Low dose compared to variable dose Warfarin and to Fondaparinux as prophylaxis for thromboembolism after elective hip or knee replacement surgery; a randomized, prospective study

When initiated prior to elective surgery low dose warfarin has been demonstrated prophylactic capacity against VTE with low risk of hemorrhage [1‐14]. Warfarin when given at 1 mg per day is known to increase serum under-gamma-carboxylated osteocalcin and plasma under-gamma-carboxylated prothrombin, without change of prothrombin times or factor VII activity [15]. It is critical in this pharmacologic format that low dose warfarin be initiated prior to the surgical trauma, thus allowing time for warfarin to partially suppress the carboxylation of glutamic acid residues attached to the cores of factors II, VII, IX and X [16]. This sequentially reduces their calcium ion dependent function [16‐21] It is this mechanism which we believe reduces the efficiency of calcium binding, thus slowing the efficiency of clotting but not so much as to cause full anticoagulation.

This study is a continuum of studies predicated upon the concept that the clotting system can be kept in a homeostatic balance, making it possible to avoid added risk of bleeding while protecting patients from thromboembolism [1‐14]. Among these studies was a prospective pilot study of 100 patients in which patients planning total hip replacement were randomized between two arms, one with warfarin starting with 5.0 mg the night prior to surgery followed by variable dose warfarin (target PT 1.3–1.5 x normal) and the other using 1.0 mg of warfarin beginning seven days prior to surgery, and both continuing for 30–45 days. There was no difference for incidence of venous thrombosis [8]. Another was a retrospective study of patients undergoing primary (n = 833) or revision (n = 170) hip replacement arthroplasty who received 1.0 mg of warfarin for seven days prior to surgery, variable dose warfarin while in hospital (target INR 1.5–2.0) followed by1.0 mg daily until follow-up at 30–45 days. Of 1,003 patients, only 3 (0.3 %) had symptomatic VTE [11].

This current investigator-initiated, single-institution, prospective, randomized, open-label assessor-blind study study compared fixed low dose of warfarin to two control arms as chemoprophylaxis against VTE among patients undergoing elective primary hip or knee replacement. Fixed low dose warfarin was initiated 7 days prior to surgery so as to allow the necessary time for its effects to be in place by the time of surgery. All patients received the same optimal non-pharmacologic support. We hypothesized that the three chemotherapeutic regimens would yield equivalent clinical findings for these patients. If confirmed as effective the fixed low dose regimen should have minimal hemorrhagic potential and would require less laboratory support, but with less cost than the modern novel oral anticoagulants that are also available [22].

Patients given no anticoagulants after hip or knee arthroplasty experience high rates of postoperative VTE [23‐28]. Heretofore, commonly used anticoagulants reduced the frequency of postoperative VTE to 4–6 %. A meta-analysis of modern low molecular weight heparins, oral Xa inhibitors or oral IIa inhibitors included 47 clinical trials and observational studies involving 44,844 patients demonstrated rates of symptomatic DVT prior to discharge of 1.09 % for patients having TKA and 0.53 % for patients having THA, with heterogeneity of results among the included reports [29]. The current study shows that our fixed low dose warfarin regimen approximates the same level of benefit.

The two agents used in this current study as controls can be considered as among the available standards-of-care agents available for DVT prophylaxis. Variable dose warfarin has been used for many years, and is effective with the current target range of INR [30, 31]. Fondaparinux, a synthesized pentasaccaride with anti-factor Xa activity, was among the newer agents with VTE prophylaxis activity when this study was designed [22, 32‐35].

As in our previous orthopedic studies and as with other investigators we selected a preoperative lead-time of 7 days for the fixed low dose warfarin used in this study [8, 11, 36, 37]. In an earlier central venous catheter study we choose 3 days [6]. We would not expect this low dose warfarin therapy to succeed if started following surgery, even though in one series it did succeed even when therapy was begun after central venous catheter insertion [12, 38‐41].

There were two previous smaller but similarly structured studies that derived negative results for low dose warfarin following major orthopedic surgery. Poller, et al., in a report of 68 evaluable patients randomized to receive either warfarin 1 mg daily starting 7 days preoperatively or 5,000 units heparin starting 2 h preoperatively, with venography as the diagnostic tool [36]. Fordyce, et al., studied 148 patients having primary hip replacement surgery were randomized to take 1 mg warfarin starting 7 days prior to surgery or to be non-treated controls. Iodine-125 labeled fibrinogen uptake (with venography confirmation for positive femoral vein uptake) was used for detection of DVT [37].

Differences in outcomes may be dependent upon the DVT detection techniques applied. Color Doppler ultrasound was used in this study to detect DVT. Ultrasound imaging is accepted for diagnosing DVT with sensitivity and specificity for detection of proximal deep vein thrombosis is over 95 %. In studies of asymptomatic patients, the sensitivity the test has been variable. Nevertheless, a single negative complete lower limb examination is considered sufficient to exclude clinically important DVT [42‐44]. New symptoms always require further imaging. In the current study patients were called at 6 and 12 months to detect any delayed symptomatic VTE events in order to detect any false negative results.

On the other hand, venography, often considered the gold standard for DVT detection studies, is far from the ideal diagnostic procedure. Venography-dependent studies often have significant numbers of patients who never get the venogram, have unilateral studies instead of bilateral studies, or are rejected by the adjudicating committees as technically inadequate [24, 45‐50]. Venography also involves added risks for patients with allergic and renal reactions, skin necrosis if contrast dye extravasates and post-injection phlebitis in up to 2 % of patients in whom conventional ionic contrast agents are used. Even with use of lower osmolar contrast agents, minor side effects occur in about 20 % of patients undergoing venography. Fibrinogen scanning may have been supersensitive.

Also, the current study was performed in a hospital with a high volume of joint replacement surgery, wherein optimal non-pharmacologic DVT prophylaxis is also applied along with chemoprophylaxis. Patients are told to discontinue smoking and estrogen supplements prior to surgery, to walk the day of surgery, and wear bilateral pneumatic compression stockings in hospital followed by elastic compression stockings after discharge until follow-up visits. Perhaps some of these elements may contribute to differences between the study outcomes.

There are clinically relevant elements within any study that cannot be stratified or controlled. In this study tourniquets were used for all patients having knee replacement, and it is assumed that the time the tourniquets were applied was equal for each study group [50]. Volume expansion by crystalloids can influence post-operative coagulation; it is assumed that the volume expansions were equivalent for each study group [51]. HES can have effects upon the clotting system [52, 53]. There were no differences for the use of HES among the three arms of this study. Also, as there are over 100 drugs, foods and supplements reported to interfere with platelet function, with unclear clinical significance for most, it would have been difficult to control for all of these agents [54]. It was decided by the protocol writing committee to track and analyze six of the more commonly used NSAIDs.

A positive D-dimer assay after conclusion of therapy for acute DVT or PE has been previously reported to be predictive of relapse of VTE. In one such study following one month of therapy for DVT, 39 % of patients had elevated D-dimer and seven of these patients went on to have recurrent VTE [55]. There is also increasing recognition that longer prophylactic therapy is beneficial in the post-operative setting [56‐62]. The current study prescribed that all study patients have measurements of D-dimer at the end of the treatment. No patient had delayed onset VTE when called 6 months and 12 months following completion of one month of therapy. Thus, in this study a positive D-dimer at the conclusion of therapy had no predictive value for delayed onset VTE after prolonger therapy of one month.

This proof of concept study builds upon prior studies examining low dose schedules for postoperative VTE chemoprophylaxis with warfarin. Trail limitations include that this is a single institution, open label but assessor-blind study study. A similar multi-institutional study with a larger number of patients would be welcomed. Perhaps it would also be useful to attempt the next such study with combined Doppler ultrasound and venography detection for DVT to confirm adequacy of Doppler ultrasound.

In conclusion, the three regimens in this study offer effective prophylaxis against thromboembolic disease following elective arthroplasty of hips and knees. It appears that fixed low dose warfarin when used as described is equivalent to two of the more intense regimens. By extending postoperative anticoagulation to four weeks there appears to be less chance for delayed VTE, even if there is a positive D-dimer at conclusion of treatment. Each regimen carries some risk and some inconvenience for the patient. The fixed low dose warfarin regimen herein described saves the patients the inconvenience of multiple blood draws, but does not eliminate that need completely, as demonstrated in our patient with vitamin K epoxide reductase genome disorder. Nevertheless, it should carry minimal hemorrhagic potential and require reduced laboratory support. It should be less expensive and easier to administer than other protocols using anti-Xa and anti-IIa agents, which has implications for health care costs.