom Line 2o Prevention CVA

• ASA or Clopidogrel or Aggrenox®– Any will do, until tie breaker trial between these

agents. – Aggrenox® might be more efficacious, but with

more side effects and less convenience.

Anticoagulants• Warfarin– Vitamin K antagonist – (clotting factors 2,7,9,10,

protein C & S)– For: Afib, VTE prophylaxis &

tx, valvular disease

• Dabigatran– Direct thrombin inhibitor

(factor 2)– For: Afib, VTE prophylaxis

post-op TKR/THA– (N.B. Ximelagatran – withdrawan

due to hepatotoxicity)

• Rivaroxaban– Factor Xa inhibitor– For: Afib, VTE

prophylaxis post-op TKR/THA, DVT tx

• Apixaban– Factor Xa inhibitor– For: Afib, VTE

prophylaxis post-op TKR/THA

Anticoagulants (VTE, Afib, Valve disease)

Agent Efficacy Toxicity

Warfarin Excellent vs placebo or ASA 1.3% - 3.5% -- major bleed< 0.25% - 0.5%/yr -- ICH

Dabigatran~ same

N.B. (~1% absolute difference)(RE-LY trial - industry funded)

Less intracranial & More GI bleeds; ?More MI?Untested > 79y.o. or CrCL < 30NO reversal agent

Rivaroxaban~ same

N.B. (<1% absolute difference)(ROCKET-AF trial – industry funded)

Less intracranial & More GI bleedsUntested > 79y.o. or CrCL < 30NO reversal agent

Apixaban~ same

N.B. (<1% absolute difference)(ARISTOTLE trial – industry

funded)

Less intracranial bleedsGI bleeding – no differenceUntested > 77y.o. or CrCL < 30NO reversal agent

Rxfil

es.c

a Co

mpa

rison

of W

arfa

rin &

New

Ora

l Anti

coag

ulan

ts (N

OAC

s) in

Non

-Val

vula

r Atr

ial F

ibril

latio

n 07

/03/

2013

Anticoagulants (VTE, Afib, Valve disease)

Agent Cost Convenience

Warfarin ~ $40/mo (with INR monitoring)

QD poINR q3d – q1mo

(ODB covered)

Dabigatran $110/moBID po

(ODB w/ LU code 431 for AFib)

Rivaroxaban $100/moQD with food

(ODB w/ LU code post-op TRK/THA)

Apixaban $140/mo BID poNo coverage yet

Summary• Antiplatelets– Small differences in efficacy or toxicity, dictate that cost will

drive selection. – = ASA– Combination therapy where indicated

• Anticoagulants– Small differences in efficacy and important unknowns in newer

agents (age effects, renal dysfunction, lack of antidotes) dictate selection of warfarin except for carefully selected patients with significant compliance barriers due to the inconvenience of INR testing.

Anti-depressants & Anxiolytics

Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD

Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team

April 2013rhalil@bruyere.org

Anti-depressants & Anxiolytics

• Selection of therapy: – Efficacy: All

equivalent!• N.B. Wouldn’t use

Bupropion for anxiety

– Therefore, tailor therapy based on potential toxicities!• Meta-analyses that

include grey literature trials show an over-estimation of efficacy and an under-appreciation of toxicity.

• SSRI’s:– Fluoxetine, sertraline, (es)citalopram,

fluvoxamine, paroxetine

• SNRI’s:– (des)venlafaxine, duloxetine

• Mirtazapine• Bupropion• TCA’s:

– Amitriptyline, nortriptyline, despramine, imipramine, clomipramine, doxepin

• MAOi’s: (+++ types)

– Moclobemide (reversible)– Phenelzine (irreversible) etc. etc.

Toxicities• Anti-cholinergic effects– Paroxetine – Mirtazipine – (des)Venlafaxine– TCAs:

• amitriptyline > nortriptyline > desipramine

• N.B. Anti-cholinergic, anti-histaminergic & weight gain effects often go hand-in-hand. – Wt gain is usually minimal– Some subpopulations gain++

• Sedation– TCAs– Fluvoxamine

• Paroxetine (less extent)

– Mirtazapine– Trazodone

• Activation– Fluoxetine– Bupropion– (des)Venlafaxine– Moclobemide

Toxicities• GI side effects– Nausea - SSRIs– Constipation - TCAs– Diarrhea - sertraline,

fluoxetine, paroxetine, duloxetine

• QTc prolongation (TdP)– TCA’s– Citalopram > 40mg/day– Escitalopram > 20mg/day

• Sexual dysfunction– SSRIs (>30% !)– TCAs

• N.B. More serotonin = less libido

• More dopamine = more libido

• Drug/disease interactions– Least with: (es)citalopram,

mirtazapine, moclobemide, sertraline, (des)venlafaxine

– Moclobemide:• no tyramine restrictions

(unlike irrev MAOi’s!)

Anti-depressants & Anxiolytics

• Cost– All ~ $25 - $35 / month– Newest agents, without

generics cost more.• Bupropion XL

– $45/mo• Escitalopram

– $65/mo• Paroxetine CR

– $60/mo– Not covered under ODB

• Desvenlafaxine– $85/mo– Not covered under ODB

• Convenience– Most once daily– Bupropion SR – BID

• Bupropion XL – QD

– Moclobemide - BID

The Evils of Benzodiazepines(Yes, this includes “z-drug, non-benzo alternatives” Eg. Zopiclone)

• Formerly one of the most commonly prescribed drug families of the 1960’s and 1970’s. – In 1975 – 100 million Rxs written in USA alone– Efficacy – excellent SHORT term efficacy

• Sedation & anxiolysis• Rapid tolerance is developed

– Toxicity – addictive! • D/C’ing after tolerance develops is VERY hard• Long term risk of dementia, falls, and memory impairment• Withdrawal can be fatal

– Cost & Convenience – Hey!, Fuggetabout-it!• http://www.youtube.com/watch?v=tfGYSHy1jQs • http://www.youtube.com/watch?v=Zf0ZyoUn7Vk • http://www.youtube.com/watch?v=J5Xu9UcOdj0

Summary

• Highly variable response in efficacy – All ~ equivalent in efficacy

• Trial and error– Tailor to potential toxicities to maintain compliance

• Focus on relative toxicities!• Efficacy often overestimated and toxicity often

underestimated• Avoid Benzodiazepines and Zopiclone (addictive)– Even Rx’s for 10 tabs often snowball into chronic use.

Anti-psychotics

Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD

Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team

April 2013rhalil@bruyere.org

Anti-psychoticsTypical (1st gen / conventional) (Relative terms) Atypical (2nd gen)

• Butyrophenones– Haloperidol & Droperidol

• Phenothiazines– Chlorpromazine & Fluphenazine – Perphenazine & Prochlorperazine – Thioridazine & Trifluoperazine – Mesoridazine & Periciazine– Promazine & Triflupromazine – Levomepromazine & Promethazine – Pimozide

• Thioxanthenes– Chlorprothixene & Clopenthixol – Flupenthixol & Thiothixene – Zuclopenthixol

• Clozapine • Olanzapine• Quetiapine• Risperidone • Aripiprazole• Ziprasidone• Paliperidone• Asenapineetc.

Anti-psychotics• Efficacy– No clinically relevant differences (variable responses)• ?Olanzapine superiority?

– See CATIE trial

– Exception: Clozapine – clearly superior

• As ever, when efficacy is ~ equivalent, choose therapy based on potential toxicities

Anti-psychotics

• Toxicities:– Clozapine: • Agranulocytosis (10x higher risk vs other antipsychotics)• Hence, mandatory CBC q2-4weeks• Therefore, last line therapy, despite superior efficacy

Toxicities• Sedation– Quetiapine– Olanzapine– Clozapine– Typicals– Least: haloperidol, risperidone,

aripiprazole?, ziprasidone?

• Weight gain– Clozapine– Olanzapine– Quetiapine– Least: haloperidol, risperidone,

aripiprazole?, ziprasidone?

• Tardive Dyskinesia– Typicals – Least: Clozapine (esp), all atypicals

• Anticholinergic effects– Clozapine– Typicals– Least: risperidone, quetiapine,

haloperidol

Toxicities

• EPS– Typicals– Least: atypicals

• QTc prolongation– Clozapine– Paliperidone– Ziprasidone– Pimozide– Asenapine– Thioridazine – Least: Risperidone, haloperidol,

aripiprazole, olanzapine, low dose quetiapine

• Hypotension– Clozapine– Risperidone – Typicals– Least: olanzapine, haloperidol,

ziprasidone, paliperidone

Antipsychotics

• Cost• ~ $20 - $40/month• More expensive: – Newest agents:

• Aripiprazole• Ziprasidone• Paliperidone• Asenapine

– Clozapine– Quetiapine (XR)– Olanzapine (Zydis)

• Convenience– Most BID po– Some injectable, long acting

forms• Risperidone • Paliperidone• Flupentixol• Pipotiazine• Fluphenazine• Zuclopenthixol• Haloperidol

– Olanzapine Zydis (melts)– Risperidone M-tab (melts)

Summary

• Choose anti-psychotics based on potential toxicities– Learn two or three very well that complement

each other. – Low threshold to confer with psychiatry or

pharmacy• Rxfiles – excellent comparison charts to help guide

therapy– http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/do

cuments/members/Cht-Psyc-Neuroleptics.pdf

Comments, Questions & Requests?

• rhalil@bruyere.org• Monday & Fridays: – 613-230-7788 ext 238

• Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327

• Twitter: @Roland Halil, PharmD