Antihypertensive pharmacotherapy: Economic outcomes in a health maintenance organization

Antihypertensive pharmacotherapy: Economic outcomes in a health maintenance organization

CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 9, SEPTEMBER1994 ANTIHYPERTENSIVE PHARMACOTHERAPY: ECONOMIC OUTCOMES IN A HEALTH MAINTENANCE ORGANIZATION D...

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CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 9, SEPTEMBER1994

ANTIHYPERTENSIVE PHARMACOTHERAPY: ECONOMIC OUTCOMES IN A HEALTH MAINTENANCE ORGANIZATION DAVID A. SCLAR,1'~ TRACY L. SKAER,1'3 LINDA M. ROBISON,1 RANDALL F. LEGG,2 AND NEIL L. NEMEC2 1College of Pharmacy, Washington State University, 2Qual-Med Health Plan of Washington, Inland Northwest Division, and 3Pullman Memorial Hospital, Pullman, Washington

ABSTRACT Hypertension is a silent disease, the full seriousness of which becomes evident only when the sequelae of long-standing high blood pressure manifest as congestive heart failure, angina, myocardial infarction, cerebral vascular accident, or end-stage renal disease. A significant barrier to the management of hypertension is the extent to which patients comply with the treatment regimen. We conducted a retrospective analysis to determine the relationship between dosing schedules for antihypertensive pharmacotherapy, regimen compliance, and the utilization of health care services. Information regarding health care service utilization was derived from the computer archive of a network-model health maintenance organization system serving 400,000 beneficiaries. The retrospective archive facilitated the abstraction of data regarding disease-specific health care service utilization. Patient-level paid-claims data for the period January 1, 1990, through December 31, 1993, were abstracted for patients who began antihypertensive therapy with either atenolol, captopril, oral clonidine, transdermal clonidine, diltiazem, enalapril, metoprolol, prazosin, terazosin, or verapamil. Multivariate regression analysis was used to determine the incremental influence on health care expenditures 1 year after diagnosis for hypertension of selected demographic characteristics, use of medical services before diagnosis for hypertension, initial antihypertensive medication, and the number of prescribed maintenance medications for diseases other than hypertension. Separate multivariate analyses were performed to determine the influence of the medication possession ratio (MPR), an index of regimen compliance with antihypertensive therapy, on health care expenditures for hypertension. Our results indicate that patients initially prescribed antihypertensive medication administered once weekly require the fewest number of changes in therapeutic regimen, require far less concomitant pharmacotherapy for blood pressure control, achieve the highest MPR for antihypertensive pharmacotherapy, and require fewer physician, hospital, and laboratory services than patients prescribed antihypertensive pharmacotherapy requiring twice daily, and in some instances once daily, administration. An increasing MPR was Address correspondenceto: David A. Sclar, BPharm, PhD, AssociateProfessorof Health Policyand Administration, BoehringerIngelheim Scholar in Pharmaceutical Economics,Collegeof Pharmacy,Washington State University, Pullman, WA 99164-6510. Received for publication on August 2, 1994. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1056

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found to be correlated with an increase in expenditures for antihypertensive therapy and a decrease in financial commitments for physician, hospital, and laboratory services. INTRODUCTION

Hypertension is a silent disease, the full seriousness of which becomes evident only when the sequelae of long-standing high blood pressure manifest as congestive heart failure, angina, myocardial infarction, cerebral vascular accident, or end-stage renal disease. 1-a An estimated 60 million Americans have an elevated blood pressure (systolic blood pressure/>140 mm Hg or diastolic blood pressure i>90 mm Hg) requiring nonpharmacologic or pharmacologic treatment. 4-6 The expressed goal of lifestyle changes and antihypertensive therapy is the achievement and long-term maintenance of a reduced blood pressure level (<140/90 mm Hg) with minimal, if any, adverse effects.7-9 A significant barrier to the management of hypertension is the extent to which patients comply with the treatment regimen. An estimated 30% to 50% of hypertensive patients withdraw from their prescribed regimen within 1 year of diagnosis. Of the remainder, nearly 33% take doses of medication that are insufficient to achieve an adequate reduction in blood pressure, l°'~1 Furthermore, noncompliance with antihypertensive therapy has been associated with an increase in hospital admissions, length of stay, and resulting health care expenditures. 12-14 We conducted a retrospective analysis designed to determine the relationship between dosing schedules for antihypertensive therapy, regimen compliance, and the utilization of health care services. MATERIALS AND METHODS

Information regarding health care service utilization was derived from the computer archive of a network-model health maintenance organization (HMO) system serving 400,000 beneficiaries. The retrospective archive facilitated the abstraction of data regarding disease-specific health care service utilization. Each patient-level file contained extensive information regarding the health care services received, including the type of service (eg, hospitalization), date of service, units of service (eg, number of days), and International Classification of Diseases, 9th revision, clinical modification, 4th edition (ICD-9-CM) code. 15 The HMO employed a pharmaceutical formulary that provided access to all approved therapeutic options for the management of hypertension. Prescription paid-claims data included information on the name of the medication, its strength, and the quantity dispensed. The HMO authorized the dispensing of pharmacotherapy in 30-day supplies with a uniform pa1057

ECONOMIC OUTCOMES WITH ANTIHYPERTENSIVE PHARMACOTHERAPY

tient co-payment per prescription. Patients who filled prescriptions for medications for hypertensive control or other disease states at a pharmacy outside the HMO network were required to pay the full market value for the prescription, thereby discouraging the patient from obtaining pharmacotherapy outside the network-model HMO. Patient-level paid-claims data for the period January 1, 1990, through December 31, 1993, were abstracted for patients diagnosed with mild-tomoderate hypertension (ICD-9-CM code 401.1: Essential hypertension benign 1~) who began antihypertensive therapy with either atenolol, captopril, oral clonidine, transdermal clonidine, diltiazem, enalapril, metoprolol, prazosin, terazosin, or verapamil. Patients were included in the study if they were between 18 and 75 years old and were initially prescribed one of the following antihypertensive regimens as monotherapy: atenolol QD, captopril BID, oral clonidine BID, transdermal clonidine once a week, diltiazem QD, enalapril BID, metoprolol QD, prazosin BID, terazosin QD, or verapamil QD. In addition, patient-level data files containing information for at least 6 months before the date on which the initial antihypertensive medication was obtained had to be available, as well as patient-level files containing at least 12 months of data after the date on which the initial antihypertensive medication was obtained. Patients were not to have used antihypertensive medications in the 6 months preceding the date that 1 of the 10 initial antihypertensive regimens was dispensed. Patients were not to have used either an intermediate or a skilled nursing facility before or after starting the initial antihypertensive regimen. The date of receipt of the initial antihypertensive medication was used to partition the patient-level data files into "prior" and "post" time periods. The time frames for analysis were specified as follows: prior was defined as the period 0 to 6 months before receipt of the initial antihypertensive regimen; post was defined as the period 0 to 12 months after receipt of the initial antihypertensive regimen. A random selection procedure was used to obtain 125 data files corresponding to each of the ten initial antihypertensive regimens. In turn, these 1250 data files were cross-matched with patient-level prescription and medical records to yield an 18-month sequential clinical and financial history of health care utilization. Patient-level expenditure data and pharmacy-level prescription profiles provided a sequential history of each patient's prescribed regimen for hypertension control. The medication possession ratio (MPR) for antihypertensive therapy was defined at the patient level as the number of days throughout the 360-day post-period in which an individual patient's entire regimen for high blood pressure control had been obtained. 16-1s In this manner, the MPR served as a proxy for the patient's compliance with antihypertensive therapy. 1058

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Patient-level archive data regarding the utilization of and expenditures for health care services in the 6-month period before receipt of the initial antihypertensive medication provided an indirect estimate of the underlying health status of the patients. To determine the incremental influence of selected demographic characteristics, use of medical services before diagnosis for hypertension, initial antihypertensive medication, and the number of prescribed maintenance medications for diseases other than hypertension on post-period expenditures (PPE) for health care, the following multivariate regression model was used (results are expressed in 1994 dollars): PPE = [~] + ~l(age) + [32(sex) + [33(prior) + ~i~i(medication)i + [~4(complexity) + [e] where Prior = ~{(prior-period prescription expenditures) ÷ (prior-period physician expenditures) + (prior-period hospital expenditures) + (prior-period laboratory expenditures)} and PPE = ~:{(post-period prescription expenditures) + (post-period physician expenditures) + (post-period hospital expenditures) + (post-period laboratory expenditures)} The variable medicationi represents a dichotomous comparison at each level of the factor. The regression coefficient 13i measures the incremental expenditure or savings associated with a patient's having been initially prescribed one of nine oral antihypertensive medications compared with that of patients prescribed transdermal clonidine. Separate multivariate equations were estimated for each component of PPE (Table I).

Table I. Variables for analysis.

Dependent variable PPE Independent variables Age Sex Prior Medication~ Complexity MPR

Post-period health service expenditures Patient's age in years = 1 if female = 0 if male Total prior-period health care service expenditures ith initial antihypertensive medication Number of maintenance medications for diseases other than hypertension Medication possession ratio (number of days' supply of antihypertensive pharmacotherapy obtained during the post-period)

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The variable complexity reflects the number of disease states other than hypertension at the patient level. Multivariate models using the patient's ICD-9-CM codes for concomitant diseases other than hypertension yielded insignificant beta-weights per ICD-9-CM code. The inclusion of the variable complexity proved significant (P < 0.05) and enhanced each respective model R 2. The multivariate models proved strong. Step-wise regression procedures indicated a significant contribution to the variance explained (R2) per theoretic construct (ie, variable) used. Moreover, the sequential removal of each theoretic construct resulted in no reduction in the significance per dichotomous comparison of antihypertensive therapy. Given the importance of patient compliance with prescribed antihypertensive therapy, the following multivariate model replaces the variable ~i(Medication)i with ~4(MPR) to determine the effect of MPR on PPE: PPE = [~] + ~l(age) + ~2(sex) + ~3(prior) + [34(MPR) + ~5(complexity) + [e]. A reduction in financial outlays for physician, laboratory, and hospital services and an increase in expenditures for prescription medication were hypothesized as being correlated with an increasing MPR. Multivariate equations were estimated for each component of PPE. Multiple comparisons were conducted using analysis of variance with Duncan's multiple-range test. Categorical data were assessed using chisquare analyses. The a priori level of significance for all statistical tests was set at P < 0.05. RESULTS

Demographic data for the 1250 HMO beneficiaries meeting the study selection criteria are presented in Table II. The analysis of variance procedures revealed no significant difference in the mean age of the patients or in prior-period health care service expenditures. The administration schedule for each initial antihypertensive regimen and the number of concomitant maintenance medications prescribed during the 1-year postperiod are shown in Table III. Patients who began antihypertensive therapy with oral clonidine, captopril, enalapril, or prazosin required significantly fewer maintenance medications (P ~< 0.05) for co-morbid diseases than did patients prescribed atenolol, diltiazem, metoprolol, terazosin, transdermal clonidine, or verapamil. Thus patients with a more complex total drug regimen were started on antihypertensive therapy requiring once-daily or once-weekly administration. Patient-level archive data and pharmacy-level prescription profiles provided a sequential history of the difference between the prescribed reg1060

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Table II. Demographic characteristics of health maintenance organization beneficiaries.

Initial Pharmacotherapy Alphal-adrenergic blockers Prazosin Terazosin ACE inhibitors Captopril Enalapril Beta-adrenergic blockers Atenolol Metoprolol Calcium channel blockers Diltiazem Verapamil Centrally acting alpha2-agonists Clonidine (oral) Clonidine (transdermal)

N

Mean _ SD Age (y)

Female (%)

Male (%)

125 125

48.3 +_ 6,5 51.4 _+ 5,2

43 44

57* 56

125 125

46.4 -+ 6.4 54.8 _+ 7.3

38 46

62 54

125 125

47.4 _+ 7.5 49.7 _+ 8.1

44 37

56 53

125 125

52.3 _+ 6.9 49.2 _+ 8.1

35 40

65 60

125 125

48.7 -+ 7.3 51.6 _+ 6.5

38 49

62 51

ACE = angiotensin-converting enzyme. *P~< 0.05.

imen for hypertension control and the patient's actual use of antihypertensive medication. Table IV presents mean data pertaining to the authorized expenditures for antihypertensive therapy, actual HMO expenditures for antihypertensive therapy, percentage of patients requiring a change in antihypertensive medication, and percentage of patients requiring two or more medications for blood pressure control during the 1-year

Table III. Clinical characteristics of health maintenance organization beneficiaries. Data are expressed as m e a n -+ SD.

Initial Pharmacotherapy Alphat-adrenergic blockers Prazosin Terazosin ACE inhibitors Captopril Enalapril Beta-adrenergic blockers Atenolol Metoprolol Calcium channel blockers Diltiazem Verapamil Centrally acting alpha2-agonists Clonidine (oral) Clonidine (transdermal)

N

Administration Schedule

Regimen Complexity

Duncan Group

125 125

BID QD

0.21 _+ 0,11 0.84 - 0.37

B A

125 125

BID BID

0.22 -+ 0.09 0.14 _+ 0.26

B B

125 125

QD QD

0.92 _+ 0.30 0.86 _+ 0.16

A A

125 125

QD QD

0.74 _+ 0.23 0.88 -+ 0,31

A A

125 125

BID QWK

0.19 _+ 0.18 0.78 _+ 0.27

B A

ACE = angiotensin-converting enzyme; BID = twice daily; QD = once daily; QWK = once weekly. Duncan group A: Significantly different from Duncan group B, P ~< 0.05, Duncan group B: Significantly different from Duncan group A. P ~< 0.05. 1061

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T a b l e IV. U t i l i z a t i o n of a n t i h y p e r t e n s i v e p h a r m a c o t h e r a p y 1 y e a r a f t e r d i a g n o s i s (N = 1250).

Initial Pharmacotherapy

Mean Authorized Prescription Expenditures ($)

Mean HMO Prescription Expenditures ($)

Clonidine (transdermal) Atenolol Terazosin Verapamil Diltiazem Metoprolol Captopdl Enalapril Clonidine (oral) Prazosin

564.48 436.58 641.52 628.56 611.52 677.16 674.26 589.62 417.63 724.79

549.02 342.93 519.63 466.76 441.24 474.95 426.53 384.78 269.57 458.46

P

Percent of Patients Requiring Change in Therapy

Percent of Patients Requiring Two or More Antihypertensive Medications

NS NS NS * * * * * * *

1 3 2 4 6 4 5 6 7 9

2 5 4 3 3 5 8 7 6 5

HMO = health maintenance organization; NS = not significant (P/> 025). * P ~< 0,05 (significant difference between mean authorized and mean HMO prescription expenditures).

post-period. These data revealed significant differences between authorized expenditures for antihypertensive therapy and actual insurance expenditures (P ~< 0.05). Patients initially prescribed an antihypertensive medication requiring a twice-daily dosing schedule were significantly more likely to require a change in antihypertensive therapy. The percentage of patients ultimately requiring two or more medications for blood pressure control was greater in the groups initially prescribed a medication requiring twice-daily administration compared with those prescribed a medication to be administered once daily or once weekly. Analysis of variance with Duncan's multiple-range test revealed a significant and hierarchical increase in MPR as the daily administration schedule declined (P ~< 0.05) (Table V). Specifically, patients initially prescribed a once-weekly transdermal medication had a significantly higher MPR (P < 0.05) than patients prescribed a medication requiring either once-daily or twice-daily administration. Table VI presents the multivariate findings for the dependent variable PPE and each respective health service area component. The analysis revealed a significant increase in aggregate per-capita post-period health care expenditures with each year of age (P ~< 0.05) and with each additional maintenance medication required for a disease state other than hypertension (P ~< 0.05). Female sex was associated with a significant reduction in PPE (P ~< 0.05). The patients initially prescribed antihypertensive therapy requiring twice-daily, or in some instances once-daily, administration had a significant increase in expenditures for physician, hospital, laboratory, and total health care services compared with patients initially prescribed a once-weekly transdermal medication (P <~ 0.05). 1062

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Table V. Medication possession ratio (MPR) for antihypertensive pharmacotherapy.

Initial Pharmacotherapy

MPR

N

Clonidine (transdermal) Atenolol Terazosin Verapamil Diltiazem Metoprolol Captopril Enalapril CIonidine (oral) Prazosin

(Mean __+SD)

125 125 125 125 125 125 125 125 125 125

0.94 0.79 0.77 0.77 0.76 0.74 0.65 0.64 0.63 0.63

Duncan Group

_+ 0.03 _+ 0.04 _+ 0.03 _+ 0.05 _+ 0.04 -+ 0.04 -+ 0.03 -+ 0.05 _+ 0.03 -+ 0.04

A B B B B B C C C C

Duncan group A: Significantly different from Duncan group B or C, P ~ 0.05. Duncan group B: Significantly different from Duncan group A or C, P ~< 0.05. Duncan group C: Significantly different from Duncan group A or B, P ~< 0.05.

Post-period health care expenditures decreased significantly with an increasing MPR (P ~< 0.05) (Table VII). Separate multivariate models revealed that an increasing MPR was correlated with an increase in expenditures for antihypertensive pharmacotherapy ($136.34; P ~< 0.05) and a decrease in financial commitments for physician (-$88.03), hospital ( - $291.87), and laboratory ( - $7.64) services (P ~< 0.05). Aggregate percapita post-period health care expenditures for patients initially prescribed one of nine oral antihypertensive medications, relative to that of patients initially prescribed transdermal clonidine, were plotted against

Table VI. Regression analysis: Estimated per capita post-period expenditures by health service area (N = 1250).

Variable Intercept Age Sex Prior Complexity Atenotol Terazosin Verapamit SR Diltiazem Metoprolol Captopril Enalapril Clonidine (oral) Prazosin R2

Prescription P $294.27 $1.65 $54.37 $0.35 $68.73 -$25.93 $47.52 $33.14 -$68.71 -$83.05 -$117.38 -$73.25

NS * * NS * NS NS NS * * * *

-$86.39 -$104.72 .3556

* *

Physician

P

Hospital

P

Laboratory

P

PPE

P

$142.73 $0.29 -$53.82 $0.37 $42.10 -$29.34 $17.05 $19.70 $49.36 $74.17 $150.32 $103.28

NS NS * NS * NS NS NS * * * *

$194.39 $0.45 -$58.13 $0.67 $9.16 $42.94 -$29.36 $56.61 $163.70 $192.46 $236.16 $302.48

* * * * NS NS NS NS * * * *

$6.32 $0,02 $9.45 $0.05 $8.96 $8.58 $6.65 -$2.59 -$1.83 $9.54 $19.27 $39.01

* NS * NS * NS NS NS NS * * *

$637.71 $2.41 -$48.13 $1.44 $128.95 -$3.75 $41.86 $106.86 $142.52 $193.12 $288.37 $371.52

NS * * * * NS NS NS * * * *

* *

$362.67 $276.92 ,3194

* *

$104.98 $193.61 .2741

$17.03 $26.17 .1283

PPE = Total for post-period expenditures; NS = not significant (P > 0.05). * P ~< 0.05.

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* *

$398.29 $391.98 .3862

* *

ECONOMIC OUTCOMES WITH ANTIHYPERTENSIVE PHARMACOTHERAPY

Table VII. Effect of medication possession ratio on h e a l t h care service utilization i year after diagnosis for hypertension (N = 1250). Health Service Area

Prescription Physician Hospital Laboratory PPE

$136.34" - $88.03" - $291.87* - $7.64* -$251.20"

PPE = Total for post-period expenditures. * P ~< 0.05.

each respective mean MPR (figure). These data graphically depict the inverse relationship between MPR and aggregate per-capita post-period health care expenditures (r = -0.97; P < 0.05). The achievement of an MPR of ~<0.77 resulted in a significant increase in aggregate per-capita post-period health care expenditures over the 1-year study period (P ~< O.O5). DISCUSSION AND CONCLUSION

The results of our quasi-experimental retrospective methodology pertain to patients classified as having benign essential hypertension (ICD-9-CM

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400 200 0 J .63 .63 .64 . 6 5 . 7 4 .76 .77 .77 .79 MPR I

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Figure. Estimated per capita post-period expenditure per oral antihypertensive medication versus m e a n medication possession ratio (MPR). 1064

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code 401.1). Generalizations beyond the clinical bounds of benign essential hypertension are unwarranted. Pharmacotherapeutic options for the treatment of mild-to-moderate hypertension include alphal-adrenergic blockers, angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, calcium channel blockers, and centrally acting alpha2-antagonists. 13 The formulary used by the HMO provided physicians with access to a variety of pharmacotherapeutic options for the management of hypertension. The therapeutic regimens selected for evaluation have been established as comparable in terms of blood pressure control. ~ Selection of antihypertensive therapy involves a multitude of factors, including the patient's age, race, and co-morbid status. 1 Moreover, the physician's experience with antihypertensive therapy remains a significant determinant in the selection of a given therapeutic option. 14 We have presented multivariate models and findings regarding the effect of the initial antihypertensive regimen on the procurement of pharmacotherapy, the requirement for either a change in, or augmentation of, a prescribed regimen, and the expenditures for health care services. Our results indicate that patients initially prescribed antihypertensive medication facilitating once-weekly administration experience the fewest number of changes in therapeutic regimen, require far less concomitant pharmacotherapy for blood pressure control, achieve the highest MPR for antihypertensive pharmacotherapy, and require fewer physician, hospital, and laboratory services compared with patients prescribed antihypertensive therapy requiring twice-daily, and in some instances once-daily, administration. These data argue for an increased use of therapeutic strategies that facilitate a reduction in the patient's dosing schedule for antihypertensive medication. Future prospective investigations incorporating microelectronic compliance monitoring systems will yield a refined measure of the effect of dosing schedule and regimen compliance on health care service expenditures for hypertension. 19'2°

Acknowledgment This research was supported in part by a grant from Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut. References: 1. Working Group on Ambulatory Blood Pressure Monitoring, National High Blood Pressure Coordinating Committee. National high blood pressure education program working group report on ambulatory blood pressure monitoring. Arch Intern Med. 1990;150:22702280. 1065

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2. Anderson KM, Wilson PWF, Odell PM, Kannel WB. An updated coronary risk profile. A statement for health professionals. Circulation. 1991;83:356-362. 3. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part. 1. Prolonged differences in blood pressure: Prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765-774. 4. Roccella EJ, Lenfant C. Regional and racial differences among stoke victims in the United States. Clin Cardiol. 1989;12:IV-18-IV-22. 5. Trials of Hypertension Prevention Collaborative Research Group. The effects of nonpharmacologic interventions of blood pressure of persons with high normal levels: Results of the trials of hypertension prevention, phase I. J A M A . 1992;267:1213-1220. 6. Treatment of Mild Hypertension Research Group. The treatment of mild hypertension study: A randomized, placebo-controlled trial of a nutritional-hygienic regimen along with various drug monotherapies. Arch Intern Med. 1992;152:131-136. 7. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. J A M A . 1991;265:3255-3264. 8. Levine DM, Bone L. The impact of a planned health education approach on the control of hypertension in a high risk population. J H u m Hypertens. 1990;4:317-321. 9. Farquhar JW, Fortmann SP, Flora JA, et al. Effects of community wide education on cardiovascular disease risk factors: The Stanford five-city project. J A M A . 1990;264:359365. 10. Eisen SA, Miller DK, Woodward RS, et al. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med. 1990;150:1881-1884. 11. Lefebvre RC, Lasater TM, Carleton RA, Peterson G. Theory and delivery of health programming in the community: The Pawtucket Heart Health Program. Prev Med. 1987;16:80-95. 12. Col M, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Arch Intern Med. 1990;150:841-845. 13. Cramer MP, Saks SR. Translating safety, efficacy, and compliance into economic value for controlled release dosage forms. PharmacoEconomics. 1994;5:482-504. 14. Sclar DA,~Skaer TL, Chin A, et al. Effect of health education on the utilization of HMO services: A prospective trial among patients with hypertension. P r i m Cardiol. 1992;18(Suppl 1):30-35. 15. International Classification of Diseases. 9th revision, clinical modification, 4th ed., 1994 hospital edition. Vols. 1, 2, and 3. Los Angeles: Practice Management Information Corporation; 1993. 16. Sclar DA, Skaer TL, Chin A, et al. Utility of a transdermal delivery system for antihypertensive therapy. Part II. A m J Med. 1991;91(Suppl 1A):57S-60S. 17. Skaer TL, Sclar DA, Markowski DJ, Won JKH. Utility of a sustained-release formulation for antihypertensive therapy. J H u m Hypertens. 1993;7:519-522. 18. Sclar DA, Skaer TL. Pharmaceutical formulation & health care expenditures. PharmacoEconomics. 1992;2:267-269. 19. Rudd P, Ahmed S, Zachary V, et al. Improved compliance measures: Applications in an ambulatory hypertensive drug trial. Clin Pharmacol Ther. 1990;48:676-685. 20. Cramer JA, Scheyer RD, Mattson RH. Compliance declines between clinic visits. Arch Intern Med. 1990;150:1509-1510. 1066