Risk of Thiazide-Induced Metabolic Adverse Events in OlderAdults

Anil N. Makam, MD, MAS,* W. John Boscardin, PhD, Yinghui Miao, MPH, andMichael A. Steinman, MD

OBJECTIVES: To evaluate the risk and predictors of thia-zide-induced adverse events (AEs) in multimorbid olderadults in real-world clinical settings.

DESIGN: Observational cohort study.

SETTING: National Veterans Affairs data from 2007 to2008.

PARTICIPANTS: Veterans aged 65 and older newly pre-scribed a thiazide (N = 1,060) compared with propensity-matched nonusers of antihypertensive medications(N = 1,060).

MEASUREMENTS: The primary outcome was a compos-ite of metabolic AEs defined as sodium less than 135 mEq/L,potassium less than 3.5 mEq/L, or a decrease in the esti-mated glomerular filtration rate (eGFR) of more than 25%from the baseline rate. Secondary outcomes included sev-ere AEs (sodium

examining the metabolic risk of thiazides in this popula-tion is unlikely to be forthcoming. Therefore, nationalobservational data using propensity scoring techniqueswere used to evaluate the risk of thiazide-induced meta-bolic AEs in older adults, predictors of this risk, and labo-ratory surveillance patterns after thiazide initiation.

METHODS

Data Sources and Study Population

An observational cohort study was conducted usingmerged national Veterans Affairs (VA) pharmacy, labora-tory, administrative, and Medicare administrative data forfiscal years 2007 and 2008. A new-user design was used tominimize bias.23 The study population included veteransaged 65 and older with essential hypertension who werenot prescribed a first-line antihypertensive medicationduring a 9-month baseline period before the index date.First-line antihypertensive medications were defined as athiazide diuretic, angiotensin-converting enzyme inhibitor(ACEi), angiotensin II receptor blocker (ARB), calciumchannel blocker (CCB), or beta-blocker (BB). Hypertensionwas defined as having two or more outpatient encounterInternational Classification of Diseases, Ninth Revision(ICD-9) codes 401 to 404. Participants were followed overa 6-month period between July and December 2007 toidentify those who were newly prescribed a thiazide diure-tic or remained untreated with a first-line antihypertensivemedication (nonusers). The index date was the date of theinitial outpatient prescription for a thiazide or the date ofa randomly selected outpatient visit during the same timeperiod for nonusers. Participants were stratified into twomutually exclusive groups, thiazide users and nonusers,and were prospectively observed for 9 months after theindex date for the occurrence of AEs. Participants wereanalyzed according to initial group stratification, allowingfor crossover between group assignments and accrual ofadditional antihypertensive medications in both groupsaccording to usual care after the index date.

To allow for complete capture of medication use andlaboratory test results, the analysis was restricted to partic-ipants who received all of their care within the VA healthsystem, defined as having two or more outpatient encoun-ters within the VA system, with at least one encounterwithin 7 days of the index date; one or more outpatientprescriptions for a nonantihypertensive medication from aVA pharmacy; and no encounters in Medicare inpatient oroutpatient settings during the study period. Because theaim was to examine the risk of metabolic AEs, individualswith abnormal baseline values for sodium (

testing showed excellent overlap, with only two subjectsdropped from the thiazide user group. The risk of eachoutcome was estimated using generalized estimating equa-tions with an independent working correlation structure toaccount for clustering of participants within medicalcenters.

Two sensitivity analyses were performed to assess thevalidity of the inferences. First, the propensity score modelwas repeated, but instead of nearest-neighbor matching,participants were stratified according to quintile of propen-sity. Second, the initial analysis was repeated using newusers of CCB as the control group in lieu of nonusers toaccount for potentially unmeasured confounding that mayarise from the decision to treat or not treat individualswith antihypertensive medications. CCBs were chosen asthe active comparison group because, unlike other first-lineantihypertensive medications (ACEi, ARB, BB), they donot themselves cause metabolic disturbances and are notused to treat heart failure and other conditions that mayincrease the risk of metabolic AEs.

Predictors of AEs in Thiazide Users

Predictors of risk of AEs in thiazide users were examinedusing generalized estimating equation models with inde-pendent working correlation structures to account for clus-tering of individuals within medical centers. The primarypredictors of interest were age, comorbid burden, andbaseline laboratory values. Separate models were devel-oped for the composite outcome and for each individualAE included. The functional form of continuous variableswas assessed using cubic splines and polynomials. TheHosmer-Lemeshow goodness-of-fit test was used to con-firm model fit.

Because unmeasured baseline laboratory tests mayhave important prognostic implications, unmeasured testswere included as indicator variables in the models. Becauseof collinearity between having unmeasured eGFR and hav-ing unmeasured sodium and potassium values at baseline,eGFR status (or

Thiazide users had a 14.3% risk of developing an AE,compared with 6.0% for matched nonusers, yielding a num-ber needed to harm (NNH) of 12 individuals (95% confi-dence interval (CI) = 917, P < .001; Table 2). Likewise,thiazide users had a greater risk for each individual AEincluded in the composite outcome. The number needed tobe prescribed a thiazide to result in one excess case of an inci-dent severe AE was 82 (NNH 95% CI = 47326, P = .008)and in one excess case of an ED visit or hospitalization withan AE was 56 (NNH 95% CI = 31323, P = .02). Findingsfrom the sensitivity analyses using an alternative analyticaltechnique and new users of CCBs as the comparison groupwere materially similar and are not reported here.

In multivariate analysis, a high comorbidity burdenwas associated with three times the odds of developing ametabolic AE and 2.6 times the odds of developing hypo-natremia as with a low comorbidity burden (Table 3).Although age was not associated with significantly greaterodds of the composite outcome, there was a trend forincreasing age being associated with the risk of hyponatre-mia (odds ratio (OR) = 1.47 for each 10 years of age,P = .06).

Low-normal baseline Na and K values and unmea-sured baseline testing for Na and K were among thestrongest predictors of hyponatremia and hypokalemia,respectively.

Other than an association between race and ethnicityand risk of kidney injury (OR = 2.32 for nonwhite vswhite individuals, 95% CI = 1.294.17, P = .005), a sig-nificant association was not found between race and eth-nicity, sex, or thiazide dose and any AE outcome.

Pattern of Laboratory Monitoring After ThiazideInitiation

Only 42% of thiazide users had laboratory monitoring forNa, K, and eGFR within 90 days after thiazide initiationand 76% within the entire follow-up period of 270 days(Figure 2). Thiazide users were more likely to have follow-up laboratory monitoring within 90 days after the indexdate than new users of CCBs or nonusers (P < .001 forboth).

DISCUSSION

This national cohort study of older veterans with hyperten-sion found that, for every 12 veterans newly prescribed athiazide diuretic, one developed a metabolic AE within a9-month follow-up period that he or she would otherwisenot have had. The number of participants needed to beprescribed a thiazide to result in one excess case of asevere AE was 82 and one excess case of an ED visit orhospitalization with a metabolic complication was 56.Comorbidity burden and baseline laboratory tests wereimportant predictors of AEs. Despite thiazide-induced AEsbeing common, fewer than half of participants had labora-tory monitoring within 90 days after thiazide initiation.

Several clinical trials have examined the metabolic riskof thiazides in older adults. Within the first year of follow-up in the Systolic Hypertension in the Elderly Programtrial, 1% of chlorthalidone users developed hypokalemia,compared with 0.1% in the placebo group, and 1.8%experienced hyponatremia, compared with 0.4% in theplacebo arm.2 In the Hypertension in the Very ElderlyTrial, mean change in potassium and creatinine valueswere similar between participants receiving indapamideand placebo, with few serious AEs attributed to the trialmedication.3 Although it is difficult to directly comparethe current findings with those of these trials given thedifferences in follow-up periods, number of laboratorymeasurements, and definitions of metabolic risks, based onthe current findings from initial laboratory testing, it islikely that the risk of thiazide-induced metabolic AEs isunderestimated in real-world clinical settings. Furthermore,these trials included highly selected participants without

Table 1. Baseline Characteristics of Study Population

Characteristic

Matched

Thiazide

Users,

n = 1,060

Matched

Nonusers,

n = 1,060 P-Value

Age, mean SD 74 6 74 6 .38Male, n (%) 1,030 (97) 1,022 (96) .32Race, n (%)White 843 (80) 858 (81) .87Black 156 (15) 147 (14)Other 61 (6) 55 (5)

23 comorbidity count,median (IQR)

3 (24) 3 (24) .75

Selected comorbidities, n(%)Congestive heart failure 7 (0.7) 9 (0.9) .80Cirrhosis 4 (0.4) 9 (0.9) .27Dementia 36 (3) 37 (3) .91Diabetes mellitus 146 (14) 136 (13) .52Malignancy 142 (13) 116 (11) .08Psychosis 14 (1) 15 (1) .85

Number of medications,median (IQR)

5 (38) 5 (38)

significant preexisting comorbidities (heart failure, renalinsufficiency, and dementia), limiting generalizability. Thisunderscores the importance of observational studies to esti-mate the metabolic risk in actual clinical settings, whereolder adults who are treated with a thiazide are morelikely to be medically complex and frail.

Few studies have examined this risk in clinical prac-tice. One followed thiazide users receiving care at one oftwo academic medical centers for 10 years with a medianof 9.5 sodium measurements and found the cumulativeincidence of hyponatremia to be 32.4%, with a numberneeded to harm of 15.18 In a recent population-basedstudy in Canada, 1-year cumulative incidences of hospital-ization with hyponatremia and hypokalemia in olderadults prescribed hydrochlorothiazide were approximately0.3% and 0.6%, respectively.27 The current analysis mark-edly extends upon these studies by providing a more-comprehensive metabolic risk assessment of thiazides in

older adults. Future research should evaluate outcomesbeyond 9 months after thiazide initiation and include abroader range of potential AEs, including acute gout,orthostatic hypotension, and falls.

The current results also build upon prior research onpredictors of thiazide-induced AEs. Multimorbid olderadults had three times greater odds of AEs than individualswith a low comorbidity burden. Although not previouslyidentified as a risk factor for thiazide-induced AEs, a highcomorbidity burden has been shown to confer a greaterrisk of adverse drug reactions in general in older adults.28

This greater risk may be due to drugdrug and drugdisease interactions, as well as altered drug distributionand metabolism.20 Although the overall risk did not varysignificantly according to age, a trend was identified foradvancing age and greater risk of hyponatremia. In studiesthat have included individuals with a wider age range,advancing age has been shown to be a strong predictor of

Table 2. Study Outcomes

Outcome

Matched Thiazide

Users

Matched

Nonusers

Number Needed

to Harm (95% CI)

Relative Risk

(95% CI) P-Valuen (%)

AEa 152 (14.3) 64 (6.0) 12 (917) 2.61 (1.913.55)

thiazide-induced hyponatremia.29,30 The inclusion of indi-viduals aged 65 and older in the current study may reflectan age threshold effect blunting this risk. Also, this studybetter controlled for comorbidity burden, which may inpart mediate the effect of aging on sodium homeostasis. Inkeeping with previous literature on average decrements insodium and potassium concentrations after thiazide initia-tion, it was noted that low-normal sodium and potassiumlevels were significant predictors of hyponatremia andhypokalemia, respectively.31,32 These findings should beinterpreted cautiously. The clinical importance of milddecrements in laboratory values is uncertain.33

This study reported the incidence of metabolic AEsdue to thiazides as a proxy of harm. The severity of meta-bolic abnormalities dictates the degree and acuity of clini-cal symptoms. Less-severe metabolic derangements maynot be as alarming but are hardly inconsequential. Mildhyponatremia and hypokalemia have been linked to mor-tality.10,12,16,17 Furthermore, mild hyponatremia is associ-ated with risk of falls, gait unsteadiness, and cognitiveimpairment, as well as healthcare use and costs,13,16,34 andmild hypokalemia is associated with a greater burden ofcardiovascular events.10,11 In light of these consequences,the high observed incidence of AEs in the setting of subop-timal monitoring is concerning. Combined with the findingthat unmeasured baseline laboratory tests are significantpredictors of metabolic AEs, closer laboratory monitoringbefore and after thiazide initiation should be striven for.Further research is needed to help delineate optimalsurveillance strategies and to examine the effect of earlysurveillance on clinical outcomes.

Without firm evidence of the benefits of early labora-tory surveillance strategies, it may be prudent to consideralternative therapy for individuals at particularly higherrisk, such as multimorbid older adults. Thiazide diureticsundoubtedly reduce cardiovascular morbidity and mortal-ity in older adults with hypertension,21,35 but other classesof antihypertensive medications are equally effective in thispopulation and are available at comparable costs in gen-eric formulations.21,22

This study had certain limitations. First, individualswithin the VA healthcare system, who are predominantlymen, were studied. Because other studies have shownthat women may be at higher risk of metabolic compli-cations from thiazides than men, these results mayunderestimate the actual incidence.30,36 Second, given theobservational design of the study, there may have beenresidual confounding between groups. However,unmatched nonusers had greater comorbidity burden,number of medications, and healthcare use than thiazideusers at baseline. If there were unmeasured differencesbetween groups, a conservative bias would be expected,attenuating the risk differences. Additionally, propensityscore techniques with excellent covariate overlap wereused to match participants between groups. Third, thestudy was designed as an intention-to-treat analysisbased on the prescription status on the index date. Asevidenced by considerable thiazide discontinuation ratesfrom previous studies, potential crossover between groupassignments would be expected to lead to a more-conser-vative estimate.18,22 Fourth, there was different labora-tory follow-up time between thiazide users and nonusers.By design, all participants included in the risk analysishad laboratory test results at least once, and time to fol-low-up testing would not be expected to influence AEsin nonusers. Fifth, data on blood pressure were notavailable. Differences in blood pressure due to thiazidetreatment and possibly other antihypertensive medica-tions accrued during the follow-up period may haveconfounded the results.

In conclusion, thiazide-induced metabolic AEs arecommon in older adults with hypertension. Findings fromthis study indicate a need for more vigilance in prescribingthiazides. At a minimum, closer laboratory monitoring iswarranted before and after thiazide initiation. For individ-uals at particularly high risk of developing AEs, such asmultimorbid older adults, it may be reasonable to consideralternative therapy, especially given the availability ofother equally effective antihypertensive medications atcomparable costs.

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

Figure 2. Cumulative proportion of participants who had laboratory tests completed at least once within selected time intervalsbefore and after the index date. aLaboratory tests included sodium, potassium, and estimated glomerular filtration rate.CCB = calcium channel blocker.

1044 MAKAM ET AL. JUNE 2014VOL. 62, NO. 6 JAGS

ACKNOWLEDGMENTS

This study was presented as an oral presentation at theSociety of General Internal Medicine Meeting, April 26,2013, Denver, Colorado.

Conflict of Interest: We have no conflicts of interest todisclose.

This study was supported by Grants K23-AG030999and RC1-AG036377 from the National Institute on Aging(NIA). Dr. Makams work on this project was completedwhile he was a primary care research fellow at the Univer-sity of California at San Francisco, funded by a federaltraining grant from the National Research Service Award(T32HP190250700).

Author Contributions: Study concept and design: allauthors. Acquisition of data: Miao, Steinman. Analysisand interpretation of data: all authors. Drafting of themanuscript: Makam. Critical revision of the manuscript:all authors. Statistical analysis: Makam, Boscardin, Miao.Study supervision: Steinman.

Sponsors Role: The design and conduct of the study;collection, management, analysis, and interpretation of thedata; preparation, review, and approval of the manuscript;and decision to submit the manuscript for publication weresolely at the discretion of the authors.

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