Baseline Characteristics and Early Blood Pressure Control in the CONVINCE Trial
Abstract—Blood pressure (BP) control rates around the world are suboptimal. Part 2 of the National Health and Nutrition Educational Survey (NHANES) III indicates that only 27.4% of hypertensive Americans aged 18 to 74 years have a BP of <140/90 mm Hg. We wanted to assess BP control during the first 2 years and to describe the baseline characteristics of patients enrolled in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Study, an international clinical trial that compares outcomes in hypertensive patients randomized to initial treatment with either controlled-onset extended-release verapamil or the investigator’s choice of atenolol or hydrochlorothiazide. At randomization, BP was <140/90 mm Hg in only 20.3% of the 16 602 subjects (average±SD age 65.6±7.4 years; 56% women, 84% white/7% black/7% Hispanic). The average BP at enrollment was 148/85 mm Hg for patients taking BP medications (n=13 879) and 161/94 mm Hg for previously untreated patients (n=2723). After medication titration, with a transtelephonic computer that recommended an increase in the dose or number of antihypertensive agents whenever the BP was 140/90 mm Hg, 84.8% of the subjects attained the goal BP. During 2 years of treatment, BP control was maintained in 67% to 69% of the subjects (69% to 71% for systolic BP of <140 mm Hg and 90% for diastolic BP of <90 mm Hg). These data suggest that the control of systolic BP is more difficult than the control of diastolic BP. The US national goal of having 50% of hypertensives with a BP of <140/90 mm Hg may be achievable if a forced titration strategy is used. Interested investigators, free care and medications, and well-educated subjects may make the attainment of such a goal easier in the CONVINCE study than in the general population.
Recent data from several countries indicate that hypertension is not being well controlled.1 2 3 4 In the United States, Healthy People 2000 set a goal of having 50% of hypertensives with a blood pressure (BP) of <140/90 mm Hg, but recent data from many sources indicate this target is not being met.3 Part 2 of the National Health and Nutrition Educational Survey (NHANES) III indicates that only 27.4% of US hypertensives (aged 18 to 74 years) have a BP of <140/90 mm Hg, even when measured in the subject’s home by specially trained visiting nurses.5 Data from several surveys (often based on the Health Plan Employer Data Information Set [HEDIS]) indicate that few organized medical care delivery systems attain the recommended level of BP control.6 7 8 9 Many reasons for the lack of hypertension control have been suggested, including nonadherence to medications, limited availability of medications, and unwillingness to intensify treatment (by either patient or physician).10 11 12
The Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Study is a double-blind, randomized, international clinical trial that compares 2 initial treatments for hypertension. One treatment begins with a physician-directed choice of hydrochlorothiazide (HCTZ) or atenolol, and the other treatment begins with controlled-onset extended-release (COER) verapamil (Covera-HS; Searle Pharmaceuticals). The protocol for this study includes an increase in antihypertensive medication (in either dose or number of agents) whenever the BP is not at goal (<140/90 mm Hg).13
The CONVINCE Study therefore provides an excellent opportunity to examine the extent of BP control in a clinical trial in which forced titration of antihypertensive medication is recommended whenever the BP is ≥140/90 mm Hg.
Subjects and Methods
Because of the large number of sites, which span half of the world, a simple automated transtelephonic system (interactive voice response system [IVRS]) was used for randomization, assignment, and tracking of subjects and blinded medication. A 1-page case report form that summarizes data for each subject at randomization (and every 6 months thereafter) was faxed to a central location (PAREXEL International, Waltham, Mass).
Once an eligible subject provided signed informed consent, site personnel called the IVRS using a toll-free number. With a touch-tone keypad, the caller entered the subject’s birthdate, gender, verification of inclusion and exclusion criteria, and confirmation of signed informed consent. The IVRS then generated the blinded treatment assignment, maintaining a continuously updated registry of enrolled subjects and their characteristics. On the completion of enrollment, the data were transferred electronically to the Data Coordinating Center (Coordinating Centers for Biometric Research at the University of Minnesota), which prepared summaries and tables that described the enrolled subjects. Blood pressure data were gathered with the same system during office visits at least every 6 months. Most subjects visited a clinical site at monthly intervals for titration of drug therapy until the BP was <140/90 mm Hg (“End of Titration (EOT)”).
Revision of Sample Size
The formal results of the power calculation and related assumptions have been published.13 The sample size was increased from 15 000 to 16 600, because the rate of subjects who discontinued blinded study medication exceeded expectations.
Statistics and Comparisons
The baseline characteristics are reported as mean±SD for continuous variables. We used χ2 tests to compare the characteristics of participants taking a diuretic versus a β-blocker as the standard of care (SOC) choice.
From September 30, 1996, through December 18, 1998, 16 602 subjects were randomized from 661 clinical sites in 15 countries. Approximately 70% of CONVINCE subjects were enrolled in the Americas (Table 1⇓). The average number of participants per site was 25. The site with the highest enrollment randomized 195 subjects; 18 sites randomized >100 subjects. Sixty-six additional sites exceeded the initial recruitment goal of 50 subjects, and 43 additional sites enrolled 41 to 50 subjects. Bulgaria, the country with the third largest enrollment (7.6% of the total), had nearly 3 times the overall average number of subjects per clinical site. Spain and Israel (5.0% and 4.2% of total enrollment, respectively) had the highest rate of recruitment (number of subjects per clinical site per month of participation).
The average CONVINCE participant was 65.6±7.4 (SD) years old at entry, with the women slightly older (66.0±7.6 years) than the men (65.0±7.1 years). Twenty-five percent of the CONVINCE participants were between 55 and 59 years old at randomization; 23.7% were between 60 and 64 years old and 22.1% were between 65 and 69 years old, with declining percentages of older individuals. Fifteen subjects (0.1%) were ≥90 years old, 1.0% were 85 to 89 years old, 3.2% were 80 to 84 years old, 9.1% were 75 to 79 years old, and 15.8% were 70 to 74 years old. The average age of CONVINCE subjects varied little among the participating countries: the lowest mean age was in Bulgaria (62.0 years old), and the highest mean age was in the United Kingdom (67.0 years old).
More women than men were enrolled in CONVINCE: 9300 (56.0%) compared with 7302 (44.0%), respectively. The gender distribution between countries varied more than did the differences in average age. The greatest percentage of enrolled women was in Mexico (68.3%), and the lowest was in the Czech Republic (45.6%).
The race/ethnicity of CONVINCE participants (determined according to the self-report of each subject) was generally representative of the country of origin. Overall, 83.9% of the CONVINCE participants were white, 7.0% were black, 7.0% were Hispanic, 1.6% were Asian, and 0.5% were of “Other” race/ethnicity. These totals reflect the local custom in assignment of race/ethnicity: all participants from Spain except 1 were categorized as “Caucasian”; all 282 Mexican subjects were categorized as “Hispanic.” In the United States, 74.2% of those recruited in CONVINCE were white, 13.9% were black, 10.9% were Hispanic, 0.6% were Asian, and 0.4% were of “Other” race/ethnicity; these percentages are very similar to those of the general US population.14 15 Canadian CONVINCE participants also closely matched their national ethnic makeup: 91.8% were white, 6.0% were Asian, 0.8% were black, 0.3% were Hispanic, and 1.1% were “Other.”
Treatment for Hypertension
Most participants (83.5%) were taking drug therapy for hypertension at the time of enrollment. There was, however, a very wide variation among countries: in Germany, only 33% of the 69 participants were taking antihypertensive drug therapy at enrollment compared with 97% of the 71 subjects enrolled in the Czech Republic. Because individuals already on treatment had only to switch from their previous antihypertensive drug regimen to blinded CONVINCE study medication at enrollment, it is not possible to determine what level (or stage) of untreated hypertension they would have had. Their average BP at enrollment was 148.0±15.7/85.4±9.5 mm Hg. The highest average on-treatment BPs were found in Germany (159.1/92.4 mm Hg, n=69) and Sweden (156.6/90.4 mm Hg, n=262); the lowest average systolic BP was found in the Czech Republic (144.1 mm Hg), and the lowest average diastolic BP was found in the United States (83.5 mm Hg).
The average BP of the 2701 subjects not taking antihypertensive medications at enrollment was higher (160.6±13.1/93.9±8.3 mm Hg) than that of the treated individuals, because the protocol required a BP of ≥140/90 mm Hg if a subject was not taking antihypertensive medication. This average BP is similar to that obtained during the placebo run-in phase in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)16 but lower than that in the Hypertension Optimal Treatment (HOT) Study.17
Choice of SOC Treatment
Table 1⇑ shows the percentage of subjects for whom the investigator chose the diuretic (HCTZ) over the β-blocker (atenolol) as the SOC treatment. Despite the concerns of some regarding the efficacy of β-blocking agents in preventing cardiovascular complications in older hypertensive subjects,18 54% of the subjects in CONVINCE had atenolol chosen for them by their physician-investigator. The choice between the diuretic or the β-blocker showed considerable country-to-country variation, probably reflecting country-specific practice preferences. At the extremes, 72.5% of the 823 Spanish subjects had the diuretic chosen for them compared with only 22.7% of the 71 Slovakian subjects.
As seen in Table 2⇓, the SOC choice varied by subgroup. Among men, 57.1% had atenolol chosen (over HCTZ) by their treating physician-investigator compared with 50.8% for women. The β-blocker was more commonly chosen than the diuretic in subjects who had previously had antihypertensive drug therapy (86.5% versus 80.4%). We do not know whether this represents more known coronary or other cardiovascular disease or its risk factors among the men, a reflection of previous adverse experiences with one or the other agent, or a greater propensity of diuretics to cause male sexual dysfunction.19 20 21 The physician-investigators tended to prefer the β-blocker over the diuretic in younger subjects (55% of those <70 years old) and the diuretic over the β-blocker in older subjects (51% of those ≥70 years old). This may be in accordance with clinical trial data in older patients that suggests better outcomes when diuretics are used compared with β-blockers.18 Blacks and Hispanics were the only racial/ethnic groups who showed a significant preference for a specific SOC choice. The physician-investigators chose HCTZ for 59% of blacks and atenolol for 72% of Hispanics.
Risk Factor Profile
The distribution of traditional cardiovascular risk factors observed on enrollment of the 16 602 subjects into CONVINCE is shown in Table 3⇓. Although only 1 additional risk factor was required for eligibility, nearly half (49.4%) of the CONVINCE subjects had >1 additional traditional risk factor. Because individual risk factors increase the future risk of cardiovascular events more than additively, the 3.2 risk factors present in the CONVINCE study population (including age in 100% and male gender in 44%) suggest that this cohort is at an even greater risk for future cardiovascular events than was shown in other recent studies.16 17 22 23 24 There was, again, a high between-country variation of the plurality of risk factors: the countries with the largest number of risk factors were Poland, Hungary, and Slovakia; the United Kingdom and Sweden enrolled patients with the fewest risk factors.
BP Control Rates
At randomization, only 20.3% of subjects had controlled hypertension (<140/90 mm Hg); this increased to ≈85% (at EOT) and remained relatively stable at ≈70% during the first 2 years of follow-up (Figure 1⇓). At every time point, control of diastolic BP (to <90 mm Hg) was achieved in a higher proportion of subjects than was control of systolic BP (to <140 mm Hg). Because the CONVINCE study protocol recommended intensified therapy whenever BP was 140/90 mm Hg, many subjects were treated with >1 antihypertensive medication; this proportion also increased during the time of follow-up (Figure 2⇓). Subjects not taking antihypertensive medication at enrollment achieved slightly better BP control, both at EOT (87.4% versus 84.3% for treated subjects) and subsequently (69% to 74% versus 64% to 69%). Even at 1 month after randomization, initially untreated subjects had slightly lower average BPs (144±16/84±9 mm Hg) than did previously treated subjects (148±19/85±10 mm Hg).
These data indicate that at randomization in this clinical trial, only 20% of subjects had controlled hypertension, but the proportion increased substantially (to ≈85%) during forced titration of antihypertensive medications and then leveled off at ≈70% during 2.5 years of follow-up. Like many other recent clinical trials16 17 25 and other studies,26 27 28 the subjects in CONVINCE were more likely to achieve the diastolic BP target of <90 mm Hg than the systolic target of <140 mm Hg, as recommended by Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)29 and World Health Organization–International Society of Hypertension (WHO-ISH) guidelines.30
Compared with other recent hypertension trials, CONVINCE has the highest proportion of enrolled subjects with controlled BPs. At 12 months after randomization, the ALLHAT Research Group reported that 53% of their 14 722 subjects had a systolic BP of <140 mm Hg31 ; the corresponding value for CONVINCE is 71.4%. The Losartan Intervention For Endpoints (LIFE) Study reported that only 25.8% of their 9194 subjects had a systolic BP of <140 mm Hg at 12 months.32
These data have several potential limitations. Subjects who are lost to follow-up or who missed scheduled visits may have poorer control of BP. Also, the better BP control observed during follow-up may be due in part to regression to the mean if participants with poorer BP control on treatment at entry were more likely to be selected for enrollment. The risk assessment for CONVINCE subjects may underestimate the true risk of cardiovascular events because not each subject was systematically assessed for all risk factors. Eligible subjects for CONVINCE needed only to have documented presence of hypertension and 1 additional traditional cardiovascular risk factor. Some subjects are therefore likely to have risk factors that were not identified at randomization, which put them at higher risk than the estimates given earlier. The CONVINCE Executive Committee consciously decided to document only the presence of known risk factors (over, for instance, making a distinction between a “present, absent, or unknown” risk factor), because of the desire to (1) mimic ordinary clinical practice, (2) maximize enrollment and generalizability of the conclusions, and (3) minimize data collection, and cost. Thus, CONVINCE conforms to the “large, simple trial” paradigm.33
These data indicate that a high prevalence of BP control (<140/90 mm Hg) can be achieved in a large hypertensive population if a forced titration strategy is used and medications are provided without charge to motivated subjects by well-trained healthcare providers. These features of CONVINCE may make it easier to achieve a higher level of BP control in this clinical trial than in the general population.
List of CONVINCE Committees and Investigators
Henry R. Black, MD, Chair (Primary Principal Investigator); Robert J. Anders, PharmD (ex-officio); Tracy Lucente, CONVINCE Senior Project Director (ex-officio); Richard H. Grimm, Jr, MD, PhD; Lennart Hansson, MD, PhD; Yves Lacoucière, MD; James Muller, MD; James D. Neaton, PhD (ex-officio); Peter Sleight, MD; Michael A. Weber, MD; William B. White, MD; Gordon Williams, MD; Janet Wittes, PhD; Alberto Zanchetti, MD; and a PAREXEL representative (ex-officio).
William B. White, MD, Chair; William C. Cushman, MD; William A. Frishman, MD; Norman K. Hollenberg, MD, PhD; Thomas G. Pickering, MD, DPhil; Thomas R. Price, MD; and Dominic A. Sica, MD.
Publications and Ancillary Studies Committee
Richard H. Grimm, Jr, MD, PhD, Chair; Stephen P. Glasser, MD; Gregory M. Grandits, MS; Suzanne Oparil, MD; Ronald M. Prineas, MBBS, PhD; and Carolyn Kong (ex-officio).
Data Safety and Monitoring Board
Lawrence S. Cohen, MD, Chair; Lawrence M. Brass, MD; David DeMets, PhD; Charles K. Francis, MD; Daniel M. Kolansky, MD; and Richard C. Pasternak, MD.
CONVINCE Principal Investigators (by country, with country leader listed first)
Decio Mion, Jr, Fernando Antonio de Almeida, Iran Castro, Paulo Cesar B. Viega Jardim, Osvaldo Kohlman, José Joaquim Fernandes Rapozo Filho, Salvador Rassi, José Márcio Ribeiro, Antonio Silveira Sbissa.
Tihomir Dascalov, Atanas Djurdjev, Anna Elenkova, Mladen Grigorov, Vallentina Grigorova, Roumiana Kermova-Grigorova, Christo Kojukharov, Georgi Kussitasev, Svoboda Lovdjieva, Stefan Mantov, Choudomir Nachev, Nikolay Iordanov Penkov, Svetla Torbova, Christo Blagoev Tsekov.
Yves Lacourcière, Carl Abbott, Michael Alexander, Don Allan, Ronnie Aronson, John Atherstone, Marie-Claude Audet, Murray Awde, Gordon Bailey, Robert Beattie, Michael Bentley-Taylor, Bruno Bernucci, Peter Bolli, Remi Bouchard, Ted Brankston, Ellen Burgess, Mathew Burnstein, Denis Callaghan, J. Harry Callaghan, Douglas Carmody, Richard Casey, Josette Castel, Martyn Chilvers, Paolo Costi, Benoit Coulu, David Crowley, I. Dan Dattani, John Davies, Jacquest de Champlain, Eric Deemsted, Sanjay Dhingra, Frank Doane, Peter Dzongowski, Connie Ellis, Neil Filipchuk, Daniel Garceau, Roger Hamilton, Paul Handa, Roy Harding, Kenneth Heaton, Breet Hennefant, James Hii, Kkandker Hoque, Marc Houde, William Hughes, Jamie Hynd, Saul Isserow, Christopher Janz, Martin Juneau, David Kendler, Carter Kennedy, Mahesh Khurana, Jan Kornder, Simon Kouz, Christopher Lai, Daniel Landry, High Langley, Pierre Larochelle, Claude Lauzon, Jacobson Le Roux, Roland Leader, Monique LeBlanc, Larry Leiter, Jacquest Lenis, Richard Lewanczuk, John Li, Robert Luton, Patrick Ma, Jonathan MacKenzie, Jamuna Makhija, Dan Malone, Jean-Marie Martel, Murray Matangi, Grant Matheson, Guiseppe Mazza, Tom McAvinue, Sheila McGrath, William McKeough, Jeanne McNeill, Pravine Mehta, Adrien Melanson, Karim Merali, Phil Morris, Robert Morrison, Shah Nawaz, Robert Nitkin, Brian O’Kelly, William O’Mahony, Robert Orchard, Yves Pesant, Robert Petrella, Denis-Carl Phaneuf, Eric Poulin, Brendan Quinn, J. Lloyd Reddington, Maurice Roy, Terrance Ruddy, Luis Salgado, Michel Sauve, Daniel Savard, Gulshan Sawhney, Larry Schmidt, Vyta Senikas, Daniel Shu, Duncan Sinclair, Randell Smith, David Spence, Richard St-Hilaire, James A. Stone, Bruno St-Pierre, Jim Swan, Paul Talbot, Kim-Weng Tan, Sheldon Tobe, Luc Trudeau, Alain Vanasse, Pradeep K. Vohora, Lorne Weiner, Richard Whatley, Paul Whitsitt, Mark Wilkinson, Noel Wright, Henry Wu.
Milena Kubickova, Renata Cifkova, Ivan Gregar, Petr Jansky, Helena Nemcova, Petr Petr, Ivana Popdrapska, Borivoj Semrad, Jarmila Siegelova, Miroslav Soucek, Zdenek Vomacka, Eva Zidkova.
Roland Schmieder, Holger Kinkernagel, Stefan Gesenhues, Ranier Häge, Jürgen Steinhauer, Henning Wiswedel, Wolfram Zingler.
Csaba Farsang, Miklos Csanady, Istvan Edes, Katalin Fugedi, Tamas Gexatesi, Czuriga Istvan, Tarjan Jeno, Ilona Pap, Andras Papp, Julit Rapi, Gyorgy Sallai, Matyas Sereg, Ferenc Szaboki, Sandor Timar, Peter Valyi, Gabor Veress.
Reuven Viskoper, Ben Ben-Valid, Lora Bregman, Henya Brenner, Hedi Feibel, Jos’ Fidel, Horla Flandra, Cilia Furman, Uzi Gafter, Jihad Ghanem, Adiv Goldhaber, Israel Hochman, Adrian Iaina, Gennady Katz, Eldad Kisch, Natan Lederman, Israel Lupinski, Alon Margalit, Oscar Minuchin, Joseph Mishael, Olga Moskovich, Shmuel Oren, Ester Paran, Eduardo Podjarni, Joseph Rosenfeld, Eli Rottenstreich, Roza Schneider, Pessah Shvartsman, Eugene Shveydel, Natali Shveydel, Naftali Stern, Alexander Strolovich, Hava Tabenkin, Joshua Weissgarte, Yoram Yagil, Chaim Yosefy, Hoze Zabludowski, David Zacharovitch.
Alberto Zanchetti, Paolo Alboni, Ettore Ambrosioni, Gianluigi Barbi, Santo Branca, Alberto Caiazzza, Giovanni Cerasola, Nino Ciampani, Giuseppe Crippa, Antonio D’Avanzo, Umberto De Martino, Giuseppe De Venuto, Ezio Degli Esposti, Valter Donadon, Michele Guglielmi, Giuseppe Licata, Francesco Locatelli, Carlo Martines, Andrea Mezzetti, Lucio Mos, Ernesto Mossuti, Angelo Musco, Carlo Pasotti, Francesco Pellegrini, Anna Pirrelli, Alessandro Rappelli, Piera Recalcati, Esio Ronchi, Ermanno Rossi, Paolo Saba, Antonio Salvetti, Anna Santucci, Mauro Sasdelli, Guiseppe Seghieri, Andrea Semplicini, Umberto Senin, Ernesto Sgarbi, Evandro Tascione, Giancarlo Torregiani, Alvaro Vaccarella, Liugi Vigna, Michele Zito.
Jorge Herrera Abarca, Pedro Fajardo Campos, Demetrio Kosturakis Garcia, Francisco Javier Gue Martinez, Jose Luis Leiva Pons, Humberto Rodriguez M. Reyes, Raul Gerardo Velasco Sanchez, Eugenio Rusga Zamora, Roberto Bravo Zamudio.
Alicja M. Kostecka-Pokrysko, Marianna Janion, Krystyna Jaworska, Marek Jedras, Barbara Kusnierz, Michal Ogorek, Wojciech Sodolski, Henryk Swierzy, Eugeniusz Szmatloch, Bozena Raszeja Wanic.
Andrej Dukat, Jozef Gonsorcik, Gabriela Kaliska, Maria Radomska, Alexandr Ruttkay, Rafael Rybar.
Luis-Miguel Ruilope, Jose-Javier Antón, Joaquin Aracil, Pedro Aranda-Lara, Julián Arenas, Andrés Ariza, Juan-Francisco Ayala, Manuel Barcariza, José Barber, M. Jesús Barreda, Manuel-Carlos Barreiro, Joan Bayó, Pedro Cabrera, Carlos Calvo-Gómez, Isable Camé, Jesús Chamorro, Josep Closas, Antonio Coca-Payeras, Natividad Cordero, Rodrigo Córdoba, Juan-Ramón Cuervo, Antoni Dalfó, José-Javier De-Castro, Alberto-J. del-Alamo, V. del-Yerro, Rafael Durá, Severo Fernandez, Angel-Pedro Fernández, Ramón Ferrer, Juan-Eugenio Forcada, Vidal Francisco-Javier, José-Javier Garcia, Blas Gil-Extremera, Manuel Gómez, Apolo Gonzáles, Gonzol Iriarte, Juan-Jose Jimenez, Jose-Ignacio Jimenez, Pedro Jimenez, Jose Luis Llisterri, Jesús López, Carlos López, Juan-Carlos López, Francisco-Javier Lora, Alberto-J. Ma-Jesus, Agustin Martinez, Jesús Martin-Garcia, Fernando Mato, Agustin Minguez, José-Ramón Moliner, Francisco Morales, Manuel Nieto, Javier Nieto-Iglesias, Esther Nuñez, Diego Nuñez, Josefina Oliván-Martinez, Francisca Paniagua, Juan-Carlos Pedrosa, José-Francisco Pensado, Julio Perete, Alvaro Pérez, Pablo Pérez-Luengo, Ascunción Peset, Jaume Plana, M. Angeles Pontes, Miguel-Angel Prieto, Luis-Antonio Ramilla, Salvador Rey, Mercedes Rodriguez, Carlos Rodriguez, Rafael Roldan, Victor Romero, Montserrat Roures, Manuel Royo, Antonio Ruiz, Jaime Ruiz, Aldjandro Salanova, M. Amor Sanchez, Javier Sobrino, Josep Soler, José-Luis Tena, Fernando Torguet, José Torres, Irama Valero, Fernando Veiga, Jose-Félix Zuazagoitia.
Hansson, Lennert, Valeria Ahgren, Hakan Ahlander, Thomas Angerbjörn, Lars-Erik Bergdahl, Hillevi Blom-Pfeiffer, Mats Boström, Thomas Brydolf, Bo Erik Kristensson, Georg Dahlen, Kent Ekenbratt, Ulla Britt Ericsson, Birger Fagher, Lars Fröberg, Magnus Geirsson, Juha Harju, Thomas Hedner, Christer Höglund, Thomas Hoheisel, Stefan Hofvendahl, Gunilla Johansson, Saima Jönsson, Ingemar Luttu, Hans Nerell, Jan Ostergren, Jan Östergren, Lars Ostling, Anna Maria Ottosson, Martin Rosengren, Aru Sandanam, Sigge Strid, Bengt Svensson, Lars Svensson, Bengt-Olov Tengmark, Thomas Thulin, Claes de Verdier, Per Westerholm.
Peter Sleight, David Birrell, Mark Blagden, Ian Clark, David Dutchman, Iain Gordon, Nigel Guest, Michael Haughney, David Huggan, Mokshad Kansagra, James Kay, Brian Lennox, Graham Martin, Grant McHattie, Douglas McKeith, Surendra Misra, Peter Mooney, Michael Mutch, Derek Neilson, Mark Reid, Christopher F. Rose, John Ross, Daya Sugar, Pauline Shearer, Barry Silvert, Roger Snook, Rory C. F. Symons, John Vernon, J. Zachariah.
Henry R. Black, Ali Abdul, Marwan Adjan, Allen B. Adolphe, Jorge Luis Aguilera-Montalvo, Alexander Alvarez, Larry Amacker, Jay Anders, Coleen Andruss, Jose S. Aponte, Jeffrey T. Apter, Peter Arcuri, H. Morgan Ashurst, Gerard P. Aurigemma, Herman Ayvazyan, James Bates, Mark A. Becker, John Bennett, Paul Benson, Lynn Bentson, Joan Benz, James Bergthold, Manick Bhardwaj, Dennis Bloomfield, Zachary T. Bloomgarden, Merle Bolton, Jeffrey L. Boone, Kenneth Boren, Ira R. Braverman, Carlos L. Brown, III, Nate Brown, Robert Burns, Bruce Burtenshaw, David A. Calhoun, James R. Campbell, Barry Caparoso, Mark Capkin, Raymond Carlson, Barry L. Carter, Inge R. Carter, Richard S. Castaldo, Robert Cesarec, C. Kohler Chapmion, Tien C. Cheng, Andrew Chubick, Robert Ciemiega, Mehmood A. Ckan, Irving M. Cohen, Selwyn A. Cohen, Harry T. Colfer, Salvatore Conte, Clinton N. Corder, Marcelo Corpuz, Bruce Corser, Robert E. Cronin, Thomas Crouch, Jairo B. Cruz, Rebecca Dailey, Michael Daniels, Richard H. Davis, Donald M. Denmark, Dolph Martel Denny, Bart G. Denys, Marcus A. DeWood, Edward J. Diamond, Richard Dickstein, Phillip M. Diller, Steven Dorfman, Steven L. Duckor, Gary Dunkerley, Donald C. Durbeck, M. El Shahawy, Samer Helm Ellahham, William J. Elliott, Georg Emlein, Gary P. Erdy, Michael Famularo, James Farrell, Hebert Fendley, Paul Fenster, James I. Fidelholtz, Justus J. Fiechtner, Larry Fields, Eugene C. Fletcher, Rex W. Force, Carl Franzetti, Francisco Fuentes, Lonnie E. Fuller Sr., John T. Funai, Marvin Galler, Walter Gaman, Garo S. Garibian, Gumaro Garza, M.R. Gedeon, Michael J. Germain, Steven Glasser, Richard L. Glenn, Sudheer T. Gogte, Ivan L. Goldsmith, Robert J. Goldstein, G.M. Gollapudi, Stephen L. Goss, Atul Goswami, Richard D. Goulah, Ray Graf, Alan Graff, Daniel Gremillion, Clarence Grimm, Colby H. Grossman, Ambrish Gupta, Narendra K. Gupta, Alexander Halkos, Robert J. Harriman, Clyde Harris, Jennifer Hedgepeth, Lynn Helmer, Mario Henriquez, Bradley T. Heppner, Donald K. Hickey, James R. Hill, Matthew Hilmi, Jon Hobson, Judith S. Hochman, Susan Hole, Joanne J. Holland, Lynne Hopkins, Mark Houston, Donald Hunninghake, Carmen D. Irizarry, Sima Issen, Syed Jafri, Avanindra Jain, Michael J. Jamieson, Oswaldo Jimenez, Joseph P. Johns, Kjel Johnson, Wayne H. Kaesemeyer, Richard O. Kamrath, Roy Kaplan, Ronald Karlsberg, H.B. Karunaratne, Gerald Keightley, James Kern, Chet Kessler, Rashid A. Khairi, Vithal Kinhal, Timothy Klein, Gary E. Kolb, Michael J. Koren, Gregory Koshkarian, Marc Kozinn, Jeffrey Kramer, Seth Krauss, Barry Kricsfeld, Steven Kulback, Peter Kurzweil, Niranjan Lal, Victor Lamin, John A. Larry, Gary M. Lattin, Robert Lee, Theodore E. Lefton, Peter M. Lemis, James Lewis, Loren Lipson, Thomas Little, Peter A. Lodewick, Charles Lucas, Sofia X. Scholar Luisa, Jane Lyssy, Gregory MacDonald, Adrian Magee, Frank Maggiacomo, Craig Maltman, Richard A. Margolin, Charles Margolis, Allan Markus, Barry L. Marmorstein, David G. Marsh, Thomas Martin, Michael Marzec, Daniel Masacarenhas, Brian McCarroll, Mary P. McGowan, Kenneth G. McGrath, Robert D. McInroy, Michael E. McIvor, Timothy Menelly, Franz Messerli, Delbert H. Meyer, Donald W. Middleton, Jr, Felise Milan, Michael Miller, Kelly Mills, Mahendra Mirani, Michael J. Mirro, C. Brendan Montana, Marc Morse, Herbert Moskow, Harvey A. Mossman, William Mroczek, Andrew Muckle, Cynthia Mulrow, Marc A. Munger, Uttam O. L. Munver, David Nash, Jeffrey Newman, Albert Olash, Jr, Roger On, John Ondrejicka, Stephen Ong, Ramin Oskoui, Meenakshi Patel, Tushar C. Patel, Andres Patron, Davita Persaud, Subhash Popli, R. Walter Powell, Rajendra Prasad, William Prechel, Dustan F. Pulle, John Pullman, Gary P. Reams, Jerry A. Reed, Harvey Resnick, Arthus Riba, Ralph W. Richter, Kenneth Rictor, Dennis Riff, Peter Ripley, Terry A. Riske, Daniel Risser, Ernesto Rivera, Jose R. Rivera del Rio, Mohammad Rizwan, Douglas Roberts, Jerry W. Robinson, Thomas Rocco, Daeyoung Roh, Robert S. Rood, Steven J. Rosansky, Herman Rose, Eli M. Roth, Robert Rouchon, Michael R. Rubin, Michael C. Ruddy, Kenneth Russ, Philip Sager, Bradley R. Sakran, Gilbert Salazar, Tariq Saleem, Albert M. Salomon, Raul Sanchez-Ramos, Milton Sands, Francisco A. Santini-Oliveri, Deepak Sant-Ram, Frederick W. Schaerf, Frederick Schaller, Ricky Schneider, John F. Seaworth, Eric Seyferth, Rajnikant Shah, Louis Shane, Jeffrey G. Shanes, Charles J. Sigmund, Anthony Silvagni, Stuart J. Simon, Satesh C. Singh, Sudeep Singh, Stan F. Slabic, John Sobolski, William Sokol, Jr, John C. Somberg, Devendra Soni, John Sorensen, Neal B. Sorensen, Vincent Sorrell, Miguel Sosa-Padilla, Daniel Sporn, Allan Stahl, Gregg W. Stone, Henry Stratman, Danny Sugimoto, John E. Sutherland, Louise A. Taber, Addison Taylor, Carmen Texidor, Gerald Timmis, Steven R. Towner, Steven R. Turner, Gregory S. Uhl, Jeffrey R. Unger, Raymond Urbanski, Russell N. Vanhouzen, Jose B. Vazquez-Tanus, Jose Vero-Miro, Michael J. Voyack, Wyatt Voyles, Robert C. Watkins, Jr, Mervyn Weerasinghe, Robert Weinstock, Marion R. Wofford, Nathan D. Wong, Laurence G. Yellen, Ralph Yung, Miguel Zabalgoita, Franklin J. Zieve.
This work was supported by grants and contracts from G.D. Searle & Company (Skokie, Ill).
↵1 A complete list of investigators and their locations appears in the Appendix.
- Received May 16, 2000.
- Revision received June 6, 2000.
- Accepted June 27, 2000.
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