J. Sanford Schwartz, MD

 To evaluate the extent of patient failure to fill antihypertensive prescriptions and to test the hypothesis that the presence of noncardiovascular disease is negatively associated with filling an antihypertensive prescription, and, conversely, that the presence of cardiovascular disease is positively associated with filling an antihypertensive prescription.

Many antihypertensive prescriptions were not filled. 

Antihypertensive adherence interventions should target patients with cardiovascular comorbidities to maximize the possible benefits of these medications.

Poor blood pressure control substantially increases the risk of ischemic heart disease and stroke.1 Although effective treatment for hypertension improves clinical outcomes and reduces healthcare costs,

 30% to 50% of treated patients continue to have uncontrolled blood pressure.4,5 Successful pharmacologic treatment of any medical condition requires patient cooperation in a multiple-step pathway that includes

: (1) keeping a scheduled appointment with a physician; (2) accepting a prescription for a medication; (3) filling the prescription at a pharmacy; (4) taking the medication as prescribed; (5) maintaining an adequate supply of the medication by refilling the prescription in a timely manner; and (6) returning to the physician for ongoing monitoring.

Our unit of analysis was an electronically generated prescription for a new or renewed antihypertensive medication during the study period. We linked claims only for medications that required the physician to provide a prescription. Prescriptions written by hand or called directly to a pharmacy were not included. Prescriptions fell into 1 of the following antihypertensive drug classes: beta-blockers, calcium channel blockers, thiazide or potassium-sparing diuretics, angiotensinconverting enzyme (ACE) inhibitors, angiotensin receptor blockers, and all other antihypertensive medications (eg, alpha-blockers, vasodilators). Diuretics (such as furosemide) that act at the Loop of Henle and prescriptions written on an as-needed basis were not included because they are most commonly used for other medical conditions.

From the electronic medical record used by the 6 primary care practices, we created a database that included demographics, insurance status, clinical diagnoses, selected physiologic measures (eg, blood pressure), selected laboratory tests (eg, lowdensity lipoprotein [LDL] cholesterol), and prescribed medications. Study patients&#8217; clinical conditions were defined from 

coded conditions at all inpatient and outpatient encounters. Cardiovascular comorbidities included diabetes, coronary artery disease, or coronary artery disease equivalent (ie, stroke, other cerebral vascular disease, peripheral vascular disease). Because of variability of 

codes used for renal insufficiency, we created a separate indicator, serum creatinine of >2 mg/dL, for this condition. Prescriptions were considered to be written for patients with cardiovascular disease if any of the previous cardiovascular diseases were present at the time that the prescription was generated.

We defined noncardiovascular comorbidities using Elixhauser&#8217;s comorbidity measure supplemented with noncardiovascular conditions that appeared in more than 5% of all hypertensive patients in study practices. We included conditions that might not affect prognosis but could be a significant focus of ongoing care (eg, osteoarthritis, diarrhea or constipation, esophageal reflux/gastritis, headache, chronic sinusitis) and strategically integrated certain comorbidities (eg, various forms of cancer) that were grouped separately in the Elixhauser index. (For a list of included noncardiovascular comorbid conditions, see the 

, available at www.ajmc.com.) Our final list included 28 conditions. The number of unrelated comorbidities was divided at the median of 4 to create a 2-level variable for analysis. Each prescription was then assigned a value for number of noncardiovascular conditions present at the time the prescription was generated.

Some patients included in the sample were written multiple prescriptions, but some had only 1 prescription. Therefore, we conducted our analysis using generalized estimating equations (GEEs), an adjusted logistic regression model that accounts for clustering of prescriptions within patients. This technique reduces the influence any single patient had on the results. Because there were 327 patients from practices with 210 providers, we did not create a model that was clustered by provider. We assumed an exchangeable correlation matrix for all GEE models and adjusted for key predictors (comorbidity, statin use, and severity of hypertension) and other covariates. All statistical analyses were performed using Stata statistical software, version 9 (StataCorp LP, College Station, TX).

The University of Pennsylvania&#8217;s institutional review board approved the study.

Consistent with our hypothesis, one quarter of prescriptions for antihypertensive medications were not filled by our study sample of Medicaid managed care primary care patients with full prescription coverage. These findings indicate that although medication cost is an adherence barrier that disproportionately affects patients with the lowest income,

 this population&#8217;s failure to fill antihypertensive prescriptions appears to be mediated by additional factors. 

Contrary to our hypothesis, prescriptions for patients with 5 or more noncardiovascular conditions were significantly more likely to be filled than similar prescriptions written for patients with fewer noncardiovascular conditions.

Previous studies of medication adherence have shown that noncardiovascular comorbidities are associated with poor adherence to cardiovascular medications.

 A recent study by Kerr et al also reported that diabetic patients with more non&#8211;diabetes-related comorbid conditions were less likely to prioritize diabetes self-management.

 Our study&#8217;s unexpected findings may be a result of our focus on antihypertensive prescription filling at the pharmacy, an aspect of antihypertensive adherence that has not been previously evaluated. The relationship between comorbidity and filling of antihypertensive prescriptions may differ from that of self-management or refill adherence. It is possible that patients taking many other medications are conditioned to fill prescriptions. However, we did not find an association between filling antihypertensive prescriptions and the number of other types of medications prescribed for a patient.

Also contrary to our hypothesis, antihypertensive prescriptions written for patients with coronary artery disease or other conditions that increase cardiovascular risk (eg, diabetes) were not more likely to be filled. These results differ from previous studies&#8217; reports that high-risk patients who take antihypertensive medications are more adherent to cardiovascular medications.

 However, a study by Taira et al found that a history of coronary artery disease was associated with poorer antihypertensive adherence.

 It is possible that specialists were prescribing antihypertensive medications different from those prescribed by the primary care provider, but this presupposes a significant lack of communication between providers. Additionally, we did not find an association between prescription filling and treatment by cardiologists or nephrologists. Some prescriptions may have been filled outside of the managed care plan. This population of Medicaid patients is very sensitive to cost, however, and these clinics do not stock sample medications, making out-of-plan filling unlikely.

Prescriptions for patients who had stage 2 hypertension were more likely to be filled than prescriptions for patients with well-controlled blood pressure. Patients with very elevated blood pressure at a visit may be more motivated to obtain prescribed medication because of either the physician&#8217;s or the patient&#8217;s concern. Additionally, prescriptions written for patients receiving concurrent statin therapy were more likely to be filled compared with prescriptions written for patients in whom high LDL cholesterol was untreated. This finding may support previous work that identifies differences in the health behaviors and characteristics of statin users. Because statin adherence has been shown to be associated with other health maintenance behaviors such as screening,

 patients prescribed statin medications may be more motivated to fill medications in order to achieve blood pressure control. On the other hand, one study of concurrent antihypertensive and lipid-lowering therapy reported that approximately one third of patients on either antihypertensive or lipid-lowering agents were nonadherent with at least 1 of these medications.

This study has several limitations. We studied a relatively small sample of African American patients in a single managed care plan. Therefore, our results are not generalizable and power to detect associations between dependent and independent variables may be limited. We may have missed prescriptions that were filled but did not generate a claim within the managed care plan (such as patients who filled prescriptions at Veterans Administration pharmacies), but as previously noted, we expected out-of-plan filling to be very limited. We did

2. Krousel-Wood M, Thomas S, Muntner P, Morisky D

. Medication adherence: a key factor in achieving blood pressure control and good clinical outcomes in hypertensive patients. 

4. Wong ND, Lopez VA, Lâ€™Italien GL, Chen R, Kline SEJ, Franklin SS

. Inadequate control of hypertension in US adults with cardiovascular disease comorbidities. 

. Interventions for improving adherence to treatment in patients with high blood pressure in ambulatory settings. 

. Corticosteroid prescription filling for children covered by Medicaid following an emergency department visit or a hospitalization for asthma. 

. Why do some patients not cash their prescriptions? 

. Primary compliance with medication prescribed for paediatric patients discharged from a regional hospital. 

16. Piette JD, Heisler M, Ganoczy D, McCarthy JF, Valenstein M

. Differential medication adherence among patients with schizophrenia and comorbid diabetes and hypertension. 

18. Morris AB, Li J, Kroenke K, Bruner-England TE, Young JM, Murray MD

. Factors associated with drug adherence and blood pressure control in patients with hypertension. 

. Persistence of use of lipidlowering medications: a cross-national study. 

22. Monane M, Bohn RL, Gurwitz JH, Glynn RJ, Levin R, Avorn J.

 The effects of initial drug choice and comorbidity on antihypertensive therapy compliance: results from a population-based study in the elderly. 

24. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [published correction appears in 

. Predictors of medication adherence in the elderly. 

. Drug affordability and prescription noncompliance in the United States: 1997-2002. 

30. Zeber JE, Grazier KL, Valenstein M, Blow FC, Lantz PM

. Effect of a medication copayment increase in veterans with schizophrenia. 

32. Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J

. Long-term persistence in use of statin therapy in elderly patients. 

34. Taira DA, Gelber RP, Davis J, Gronley K, Chung RS, Seto TB

. Antihypertensive adherence and drug class among Asian Pacific Americans. 

36. Glynn RJ, Schneeweiss S, Wang PS, Levin R, Avorn J

. Selective prescribing led to overestimation of the benefits of lipid-lowering drugs. 

Articles

Patients in a Medicaid managed care plan who had cardiovascular comorbidities were not more likely to fill antihypertensive prescriptions than patients without these conditions.

Effect of Patient Comorbidities on Filling of Antihypertensive Prescriptions

High-Versus Low-dose Angiotensin Converting Enzyme Inhibitor Therapy in the Treatment of Heart Failure: An Economic Analysis of the Assessment of Treatment with Lisinopril and Survival (ATLAS) Trial

J. Sanford Schwartz, MD

Articles

Effect of Patient Comorbidities on Filling of Antihypertensive Prescriptions

High-Versus Low-dose Angiotensin Converting Enzyme Inhibitor Therapy in the Treatment of Heart Failure: An Economic Analysis of the Assessment of Treatment with Lisinopril and Survival (ATLAS) Trial

A New Era of Leadership

Cost-Effectiveness Analysis under Managed Care: Not Yet Ready for Prime Time?

Antibiotic Therapy of Helicobacter pylori Infection Reduces Healthcare Expenditures Related to Duodenal Ulcer