tion in the prediction of cardiovascular diseases inwomen. N Engl J Med 2000;342:836–843.4. Koenig W, Sund M, Frohlich M, Fischer HG,Lowel D, Doring A, Hutchinson WL, Pepys MB.C-reactive protein, a sensitive marker of inflamma-tion, predicts future risk of coronary heart disease ininitially healthy middle-aged men: results from theMONICA (Monitoring Trends and Determinants inCardiovascular Disease) Augsburg Cohort Study,1984 to 1992. Circulation 1999;99:237–242.5. Danesh J, Whincup P, Walker M, Lennon L,Thomson A, Appleby P, Gallimore JR, Pepys MB.Low grade inflammation and coronary heart disease:prospective study and updated meta-analyses. BMJ2000;321:199–204.6. Mendall MA, Strachan DP, Butland BK, BallamL, Morris J, Sweetnam PM, Elwood PC. C-reactiveprotein: relation to total mortality, cardiovascularmortality and cardiovascular risk factors in men. EurHeart J 2000;21:1584–1590.7. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR.Comparison of C-reactive protein and low-densitylipoprotein cholesterol levels in the prediction of firstcardiovascular events. N Engl J Med 2002;347:1557–1565.8. Ross R. Atherosclerosis—an inflammatory dis-ease. N Engl J Med 1999;340:115–126.9. Cheng TO. Tea is good for the heart. Arch InternMed 2000;160:2397.10. Cheng TO. Antioxidants in Chinese green tea.J Am Coll Cardiol 1998;31:1214.11. Inoki L. Green tea that is as grassy as a springday. Financial Times May 5/6, 2001; XIII.

doi:10.1016/S0002-9149(03)00103-6

Significance of QT Dispersion

Our apologies; had we recog-nized that the purpose of Sombergand Molnar’s1 recent review of QTdispersion (QTd) was “to dispel thenotion of Lee et al . . . that QTdwas an artifact,” we would havewritten sooner. We agree withmany of the recent observations ofMalik and Batchvarov2 regardingQTd, but here we limit our com-ments to what we believe is animportant misinterpretation of ourfindings by Somberg and Mol-nar.1,3 We do accept the clinicalusefulness and prognostic value ofmeasured QTd as observed in prac-tice. However, we do not think thatQTd on the surface electrocardio-gram (ECG) should be consideredequivalent to localized heterogene-ity of repolarization within the ven-tricle. Our paper indicates that QTdis found in 12-lead ECGs evenwhen none exists,4 as also shownby Macfarlane et al.5 As we tried tomake clear in our study, the trans-formation that we used to simulate12-lead ECGs from a derived heartvector could not restore any non-dipolar content that may have beenpresent in the original tracing. Thisis because there is no non-dipolarinformation in the heart vector, and

the transformation is not, as statedby Somberg and Molnar,1 “likeflipping a dice over and back.”Rather, dispersion was found inour simulated 12-lead ECGs underthese conditions because isoelec-tric projection of the T loop insome leads resulted in measureddifferences of QT. Accordingly,some, but not necessarily all, QTdcan be explained by this T-waveprojection phenomenon when theT loop is open rather than elon-gated. This is neither “artifact” norlocalized heterogeneity of repolar-ization, but perhaps a clinicallyuseful alternate definition of abnor-mal repolarization or T-wave mor-phology.

Paul Kligfield, MD

Peter M. Okin, MD

Ken W. Lee, MD

Gordon E. Dower, MD

New York, New York14 January 2003

1. Somberg JC, Molnar J. The heart vector, theregional information in the electrocardiogram, andQT dispersion: reply (letter). Am J Cardiol 2002;90:1277.2. Malik M, Batchvarov V. The heart vector, theregional information in the electrocardiogram, andQT dispersion (letter). Am J Cardiol 2002;90:1276–1277.3. Somberg JC, Molnar J. Usefulness of QT disper-sion as an electrocardiographically derived index.Am J Cardiol 2002;89:291–294.4. Lee KW, Kligfield P, Dower GE, Okin PM. QTdispersion, T-wave projection, and heterogeneity ofrepolarization in patients with coronary artery dis-ease. Am J Cardiol 2001;87:148–151.5. Macfarlane PW, McLaughlin SC, Rodger JC.Influence of lead selection and population on auto-mated measurement of QT dispersion. Circulation1998;98:2160–2167.

doi:10.1016/S0002-9149(03)00239-0

Blood Pressure Control and Ratesof Edema Following theAdministration of theCyclooxygenase-2 SpecificInhibitors Celecoxib versusRofecoxib in Patients WithSystemic Hypertension andOsteoarthritis

A clinical study was designed tocompare the renovascular effects of 2selective cyclooxygenase (COX)-2;inhibitors, celecoxib and rofecoxib, inpatients �65 years of age with osteo-arthritis and controlled systemic hy-pertension treated with various antihy-pertensives.1 In this study, somewhatlower rates of edema and hypertensionwere reported in the celecoxib treat-

ment group.1 The authors concludedthat the observed differences reflecteda drug effect.

We believe that there is anotherequally plausible explanation for theobserved imbalance in the incidenceof hypertension and edema betweenthe two COX-2 inhibitors. Namely,the doses were not appropriatelymatched. Given the dose- dependentnature of renal side effects, equallyefficacious doses should have beencompared. Available data suggestthat the most appropriate compari-son for the celecoxib 200-mg dosewould have been rofecoxib 12.5 mgonce daily (instead of the 25 mg thatwas tested).2 Baseline patient char-acteristics and the number of patientstaking various anti-hypertensivetreatments at baseline were compa-rable in both treatment groups. Se-lective COX-2 inhibitors and nonse-lective nonsteroidal anti-inflamma-tory drugs (NSAIDs) have subtleeffects on kidney function due totheir inhibition of renal prostaglan-dins. Renal physiologic studies havedemonstrated dose-dependent changesin glomerular filtration rate and so-dium excretion with both rofecoxiband celecoxib that are similar tononselective NSAIDs.3 Based onthese studies, it had been predictedthat selective COX-2 inhibitorswould share with NSAIDs thewell-recognized renal-based side-effects, specifically, edema, bloodpressure increase, and attenuationof the effects of antihypertensiveagents, as well as the less frequentside-effects of heart failure andacute renal failure4–6 that occur ina minority of patients. Celecoxiband rofecoxib product labels reflectthis concern and advise the samerenal precautions with both agents,as currently advised with conven-tional NSAIDs.

It is also important to criticallyassess the clinical importance ofthese drug effects. Because a com-plete safety and tolerability com-parison of celecoxib and rofecoxibwas not presented,1 a reader maymisinterpret the safety profile ofthese compounds. Fluid retentionis one of the most commonNSAID-related renal effects and isreported in approximately 5% ofNSAID-treated patients, but it israrely clinically significant.7 The

READERS’ COMMENTS 1291

most serious complication of fluidretention is congestive heart fail-ure; the risk of congestive heartfailure was not significantly differ-ent between the 2 groups. In addi-tion, the proportion of patients whorequired a change or adjustment ofmedication regimen for either hy-pertension or edema was not sig-nificantly different between the 2groups.

In summary, although there weredifferences observed in rates ofedema and hypertension when com-paring rofecoxib versus celecoxib inthis study, it is possible that inappro-priate selection of drug doses and/orthe dosing regimen may have con-

tributed to these findings. In addi-tion, no definitive differences in clin-ically important events, such as con-gestive heart failure and adjustmentsin medication for hypertension oredema, were reported.

Arthur Weaver, MDPequot Lakes, Minnesota

Michael Alderman, MDBronx, New York

Rhoda Sperling, MDNew York, New York

24 January 2003

1. Whelton A, White WB, Bello AE, Puma JA, FortJG, and the SUCCESS-VII Investigators. Effects ofcelecoxib and rofecoxib on blood pressure andedema in patients �65 years of age with systemichypertension and osteoarthritis. Am J Cardiol 2002;90:959–963.2. Geba G, Weaver AL, Polis AB, Dixon ME,

Schnitzer TJ, for the VACT Group. Efficacy of ro-fecoxib, celecoxib, and acetaminophen in osteoar-thritis of the knee: a randomized trial. JAMA 2002;287:64–71.3. Brater DC, Harris C, Redfern JS, Gertz BJ. Renaleffects of COX-2 selective inhibitors. Am J Nephrol2001;21:1–15.4. Brater DC. Effects of nonsteroidal anti-inflamma-tory drugs of renal function: focus of cycloosygen-ase-2-selective inhibition. Am J Med 1999;107:65S–71S.5. Boyd IW, Matthew TH, Thomas MC. COX-2inhibitors and renal failure: the triple whammy re-visited. Med J Aust 2000;173:274–274.6. Balasubramaniam J. Selective COX-2 inhibitorsand nephrotoxicity. Am J Kidney Dis 2000;613:675–676.7. Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory drugs: effects on kidney function.J Clin Pharmacol 1991;31:588–598.

doi:10.1016/S0002-9149(03)00369-2

1292 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 91 MAY 15, 2003