Letters To The Editor

In Reply: Both Dr. Fee and Dr. Porat recommend cautious utilization of ezetimibe until outcome studies are completed. As I stated in my article, it is unfortunate that for ezetimibe, hard outcome trials are not yet available (the SEAS trial showed a cardiovascular benefit for the combination of simvastatin/ezetimibe, but it was not the primary end point). The main point of my article is that the weight of evidence for the benefits of LDL-C lowering is one of the most proven surrogate measures in clinical medicine. The biology, epidemiology, and clinical trials with multiple LDL-C-lowering therapies (bile-acid resin, niacin, fibrates, diet, ileal bypass surgery, and statins) convincingly demonstrate the validity of this surrogate measure for regulatory approval. In fact, every drug that has been approved for the treatment of hypercholesterolemia has been based on LDL-C reduction and not on outcome trials.

If this requirement was in place, it is doubtful that statins would have been approved. Lovastatin was approved by the US Food and Drug Administration in 1987; the Scandinavian Simvastatin Survival Study (4S) trial¹ was completed in 1994. The 4S trial showed, for the first time, a reduction in total mortality with an LDL-C-lowering therapy. Millions of patients were placed on statins prior to 1994, and it is unlikely the 4S trial would have been funded unless there had been prior regulatory approval.

As a researcher, I truly believe hard outcome trials are essential, but as a clinician, I realize that most of our medical care is based on drugs approved utilizing surrogate measures. Hard outcome trials are not required for antihypertensives, oral hypoglycemics, or smoking cessation treatments prior to approval. Ezetimibe lowers LDL-C by a known mechanism and is well tolerated. The ENHANCE trial, with its well-recognized flaws, should not refute the benefits of LDL-C reduction. For patients not at goal on statin therapy, ezetimibe should remain a widely used option.

In Reply: Both Dr. Fee and Dr. Porat recommend cautious utilization of ezetimibe until outcome studies are completed. As I stated in my article, it is unfortunate that for ezetimibe, hard outcome trials are not yet available (the SEAS trial showed a cardiovascular benefit for the combination of simvastatin/ezetimibe, but it was not the primary end point). The main point of my article is that the weight of evidence for the benefits of LDL-C lowering is one of the most proven surrogate measures in clinical medicine. The biology, epidemiology, and clinical trials with multiple LDL-C-lowering therapies (bile-acid resin, niacin, fibrates, diet, ileal bypass surgery, and statins) convincingly demonstrate the validity of this surrogate measure for regulatory approval. In fact, every drug that has been approved for the treatment of hypercholesterolemia has been based on LDL-C reduction and not on outcome trials.

If this requirement was in place, it is doubtful that statins would have been approved. Lovastatin was approved by the US Food and Drug Administration in 1987; the Scandinavian Simvastatin Survival Study (4S) trial¹ was completed in 1994. The 4S trial showed, for the first time, a reduction in total mortality with an LDL-C-lowering therapy. Millions of patients were placed on statins prior to 1994, and it is unlikely the 4S trial would have been funded unless there had been prior regulatory approval.

As a researcher, I truly believe hard outcome trials are essential, but as a clinician, I realize that most of our medical care is based on drugs approved utilizing surrogate measures. Hard outcome trials are not required for antihypertensives, oral hypoglycemics, or smoking cessation treatments prior to approval. Ezetimibe lowers LDL-C by a known mechanism and is well tolerated. The ENHANCE trial, with its well-recognized flaws, should not refute the benefits of LDL-C reduction. For patients not at goal on statin therapy, ezetimibe should remain a widely used option.

In Reply: Both Dr. Fee and Dr. Porat recommend cautious utilization of ezetimibe until outcome studies are completed. As I stated in my article, it is unfortunate that for ezetimibe, hard outcome trials are not yet available (the SEAS trial showed a cardiovascular benefit for the combination of simvastatin/ezetimibe, but it was not the primary end point). The main point of my article is that the weight of evidence for the benefits of LDL-C lowering is one of the most proven surrogate measures in clinical medicine. The biology, epidemiology, and clinical trials with multiple LDL-C-lowering therapies (bile-acid resin, niacin, fibrates, diet, ileal bypass surgery, and statins) convincingly demonstrate the validity of this surrogate measure for regulatory approval. In fact, every drug that has been approved for the treatment of hypercholesterolemia has been based on LDL-C reduction and not on outcome trials.

If this requirement was in place, it is doubtful that statins would have been approved. Lovastatin was approved by the US Food and Drug Administration in 1987; the Scandinavian Simvastatin Survival Study (4S) trial¹ was completed in 1994. The 4S trial showed, for the first time, a reduction in total mortality with an LDL-C-lowering therapy. Millions of patients were placed on statins prior to 1994, and it is unlikely the 4S trial would have been funded unless there had been prior regulatory approval.

As a researcher, I truly believe hard outcome trials are essential, but as a clinician, I realize that most of our medical care is based on drugs approved utilizing surrogate measures. Hard outcome trials are not required for antihypertensives, oral hypoglycemics, or smoking cessation treatments prior to approval. Ezetimibe lowers LDL-C by a known mechanism and is well tolerated. The ENHANCE trial, with its well-recognized flaws, should not refute the benefits of LDL-C reduction. For patients not at goal on statin therapy, ezetimibe should remain a widely used option.

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.

To the Editor: I must strongly disagree with Deitelzweig and colleagues’ recommendations against the use of aspirin for thromboprophylaxis in elective joint replacement surgery.¹ The references cited^2–5 are outdated. In the last few years, in patients undergoing minimally invasive hip replacement (done either posterolaterally or via an anterior approach with epidural anesthesia), early ambulation and thromboprophylaxis with compression boots and enteric-coated aspirin (or alternative antiplatelet agents in patients allergic to aspirin) has been associated with a lower incidence of deep vein thrombosis (DVT) and postoperative bleeding than either enoxaparin or fondaparinux.^6–9

Our experience in Los Angeles under the direction of Dr. Lawrence Dorr, past president of the Hip Society, is also instructive: minimally invasive hip replacement performed via a posterior approach with a 2- to 3-day length of stay and with the use of multimodal thromboprophylaxis including aspirin (or an alternate antiplatelet) has resulted in a low incidence of proximal DVT and no deaths from pulmonary embolism.¹⁰ Our experience with total knee replacement is similar but has included a slightly higher rate of DVT in patients older than 75 years of age.¹⁰

The American Academy of Orthopaedic Surgeons has clearly supported the use of aspirin as an effective modality for DVT prophylaxis.¹¹ We are patiently awaiting the newest recommendations from the American College of Chest Physicians, which I believe should incorporate aspirin in DVT prophylaxis and thus get medical physicians on the same page as orthopedic surgeons.

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.

To the Editor: I must strongly disagree with Deitelzweig and colleagues’ recommendations against the use of aspirin for thromboprophylaxis in elective joint replacement surgery.¹ The references cited^2–5 are outdated. In the last few years, in patients undergoing minimally invasive hip replacement (done either posterolaterally or via an anterior approach with epidural anesthesia), early ambulation and thromboprophylaxis with compression boots and enteric-coated aspirin (or alternative antiplatelet agents in patients allergic to aspirin) has been associated with a lower incidence of deep vein thrombosis (DVT) and postoperative bleeding than either enoxaparin or fondaparinux.^6–9

Our experience in Los Angeles under the direction of Dr. Lawrence Dorr, past president of the Hip Society, is also instructive: minimally invasive hip replacement performed via a posterior approach with a 2- to 3-day length of stay and with the use of multimodal thromboprophylaxis including aspirin (or an alternate antiplatelet) has resulted in a low incidence of proximal DVT and no deaths from pulmonary embolism.¹⁰ Our experience with total knee replacement is similar but has included a slightly higher rate of DVT in patients older than 75 years of age.¹⁰

The American Academy of Orthopaedic Surgeons has clearly supported the use of aspirin as an effective modality for DVT prophylaxis.¹¹ We are patiently awaiting the newest recommendations from the American College of Chest Physicians, which I believe should incorporate aspirin in DVT prophylaxis and thus get medical physicians on the same page as orthopedic surgeons.

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.

To the Editor: I must strongly disagree with Deitelzweig and colleagues’ recommendations against the use of aspirin for thromboprophylaxis in elective joint replacement surgery.¹ The references cited^2–5 are outdated. In the last few years, in patients undergoing minimally invasive hip replacement (done either posterolaterally or via an anterior approach with epidural anesthesia), early ambulation and thromboprophylaxis with compression boots and enteric-coated aspirin (or alternative antiplatelet agents in patients allergic to aspirin) has been associated with a lower incidence of deep vein thrombosis (DVT) and postoperative bleeding than either enoxaparin or fondaparinux.^6–9

Our experience in Los Angeles under the direction of Dr. Lawrence Dorr, past president of the Hip Society, is also instructive: minimally invasive hip replacement performed via a posterior approach with a 2- to 3-day length of stay and with the use of multimodal thromboprophylaxis including aspirin (or an alternate antiplatelet) has resulted in a low incidence of proximal DVT and no deaths from pulmonary embolism.¹⁰ Our experience with total knee replacement is similar but has included a slightly higher rate of DVT in patients older than 75 years of age.¹⁰

The American Academy of Orthopaedic Surgeons has clearly supported the use of aspirin as an effective modality for DVT prophylaxis.¹¹ We are patiently awaiting the newest recommendations from the American College of Chest Physicians, which I believe should incorporate aspirin in DVT prophylaxis and thus get medical physicians on the same page as orthopedic surgeons.

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.

To the Editor: I must make several comments regarding the review by Deitelzweig and colleagues.¹

First, all but one of the article’s six authors report having received honoraria, consulting fees, or research funding from companies that market medical products; therefore, their observations are not going to be “clean.”

Second, the most worrisome part of the article is that the authors downplay the issue of bleeding. As recently reported by surgeons from the Rothman Institute of Orthopedics at Thomas Jefferson University, there is a very clear connection in their practice between periprosthetic infection and an international normalized ratio (INR) greater than 1.5.¹² All of us in the Hip Society and the American Association of Hip and Knee Surgeons have seen cases with infection directly related to hematoma formation. This has been totally underreported and understated, and was thought not to be scientific until this recent report from the Rothman Institute.¹²

Third, as an orthopedic surgeon, I have to follow the guidelines of the American Academy of Orthopaedic Surgeons.¹¹ To blindly follow the guidelines of the Surgical Care Improvement Project (http://www.medqic.org) is asking for less than ideal results in orthopedic cases.

I see a very strong trend toward aspirin. A number of academics in prominent institutions are using aspirin, particularly in knee surgery.

I personally have experience with a group of 350 orthopedic surgery patients whom I have managed based on the approach recently reported by Bern et al—ie, warfarin 1 mg/day for 7 days prior to surgery, followed by variable warfarin dosing during the hospital stay to achieve a target INR of 1.5 to 2.0, followed by a maintenance warfarin dose of 1 mg daily for 30 days after discharge.¹³ I am very pleased with the results of this regimen. I have not encountered any wound issues, unlike my prior experience when using warfarin dosed to an INR of 2.0 to 3.0. I have currently modified this approach so that all male patients first receive two 325-mg aspirin tablets daily for 2 weeks, then warfarin 1 mg/day for the 7 days before surgery, followed by postoperative warfarin dosed to an INR of 1.5 to 2.0 during hospitalization, and then warfarin 2 to 5 mg/day for 30 days based on the patient’s INR response during hospitalization. The postoperative warfarin dosing requires monitoring, of course.

The results have been far superior to the bleeding rates reported from the Rothman Institute.¹² It is unfortunate that an approach such as this, as well as the rationale behind it, was not discussed in your supplement.

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.

To the Editor: I must make several comments regarding the review by Deitelzweig and colleagues.¹

First, all but one of the article’s six authors report having received honoraria, consulting fees, or research funding from companies that market medical products; therefore, their observations are not going to be “clean.”

Second, the most worrisome part of the article is that the authors downplay the issue of bleeding. As recently reported by surgeons from the Rothman Institute of Orthopedics at Thomas Jefferson University, there is a very clear connection in their practice between periprosthetic infection and an international normalized ratio (INR) greater than 1.5.¹² All of us in the Hip Society and the American Association of Hip and Knee Surgeons have seen cases with infection directly related to hematoma formation. This has been totally underreported and understated, and was thought not to be scientific until this recent report from the Rothman Institute.¹²

Third, as an orthopedic surgeon, I have to follow the guidelines of the American Academy of Orthopaedic Surgeons.¹¹ To blindly follow the guidelines of the Surgical Care Improvement Project (http://www.medqic.org) is asking for less than ideal results in orthopedic cases.

I see a very strong trend toward aspirin. A number of academics in prominent institutions are using aspirin, particularly in knee surgery.

I personally have experience with a group of 350 orthopedic surgery patients whom I have managed based on the approach recently reported by Bern et al—ie, warfarin 1 mg/day for 7 days prior to surgery, followed by variable warfarin dosing during the hospital stay to achieve a target INR of 1.5 to 2.0, followed by a maintenance warfarin dose of 1 mg daily for 30 days after discharge.¹³ I am very pleased with the results of this regimen. I have not encountered any wound issues, unlike my prior experience when using warfarin dosed to an INR of 2.0 to 3.0. I have currently modified this approach so that all male patients first receive two 325-mg aspirin tablets daily for 2 weeks, then warfarin 1 mg/day for the 7 days before surgery, followed by postoperative warfarin dosed to an INR of 1.5 to 2.0 during hospitalization, and then warfarin 2 to 5 mg/day for 30 days based on the patient’s INR response during hospitalization. The postoperative warfarin dosing requires monitoring, of course.

The results have been far superior to the bleeding rates reported from the Rothman Institute.¹² It is unfortunate that an approach such as this, as well as the rationale behind it, was not discussed in your supplement.

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.

To the Editor: I must make several comments regarding the review by Deitelzweig and colleagues.¹

First, all but one of the article’s six authors report having received honoraria, consulting fees, or research funding from companies that market medical products; therefore, their observations are not going to be “clean.”

Second, the most worrisome part of the article is that the authors downplay the issue of bleeding. As recently reported by surgeons from the Rothman Institute of Orthopedics at Thomas Jefferson University, there is a very clear connection in their practice between periprosthetic infection and an international normalized ratio (INR) greater than 1.5.¹² All of us in the Hip Society and the American Association of Hip and Knee Surgeons have seen cases with infection directly related to hematoma formation. This has been totally underreported and understated, and was thought not to be scientific until this recent report from the Rothman Institute.¹²

Third, as an orthopedic surgeon, I have to follow the guidelines of the American Academy of Orthopaedic Surgeons.¹¹ To blindly follow the guidelines of the Surgical Care Improvement Project (http://www.medqic.org) is asking for less than ideal results in orthopedic cases.

I see a very strong trend toward aspirin. A number of academics in prominent institutions are using aspirin, particularly in knee surgery.

I personally have experience with a group of 350 orthopedic surgery patients whom I have managed based on the approach recently reported by Bern et al—ie, warfarin 1 mg/day for 7 days prior to surgery, followed by variable warfarin dosing during the hospital stay to achieve a target INR of 1.5 to 2.0, followed by a maintenance warfarin dose of 1 mg daily for 30 days after discharge.¹³ I am very pleased with the results of this regimen. I have not encountered any wound issues, unlike my prior experience when using warfarin dosed to an INR of 2.0 to 3.0. I have currently modified this approach so that all male patients first receive two 325-mg aspirin tablets daily for 2 weeks, then warfarin 1 mg/day for the 7 days before surgery, followed by postoperative warfarin dosed to an INR of 1.5 to 2.0 during hospitalization, and then warfarin 2 to 5 mg/day for 30 days based on the patient’s INR response during hospitalization. The postoperative warfarin dosing requires monitoring, of course.

The results have been far superior to the bleeding rates reported from the Rothman Institute.¹² It is unfortunate that an approach such as this, as well as the rationale behind it, was not discussed in your supplement.

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.

To the Editor: In regard to the article on hematuria by Drs. Rao and Jones in the March issue of the Cleveland Clinic Journal of Medicine, I work in the emergency department and see a lot of cases of hematuria associated with indwelling Foley catheters and in patients on anticoagulants. I realize that gross hematuria usually needs a workup; however, in my clinical experience, the presence of a Foley and/or the use of anticoagulants often confuses the clinical scenario. I prefer to wait to refer the patient until either the Foley is removed or the anticoagulation is in the therapeutic range. I’d be eager to hear of your advice or experience with such patients.

To the Editor: In regard to the article on hematuria by Drs. Rao and Jones in the March issue of the Cleveland Clinic Journal of Medicine, I work in the emergency department and see a lot of cases of hematuria associated with indwelling Foley catheters and in patients on anticoagulants. I realize that gross hematuria usually needs a workup; however, in my clinical experience, the presence of a Foley and/or the use of anticoagulants often confuses the clinical scenario. I prefer to wait to refer the patient until either the Foley is removed or the anticoagulation is in the therapeutic range. I’d be eager to hear of your advice or experience with such patients.

To the Editor: In regard to the article on hematuria by Drs. Rao and Jones in the March issue of the Cleveland Clinic Journal of Medicine, I work in the emergency department and see a lot of cases of hematuria associated with indwelling Foley catheters and in patients on anticoagulants. I realize that gross hematuria usually needs a workup; however, in my clinical experience, the presence of a Foley and/or the use of anticoagulants often confuses the clinical scenario. I prefer to wait to refer the patient until either the Foley is removed or the anticoagulation is in the therapeutic range. I’d be eager to hear of your advice or experience with such patients.

In Reply: Although a Foley catheter can contribute to macroscopic (gross) hematuria, to assume that it is the cause of the hematuria carries some undefined, but presumably small, risk of missing a more serious diagnosis. A more serious potential for misdiagnosis is in the setting of anticoagulation. As we discuss in our review, hematuria is analagous to hematochezia in the setting of anticoagulants. The possibility that anticoagulation has simply exposed an underlying bleeding source such as a tumor in either setting must not be underestimated, and we recommend that all patients with macroscopic hematuria undergo urologic evaluation unless there is a documented benign physical cause of bleeding such as traumatic catheterization.

In Reply: Although a Foley catheter can contribute to macroscopic (gross) hematuria, to assume that it is the cause of the hematuria carries some undefined, but presumably small, risk of missing a more serious diagnosis. A more serious potential for misdiagnosis is in the setting of anticoagulation. As we discuss in our review, hematuria is analagous to hematochezia in the setting of anticoagulants. The possibility that anticoagulation has simply exposed an underlying bleeding source such as a tumor in either setting must not be underestimated, and we recommend that all patients with macroscopic hematuria undergo urologic evaluation unless there is a documented benign physical cause of bleeding such as traumatic catheterization.

In Reply: Although a Foley catheter can contribute to macroscopic (gross) hematuria, to assume that it is the cause of the hematuria carries some undefined, but presumably small, risk of missing a more serious diagnosis. A more serious potential for misdiagnosis is in the setting of anticoagulation. As we discuss in our review, hematuria is analagous to hematochezia in the setting of anticoagulants. The possibility that anticoagulation has simply exposed an underlying bleeding source such as a tumor in either setting must not be underestimated, and we recommend that all patients with macroscopic hematuria undergo urologic evaluation unless there is a documented benign physical cause of bleeding such as traumatic catheterization.

To the Editor: We read the interesting paper by Dr. Susan Rehm on the recently changing epidemiology and increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.¹ We feel these trends may be related in part to the increasing use of statin therapy in both outpatient and hospital settings.

In a case-control study,² skin and soft tissue infections as the source of bacteremia were significantly more prevalent among patients treated with statins compared with patients not receiving statin therapy. Additionally, there have been isolated reports of recurrent community-acquired MRSA skin infections in subjects on therapy with high-dose statins and no obvious risk factors for skin infection.³

The epidermis is a very active site of cholesterol synthesis, and after barrier disruption in the murine model, there is a brisk increase in epidermal cholesterol synthesis.⁴ Moreover, if the increase in epidermal cholesterol synthesis is inhibited by the topical application of statins, barrier function is impaired.⁴

Therefore, it is plausible that systemic statin therapy alters epidermal cholesterol homeostasis, resulting in barrier inadequacy and impaired innate immune function of the skin,⁵ leaving it more vulnerable to external pathogens and resulting bacteremia. Importantly, this needs to be investigated, particularly in light of the increasing and widespread use of high-dose statin therapy.

To the Editor: We read the interesting paper by Dr. Susan Rehm on the recently changing epidemiology and increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.¹ We feel these trends may be related in part to the increasing use of statin therapy in both outpatient and hospital settings.

In a case-control study,² skin and soft tissue infections as the source of bacteremia were significantly more prevalent among patients treated with statins compared with patients not receiving statin therapy. Additionally, there have been isolated reports of recurrent community-acquired MRSA skin infections in subjects on therapy with high-dose statins and no obvious risk factors for skin infection.³

The epidermis is a very active site of cholesterol synthesis, and after barrier disruption in the murine model, there is a brisk increase in epidermal cholesterol synthesis.⁴ Moreover, if the increase in epidermal cholesterol synthesis is inhibited by the topical application of statins, barrier function is impaired.⁴

Therefore, it is plausible that systemic statin therapy alters epidermal cholesterol homeostasis, resulting in barrier inadequacy and impaired innate immune function of the skin,⁵ leaving it more vulnerable to external pathogens and resulting bacteremia. Importantly, this needs to be investigated, particularly in light of the increasing and widespread use of high-dose statin therapy.

To the Editor: We read the interesting paper by Dr. Susan Rehm on the recently changing epidemiology and increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.¹ We feel these trends may be related in part to the increasing use of statin therapy in both outpatient and hospital settings.

In a case-control study,² skin and soft tissue infections as the source of bacteremia were significantly more prevalent among patients treated with statins compared with patients not receiving statin therapy. Additionally, there have been isolated reports of recurrent community-acquired MRSA skin infections in subjects on therapy with high-dose statins and no obvious risk factors for skin infection.³

The epidermis is a very active site of cholesterol synthesis, and after barrier disruption in the murine model, there is a brisk increase in epidermal cholesterol synthesis.⁴ Moreover, if the increase in epidermal cholesterol synthesis is inhibited by the topical application of statins, barrier function is impaired.⁴

Therefore, it is plausible that systemic statin therapy alters epidermal cholesterol homeostasis, resulting in barrier inadequacy and impaired innate immune function of the skin,⁵ leaving it more vulnerable to external pathogens and resulting bacteremia. Importantly, this needs to be investigated, particularly in light of the increasing and widespread use of high-dose statin therapy.

In Reply: While there may be some theoretical increased risk of S aureus cutaneous infections because of the effect of statins on lipids in the skin, it is not clear what role statin use has played in the changing epidemiology of S aureus infections. Other studies suggest that statins may ameliorate sepsis because of their anti-inflammatory effect.¹

In Reply: While there may be some theoretical increased risk of S aureus cutaneous infections because of the effect of statins on lipids in the skin, it is not clear what role statin use has played in the changing epidemiology of S aureus infections. Other studies suggest that statins may ameliorate sepsis because of their anti-inflammatory effect.¹

In Reply: While there may be some theoretical increased risk of S aureus cutaneous infections because of the effect of statins on lipids in the skin, it is not clear what role statin use has played in the changing epidemiology of S aureus infections. Other studies suggest that statins may ameliorate sepsis because of their anti-inflammatory effect.¹

To the Editor: In their otherwise excellent review, “Masquerade: Medical causes of back pain” (Cleve Clin J Med 2007; 74:905–913), Dr. Klineberg et al seem to confuse two distinct pathologic processes—aortic dissection and rupture of an aortic aneurysm. Parts of their description seem to fit the pathology of abdominal aortic aneurysm, with a pulsatile abdominal mass, sentinel bleeding, and rupture risk with a size over 6 cm, whereas other parts seem to correspond to aortic dissection, with severe, ripping pain and an association with Marfan syndrome. They also use the terminology “dissecting aortic aneurysm,” which again implies a single entity, when in fact the two conditions rarely occur together. The authors are not alone in their use of this misnomer: a review of the Web sites of renowned universities reveals use of the same terminology. The readers would have been better served if the authors had discussed “acute aortic dissection” and “ruptured aortic aneurysm” as two separate causes of back pain, with a note that in rare cases an aortic aneurysm can develop a dissection.

To the Editor: In their otherwise excellent review, “Masquerade: Medical causes of back pain” (Cleve Clin J Med 2007; 74:905–913), Dr. Klineberg et al seem to confuse two distinct pathologic processes—aortic dissection and rupture of an aortic aneurysm. Parts of their description seem to fit the pathology of abdominal aortic aneurysm, with a pulsatile abdominal mass, sentinel bleeding, and rupture risk with a size over 6 cm, whereas other parts seem to correspond to aortic dissection, with severe, ripping pain and an association with Marfan syndrome. They also use the terminology “dissecting aortic aneurysm,” which again implies a single entity, when in fact the two conditions rarely occur together. The authors are not alone in their use of this misnomer: a review of the Web sites of renowned universities reveals use of the same terminology. The readers would have been better served if the authors had discussed “acute aortic dissection” and “ruptured aortic aneurysm” as two separate causes of back pain, with a note that in rare cases an aortic aneurysm can develop a dissection.

To the Editor: In their otherwise excellent review, “Masquerade: Medical causes of back pain” (Cleve Clin J Med 2007; 74:905–913), Dr. Klineberg et al seem to confuse two distinct pathologic processes—aortic dissection and rupture of an aortic aneurysm. Parts of their description seem to fit the pathology of abdominal aortic aneurysm, with a pulsatile abdominal mass, sentinel bleeding, and rupture risk with a size over 6 cm, whereas other parts seem to correspond to aortic dissection, with severe, ripping pain and an association with Marfan syndrome. They also use the terminology “dissecting aortic aneurysm,” which again implies a single entity, when in fact the two conditions rarely occur together. The authors are not alone in their use of this misnomer: a review of the Web sites of renowned universities reveals use of the same terminology. The readers would have been better served if the authors had discussed “acute aortic dissection” and “ruptured aortic aneurysm” as two separate causes of back pain, with a note that in rare cases an aortic aneurysm can develop a dissection.

In Reply: We appreciate Dr. Hirsch’s comments and are pleased to expand the discussion of this important point.

He is correct in his assertion that dissection and aneurysm are distinct processes. But the goal of this review was to remind practitioners to consider the aorta as a possible source of pain when it occurs acutely or in an atypical manner.

A number of aortic processes can cause back pain, and aneurysm and dissection are two of them, aneurysm being more common than aortic dissection. But the pain can also be from aortic ulceration, aortitis, contained rupture of an aneurysm, and other more esoteric problems.

Aortic dissection often presents as a tearing, severe, thoracic back pain. Pain from a progressive abdominal aneurysm is more commonly referred to the lower back or flank and can be severe and unrelenting. It is rarely described as a tearing pain like that of dissection.

It is difficult on initial physical examination to distinguish aneurysm from dissection. The key to diagnosing aneurysm is to detect the pulsatile abdominal mass. A pulsatile, tender abdominal mass with hypotension and back pain is classically associated with rupture of an abdominal aortic aneurysm. The combination of back pain, a deficit in peripheral pulses, and hypertension is more often associated with dissection.

Without imaging and appropriate consultation, it is difficult for even an experienced provider to definitively diagnose these disorders. Without a bit of suspicion, even with a careful physical examination either disorder might be overlooked entirely, with disastrous effect. The purpose of our review was to remind the reader that these conditions, while uncommon or even rare, do occur and should be sought out in patients presenting with acute, atypical lumbar and thoracic back pain. As with each of the conditions discussed in this review, the decision to linger a bit over the patient’s history and then perform a basic, focused physical examination can be life-saving.

In Reply: We appreciate Dr. Hirsch’s comments and are pleased to expand the discussion of this important point.

He is correct in his assertion that dissection and aneurysm are distinct processes. But the goal of this review was to remind practitioners to consider the aorta as a possible source of pain when it occurs acutely or in an atypical manner.

A number of aortic processes can cause back pain, and aneurysm and dissection are two of them, aneurysm being more common than aortic dissection. But the pain can also be from aortic ulceration, aortitis, contained rupture of an aneurysm, and other more esoteric problems.

Aortic dissection often presents as a tearing, severe, thoracic back pain. Pain from a progressive abdominal aneurysm is more commonly referred to the lower back or flank and can be severe and unrelenting. It is rarely described as a tearing pain like that of dissection.

It is difficult on initial physical examination to distinguish aneurysm from dissection. The key to diagnosing aneurysm is to detect the pulsatile abdominal mass. A pulsatile, tender abdominal mass with hypotension and back pain is classically associated with rupture of an abdominal aortic aneurysm. The combination of back pain, a deficit in peripheral pulses, and hypertension is more often associated with dissection.

Without imaging and appropriate consultation, it is difficult for even an experienced provider to definitively diagnose these disorders. Without a bit of suspicion, even with a careful physical examination either disorder might be overlooked entirely, with disastrous effect. The purpose of our review was to remind the reader that these conditions, while uncommon or even rare, do occur and should be sought out in patients presenting with acute, atypical lumbar and thoracic back pain. As with each of the conditions discussed in this review, the decision to linger a bit over the patient’s history and then perform a basic, focused physical examination can be life-saving.

In Reply: We appreciate Dr. Hirsch’s comments and are pleased to expand the discussion of this important point.

He is correct in his assertion that dissection and aneurysm are distinct processes. But the goal of this review was to remind practitioners to consider the aorta as a possible source of pain when it occurs acutely or in an atypical manner.

A number of aortic processes can cause back pain, and aneurysm and dissection are two of them, aneurysm being more common than aortic dissection. But the pain can also be from aortic ulceration, aortitis, contained rupture of an aneurysm, and other more esoteric problems.

Aortic dissection often presents as a tearing, severe, thoracic back pain. Pain from a progressive abdominal aneurysm is more commonly referred to the lower back or flank and can be severe and unrelenting. It is rarely described as a tearing pain like that of dissection.

It is difficult on initial physical examination to distinguish aneurysm from dissection. The key to diagnosing aneurysm is to detect the pulsatile abdominal mass. A pulsatile, tender abdominal mass with hypotension and back pain is classically associated with rupture of an abdominal aortic aneurysm. The combination of back pain, a deficit in peripheral pulses, and hypertension is more often associated with dissection.

Without imaging and appropriate consultation, it is difficult for even an experienced provider to definitively diagnose these disorders. Without a bit of suspicion, even with a careful physical examination either disorder might be overlooked entirely, with disastrous effect. The purpose of our review was to remind the reader that these conditions, while uncommon or even rare, do occur and should be sought out in patients presenting with acute, atypical lumbar and thoracic back pain. As with each of the conditions discussed in this review, the decision to linger a bit over the patient’s history and then perform a basic, focused physical examination can be life-saving.