Journal of Human Hypertension (2001) 15, 475–480
 2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00
A forced titration study of
antihypertensive efficacy of candesartan
cilexetil in comparison to losartan: CLAIM
Study II

DG Vidt1, WB White2, E Ridley3, M Rahman4, S Harris5, J Vendetti5, EL Michelson5,R Wang5, and CLAIM Study investigators61Cleveland Clinic Foundation, Cleveland, OH, USA; 2Section of Hypertension and Clinical Pharmacology,University of Connecticut Health Center, Farmington, CT, USA; 3Medical College of VirginiaCommonwealth University, Richmond, VA, USA; 4Case Western Reserve University, Cleveland, OH, USA;5AstraZeneca LP, Chesterbrook, PA, USA An 8-week, multicentre (72 sites in the US), double-
mm Hg, and 48-h BP by 5.9/7.0 mm Hg by losartan. The
blind, randomised, parallel group, forced titration study
responder and control rates were numerically higher in
compared the antihypertensive efficacy of candesartan
the candesartan cilexetil group, but the differences did
cilexetil and losartan. A total of 611 patients with essen-
not reach statistical significance; the responder rates
tial hypertension (diastolic blood pressure 95 to 114
were 58.8% for the candesartan cilexetil group and
mm Hg) were randomised initially to candesartan cilexe-
52.1% for the losartan group and control rates were
til 16 mg once daily or losartan 50 mg once daily. After
49.0% for the candesartan cilexetil group and 44.6% for
2 weeks of randomised treatment, the doses of candes-
the losartan group. Overall, both treatment regimens
artan cilexetil and losartan were doubled to 32 mg and
were well tolerated. A total of 15 of the 611 (2.5%)
100 mg once daily and continued respectively for 6
patients withdrew from the study due to an adverse
weeks. At week 8, candesartan cilexetil lowered the
event, including nine (2.9%) in the candesartan cilexetil
blood pressure (BP) at 24 h (trough), 6 h (peak) and 48 h
group and six (2.0%) in the losartan group. In con-
post dose to a significantly greater extent (P Ͻ 0.05)
clusion, this forced titration study confirms that candes-
than losartan: candesartan cilexetil lowered trough BP
artan cilexetil is more effective in lowering BP than los-
by 13.4/10.5 mm Hg, peak BP by 15.5/12.9 mm Hg and
artan when compared at once daily maximum doses.
48-h BP by 10.5/9.9 mm Hg compared to a reduction of
Journal of Human Hypertension (2001) 15, 475–480
trough BP by 10.1/9.1 mm Hg, peak BP by 12.0/9.5
Keywords: candesartan cilexetil; losartan; CLAIM Study II
behaved like surmountable or partially surmount-able antagonists with a relatively short duration of The two angiotensin II type 1 receptor blockers action. Vanderheyden et al2 found that the dis- (ARBs), candesartan and losartan, exhibit different 152 min for candesartan, 5 min for losartan and angiotensin II receptor. Morsing et al1 demonstrated that candesartan acted as an insurmountable antag- Three previous randomised, controlled trials have onist with a marked and long-lasting blockade of the demonstrated greater antihypertensive effects of vascular contractile effects of angiotensin II whereas candesartan cilexetil over losartan. These studies losartan and its active metabolite, EXP 3174, either evaluated the starting doses of both drugs orused a response titration design for comparison oftheir maximum doses.3–5 A fourth study by Bakris Correspondence: Dr Donald Vidt, Cleveland Clinic Foundation, et al6 (CLAIM Study I) and the present study Department of Hypertension and Nephrology, A-51, 9500 Euclid (CLAIM Study II), are two identically designed, con- Avenue, Cleveland, OH 44195, USA. E-mail: vidtdȰccf.org Sup- currently conducted, double-blind, randomised for- ported by a grant from AstraZeneca LP, Wayne, PA, USA6See Appendix ced titration studies to provide direct comparison of Received 24 October 2000; revised 18 December 2000; accepted the blood pressure (BP) lowering effects at once daily maximum doses. CLAIM Study I showed that Candesartan cilexetil vs losartan
candesartan cilexetil lowered all the primary and in the diastolic BP readings were required to be no secondary BP parameters by a significantly greater more than 5 mm Hg with additional readings perfor- amount (P Ͻ 0.05) than losartan in 654 hypertensive med if necessary until such consistency was obtain- patients.6 The present report summarises the find- ings of CLAIM Study II on 611 patients with sys- At each visit, trough sitting diastolic (D) and sys- tolic (S) BP (24 ± 3 h after dose), heart rate, concomi-tant medications and adverse events were recorded.
An adverse event is defined as any unfavourable Patients and methods
changes in symptoms, signs or laboratory data tem- Patients
porally associated with the use of study medicationwhether or not considered related to the use of study A total of 611 men or women (without child bearing medication. In addition, peak BP (6 ± 2.5 h after potential) between 18 and 80 years of age, with dose) was measured at week 3 or 4 of the placebo essential hypertension (diastolic BP (DBP) 95–114 run-in period and also at week 8 of the double-blind mm Hg) were enrolled into the study. Major period. The definition of a peak effect at 6 h after exclusion criteria included systolic BP у180 mm Hg dose was chosen as previous studies indicated that or diastolic BP у115 mm Hg, known hypersensitiv- the peak effect of losartan occurred approximately ity reaction to ARBs, secondary hypertension, sever- 6 h and that of candesartan cilexetil occurred after ely impaired liver function, significant renal impair- 4 to 8 h.8,9 The trough-to-peak ratio was determined ment, haemodynamically significant valvular heart from dividing the trough DBP effect by the peak DBP disease, angina pectoris requiring more than short- effect. Laboratory tests including blood counts, renal acting nitrates, recent history of myocardial infarc- and liver function tests were performed by a central tion, coronary revascularisation procedures, stroke laboratory (SmithKline Beecham Clinical Labor- or transient ischaemic attack. Current use of an anti- atories) at week 3 of the placebo run-in period and hypertensive agent was cause for exclusion unless also at week 8 of the double-blind period. Any it could be discontinued safely by the first week of abnormal laboratory values from week 8 were re- evaluated at the 2-week follow-up visit.
Study design
Statistical methods
This was an 8-week, multicentre (72 sites in US), The primary efficacy parameter was mean change double-blind, randomised, parallel group, forced from baseline to week 8 in trough DBP. Based on titration study. After a 4- or 5-week single-blind, pla- this sample size and the 1:1 randomisation scheme, cebo run-in period, enrolled patients were random- the study had at least 90% power to detect a true ised centrally with a computer generated randomis- difference in mean change from baseline in trough ation list in a 1:1 ratio to candesartan cilexetil 16 mg sitting diastolic BP of 2.0 mm Hg between the two tablet once daily or losartan 50 mg once daily. After treatment groups. This estimate assumes a standard 2 weeks of randomised treatment, the doses of can- deviation of 7.5 mm Hg and is based on a two-tailed desartan cilexetil and losartan were doubled and test with ␣ = 0.05. Secondary efficacy variables continued for 6 weeks. The patients were asked to included change from baseline to week 8 in trough take the study medication in the morning with no SBP and peak SBP/DBP, proportion of responders specific instruction regarding food. In general, food (patients with either a DBP of Ͻ90 mm Hg or a does not affect the absorption of candesartan and decrease from baseline in DBP of у10 mm Hg at has only minor effects on the AUC of losartan and week 8) and controlled patients (DBP of Ͻ90 mm Hg its metabolite.7 Visits were scheduled at weeks 1, 2, at week 8), and the change from baseline BP at 48 h 4 and 8 of the 8-week double-blind treatment period.
post last dose of study medication. An analysis of Patients were also seen 48 h following their last dose covariance for a randomised block design was used of study medication and 2 weeks after they discon- to assess the primary and secondary variables, with tinued therapy with the study medication for fol- baseline as the covariate and the study site as the low-up visits. Post-study treatment for hypertension block. All data analyses are presented using the was not instituted until after the 48-h assessment least-squares means (LSM) and 95% confidence intervals (CI). Efficacy analyses for trough sitting For each patient, visits were scheduled at the DBP, SBP were performed using an intent-to-treat same time in the morning. Patients were instructed approach with the last observation carried forward.
to refrain from taking the study medication on the Efficacy analyses with peak sitting and 48 h post last morning of clinic visits until after BP was measured.
dose BP were performed with actual values as these All BP determinations were performed in the sitting readings were taken at baseline and once again at position using a mercury sphygmomanometer from their respective and points—either at week 8 or 48 h the right arm after the patient had sat quietly for at after the week 8 visits. The statistical difference in least 5 min. BP was measured 3 times at 2-min inter- the responder and control rates between the treat- vals and the mean value computed. The differences ment groups at week 8 were determined using Fish- Candesartan cilexetil vs losartan
DG Vidt et al
Table 1 Patient characteristics at baseline
Candesartan cilexetil (n = 307) aExpressed as mean (s.d.).
bExpressed as number (%).
Table 2 Least squares mean changes from baseline to week 8 in blood pressure
LSM, least squares mean.
aIntent-to-treat, last-observation-carried forward population (candesartan cilexetil: n = 306; losartan: n = 303).
bPatients with data available: peak sitting BP (candesartan cilexetil: n = 274; losartan: n = 266); 48-h, post-dosing BP (candesartan cilexe-til: n = 246; losartan: n = 247).
er’s exact test. Both descriptive and inferential stat-istics between treatment groups were calculated forthe primary and secondary BP parameters. Patientcharacteristics at baseline, trough-to-peak ratios,adverse events and laboratory data were compareddescriptively between the two treatment groups.
Laboratory data were evaluated according to prede-fined limits of change and mean change from base-line.
Of the 611 patients, 307 patients were randomisedto candesartan cilexetil and 304 patients to losartan.
A total of 535 patients (88%) completed the study: Figure 1 Effects of candesartan cilexetil and losartan on trough
87% for candesartan cilexetil and 88% for losartan.
blood pressure (BP). Labels within bars are means of intent-to- The study population was 58.6% male, 19.8% black treat, last value carried forward, readings of the trough sitting BP with a mean age of 55 years and a baseline BP of readings (24 ± 3 h after dosing) at week 8. CI, confidence intervals; 152.9/100.3 mm Hg. Patient characteristics at base- line were similar in the two treatment groups(Table 1).
Table 2 lists the comparison between the candes- significant. Figure 1 shows the mean trough BP at artan cilexetil and losartan treatment groups in low- week 8 in each group with candesartan cilexetil low- ering the trough, peak and 48-h post last dose dias- ering trough SBP/DBP by 13.4/10.5 mm Hg com- pared to 10.1/9.1 mm Hg by losartan (P Ͻ 0.05).
Candesartan cilexetil vs losartan
common adverse events for the candesartan cilexetilgroup were headache (7.2%), respiratory infection(3.9%), and sinusitis (3.9%), whereas those for thelosartan group were respiratory infection (7.9%),headache (5.9%), and rhinitis (3.6%). A total of 15of the 611 (2.5%) patients withdrew from the studydue to an adverse event, including nine (2.9%) inthe candesartan cilexetil group and six (2.0%) in thelosartan group. Only four of the 611 (0.7%) patientsreported adverse events that were considered seri-ous due to hospitalisation during the double-blindtreatment period; two were in the candesartan cilex-etil group and two were in the losartan group. Therewere no deaths during this trial. Minor changes from Figure 2 Effects of candesartan cilexetil and losartan on peak
baseline in laboratory values were observed in blood pressure (BP). Labels within bars are means of the peak isolated individuals. There were no clinically mean- sitting BP readings (6 ± 2.5 h after dosing) at week 8. CI, confi- ingful changes in mean laboratory values in either dence intervals; CC, candesartan cilexetil.
treatment group and no laboratory evidence ofdeterioration in renal, hepatic, or metabolic func- Figure 2 shows the mean peak BP at week 8 in each group with candesartan cilexetil reducing peakSBP/DBP by 15.5/12.9 mm Hg compared to 12.0/9.5 Discussion
mm Hg by losartan (P Ͻ 0.005). Figure 3 shows themean 48-h BP at week 8 in each group with candes- The present study was designed to provide an effec- artan cilexetil lowering the 48-h post last dose tive comparison of the BP lowering effects of these SBP/DBP by 10.5/9.9 mm Hg vs 5.9/7.0 mm Hg by two ARBs. Candesartan is a once-daily drug losartan (P Ͻ 0.0005). At the week 8 visit, the although losartan is occasionally used twice daily as trough-to-peak ratios were 0.86 for candesartan its package insert states that peak effects are uni- cilexetil and 0.92 for losartan. Candesartan cilexetil formly but moderately larger than trough effects.
also produced a numerically higher responder rate Thus, the study measured not only trough SBP/DBP (58.8% for candesartan cilexetil and 52.1% for but also peak and 48 h post dose BP. Although the losartan) and control rate (49.0 for candesartan trough-to-peak ratio did not give any details of the cilexetil and 44.6% for losartan) but the differences actual BP effects during the 24-h period, a high did not reach statistical significance.
trough/peak ratio confirms a substantial persistence Overall, the incidence and intensity of adverse of the peak BP lowering effects of the drug before events were similar in the two treatment groups. A the next dosing. With the value exceeding 80% for total of 276 of 611 (45.2%) patients reported adverse each drug, both drugs were effective as once daily event: 45.6% in the candesartan cilexetil group and antihypertensive agents. The 48-h post dose BP was 44.7% in the losartan group. Most adverse events measured to evaluated whether the insurmountable were mild in intensity and resolved with continued AT1 receptor binding characteristics of candesartan treatment including dose escalation. The three most translated clinically into more sustained BP lower-ing effects. Although only about 80% of patientsshowed up for the 48-h post dose BP measurement,the drop outs were comparable from each group andthe reading was available in a fairly large number ofpatients (a total of 493 patients). The findings of theimpressive extended therapeutic BP lowering effectsof candesartan cilexetil compared to losartan suggestthat the different receptor binding properties of thetwo ARBs resulted in tangible clinical benefits incase of a missed dose. Candesartan had an AT1 bind-ing affinity in rabbit aorta 80 times greater than thatof losartan and 10 times greater than that of EXP3174.10 In summary, the superior blockade of cande-sartan on the AT1 receptor of angiotensin II than los-artan probably accounted for the greater antihyper-tensive efficacy of the drug with the results of thestudy Figure 3 Effects of candesartan cilexetil and losartan on blood
trough, peak and 48 h post dose BP to a greater pressure (BP) 48 h after the last dose of study medications. Labelswithin bars are means of the 48 h BP readings at week 8. CI, con- extent than losartan (P Ͻ 0.05).
fidence intervals; CC, candesartan cilexetil.
The findings of this study are similar to those of Candesartan cilexetil vs losartan
DG Vidt et al
CLAIM Study I, the other identically-designed, com- the meta-analysis. Thus, the conclusions of this parative study of candesartan cilexetil (n = 332) and meta-analysis are probably applicable to the earlier losartan (n = 322).6 CLAIM Study I showed that at ARBs but not to candesartan cilexetil.
week 8, candesartan cilexetil 32 mg once daily wasmore effective in lowering all the measured BP para- Conclusion
meters than losartan 100 mg once daily (P Ͻ 0.05):candesartan This randomised, controlled, forced titration study 13.3/10.9 mm Hg, peak BP by 15.2/11.6 mm Hg and demonstrated consistently that candesartan cilexetil 48-h post dose BP by 11.2/10.2 mm Hg compared to 32 mg once daily, lowered trough, peak and 48 h a reduction of trough BP by 9.8/8.7 mm Hg, peak BP post dose BP more effectively than losartan 100 mg by 12.6/10.1 mm Hg, and 48-h post dose BP by once daily in a diverse population with systemic 5.3/6.0 mm Hg by losartan. In addition, CLAIM hypertension in the US. Both drugs were well toler- Study I showed that candesartan cilexetil produced higher responder and control rates (62% and 56%)than losartan (54% and 47%); the differences beingstatistically Acknowledgements
independent studies showing the greater efficacy of We gratefully acknowledge the diligent efforts of the clinical study coordinators at the 72 investigative occurring by chance is minimal as the one-sided P- sites. We also recognise the contributions of Chan- neary McDowell, BS, Jeanine Parsons, BS, Melissa 0.025 × 0.025 = 0.000625, and the corresponding Grozinski, BS, Anne Kezer, BS, Conrad Tou, PhD, two-sided P value is 0.00125.11 Overall, including Terry Flanagan MPH, James Gaddy, PhD, Oliver the present study, there have been five sizable, dou- Yeh, BA and Debbie Brangman, MBA, for invaluable ble-blind, randomised, controlled studies providing assistance in the conduct of the study and manu- direct comparison between candesartan cilexetil and losartan.3–6 The Andersson and Neldam study3showed that candesartan cilexetil 16 mg once dailylowered SBP/DBP more effectively than losartan References
50 mg once daily by 4.6/3.7 mm Hg with the differ- 1 Morsing P et al. Mechanistic differences of various ence in DBP statistically significant. In the CANDLE AT1-receptor blockers in isolated vessels of different (Candesartan Versus Losartan Efficacy Comparison origin. Hypertension 1999; 33: 1406–1413.
Study), candesartan cilexetil 16 mg dose-titrated if 2 Vanderheyden PML, Fierens FLP, De Backer JP, Vau- needed to 32 mg once daily reduced SBP/DBP more quelin G. Reversible and syntopic interaction between than losartan 50 mg dose titrated if needed to angiotensin receptor antagonists on Chinese hasmster 100 mg once daily by 1.9/2.1 mm Hg, with the differ- ovary cells expressing human angiotensin II type I ence in DBP statistically significant.4 In a forced receptors. Biochem Pharmacol 2000; 59: 927–935.
3 Andersson OK, Neldam S. The antihypertensive effect titration study, candesartan cilexetil 16 mg once and tolerability of candesartan cilexetil, a new gener- daily lowered 24-h ambulatory SBP/DBP more than ation angiotensin II antagonist, in comparison with losartan 100 mg by 4.1/1.8 mm Hg, with the differ- losartan. Blood Pressure 1998; 7: 53–59.
ence in SBP statistically significant.5 These three 4 Gradman AH et al, for the Candesartan Versus Losar- studies, however, did not test the recommended tan Efficacy Comparison (CANDLE) Study Group.
once daily maximum doses of the two drugs by a Comparative effects of candesartan cilexetil and losar- forced titration design. Thus, with the strikingly tan in patients with systemic hypertension. Heart Dis- consistent demonstration of greater peak, trough and ease 1999; 1: 52–57.
48-h post dose BP lowering of candesartan cilexetil, 5 Lacourciere Y, Asmar R, for the Candesartan/Losartan these two CLAIM studies establish convincingly the study investigators. A comparison of the efficacy andduration of action of candesartan cilexetil and losartan greater antihypertensive efficacy of candesartan as assessed by clinic and ambulatory blood pressure cilexetil over losartan when compared at once daily after a missed dose, in truly hypertensive patients: a placebo-controlled, forced titration study. Am J Hyper- These head-to-head comparisons are important to tens 1999; 12: 1181–1187.
differentiate the antihypertensive efficacy of ARBs.
6 Bakris G et al. Antihypertensive efficacy of candesar- A recent meta-analysis of 43 published, randomised, tan in comparison to losartan: The CLAIM study. J Clin controlled trials concluded comparable antihyper- Hypertens, 2001; 3: 16–21.
tensive efficacy of losartan, valsartan, irbesartan and 7 Physician’s Desk Reference. 54th edn. Medical Eco- candesartan cilexetil and a near flat dose response nomics: Montvale (NJ), 2000. (a) Atacand (candesartan of these ARBs.12 The meta-analysis consists essen- cilexetil), pp 592–594; (b) Cozzar (losartan), pp 1769–1772.
tially of data on the two earlier ARBs, losartan and 8 Munafo A et al. Drug concentration response relation- valsartan (81% of the ARB monotherapy starting ships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist. Clin titration data). It is also noteworthy that only 8– Pharmacol Ther 1992; 51: 513–515.
16 mg candesartan cilexetil doses were evaluated in 9 Delacretaz E, Nussberger J, Biollaz J, Weber B, Brunner Candesartan cilexetil vs losartan
HR. Characterization of the angiotensin II receptor Research Inc, Tuscon, AZ; Theodore E. Lefton, MD, antagonist TCV-116 in healthy volunteers. Hyperten- ICSL-Clinical Studies, Melbourne, FL; Alan Levin, sion 1995; 25: 14 –21.
MD, Glenville, NY; Hari Malik, MD, Cedarwood 10 Burnier M, Brunner HR. Angiotensin II receptor antag- Medical Center, St. Joseph, MI; Abe Marcadis, MD, onists. Lancet 2000; 355: 637–645.
ICSL-Clinical Studies, Boynton Beach, FL; R Eric 11 Fisher LD, Moye LA. Carvedilol and the Food and Drug Administration approval process: an introduc- McAllister, MD, MEDStudies Inc, Ukiah, CA; James tion. Controlled Clin Trials 1999; 20: 1–15.
McMechan, DO, Jefferson Country Medical Clinic 12 Conlin PR et al. Angiotensin II antagonists for hyper- PA, Oskaloosa, KS; John Mihalik, MD, Northern Cal- tension: are there differences in efficacy? Am J Hyper- ifornia Medical Associates, Cloverdale, CA; David tens 2000; 13: 418– 426.
Miller, MD, Bucks County Clinical Research,Moorisville, PA; Michael Miller, MD, University of Appendix
MD School of Medicine, Baltimore, MD; RafaelMontoro, MD, Clinical Therapeutics Corp, Coral CLAIM Study 230 Investigators:
Gables, FL; Jane Mossberg, MD, Research Studies, Frank G Baratta, MD, Ft Lauderdale, FL; Scott Blesser, DO, Midwest Regional Research Inc., Bell- Research of Northern Virginia, Falls Church, VA; brook, OH; Paul J Bresnan, MD, Watson Clinic LLP, Lakeland, FL; Joan Brigham, MD, ICSL-Clinical Research, Greer, SC; Larry Neuman, MD, New York, Studies, Charlotte, NC; David Calhoun, MD, Univer- NY; Margarita C Nunez, MD, ICSL-Clinical Studies, sity of Alabama at Birmingham, Birmingham, AL; St. Petersburg, FL; Thomas O’Barr, MD, Health Julian A Colton, MD, Health Advance Institute, St.
Advance Institute, Marietta, GA; Mark Okusa, MD, Petersburg, FL; Martin Conway, MD, Lovelace University of Virginia Medical Center, Charlottes- Scientific Research, Albuquerque, NM; Pamela ville, VA; Vasilios Papademetriou, MD, VAMC- Craven, MD, Health Advance Institute, Oklahoma Hypertension Research Clinic, Washington, DC; City, OK; William Cushman, MD, VAMC-Memphis, Kavita Persaud, MD, St. Joseph Senior Health Ser- Memphis, TN; Stephen D’Amico, MD, GRAE, Inc, vices, Fort Wayne, PA; Frank Pettyjohn, MD, Uni- Franklin, TN; Vincent DeQuattro, MD, Los Angeles, versity of South Alabama, Mobile, AL; James L Pool, CA; Lance D Dworkin, MD, Rhode Island Hospital, MD, Baylor College of Medicine Methodist Hospital, Providence, RI; David J. Frid, MD, OSU Center for Houston, TX; Anthony Puopolo, MD, Milford Wellness and Prevention, Columbus, OH; Debra Emergency Associates, Inc, Milford, MA; Promod Ann Friesen, MD, Exempla Internal Medicine, Raval, MD, Oak Park, MI; Albert J Razzetti, MD, Uni- Wheat Ridge, CO; W Thomas Garland, MD, Lawr- versity Clinical Research-DeLand, DeLand, FL; ence Clinical Research, Lawrenceville, NJ; Larry I Steven Rosansky, MD, Three Rivers Medical-Carol- Gilderman, DO, University Clinical Research Inc, ina Research Assoc, Columbia, SC; Herman Rose, Pembroke Pines, FL; Edward Gillie, MD, Medical MD, Fort Worth, TX; Eli Roth, MD, Sterling Research Studies, Florida, Fort Myers, FL; Ivan Goldsmith, Group Ltd, Cincinnati, OH; Henry Rothschild, MD, MD, West Trop Medical Centre, Las Vegas, NV; Ron- Louisiana State University Medical Center, New ald C Gove, MD, Jersey Research Foundation Inc, Orleans, LA; John Rubino, MD, Raleigh Medical Linwood, NJ; Maria Gutierrez, MD, ICSL-Clinical Group, Raleigh, NC; Susan Savage, MD, ICSL-Clini- Studies, Fort Lauderdale, FL; Kathy Harvey, DO, cal Studies, Denver, CO; Kevin T Scully, MD, Lex- Internal Medicine, Logan, WV; Bradley Heppner, ington Cardiology Consultants, Lexington, KY; Stan MD, ICSL-Clinical Studies, Pittsburgh, PA; John A Slabic, MD, Slabic & Slabic Internal Medicine, Erie, Holmes, MD, Heart of America Research Institute, PA; William B Smith, MD, New Orleans Center for Mission, KS; E Walter Hood, DO, ICSL-Clinical Clinical Research, New Orleans, LA; John A Stou- Studies, Atlanta, GA; David B Jack, MD, Physicians kides, MD, ICSL-Clinical Studies, East Providence, Research Options, Sandy, UT; Edwin Jacobson, MD, RI; Malcolm Taylor, MD, Jackson Cardiology Associ- Los Angeles, CA; Ashok Jain, MD, Dearborn, MI; Roy ates, PA, Jackson, MS; Thomas Tse, MD, Bellville, Kaplan, MD, East Bay Clinical Trial, Concord, CA; IL; Margaret Wagner, MD, Idaho Falls, IN; Mervyn Edward M Kerwin, MD, Clinical Research Institute Weerasinghe, MD, Rochester Clinical Research, of Southern Oregon, LLC, Medford, OR; Robert Rochester, NY; Susan Wehle, MD, ICSL-Clinical Kloner, MD, Los Angeles Cardiology Assoc, Los Studies, Brandon, FL; Gerald D Wolfley, MD, Hill Angeles, CA; Robert Leff, MD, Hill Top Argus

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