A Process for Rational Prescribing

Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDAssistant Professor, Department of Family Medicine, University of Ottawa

Clinical Pharmacist, Bruyere Academic Family Health Teamrhalil@bruyere.org

Twitter: @RolandHalil

May 2015

Adding Pharmacology to your Knowledge Base

(Pharmacology Informs Therapeutics)

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

Pharmacist, Bruyere Academic FHTAssistant Professor, Dept Family Medicine, U of Ottawa

March 2015

Objectives

• To promote an efficient process for incorporating pharmacology into your body of knowledge

• To promote the creation of a “personal formulary” during your residency.

Pharmacology

• Impossible to know during clerkship– Every drug in every specialty? Get real.

• Possible to know during residency!– Build your Personal Formulary

• Drugs that will be bread & butter during your career.

– How?

Personal FormularyPharmacology

• Pick one drug per class to become the workhorse in your personal formulary.– Need help? Ask a Pharmacist:

• What is your favourite member of any drug class?• Why?

• Knows the in’s and out’s of that drug:– Learn its Pharmacology

• (Pharmacology = M.O.A. + PK + PD)

+– Dosing range, Cost / Drug coverage status, Dosage

forms available

Learning PharmacologyOpen your

Drug Database Software (Eg. LexiComp,

Micromedex, eCPS, etc)

Review Mechanism

of Action

Review Pharmaco-Kinetics

• Clearance: Renal or Hepatic?• Hepatic:

CYP-450 or not?

Review Pharmaco-Dynamics(ie. Top 3 Side

Effects)• Rare &

Severe• Common &

Bothersome

Total: 3 min

Pharmacology

• Learn the drugs that will be part of your personal formulary.

• Build your formulary wisely.• Brief, but regular, review will help you own it.

– Patients are treated more optimally– Fewer side effects– Less risk of litigation– Better use of health care dollars– Better likelihood of compliance

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

A Process for Rational Prescribing

Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDAssistant Professor, Department of Family Medicine, University of Ottawa

Clinical Pharmacist, Bruyere Academic Family Health Teamrhalil@bruyere.org

Twitter: @RolandHalil

May 2015

Objectives

1. Describe a process for choosing pharmacotherapy and prioritizing prescribing dilemmas

2. Highlight how such a process can save time and enhance comfort with applying evidence-based medicine to individual patients

3. Dispel marketing myths in pharmacotherapy

Prescribing

Jaski M.E. et al. Effective Clinical Practice, MEDICATION REVIEW AND DOCUMENTATION IN PHYSICIAN OFFICE PRACTICE. ACP Internal Medicine Jan/Feb 2000. http://www.acponline.org/journals/ecp/janfeb00/jaski.htm Accessed Nov 1/14.

“Two thirds of all physician office visits result in a Rx.”

“Patients are likely to visit several [providers] for a variety of conditions and thus are

likely to receive multiple prescriptions.“

“In addition to receiving prescribed drug therapies, patients are likely to "self-medicate" with over-the-counter (OTC) drugs, nutritional supplements, and herbal and other alternative remedies.”

Therapy Dilemmas

To prescribe or not to prescribe? That is the question…

Options

• First, lay out therapeutic options: – Drug A– Drug B– Drug C– Non-drug options D, E, & F– No treatment

• (always an option!)

Thought StructureBased on what?

• Rational prescribing requires a process for selecting therapy:

Patient Preference

Direct to Consumer Advertising

Expert Opinion

Guidelines

Evidence Based Medicine

PubMed searches

Common Sense

Pharma Rep info

Monograph data

Rational Prescribing

• Four steps to Rational Prescribing:1. EFFICACY

2. TOXICITY

3. COST

4. CONVENIENCE

Step 1: Efficacy(How good is good?)

EfficacyAsk yourself about…

1. Type of intervention:What will reduce:

1. Mortality based on hard outcomes

2. Morbidity 3. Surrogate markers based on soft outcomes

4. Symptoms

Efficacy2. Quantity of evidence? ie. effect size

a) Absolute is more important than relative• Eg. 2% 1%

= 1% absolute risk reduction (i.e. 50% relative risk reduction)

b) Number-needed to treat (NNT) • The inverse of the ARR. (NNT = 100)(=1/0.01)• Useful for the shepherd (population health)

c) Converse is more clinically informative than inverse• Eg. Without treatment, 98% will be unaffected• With treatment, 99% will be unaffected• Useful for the flock (individual health)

Number Needed to Treat http://www.med.uottawa.ca/sim/data/Number_Needed_to_Treat_e.htm Accessed Nov 2/14

Efficacy3. Quality of evidence? (Hierarchy of evidence)

Robert Yokl. Good Evidence: The Missing Link. Apr 08, 2013. http://valueanalysismag.com/good-evidence-the-missing-link/

Efficacy4. Time to benefit?

– The fourth dimension!

Type

Quality

Quantity

Efficacy

Therefore, the key is the prioritization of efficacy endpoints, evidence quality and time to benefit

Quantity (Effect Size) Quality

MortalityMorbiditySurrogate outcomesSymptomatic relief

Efficacy• If there is no efficacy, why waste your time on

the potential toxicity, cost and inconvenience of a drug?

• If there is efficacy, it is proven in populations. Balance this against the potential toxicity to the individual.

A simple example:

Metformin

VS

Sitagliptin (Januvia®)

)

Efficacy

1. HARD Outcomes– Mortality benefit

» Metformin – per UKPDS-34 trial (RCT)– Morbidity benefit

» Metformin – reduction in microvascular complications

2. SURROGATE Outcomesa) Hgb-A1c Lowering Effects

a) Metformin ~ 1% - 2%b) Sitagliptin ~ 0.5% - 0.8%

b) Insulin Sparing Effectsa) Metformin

Primum non nocere

• When EBM is strong: – Efficacy easily outweighs

Toxicity– Only very specific

contraindications to pursuing therapy

• When EBM is weak– It is easy for Toxicity to

outweigh Efficacy– First, do no harm

Step 2: Toxicity(How bad is bad?)

Toxicity

Like Efficacy, the key is prioritization of toxicity endpoints, effect size, evidence quality and time to

benefit.

• What will: 1. Kill me?2. Maim me?3. Make me feel crappy? (bothersome side effects)

• Size of toxic effect (Quantity)?• Evidence Quality to show effect?• Time to harm?

Toxicity

Common Not legal

Rare Who cares

Bothersome Severe

Like

lihoo

d

Severity

ToxicityTime: The 4th parameter

• Most drugs are approved based on their efficacy against nothing – (ie. placebo, not the current gold-standard)

• Studies are usually powered for efficacy, not toxicity – (eg. Phase III study)

• Tox data is accumulated over time – (eg. Phase IV, post-marketing surveillance study)– Slower than accumulation of efficacy data

• Time lag!

ToxicityAge Before Beauty

Newer agents = Less Safety DataOlder agents = More Safety Data

Prexige

Arcoxia

Vioxx

Bextra

Zelnorm

Prepulsid

Meridia

Baycol

Actos

Avandia

Toxicity4. Time to harm?

– Versus: time to benefit!

Type

Quality

Quantity

Efficacy: a population-based parameter

Toxicity: an individual risk

Robust EBM • Eg. ACE-inh post MI

– Clear mortality benefit in secondary prevention as per many RCTs

– Patient A: K+ = 4.0 mmol/L– Patient B: K+ = 6.0 mmol/L

• Will both get an ACEinh?

Weak EBM• Eg. Anti-seizure meds

for migraine prophylaxis– Questionable reduction

in severity & frequency– Risk of:

• Hepatitis• blood dyscrasias• strong drug interactions

etc.

Example: Choosing Anti-DepressantsSelection of therapy:

1. Efficacy: ~equivalent to CBT & with eachother

2. Therefore, choose based on potential toxicities!

– (pick your poison)– Meta-analyses show an

over-estimation of efficacy and an under-appreciation of toxicity.

Options• SSRI’s: (5-HT)

– Fluoxetine, sertraline, (es)citalopram, fluvoxamine, paroxetine

• SNRI’s: (5-HT & NE)

– (des)venlafaxine, duloxetine

• Mirtazapine (5-HT & NE)

• TCA’s: (5-HT & NE)

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

• Bupropion (DA)

• MAOi’s: (+++ types)

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

Ikhlaaq Ahmed et al. BMJ 2012;344:d7762 http://www.bmj.com/content/344/bmj.d7762 Accesssed Nov 4/14John PA Ioannidis. Philosophy, Ethics, and Humanities in Medicine 2008, 3:14 http://www.peh-med.com/content/3/1/14 Accessed Nov 4/14

Toxicities• Anti-cholinergic effects

– Paroxetine – Mirtazipine – (des)Venlafaxine– TCAs:

• amitriptyline > nortriptyline > desipramine

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

• N.B. More serotonin = less libido

• More dopamine = more libido

• Sedation– TCAs– Fluvoxamine

• Paroxetine (lesser extent)

– Mirtazapine– (Trazodone)

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

Toxicities• GI side effects

– Nausea – SSRIs• ? 5-HT effect in visceral

insular cortex?

– Diarrhea – SSRIs • (esp. sertraline, fluoxetine,

paroxetine, duloxetine)

– Constipation - TCAs

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

• Drug/Disease interactions & Drug/Drug interactions

– Moclobemide:• no dietary tyramine

restrictions • (unlike irrev MAOi’s!)

– Pharamacokinetic P450 interactions:

• Fewer with: (es)citalopram, mirtazapine, moclobemide, sertraline, (des)venlafaxine

Anti-depressants

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

generics cost more.• Bupropion XL

– ~$45/mo• Escitalopram

– ~$65/mo• Paroxetine CR

– ~$60/mo– Not covered in Ontario

• Desvenlafaxine– ~$85/mo– Not covered in Ontario

• Convenience– Most are Once Daily– Bupropion SR – BID

• (XL formulation is QD)

– Moclobemide - BID

Step 3: Cost(Who pays the piper?)

Cost ($) – Ask…

• Patient cost vs Societal cost

• Rx cost?• Provincial plan?• Private plan?

A simple example: CostChoosing an ACEinh

• Efficacy: equivalent• Toxicity: equivalent• Cost: all cheap,

generic– Except: trandolapril

& perindopril• Convenience: all

once daily– Except: captopril TID

ACE INHIBITOR (ACEI) / ANGIOTENSIN II RECEPTOR BLOCKER (ARB): Oct 2014 Comparison Chart http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/documents/members/CHT-HTN-ace-arb.pdf Accessed Nov 4/14

Step 4: Convenience(How much work is this?)

ConvenienceHow much work is this drug?

1. How often to take? – QD vs QID?

2. Special restrictions (eg. bisphosphonates)– PO vs SC/IV? – Home vs Office vs Hospital therapy?

3. Many potential interactions? (eg. Rifampin)

4. Special monitoring requirements? (eg. Warfarin)

Summary

• Applying EBM requires a process– It distills out high quality information

• (Efficacy)– It protects patients from unnecessary harm (and

you from medico-legal harm!) • (Toxicity)

– It saves time • (Cost and Convenience)

• Everybody wins!

Summary

• Practicing this process can be clunky at first. But with practice:– You will internalize this process– You will get faster– You will prescribe with greater confidence– You will sleep better at night

• …and that is priceless!

Questions?

Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDAssistant Professor, Department of Family Medicine, University of Ottawa

Clinical Pharmacist, Bruyere Academic Family Health Teamrhalil@bruyere.org

Twitter: @RolandHalilNov 22, 2014

Workshop: Application of a Process for

Rational Prescribing

Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDAssistant Professor, Department of Family Medicine, University of Ottawa

Clinical Pharmacist, Bruyere Academic Family Health Teamrhalil@bruyere.org

Twitter: @RolandHalilMay 2015

Objectives

1. Apply a process for choosing therapy to a selection of cases requiring pharmacotherapy

2. Describe how this process can improve outcomes as well as save time, energy and money

3. Reflect on how this process can be incorporated into your daily practice

EfficacyPopulation average

ToxicityIndividual risk

Cost & ConvenienceEffort to obtain benefit or avoid harm

Prioritize: • Type of harm• Quantity of harm• Quality of evidence• Time to harm

Prioritize: • Type of benefit• Quantity of benefit • Quality of evidence• Time to benefit

Rational Prescribing Needs a Process to Provide Structure

Case 1

• Ms. B.Mo., 58 y.o. hypertensive patient with PMHx of OA and dependent edema– BP: 155/95, HR: 85– CrCL 75mL/min; lytes N– On fixed income– Meds:

• Acetaminophen 500mg BID

Options?

Options

1. Angiotensin Receptor Blocker (ARB)2. ACE inhibitor3. Beta-Blocker4. Calcium Channel Blocker (CCB)5. Diuretic – Thiazide

Case 1b• Four years later, now 62 y.o., Ms BMo’s

pressure is lower, but still not controlled. She has developed Stage 1-2 CKD

• Currently on Chlorthalidone 12.5mg qam– BP: 150/90, HR 85

• CrCL ~ 50ml/min • urACR 3.5

– Labs nl, still some pedal edema

Options?

Options

1. Alpha Blocker2. Angiotensin Receptor Blocker (ARB)3. ACE inhibitor4. Beta-Blocker5. Calcium Channel Blocker (CCB) – DHP

Case 1c• Three years later, MS. BMo’s (now 65 y.o.)

develops CHF. She has both pulmonary and worsening pedal edema. – Meds:

• Chlorthalidone 12.5mg qam • Ramipril 5mg daily

– ECHO: LVEF 25%– BP 145/88, HR 85 – CrCL 35mL/min, lytes nl

Options?

Options

1. Angiotensin Receptor Blocker (ARB)2. Beta-Blocker3. Calcium Channel Blocker (CCB)4. Hydralazine & Nitroglycerin (long acting)5. Furosemide

Case 2• Mr TD is a 68 year old gentleman with a history

of NSTEMI and CKD. He isn’t sure about “all these pills” and complains of OA and leg cramps

• eGFR ~ 40mL/min; BP: 125/75; HR: 65 bpm• On:

– Ramipril 5mg qd– Bisoprolol 5mg qd– ASA 81mg po qd– Atorvastatin 40mg qd

• His most recent lipid profile shows LDL = 2.8

Options?

Options

• Statins• Fibrates• Ezetimibe• Niacin• Bile acid sequestrants• Non-pharm modalities

Case 3• Mr RBC is a 55 year old gentleman with multiple

gout attacks and a history of a narcotic abuse. He has had terrible diarrhea with low dose colchicine and a previous psychotic episode with prednisone.

• eGFR ~ 90mL/min; BP: 130/78; UA = 450• On:

– Acetaminophen 1g QID – Allopurinol 100mg qd (with slow titration to target

UA < 360)Options?

NSAIDs1. Efficacy – equivalent at equipotent doses2. Toxicity –

– Renal – equivalent risk– GI – dose and duration dependent

• Higher with some NSAIDs (eg. Ketorolac)– CV - COX-2 inhibitors > NSAIDs

• AVOID COX-2 inh.• Higher risk with Diclofenac

– Other COX-2 weighted NSAIDs (eg. Meloxicam?)• ?Safer with Naproxen / Ibuprofen?

– Safer with lower doses?

3. Cost – cheap & generic! 4. Convenience

– Naproxen for BID convenience– Ibuprofen for short half-life (eg. Gout tx)

• (Fast in, fast out)

Questions?

Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDAssistant Professor, Department of Family Medicine, University of Ottawa

Clinical Pharmacist, Bruyere Academic Family Health Teamrhalil@bruyere.org

Twitter: @RolandHalil