Alpesh N. Amin, MD

Editor's Note: This letter concerns an article in a Cleveland Clinic Journal of Medicine supplement (Preventing Venous Thromboembolism Throughout the Continuum of Care) distributed to only a portion of the Journal's regular readership, owing to the terms of the grant supporting the supplement.

In Reply: We appreciate the comments by Drs. Fishmann and Boyd, but we strongly disagree with their suggestion that aspirin monotherapy is an appropriate option for the prevention of venous thromboembolism (VTE) following major orthopedic surgery.

As discussed in our original article,¹ multiple large-scale clinical trials in patients undergoing elective hip arthroplasty, knee arthroplasty, or hip fracture surgery have demonstrated the thromboprophylactic efficacy of warfarin, unfractionated heparin, low-molecular-weight heparin (LMWH), fondaparinux, and oral direct thrombin inhibitors. The relative risk reduction with these agents has been greater than 50% in most studies. In contrast, in a large meta-analysis of VTE prophylaxis following total hip replacement, which included data from 56 randomized trials published between 1966 and 1993, aspirin was not beneficial in preventing DVT.¹⁴

The largest prospective randomized trial comparing aspirin with placebo for VTE prevention was conducted between 1992 and 1998 among 17,444 patients in five countries.⁵ It involved 13,356 patients requiring hip fracture surgery and 4,088 patients requiring elective hip arthroplasty. Patients were randomized to receive aspirin 160 mg/day or placebo for 35 days. However, additional forms of VTE prophylaxis were allowed if deemed necessary by the clinician. In fact, 26% of patients received LMWH in addition to aspirin, and dual therapy was probably more common in those patients at highest thromboembolic risk. As such, the 36% relative risk reduction in VTE ascribed to aspirin should be viewed with caution. Further, this is a smaller risk reduction than that observed in trials of other anticoagulant agents.

A large, well-designed, randomized clinical trial comparing aspirin to LMWH or fondaparinux remains to be conducted.

Dr. Fishmann cites a small study of patients undergoing knee arthroplasty who received spinal anesthesia and intermittent calf compression devices.⁷ In this underpowered study, 275 patients were randomized to receive aspirin 325 mg twice daily or enoxaparin 30 mg twice daily for 3 weeks. The overall DVT rates were 14.1% in the enoxaparin group vs 17.8% in the aspirin group (P = .27).⁷ Patients who received aspirin had significantly more postoperative drainage than those randomized to enoxaparin. In addition, the protocol for scheduling enoxaparin 48 hours postoperatively is not consistent with recommendations of the American College of Chest Physicians (ACCP) and may have reduced the efficacy of enoxaparin.

The other evidence in support of aspirin cited by Dr. Fishmann includes an editorial,⁹ an uncontrolled retrospective analysis,⁸ a single-center retrospective review,¹⁰ and a review article.⁶ Although there is evidence that the use of aspirin is probably associated with a modest reduction in postoperative VTE risk, it has been unequivocally surpassed in efficacy by other anticoagulants.

Both the latest (2004) ACCP guidelines on VTE² and the 2006 International Consensus Statement on VTE prevention and treatment¹⁵ advise against aspirin monotherapy as VTE prophylaxis in any patient groups. It is likely that the upcoming 2008 ACCP guidelines will also advocate against using aspirin as well.

Lastly, the most recent guideline from the American Academy of Orthopaedic Surgeons advocating aspirin as monotherapy¹¹ is based on the assumption that the major important clinical end point in the orthopedic surgery patient is clinical pulmonary embolism, an end point that was not included as a lone primary end point in any of the modern randomized controlled studies in major orthopedic surgery. This represents a flawed logic for the development of evidence-based guideline recommendations, and this recommendation has not been advocated by well-respected bodies such as the ACCP and the international groups that developed the International Consensus Statement. Furthermore, if this practice is going to be advocated by the American Academy of Orthopaedic Surgeons, then large rigorously designed randomized trials must be conducted to compare aspirin to currently available anticoagulants, and the type of joint surgery should be clearly defined.

Editor's Note: This letter concerns an article in a Cleveland Clinic Journal of Medicine supplement (Preventing Venous Thromboembolism Throughout the Continuum of Care) distributed to only a portion of the Journal's regular readership, owing to the terms of the grant supporting the supplement.

In Reply: We appreciate the comments by Drs. Fishmann and Boyd, but we strongly disagree with their suggestion that aspirin monotherapy is an appropriate option for the prevention of venous thromboembolism (VTE) following major orthopedic surgery.

As discussed in our original article,¹ multiple large-scale clinical trials in patients undergoing elective hip arthroplasty, knee arthroplasty, or hip fracture surgery have demonstrated the thromboprophylactic efficacy of warfarin, unfractionated heparin, low-molecular-weight heparin (LMWH), fondaparinux, and oral direct thrombin inhibitors. The relative risk reduction with these agents has been greater than 50% in most studies. In contrast, in a large meta-analysis of VTE prophylaxis following total hip replacement, which included data from 56 randomized trials published between 1966 and 1993, aspirin was not beneficial in preventing DVT.¹⁴

The largest prospective randomized trial comparing aspirin with placebo for VTE prevention was conducted between 1992 and 1998 among 17,444 patients in five countries.⁵ It involved 13,356 patients requiring hip fracture surgery and 4,088 patients requiring elective hip arthroplasty. Patients were randomized to receive aspirin 160 mg/day or placebo for 35 days. However, additional forms of VTE prophylaxis were allowed if deemed necessary by the clinician. In fact, 26% of patients received LMWH in addition to aspirin, and dual therapy was probably more common in those patients at highest thromboembolic risk. As such, the 36% relative risk reduction in VTE ascribed to aspirin should be viewed with caution. Further, this is a smaller risk reduction than that observed in trials of other anticoagulant agents.

A large, well-designed, randomized clinical trial comparing aspirin to LMWH or fondaparinux remains to be conducted.

Dr. Fishmann cites a small study of patients undergoing knee arthroplasty who received spinal anesthesia and intermittent calf compression devices.⁷ In this underpowered study, 275 patients were randomized to receive aspirin 325 mg twice daily or enoxaparin 30 mg twice daily for 3 weeks. The overall DVT rates were 14.1% in the enoxaparin group vs 17.8% in the aspirin group (P = .27).⁷ Patients who received aspirin had significantly more postoperative drainage than those randomized to enoxaparin. In addition, the protocol for scheduling enoxaparin 48 hours postoperatively is not consistent with recommendations of the American College of Chest Physicians (ACCP) and may have reduced the efficacy of enoxaparin.

The other evidence in support of aspirin cited by Dr. Fishmann includes an editorial,⁹ an uncontrolled retrospective analysis,⁸ a single-center retrospective review,¹⁰ and a review article.⁶ Although there is evidence that the use of aspirin is probably associated with a modest reduction in postoperative VTE risk, it has been unequivocally surpassed in efficacy by other anticoagulants.

Both the latest (2004) ACCP guidelines on VTE² and the 2006 International Consensus Statement on VTE prevention and treatment¹⁵ advise against aspirin monotherapy as VTE prophylaxis in any patient groups. It is likely that the upcoming 2008 ACCP guidelines will also advocate against using aspirin as well.

Lastly, the most recent guideline from the American Academy of Orthopaedic Surgeons advocating aspirin as monotherapy¹¹ is based on the assumption that the major important clinical end point in the orthopedic surgery patient is clinical pulmonary embolism, an end point that was not included as a lone primary end point in any of the modern randomized controlled studies in major orthopedic surgery. This represents a flawed logic for the development of evidence-based guideline recommendations, and this recommendation has not been advocated by well-respected bodies such as the ACCP and the international groups that developed the International Consensus Statement. Furthermore, if this practice is going to be advocated by the American Academy of Orthopaedic Surgeons, then large rigorously designed randomized trials must be conducted to compare aspirin to currently available anticoagulants, and the type of joint surgery should be clearly defined.

Editor's Note: This letter concerns an article in a Cleveland Clinic Journal of Medicine supplement (Preventing Venous Thromboembolism Throughout the Continuum of Care) distributed to only a portion of the Journal's regular readership, owing to the terms of the grant supporting the supplement.

In Reply: We appreciate the comments by Drs. Fishmann and Boyd, but we strongly disagree with their suggestion that aspirin monotherapy is an appropriate option for the prevention of venous thromboembolism (VTE) following major orthopedic surgery.

As discussed in our original article,¹ multiple large-scale clinical trials in patients undergoing elective hip arthroplasty, knee arthroplasty, or hip fracture surgery have demonstrated the thromboprophylactic efficacy of warfarin, unfractionated heparin, low-molecular-weight heparin (LMWH), fondaparinux, and oral direct thrombin inhibitors. The relative risk reduction with these agents has been greater than 50% in most studies. In contrast, in a large meta-analysis of VTE prophylaxis following total hip replacement, which included data from 56 randomized trials published between 1966 and 1993, aspirin was not beneficial in preventing DVT.¹⁴

The largest prospective randomized trial comparing aspirin with placebo for VTE prevention was conducted between 1992 and 1998 among 17,444 patients in five countries.⁵ It involved 13,356 patients requiring hip fracture surgery and 4,088 patients requiring elective hip arthroplasty. Patients were randomized to receive aspirin 160 mg/day or placebo for 35 days. However, additional forms of VTE prophylaxis were allowed if deemed necessary by the clinician. In fact, 26% of patients received LMWH in addition to aspirin, and dual therapy was probably more common in those patients at highest thromboembolic risk. As such, the 36% relative risk reduction in VTE ascribed to aspirin should be viewed with caution. Further, this is a smaller risk reduction than that observed in trials of other anticoagulant agents.

A large, well-designed, randomized clinical trial comparing aspirin to LMWH or fondaparinux remains to be conducted.

Dr. Fishmann cites a small study of patients undergoing knee arthroplasty who received spinal anesthesia and intermittent calf compression devices.⁷ In this underpowered study, 275 patients were randomized to receive aspirin 325 mg twice daily or enoxaparin 30 mg twice daily for 3 weeks. The overall DVT rates were 14.1% in the enoxaparin group vs 17.8% in the aspirin group (P = .27).⁷ Patients who received aspirin had significantly more postoperative drainage than those randomized to enoxaparin. In addition, the protocol for scheduling enoxaparin 48 hours postoperatively is not consistent with recommendations of the American College of Chest Physicians (ACCP) and may have reduced the efficacy of enoxaparin.

The other evidence in support of aspirin cited by Dr. Fishmann includes an editorial,⁹ an uncontrolled retrospective analysis,⁸ a single-center retrospective review,¹⁰ and a review article.⁶ Although there is evidence that the use of aspirin is probably associated with a modest reduction in postoperative VTE risk, it has been unequivocally surpassed in efficacy by other anticoagulants.

Both the latest (2004) ACCP guidelines on VTE² and the 2006 International Consensus Statement on VTE prevention and treatment¹⁵ advise against aspirin monotherapy as VTE prophylaxis in any patient groups. It is likely that the upcoming 2008 ACCP guidelines will also advocate against using aspirin as well.

Lastly, the most recent guideline from the American Academy of Orthopaedic Surgeons advocating aspirin as monotherapy¹¹ is based on the assumption that the major important clinical end point in the orthopedic surgery patient is clinical pulmonary embolism, an end point that was not included as a lone primary end point in any of the modern randomized controlled studies in major orthopedic surgery. This represents a flawed logic for the development of evidence-based guideline recommendations, and this recommendation has not been advocated by well-respected bodies such as the ACCP and the international groups that developed the International Consensus Statement. Furthermore, if this practice is going to be advocated by the American Academy of Orthopaedic Surgeons, then large rigorously designed randomized trials must be conducted to compare aspirin to currently available anticoagulants, and the type of joint surgery should be clearly defined.