use of combination antihypertensive therapy initiation in older americans without prevalent...

Use of Combination Antihypertensive Therapy Initiation inOlder Americans without Prevalent Cardiovascular Disease

Xiaojuan Li, MSPH,* Wendy Camelo Castillo, MD, PhD,* Til St€urmer, MD, PhD,* Virginia Pate,MS,* Christine L. Gray, MPH,* Ross J. Simpson, Jr., MD, PhD,† Soko Setoguchi, MD, Dr PH,‡

Laura C. Hanson, MD,§ and Michele Jonsson Funk, PhD*

OBJECTIVES: To describe new users of antihypertensivemedications and identify predictors of combination ther-apy initiation in older Americans.

DESIGN: Retrospective observational cohort study.

SETTING: Population-based study using U.S. Medicarefee-for-service healthcare claims (2007–2010).

PARTICIPANTS: Medicare beneficiaries aged 65 andolder with no recent diagnoses, procedures, or medicationsfor cardiovascular disease who newly initiated an antihy-pertensive therapy (n = 275,493; 210,605 initiated mono-therapy, 64,888 initiated combination therapy).

MEASUREMENTS: Multivariable Poisson regression wasused to assess factors associated with initiation ofcombination therapy versus monotherapy, including partic-ipant characteristics, prescriber characteristics, and partici-pant encounters with the healthcare system.

RESULTS: Initiation of combination therapy increasedfrom 21.9% in 2007 to 24.7% in 2010. The most fre-quently initiated combinations were angiotensin-convertingenzyme inhibitors with thiazide (29.7%) and angiotensin IIreceptor antagonists with thiazide (18.7%). Blacks (preva-lence ratio (PR) = 1.48, 95% confidence interval(CI) = 1.45–1.51 vs whites), individuals seeing a generalist(PR = 1.10, 95% CI = 1.07–1.14), individuals seeing morethan one doctor (PR = 3.38, 95% CI = 3.33–3.44), andparticipants with no pharmacy claims in the previous6 months (PR = 1.34, 95% CI = 1.30–1.37 vs ≥3 uniquedrug classes) were more likely to initiate combinationtherapy, whereas those who had more outpatient visitsin the previous 12 months were less likely to initiate

combination therapy (per five visits, PR = 0.82, 95%CI = 0.80–0.83).

CONCLUSION: Nearly one in four new users of antihy-pertensive medications aged 65 and older started treat-ment with combination therapy. Blacks, individuals livingin the south, and those with fewer outpatient physicianoffice visits were more likely to initiate combinationtherapy. Further research is needed to determine whetherthis approach to managing hypertension is being welltargeted to individuals who will require combination treat-ment. J Am Geriatr Soc 62:1729–1735, 2014.

Key words: antihypertensive agents; combination ther-apy; epidemiology; initial treatment; Medicare benefi-ciaries

The prevalence of hypertension is high in older Ameri-cans, affecting more than 65% of people aged 65 and

older.1 The incidence of hypertension rises with age, andindividuals who were normotensive at age 55 have anapproximately 90% lifetime risk of hypertension.2 Hyper-tension is an important risk factor for cardiovascular dis-ease (CVD) and a leading risk factor for premature deathand loss of disability-adjusted life-years in the UnitedStates.3 Because the population is aging, the importance ofmanaging hypertension in older adults continues toincrease in terms of the effect on public health.

Advances in drug therapy have made a wide variety ofblood pressure–lowering antihypertensive agents available.Clinical trials have demonstrated the benefit of antihyper-tensive medications on cardiovascular events4,5 andaffirmed the benefit of treating hypertension even in indi-viduals aged 80 and older.6,7 Most single antihypertensiveagents can reduce blood pressure by 10% to 15%, but themajority of individuals ultimately require two or moreagents to achieve effective control.8

Of the many options for antihypertensive therapy,combination therapy has been gaining more attention.

From the *Department of Epidemiology; †Division of Cardiology, Schoolof Medicine, University of North Carolina at Chapel Hill, Chapel Hill,North Carolina; ‡Duke Clinical Research Institute, Durham, NorthCarolina; and §Division of Geriatric Medicine, School of Medicine,University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Address correspondence to Michele Jonsson Funk, Department ofEpidemiology, 2103A McGavran-Greenberg Hall, Gillings School ofGlobal Public Health, CB #7435, University of North Carolina at ChapelHill, Chapel Hill, NC 27599. E-mail: [email protected]

DOI: 10.1111/jgs.12976

JAGS 62:1729–1735, 2014

© 2014, Copyright the Authors

Journal compilation © 2014, The American Geriatrics Society 0002-8614/14/$15.00

Combination therapy is defined as treatment with two ormore agents administrated separately or in a fixed-dosecombination pill.4,5 Initiating treatment with combinationtherapy has potential benefits including a greater rate ofblood pressure control and, in the case of fixed-dose com-bination pills, simplified treatment regimens and betteradherence.9–11 Potential disadvantages include greater costfor some combinations, individual perceptions of beingsicker when prescribed more medications, risk of adverseeffects, drug burden, and lower adherence rates if two pillsare required.12 Given these complex risk–benefit trade-offs,initiation of antihypertensive treatment with combinationversus monotherapy remains controversial.11–15

Because the evidence and guidelines are continuouslyevolving, little is known about the initial management ofhypertension for older adults in the real-world setting ofclinical practice. Furthermore, individual and health care–related factors associated with initiation of combinationare not well understood. The objectives of the currentstudy were to describe the initial drug management ofhypertension in a large cohort of older Americans withoutprevious cardiovascular conditions and to identify factorsassociated with the initiation of combination therapyversus monotherapy.

METHODS

Data Sources and Study Population

Using a deidentified random 20% sample of Medicare ben-eficiaries aged 65 and older with fee-for-service Part A, B,and D coverage simultaneously in at least 1 calendarmonth between 2007 and 2010, a cohort of individualswho initiated antihypertensive therapy between July 1,2007, and December 31, 2010, were identified. Eligiblenew users had been continuously enrolled in Parts A and Bfor at least 1 year and in Part D for at least 6 months.Antihypertensive drug classes in this study included angio-tensin-converting enzyme inhibitors (ACEIs), angiotensin IIreceptor antagonists (ARBs), beta-blockers, calcium chan-nel blockers (CCBs), and thiazide. New users of antihyper-tensive medications were defined as individuals who filleda prescription claim for any antihypertensive formulationof interest after 6 antihypertensive prescription–freemonths. The index date was defined as the fill date of anantihypertensive prescription. The index period rangedfrom the index date through the 14th day after the indexdate. Eligible new users who received more than one classof antihypertensive drug in the form of fixed-dose combi-nation pills or multiple single-drug combinations withinthe index period were defined as combination therapy ini-tiators. Individuals with one unique antihypertensive drugclass dispensed during the index period were defined asmonotherapy initiators. Individual demographic character-istics and clinical conditions were characterized based onoutpatient and inpatient claims occurring in the 12-monthperiod before the index date and pharmacy claims duringthe 6 months before the index date.

To limit the study population to individuals who initi-ated antihypertensive medications without recent claims forCVD-related diagnoses or treatments, individuals who hadany code for stroke, heart failure, myocardial infarction,

angina pectoris, atrial fibrillation, revascularization, orother CVD during the 12 months preceding the index datewere excluded. Individuals who had any prescription claimfor warfarin, cardiac glycosides, antiplatelet drugs, nitrates,or antiarrhythmic medications during the 6 months preced-ing the index date were also excluded. The institutionalreview board at the University of North Carolina at ChapelHill approved this study.

Statistical Analyses

New users in the final study cohort were categorized basedon the index drug classes. The prevalence ratios (PRs) and95% confidence intervals (CIs) for initiating combinationtherapy versus monotherapy were estimated using multi-variable Poisson regression.16 Potential predictors of com-bination versus monotherapy initiation includeddemographic characteristics, comorbidities, procedures,number of prescribers for antihypertensive medications,prescriber specialty, number of comedications during the6 months before the index date, number of outpatient vis-its, and days of hospitalization. All analyses were con-ducted using SAS version 9.3 (SAS Institute, Inc., Cary,NC).

RESULTS

Between July 1, 2007, and December 31, 2010, 275,493Medicare beneficiaries without recent claims for CVD initi-ating an antihypertensive after at least 6 antihypertensiveprescription–free months were identified. As shown inTable 1, the median age of participants at initiation was73 (interquartile range 69–79). They were predominatelyfemale (67.0%) and white (79.8%); blacks accounted for10.1% of the population. A large proportion (40.4%)were from the South, 18.9% had type 2 diabetes mellitus,55.3% had hyperlipidemia, and a cardiologist hadprescribed antihypertensive medications for 4.9%.

Of all new antihypertensive users, 23.6%(n = 64,888) initiated combination therapy. They weremore likely to be black, younger, and from the South, thaninitiators of monotherapy. Counties with 30% or morecombination therapy initiation were concentrated in theSoutheast. Combination therapy users had fewer outpa-tient office visits in the previous 12 months and fewer dif-ferent comedication drug classes. A generalist was morelikely to prescribe their antihypertensive medications.

The most commonly prescribed initial monotherapydrug class was ACEIs (25.2%), followed by thiazide(15.4%), whereas the most frequently initiated combina-tions were ACEIs/thiazide (7.0%), ARBs/thiazide (4.4%),and ACEIs/CCBs (2.3%). The proportion of participantsbeing started on combination therapy increased slightly,from 21.9% in 2007 to 24.7% in 2010. The examinationof trends of initial first-line antihypertensive therapy overthe study period showed changes in the frequency of use(Appendix S1). Small increases were observed for the useof ACEIs/thiazide, whereas the use of ARBs/thiazidedecreased slightly. Of monotherapy options, the propor-tion of people initiating ACEIs and CCBs increased,whereas the use of beta-blockers and thiazide decreased.The use of ARBs was stable.

1730 LI ET AL. SEPTEMBER 2014–VOL. 62, NO. 9 JAGS

Table 1. Characteristics of New Users of Antihypertensive Medications in Medicare Beneficiaries with NoEvidence of Cardiovascular Disease, United States, 2007–2010

Characteristic All, n = 275,493 Monotherapy, n = 210,605, 76.4% Combination, n = 64,888, 23.6%

Female, % 67.0 67.1 66.6Race or ethnicity, %a

White 79.8 82.0 72.9Black 10.1 8.2 16.0Hispanic 3.9 3.7 4.7Other 6.2 6.1 6.4Age,b median (IQR) 73 (69–79) 73 (69–80) 73 (69–79)Age, %66–69 28.8 28.3 30.470–74 27.5 27.1 28.775–79 18.8 18.9 18.580–84 13.4 13.8 12.485–89 7.6 7.8 6.8≥90 3.9 4.1 3.2Region, %Midwest 23.8 24.0 23.2Northeast 16.0 16.5 14.7South 40.4 39.2 44.1West 19.3 19.9 17.5U.S. territories 0.4 0.4 0.5Number of outpatient physician visits in previous12 months, median (IQR)

5 (2–8) 5 (2–9) 4 (1–7)

Number of outpatient physician visits in previous12 months, %0 9.4 8.1 13.51–3 30.1 28.3 36.24–7 30.7 31.7 27.8≥8 29.7 31.9 22.6Comorbidities, %c

Chronic kidney diseases 3.3 3.4 3.2Type 2 diabetes mellitus 18.9 18.9 18.8Hyperlipidemia 55.3 56.2 52.5Chronic obstructive pulmonary disease 7.4 8.0 5.7Tobacco use 6.0 6.3 5.0Procedures, %Electrocardiography 8.1 8.4 7.0Lipid test 44.1 45.1 41.0Stress test 3.9 4.2 3.1Number of prescribers, median (IQR) 1 (1–1) 1 (1–1) 1 (1–1)Prescriber specialty, %d

Cardiologist 4.9 4.8 5.3Other internist 34.7 34.3 35.8Generalist 34.3 32.9 38.6Other medical doctore 7.2 8.5 2.9Nurse practitioner or physician assistant 5.7 5.6 5.7Other provider 0.8 0.9 0.3Unknown 12.5 12.9 11.5Baseline medicationsf

Number of classes0 44.3 41.6 52.71 27.5 28.4 24.82 16.0 16.9 13.2≥3 12.2 13.1 9.3

AnalgesicsNonsteroidal anti-inflammatory drugs 12.0 12.4 10.7Opioids 11.3 11.7 9.8Paracetamol 9.1 9.5 7.8

AntidiabeticsInsulin 2.5 2.5 2.5Oral antidiabetics 8.6 8.8 7.9

Mental health

(Continued)

JAGS SEPTEMBER 2014–VOL. 62, NO. 9 COMBINATION ANTIHYPERTENSIVE THERAPY INITIATION 1731

In multivariable analyses, no factors were found tobe strongly associated (PR > 4.00) with initiation of com-bination versus monotherapy, but several were modestlyassociated with initiation of combination therapy afteradjusting for other characteristics (Table 2). Of statisti-cally significant predictors, the strongest were race,region, prescriber specialty, number of prescribers, outpa-tient physician visits, and number of comedications.Blacks were more likely to be prescribed a combinationtherapy than whites (PR = 1.48, 95% CI = 1.45–1.51).The effect was attenuated from a crude association(PR = 1.75, 95% CI = 1.72–1.78) when race and ethnic-ity was the only predictor considered in the model. Indivi-duals residing in the South, seeing more prescribers fromdifferent specialties, seeing a generalist, or with no phar-macy claims in the previous 6 months were also morelikely to initiate combination therapy. Individuals whohad any hospital stay or had more outpatient visits in thelast 12 months were less likely to initiate combinationtherapy. Having had a lipid test or a stress test was alsoassociated with less likelihood of combination therapyinitiation.

After controlling for other factors, the year of initia-tion of antihypertensive therapy remained modestly predic-tive of combination therapy use, indicating that changes inthe population did not fully explain the observed increasein prevalence. Participants with type 2 diabetes mellitus orhyperlipidemia were more likely to initiate combinationtherapy, but participants with a code for tobacco use orchronic obstructive pulmonary disease were less likely.

DISCUSSION

In this large, national sample of older Americans withoutrecent claims related to CVD who began antihypertensive

treatment, one in four participants initiated combinationtherapy. The use of combination therapy as first-line treat-ment increased slightly from 2007 to 2010. Nationally,counties in which at least 30% of new users received com-bination therapy were concentrated in the Southeast andoverlapped, to some extent, with the “stroke belt,” wherehigher rates of stroke and other CVDs cluster.18

In participants initiating combination therapy, thethree most-frequent combinations were ACEIs/thiazide,ARBs/thiazide, and ACEIs/CCBs. These combinations havedemonstrated synergistic or complementary effects: ACEIs/thiazide,19 ARBs/thiazide,20 and ACEIs/CCBs21 and havebeen recommended as preferred choice of two-drug combi-nations.8 They are also available in single-pill form, makingthem easier to manage and possibly reducing out-of-pocketcosts.

The choice of antihypertensive therapy is normallybased on blood pressure, stage of hypertension, age, sex,race or ethnicity, coexisting conditions, and the responseto previously used drugs, including the presence or absenceof adverse reactions.15 In this population of individualsstarting antihypertensive medications, with blood pressureand stage of hypertension unobserved, the strongest predic-tors of combination therapy were black race, number ofcomedication classes, and living in the South. Thesefindings are consistent with those of other researchstudies.14,22 Blacks are more likely to have Stage 2 hyper-tension, which typically requires two or more agents toachieve blood pressure control.4,23,24 Chronic conditionsare common in older adults, with more than one-third ofMedicare beneficiaries having four or more chronic condi-tions,25 and many of these require medication. Concernsabout additional pill burden leading to difficulty withadherence and potential drug interactions may underlie theinverse association between the number of other

Table 1 (Contd.)

Characteristic All, n = 275,493 Monotherapy, n = 210,605, 76.4% Combination, n = 64,888, 23.6%

Antidementia 2.7 2.9 1.8Antidepressants 11.8 12.7 8.6Antiparkinson 1.7 1.9 1.1Anxiolytics 2.3 2.4 1.8Hypnotics 3.8 4.1 3.0

OtherAntiasthma 8.4 8.9 6.7Hormone replacement therapy 3.9 4.3 2.9Osteoporosis treatment 7.5 8.2 5.2Statin 17.3 18.2 14.4

IQR = interquartile range.

From a cohort of 513,669 new users of antihypertensive medications, 15,785 who initiated alpha blockers) and 222,391 who had claims for cardiovascu-

lar-related diagnoses, procedures, or medications were excluded.a From Medicare denominator file.b At time of initiation.c Clinical conditions were identified using definitions consisting of diagnoses with relevant International Classification of Diseases, Ninth Revision, Clinical

Medication codes and procedures with Current Procedural Terminology codes.d Information on prescriber specialty was extracted from the pharmacy claims file. For individuals who initiated combination therapy and had multiple

prescribers during the index period, the specialty type of the second prescriber was used.e Includes physicians practicing in emergency medicine, dermatology, otolaryngology, pain medicine, pathology, pediatrics, psychiatry and neurology, and

surgery.f Data regarding prescription medication fills were extracted from Part D prescription drug event files using a crosswalk between the Anatomical Therapeu-

tic Chemical identifier and the National Drug Codes adapted from First DataBank’s National Drug Data File Plus.17


medications an individual uses and the initiation of combi-nation (rather than mono-) therapy.

In addition to demographic characteristics, individualencounters with the healthcare system were associatedwith initiation of combination therapy. Individuals seeingmultiple prescribers were more than twice as likely asthose seeing one prescriber to start on a combination ther-apy. Of participants initiating combination therapy, 8.2%received different prescriptions within 14 days from differ-ent prescribers. Although the use of another drug class inthe index period might be due to adverse side effects ofthe initial therapy, it is unlikely, because most of theseparticipants filled another prescription of the initial ther-apy after adding the second drug class. It is possible thatthe initial therapy was not sufficient to reach target bloodpressure level and that additional drug classes weredeemed necessary. Alternatively, concurrent initiation mayhave been inadvertent if the providers were not aware ofother interactions with the healthcare system.

These findings should be interpreted in light of theinherent limitations of claims data. These data do notinclude blood pressure levels or stage of hypertension,which should affect choice of first-line treatment.4,15,23

Because the indication for the prescription is not reportedon the claim, it might have been that some individualswho were identified as new users of antihypertensive medi-cations were being treated for reasons other than bloodpressure control. The effect of this was limited by exclud-ing individuals who were likely to be prescribed antihyper-tensive medications for secondary prevention and newusers of antihypertensive medications with known primarytargets other than blood pressure control (e.g., alphablockers). Third, Medicare pharmacy drug claims captureonly dispensed prescriptions that insurance reimburses. Itis possible that the cohort included individuals who werenot truly new initiators because they were previously pre-scribed an antihypertensive medication or were currentusers who recently changed from paying out of pocket tousing the Medicare drug benefit,26,27 but it is unlikely thatthis adversely affected the interpretation of the findings.Moreover, Medicare data, as administrative claims data,are lacking information on alternative approaches to man-aging hypertension, with some being used as complemen-tary to these pharmaceutical agents. Last, these findingswould not generalize to other populations, such as thosewith recent cardiovascular complications. This was ahealthier cohort than Medicare beneficiaries in general.For instance, the average number of comedication classeswas lower than that reported in other studies of elderlyadults.28 Given that individuals with any prevalent use ofcardiovascular drugs (the top prescribed therapeutic classin elderly adults29) were excluded, this is expected.

This study also has several strengths. The existing lit-erature on the “real world” practice of antihypertensivemanagement in older Americans is restricted to regional12

and specific groups of individuals.22 Using Medicareclaims, the largest nationally representative data source inthe United States, it was possible to examine the use ofantihypertensive therapy and provide an update of theexisting literature on current clinical practice in olderadults on a large scale. Unlike data from electronic medi-cal records, dispensed prescriptions represent medications

Table 2. Determinants of Combination or Monothera-py Antihypertensive Therapy Initiation in MedicareBeneficiaries with No Evidence of CardiovascularDisease, United States, 2007–2010

Determinant

Unadjusteda Multivariable Adjustedb

Prevalence Ratio

(95% Confidence Interval)

Year (reference 2007)2008 1.05 (1.02–1.07) 1.03 (1.01–1.06)2009 1.09 (1.06–1.11) 1.06 (1.04–1.09)2010 1.12 (1.10–1.15) 1.08 (1.06–1.11)Female (reference male) 0.98 (0.97–1.00) 1.03 (1.02–1.05)Race and ethnicity (reference white)c

Black 1.75 (1.72–1.78) 1.48 (1.45–1.51)Hispanic 1.30 (1.26–1.34) 1.21 (1.17–1.26)Other 1.14 (1.11–1.17) 1.12 (1.09–1.15)Aged per 5 years older 0.96 (0.95–0.96) 0.96 (0.95–0.96)Region (reference west)Midwest 1.08 (1.06–1.10) 1.08 (1.06–1.11)Northeast 1.01 (0.99–1.03) 1.03 (1.00–1.05)South 1.21 (1.18–1.23) 1.18 (1.16–1.21)U.S. territories 1.30 (1.19–1.42) 1.25 (1.11–1.40)Hospitalizations in the last 12 months (reference none)≥1 0.84 (0.81–0.86) 0.94 (0.91–0.97)Per 1 more day in thehospitale

1.00 (0.99–1.00) 1.00 (0.99–1.00)

Outpatient visits (reference none)≥1 in last 30 days 0.90 (0.89–0.91) 0.85 (0.83–0.86)Per five visits in last12 monthsf

0.70 (0.69–0.71) 0.82 (0.80–0.83)

ComorbiditiesChronic kidneydiseases

0.96 (0.92–1.00) 1.00 (0.96–1.04)

Type 2 diabetesmellitus

1.00 (0.98–1.02) 1.06 (1.04–1.08)

Hyperlipidemia 0.89 (0.88–0.90) 1.06 (1.04–1.08)Chronic obstructivepulmonary disease

0.75 (0.73–0.77) 0.92 (0.89–0.95)

Tobacco use 0.83 (0.80–0.85) 0.93 (0.90–0.96)ProcedureElectrocardiography 0.86 (0.83–0.88) 1.00 (0.97–1.03)Lipid test 0.88 (0.87–0.89) 0.94 (0.93–0.96)Stress test 0.77 (0.74–0.81) 0.89 (0.85–0.93)≥2 prescribers(reference one)

3.54 (3.49–3.59) 3.38 (3.33–3.44)

Prescriber specialty (reference cardiologist)Other internist 0.96 (0.93–0.99) 1.03 (1.00–1.06)Other medical doctorg 0.38 (0.36–0.40) 0.39 (0.37–0.41)Generalist 1.05 (1.02–1.09) 1.10 (1.07–1.14)Nurse practitioner orphysician assistant

0.94 (0.90–0.98) 0.98 (0.94–1.02)

Other provider 0.33 (0.29–0.38) 0.31 (0.27–0.35)Number of comedication classes (reference ≥3)0 1.57 (1.53–1.60) 1.34 (1.30–1.37)1 1.18 (1.15–1.21) 1.11 (1.08–1.14)2 1.09 (1.05–1.12) 1.05 (1.02–1.08)

a Poisson models included only the variables under consideration.b Poisson models adjusted for all variables listed in table.c From Medicare denominator file.d At time of initiation, included as a linear continuous variable in the model.e Modeled as a continuous variable with a linear term and a quadratic term.f Modeled as a continuous variable with a linear term, a quadratic term

and a cubic term.g Includes physicians practicing in emergency medicine, dermatology, oto-

laryngology, pain medicine, pathology, pediatrics, psychiatry, neurology,

and surgery.


that participants received. With extensive informationcaptured in the claims, it was possible to study new usersof antihypertensive medications and assess the relation-ship between combination therapy as initial treatmentand participant demographic characteristics, comorbidi-ties, comedications, encounters with the healthcaresystem, and prescriber characteristics. Some of the predic-tors, such as comorbidities and prescriber characteristics,were lacking in previous studies.12,22 With potential con-founding controlled for using this multivariable regres-sion, this study identifies several important predictors ofchoice of initial antihypertensive treatment among manypotential factors.

In summary, nearly one in four new users of antihy-pertensive medications aged 65 and older started treatmentwith combination therapy. Blacks were more likely to initi-ate combination therapy. More research is needed to deter-mine whether this approach to managing hypertension isbeing well targeted and results in better outcomes.

ACKNOWLEDGMENTS

The authors thank Dr. Stacie B. Dusetzina for helpfulcomments. A poster presentation based on an abstract ofthe study was presented at the 29th International Confer-ence on Pharmacoepidemiology and Therapeutic RiskManagement, August 25–28, 2013, Montreal, Canada.

Conflict of Interest: XL is a recipient of the Amgen Pre-doctoral Fellowship in Pharmacoepidemiology. WCC is ajoint postdoctoral fellow in the Department of Environmen-tal Health Sciences, Johns Hopkins Bloomberg School ofPublic Health, Baltimore, Maryland, and the Center forHealth Research, Geisinger Health System, Danville,Pennsylvania. RS has received research support from Merckand honoraria from Merck and Pfizer. Salary support isprovided by investigator-initiated grants from Sanofi (TS,VP), Merck (TS, VP) and Amgen (VP), National Instituteon Aging (NIA) (LCH, TS, R01 AG023178), Agency forHealthcare Research and Quality (AHRQ) (MJF,K02HS017950), PCORI (TS, MJF, VP, PFA 12001), andJohnson and Johnson (SS). SS serves on advisory boards forNovartis and Affymax and is supported by AHRQ Mid-Career Awards. MJF and TS receive salary support fromthe Center for Pharmacoepidemiology, which is currentlyfunded by GlaxoSmithKline, UCB Biosciences, and Merck.

This project was supported by a competitive GillingsInnovation Laboratory award (GIL 200811.0010) fromthe University of North Carolina Gillings School of GlobalPublic Health, Grant K02HS017950 from AHRQ, andR01 AG023178 from the NIA. The content is solely theresponsibility of the authors and does not necessarily rep-resent the official views of AHRQ.

Author Contributions: Study concept and design: Li,Camelo Castillo, St€urmer, Gray, Jonsson Funk. Dataanalysis: Li, Pate. Interpretation of data: Li, CameloCastillo, St€urmer, Simpson, Setoguchi, Hanson, JonssonFunk. Preparation of manuscript: Li, Jonsson Funk. Criti-cal revision of the manuscript for important intellectualcontent: Li, Camelo Castillo, St€urmer, Gray, Simpson, Se-toguchi, Hanson, Jonsson Funk.

Sponsor’s Role: The grant sponsors had no input onthe design, methods, analysis, or preparation of this paper.

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SUPPORTING INFORMATION

Additional Supporting Information may be found in theonline version of this article:

Appendix S1. Trend of Initiation of AntihypertensiveMedications According to Drug Class in Medicare Benefi-ciaries with No Evidence of Cardiovascular Disease, Uni-ted States, 2007–2010.

Please note: Wiley-Blackwell is not responsible for thecontent, accuracy, errors, or functionality of any support-ing materials supplied by the authors. Any queries (otherthan missing material) should be directed to the corre-sponding author for the article.


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