1. LINKING MICRO- AND MACRO- UTILIZATION DATA Euro-DURG Meeting, Prague, June 8, 2001
John Urquhart, MD, FRCP(Edin)
Pharmaco-epidemiology Group
Maastricht University,
Maastricht, Netherlands

2. PHARMACO-EPIDEMIOLOGIC DATA
MAIN SOURCES OF
PHARMACO-EPIDEMIOLOGIC DATA
MACRO
MARKET
SEMI-MICRO
PHARMACY
MICRO
PATIENT

3. Definitions at the MICRO level of Ambulatory Pharmacotherapy - 1
Acceptance -- does the patient accept or not the recommended treatment?
Execution -- how well does the patient execute the recommended regimen?
Discontinuation -- when does the patient stop taking the medicine?

4. Definitions at the MICRO level of Ambulatory Pharmacotherapy -2
Acceptance -- dichotomous
Execution -- continuous
Discontinuation -- dichotomous

5. Definitions at the MICRO level of Ambulatory Pharmacotherapy -3
‘Adherence’ is a useful overall term, subsuming
Acceptance,
Execution, the quality of which is called
compliance
the extent to which the actual dosing history corresponds to the prescribed drug regimen
Discontinuation
The length of time between acceptance and discontinuation is called
persistence

6. PRESENT VIEWS ABOUT COMPLIANCE ARISE FROM A METHODOLOGIC REVOLUTION
Electronic monitoring methods, introduced in the late 1980’s, revealed that pre-electronic methods grossly overestimated compliance
histories
diaries
returned tablet counts, canister weights
drug levels in plasma (white-coat compliance)
These methods allow patients easily to censor evidence for delayed or omitted doses.

7. 25 YEARS OF DEVELOPMENTS IN ELECTRONIC MONITORING
quick overview

8. 1976
$500 each
($1200 today)

9. 1986
$400 each

10. 1991
$250 each

11. 2000
$80 each

14. Transition from punctual to erratic
holiday

16. WHITE-COAT COMPLIANCE-- taking the medicine just before the scheduled visit

17. RELATIONSHIP BETWEEN ADHERENCE AND VIROLOGIC FAILURE IN HIV INFECTION94 75
% WITH VIROLOGIC
FAILURE 50 36 19
% PRESCRIBED DOSES TAKEN
1/3 <70%
1/3 >95%
Paterson, , et al., Ann Int Med 133: 21-30, 2000

18. Patterns of compliance in medically unselected patients: 1 patient in ca. 6...
punctual dosing
all doses taken but slightly erratic timing
5-20% of doses omitted, but never more than 1 at a time
many doses missed; has a drug holiday 3-4 times /yr
many doses missed; has at least 1 drug holiday/mo.
takes few or no doses, but presents as compliant
“rule of sixes”

19. Similarity of dosing patterns between fields
Compliance appears to be more or less independent of
drug
disease
prognosis
symptoms
The usual patterns of poor & partial compliance prevail in asymptomatic diseases, treated with convenient drugs without attributable side-effects
Compliance is mostly a patient-attribute, rather than a disease- or drug-attribute.

20. BJR 35:60-5, 1996

21. Effect of typical compliance patterns on refill intervals: 60-day prescription
% of prescriptions in category
Median: 71days
Mean: 78 days--4.7 refills/yr, not 6
Days needed to empty a 60-day prescription
100
80-89
60-69
40-49
20-29
90-99
70-79
50-59
30-39
10-19
% of prescribed doses taken

22. Role of Prior Selection - 1
30-40% of medically unselected patients will substantially underdose, per the ‘rule of sixes’
‘medically unselected’ means that the patients have had
no prior medical treatment
‘the usual’ interactions with a physician-prescriber and a pharmacy-dispenser

23. Role of Prior Selection - 2
Patients who have failed to respond to a prior course of rationally-prescribed drug treatment will include more than the usual proportion of poor/partial compliers
EXAMPLE: Burnier & Brunner found that 53% of hypertensives who had been escalated to triple therapy without responding, were clinically unrecognized poor compliers

24. Role of Prior Selection - 3
Patients who have responded well to a prior course of rationally-prescribed drug treatment will include more than the usual proportion of good compliers
EXAMPLE: de Geest found poor compliance in 5% of patients with severe heart failure who had endured a long wait for a suitable heart and then had successfully received a cardiac transplant

25. Role of Selection by Compliance in a Prior Course of Medical Treatment
good-enough
not good-
enough
unselected

26. Role of Selection by Compliance in a Prior Course of Medical Treatment
good-enough
not good-
enough
unselected
‘drug
refractory’
hypertension
cardiac
transplant
recipients

27. SHIFTING GEARS ...
We turn to
PERSISTENCE

28. WHAT DO WE KNOW ABOUT PERSISTENCE?
Example: statins in Quebec*
median persistence 173 days
33% persistence at 1 year
despite full reimbursement & optimal convenience, side-effect profile, efficacy
Similar stories in hypertension and other chronic-use medicines
Major public health disappointment - but not widely recognized...
*Catalan & LeLorier, Val Hlth, 3: 417, 00

29. HUGE CHASM BETWEEN PUBLIC HEALTH OBJECTIVES AND REALITY
A fortnight ago the US National Heart, Lung & Blood Institute issued revised guidelines on treatment of lipid disorders
The guidelines would result in statin treatment of ca. 20% of people over age 40
To realize the goals of this program, median persistence should be 20 years, not 6 months
Closing that huge chasm has huge economic implications

30. COMMON-SENSE BASICS ABOUT PERSISTENCE
Persistence increases one dose at a time
The link between compliance and persistence is the patient’s confidence in the values of ...
the treatment program
correct compliance with the dosing regimen
continuation
Regular review of the patient’s dosing history is a natural way to achieve two desirable goals...
assure satisfactory compliance
reinforce the importance of correct, ongoing dosing

31. WHO PAYS?
Lengthening persistence proportionally increases the manufacturer’s revenues
Gross margins on premium-priced medicines ($2-4/day or more) are >80%
One added year of persistence with a $3/day product returns $800 in gross margins
In commercial quantities, electronic monitors with a 2-year lifetime now cost $50.
A good economic return is possible, IF indeed compliance is a main link to persistence.

32. SOME CONSEQUENCES OF SHORT PERSISTENCE WITH DRUGS INDICATED FOR LONG-TERM USE
high ratio of new to refill prescriptions but slow or no growth in the total market
heavy promotional expenses
poor cost-effectiveness
resources wasted on both diagnostics and drugs
short persistence is in no-one’s interest

33. PERSISTENCE High priority topic linking micro- and macro-aspects of
drug utilization research
COMMENTS :
500+ paper bibliography of published studies
based on electronic monitoring: