Antihypertensive Drug Prescribing and Persistence Among New Elderly Users: Implications for Persistence Improvement Interventions

Accepted Manuscript Antihypertensive drug prescribing and persistence among new elderly users in Ontario, Canada Karen Tu, MD, MSc Laura N. Anderson, PhD, MSc Debra A. Butt, MD, MSc Hude Quan, MD, PhD Brenda R. Hemmelgarn, MD, PhD Norm R. Campbell, MD Finlay A. McAlister, MD, MSc PII:

S0828-282X(14)00163-9

DOI:

10.1016/j.cjca.2014.03.017

Reference:

CJCA 1149

To appear in:

Canadian Journal of Cardiology

Received Date: 31 October 2013 Revised Date:

7 March 2014

Accepted Date: 9 March 2014

Please cite this article as: Tu K, Anderson LN, Butt DA, Quan H, Hemmelgarn BR, Campbell NR, McAlister FA, , Antihypertensive drug prescribing and persistence among new elderly users in Ontario, Canada, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.03.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Antihypertensive drug prescribing and persistence among new elderly users in Ontario, Canada

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Authors: Karen Tu, MD, MSc,a,b,c Laura N. Anderson, PhD, MSc,a Debra A. Butt, MD, MSc,a,b Hude Quan, MD, PhD,d Brenda R. Hemmelgarn, MD, PhD,d,e Norm R. Campbell, MD d Finlay A. McAlister, MD, MScf, on behalf of the Hypertension Outcomes and Surveillance Team

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Author Affiliations: aInstitute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada; b Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada; cUniversity Health Network-Toronto Western Hospital Family Health Team, Toronto, Ontario Canada; dDepartment of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; eDepartment of Medicine, University of Calgary, Calgary, Alberta, Canada; f Division of General Internal Medicine, University of Alberta, Edmonton, Canada

Short title: Antihypertensive drug prescribing and persistence

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Word Count: 4499

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Corresponding Author: Dr. Karen Tu, ICES Central, 2075 Bayview Avenue, Toronto, Ontario Canada M4N 3M5; phone: 416-480-4055 ext.3871; fax: 416-480-6048; email: [email protected]

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Brief Summary (75 words): Over the past decade prevalence of antihypertensive use in the elderly has increased whereas the initiation has decreased thereby suggesting that patients are increasingly being initiated on antihypertensives at younger ages. Although still suboptimal, persistence on antihypertensive therapy has improved over time, and this persistence on antihypertensives is lower for patients initiating on diuretics, with increased age, lower socioeconomic status, men, urban residence, presence of more comorbidities but no previous history of a cardiovascular related condition.

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Abstract Background: The objective of this study was to examine persistence rates, and factors

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influencing persistence, for new elderly users of antihypertensive drugs.

Methods: We conducted a population-based cohort study in Ontario of adults aged 66 years or older to identify new users of antihypertensive medications between 1999 and 2010. Two-year

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therapy and class persistence were defined as persistence on any antihypertensive medication

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and persistence only on the same antihypertensive medication class, respectively. Results: From 1999 to 2010, the prevalence of antihypertensive drug use increased from 47.8% to 60.5% (p<0.0001). Persistence was evaluated in 420,148 new users of antihypertensive drugs. After two-years, therapy persistence was 58.9% and varied according to initial class prescribed from 52.3% for diuretics to 64.1% for angiotensin-converting enzyme inhibitors.

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Class persistence ranged from 25.3% for diuretics to 35.8% for angiotensin II receptor blockers. Therapy persistence rates were greater in new users from more recent years (adjusted odds

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ratio [aOR]=1.24, 95% CI: 1.21-1.27). Subgroups who demonstrated poorer persistence included: patients older than 75 years (aOR=0.95, 95% CI: 0.94-0.96), those with lowest

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neighborhood income quintile (aOR=0.81, 95% CI: 0.80-0.83, compared to the highest quintile), those from urban versus rural areas (OR=0.83, 95% CI: 0.81-0.84), and those who started on diuretics as initial monotherapy compared to all other drug classes. Conclusions: Although two-year therapy and class persistence were low for new users of antihypertensive drugs, improvements have occurred over the past decade. Our data highlights subgroups to target for future persistence improvement interventions.

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Introduction Hypertension is a leading cause of cardiovascular disease and mortality, 1 and uncontrolled blood pressure is associated with cardiac, cerebrovascular and renal diseases, and

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death.2 Blood pressure lowering medications are one of the most commonly prescribed

medications in Canada with a total of 104.3 million prescriptions in 2003.3 Antihypertensive drug use is associated with a significant reduction in both blood pressure and cardiovascular

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events, including myocardial infarction (MI), stroke, and death.3-5

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Higher adherence to antihypertensive drugs is associated with lower risk of congestive heart failure (CHF),6 coronary artery disease,7 cerebrovascular events,8 and cardiovascular outcomes in general and all-cause mortality.9 Furthermore, previous research has shown that better adherence to antihypertensives and other cardiovascular drugs are associated with

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lower costs of care.10-14 Despite the benefits of higher adherence, two recent meta-analyses using prescription refill data have found relatively poor antihypertensive drug adherence, with less than two-thirds of patients adhering to their medications over a median of one15 or two16

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years of follow-up after initiating an antihypertensive drug. While both papers reported poor long-term adherence rates, they differed in their conclusions about whether there were class-

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specific differences or not. The studies included in these meta-analyses used various definitions of adherence and were performed in developed countries with/without universal health care access. In contrast, self-reported findings from the Canadian Community Health Study found that only 5% of patients initiating antihypertensive therapy self-reported stopping within one year and only 10% self-reported occasionally missing a dose.17

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With the increasing experience with newer drug classes, such as angiotensin II receptor blockers (ARBs), and the contradictory findings as to the impact of drug class on persistence in

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the existing literature, we set out to assess antihypertensive drug prescribing patterns and persistence from 1999 to 2010 among new elderly users of antihypertensive drugs in Ontario, Canada and to evaluate characteristics associated with persistence.

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Study Methods Study Design

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A retrospective population-based cohort study was conducted using Ontario administrative data housed at the Institute for Clinical Evaluative Sciences (ICES). Universal health care access is available to residents of Ontario through the publicly funded Ontario Health Insurance Plan (OHIP), the single payer for all medically necessary services. Service

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details for residents, providers and hospitals are captured in health administrative databases which can be linked on an individual level to provide a comprehensive health services profile for each resident. This study received ethics approval from Sunnybrook Health Sciences Centre

Data Sources

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Research Ethics Board.

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We used the Ontario Drug Benefit database (ODB), the Registered Persons Database (RPDB), the Ontario Health Insurance Plan (OHIP), and the Canadian Institute for Health Information Discharge Abstract Database (CIHI-DAD). These data sets were held securely in a linked, de-identified form and analyzed at the Institute for Clinical Evaluative Sciences (ICES). The ODB database contains comprehensive records of prescription medication dispensations from a minimally restricted formulary, including antihypertensive medications for

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residents in Ontario aged 65 years and older. The RPDB is a roster of all Ontarians eligible for OHIP and contains information on sex, date of birth, date of death, and postal code.18 Neighborhood income quintiles and rurality were defined through linkage of postal codes to

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Canadian census data.19 Data on pre-existing cardiovascular related comorbid conditions

(congestive heart failure (CHF), myocardial infarction (MI) and stroke) were obtained using the CIHI-DAD hospitalization database back to 1988 using ICD9 and ICD10 diagnostic codes in all

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possible coding fields.20-22 The presence of diabetes was defined using the Ontario Diabetes

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Database (ODD),23 which uses a validated administrative data definition (including both OHIP and CIHI data) to define diabetes cases in Ontario. Additionally for a more general assessment of the potential impact of co-morbidities on persistence, we examined (i) the number of Ambulatory Diagnostic Groups (ADGs),24 a common comorbidity measure applied to patients in

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the primary care setting, and (ii) the number of different drug prescriptions in the year prior to initiation of an antihypertensive. ADGs are based on diagnosis codes and take into consideration duration, severity and etiology of the condition, diagnostic certainty and specialty

Study Population

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care involvement.

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Cohorts of Ontarians older than 66 years in each fiscal year from 1999 to 2010 were evaluated to calculate the incidence and prevalence of antihypertensive drug use and new users in each fiscal year were pooled to report results in two-year groups. The study population consisted of all adults included in the RPDB aged 66 years or older at the start of each fiscal year. The cohort accumulation was started at age 66 because patients only become eligible for ODB at age 65, thus allowing for a 1-year ‘wash out period’ to ensure that new prescriptions

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were truly for new users and not simply appearing as new prescriptions because the patient just became eligible for ODB. Residents were excluded if they were less than 66 or greater than

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100 years of age, missing data on sex, not alive before April 1st of each fiscal year, or if they had no contact with the health care system in the five years prior to the beginning of each fiscal year to avoid including patients new to the province who would likely have incomplete

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historical administrative data information in the Ontario databases. Outcome variable

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Incident antihypertensive drug use was defined using a one-year look back period; adults with antihypertensive drug use in the prior year were classified as prevalent. The cohort of patients initiating antihypertensive drug therapy between April 1, 1999 and March 31, 2011 was identified for the following classes of drugs: angiotensin-converting enzyme (ACE)

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inhibitors, ARBs, calcium channel blockers (CCBs), beta-adrenergic blockers (BBs), thiazide and thiazide-like diuretics and combination agents (see Supplemental Table S1 for drug list). Class and therapy persistence was evaluated among new antihypertensive users who had a minimum

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of two prescriptions dispensed; patients were followed for two years from the initial prescription to evaluate therapy and class persistence. Therapy persistence (continuation with

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any antihypertensive medication) and class persistence (continuation with the same drug class) were defined as a repeat prescription filled within an interval defined by the duration of the previous prescription plus a 50% grace period (i.e., 1.5 times the number of days of the previous prescription).25,26 Patients initiating on combination agents were only considered class persistent if they remained on any combination agent. Study participants were defined as

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persistent if they reached the end of the two-year follow-up or died without a gap in prescription refills.

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Statistical Analysis All statistical analyses were conducted using SAS v9.3. The rate of new antihypertensive drug use was calculated by dividing the number of new users by the rest of the population –

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excluding prevalent users from the denominator. Logistic regression was used to evaluate characteristics associated with both class and therapy persistence; defined as persistent or not

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at the end of two-years. Unadjusted odds ratios (OR) were obtained from simple logistic regression models for each variable and adjusted ORs were obtained from an adjusted multivariate model that included all of the following variables simultaneously: age group, sex, neighborhood income quintile, rural/urban residence and cohort year over the follow-up

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period. Sensitivity analyses were conducted to evaluate the impact of removing patients with a history of any cardiovascular comorbid condition at baseline (i.e., time of new prescription fill). Results

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From 1999/2000 to 2009/10, there was a significant decrease in the overall incidence of new antihypertensive drug use from 10.6% to 7.9%, p<0.0001 and over the same period,

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prevalence of use increased from 47.8% to 60.5%, p<0.0001 (Supplemental Table S2). Among the entire population, the proportion of new antihypertensive users decreased significantly within all age groups from 1999/2000 to 2009/2010 (Supplemental Table S2). Similar decreases over time were observed among both males and females, all neighborhood income quintiles, rural and urban dwellers and for all comorbid conditions; however, within any given year, the

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proportion of new users was greatest among patients previously diagnosed with an MI, CHF, stroke or diabetes.

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From 1999/2000 to 2009/2010, a significant increase was observed in the proportion of new users initiating ARBs from 1.3% to 14.2% and combination drugs from 0.8% to 5.0% (Figure 1). Over the same time period the proportion of new users significantly decreased for patients

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initiating on ACE inhibitors (41.5% to 36.7%), BBs (19.0% to 17.7%), CCBs (14.4% to 10.1%) and diuretics (23.1% to 16.5%) (Figure 1).

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Over the first year of treatment, therapy persistence was 64.6% and class persistence was 42.6%. By the end of the second year, therapy and class persistence decreased to 58.9% and 30.5%, respectively (Figure 2). Two-year class persistence was higher for patients who started on ACEs, ARBs, CCBs, combination drugs, or BBs compared to patients initiated on

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diuretics. (Supplemental Table S3).

Therapy and class persistence increased over time during the study period (Supplemental Table S3). While patients first treated in 1999/2000 exhibited two year therapy

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persistence of 55.8%, 60.9% of the cohort first treated in 2007/ 2008 were still persistent at two years (adjusted OR= 1.23; 95%CI: 1.20-1.26) and class persistence increased from 29.2% to

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33.6% (adjusted OR=1.24; 95% CI: 1.21-1.27) (Supplemental Table S3). Class and therapy persistence were lower for individuals older than 75, those living in urban areas, with lower household incomes, and for patients without diabetes, CHF, MI, or stroke (Supplemental Table S3). Therapy persistence was also lower for patients with more comorbidities and lower for those taking greater numbers of drugs in the year prior to antihypertensive initiation.

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The adjusted odds ratios for all characteristics and both class and therapy persistence were not appreciably different in the sensitivity analysis when individuals with cardiovascular

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related comorbidities (diabetes, CHF, Stroke, MI) were removed (Supplemental Table S4). Discussion

Using a large population-based cohort from Ontario, we found that the frequency of

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new users of antihypertensive drugs among adults 66 years of age and older decreased slightly from 1999 to 2010, while prevalence of use increased substantially. This suggests that a greater

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number of patients are being initiated on antihypertensive therapy before age 66, which implies that patients are being diagnosed with hypertension at earlier ages. The rates of antihypertensive persistence we found are similar to those reported in other studies using medication dispensation databases15,16 and substantially lower than those reported in patient

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surveys, suggesting that self-report17,27 assessments of persistence may perhaps be overestimated. Among new users, we observed a large increase in the number of patients initiated on ARBs (from 1.3% to 14.2%) and combination therapy (from 0.8% to 5.0%) over the

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decade studied, while a decrease was observed for all other drug classes. Our findings of higher persistence in those with other cardiovascular conditions at

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baseline is consistent with the previous meta-analysis showing better adherence for secondary prevention.16 Our findings of higher rates of ARB and ACE persistence in terms of both class and overall antihypertensive therapy persistence are consistent with previous studies.15,28-32 Of note we found that class persistence was highest with ARBs and combination agents and that therapy persistence with patients initiating on combination agents was substantially higher than those initiating on B-blockers or diuretics. Although initiation of combination therapy

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increased over time, it only reached a peak of 5% thus identifying an area that could be targeted for educational interventions designed to improve antihypertensive persistence. From previous studies the impact of age on persistence is not clear. While some have

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reported no association,33,34 others report higher persistence in older users.35-37 However, most studies reporting on the impact of age on persistence have defined older as 65+ compared to

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younger adults. We have further refined this by examining differences across age strata in a cohort where all patients are older than 65. We found increased class persistence with

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increasing age but therapy persistence was lower in the older age groups. Similarly we found higher class persistence and lower therapy persistence with more comorbidities and a greater number of medications in the year prior to antihypertensive initiation. It is possible that this lower persistence with increasing age and higher complexity are related to the presence of

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other more pressing medical conditions that require attention and the preventative nature of controlling hypertension are viewed to be less important closer to the end of life. A previous study also found poorer persistence with urban dwelling users. It may be possible that people

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living in urban settings are more likely to see multiple providers and/or have more comorbidities and/or take more multiple medications which all could lead to poorer persistence.

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A strength of our study is the data source which consisted of population-based administrative databases with universal drug coverage representative of all Ontario adults age 66 and older; however, some limitations of this study should be considered. First, drug data were not available for the entire population under 65 years of age and thus we could only examine persistence rates in older new users of antihypertensive therapy. Additionally patients under age 66 that had previously started on an antihypertensive and stopped for over a year

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and then restarted would have erroneously been considered as new users in our study. Second, we were unable to determine the indication for the drugs dispensed, and thus our study is of

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new users of antihypertensive therapy rather than new hypertension patients; however, our results were consistent even after excluding patients with other indications for

antihypertensive agents such as diabetes, CHF, MI and stroke. Third, it was unknown if patients

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were advised to stop taking their antihypertensive medication as no data were available on blood pressure control. Fourth, our results were based on a medication dispensed from a

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pharmacy and therefore we were unable to assess medication prescription rates, nor were we able to determine if the patient took the medication. Fifth our calculation of persistence may have been underestimated if patients received medication samples from their physicians, however, the newer medications (ARBs, combination agents) are more likely to be sampled

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than older medications like diuretics and may have led to bias in favour of better persistence for the newer medications as patients would likely not have then filled a prescription that they tried initially through a sample and had side effects. Sixth, our study was not able to determine

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if those who were not persistent during the two-year follow-up timeframe were restarted on antihypertensive medications in a later year. Last, a full economic analysis of the potential

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population-level impact of poorer persistence related to first line use of the cheaper subclasses of medication (diuretics, BBs) or the impact of ethnicity was beyond the scope of this study but would be useful to analyze in future studies. In conclusion, we found that despite improvements over the decade we studied, two year class and therapy persistence for antihypertensive drugs remains suboptimal. The differences we observed in class persistence with choice of first line therapy may be useful for

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physician decision making about initiating antihypertensive therapy. More efforts are needed to improve persistence for all patients starting antihypertensive therapy, and in particular those

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from urban and low income settings.

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Acknowledgements The following are members of the Hypertension and Outcomes Surveillance Team of the

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Canadian Hypertension Education Program: Oliver Baclic, Gillian Bartlett, Debra Butt, Norm Campbell, Guanmin Chen, Sulan Dai, Brenda Hemmelgarn, Michael Hill, Helen Johansen, Nadia Khan, Lisa Lix, Finlay McAlister, Jay Onysko, Hude Quan, Mark Smith, Larry Svenson, Gary Teare,

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Karen Tu, Robin Walker, and Andy Wielgosz. We thank Brogan Inc., Ottawa for use of their Drug Product and Therapeutic Class Database.

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Funding

This project was funded by the Canadian Institutes of Health Research (grant number: MOP97823). This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care

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(MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Dr. Karen Tu is supported by a Canadian Institutes of

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Health Research Fellowship Award in Primary Care and Dr. Karen Tu and Dr. Debra Butt are

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supported by Investigator Awards from the Department of Family and Community Medicine, University of Toronto. Dr. McAlister and Quan are supported by salary awards from Alberta Innovates: Health Solutions and Dr. McAlister is also supported by a salary award from the University of Alberta Chair in Cardiovascular Outcomes Research Disclosures Dr. Norm Campbell has received funding for travel to a meeting in 2012 from Novartis.

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ACCEPTED MANUSCRIPT K. Tu Figure 1. Percentage of new antihypertensive drug prescriptions by initial drug class from 1999/2000 to 2009/2010 in Ontario adults ≥66 years of age

45.0

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40.0 35.0

ACE

30.0

ARB

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20.0 15.0

5.0 0.0 1999/00

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2007/08

Calc Diuretics Combination

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Percentage of new antihypertensive users

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ACCEPTED MANUSCRIPT K. Tu Figure 2. One and two-year class and therapy persistence for patients with a minimum of two antihypertensive drug claims (n=420,148) - persistence was defined as continuation with treatment within 1.5x the number of days of previous prescription in Ontario.

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64.6% 58.9%

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70.0%

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30.5% 30.0%

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20.0% 10.0% 0.0%

Class persistence (not discontinued or switched)

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Therapy persistence (not discontinued)

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% persistent

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ACCEPTED MANUSCRIPT Supplemental Table S1. Antihypertensive drugs included in the analysis

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Class Drug Name Angiotensin-converting enzyme (ACE) inhibitors Benazepril HCl Captopril Cilazapril Enalapril Maleate Fosinopril Fosinopril Sodium Lisinopril Perindopril Erbumine Quinapril HCL Ramipril Trandolapril Angiotensin II Receptor Blockers Candesartan Candesartan Cilexetil Eprosartan Mesylate Eprosartan Mesylate & Hydrochlorothi Irbesartan Losartan Potassium Olmesartan Medoxomil Telmisartan Valsartan Beta-adrenergic Blockers Acebutolol HCL Atenolol Bisoprolol Fumarate Labetalol HCL Metoprolol Metoprolol Succinate Metoprolol Tartrate Nadolol Oxprenolol HCL Pindolol Propranolol HCL Timolol Maleate Calcium channel blockers Amlodipine Besylate Diltiazem HCL Felodipine Nicardipine HCL Nifedipine Nimodipine Verapamil HCL Thiazide and Thiazide-like Diuretics Bumetanide Chlorthalidone Hydrochlorothiazide Indapamide Amiloride HCL Amiloride HCL & Hydrochlorothiazide

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Combination Agents

Spironolactone & Hydrochlorothiazide Triamterene & Hydrochlorothiazide Benazepril HCL & Hydrochlorothiazide Cilazapril & Hydrochlorothiazide Enalapril Sodium & Hydrochlorothiazide Hydrochlorothiazide & Ramipril Indapamide & Perindopril Tert.Butyla Lisinopril & Hydrochlorothiazide Perindopril Erbumine & Indapamide Quinapril HCL & Hydrochlorothiazide Ramipril & Hydrochlorothiazide Amlodipine Besylate & Telmisartan Candesartan Cilexetil & Hydrochlorothiazide Hydrochlorothiazide & Irbesartan Hydrochlorothiazide & Losartan Potas Hydrochlorothiazide & Olmesartan Med Hydrochlorothiazide & Telmisartan Hydrochlorothiazide & Valsartan Irbesartan & Hydrochlorothiazide Losartan Potassium & Hydrochlorothiazide Telmisartan & Hydrochlorothiazide Valsartan & Hydrochlorothiazide Atenolol & Chlorthalidone Felodipine & Metroprolol Nadolol & Bendroflumethiazide Pindolol & Hydrochlorothiazide Propranolol HCL & Hydrochlorothiazide Timolol Maleate & Hydrochlorothiazide Felodipine & Ramipril Verapamil HCL & Trandolapril Chlorthalidone & Reserpine Methyldopa & Clorothiazide Methyldopa & Hydrochlorothiazide Reserpine & Hydrochlorothiazide Reserpine & Hydrochlorothiazide & Hydralazine HCL

ACCEPTED MANUSCRIPT Supplemental Table S2 Antihypertensive drug use among adults ≥ 66 years of age over time by age, sex, income, rurality, and cardiovascular related conditions in Ontario. 2001-2002

2003-2004

2005-2006

2007-2008

2009-2010

N (%) 2,823,965 1,351,741 (47.8%) 155,970 (10.6%)

N (%) 2,962,936 1,539,913 (51.9%) 151,823 (10.7%)

N (%) 3,102,558 1,721,717 (55.5%) 145,598 (10.5%)

N (%) 3,248,437 1,894,516 (58.3%) 130,556 (9.6%)

N (%) 3,409,599 2,041,886 (59.9%) 120,603 (8.8%)

N (%) 3,603,416 2,179,752 (60.5%) 112,882 (7.9%)

RI PT

Total population ≥66 yrs Prevalence of antihypertensive drug use New use of i antihypertensive drug

1999-2000

ii

i

AC C

EP

TE D

M AN U

SC

New antihypertensive drug use by characteristic, N (% of new users among each population strata) Age 66-70 yrs 51,684 49,523 47,427 42,935 40,682 (9.5%) (9.6%) (9.6%) (8.9%) (8.3%) 71-75 yrs 42,887 41,534 39,024 34,320 30,851 (10.6%) (10.8%) (10.6%) (9.9%) (9.1%) 76-80 yrs 31,837 31,646 29,690 25,904 23,454 (11.9%) (12.0%) (11.7%) (10.6%) (9.7%) 81-85 yrs 17,497 17,224 17,869 16,743 15,518 (12.2%) (12.1%) (11.9%) (10.8%) (9.8%) >86 yrs 12,065 11,896 11,588 10,654 10,098 (10.5) (10.1%) (9.7%) (8.6%) (7.4%) Sex Male 68,060 66,737 64,532 59,115 54,941 (10.3%) (10.4%) (10.3%) (9.6%) (8.8%) Female 87,910 85,086 81,066 71,441 65,662 (10.8%) (10.9%) (10.7%) (9.7%) (8.8%) Income Quintile First (lowest) 33,448 31,401 29,863 27,173 24,118 (11.2%) (11.1%) (10.8%) (9.9%) (8.9%) Second 34,403 32,799 31,297 27,769 25,126 (10.8%) (10.9%) (10.8%) (9.9%) (9.0%) Third 30,780 30,570 28,408 25,127 23,652 (10.5%) (10.8%) (10.6%) (9.8%) (9.2%) Fourth 27,768 27,857 27,443 24,602 23,576 (10.4%) (10.6%) (10.5%) (9.5%) (8.9%) Fifth (highest) 29,174 28,836 28,189 25,477 23,748 (10.0%) (10.0%) (10.0%) (9.1%) (8.2%) Geography Urban 132,356 129,756 125,287 112,825 104,229 (10.0%) (10.6%) (10.5%) (9.6%) (8.7%) Rural 23,540 21,997 20,241 17,681 16,329 (11.2%) (11.1%) (11.0%) (10.2%) (9.5%)

39,161 (7.5%) 28,391 (8.3%) 21,325 (8.8%) 14,055 (8.6%) 9,950 (6.4%) 51,685 (7.9%) 61,197 (7.9%) 21,644 (7.9%) 23,347 (8.2%) 21,976 (8.2%) 22,724 (8.1%) 22,834 (7.4%) 97,521 (7.8%) 15,316 (8.6%)

Prevalent antihypertensive drug users are excluded from the denominator when calculating the percentage of incident antihypertensive drug users. ii Percentages are calculated as the number of new antihypertensive users divided by the total population size for each strata. For example, for the fiscal years 1999-2000, 9.5% of all 66-70 year olds in Ontario were new users of antihypertensive drugs.

ACCEPTED MANUSCRIPT Supplemental Table S3 Characteristics associated with therapy and class persistence within two years of new antihypertensive drug prescription among adults ≥66 years of age in Ontario (n=420,148) Variable N (%)

Therapy Persistence (not discontinued) OR (95% CI) aOR*(95% CI)

Class persistence (not discontinued or switched) N (%) OR (95% CI) aOR (95% CI)

AC C

EP

TE D

M AN U

SC

RI PT

Drug class ACE 106344 (64.1) 1.63 (1.60-1.65) 1.67 (1.64-1.70) 56272 (33.9) 1.52 (1.49-1.55) 1.53 (1.50-1.56) ARB 12396 (63.7) 1.60 (1.55-1.65) 1.58 (1.53-1.63) 6968 (35.8) 1.65 (1.60-1.70) 1.66 (1.60-1.71) Beta 39096 (53.6) 1.06 (1.03-1.08) 1.07 (1.05-1.09) 19364 (26.6) 1.07 (1.05-1.09) 1.07 (1.05-1.10) Calcium 32619 (60.0) 1.37 (1.34-1.40) 1.41 (1.38-1.44) 17598 (32.4) 1.42 (1.38-1.45) 1.43 (1.39-1.46) Combination 5400 (58.5) 1.29 (1.23-1.34) 1.27 (1.22-1.33) 3203 (34.7) 1.57 (1.50-1.65) 1.60 (1.52-1.67) Diuretic 51436 (52.3) 1.00 1.00 24841 (25.3) 1.00 1.00 Age 66-70 yrs 86739 (58.9) 1.00 1.00 43043 (29.3) 1.00 1.00 71-75 yrs 66532 (59.9) 1.04 (1.02-1.06) 1.04 (1.03-1.06) 33245 (29.9) 1.03 (1.02-1.05) 1.04 (1.02-1.06) 76-80 yrs 48195 (58.6) 0.98 (0.97-0.99) 0.99 (0.97-1.01) 24877 (30.2) 1.05 (1.03-1.07) 1.06 (1.04-1.08) 81-85 yrs 27330 (57.5) 0.94 (0.92-0.96) 0.95 (0.93-0.97) 15047 (31.7) 1.12 (1.09-1.14) 1.13 (1.11-1.16) >86 yrs 18495 (57.5) 0.94 (0.92-0.96) 0.95 (0.92-0.97) 12034 (37.4) 1.44 (1.41-1.48) 1.47 (1.43-1.51) Sex Male 110080 (58.7) 0.99 (0.97-1.0) 0.97 (0.96-0.98) 58429 (31.1) 1.05 (1.04-1.07) 1.06 (1.05-1.08) Female 137211 (59.0) 1.00 1.00 69817 (30.0) 1.00 1.00 Income Quintile First (lowest) 47734 (55.9) 0.81 (0.80-0.83) 0.81 (0.80-0.83) 24712 (28.9) 0.88 (0.86-0.90) 0.87 (0.86-0.89) Second 52550 (58.4) 0.90 (0.88-0.92) 0.90 (0.88-0.92) 27288 (30.3) 0.94 (0.92-0.96) 0.94 (0.92-0.96) Third 49292 (59.5) 0.94 (0.93-0.96) 0.94 (0.92-0.96) 25582 (30.9) 0.96 (0.94-0.98) 0.97 (0.95-0.99) Fourth 47084 (60.0) 0.97 (0.95-0.98) 0.96 (0.94-0.98) 24330 (31.0) 0.97 (0.95-0.99) 0.97 (0.95-0.99) Fifth (highest) 49824 (60.9) 1.00 1.00 25918 (31.7) 1.00 1.00 Geography Urban 208384 (58.3) 0.84 (0.82-0.85) 0.83 (0.81-0.84) 107398 (30.0) 0.85 (0.84-0.87) 0.85 (0.83-0.86) Rural 38665 (62.5) 1.00 1.00 20718 (33.5) 1.00 1.00 Diabetes No 196431 (58.6) 1.00 1.00 101304 (30.2) 1.00 1.00 Yes 50860 (59.7) 1.05 (1.03-1.06) 1.06 (1.04-1.07) 26942 (31.6) 1.07 (1.05-1.09) 1.08 (1.06-1.10) Stroke No 239321 (58.7) 1.00 1.00 123152 (30.2) 1.00 1.00 Yes 7970 (64.1) 1.26 (1.21-1.30) 1.29 (1.24-1.34) 5094 (41.1) 1.60 (1.55-1.66) 1.55 (1.49-1.60) CHF No 240116 (58.8) 1.00 1.00 123585 (30.3) 1.00 1.00 Yes 7175 (60.8) 1.08 (1.04-1.13) 1.14 (1.09-1.18) 4661 (39.4) 1.50 (1.45-1.56) 1.42 (1.37-1.47) MI No 237533 (58.8) 1.00 1.00 122888 (30.4) 1.00 1.00 Yes 9758 (60.8) 1.09 (1.05-1.12) 1.12 (1.09-1.16) 5358 (33.4) 1.15 (1.11-1.19) 1.12 (1.08-1.16) Cohort year 1999/2000 60253 (55.8) 1.00 1.00 31495 (29.2) 1.00 1.00 2001/2002 60993 (60.3) 1.20 (1.18-1.23) 1.20 (1.18-1.22) 31486 (31.1) 1.10 (1.08-1.12) 1.10 (1.08-1.12) 2003/2004 53898 (59.1) 1.14 (1.12-1.16) 1.14 (1.12-1.16) 26943 (29.5) 1.02 (1.00-1.04) 1.02 (1.00-1.04) 2005/2006 45873 (59.9) 1.18 (1.16-1.20) 1.18 (1.16-1.20) 23843 (31.1) 1.10 (1.08-1.12) 1.10 (1.08-1.13) 2007/2008 26274 (60.9) 1.24 (1.21-1.27) 1.23 (1.20-1.26) 14479 (33.6) 1.23 (1.20-1.26) 1.24 (1.21-1.27) ADG 0-4 13786 (59.7) 1.00 1.00 5961 (25.8) 1.00 1.00 5-9 32071 (59.9) 1.01 (0.97-1.04) 1.01 (0.98-1.04) 15817 (29.5) 1.20 (1.16-1.25) 1.21 (1.17-1.26) 10-14 78885 (59.8) 1.01 (0.98-1.04) 1.00 (0.97-1.03) 41193 (31.3) 1.31 (1.27-1.35) 1.30 (1.26-1.35) 15-19 92353 (58.5) 0.95 (0.93-0.98) 0.94 (0.91-0.97) 48866 (31.0) 1.29 (1.25-1.33) 1.26 (1.22-1.30) ≥20 30196 (56.2) 0.86 (0.8-0.89) 0.85 (0.82-0.88) 16409 (30.5) 1.26 (1.22-1.31) 1.20 (1.16-1.24) Drugs in year prior to initiation of antihypertensive ≤3 73916 (59.9) 1.00 1.00 35821 (29.0) 1.00 1.00 4-6 76409 (59.8) 0.99 (0.98-1.01) 1.00 (0.98-1.01) 39515 (30.9) 1.09 (1.08-1.11) 1.09 (1.07-1.11) ≥7 96966 (57.4) 0.90 (0.89-0.91) 0.92 (0.90-0.93) 52910 (31.3) 1.11 (1.10-1.13) 1.10 (1.08-1.12) *Multivariate adjusted odds ratios (aOR) from logistic regression, adjusted for age, sex, income, geography, and cohort year. ADG=Ambulatory Diagnostic Groups

ACCEPTED MANUSCRIPT Supplemental Table S4 Characteristics associated with therapy and class persistence within two years of new antihypertensive drug prescription among adults ≥66 years of age in Ontario among individuals with no comorbid conditions (n=309,084).

N (%)

i

Class persistence (not discontinued or switched) N (%) OR (95% CI) aOR (95% CI)

1.70 (1.67-1.74) 1.62 (1.56-1.68) 1.00 (0.98-1.03) 1.32 (1.29-1.35) 1.26 (1.21-1.33) 1.00

1.75 (1.72-1.78) 1.57 (1.51-1.63) 1.02 (1.00-1.04) 1.36 (1.33-1.40) 1.24 (1.18-1.30) 1.00

31849 (32.5) 5207 (35.7) 15242 (26.5) 14476 (32.6) 2710 (35.5) 22253 (25.6)

63527 (58.7) 49010 (59.6) 35534 (58.2) 19788 (56.9) 12728 (55.9)

1.00 1.04 (1.02-1.06) 0.98 (0.96-1.00) 0.93 (0.91-0.95) 0.90 (0.87-0.92)

1.00 1.05 (1.03-1.07) 0.99 (0.97-1.01) 0.94 (0.92-0.96) 0.90 (0.88-0.93)

31270 (28.9) 24098 (29.3) 17894 (29.3) 10486 (30.1) 7989 (35.1)

74015 (58.1) 106572 (58.7)

0.98 (0.96-0.99) 1.00

0.96 (0.94-0.97) 1.00

33257 (55.3) 37725 (57.9) 36045 (59.0) 34918 (59.6) 38056 (60.4)

0.81 (0.80-0.83) 0.90 (0.88-0.92) 0.95 (0.92-0.97) 0.97 (0.95-0.99) 1.00

0.81 (0.79-0.83) 0.90 (0.88-0.92) 0.94 (0.92-0.97) 0.97 (0.94-0.99) 1.00

152197 (57.9) 28198 (61.9)

0.85 (0.83-0.86) 1.00

41900 (54.5) 43955 (59.8) 40408 (58.8) 34402 (59.8) 19922 (61.3)

1.40 (1.38-1.43) 1.59 (1.54-1.66) 1.05 (1.02-1.08) 1.42 (1.38-1.45) 1.60 (1.52-1.68)

1.00 1.02 (1.00-1.04) 1.02 (1.00-1.05) 1.06 (1.04-1.09) 1.33 (1.29-1.37)

1.00 1.03 (1.01-1.05) 1.03 (1.01-1.06) 1.07 (1.05-1.10) 1.35 (1.31-1.40)

38197 (29.9) 53540 (29.5)

1.02 (1.01-1.04) 1.00

1.02 (1.01-1.04) 1.00

16896 (28.1) 19167 (29.4) 18333 (30.0) 17646 (30.1) 19415 (30.8)

0.88 (0.86-0.90) 0.94 (0.91-0.96) 0.96 (0.94-0.99) 0.97 (0.95-0.99) 1.00

0.88 (0.85-0.90) 0.93 (0.91-0.96) 0.96 (0.94-0.99) 0.97 (0.95-0.99) 1.00

0.83 (0.82-0.85) 1.00

76895 (29.2) 14743 (32.4)

0.86 (0.85-0.88) 1.00

0.87 (0.84-0.87) 1.00

1.00 1.24 (1.21-.127) 1.19 (1.17-1.22) 1.24 (1.21-1.27) 1.32 (1.29-1.35)

1.00 1.24 (1.21-1.26) 1.19 (1.16-1.21) 1.24 (1.21-1.26) 1.31 (1.28-1.35)

21413 (27.9) 22184 (30.2) 19768 (28.8) 17505 (30.4) 10867 (33.4)

1.00 1.12 (1.09-1.14) 1.05 (1.02-1.07) 1.13 (1.11-1.16) 1.30 (1.26-1.34)

1.00 1.12 (1.09-1.15) 1.05 (1.02-1.07) 1.13 (1.10-1.16) 1.29 (1.26-1.34)

1.00 1.00 (0.96-1.03) 1.00 (0.97-1.03) 0.94 (0.91-0.97) 0.84 (0.81-0.87)

1.00 1.00 (0.97-1.04) 1.00 (0.96-1.03) 0.92 (0.89-0.95) 0.82 (0.79-0.85)

4972 (25.9) 12025 (28.9) 30368 (30.6) 34279 (30.1) 10093 (28.8)

1.00 1.16 (1.12-1.21) 1.26 (1.22-1.31) 1.23 (1.19-1.28) 1.16 (1.11-1.20)

1.00 1.18 (1.13-1.23) 1.26 (1.22-1.31) 1.21 (1.17-1.25) 1.10 (1.06-1.15)

1.00 0.98 (0.96-1.00) 0.86 (0.84-0.87)

1.00 0.98 (0.97-1.00) 0.87 (0.86-0.89)

30733 (28.9) 29115 (30.3) 31891 (29.8)

1.00 1.07 (1.05-1.09) 1.04 (1.02-1.06)

1.00 1.06 (1.04-1.09) 1.04 (1.02-1.06)

63545 (59.9) 57020 (59.4) 60022 (56.2)

M AN U

TE D

EP

11414 (59.5) 24716 (59.4) 59085 (59.5) 65983 (57.9) 16389 (55.3)

1.40 (1.37-1.43) 1.61 (1.55-1.68) 1.04 (1.02-1.07) 1.41 (1.37-1.44) 1.60 (1.52-1.68) 1.00

SC

64179 (65.5) 9368 (64.3) 30400 (52.8) 26425 (59.6) 4459 (58.5) 45756 (52.7)

AC C

Drug class ACE ARB Beta Calcium Combination Diuretic Age 66-70 yrs 71-75 yrs 76-80 yrs 81-85 yrs >86 yrs Sex Male Female Income Quintile First (lowest) Second Third Fourth Fifth (highest) Geography Urban Rural Cohort year 1999/2000 2001/2002 2003/2004 2005/2006 2007/2008 ADG 0-4 5-9 10-14 15-19 ≥20 Drugs in year prior to initiation of antihypertensive ≤3 4-6 ≥7

Therapy Persistence (not discontinued) OR (95% CI) aORi (95% CI)

RI PT

Variable

Multivariate adjusted odds ratios (aOR) from logistic regression, adjusted for age, sex, income, geography, and cohort year. ADG=Adjusted Diagnostic Groups