Medication Nonadherence: An Unrecognized Cardiovascular Risk Factor

Mark A. Munger, PharmD; Benjamin W. Van Tassell, PharmD; Joanne LaFleur, PharmD, MSPH


September 19, 2007

Factors Contributing to Nonadherence With Antihypertensive Medication

Although a significant number of patients have cardiovascular disease, hypertension remains a silent and under treated risk factor. Only 59% of people with hypertension are receiving treatment, but -- most importantly -- only 34% of those receiving treatment achieve adequate control of blood pressure.[8] Patients with hypertension are at an increased rate for stroke, end-stage renal disease, and heart failure.[9,10,11] In addition, hypertension contributes to the prevalence of other cardiovascular risk factors, such as insulin resistance, lipid abnormalities, changes in renal function, endocrine abnormalities, obesity, left ventricular hypertrophy, diastolic dysfunction, and abnormalities in vascular structure and elasticity.[11] The clustering of these risk factors associated with the hypertensive state supports the importance of adherence with chronic treatment of hypertension. To this end, several studies of antihypertensive medication adherence have examined the effect of contributory factors, such as age, race and ethnicity, gender, and external factors, such as drug class, type of adverse effects, polypharmacy, and drug costs.[12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]

Studies of elderly patients (age ≥ 65 years) in Medicaid programs show that only 20% of patients exhibit "good adherence" (defined as 80% or more days that patients had antihypertensive medication available).[12] In these studies, adherence was greatest among patients taking angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers (CCBs), compared with those taking beta-blockers or diuretics.[13,14] In general, blood pressure is more difficult to control with increasing age. A cross-sectional study of outpatients at a Veterans Health Administration site showed that concomitant use of more than 1 antihypertensive medication increases with patient age (up to age 80, after which it then decreases) and may have an impact on the patient's willingness or ability to comply with the overall regimen. Interestingly, the oldest patients (> 80 years of age), with the least favorable blood pressure control, in the Veteran's Health Administration study were treated less aggressively, with fewer medications, than those patients 60-79 years of age.[23] It is well recognized that uncontrolled hypertension and coronary heart disease together contribute to heart failure (HF) in the elderly; HF affects more than 5% of persons between 65 and 79 years of age and 10% to 20% of those older than 80.[16] Medication nonadherence is the greatest risk factor associated with increased incidence of HF in the elderly.[16] A retrospective cohort study was conducted in the Pennsylvania Pharmaceutical Assistance Contract for the Elderly (PACE) Program.[15] Logistic regression analysis showed that adherence with antihypertensives was consistently lower in elderly patients with asthma or chronic obstructive pulmonary disease (odds ratio [OR] = 0.43), depression (OR = 0.5), gastrointestinal disorders (OR = 0.59), and osteoarthritis (OR = 0.63), compared to elderly patients without these conditions (reference, OR = 1.0). The findings suggest that even noncardiovascular comorbidities negatively affect the use of antihypertensive medication in the elderly.[15]

Race and ethnicity may predispose certain patients to hypertension. For example, the National Health and Nutrition Examination Survey (NHANES) III study indicates that hypertension is more prevalent in African Americans (32.4% [age-adjusted]) than in Hispanics (22.6%) and whites (23.3%),[17] possibly attributed to the presence of the CYP3A5 genotype in African Americans.[18] In a study involving veterans with hypertension and minimal financial barriers, inadequate blood pressure control of hypertension was reported to be 63% in African Americans compared with 50% in whites (P < .003), and African Americans were more likely to be noncompliant with medication (OR = 1.81).[24] A comparative analysis demonstrated that antihypertensive use was even lower in Hispanic (52.5%) compared with African-American (72.6%) and white (63.6%) adults (P < .001 across all 3 groups).[25] This difference was not attributed to demographics, socioeconomic status, health insurance coverage, health status, or health risk behaviors.[25] Rather, language proficiency, cultural beliefs, and attitudes toward healthcare might have contributed to these results.[26] A population study from a multiethnic study of atherosclerosis also showed that the percentage of uncontrolled, treated hypertension was significantly higher in African Americans (35%, P < .0001), Chinese (33%, P = .003), and Hispanics (32%, P = .0005) than in whites (24%).[19] In addition, adherence with diuretic drug therapy was significantly lower in Chinese (22%) and Hispanics (32%) than in whites (47%, P < .001 for both comparisons).[19,20]

Although inconsistent across some ethnic backgrounds, women tend to exhibit more nonadherence than men. In a nested case-control study within a cohort of treatment-naive patients, nonadherence with antihypertensive medication was higher in women (OR = 1.64) than in men (OR = 1.14) and increased if the duration of treatment was longer than 6 months (adjusted ORs for men and women were = 1.71 and 1.88, respectively).[21] The PACE study of patients more than 65 years old also showed reduced adherence with antihypertensive medication in women.[15] A multiethnic study of premenopausal and perimenopausal women showed that goal blood pressure control was highest among white (43%) and Japanese (38.7%) women, but significantly lower among Hispanic women (11.4%; P < .001 vs non-Hispanic white subjects).[22]

The incidence of adverse effects from antihypertensive treatment also contributes to nonadherence. Adverse effects vary according to antihypertensive class ( Table 1 ).[39,40] For example, when the incidence of adverse effects was compared for each drug vs the pooled average incidences of the other drugs in the study, ACE inhibitors were associated with the highest incidence of dry cough (28% vs 8%, respectively; P < .001); dihydropyridine calcium channel blockers with the highest incidence of peripheral edema (22% vs 12%, respectively; P < .001); and beta-blockers with the highest incidence of sexual dysfunction (17% vs 10%, respectively; P < .01) and poor temperature perception in the extremities (26% vs 12%, respectively; P < .001).[27] Adverse effects reported with angiotensin receptor blockers (ARBs) were substantially lower than those reported for other classes of antihypertensives.[28] Additional studies also showed a significantly lower incidence of adverse effects in patients receiving losartan (adjusted OR = 1.0), an ARB, than the ACE inhibitors (OR = 1.78) or calcium channel blockers (OR = 2.65).[29] A 3-month cumulative study among first-time users of losartan, ACE inhibitors, and calcium channel blockers showed that the rates of perceived adverse effects were 52.5%, 60.2%, and 69.6%, respectively.[29] Users of calcium channel blockers had the highest probability of reporting an adverse effect after adjustments were made for sex, age, level of education, number of symptoms perceived before entering the study, insurance coverage, and duration of hypertension.[29] Collectively, the incidence of adverse effects can lead to adherence interruptions with antihypertensive medication.

Drugs with short durations of action, such as some alpha-blockers, ACE inhibitors, and dihydropyridines, may decrease blood pressure control when not taken in a consistent daily pattern.[30] In addition, interrupted adherence can lead to excessive adverse effects when the drug is reintroduced. Short-acting ACE inhibitors, beta-blockers, and clonidine (an alpha-agonist) have been shown to induce periods of rebound effects, such as enhanced beta-receptor responsiveness and increased risk for acute coronary syndrome event (relative risk [RR] = 4.60), with dosing interruptions.[30] Additionally, uncontrolled hypertension can lead to significant adverse sequelae, including increased incidence of chronic kidney disease, atherosclerosis, stroke, and diabetes.[41,42] These data point to the importance of patient drug counseling with both new and refill prescriptions.

The choice of drug treatment can also affect patient adherence with therapy for hypertension. A retrospective cohort study of Medicaid enrollees showed a lower refill rate among patients taking alpha-blockers (11%) than among those taking beta-blockers (30%), adrenergic agents (34%), calcium channel blockers (39%), ACE inhibitors (44%), direct vasodilators (45%), or thiazide diuretics (46%).[33] Furthermore, studies showed patients receiving initial therapy with ARBs showed greater adherence than those receiving other classes of drugs. Although definitions of adherence differed in these studies values ranged from 63% to 71% for patients treated with ARBs.[34,35,36,37]

Most patients with hypertension require 2 or more antihypertensive drugs to achieve effective blood pressure control,[8] and patients with hypertension may have 1 or more comorbidities, such as type 2 diabetes mellitus, that necessitate the use of additional medications.[38,43]

Many other studies on the effects of polypharmacy have involved patients with HIV infection. The management of HIV infection often involves complex regimens, requiring multiple medications and a high level of adherence to maintain virologic control. Studies of hypertensive patients with HIV have consistently found that medication adherence is suboptimal or poor in patients receiving polypharmacy, especially where regimens require greater than once-daily dosing frequency. Polypharmacy has a detrimental effect on adherence because many patients do not understand their complex regimens and have difficulty organizing their schedules to accommodate these regimens.[44,45,46] Healthcare professionals may be able to improve adherence by educating patients about the importance of adhering to their prescribed regimens,[47] simplifying regimens,[45,46] helping patients to improve their organizational skills,[46] and acquiring and using adherence aids.[45] Simplifying regimens can be accomplished by using combination products. One retrospective study of persistence with single-pill combination therapy compared to concurrent 2-pill therapy showed that as many as 20% more subjects continue to take prescribed medication for 12 months.[48]

Drug costs also provide another barrier to adherence with drug therapy. Although the high cost of drug acquisition can be an obstacle to adherence, results of a cross-sectional study of Medicaid recipients illustrates the detrimental effects of even modest tiered copayments on prescription fill rates.[49] Among patients who rated their health as fair, residents of states that require prescription copayments filled nearly 40% fewer prescriptions than their counterparts in non-copay states. Among those who rated their health as poor, the difference was 27%.[49]

The high cost of antihypertensive medications also contributes to nonadherence in developing countries. For example, 93% of patients in Ghana were noncompliant with their antihypertensive regimens, and 96% of these patients cited unaffordable drug prices as the main reason.[31] Ambrosioni and colleagues[32] suggest that low-dose combination therapy should be considered a cost-effective method to ensure universal improvements in tolerability, efficacy, and adherence with antihypertensive medication (a major global health economic burden). Another economic factor that can lead to nonadherence is the presence of restricted formularies, which may necessitate a switch to a cheaper but less well-tolerated antihypertensive agent within the same therapeutic class.[50]

Differential adherence to long-term antihypertensive drug therapy can translate to higher healthcare costs and increased healthcare needs.[51] Patients in a California Medicaid program who interrupted their antihypertensive treatment within the first year had higher healthcare expenses centered around increased rates of hospitalization.[52] Sokol and colleagues[53] recently reported that increased adherence with antihypertensive medication can result in decreased healthcare utilization if treatment follows a guidelines-based therapy. In addition, a study in the United Kingdom of patients with newly diagnosed hypertension showed that switching and discontinuation of the initial therapy led to an excess expenditure of ₤ 26.9 million per year (approximately $53 million).[54] A similar analysis in a tertiary hypertension clinic showed that switching to an alternative drug treatment resulted in $1333 in additional medical care costs over the next 12 months.[51] Additional costs were accrued by blood pressure monitoring and laboratory costs.


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