First-Fill Medication Discontinuations and Nonadherence to Antihypertensive Therapy: An Observational Study

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1 nature publishing group First-Fill Medication Discontinuations and Nonadherence to Antihypertensive Therapy: An Observational Study Charity D. Evans 1,3, Dean T. Eurich 2, Alfred J. Remillard 1, Yvonne M. Shevchuk 1 and David Blackburn 1 Background Medication nonadherence is a barrier to successfully managing hypertension, but little is known about the contribution that immediate discontinuations have on antihypertensive (AHT) nonadherence. The purpose of this study was to determine the proportion of new AHT users who discontinue after a single dispensation, and to examine potential predictors of these discontinuations. Methods This retrospective cohort study utilizing linked administrative data from Saskatchewan, Canada. Subjects were 40 years of age and received a new AHT between The primary end point was the proportion of subjects who discontinued their AHT after the first dispensation (first-fill discontinuation). The proportion of nonadherence attributed to first-fill discontinuations was then calculated. Multivariate regression identified factors associated with first-fill discontinuations. Results 52,039 subjects were included in the analyses. Mean age was 59.4 (s.d. 12.5) years, and 42% were male. Overall, 25,812/52,039 (50%) subjects were nonadherent at 1 year; first-fill discontinuations accounted for 39.1% (10,081/25,812) of this nonadherence. Approximately 20% (10,081/52,039) of all subjects discontinued all AHT therapy after the first fill. A higher chronic disease score (adjusted odds ratio (OR) 1.09, 95% confidence interval (CI) ) and antidepressant medication usage during the observation year (adjusted OR 1.17, 95% CI ) was associated with increased risk for first-fill discontinuations. Older age, starting AHT therapy after 1994, frequent physician visits, or use of a statin, acetylsalicylic acid, warfarin or antihyperglycemic during the observation year was associated with a lower risk for first-fill discontinuations. Conclusion A substantial proportion of nonadherence to AHT medications is due to discontinuations after only a single dispensation. Keywords: adherence; antihypertensive therapy; blood pressure; hypertension; observational study American Journal of Hypertension, advance online publication 17 November 2011; doi: /ajh Nonadherence to antihypertensive (AHT) medications remains a major barrier to the overall protection afforded by therapy. 1,2 Individuals may exhibit nonadherence through primary nonadherence (failing to ever fill a prescription), 3,4 a lack of proper execution of a defined dosing regimen (missing or adjusting doses), or by discontinuing the medication altogether (nonpersistence). 2 Although the first year of therapy has been associated with the greatest risk for medication nonadherence, 5 8 the patterns of nonadherence to AHTs within the first year remain unclear. Short persistence to AHT medications is known to be problematic but two studies suggest that immediate discontinuations (discontinuations after the first dispensation) 1 College of Pharmacy & Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 2 School of Public Health, University of Alberta, Edmonton, Alberta, Canada; 3 Present address: Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Correspondence: David Blackburn (d.blackburn@usask.ca) Received 20 May 2011; first decision 9 July 2011; accepted 16 September American Journal of Hypertension, Ltd. might contribute disproportionately to the overall rate of AHT nonadherence. 9,10 In contrast, immediate discontinuations did not appear to make a unique contribution to overall adherence in a recent review of AHT clinical trial populations. 2 However, subjects in clinical trials likely differ from those in the general population, 11 and the requirement for informed consent might have influenced the observed adherence patterns in this study. Interestingly, studies of adherence to statin medications suggest that nonadherence in the first year of therapy might also be frequently attributed to a high rate of immediate discontinuations. 7,12 Ultimately, identifying patterns of nonadherence that are consistent between distinct classes of medications such as statins and AHTs would provide objective evidence that a major contributor to nonadherence may be organizational and procedural factors, while the influence of the actual medication class may be small. The purpose of this study was to determine the proportion of new users of AHT medications who discontinue after only a single dispensation, and to examine potential predictors of these discontinuations. AMERICAN JOURNAL OF HYPERTENSION VOLUME 25 NUMBER February

2 First-Fill Discontinuations in Antihypertensive Therapy Methods New users of AHT therapy between 1 January 1994 and 31 December 2002 were identified using the linked administrative databases from the province of Saskatchewan, Canada. The Saskatchewan Ministry of Health maintains several health services databases including prescription drug data, physician services utilization, hospital services utilization, and vital statistics. Health services information captured by these distinct databases can be linked electronically at the individual level through a unique identification number. All Saskatchewan residents are eligible for provincial health insurance coverage, except inmates of federal penitentiaries and members of the Royal Canadian Mounted Police and Canadian Forces (<1% of the Saskatchewan population); approximately 90% of the Saskatchewan population is eligible for provincial prescription drug coverage. Residents ineligible for coverage under the drug plan are primarily Registered Indians who have their prescription costs paid for by another government agency. 13 These databases have served as the basis for many observational studies of medication adherence and are considered to be of high quality. 6,14 17 To be eligible, subjects must have been at least 40 years of age and filled a new AHT prescription in one of the following pre-specified categories: β blockers, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blockers, or diuretic (thiazide and potassium-sparing). Those subjects who received a fixed-combination AHT product (two medications in a single pill/capsule) or dispensations for 2 distinct AHT medications on the index date were categorized as combination therapy (Appendix I). A new prescription was defined as having no dispensations for any AHT agent in the 5 years prior to the first AHT prescription (index date). Subjects were followed for 1 year (365 days) from their index date. To ensure that the AHT was being prescribed for uncomplicated hypertension (i.e., without significant comorbidities), subjects who had a history of hospitalization or outpatient physician services in the previous 5 years for any of the following: cardiovascular events (e.g., myocardial infarction, unstable angina, congestive heart failure), diabetes, HIV/AIDS, renal or liver disease, esophageal varices, or solid organ transplant were excluded. In addition, because the Saskatchewan Ministry of Health does not capture medication use during hospitalizations, subjects who were hospitalized for any reason during the observation period were also excluded. Last, to ensure reliable estimates of adherence for all patients, only subjects with a full 365 days of follow-up (i.e., still receiving Saskatchewan Ministry of Health and provincial prescription benefits) after the initial AHT dispensation were included in the analysis. Outcomes. The primary outcome was the proportion of subjects who discontinued their AHT after the first dispensation (i.e., first-fill discontinuation). The AHT was considered discontinued if there were no subsequent fills for any AHT drug throughout the entire year of follow-up. As we were primarily interested in first-fill discontinuations, we estimated overall adherence to AHT medications during the first year of follow-up by identifying subjects who obtained enough AHT medication to cover 80% of the observation period (365 days) with at least one AHT medication, regardless of the total number of different AHT categories prescribed during that period. 18 For example, a subject who initially filled an angiotensin-converting enzyme inhibitor and then subsequently switched to a β-blocker would be considered adherent if sufficient medication was available between the agents to cover 80% of the observation period. The 80% threshold is easily defined and is commonly used in studies measuring adherence. 14,19,20 We then calculated the proportion of all cases of nonadherence that was attributed to first-fill discontinuations. Adherence was estimated with the cumulative mean gap ratio (the number of days when medication was unavailable in relation to the total number of days of the observation period). 21 This was calculated by dividing the number of days that any AHT medication was unavailable by the number of days in the observation period (365 days), then subtracting that number from 1 to obtain an adherence value. 22,23 For example, a subject with only 275 days of medication would have insufficient medication for 90 days out of 365 (25% of the time); therefore their adherence would be 75 (i.e., 1 minus 0.25). In Saskatchewan, AHT prescriptions are primarily dispensed on a monthly (34 day) basis, so we calculated the number of days medication was unavailable by subtracting the expected gap (34 days) from the actual gap (number of days between AHT dispensation dates). Negative values indicated All new users of antihypertensive agents ( ) n = 67,939 Subjects for analyses: Minimum 365 days follow-up after first antihypertensive prescription Reasons for exclusion: -Hospitalization in observation year (n = 7,874) -Death (n = 312) -Coverage terminated (n = 372) -First prescription filled <365 days prior to study end (31 December, 2003) (n = 7,276) -Prescription dispensation for non-study antihypertensive (n = 66) n = 52,039 Figure 1 Selection of study subjects. 196 february 2012 VOLUME 25 NUMBER 2 AMERICAN JOURNAL OF HYPERTENSION

3 First-Fill Discontinuations in Antihypertensive Therapy Table 1 Baseline characteristics Characteristic Overall Diuretics β Blocker ACEI ARB Mean age (years) at index (s.d.) CCB (Non-DHP) CCB (DHP) Multiple AHT or combination product at index date n = 52,039 n = 19,723 n = 8,720 n = 13,011 n = 2,434 n = 1,548 n = 3,174 n = 3,429 P-value a 59.4 (12.5) 60.4 (13.3) 56.4 (11.9) 59.3 (12.0) 58.3 (11.5) 60.1 (12.3) 61.8 (12.4) 59.4 (11.6) < Male (%) 21,575 (41.5) 5,985 (30.3) 3,643 (41.8) 6,645 (51.1) 1,280 (52.6) 722 (46.6) 1,509 (47.5) 1,791 (52.2) < Mean CDS at index (s.d.) 2.9 (1.8) 2.5 (1.7) 2.0 (1.6) 3.9 (1.6) 2.9 (1.6) 3.8 (2.2) 3.0 (1.8) 3.5 (1.9) < Index year (%) ,287 (8.7) 1,850 (9.4) 657 (7.5) 1,031 (7.9) (14.9) 364 (11.5) 154 (4.5) < ,659 (9.0) 1,832 (9.3) 792 (9.1) 1,253 (9.6) (16.9) 338 (10.6) 183 (5.3) ,608 (8.9) 1,930 (9.8) 873 (10.0 1,174 (9.0) 3 (0.1) 177 (11.4) 252 (7.9) 199 (5.8) ,533 (10.6) 2,273 (11.5) 997 (11.4) 1,449 (11.1) 68 (2.8) 152 (9.8) 321 (10.1) 273 (8.0) ,592 (10.7) 2,215 (11.2) 1, ) 1,268 (9.7) 196 (8.1) 175 (11.3) 337 (10.6) 297 (8.7) ,286 (12.1) 2,357 (12.0) 1,164 (13.3) 1,484 (11.4) 391 (16.1) 162 (10.5) 322 (10.1) 406 (11.8) ,894 (13.2) 2,519 (12.8) 1,106 (12.7) 1,701 (13.1) 475 (19.5) 144 (9.3) 428 (13.5) 521 (15.2) ,174 (13.7) 2,468 (12.5) 1,032 (11.8) 1,804 (13.9) 619 (25.4) 134 (8.7) 445 (14.0) 639 (18.6) ,039 (13.5) 2,279 (11.6) 995 (11.4) 1,847 (14.2) 682 (28.0) 112 (7.2) 367 (11.6) 757 (22.1) Physician visits b in observation year (%) (0.7) 130 (0.7) 63 (0.7) 103 (0.8) 18 (0.7) 11 (0.7) 27 (0.9) 37 (1.1) < ,903 (9.4) 2,018 (10.2) 804 (9.2) 1,137 (8.7) 207 (8.5) 110 (7.1) 297 (9.4) 330 (9.6) ,977 (53.8) 10,636 (53.9) 4,338 (49.7) 7,229 (55.6) 1,446 (59.4) 730 (47.2) 1,618 (51.0) 1,980 (57.7) ,770 (36.1) 6,939 (35.2) 3,515 (40.3) 4,542 (34.9) 763 (31.3) 697 (45.0) 1,232 (38.8) 1,082 (31.6) Total concurrent non-aht medications in observation year (%) 0 21,327 (41.0) 8,192 (41.5) 3,215 (36.9) 5,548 (42.6) 1,070 (44.0) 413 (26.7) 1,360 (428) 1,529 (44.6) < ,025 (48.1) 9,537 (48.4) 4,354 (49.9) 6,102 (46.9) 1,165 (47.9) 826 (53.4) 1,486 (46.8) 1,555 (45.3) 3 4 5,019 (9.6) 1,773 (9.0) 1,014 (11.6) 1,210 (9.3) 172 (7.1) 262 (16.9) 280 (8.8) 308 (9.0) (1.3) 137 (1.6) 137 (1.6) 151 (1.2) 27 (1.1) 47 (3.0) 48 (1.5) 37 (1.1) Concurrent non-aht medication in observation year (%) Diabetes/insulin 800 (1.5) 191 (1.0) 62 (0.7) 381 (2.9) 32 (1.1) 26 (1.7) 31 (1.0) 77 (2.2) < Nitrates 2,030 (3.9) 256 (1.3) 837 (9.6) 297 (2.3) 27 (1.1) 354 (22.9) 151 (4.8) 108 (3.1) < Statins 4,294 (8.3) 1,116 (5.7) 637 (7.3) 1,418 (10.9) 316 (13.0) 134 (8.7) 270 (8.5) 403 (11.8) < ASA 1,055 (2.0) 281 (1.4) 280 (3.2) 226 (1.7) 26 (1.1) 80 (5.2) 82 (2.6) 80 (2.3) < Warfarin 570 (1.1) 157 (0.8) 128 (1.5) 142 (1.1) 20 (0.8) 58 (3.7) 27 (0.9) 38 (1.1) < Antidepressants 6,936 (13.3) 2,640 (13.4) 1,792 (20.6) 1,325 (10.2) 240 (9.9) 265 (17.1) 327 (10.3) 347 (10.1) < Income security benefits c (%) None 41,174 (79.1) 15,104 (76.6) 7,136 (81.8) 10,417 (80.1) 2,065 (84.8) 1,237 (79.9) 2,428 (76.5) 2,787 (81.3) < SAP 1,370 (2.6) 529 (2.7) 300 (3.4) 306 (2.4) 32 (1.3) 46 (3.0) 75 (2.4) 82 (2.4) Family-based 556 (1.1) 182 (0.9) 124 (1.4) 139 (1.1) 36 (1.5) 15 (1.0) 19 (0.6) 41 (1.2) Senior-based 8,939 (17.2) 3,908 (19.8) 1,160 (13.3) 2,149 (16.5) 301 (12.4) 250 (16.1) 652 (20.5) 519 (15.1) ACEI, angiotensin-converting enzyme inhibitor; AHT, antihypertensive; ARB, angiotensin receptor blocker; ASA, acetylsalicylic acid; CCB, calcium channel blocker; CDS, chronic disease score (Von Korff ) 21 ; DHP, Dihydropyridine; SAP Saskatchewan Assistance Program; s.d., standard deviation. a Comparison between antihypertensive categories (ANOVA or χ 2, as appropriate). b Number of distinct days where at least one service was provided to an individual subject by as Saskatchewan physician. c None, no income security benefits; SAP, a program of last resort for families and individuals who, for various reasons, including disability, illness, low income or unemployment, cannot meet basic living costs; Family-based, supplements the financial resources of low-income families with dependent children eligibility based on annual family income and assets; Senior-based, supplementary income for subjects 65 years who have little or no income other than the federal Old Age Security pension and Guaranteed Income Supplement. AMERICAN JOURNAL OF HYPERTENSION VOLUME 25 NUMBER 2 february

4 First-Fill Discontinuations in Antihypertensive Therapy Subjects for analyses n = 52,039 Single AHT category filled at index n = 48,610 Combination therapy n = 3,429 Adherence 80% n = 23,871 Adherence <80% n = 24,739 Combination AHT product n = 1, AHT categories filled on index date n = 1,776 Adherence 80% n = 1,099 Adherence <80% n = 554 Adherence 80% n = 1,257 Adherence <80% n = 519 Discontinued after first fill n = 9,938 Discontinued after first fill n = 120 All AHT categories filled at index discontinued after first fill n = 23 Figure 2 Adherence and first-fill discontinuations flow diagram. AHT, antihypertensive. early refills, and therefore a surplus of medication; positive values indicated late refills, and a period of days when medication was not available. Statistical analysis. Baseline characteristics of subjects within each drug category were compared using χ 2 and analysis of variance, as appropriate. Multivariate logistic regression was used to adjust for factors that may have influenced the proportion of nonadherent subjects discontinuing after the first fill. The following covariates were either considered as potentially important (P < 0.1) on univariate analysis or considered to be clinically relevant: sex, age at index, Von Korff chronic disease score at index (a well validated measure of comorbidity derived from medication usage), 24 income security benefits at index (used as a proxy measure for socioeconomic status), AHT category, year that the index prescription was dispensed, and number of physician visits during the observation year, as adherence may be higher in subjects receiving regular follow-up. 25 We also adjusted for concurrent dispensations of the following medications during the observation year: antihyperglycemic medications, nitrates, statins, acetylsalicylic acid, warfarin, and antidepressants. In addition, we estimated the overall prescription burden by totalling the number of selected non- AHT prescription medication classes filled (Appendix I) during the observation year as total prescription burden is know to affect adherence. 21 All first order interactions were tested, with no interactions observed (P > 0.1). All analyses were carried out using SPSS version 16.0 for Windows (SPSS, Chicago, IL). The study protocol was granted a letter of exemption by the University of Saskatchewan Biomedical Research Ethics Board. Sensitivity analyses. We performed a number of sensitivity analyses to evaluate the robustness of our results. First, we examined those subjects who were excluded due to a hospitalization during the observation year, to determine if there was any difference from the overall cohort. Second, we repeated our main analyses according to the use of AHT therapy as monotherapy or combination therapy. Third, to ensure that the diuretic category (which may be used transiently to treat conditions other than hypertension) was not biasing our results, we excluded the diuretic category and repeated the main analyses. Fourth, to ensure inclusion of medication oversupply was not influencing our study results, we excluded medication oversupply from our adherence calculation by setting all surplus medication values to 0, and then summed all days where medication was unavailable (i.e., assuming all previously dispensed medications were discarded or not taken). Finally we re-calculated adherence after modifying the expected gap variable to 30 and 40 days in place of 34. Results We identified 67,939 subjects who were newly initiated on AHT therapy between January 1994 and December 2002 with 52,039 having a minimum follow-up of 365 days without being hospitalized (Figure 1). The mean age was 59.4 (s.d. 12.5) years, mean chronic disease score was 2.9 (s.d. 1.8), and 42% were male (Table 1). Overall, 48,610 subjects (93.4%) received a single AHT at the index date (monotherapy), and 3,429 (6.6%) were initiated on combination therapy, evidenced by the dispensation of a combination AHT product (two medications in a single pill/capsule) or dispensations for 2 distinct AHT medications on the index date (Figure 2). Overall, 19.4% (10,081/52,039) of new users discontinued all AHT therapy after the first dispensation as evidence by no record of any further AHT dispensations for the entire year of follow up. Multivariate analysis of all new users revealed several predictors of first-fill discontinuation, including subjects who had a higher chronic disease score (adjusted odds ratio (OR) 1.09, 95% confidence interval (CI) ) and those receiving an antidepressant medication during the observation year (adjusted OR 1.17, 95% CI ) (Table 2). Subjects who were older (adjusted OR 0.986, 95% CI per 1 year increments), visited their physician more often, or were taking a statin, acetylsalicylic acid, warfarin or antihyperglycemic during the observation year were less likely to discontinue their 198 february 2012 VOLUME 25 NUMBER 2 AMERICAN JOURNAL OF HYPERTENSION

5 First-Fill Discontinuations in Antihypertensive Therapy Table 2 Predictors of first-fill discontinuations Predictor n Unadjusted OR (95% CI) Adjusted OR (95% CI) P-value Sex Male 21,575 Female 30, ( ) 1.05 ( ) 0.08 Age 52, ( ) 0.99 ( ) < Chronic disease score a 52, ( ) 1.09 ( ) < Index AHT Combination therapy 3,429 Diuretics 19, ( ) ( ) < β blocker 8, ( ) 8.53 ( ) < ACEI 13, ( ) 1.96 ( ) < ARB 2, ( ) 1.61 ( ) < CCB (Non DHP) 1, ( ) 8.53 ( ) < CCB (DHP) 3, ( ) 3.10 ( ) < Income security benefit b None 41,174 Saskatchewan Assistance Program 1, ( ) 1.14 ( ) 0.05 Family-based ( ) 1.60 ( ) < Senior-based 8, ( ) 1.05 ( ) 0.23 Number of physician visitsduring observation year c None , ( ) 0.60 ( ) < , ( ) 0.19 ( ) < , ( ) 0.13 ( ) < Index year , , ( ) 0.98 ( ) , ( ) 0.92 ( ) , ( ) 0.84 ( ) < , ( ) 0.80 ( ) < , ( ) 0.66 ( ) < , ( ) 0.71 ( ) < , ( ) 0.69 ( ) < , ( ) 0.63 ( ) < Concurrent non-aht medications during observation year None 21, , ( ) 1.18 ( ) < , ( ) 1.26 ( ) < ( ) 1.11 ( ) 0.42 Specific therapies during observation year Antihyperglycemics No 51,239 Yes ( ) 0.68 ( ) < Nitrates No 50,009 Yes 2, ( ) 0.88 ( ) 0.05 Table 2 Continued on next page AMERICAN JOURNAL OF HYPERTENSION VOLUME 25 NUMBER 2 february

6 First-Fill Discontinuations in Antihypertensive Therapy Table 2 Continued Predictor Statin No 47,745 n Unadjusted OR (95% CI) Adjusted OR (95% CI) P-value Yes 4, ( ) 0.50 ( ) < ASA No 50,984 Yes 1, ( ) 0.68 ( ) < Warfarin No 51,469 Yes ( ) 0.76 ( ) < Antidepressant No 45,103 Yes 6, ( ) 1.17 ( ) < AHT, antihypertensive; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASA, acetylsalicylic acid; CCB, calcium channel blocker; DHP, dihydropyridine. All listed variables were included in the model. a VonKorff 21. b None, no income security benefits; Saskatchewan Assistance Program, a program of last resort for families and individuals who, for various reasons, including disability, illness, low income or unemployment, cannot meet basic living costs; Family-based, supplements the financial resources of low-income families with dependent children eligibility based on annual family income and assets; Senior-based, supplementary income for subjects 65 years who have little or no income other than the federal Old Age Security pension and Guaranteed Income Supplement. c Number of distinct days where at least one service was provided to an individual subject by as Saskatchewan physician. AHT after the first-fill (Table 2). Subjects who received an AHT after 1994 were also less likely to discontinue after the first dispensation compared to those who started AHT therapy in 1994 (P < for trend). Predictors of adherence were similar to those of first fill discontinuations. A total of 26,227/52,039 (50.4%) subjects remained adherent to AHT therapy, defined as adherence of 80% at 1 year. Interestingly, subjects who discontinued therapy after the first fill accounted for 39.1% (10,081/25,812) of all cases of nonadherence calculated at 1 year; 15,731/25,812 (60.9%) of subjects exhibited nonadherence due to another cause (e.g., missed doses, discontinuation other than after first fill). The proportion of nonadherent subjects who discontinued after the first fill differed depending on the AHT category filled at the index date (P < 0.001), and ranged from 4.2 % (143/3,429) to 29.5% (5,810/19,723) in the combination therapy and diuretic categories, respectively (Figure 3). Sensitivity results Of the 7,874 subjects excluded because of a hospitalization, 1,320 (16.8%) discontinued after the first fill, which is similar to the overall cohort. The subjects starting AHT monotherapy were the largest subgroup of new users at 93.4% (48,610/52,039). Of these subjects, the proportion that discontinued after the first fill was 20.4% (9,938/48,610) and the proportion with adherence 80% at 1 year was 49.1% (23,871/48,610) (Figure 2). Similar to the overall cohort, firstfill discontinuations made up 40.2% (9,938/24,739) of all cases of nonadherence. In contrast, among the 3,429 subjects receiving combination therapy (1,653 as a combination product and 1,776 as 2 distinct AHT products (Figure 2)), only 143/3,429 (4.2%) subjects discontinued AHT therapy after the first fill. Adherence at one year was also higher in this subgroup (68.7%; 2,356/3,429) compared to our monotherapy group. Unlike the monotherapy group, first-fill discontinuations contributed to only 13.3% (143/1,073) of all cases of nonadherence in this group; however, this group made up <7% of all new AHT users. Factors associated with first-fill discontinuations in the monotherapy group were similar to the overall cohort. Only the number of physician visits and concurrent antidepressant use in the observation year were associated with first-fill discontinuations in the combination therapy group; all other factors were nonsignificant (data not shown). First-fill discontinuations occurred in 13.2% (4,271/32,316) of subjects when diuretics were excluded from the analyses, and accounted for 31.2% (4,271/13,670) of all nonadherence. When adherence was estimated by excluding medication oversupply (i.e., setting all surplus medication values to 0), 38.1% (19,843/52,039) of subjects in the overall cohort were classified as adherent ( 80%) at 1 year compared to 50.4% in the primary analysis (P < 0.001), with first-fill discontinuation accounting for 31% (10,081/32,196) of all cases of nonadherence in this group. We also re-analyzed adherence using an expected gap of 30 days and 40 days between each dispensation and adherence rates were similar at 45.4% (23,608/52,039) and 54.7% (28,468/52,039) (P < 0.001). Although statistically significant differences were noted, adherence overall was still poor. Discussion In this retrospective cohort study, 19% of all new users of AHT medications discontinued therapy after the first dispensation. These cases of immediate discontinuations made up 39% of the entire burden of nonadherence after 1 year. Although the odds of discontinuing decreased over time, the problem remained significant throughout the follow-up period. 200 february 2012 VOLUME 25 NUMBER 2 AMERICAN JOURNAL OF HYPERTENSION

7 First-Fill Discontinuations in Antihypertensive Therapy % Of Subjects Diuretics (n = 19,723) β Blocker (n = 8,720) ACEI (n = 13,011) ARB (n = 2,434) CCB (Non-DHP) (n = 1,548) CCB (DHP) (n = 3,174) Combination therapy (n = 3,429) Figure 3 Proportion of subjects who discontinue after the first fill. χ 2 P < ; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; DHP, Dihydropyridine. Although the phenomenon of short persistence to AHT medications is well known, to the best of our knowledge, this is one of the first papers to specifically quantify the relative importance of immediate discontinuations among new users of AHTs. Two previous publications have briefly commented on discontinuations after only a single fill, and reported almost identical rates of 18% 10 and 19%. 9 However, neither study was specifically evaluating this outcome and presented rates that were not specific to nonadherent subjects; 9,10 also, we could not be certain that their study population consisted only of new users. Our findings contrast those of Vrijens et al. who examined adherence among subjects involved in clinical trials of AHT medications. 2 Although first-fill discontinuations did not appear to contribute disproportionately to AHT nonadherence, their study was restricted to subjects enrolled in clinical trials only. Furthermore, it appears that this pattern of first-fill discontinuations contributing to nonadherence can be seen with other medications. For example Pedan et al. found that 19% of statin users did not receive any medication refills after the initial dispensation. 12 Individuals filling greater than one agent on the index date may have perceived their condition to be more severe than those starting a single product. Indeed, perceived disease severity has been shown to be associated with increased adherence, 19,26 and may partially explain why adherence was higher, and first-fill discontinuations were lower in this group. Also, these individuals were only considered to demonstrate first-fill discontinuations if they stopped all AHT medications after the index date. Despite these conditions, >13% of these subjects only filled their AHT prescriptions once. Nonadherence to AHT therapy has been identified as a major cause of inadequate blood pressure control, leaving patients at significant risk for complications related to hypertension. 1 The high prevalence of first-fill discontinuations observed in this study, as well as the fact that this phenomenon may be occurring in users of other distinct medication classes such as statins, suggests that one of the fundamental causes of nonadherence may lie within the process of initiating new medications. If these assumptions are correct, it would follow that interventions aimed at improving adherence should be focused on those subjects presenting with a first ever prescription. There are limitations which must be considered when examining the results. First, we only evaluated subjects after 1 year of therapy, and therefore can not comment on adherence past the first year. However, because the first year of therapy has been identified as the highest risk period for nonadherence, 5 7, 19 we believe these findings are extremely important. Second, because those subjects who were hospitalized or died within the observation year were excluded from the analysis, there is the potential for survival bias. However, examination of those excluded due to hospitalizations revealed that 16,8% of subject discontinued after the first fill, which is similar to the 19.4% observed in the overall cohort. Third, it is possible that not all subjects were prescribed an AHT for hypertension. Specifically, certain subjects may have been receiving treatment for conditions that were more acute and periodic, such as transient edema, migraine prophylaxis, or transient heart rhythm issues. However, our inclusion criteria is comparable to hypertensive definitions used in similar observational studies using administrative data, 27,28 and we attempted to ensure that the AHT agent had been prescribed for uncomplicated hypertension by excluding all subjects who were previously hospitalized for any complicating reason in the previous 5 years. We also performed a sensitivity analysis that excluded diuretics and found that first-fill discontinuations still occurred in a significant proportion of our overall cohort, and was responsible for approximately one-third of all nonadherence. Fourth, administrative databases inherently lack detailed patient-level clinical information so we were unable to assess baseline blood pressure levels, or the reasons for nonadherence. As well, we assumed that filling a prescription meant the medication was actually taken. Although this assumption would appear realistic, 22 we cannot say with complete certainty that the medication was consumed. Therefore, our reported rates of adherence may be lower than estimated. Fifth, because days supply was not captured by Saskatchewan Ministry of Health and Extended Benefits Branch during the period of this study, we had to estimate it. However, the majority of the drugs in the analysis were dispensed on a monthly (34 days) basis, and we performed two sensitivity analyses which demonstrated similar results. AMERICAN JOURNAL OF HYPERTENSION VOLUME 25 NUMBER 2 february

8 First-Fill Discontinuations in Antihypertensive Therapy Finally, because our data were only inclusive to 2002, it is possible that first fill discontinuations have continued to decrease in more recent years. However, first-fill discontinuations were still substantial in 2002 (1,015/7,039; 14.4%) and contributed to more than one-third of all nonadherence (1,015/2,967; 34.2%). The results from the present study confirm that a substantial proportion of nonadherence to AHT medications can be attributed to subjects who discontinue after only a single dispensation. Given that nonadherence to AHT medications is not only associated with an increase in blood pressure, but also an increase in vascular events, hospitalizations, and healthcare costs, 28,29 adherence strategies aimed at those presenting with their first ever AHT prescription for an AHT medication will likely have a significant impact. Acknowledgments: This study was funded by a research grant from the Saskatchewan Health Research Foundation (SHRF). This funding agency was not involved in the study design, drafting of the manuscript, or the decision to submit the manuscript. Charity Evans received funding through a Clinical Research Initiative Fellowship from the Canadian Institute of Health Research (CIHR). Dean Eurich receives a salary support award from the Alberta Heritage Foundation for Medical Research (Population Health Investigator). David Blackburn s position at the University of Saskatchewan is funded through unrestricted financial support from AstraZeneca Canada, Merck Frosst Schering, Pfizer Canada, and the Saskatchewan Ministry of Health. The authors thank Dr Jeff Taylor and Mary Rose Stang for their review of the manuscript. This Study is based in part on de-identified data provided by the Saskatchewan Ministry of Health. The interpretation and conclusions contained herein do not necessarily represent those of the Government of Saskatchewan or the Saskatchewan Ministry of Health. Disclosure: The authors declared no conflict of interest. 1. Burnier M. Medication adherence and persistence as the cornerstone of effective antihypertensive therapy. Am J Hypertens 2006; 19: Vrijens B, Vincze G, Kristano P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ 2008;336: Fischer MA, Stedman MR, Lii J, Vogeli C, Shrank WH, Brookhart MA, Weissman JS. Primary medication non-adherence: analysis of 195,930 electronic prescriptions. J Gen Intern Med 2010; 25: Shah NR, Hirsch AG, Zacker C, Wood GC, Schoenthaler A, Ogedegbe G, Stewart WF. Predictors of first-fill adherence for patients with hypertension. Am J Hypertens 2009; 22: Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005; 353: Blackburn DF, Dobson RT, Blackburn JL, Wilson TW, Stang MR, Semchuk WM. Adherence to statins, beta-blockers and angiotensin-converting enzyme inhibitors following a first cardiovascular event: a retrospective cohort study. Can J Cardiol 2005; 21: Larsen J, Andersen M, Kragstrup J, Gram L. High persistence of statin use in a Danish population: Compliance study Br J Clin Pharmacol 2002;53: Wong MC, Jiang JY, Gibbs T, Griffiths SM. Factors associated with antihypertensive drug discontinuation among Chinese patients: a cohort study. Am J Hypertens 2009; 22: Simons L, Ortiz M, Calcino G. Persistence with antihypertensive medication: Australia-wide experience, Med J Australia 2008;188: Poluzzi E, Strahinja P, Vargiu A, Chiabrando G, Silvani MC, Motola D, Sangiorgi Cellini G, Vaccheri A, De Ponti F, Montanaro N. Initial treatment of hypertension and adherence to therapy in general practice in Italy. Eur J Clin Pharmacol 2005; 61: Rothwell PM. External validity of randomised controlled trials: to whom do the results of this trial apply?. Lancet 2005; 365: Pedan A, Varasteh L, Schneeweiss S. Analysis of factors associated with statin adherence in a hierarchical model considering physician, pharmacy, patient, and prescription characteristics. J Manag Care Pharm 2007; 13: Downey W, Stang MR, Beck P, Osei W, Nichol J. Health Services Databases in Saskatchewan. In: Strom B, ed. Pharamcoepidemiology. 4th edn, Wiley: Philadelphia, PA, 2005, pp Blackburn DF, Dobson RT, Blackburn JL, Wilson TW. Cardiovascular morbidity associated with nonadherence to statin therapy. Pharmacotherapy 2005; 25: Blackburn DF, Lamb DA, Eurich DT, Johnson JA, Wilson TW, Dobson RT, Blackburn JL. Atenolol as initial antihypertensive therapy: an observational study comparing first-line agents. J Hypertens 2007; 25: Evans CD, Eurich DT, Lamb DA, Taylor JG, Jorgenson DJ, Semchuk WM, Mansell KD, Blackburn DF. Retrospective observational assessment of statin adherence among subjects patronizing different types of community pharmacies in Canada. J Manag Care Pharm 2009; 15: Lamb D, Eurich D, McAlister F, Tsuyuki R, Semchuk W, Wilson T, Blackburn D. Changes in adherence to evidence-based medications in the first year after initial hospitalization for heart failure: observational cohort study from 1994 to Circ Cardiovasc Qual Outcomes 2009;2: Choudhry NK, Shrank WH, Levin RL, Lee JL, Jan SA, Brookhart MA, Solomon DH. Measuring concurrent adherence to multiple related medications. Am J Manag Care 2009; 15: Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J. Long-term persistence in use of statin therapy in elderly patients. JAMA 2002; 288: Insull W. The problem of compliance to cholesterol altering therapy. J Intern Med 1997; 241: Benner JS, Chapman RH, Petrilla AA, Tang SS, Rosenberg N, Schwartz JS. Association between prescription burden and medication adherence in patients initiating antihypertensive and lipid-lowering therapy. Am J Health Syst Pharm 2009; 66: Grymonpre R, Cheang M, Fraser M, Metge C, Sitar DS. Validity of a prescription claims database to estimate medication adherence in older persons. Med Care 2006; 44: Dolder CR, Lacro JP, Dunn LB, Jeste DV. Antipsychotic medication adherence: is there a difference between typical and atypical agents? Am J Psychiatry 2002; 159: Von Korff M, Wagner EH, Saunders K. A chronic disease score from automated pharmacy data. J Clin Epidemiol 1992; 45: Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: a randomized controlled trial. JAMA 2006; 296: DiMatteo MR, Haskard KB, Williams SL. Health beliefs, disease severity, and patient adherence: a meta-analysis. Med Care 2007; 45: Burke TA, Sturkenboom MC, Lu SE, Wentworth CE, Lin Y, Rhoads GG. Discontinuation of antihypertensive drugs among newly diagnosed hypertensive patients in UK general practice. J Hypertens 2006; 24: Mazzaglia G, Ambrosioni E, Alacqua M, Filippi A, Sessa E, Immordino V, Borghi C, Brignoli O, Caputi AP, Cricelli C, Mantovani LG. Adherence to antihypertensive medications and cardiovascular morbidity among newly diagnosed hypertensive patients. Circulation 2009; 120: Dragomir A, Côté R, Roy L, Blais L, Lalonde L, Bérard A, Perreault S. Impact of adherence to antihypertensive agents on clinical outcomes and hospitalization costs. Med Care 2010; 48: february 2012 VOLUME 25 NUMBER 2 AMERICAN JOURNAL OF HYPERTENSION

9 First-Fill Discontinuations in Antihypertensive Therapy Appendix 1 Drugs available for inclusion in analysis Nonantihypertensive Antihypertensive agents drug categories a Single entity agents Combination products Cardiac agents β blockers Beta Blocker + Statins Thiazide Acebutolol Atenolol/ Other lipid agents chlorthalidone* Atenolol* Propanolol/HCTZ Anticoagulants Metoprolol Timolol/HCTZ Antiplatelets Nadolol ACEI + HCTZ Insulin Propanolol Cilazepril/HCTZ Oral diabetes agents Timolol Enalapril/HCTZ Glucose testing agents ACEI Lisinopril/HCTZ* Antidepressants Benazepril Quinapril/HCTZ Older antipsychotics Captopril ARB + HCTZ Newer antipsychotics Cilazepril Candesartan/HCTZ Glucocorticosteroids Enalapril Irbesartan/HCTZ Oral Fosinopril Losartan/HCTZ* Inhaled Lisinopril* Telmisartan/HCTZ Parenteral Perindopril Valsartan/HCTZ Bisphosphonates Quinapril HRT Ramipril Uric acid agents ARB Migraine agents Candesartan NSAIDs Eprosartan Proton pump inhibitors Irbesartan H2 antagonists Losartan* Misoprostol Telmisartan Other gastrointestinal agents Valsartan Transplant CCB (Non-DHP) Diltiazem* Verapamil CCB (DHP) Amlodipine Felodipine Nifedipine SR* Diuretics Chlorthalidone HCTZ* Indapamide Metolazone Amiloride/HCTZ b Spironolactone/ HCTZ b Triamterene/HCTZ b, * ACEI, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; DHP, dihydropyridine; SR, slow release; HCTZ, hydrochlorothiazide; K, potassium; HRT, hormone replacement therapy; NSAID, nonsteroidal anti-inflammatory drug. *Used for the Modified Proportion of Days Covered calculation. a Drug class categorization determined by SASK MOH personnel. b Categorized as a single entity agent because potassium-sparing component typically not prescribed for alone for hypertension. AMERICAN JOURNAL OF HYPERTENSION VOLUME 25 NUMBER 2 february