Chlorthalidone Versus Hydrochlorothiazide

TO THE EDITOR: Dhalla and colleagues' (1) retrospective observa-tional cohort study among older adults comparing chlorthalidonerecipients with hydrochlotothiazide (HCTZ) recipients departsmethodologically From other studies of antihypertensive drugs andhealth outcomes. First, there was no standardization in diagnosingcardiovascular events (CVEs). Second, the median follow-up forchlorthalidone recipients was only 255 days (8.4 months). The dif-ference in CVEs between the 2 drugs does not manifest until about9 months (Figure 1), implying that one half of the effect of chlottha-lidone is not reflected in the hazard ratio (HR). Third, the analysisincorporated total mortality into the primary outcome, somethingnot generally done because these medications have no effect on non-cardiovascular deaths.These problems bias the HR toward 1.00 (that is, toward find-ing no difference in health outcomes between the 2 medications).Despite these factors, the HR from DhaJla and associates' article is0.93, not different statistically from the HR of 0.79 (95% CI, 0.68to 0.92) from another retrospective observational cohort study thatavoids these methodological problems (2). Pooling these 2 HRs givesan HR of 0.87 (CI, 0.78 to 0.96; P = 0.005), an underestimate ofthe true benefit of chlorthalidone relative to HCTZ.Among chlorthalidone recipients and HCTZ recipients inDhalla and cowotkets' study, what are the HRs (95% CIs) for hos-pitalization for CVEs in those who became hypokalemic versus thosewith sustained notmokalemia? An analysis of ALLHAT (Antihyper-tensive and Lipid-Lowering Treatment to Prevent Heart AttackTtial), the largest hypertension trial available with approximately9000 chlotthalidone recipients, concludes, "Thus, for most patients,concerns about potassium levels shotild not influence clinician's de-cision about initiating hypertension treatment with low-moderatedoses of thiazide diuretics (12.5-25.0 mg of chlorthalidone)" (3).Dhalla and colleagues state incorrectly that our peet-teviewednetwork analysis (4) is "conflicting" with the network analysis pre-sented by Psaty and colleagues (5) in their letter to the editor andthat the latter analysis "compared cblotthalidone and hydtochlo-rothiazide." Pet the title of their letter—"Meta-analysis of HealthOutcomes of Chlorthalidone-Based vs Nonchlorthalidone-BasedLow-Dose Diuretic Thetapies"—Psaty and associates comparedchlorthalidone-based diuretics with non-chlorthalidone-based di-uretics and used jtjst 3 trials for the nonchlorthalidone side of thenetwork: indapamide, HCTZ plus amlloride, and HCTZ plus tti-amtetene. Also, Psaty and coworkets did not include ALLHAT, theACCOMPLISH (Avoiding Catdiovasctilar Events Through Combi-nation Therapy in Patients Living With Systolic Hypertension) trial,ANBP2 (Second Australian National Blood Pressure Study), and theHDFP (Hypertension Detection and Follow-up Program) study, 4large trials strongly favoring chlorthalidone over HCTZ in networkanalysis (4).George C. Roush, MD, MPHUniversity of Connecticut School of Medicine and St. Vincent'sMedical CenterBridgeport, ConnecticutTheodore R. Holford, PhDYale University School of Public HealthNew Haven, ConnecticutAchuta K. Guddati, MBBS, PhDMassachusetts General HospitalBoston, MassachusettsPotential Conflicts of interest: None disclosed.References