Prescribing a Drugectomy – Who, Why, What, When,

Where, and HowJames McCormack !

B.Sc. (Pharm), Pharm.D.!Professor!

Faculty of Pharmaceutical Sciences!University of British Columbia!

Vancouver, BC!

therapeuticseducation.org!mystudies.org!@medmyths

Any patient that has ongoing “side-effects/cost”

Any patient that has had a drug added WITHOUT being given an informed choice !

Understanding of the ballpark numbers - benefits and harms!

Do the experiment!

Re-evaluate!

No guilt

Any drug that was not started at the VERY lowest dose

No hurry!

Most standard doses are excessive!

DON’T start with low doses!

Start with VERY low doses

Efficacy and Safety of Three Different Doses of Doxepin in Adults with Primary

Depression - start 25-50 mg - optimal 75mg -150mg up to 300mg!

All three doses worked better than placebo!AND

NO side effects over placebo

“The results support the effectiveness of low doses (25-50 mg) of doxepin to improve sleep”

J Clin Psychiatry 2001;62:453-63

Doxepin (Sinequan)

Sleep 2007; 30: 1555–61

A recommended low dose was still 25-50 times TOO HIGH

Any patient/drug you haven’t re-eVALUated annually

“starting drugs is like the bliss of marriage, stopping them is like the agony of divorce”!

Need!

Dose!

Duration!

Guiltless choice

Medication Use

Canada - 2008 data!Patients over the age of 65!5 or more drug classes - 62%!10 or more - 21%!15 or more - 6%!

BC - 2010 data!10-25% use 5 or more Rx drugs!

Issues to Consider~ 25-50% of people diagnosed with HTN don’t have

elevated blood pressure - BMJ 2002;325:815–7!

~ 1/3 of patients diagnosed with asthma don’t have asthma - CMAJ 2008;179:1121-31!

~ 90% of COPD patients don’t get a clinically important benefit from their inhalers - N Engl J Med 2008;359:1543-54!

~ 85% of depressed patients don’t get a benefit from their antidepressant - Cochrane Library CD007954!

~ 50% of type 2 diabetics have an A1c level that if treated has been shown to NOT provide benefit and maybe even cause harm - Diabetes Care 2008;1:81-6, ACCORD, ADVANCE, VADT

Issues to Consider

Symptoms - many clinical trials show a placebo group response of 20-30%!

Disease states fluctuate!

Prevention - patients believe “prevention” drugs produce a 70% absolute benefit over 5 years Clin Med

2002;2:527-33 when at most only ~ 20% could benefit over a lifetime!

The frequency and dose used for many drugs is often way too much

When you do a!Patient Medication History!

UNTIL PROVEN OTHERWISE!!

The drug and the dose are wrong!!!!!!

HOW TO START THINKING

CRITICALLY

Guides to safe prescribingBeers, the most popular: weak evidence1!

Assoc with hospitalization in community elderly!No other consistent associations!

Drug Burden Index (DBI) !DBI assoc decreased physical function & falls2!Beers not3!

STOPP5 may be better!STOPP slightly better to predict ADE & hospitalization

1) Ann Pharmacother 2007;41:438-48. 2) Am J Med (2009) 122, 1142-1149. J Am Geriatr Soc. 2011 May;59(5):875-80. 3) J Clin Pharmacol published online 2 February 2011 2) Ann Pharmacother 2010;44:1725-32. 5) Age & Ageing 2008; 37: 673–79 Arch Intern Med. 2011;171:1013-1019.

Are these associations helpful?Hospitalization for Drug-related Adverse Events !In people ≥65 !

Half happened in ≥80!66% were unintentional overdoses !

67% were: !warfarin (33%), insulins (14%), oral antiplatelet agents (13%), and oral hypoglycemic agents (11%)!

Prescribing rules (HEDIS, BEERS) would identify only 1-6% of the problems

N Engl J Med 2011;365:2002-12

18 “NEGATIVE” STUDIES IN A ROWLIPIDS!AIM-HIGH, HPS2-THRIVE (niacin)!ACCORD (fibrates)!dalOUTCOMES (dalcetrapib)!

BLOOD PRESSURE!ALTITUDE (aliskiren)!VALISH, AASK, ACCORD !(aggressive BP lowering)!

DIABETES!ACCORD, ADVANCE, VADT !(aggressive A1c lowering)!ROADMAP (olmesartan)!ORIGIN (insulin)!SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin)!

GENERAL!ACTIVE (irbesartan/afib)!CRESCENDO (rimonabant)!VISTA-16 (Varespladib)

Level A = recommendation based on evidence from !multiple randomized

trials or meta-analyses

“The Expert Panel was UNABLE TO FIND RCT EVIDENCE to support titrating cholesterol-lowering drug therapy to achieve target LDL–C or non-HDL-C

levels, as recommended by ATP III”!

TREATMENT !TARGETS

<2 mmo/L/80mg/dL

“Antihypertensive drugs used in the treatment of adults (primary prevention) with mild hypertension (systolic BP 140-159 mmHg and/or diastolic BP 90-99 mmHg) have not been shown to reduce mortality or morbidity in RCTs”!

“Treatment caused 9% of patients to discontinue treatment due to adverse effects.”

August 2012

Typically “evidence-based” guideline recommendations!are not based on “solid” evidence

11% Evidence Level (1 or A)!based on RCTs

14%

48% Evidence Level (3 or C)!based on opinion

55%

Canadian chronic disease state guidelines!blood pressure, cholesterol, glucose, and bone density

197 PAGES - 90,000 Words!99 words (0.1%) - relevant to the issues

of patients’ values and preferences

“clinicians spend time exploring ways of reducing the level of the surrogate, even when the only options are interventions that do not

improve, or may even worsen, a patient’s outlook”

Comprehensive diabetes care 0.64

Quality of life comparisons

Diabetes Care 2007;30:2478-83

QOL utilities

Mild stroke 0.7Angina 0.64Diabetic neuropathy 0.66

Ann Int Med 2011;155:340-1

A1C of 8 - 14

HYPOGLYCEMIA

Diabetes Care 2012;35:1364-79

“the desires and values of the patient should also be considered, since the achievement of any degree of glucose

control requires active participation and commitment”!

“Importantly, utilizing the percentage of diabetic patients who are achieving an HbA1c ,7.0% as a quality indicator, as promulgated by various health care organizations, is

inconsistent with the emphasis on individualization of treatment goals”!

!

2012

cvdcalculator.com

FREE

PRIMARY PREVENTION!

Helps you make an

estimate of CVD risks for

any patient!and then figure

out benefits and harms for any CVD drug/

non-drug treatment

Drugs for Symptoms!Acute self-limiting symptoms!

You really can’t!

“Chronic” symptoms - Maybe - with reassessment - Drugectomy or dose reduction!

Need to have a rough idea of the response in the placebo group

How to tell if a drug worked/is working?

“ACUTE” Heartburn HEALING SYMPTOM/RESOLUTION

Patients who respond in the PPI group!

≈ 65% at 4 weeks, 85% at 8 weeks - DOUBLE DOSE ANOTHER 5%? !

Patients who respond to H2RA!

≈ 40% at 4 weeks, 55% at 8 weeks !

Patients who respond in the placebo group !

≈ 15% at 4 weeks, 30% at 8 weeks

8-9/10 patients will respond to a PPI!3 of these improved not because of a drug!an additional 2-3 of these would have improved with an H2RA

Cochrane Library CD003244

Drugs for Prevention!HTN, statins, diabetes, osteoporosis!

YOU really CAN’T!And likely over a lifetime a patient won’t

benefit ...

How to tell if a drug worked/is working?

50 year-old male - non smoker !CHOL/HDL 4/SBP120 vs 7/180

20% abs diff

10% abs diff

20 years ≈ 90% no benefit?!45 years ≈ 80% no benefit?

QRISK Lifetime risk of CVD

Prevention drugs

http://www.qrisk.org/lifetime/index.php

Risk reduction meds

ASA, statins - you can just stop them!

Fibrates - please just stop them!

Blood pressure and diabetes drugs?!

dosage should be reduced by 50%, with reassessment of blood pressure at 2 weeks!

if the patient is still normotensive, reduce the dosage by another 50% (i.e., to 25% of the initial dose) and recheck the blood pressure in another 2 weeks

Symptom meds PPIs, NSAIDs etc

Typically one should reduce the dose slowly - cut the dose in half or do something similar - change interval!

The dose likely wasn’t right in the first place!

Put the onus on, and give the power to the patient to find the right dose

Advantages of starting with “very” low doses !

1)!Get the potential “placebo group effect” !

2)!Patients are engaged in the process of finding the best dose for them!

3)!Cost savings can be considerable and reduced adverse events!

4)!Most clinically relevant drug interactions can be avoided

Rationale for starting with “very” low doses

1)!There is rarely a need to get an immediate response!

2)!For many marketed drugs the recommended starting doses are too high !

3) Cannot reliably predict pharmacodynamic variability - typically exceeds pharmacokinetic variability !

4)!Approximately ¾ of side effects of drugs are dose related!

5) In animal research there is a wide dose-response relation - humans are genetic mongrels

Limitations of using “very” low doses

1) Does not apply to life threatening conditions!

2) Problem if you can’t easily identify a clinical endpoint - in frequents seizures!

3) Target doses - ACEI etc - HOWEVER!!

Target DOSESACE inhibitors, betablockers, ARBs - CHF!

Class 1 recommendation “with a special focus on adherence, persistence, and up titration to recommended doses of ACE inhibitor/ARB and beta-blocker medication”

“every effort should be made to place virtually all patients on ACEIs and achieve the target dose for that ACEI”!

”achieving target doses should continue to be an important goal for practitioners”

All the TARGET dose evidenceDrug High/low

doseDuration!(years)

Absolute Benefits!

Absolute!Harms

Enalapril 4x 0.5 None 8%

Lisinopril 7-15x 4 4/6% 3/7%

Carvedilol 4x 0.5 None 10%

Carvedilol 8x 4 None 20%

Losartan 3x 5 3% 3/7%

Benefits - primarily hospitalizations!Harms - hypotension, withdrawal, dose reduction

883 heart failure patients - age - 73!

66% class II, 29% class III!

Randomised to bisoprolol (10 mg daily) or carvedilol (25 mg BID) and slowly up-titrated patients to the “RECOMMENDED” doses

Fraction of dose

0 1/8 1/4 1/2 FULL

Patients on dose at end

10% 10% 25% 25% 30%

Eur J Heart Fail 2011;13:670-80

What you should shoot forStart with really low doses!

No hurry!

Surrogate markers!

Is the benefit because of the effect on the surrogate?!

Don’t measure obsessively!

The most benefit is getting them from really HIGH, not getting to really low!

Target Doses!

If you can get them to the doses in the studies GREAT but don’t sweat it nor let your patients sweat it!

% reduction in LDL cholesterol

0

15

30

45

60

Rosuvastatin Atorvastatin Simvastatin Pravastatin

10mg20mg40mg80mg

10 mg - 70% of the effect!20 mg - 85% of the effect!40 mg - 90% of the effect

CD008226

Atorvastatin % LDL reduction

10 mg 3720 mg 4340 mg 4880 mg 53

Ann Intern Med 2008;148:656-61

“After initial change only measure every 3-5 years”

Within-person coefficient of variation is ~7%!Single measurement - 95% CI!

Total chol ~ - 0.80 to 0.80 mmol/L!LDL chol ~ - 0.5 to 0.5 mmol/L

Average increase!in cholesterol!is 0.5-1%/year

REMEMBER!Doubling the dose from 20-40mg or 40-80 mg changes

cholesterol by ~5%

Practical issues/ suggestions for cutting doses

1) Start with half of the lowest marketed dose for older established products!

2) For newly marketed medications start with a half or even a quarter of the lowest available dose!

3) Need a discussion with the patient!

4) Dosage forms - pill cutters, capsules, liquid!

5) Increase interval if can’t decrease dose

Guidelines and the Law“As per the Canadian Medical Association Handbook on Clinical Practice Guidelines,

guidelines should NOT be used as a legal resource in malpractice cases as “their more general nature renders them insensitive to the particular circumstances of the individual cases.”