We appreciate the opportunity to address the questions raised by Dr. Lotke and colleagues with respect to our paper. Their major concern is whether our conclusions accurately reflect the EXULT B TKA data.

The conclusion that ximelagatran demonstrates superior efficacy (as defined by our prespecified endpoint of total VTE + all-cause mortality) is valid. There is a statistically significant difference in the efficacy endpoint between ximelagatran and warfarin. The use of total VTE including venographically detected asymptomatic DVT as a surrogate for the efficacy of an antithrombotic has been well accepted by clinicians and regulatory authorities. VTE can be thought of as a "pyramid” with asymptomatic calf DVT the most common and at the bottom, and fatal PE very infrequent and at the top. In between are symptomatic and asymptomatic calf and proximal DVT, and non-fatal PE. In the EXULT B study, all sub-group analysis of VTE favored ximelagatran, including asymptomatic calf and proximal DVT, symptomatic DVT, and PE. For asymptomatic proximal DVT the rates were 3.1% for ximelagatran-treated patients and 3.4% for warfarin-treated, an absolute difference of 0.3%. For symptomatic DVT and symptomatic PE, the rates were 0.7% and 0.2%, respectively for ximelagatran-treated patients and 1.3% and 0.4% respectively for warfarin-treated patients (absolute differences of 0.6% and 0.2%, respectively). When pooled together in the prespecified endpoint, the difference in favor of ximelagatran is statistically significant.

Issue is taken with analysis of death in EXULT B. In our report none of the 3 deaths in 1151 patients (0.3%) in the ximelagatran group had an autopsy performed. We conservatively categorized them as “PE could not be ruled out” to try to capture and not hide events, even though two of these deaths were listed as myocardial infarction by the investigator based on EKG and clinical findings; one occurred while the patient was receiving ximelagatran and one during the followup period when patient treatment was not controlled. The third of these deaths also occurred during the followup period and was listed by the investigator as unknown. Studies over the last 10 years indicate fatal PE rates following total joint replacement range from 0% to 0.5% (1), therefore even taking the worst-case scenario of 0.3% being fatal PEs, this is well within the reported range. No confirmed fatal PEs occurred during this study of 2303 patients undergoing TKA. Cardiac deaths have not usually been reported. It is not biologically plausible for a drug to be more effective at preventing all the non-fatal VTE described above and less effective in preventing fatal PE. Since the non-fatal events were all verified with objective diagnostic testing, followed by their adjudication by an independent central committee of experts, it is highly likely that the assessment is accurate.

The opinion of Drs. Lotke, et al, that the “9.7% diminution in the incidence of distal DVT in the ximelagatran group…is a finding of dubious significance” is not one shared by investigators worldwide. No doctor can guess in which patients distal clots will become significant. Ximelagatran did decrease overall DVT rates, most of which were distal; this reflects previous thrombophlebitis prevention studies which report significant reduction in clots below the knee, not above. In a TKA meta- analysis, distal DVT is reported to occur in the range of 21% to 71% and proximal DVT in the range of 1.7% to 12.8%. (2) Although proximal DVT is more important with respect to PEs and potential PE deaths than distal DVT, distal DVTs have a 20% propagation rate. (3) Many of the long-term complications of DVT, such as chronic venous insufficiency and post thrombotic syndrome (PTS), are secondary to the distal DVT. However, in an individual surgeon’s practice, they occur too uncommonly for him/her to note. When the long-term sequelae occur, they rarely come to the attention of the orthopedic surgeon for care but rather to other physicians. Therefore, we do consider this reduction in events to be of clinical significance to both physicians and patients.

Bleeding in TKA studies has been reported to range from 8.6% to 18.9%, with major bleeding ranging from 0% to 2.4% with no significant difference detectable. (2) In our study, any bleeding was below the lower range (5.0% for ximelagatran and 3.8% for warfarin) and within the range of major bleeding reported in other studies, with no detectable statistical difference. We state in the abstract that “Major bleeding was noted in 1% (twelve) of the ximelagatran-treated patients and in 0.4% (five) of the warfarin-treated patients (p = 0.09).” In such a large TKA trial where the number of major bleeding events is so low (and therefore the major bleeding rates are low), saying that the major bleeding event rate with ximelagatran is “more than twice that of the warfarin group” is misleading. For this statement to be accurate the denominator would have to be small and the numerator large, the opposite of our findings where the denominator (number of patients) is large and the numerator (number of bleeds) is small. The major bleeding rates were neither statistically different nor is the absolute difference of 0.6% (1.0%-0.4%) clinically perceptible to physicians.

Dr. Lotke and colleagues asked for more parameters of patient evaluation, and we concur. For example, once a bleeding event was documented, it would have been more helpful to clinicians if we had done a more complete follow-up of all events to their final clinical outcome. However, as with the prior 45,000 patients that have been studied worldwide either in a prospective randomized manner or merely as cohort studies, this was not fully accomplished.

Multiplying endpoint rates in both arms as a way to “enlarge” a clinical trial to provide more precision around the point estimate of the events is counter to the scientific principles of good clinical trial analysis and does not provide more certainty around the differences in endpoints. In reality the differences in the endpoints could either be magnified or diminished. The suggestion that if a greater number of patients were studied, a significantly higher rate of patient-related complications and adverse events might occur may be true, but there is an equal chance that it would be untrue. We reported what we found in this study with the point estimates, confidence intervals, and statistical significance included. For a little more insight, when we combine the numbers in the group dosed with 36 mg in the Exult A study (4) with those in the Exult B study (5) it provides a greater than 50% increase in patients, but the percentages of patient related complications and adverse events does not change.

We conclude in the abstract that the new drug “demonstrates superior efficacy compared to warfarin prophylaxis” based on the prespecified endpoints and prespecified statistical analysis. We believe in the validity of our conclusions and that the facts presented justify them.

References:

1. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:338S-400S.

2. Brookenthal KR, Freedman KB, Lotke PA, Fitzgerald RH, Lonner JH. A meta-analysis of thromboembolic prophylaxis in total knee arthroplasty. J Arthroplasty. 2001;16:293-300.

3. Grady-Benson JC, Oishi CS, Hanson PB, Colwell CW, Jr., Otis SM, Walker RH. Postoperative surveillance for deep venous thrombosis with duplex ultrasonography after total knee arthroplasty. J Bone Joint Surg Am. 1994;76:1649-1657.

4. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW, Jr. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med. 2003;349:1703-1712.

5. Colwell CW, Jr., Berkowitz SD, Lieberman JR, Comp PC, Ginsberg JS, Paiement G, McElhattan J, Roth AW, Francis CW. Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. J Bone Joint Surg Am. 2005;87:2169-2177

To The Editor:

In the article by Colwell, et al, “Oral Direct Thrombin Inhibitor Ximelagatran Compared with Warfarin for the Prevention of Venous Thromboembolism after Total Knee Arthroplasty”, reported in the JBJS 87A, 2169-77 October 2005, we are concerned that the facts presented by the authors do not appear to justify their conclusions and that some important parameters of patient evaluations are lacking.

In this report the authors note 0.3% of the patients in the Ximelagatran group died from a cause in which “PE could not be ruled out” as compared to no “deaths from PE” in the warfarin group. This incidence is relatively high when compared to most recent studies which note a 0.1% incidence of fatal pulmonary embolism (PE) following total joint surgery. More detailed information regarding these deaths would be helpful to assist the reader in differentiating the patients in whom “PE could not be ruled out” from patients with “fatal PE”.

Major bleeding complications are noted in 1% of the Ximelagatran group, compared to 0.4% of the warfarin group. Major bleeding was defined as critical site bleeding, such as intracranial, or retroperitoneal; bleeding requiring surgical intervention; or fatal bleeding, etc. In the Ximelagatran group major bleeding included 1 fatal GI bleed and 1 subdural hematoma. All other recorded bleeding was considered minor. Although the number of patients with major bleeding is small, it is more than twice that of the warfarin group. If this study was five fold larger, the difference could be statistically significant. With more than 300,000 total knees being done each year, these small differences can become clinically and statistically important.

In addition and most importantly, there is no mention of the clinical outcomes or how the major and/or minor bleeds affected patient health.

The venographic data in the article shows no difference between the two study drugs in the incidence of proximal deep venous thrombosis (DVT), the more worrisome clots. They also show only a 9.7% diminution in the incidence in distal DVT in the Ximelagatran group, a finding in our opinion of dubious significance.

Therefore, in this report, Ximelagatran is associated with a 0.3% fatal PE compared to none in the warfarin group; it has more than two times the major bleeding rate compared to warfarin; and it has an equal incidence of proximal DVT. The only finding in favor of Ximelagatran is a limited reduction in distal DVT, which may be of little clinical importance.

Yet in the abstract the authors conclude that “the new drug demonstrates superior efficacy compared to warfarin prophylaxis with no wound complications and no significant difference with respect to bleeding events†” We are not persuaded that the new drug warrants this conclusion. To the contrary, Ximelagatran appears to be no more effective than warfarin, and if a greater number of patients were included in the study, a significantly higher incidence of patient-related complications and adverse events might be revealed.

For the above reasons, we remain concerned about the conclusions published in this article.

Respectfully submitted,

Paul A. Lotke MD, John J. Callahan MD, Lawrence D. Dorr MD, Gerald H. Engh MD, Arlen D. Hanssen MD, William L. Healy MD, Paul F. Lachiewicz MD, Jess H. Lonner MD, Charles Nelson MD, Chitranjan S. Ranawat MD, Merrill A. Ritter MD, Eduardo A. Salvati MD, Thomas P. Sculco MD, Thomas S. Thornhill MD.