Dabigatran versus Warfarin in Patients with Atrial Fibrillation

Trial Design

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) was a randomized trial designed to compare two fixed doses of dabigatran, each administered in a blinded manner, with open-label use of warfarin in patients who had atrial fibrillation and were at increased risk for stroke. The design of this study has been described previously.⁹

The study was funded by Boehringer Ingelheim and was coordinated by the Population Health Research Institute (Hamilton, ON, Canada), which independently managed the database and performed the primary data analyses. An operations committee, with assistance from an international steering committee and with participation by the sponsor, was responsible for the design, conduct, and reporting of the study. The study was approved by all appropriate national regulatory authorities and ethics committees of the participating centers. All the authors vouch for the accuracy and completeness of the data and the analyses.

Study Participants

Patients were recruited from 951 clinical centers in 44 countries. In brief, patients were eligible if they had atrial fibrillation documented on electrocardiography performed at screening or within 6 months beforehand and at least one of the following characteristics: previous stroke or transient ischemic attack, a left ventricular ejection fraction of less than 40%, New York Heart Association class II or higher heart-failure symptoms within 6 months before screening, and an age of at least 75 years or an age of 65 to 74 years plus diabetes mellitus, hypertension, or coronary artery disease. Reasons for exclusion were the presence of a severe heart-valve disorder, stroke within 14 days or severe stroke within 6 months before screening, a condition that increased the risk of hemorrhage, a creatinine clearance of less than 30 ml per minute, active liver disease, and pregnancy. (Detailed inclusion and exclusion criteria are available in Table 1 and Table 2 of the Supplementary Appendix, available with the full text of this article at NEJM.org.)

Procedures

After providing written informed consent, all trial participants were randomly assigned to receive one of two doses of dabigatran, or to receive warfarin, by means of a central, interactive, automated telephone system. Dabigatran was administered, in a blinded fashion, in capsules containing either 110 mg or 150 mg of the drug, to be taken twice daily. Warfarin was administered, in an unblinded fashion, in tablets of 1, 3, or 5 mg and was adjusted locally to an international normalized ratio (INR) of 2.0 to 3.0, with the INR measured at least monthly. The time that the INR was within the therapeutic range was calculated with the use of the method of Rosendaal et al.,¹⁰ excluding INRs from the first week and after discontinuation of the study drug. These data were reported back to the participating centers with advice for optimal INR control. Concomitant use of aspirin (at a dose of <100 mg per day) or other antiplatelet agents was permitted. Quinidine use was permitted until 2 years after the trial started, when the protocol was amended to prohibit its use, because of its potential to interact with dabigatran.

Follow-up visits occurred 14 days after randomization, at 1 and 3 months, every 3 months thereafter in the first year, and then every 4 months until the study ended. Liver-function testing was performed monthly during the first year of the follow-up period. On the basis of a prespecified evaluation of liver-function tests in at least 6000 patients in the dabigatran group after they had been followed for 6 months or more, the data safety monitoring board recommended that the frequency of liver-function testing be reduced, with such testing performed only at the regular visits.

Outcomes

The primary study outcome was stroke or systemic embolism. The primary safety outcome was major hemorrhage. Secondary outcomes were stroke, systemic embolism, and death. Other outcomes were myocardial infarction, pulmonary embolism, transient ischemic attack, and hospitalization. The primary net clinical benefit outcome was the composite of stroke, systemic embolism, pulmonary embolism, myocardial infarction, death, or major hemorrhage. Stroke was defined as the sudden onset of a focal neurologic deficit in a location consistent with the territory of a major cerebral artery and categorized as ischemic, hemorrhagic, or unspecified. Hemorrhagic transformation of ischemic stroke was not considered to be hemorrhagic stroke. Intracranial hemorrhage consisted of hemorrhagic stroke and subdural or subarachnoid hemorrhage. Systemic embolism was defined as an acute vascular occlusion of an extremity or organ, documented by means of imaging, surgery, or autopsy. Major bleeding was defined as a reduction in the hemoglobin level of at least 20 g per liter, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. Life-threatening bleeding was a subcategory of major bleeding that consisted of fatal bleeding, symptomatic intracranial bleeding, bleeding with a decrease in the hemoglobin level of at least 50 g per liter, or bleeding requiring transfusion of at least 4 units of blood or inotropic agents or necessitating surgery. All other bleeding was considered minor.

An international team of adjudicators reviewed documents in local languages after blinding, or documents were translated by an independent group and were centrally blinded. Each primary and secondary outcome event was adjudicated by two independent investigators who were unaware of the treatment assignments. All transient ischemic attacks were reviewed to ensure that strokes had not been missed. To detect possible unreported events, symptom questionnaires were regularly administered to patients, and adverse-event and hospitalization reports were scrutinized for unreported primary or secondary outcomes.

Statistical Analysis

The primary analysis was designed to test whether either dose of dabigatran was noninferior to warfarin, as evaluated with the use of Cox proportional-hazards modeling. To satisfy the noninferiority hypothesis, the upper bound of the one-sided 97.5% confidence interval for the relative risk of an outcome with dabigatran as compared with warfarin needed to fall below 1.46. This noninferiority margin was derived from a meta-analysis of trials of vitamin K antagonists as compared with control therapy in patients with atrial fibrillation, with the margin defined according to the upper bound of the 95% confidence interval for the relative risk of the primary outcome in the control group versus the warfarin group.¹¹ The margin of 1.46 represents half the 95% confidence interval of the estimated effect of control therapy over warfarin. To account for testing of both dabigatran doses against warfarin, we planned to determine whether the higher of the two one-sided P values for the two doses was less than 0.025, in which case both treatments would be declared to be noninferior. If the higher of the two one-sided P values was 0.025 or greater, the lower of the two was required to be less than 0.0125 to permit a claim of statistical significance. All analyses were based on the intention-to-treat principle. After noninferiority of both doses of dabigatran was established, all subsequent P values were reported for two-tailed tests of superiority. Cox regression was used to calculate relative risks, confidence intervals, and P values. Chi-square testing was used to compare rates of medication discontinuation and adverse events.

We planned to enroll 15,000 patients, an enrollment that we estimated would provide 84% power to evaluate the noninferiority of each dose of dabigatran. Two protocol changes were made by the operations committee during the enrollment period, without knowledge of emerging treatment effects. These were the enforcement of balanced enrollment of patients who had not received long-term therapy with a vitamin K antagonist (i.e., had a total lifetime use of <61 days) and those who had (i.e., had a total lifetime use of ≥61 days), and an increase in the sample size to 18,000 patients to maintain the statistical power in case of a low event rate. An independent data safety monitoring board reviewed the unblinded study data and performed two prespecified interim analyses of efficacy, with a plan to recommend study termination if the benefit of dabigatran exceeded 3 SD from unity of the parameter estimate and if that benefit persisted on repeat analysis 3 months later.

Characteristics of the Study Patients

Table 1. Table 1. Baseline Characteristics of the Study Participants, According to Treatment Group.

A total of 18,113 patients were enrolled between December 22, 2005, and December 15, 2007. The three treatment groups were well balanced with respect to baseline characteristics (Table 1). The mean age of the patients was 71 years, and 63.6% were men. Half the patients had received long-term therapy with vitamin K antagonists. The mean CHADS₂ score was 2.1 (Table 1).

Follow-up Data

Final follow-up visits occurred between December 15, 2008, and March 15, 2009. The median duration of the follow-up period was 2.0 years, and complete follow-up was achieved in 99.9% of patients, with 20 patients lost to follow-up. The rates of discontinuation for 110 mg of dabigatran, 150 mg of dabigatran, and warfarin were 14.5%, 15.5%, and 10.2%, respectively, at 1 year and 20.7%, 21.2%, and 16.6% at 2 years. Aspirin was used continuously during the treatment period in 21.1%, 19.6%, and 20.8% of patients receiving 110 mg of dabigatran, 150 mg of dabigatran, and warfarin, respectively. In the warfarin group, the mean percentage of the study period during which the INR was within the therapeutic range was 64%.

Primary Outcome

Table 2. Table 2. Efficacy Outcomes, According to Treatment Group.

Figure 1. Figure 1. Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group.

Stroke or systemic embolism occurred in 182 patients receiving 110 mg of dabigatran (1.53% per year), 134 patients receiving 150 mg of dabigatran (1.11% per year), and 199 patients receiving warfarin (1.69% per year) (Table 2 and Figure 1). Both doses of dabigatran were noninferior to warfarin (P<0.001). The 150-mg dose of dabigatran was also superior to warfarin (relative risk, 0.66; 95% confidence interval [CI], 0.53 to 0.82; P<0.001), but the 110-mg dose was not (relative risk, 0.91; 95% CI, 0.74 to 1.11; P=0.34). Rates of hemorrhagic stroke were 0.38% per year in the warfarin group, as compared with 0.12% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.31; 95% CI, 0.17 to 0.56; P<0.001) and 0.10% per year in the group that received 150 mg of dabigatran (relative risk, 0.26; 95% CI, 0.14 to 0.49; P<0.001).

Other Outcomes

Rates of death from any cause were 4.13% per year with warfarin, as compared with 3.75% per year with 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% CI 0.80 to 1.03; P=0.13) and 3.64% per year with 150 mg of dabigatran (relative risk, 0.88; 95% CI, 0.77 to 1.00; P=0.051). The rate of myocardial infarction was 0.53% per year with warfarin and was higher with dabigatran: 0.72% per year in the 110-mg group (relative risk, 1.35; 95% CI, 0.98 to 1.87; P=0.07) and 0.74% per year in the 150-mg group (relative risk, 1.38, 95% CI, 1.00 to 1.91; P=0.048).

Bleeding

Table 3. Table 3. Safety Outcomes, According to Treatment Group.

The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.80; 95% CI, 0.69 to 0.93; P=0.003) and 3.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.93; 95% CI, 0.81 to 1.07; P=0.31) (Table 3). Rates of life-threatening bleeding, intracranial bleeding, and major or minor bleeding were higher with warfarin (1.80%, 0.74%, and 18.15%, respectively) than with either the 110-mg dose of dabigatran (1.22%, 0.23%, and 14.62%, respectively) or the 150-mg dose of dabigatran (1.45%, 0.30%, and 16.42%, respectively) (P<0.05 for all comparisons of dabigatran with warfarin). There was a significantly higher rate of major gastrointestinal bleeding with dabigatran at the 150-mg dose than with warfarin.

The net clinical benefit outcome consisted of major vascular events, major bleeding, and death. The rates of this combined outcome were 7.64% per year with warfarin and 7.09% per year with 110 mg of dabigatran (relative risk with dabigatran, 0.92; 95% CI, 0.84 to 1.02; P=0.10) and 6.91% per year with 150 mg of dabigatran (relative risk, 0.91; 95% CI, 0.82 to 1.00; P=0.04).

Comparison of Dabigatran Doses

As compared with the 110-mg dose, administration of the 150-mg dose of dabigatran reduced the risk of stroke or systemic embolism (P=0.005). This difference was driven mostly by a decrease in the rate of stroke with ischemic or unspecified cause, whereas rates of hemorrhagic stroke were similar in the two dabigatran groups. There was no significant difference in the rates of death from either vascular causes or any cause between the two doses. On the other hand, as compared with the 110-mg dose, the 150-mg dose of dabigatran was associated with a trend toward an increased risk of major bleeding (P=0.052) and also with increased risks of gastrointestinal, minor, and any bleeding. The net clinical benefit was almost identical for the two doses.

Adverse Events and Liver Function

Table 4. Table 4. Discontinuation of the Study Drug, Adverse Events, and Liver Function According to Treatment Group.

The only adverse effect that was significantly more common with dabigatran than with warfarin was dyspepsia (Table 4). Dyspepsia occurred in 348 patients (5.8%) in the warfarin group and in 707 patients (11.8%) and 688 patients (11.3%) in the 110-mg and 150-mg dabigatran groups, respectively (P<0.001 for both comparisons) (Table 4). Elevations in the serum aspartate aminotransferase or alanine aminotransferase level of more than 3 times the upper limit of the normal range did not occur more frequently with dabigatran, at either dose, than with warfarin.

Subgroup Analyses

Figure 2. Figure 2. Relative Risk of the Primary Outcome of Stroke or Systemic Embolism with Dabigatran versus Warfarin, According to Subgroup.

Ethnic group was self-reported. Long-term therapy with a vitamin K antagonist (VKA) denotes a total lifetime use of a VKA of 61 days or more. The body-mass index is the weight in kilograms divided by the square of the height in meters. The CHADS₂ score is a measure of the risk of stroke in which congestive heart failure, hypertension, an age of 75 years or older, and diabetes mellitus are each assigned 1 point and previous stroke or transient ischemic attack is assigned 2 points; the score is calculated by summing all the points for a given patient.¹² Creatinine clearance was calculated according to the Cockcroft–Gault method. The squares with horizontal lines are hazard ratios and corresponding 95% confidence intervals; the sizes of squares are proportional to the sizes of the subgroups. PPI denotes proton-pump inhibitor.

For the subgroups shown in Figure 2, no significant interaction was seen with the treatment effect of dabigatran (at either dose). There was no significant interaction between the treatment effect of dabigatran and presence or absence of long-term therapy with a vitamin K antagonist. Although 80% of the dabigatran dose is renally excreted, there was no significant interaction in the treatment effect of dabigatran across levels of the baseline calculated creatinine clearance.

We compared two fixed-dose regimens of dabigatran (110 mg twice daily and 150 mg twice daily), administered in a blinded fashion, with adjusted-dose warfarin, administered in an unblinded fashion, in patients who had atrial fibrillation and were at risk for stroke. Both dabigatran doses were noninferior to warfarin with respect to the primary efficacy outcome of stroke or systemic embolism. In addition, the 150-mg dose of dabigatran was superior to warfarin with respect to stroke or systemic embolism, and the 110-mg dose was superior to warfarin with respect to major bleeding.

Previous studies seeking to identify a safe and effective alternative to warfarin for patients with atrial fibrillation have all had specific limitations. The combination of clopidogrel and aspirin was more effective than aspirin alone¹³ but less effective than warfarin.¹⁴ Subcutaneous idraparinux was more effective than warfarin but was associated with a substantially higher risk of bleeding.¹⁵ Ximelagatran, an earlier direct thrombin inhibitor, appeared to be similar to warfarin with respect to efficacy and safety but was found to be hepatotoxic.¹⁶ In our serial measurement of liver function, we did not find evidence of hepatotoxicity with dabigatran.

The rate of myocardial infarction was higher with both doses of dabigatran than with warfarin. An explanation might be that warfarin provides better protection against coronary ischemic events than dabigatran, and warfarin is known to reduce the risk of myocardial infarction.¹⁷ However, rates of myocardial infarction were similar between patients with atrial fibrillation who were receiving warfarin and those who were receiving ximelagatran, another direct thrombin inhibitor.¹⁶ The explanation for this finding is therefore uncertain.

The most devastating complication of warfarin therapy is intracranial hemorrhage, especially hemorrhagic stroke. As compared with aspirin, warfarin doubles the risk of intracranial hemorrhage.¹ Thus, our finding that the rate of this complication with both doses of dabigatran was less than one third the rate with warfarin, without a reduction in the efficacy against ischemic stroke, suggests an important advantage of dabigatran. The rate of major bleeding with warfarin was higher in our study than in some previous trials.^11,13,14 This is partly explained by the more inclusive definition of major bleeding in our study. There was an increase in the rate of gastrointestinal bleeding with the higher dabigatran dose, despite the overall lower rates of bleeding at other sites. To enhance absorption of dabigatran, a low pH is required. Therefore, dabigatran capsules contain dabigatran-coated pellets with a tartaric acid core. This acidity may partly explain the increased incidence of dyspeptic symptoms with both dabigatran doses and the increased risk of gastrointestinal bleeding with the 150-mg dose.

The benefit of dabigatran may be explained in part by the twice-daily dosing regimen. Since dabigatran has an elimination half-life of 12 to 17 hours, twice-daily dosing reduces variability in the anticoagulation effect, especially as compared with the anticoagulation effect of warfarin, which is difficult to control. Warfarin broadly inhibits coagulation (inhibiting factors II, VII, IX, and X and proteins C and S). By selectively inhibiting only thrombin, dabigatran may have antithrombotic efficacy while preserving some other hemostatic mechanisms in the coagulation system and thus potentially mitigating the risk of bleeding.

The use of open-label warfarin could have introduced a bias in the reporting or adjudication of events. This risk was reduced by the implementation of several validated procedures, including blinded evaluation of outcome events. The unexpectedly different rates of myocardial infarction and gastrointestinal bleeding among the three treatment groups support an absence of bias. Control of anticoagulation with warfarin in our study was similar to that in previous international clinical trials, even though half our patients had not previously had extensive treatment with warfarin.^10,17

The net clinical benefit outcome, which is a measure of the overall benefit and risk, was similar between the two doses of dabigatran, owing to the lower risk of ischemia with the 150-mg dose and the lower risk of hemorrhage with the 110-mg dose. These findings suggest that the dose of dabigatran could potentially be tailored to take into consideration the risk characteristics of a specific patient, although this concept was not specifically tested in our trial.

In conclusion, we compared two doses of dabigatran with warfarin in patients who had atrial fibrillation and who were at risk for stroke. As compared with warfarin, the 110-mg dose of dabigatran was associated with similar rates of stroke and systemic embolism and lower rates of major hemorrhage; the 150-mg dose of dabigatran was associated with lower rates of stroke and systemic embolism but with a similar rate of major hemorrhage.

Members of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Study Group are as follows (a full list of investigators is included in the Supplementary Appendix): Operations Committee: S.J. Connolly (principal investigator), M.D. Ezekowitz (principal investigator), S. Yusuf (chair, steering committee), J. Eikelboom, J. Oldgren, A. Parekh, P.A. Reilly, E. Themeles, J. Varrone, S. Wang, E. Palmcrantz-Graf, M. Haehl, L. Wallentin (chair, steering committee). Steering Committee: A.M.W. Alings, J.V. Amerena, A. Avezum, I. Baumgartner, J. Brugada, A. Budaj, V. Caicedo, L. Ceremuzynski, J.H. Chen, P.J. Commerford, S.J. Connolly, A.L. Dans, H. Darius, G. Di Pasquale, R. Diaz, C. Erol, M.D. Ezekowitz, J. Ferreira, G.C. Flaker, M.D. Flather, M.G. Franzosi, R. Gamboa, S.P. Golitsyn, J.A. Gonzalez Hermosillo, D. Halon, H. Heidbuchel, S.H. Hohnloser, M. Hori, K. Huber, P. Jansky, G. Kamensky, M. Keltai, S. Kim, C.P. Lau, J.Y.F. Le Heuzey, B.S. Lewis, L.S. Liu, J. Nanas, J. Oldgren, P.S. Pais, A.N. Parkhomenko, K.E. Pedersen, L.S. Piegas, D. Raev, O. Razali, T.A. Simmers, P.J. Smith, M. Talajic, R.S. Tan, S. Tanomsup, L. Toivonen, D. Vinereanu, L. Wallentin, D. Xavier, S. Yusuf, J. Zhu. Core Adjudication–Stroke Advisory Committee: H.C. Diener (cochair), C.D. Joyner (cochair), A. Diehl, G. Ford, M. Robinson (core adjudication only), J. Silva. Data Safety Monitoring Board: P. Sleight (cochair), D.G. Wyse (cochair), J. Collier, D. De Mets, J. Hirsh, E. Lesaffre, L. Ryden, P. Sandercock. Investigators who recruited at least 12 patients: Argentina: A. Caccavo, L. Cartasegna, C.A. Cuneo, M.V. Elizari, A.J. Gabito, M.A. Hominal, A.D. Hrabar, I.J. Mackinnon, M.A. Rodriguez, A.S. Sanchez, D.R. Vogel; Australia: D.M. Colquhoun, R.G. Lehman, B.B. Singh, J.H. Waites; Austria: F. Gazo, A. Podczeck, P. Siostrzonek; Belgium: J.L. Boland, A. de Meester, L. De Wolf, D. Dilling-Boer, M. Goethals, P. Goethals, O. Gurne, S. Hellemans, B. Ivan, M. Jottrand, I. Kersschot, F. Provenier, W. van Mieghem, Y. Vandekerckhove; Brazil: J.C.F. Braga, J.F. Kerr Saraiva, A.M. Lorga-Filho, L.N. Maia, C.S. Melo, D.B. Precoma, S. Rassi, P.R. Rossi; Bulgaria: E.S. Baldjiev, I.G. Filibev, N.N. Gotcheva, A.R. Goudev, D.T. Guenova, E.I. Manov, A.L. Radoslavov, D.A. Spirova, V.M. Tsanova, M.L. Tzekova; Canada: A.I. Bakbak, J.C. Berlingieri, K. Blackburn, A.W. Booth, S. Bose, P. Boucher, C. Constance, P. Costi, B. Coutu, M.S. Green, J. Habot, S. Kouz, A.V. Lalani, A.S. Lam, P.T.S. Ma, L.B. Mitchell, C.A. Morillo, G. O'Hara, A.S. Pandey, Y. Pesant, C.N. Powell, T.M. Rebane, D. Savard, S. Schulman, M.J. Sehl, D. Shu, L.D. Sterns, R. St-Hilaire, G.S. Syan, P. Talbot, I. Teitelbaum, S.A. Vizel; China: X.J. Bai, W. Gao, Z.S. He, Q. Hua, L. Li, W.M. Li, G.P. Lu, S. Lv, N.L. Sun, N.F. Wang, Y.M. Yang, F. Zhang, L. Zhang; Czech Republic: J. Belohlavek, M. Cernohous, M. Choura, V. Dedek, B. Filipensky, K. Kovarova, Z. Poklopova, H. Skalicka, J. Spinar; Denmark: K.K. Dodt, K. Egstrup, S. Husted, K.K. Klarlund, S. Lind Rasmussen, T.M. Melchior, M.E. Olsen, N. Ralfkiaer, L.H. Rasmussen, K. Skagen; Finland: K.E. Airaksinen, H.V. Huikuri, M. Mänttäri, J.H. Melin, K. Peuhkurinen, V.K. Virtanen, A. Ylitalo; France: L. Boucher, A. Boye, P. Igigabel, C. Magnani, M. Martelet, J.E. Poulard; Germany: K.F. Appel, C.E.H. Dempfle, A. Dormann, J. Harenberg, W.L. Haverkamp, T. Horacek, D. Koudonas, J. Kreuzer, A. Müegge, T.F. Munzel, P.B. Salbach, W. Schoels, R. Veltkamp, E. Von Hodenberg; Greece: M.I. Anastasiou-Nana, K. Karamitsos, C. Lappas, A. Manolis; Hong Kong (China): W.K. Chan, H.F. Tse, P.T. Tsui, C.M. Yu; Hungary: A. Jánosi, A. Kadar, P. Karpati, K. Keltai, J. Rapi, L.I. Regos, I. Szakal; India: R.K. Aggarwal, A. Bharani, J.S. Bhuvaneswaran, R.B. Byrapaneni, J.B. Gupta, K.K. Haridas, J. Hiremath, A.S. Jain, J. Joseph, A.M. Naik, R.B. Panwar, J.P.S. Sawhney, N. Sinha, A. Srinivas, P.S. Vadagenalli; Israel: J. Benhorin, N.M. Bornstein, B. Brenner, A. Butnaru, A. Caspi, M. Elias, E. Grossman, S. Hamoud, R. Ilia, E.I. Klainman, M. Lishner, C. Lotan, A. Marmor, M. Motro, L.H. Reisen, E. Schwammenthal, M. Shochat, B. Strasberg, Y. Turgeman, A.T. Weiss, D.H. Wexler, R. Wolff, D. Zeltser, R. Zimlichman; Italy: G. Argiolas, M. Barbiero, A. Fraticelli, M. Mennuni, L. Moretti, L. Mos, S. Pirelli; Japan: J. Furuya, S. Hara, M. Hiroe, S. Kakinoki, N. Miyamoto, M. Yokochi; Malaysia: K.H. Chee, A.F.Y. Fong, O. Ismail, S. Jeyaindran; Mexico: J. Carrillo, P.A. Fernandez Bonetti; the Netherlands: G.L. Bartels, T.A. Bruning, R. Ciampricotti, L. Cozijnsen, H.J. Crijns, M.C.G. Daniels, D.E.P. de Waard, F.R. den Hartog, W.F. Heesen, P.A. Hoogslag, A. Huizenga, J.A. Kragten, G.C. Linssen, D.J. Lok, H.R. Michels, J. Plomp, L. Pos, P.G. Postema, R. Salomonsz, I. Stoel, J.G. Tans, H.J. Thijssen, A.J.M. Timmermans, H.A. van de Klippe, C. van der Zwaan, I.C. van Gelder, L.H. van Kempen, H.A. van Kesteren, P. van Rossum; Norway: O. Breder, P.A. Sirnes, A. Tveit; Peru: W. Cabrera, J.M. Heredia, M.E. Horna, P.M. Salazar; Philippines: M.T.B. Abola, J.C. Anonuevo, D.D. Morales, G.G. Rogelio, A.A. Roxas, Jr.; Poland: B. Bacior, J. Grodecki, Z.F. Kalarus, P. Miekus, F. Monies, J. Rekosz, M. Szpajer, A. Wasilewska-Piepiorka, B. Zaborska; Portugal: L. Cunha, L.A. Providencia; Romania: M.A. Cinteza; Russia: I.G. Gordeev, A.Y. Ivleva, T.N. Novikova, E.P. Panchenko, E.V. Shlyakhto, S.B. Shustov, B.A. Sidorenko, V. Sulimov, A.L. Syrkin, D.A. Zateyshchikov; Singapore: D. Foo; Slovak Republic: V. Bugan, J. Dúbrava, G. Kaliska, M. Masarovicova, D. Pella, J. Sedlák, R. Uhliar; South Africa: J.M. Engelbrecht, D. Jankelow, R.J. Routier, F.A. Snyders, H.D. Theron; South Korea: T.J. Cha, J.G. Cho, I.S. Choi, K.J. Choi, K.S. Kim, Y.N. Kim, M.H. Lee, M.Y. Lee, D.J. Oh, T.H. Rho; Spain: L. Cano, A. Martinez-Rubio, L. Mont; Sweden: S. Bandh, C.M. Blomstrom Lundqvist, P. Cherfan, E. Fengsrud, J. Herlitz, T. Juhlin, F. Maru, O.R. Nilsson, F. Ronn, M. Rosenqvist; Taiwan: H.H. Hu, C.J. Jack, W.T. Lai, C.H. Liu, H.L. Po, S.J. Ryu, C.D. Tsai, C.D. Tseng, J.H. Wang, S.P. Yang; Thailand: S. Kiatchoosakun, R. Krittayaphong, S. Kuanprasert, T. Simtharakaew; Turkey: A. Usal; Ukraine: K.M. Amosova, O.I. Karpenko, O. Kuryata, L. Martynova, S.S. Pavlyk, L.V. Rudenko, V. Tseluyko, N. Usan, L.G. Voronkov, O.J. Zharinov; United Kingdom: J.G. Cleland, A.T. Cohen, P. Davey, J. Davies, H.H. Kadr, G.H. Lip, G.T. McInnes, A.J. Moriarty, M. Pye, S.H.L. Thomas, P.R. Wilkinson; United States: Z.A. Abbud, K.V. Adams, I.S. Ahmed, R. Arora, G.R. Aycock, A.J. Bartkowiak, Jr., B. Bean, N.W. Bedwell, A.D. Belber, D.R. Bensimhon, R.E. Benton, O. Ben-Yehuda, B.D. Bertolet, S.D. Bilazarian, D.E. Bolster, J. Bomba, C.R. Bricker, R.I. Brock, K.F. Browne, F. Cardona, T. Carlson, K.W. Carr, W.R. Cashion, Y.S. Chandrashekar, J.H. Chappell, Y. Chen, J.H. Cieszkowski, D.M. Clark, J.F. Cole, S.F. Cossu, D.M. Denny, V.S. Desai, N.J. Deumite, L. Dewey, D.W. Dunning, C. East, W.A. Edmiston, H.S. Ellison, M. Elshahawy, G. Emlein, B. Ewing, P.W. Farrell, P.G. Fattal, J.A. Fialkow, R.H. Fields, M.S. Finkel, G.J. Fishbein, F.J. Fleischhauer, M.A. Frais, D.C. Friedman, M.D. Gelernt, H.C. Genovely, E.L. Gillespie, R.K. Goldberg, D.A. Goldscher, M. Goldstein, A.J. Greenspon, T.C. Hack, S.W. Halpern, C. Hamburg, G.S. Hamroff, G.D. Hanovich, E.J. Haskel, W.H. Haught, S.E. Hearne, J.A. Hemphill, C.H. Henes, P.R. Hermany, W.R. Herzog, T.C. Hilton, M.B. Honan, D.A. Hotchkiss, V.N. Howard, R.K. Ison, A.K. Jacobson, N.F. Jarmukli, D.B. Joyce, P.L. Judson, S. Kaatz, K.J. Kaplan, H.B. Karunaratne, R.N. Khant, M.J. Koren, E.J. Kosinski, P. Kosolcharoen, J.H. Kramer, S.J. Kulback, A. Kumar, J.S. Landzberg, D.T. Lang, T.K. Lau, J.K. Lee, R.M. Levy, D. Linzer, L. Maletz, M.F. McGough, W.P. McGuinn, M.D. McMillen, C.A. McPherson, M.E. Meengs, W.L. Meengs, A.W. Meholick, M.B. Melucci, S.K. Meymandi, R.H. Miller, S.T. Minor, M. Modi, J.F. Moloney, S.K. Mukherjee, V.K. Nadar, M. Nallasivan, J.P. Navas, E.N. Nsah, J.L. Nunamaker, D.J. O'Dea, B. Olliff, P.G. O'Neill, J.R. Onufer, R.C. Orchard, P. Pandey, S. Pezzella, D. Phillips, S.G. Pollock, S.D. Promisloff, J.T. Rittelmeyer, T.A. Rocco, Jr., D. Rosenbaum, D.M. Salerno, K.A. Saxman, R.M. Schneider, K.H. Sheikh, N.K. Shemonsky, W.G. Short, N. Singh, R. Sperling, A.D. Steljes, D.P. Suresh, S.M. Teague, J.M. Teixeia, R.W. Terry, J.A. Trippi, J.E. Usedom, R.M. Vicari, N. Vijay, K.N. Vora, R.B. Vranian, J.L. Walker, R.L. Walsh, S. Weiner, R.J. Weiss, W. Wera-Archakul, J.H. Whitaker, R.H. White, J.N. Whitehill, M.L. Williams, V.E. Wilson, W.W. Wilson, C.W. Wulff, K.A. Yousuf, B.G. Zakhary, P. Zimetbaum, R. Zoble, P.L. Zwerner.