Impact of New Antihypertensives on Healthcare Utilization by Hypertensive Patients

Transcription

1 At a Glance Pharmacoeconomics Practical Implications p 139 Author Information p 144 Full text and PDF Impact of New Antihypertensives on Healthcare Utilization by Hypertensive Patients Arijit Ganguli, PhD, MBA; and Song Hee Hong, PhD The rising cost of healthcare has always been a prime concern for policymakers, healthcare economists, healthcare payers, and society at large. It has been suggested that a significant reason for this escalating cost is use of the newer and more costly medications that are introduced in the market each year. Advocates who support acceptance and use of newer drugs argue that newer medications have better clinical outcomes, tend to reduce the overall healthcare cost, and contribute to increased quality of life and longevity. 1 The objective of this study was to verify the hypothesis that adoption of newer medications is associated with decreased healthcare cost and utilization of healthcare services among patients with hypertension. Our intention was to understand the relationship between new drug adoption and healthcare utilization from the patient s perspective. BACKGROUND Prescription drug expenditures accounted for 13% of total US healthcare expenditures in This cost soared from $50 billion spent in 1990 to $219 billion in Despite strong evidence from the famous Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial supporting the superiority of thiazide-type diuretics over other groups of antihypertensive medications, both in terms of clinical outcomes and treatment costs, use of newer medications has increased more than use of diuretics. 3-5 Joint National Committee guidelines recommend diuretics as the first choice in hypertensive patients with no comorbidities. 6 However, differences still exist between these guidelines and the initial drug of choice in clinical practice. 7 It is estimated that nearly $60 billion is spent on managing hypertension and its complications annually in the United States, yet only 34% of the patients treated with antihypertensive medications reach desired blood pressure goals. 6,8 Recent studies have stated that much of this increase in cost is attributable to the introduction of new and generally more costly brand name drugs that replace older, less expensive medications. 9 It is crucial to understand this current healthcare spending, as current ABSTRACT Objective: To investigate the hypothesis that adoption of newer antihypertensive medications is associated with decreased healthcare utilization in patients with hypertension. Study Design: Retrospective follow-up study. Methods: Hypertensive patients were identified during the first round of the 1999 Medical Expenditure Panel Survey database and followed until the end of the year. Antihypertensive drugs approved by the US Food and Drug Administration (FDA) in were defined as new antihypertensive drugs. New drug adopters were those hypertensive patients who were prescribed at least 1 new antihypertensive medication. Total healthcare expenditures, nondrug healthcare expenditures, and emergency department (ED) visits were the variables signifying healthcare utilization. Results: The FDA approved 14 new antihypertensive drugs in 1996, 1997, and Of the 1149 patients who met inclusion criteria, 63 (5.48%) were new drug adopters. The total healthcare and nondrug healthcare expenditures of the new drug adopters were found to be 1.63 (P =.019) and 1.78 (P =.013) times higher, respectively, than they were for patients who were not new drug adopters. The difference in ED visits between the 2 groups was not significant (P =.089). Conclusion: Adoption of new antihypertensive drugs led to higher healthcare costs with no significant difference in ED visits compared with old antihypertensive drugs. This result signifies the need to do a pharmacoeconomic evaluation of each new drug before acceptance by formulary strategists, physicians, and pharmacy managers. (Am J Pharm Benefits. 2009;1(3): ) Author affiliations and disclosures provided at the end of the text. 138 The American Journal of Pharmacy Benefits Fall

2 drug expenditures have been identified as strong predictors of future nondrug expenditures. 10 Policymakers, both private and public, have devised numerous ways to reject the replacement of older, less expensive drugs with newer costly drugs in the absence of proven improvement in outcomes. 2 The question every healthcare provider should address before prescribing a new and expensive treatment is whether the drug is worth the cost. Lichtenberg found that use of newer drugs reduced nondrug costs 3.9 to 7.2 times as much as it increased drug expenditures. 9 This study compared the drug age with healthcare expenditures. The drug age was defined as the number of years prior to 1996 that the active ingredient was first approved by the US Food and Drug Administration (FDA). Lichtenberg used the number of prescriptions as the unit of observation and found that, on average, replacing a 15-year-old drug with a 5.5-year-old drug would save $72 in nondrug healthcare spending and cost $18 more in drug spending, resulting in a drug offset effect of $54. In another study, Lichtenberg used the medical condition instead of prescriptions as the unit of observation and estimated a larger drug offset of $ One of the major limitations of this study was that it did not take into consideration the severity of illness of the patient. Zhang and Soumerai used a generalized linear model with a log link function and gamma distribution with the Medical Expenditure Panel Survey (MEPS) data and estimated $23 as the cost of new drugs after adjusting for illness severity, compared with $18 in the Lichtenberg study. 2 In a study of the new cardiovascular drugs, Miller et al controlled for the number or mix of drugs and found the relationship between the new drug spending and drug age to be statistically insignificant. 10 So these studies highlighted the fact that, on an aggregate level, the new drugs seemed to be worth the cost, although that may not be the case in specific disease states. The objective of this study was to analyze the impact of prescribing a new antihypertensive drug on total healthcare expenditures, nondrug healthcare expenditures, and emergency department (ED) visits in US patients with hypertension. We examined whether adopting a new antihypertensive drug was associated with changes in (1) total healthcare expenditures, (2) nondrug healthcare expenditures, and (3) total number of ED visits. This study included certain new drugs approved by the FDA after 1996 that were not considered in previous studies. METHODS We performed a retrospective follow-up study using the 1999 MEPS database. Patients were defined as Practical Implications Although previous studies have shown that new drugs decrease overall healthcare costs, this retrospective follow-up study of hypertensive patients came to the opposite conclusion. n Adopting new antihypertensive drugs increased total as well as nondrug costs in a real-world setting. n Pharmacoeconomic evaluation of new antihypertensive drugs should be done before they are accepted by formulary decision makers, payers, physicians, and pharmacy managers. hypertensive when they had a diagnosis of hypertension (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes ). Hypertensive patients during the first round of the year (round 3 of 1998 and round 1 of 1999) who had been prescribed at least 1 antihypertensive drug during that period (first round) were included in the study (see Figure). Analytic Overview Antihypertensive drugs approved by the FDA during 1996, 1997, and 1998 were defined as new antihypertensive drugs in this study. New drug adopters were those hypertensive patients who had been prescribed at least 1 of the identified new antihypertensive medications during the first round in Non new drug adopters were defined as those hypertensive patients in round 1 of 1999 who had not been prescribed any of the new antihypertensive drugs. Both populations were followed until the end of the year. The healthcare expenditure data at the end of the year were compared between the 2 groups. The number of unique medications for all conditions was used as a surrogate marker for the patient s comorbidity index. Prescriptions with similar active ingredient(s), irrespective of dosage form and strength, were considered unique medications. Total healthcare expenditure, as defined in MEPS, was the sum of direct payments for care provided during the year, including out-of-pocket payments and payments by private insurance, Medicaid, Medicare, and other sources. Payments for nonprescription drugs and alternative care services were not included in the MEPS total expenditures. Indirect payments not related to specific medical events, such as Medicaid Disproportionate Share and Medicare Direct Medical Education subsidies, also were not included. 12 Nondrug costs were determined by subtracting prescription drug costs from total healthcare costs. The VOL. 1, NO. 3 The American Journal of Pharmacy Benefits 139

3 n Ganguli Hong Figure. Diagrammatic Representation of the Study Rounds in the Medical Expenditure Panel Survey 1998 and 1999 Database January January December January Round 1 Round 2 Round 3 Round 1 Study period Round 4 Round 2 number of ED visits was taken as one of the outcome measures. All the results were adjusted for sex, age, race, ethnicity, severity of disease, income level, and type of insurance. The type of insurance was categorized as private, public, or uninsured. According to the Center for Drug Evaluation and Research data briefing, the FDA approved 102, 101, and 65 standard new drug applications (NDAs) in the years 1996, 1997, and 1998, respectively; of these standard NDAs, 35, 30, and 14 approvals were for standard new molecular entities for the years 1996, 1997, and 1998, respectively. 13 In the years 1996, 1997, and 1998, the FDA approved 3, 7, and 4 NDAs, respectively, for treatment of hypertension. 14 New drugs for this study included all new molecular entities, new molecules in previously existing drug classes, new product extensions (eg, extended/sustained-release dosage forms), and new combination drugs with an existing patent. Generic drugs and drugs with expired patents were not classified as new drugs. Hypertensive patients taking any 1 of these 14 new drugs were identified as new drug adopters. Of these 14 drugs, 7 were new molecules from previously existing drug classes, 3 were new product extensions, and 4 were new drug combinations. Round 5 Round 3 Table 1. Number of Observations in Each Step During Identification of Study Population in the MEPS 1999 Database Identification Step Unweighted Observations, n Total core survey (HC) file 24,618 Hypertensive patients 2721 Round Hypertensive with 1 antihypertensive medication 1149 New drug adopters 63 Non new drug adopters 1071 HC indicates Household Component of the MEPS; MEPS, Medical Expenditure Panel Survey. Data Analysis New drug adopters and non new drug adopters were compared for differences in demographic characteristics, income level, and type of insurance with the χ 2 test. A multiple regression analysis using a generalized linear model with a log link function and gamma distribution was used to analyze the association between new drug adopters and healthcare expenditures, adjusting for age, sex, race, ethnicity, income, severity of disease, and insurance type. Interpretation was done by taking the natural exponential [exp(β 1 )] of the regression coefficient for the expenditure variables. The association between new drug adoption and ED visits was analyzed using the ordinary least squares regression method. The variables that were compared and reported were total healthcare cost, nondrug cost, and total number of ED visits. All analysis was performed without any reference to the sample weights. The study sample was treated as simple random rather than stratified random. The level of statistical significance was P.05, and all statistical computations were done with SAS 9.1 software (SAS Institute Inc, Cary, NC). RESULTS Of 24,618 unweighted observations, 2721 (11.05%) represented patients who had been diagnosed with hypertension (ICD-9-CM codes ) in the 1999 MEPS database. A total of 1306 (47.99%) patients had been diagnosed as hypertensive in the first round of the 1999 MEPS survey; 1149 (87.97%) had been prescribed at least 1 antihypertensive medication and formed the final population for this study. Sixty-three patients (5.48%) were prescribed new antihypertensive drugs and hence grouped as new drug adopters (Table 1). No significant differences were observed between new drug users and non new drug users in terms of age, race, ethnicity, income, and insurance status, although new drug users were significantly more likely to be female (Table 2). The majority of new drug users and non new drug users (60.32% and 64.27%, respectively) were 140 The American Journal of Pharmacy Benefits Fall

4 Impact of New Antihypertensives younger than age 45 years. More than a third in both groups had an annual income below $20,000. About 79% of the new drug adopters were insured versus 88% of the non new drug users. Among insured patients, 80.0% of new drug adopters and 80.33% of non new drug adopters had private insurance. Both groups were dominated by Caucasians, mostly white non-hispanics; 77.78% and 78.55% of the new drug adopters and non new drug adopters, respectively, were whites. The results of the regression analysis showed that the total healthcare expenditure and the nondrug expenditure were significantly associated with adoption of new antihypertensive drugs (Table 3). Upon converting these values into their natural exponential form, the total healthcare expenditures and the nondrug healthcare expenditures of new drug adopters were found to be 1.63 (P =.019) and 1.79 (P =.013) times higher, respectively, than the corresponding expenditures of the non new drug adopters (Table 4). Though the new drug adopters had more ED visits than non new drug adopters, this difference was insignificant (P =.089). Age and income were significantly associated with total and nondrug expenditures. Hypertensive patients older than age 64 years had a 2-fold increase (P.001) in the total healthcare expenditure and about a 1.7-fold (P.001) increase in the nondrug expenditure compared with patients age 44 years or younger. Hypertensive patients age 45 to 64 years had total and nondrug healthcare expenditures 1.6 times (P.001) and 1.39 times (P =.011), respectively, greater than those of patients age 44 years or younger. The total and nondrug expenses of patients with annual incomes between $50,000 and $100,000 were 41% (P =.002) and 42% (P =.004) lower than those of patients with an annual income lower than $20,000. Those with annual incomes higher than $100,000 spent almost 52% (P =.017) and 60% (P =.007) less in terms of the total and nondrug expenses, respectively, than patients with an annual income lower than $20,000. African American patients had lower total and nondrug healthcare expenses than the Caucasians (0.16 times lower [P =.01] and 0.18 times lower [P =.027], respectively). Sex and ethnicity had no significant association with total and nondrug healthcare expenditures. Table 2. Characteristics of New Drug Adopters and Non New Drug Adopters New Drug Adopters Non New Drug Adopters Characteristic No. (%) No. (%) P Total number 63 (5.48) 1086 (94.52) Sex Male 21 (33.33) 545 (50.18).0093 Female 42 (66.67) 541 (49.82) Age, y (60.32) 698 (64.27) (15.87) 215 (19.80) >64 15 (23.81) 158 (14.55) Race White 49 (77.78) 853 (78.55).47 Black 12 (19.05) 165 (15.19) Other 2 (3.17) 68 (6.26) Race/ethnicity Hispanic 12 (19.05) 206 (18.97).65 Black/non-Hispanic 12 (19.05) 162 (14.92) Other 39 (61.90) 718 (66.11) Income, $ <20, (36.51) 383 (35.27).98 20,000-49, (25.40) 257 (23.66) 50, ,000 5 (7.94) 78 (7.18) >100,000 1 (1.59) 18 (1.66) Missing 18 (28.57) 350 (32.23) Insurance status Privately insured 40 (63.49) 768 (70.72).12 Publicly insured 10 (15.87) 188 (17.31) Uninsured 13 (20.63) 130 (11.97) Patients with public insurance spent 4.81 times (P.001) and 4.44 times (P.001) more, whereas those with private insurance spent 2.10 times (P =.002) and 1.94 times (P =.027) more than those patients without any healthcare insurance in terms of total and nondrug costs. DISCUSSION In this study, the association between adopting a new drug and increased healthcare expenditure was found to be significant. Results showed that patients taking new antihypertensive drugs had higher annual total healthcare costs and nondrug costs, and more ED visits than patients taking old antihypertensive drugs; however, only the total cost and nondrug cost were statistically significant. So this study refutes the VOL. 1, NO. 3 The American Journal of Pharmacy Benefits 141

5 n Ganguli Hong Table 3. Factors Affecting Differences in Use of Healthcare Resources Total Healthcare Expenditure a Nondrug Expenditure a Total Emergency Department Visits b Variable Estimate P Estimate P Estimate P Intercept 6.71 < < New drug adopters c Comorbidity index d Sex Female Reference Reference Reference Male Age, y 44 Reference Reference Reference < > < < Income, $ <20,000 Reference Reference Reference 20,000-49, , , >100, Race White Reference Reference Reference Black Other Race/ethnicity Hispanic Reference Reference Reference Black/non-Hispanic Other Insurance status Uninsured Reference Reference Reference Any private Public only 1.57 < < a Regression was done using log-transformed values. b Regression was done using ordinary least squares regression with actual values. c Reference group is the non new drug adopters. d The number of unique prescriptions was used to indicate the comorbidity index. argument that new medications reduce nondrug costs in the short run, as well as contradicting the argument that in real-world settings new antihypertensive drugs reduce ED visits compared with old medications, as concluded in some studies. 2,9 Because new drugs definitely cost more than the older medications, an increase in the total cost is understandable. However, the increase in the nondrug cost among the new drug adopters counters the argument that new drugs always are cost-effective. The increase in the nondrug cost could be explained by the increase in healthcare utilization. The results show new drug adopters have more ED visits, which though statistically insignificant could have contributed to the higher nondrug cost. Similarly, new drug adopters also may have utilized more healthcare services. In this study all drugs newly approved by the FDA in were defined as new drugs, including all new drug molecules, new product extensions, and new drug combinations still in their patent period. It is possible that these new drugs still had a high price because of ongoing or extended patent protection, but clinically they may have limited 142 The American Journal of Pharmacy Benefits Fall

6 Impact of New Antihypertensives or marginal benefits compared with the older, off-patent drugs. Of the 14 new drugs considered in this study, 7 were product extensions or new combinations rather than new chemical entities, which could have influenced the study findings. We know that product extensions and new combinations are some of the successful strategies used by companies to counter generic entry in the postpatent period. 15 Of the 1035 new drugs approved by the FDA between 1989 and 2000, 674 (65%) were modified versions of the existing drugs, according to the National Institute for Health Care Management. 16 The strategy of introducing product line extensions and new combinations has been quite successfully used to shift consumers from expired/soonto-expire original formulations. 17 We acknowledge that new breakthrough molecules are cost-effective, but that may not be true for drugs that are mere structural modifications of existing molecules. Nonadherence and compromised behavior are a few of the factors that deter drug treatment in real-world scenarios. 18 It is possible that the new drug adopters in this study had suboptimal drug adherence rates. The other factor that might explain these study findings is the lifestyle behavior of patients adopting new antihypertensive medications. Patients on new medications may have or been given an impression that the new drug will take care of their high blood pressure, and this perception enticed them to compromise the behavior modifications required as an adjunct to their drug treatment to achieve the desired outcomes. This study was adjusted for health condition (comorbidity); hence, the notion that new drug adopters had worse health was not supported. But the possibility that the new drug adopters had more severe hypertension than the non new drug adopters cannot be denied. Study patients with government-sponsored health insurance spent more than the patients with private insurance, possibly signifying overutilization of healthcare services. This difference also may be attributable to different reimbursement rates for similar services and/or Table 4. Significant Factors Affecting Differences in Use of Healthcare Resources a Variable Ratio b Total Healthcare Expenditure 1.63 (1.08, 2.47) Nondrug Expenditure 1.79 (1.12, 2.80) Unit Change in Emergency Department Visits 0.12 (0.09, 0.15) New drug adopters (95% confidence interval) Age, y 44 Reference Reference Reference > Income, $ <20,000 Reference Reference Reference 20,000-49,999 50, , >100, Race White Reference Reference Reference Black Other Insurance status Uninsured Reference Reference Reference Any private Public only a Results were significant at P.05. b Values are the natural exponential [exp(β 1 )] of the regression coefficient. products, or utilization of more costly services. Also, publicly insured hypertensive patients had more ED visits than privately insured and uninsured populations. People with higher incomes (>$50,000 per year) had the lowest total healthcare and nondrug expenditures and even fewer ED visits. Perhaps because they were affluent, they had access to and the ability to avail themselves of healthcare services and hence enjoyed better health than low-income patients. The study also found that patients older than age 64 years had higher healthcare costs, a finding supported by previous studies. 19 This study had certain limitations that may have influenced the results. MEPS data lacked information on the severity of disease. Although the results were adjusted for the comorbidity index, availability of clinical measures such as the blood pressure of the patient would have been helpful. MEPS data provide cross-sectional information; hence, the analysis was done with the assumption that all study participants had similar healthcare utilization prior to the study period. Also, new drugs were defined as those drugs approved by the FDA during the years 1996, 1997, VOL. 1, NO. 3 The American Journal of Pharmacy Benefits 143

7 n Ganguli Hong and 1998, and the study used the 1999 MEPS data. So the new drugs approved in 1996 had 3 years of effective time in the market, whereas those approved in 1997 and 1998 had 2 years and 1 year, respectively, as the effective time in the market to analyze visible impact. This difference in the effective market presence may limit the exactness of study findings. CONCLUSION Overall, adopting new antihypertensive drugs was associated with higher healthcare cost and healthcare utilization among hypertensive patients. New drugs are cost-effective when they prevent the use of more expensive healthcare resources. Certainly they are costeffective when they come as breakthroughs. However, the cost-effectiveness of new drugs has been challenged when new drugs are line extensions of existing drugs that had been successful in the market. In fact, this study sample mostly consisted of extensions rather than new breakthroughs. Further research is required to understand the exact relationship between the adoption of new antihypertensive medications and healthcare cost. The results of this study essentially suggest that prescribers of new drugs should exhibit caution before acceptance. The results also signify the need to scrutinize the pharmacoeconomic evaluation of each new drug before acceptance by formulary decision makers, payers, physicians, and pharmacy managers. Acknowledgment We thank La Marcus Wingate, PharmD, from the Department of Pharmaceutical Sciences at the University of Tennessee for his valuable assistance during the editing of this manuscript. Author Affiliations: From the Department of Pharmaceutical Sciences (AG, SHH), University of Tennessee, Memphis, TN. Dr Ganguli is now with Abbott Laboratories, Abbott Park, IL. Funding Source: None reported. Author Disclosures: The authors (AG, SHH) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. Authorship Information: Concept and design (AG); acquisition of data (AG); analysis and interpretation of data (AG, SHH); drafting of the manuscript (AG); critical revision of the manuscript for important intellectual content (AG, SHH); statistical analysis (AG); provision of study materials or patients (AG); administrative, technical, or logistic support (AG); and supervision (SHH). Address correspondence to: Song Hee Hong, PhD, Department of Pharmaceutical Sciences, University of Tennessee, 847 Monroe Ave, Rm 205D, Memphis, TN shong6@utmem.edu. REFERENCES 1. Lichtenberg FR. The economic and human impact of new drugs. J Clin Psychiatry. 2003;64(suppl 17): Zhang Y, Soumerai SB. Do newer prescription drugs pay for themselves? A reassessment of the evidence. Health Aff (Millwood). 2007;26(3): ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [published corrections appear in JAMA. 2003;289(2):178 and JAMA. 2004;291(18):2196]. JAMA. 2002;288(23): Davis BR, Piller LB, Cutler JA, et al; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Role of diuretics in the prevention of heart failure: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2006;113(18): Heidenreich PA, Davis BR, Cutler JA, et al. Cost-effectiveness of chlorthalidone, amlodipine, and lisinopril as first-step treatment for patients with hypertension: an analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Gen Intern Med. 2008;23(5): Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published correction appears in JAMA. 2003;290(2):197]. JAMA. 2003;289(19): Ganguli A, Hong SH. Profiles of initial drug therapies among newly diagnosed hypertensive patients with no compelling indications. Poster (PCV53) presented at: International Society for Pharmacoeconomics and Outcomes Research 12th Annual International Meeting; May 2007; Arlington, VA. 8. After the diagnosis: adherence and persistence with hypertension therapy. Am J Manag Care. 2005;11(13 suppl):s395-s Lichtenberg FR. Are the benefits of newer drugs worth their cost? Evidence from the 1996 MEPS. Health Aff (Millwood). 2001;20(5): Miller GE, Moeller JF, Stafford RS. New cardiovascular drugs: patterns of use and association with non-drug health expenditures. Inquiry. 2005;42(4): Lichtenberg FR. Benefit and Costs of Newer Drugs: An Update. June National Bureau of Economic Research Working Paper No Accessed May 5, Center for Financing, Access and Cost Trends, Agency for Healthcare Research and Quality. MEPS HC-038: 1999 Consolidated Data File. October stats/download_data/pufs/h38/h38doc.pdf. Accessed May 5, Galson S. CDER data briefing accessible version. whatwedo/ucm pdf. Accessed May 5, CenterWatch. Approved drugs for cardiology/vascular diseases. Accessed November 13, Hong SH, Shepherd MD, Scoones D, Wan TT. Product-line extensions and pricing strategies of brand-name drugs facing patent expiration. J Manag Care Pharm. 2005;11(9): The National Institute for Health Care Management Research and Educational Foundation. Changing Patterns of Pharmaceutical Innovation. Washington, DC: National Institute for Health Care Management; May 28, innovations.pdf. Accessed May 5, Grabowski HG, Vernon JM. Brand loyalty, entry, and price competition in pharmaceuticals after the 1984 drug act. J Law Econ. 1992;35(2): Lagi A, Rossi A, Passaleva MT, Cartei A, Cencetti S. Compliance with therapy in hypertensive patients. Intern Emerg Med. 2006;1(3): Hartman M, Catlin A, Lassman D, Cylus J, Heffler S. U.S. health spending by age, selected years through Health Aff (Millwood). 2008;27(1):w1-w The American Journal of Pharmacy Benefits Fall