Prescribing a Drugectomy – Who, Why, What, When, Where, and How
Prescribing a Drugectomy –
Who, Why, What, When,
Where, and How
Any patient that has ongoing
James McCormack !
B.Sc. (Pharm), Pharm.D.!
Faculty of Pharmaceutical Sciences!
University of British Columbia!
Any patient that has had a drug added
WITHOUT being given an informed choice !
Any drug that was not started
at the VERY lowest dose
Understanding of the ballpark numbers
- beneﬁts and harms!
Do the experiment!
DON’T start with low doses!
Start with VERY low doses
Most standard doses are excessive!
Depression - start 25-50 mg - optimal 75mg -150mg up to 300mg!
J Clin Psychiatry
“The results support the effectiveness of low doses
(25-50 mg) of doxepin to improve sleep”
Sleep 2007; 30: 1555–61
Efficacy and Safety of Three Different Doses of Doxepin in Adults with Primary
All three doses worked better than placebo!
NO side effects over placebo
A recommended low dose was still 25-50 times TOO HIGH
Any patient/drug you haven’t
“starting drugs is like the bliss of marriage,
stopping them is like the agony of divorce”!
Issues to Consider
~ 25-50% of people diagnosed with HTN don’t have
elevated blood pressure - BMJ 2002;325:815–7!
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
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
Guides to safe prescribing
Beers, 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!
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.
~ 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
When you do a!
Patient Medication History!
HOW TO START
UNTIL PROVEN OTHERWISE!
The drug and the
dose are wrong!!!!!!
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 ROW
AIM-HIGH, HPS2-THRIVE (niacin)!
Level A = recommendation
based on evidence from !
VALISH, AASK, ACCORD !
(aggressive BP lowering)!
trials or meta-analyses
ACCORD, ADVANCE, VADT !
(aggressive A1c lowering)!
SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin)!
“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”!
Typically “evidence-based” guideline recommendations!
are not based on “solid” evidence
“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
“Treatment caused 9% of patients to discontinue treatment
due to adverse effects.”
Evidence Level (1 or A)!
based on RCTs
Evidence Level (3 or C)!
based on opinion
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
Quality of life comparisons
Comprehensive diabetes care 0.64
Ann Int Med
Diabetes Care 2007;30:2478-83
A1C of 8 - 14
“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
Diabetes Care 2012;35:1364-79
CVD risks for
and then ﬁgure
and harms for
any CVD drug/
How to tell if a drug
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
Patients who respond in the PPI group!
How to tell if a drug
≈ 65% at 4 weeks, 85% at 8 weeks - DOUBLE DOSE ANOTHER 5%? !
Patients who respond to H2RA!
Drugs for Prevention!
≈ 40% at 4 weeks, 55% at 8 weeks !
HTN, statins, diabetes, osteoporosis!
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
YOU really CAN’T!
And likely over a lifetime a patient won’t
Cochrane Library CD003244
QRISK Lifetime risk of CVD
50 year-old male - non smoker !
CHOL/HDL 4/SBP120 vs 7/180
Risk reduction meds
ASA, statins - you can just stop them!
Fibrates - please just stop them!
10% abs diff
Blood pressure and diabetes drugs?!
20% abs diff
20 years ≈ 90% no beneﬁt?!
45 years ≈ 80% no beneﬁt?
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
PPIs, NSAIDs etc
Typically one should reduce the dose slowly - cut
the dose in half or do something similar - change
Advantages of starting with
“very” low doses !
1)!Get the potential “placebo group effect” !
The dose likely wasn’t right in the ﬁrst place!
2)!Patients are engaged in the process of ﬁnding the
best dose for them!
Put the onus on, and give the power to the
patient to ﬁnd the right dose
3)!Cost savings can be considerable and reduced
4)!Most clinically relevant drug interactions can be
Rationale for starting with
“very” low doses
Limitations of using “very”
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!
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!!
5) In animal research there is a wide dose-response relation humans are genetic mongrels
ACE 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
All the TARGET dose evidence
”achieving target doses should
continue to be an important
“every effort should be made to
place virtually all patients on ACEIs and
achieve the target dose for that ACEI”!
Beneﬁts - primarily hospitalizations!
Harms - hypotension, withdrawal, dose reduction
What you should shoot for
Start with really low doses!
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
dose at end
Eur J Heart Fail 2011;13:670-80
Is the beneﬁt because of the effect on the surrogate?!
Don’t measure obsessively!
The most beneﬁt is getting them from really
not getting to really low!
If you can get them to the doses in the studies GREAT
but don’t sweat it nor let your patients sweat it!
Doubling the dose
from 20-40mg or
40-80 mg changes
cholesterol by ~5%
% reduction in LDL cholesterol
10 mg - 70% of the effect!
20 mg - 85% of the effect!
40 mg - 90% of the effect
1) Start with half of the lowest marketed dose for older
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
Ann Intern Med 2008;148:656-61
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
“After initial change only
measure every 3-5 years”
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.”