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

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

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?

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

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

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.

25 YEARS OF DEVELOPMENTS IN ELECTRONIC MONITORING quick overview

1976 $500 each ($1200 today)

1986 $400 each

1991 $250 each

2000 $80 each

Transition from punctual to erratic holiday

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

RELATIONSHIP BETWEEN ADHERENCE AND VIROLOGIC FAILURE IN HIV INFECTION 94 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

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”

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.

BJR 35:60-5, 1996

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

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

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

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

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

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

SHIFTING GEARS ... We turn to PERSISTENCE

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

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

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

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.

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

PERSISTENCE High priority topic linking micro- and macro-aspects of drug utilization research COMMENTS : urquhart@ix.netcom.com 500+ paper bibliography of published studies based on electronic monitoring: www.aardex.ch