Pellegrini Battles Padgett Over DVT Anticoagulants

“Balance, ” argues Vincent Pellegrini. “I accept less effective prevention of venographic disease to avoid bleeding complications, but I still want effective prevention of clinical events.” “The biggest issue now is safety, ” says Doug Padgett. “And there are better and safer alternatives to chemoprophylaxis.”

This week’s Orthopaedic Crossfire® debate is “DVT Anticoagulants: Contemporary Standard of Care.” For the proposition was Vincent D. Pellegrini, Jr., M.D. of the University of Maryland School of Medicine in Baltimore. Against the proposition was Douglas E. Padgett, M.D. from the Hospital for Special Surgery (HSS). Moderating was Steven J. MacDonald, M.D., F.R.C.S.(C) of the University of Western Ontario.

Dr. Pellegrini: “If we choose to prevent every venographic clot by definition we will have to accept more bleeding. If we choose to be more selective in our prevention and worry about clinical pulmonary embolism (PE) and death, we can have less bleeding and accept some venographic clots.”

“The American College of Chest Physicians (ACCP) guidelines came out against aspirin…and gave a seal of approval to Warfarin, fractionated Heparin, and Fondaparinux. The softer recommendation is duration, but they landed on about 35 days. The American Academy of Orthopaedic Surgeons (AAOS) charged a task force to focus on clinical events and bleeding risk. There is a paucity of data and the AAOS recommendations pointed to bleeding as a concern. As you elevate the risk of bleeding from standard prophylaxis or standard risk, aspirin and Warfarin are the only two drugs that survive. When there’s an elevated risk of thrombosis, as well as an elevated risk of bleeding, aspirin and Warfarin are still the only ones, so bleeding risk trumps PE risk.”

“One classic argument that orthopedists have is that there’s a poor correlation between venographic clot and clinical events, and while they aren’t synonymous, there is a well proven relationship between the two—if you reduce one the other also reduces. Traditionally, Warfarin has a residual clot risk of about 20%, with general [anesthesia], and 10% with regional anesthesia after hip replacement. Fractionated Heparin gets that residual clot rate down to 10%. If we look at knees, they’ve been rather refractory to effective prophylaxis; even to fractionated Heparin their residual clot rate is around 30%. But with fractionated Heparin the bleeding risk increases two- to three-fold.”

“So our therapeutic compromise is based on a balance. I accept less effective prevention of venographic disease to avoid bleeding complications, but I still want highly effective prevention of clinical events. Over the last 20 years we’ve looked at this with venogram surveillance. For the first decade if the patient didn’t get a venogram we did not continue their prophylaxis. For the second decade if they got no venogram we were concerned and had seen some adverse events and gave Warfarin upon discharge. If you left the hospital on Warfarin you had nearly seven-fold reduced risk of being readmitted for a clot after hip arthroplasty. The data were similar for knees, with about a four-fold reduction; if you combine the data there wasn’t a single PE in 20 years that occurred in a patient that left the door with Warfarin.”

“The risk of bleeding with low intensity Warfarin was one tenth of 1%. What the Warfarin does in low intensity is provide effective secondary prophylaxis even though it doesn’t prevent the initial clot from forming; it effectively prevents embolization.”

“Other modalities: the greatest advance in the ACCP guidelines two versions ago was that they acknowledged a high risk of bleeding perioperatively is optimally managed with mechanical prophylaxis. But after that bleeding risk resolves, you must use a chemoprophylaxis of some sort. The study by Paiement suggested a twice high rate of proximal clots with pneumatic compression alone. Our data suggests it’s four fold with pneumatic compression alone, without chemoprophylaxis after hip arthroplasty.”

“The NIH [National Institutes of Health] some 20 years ago told us aspirin wasn’t very good; it became more popular in the 90s, largely because of the problems with fractionated Heparin. The Antiplatelet Trialists’ Study is frequently studied: with elective hip and knee arthroplasty with aspirin alone only 24-60 patients…doesn’t really tell us anything.”

“The Pulmonary Embolism Prevention Trial—a hip fracture trial. If you look at elective arthroplasty there was no difference between aspirin and placebo. If you look at meta-analysis, a study from the University of Pennsylvania suggests that the anesthetic effect of aspirin is irrefutable. A study from the Hospital for Special Surgery showed a very effective prophylaxis with hypotensive epidural anesthesia and unfractionated Heparin, with very low PE rate. With regional anesthesia there was a readmission rate of only 0.5%”

“Some newer agents have no known antidote, and we often recognize new and untoward side effects, but they’re never telling us new drugs have greater safety. Rivaroxaban, a factor 10 inhibitor, is the most highly studied new drug—nearly 13, 000 new patients in trials. There were so many patients that they’ve shown us there was a clinically increased risk of major bleeding and clinically important bleeding with this drug. Dabigaran—similar bleeding rate to Enoxaparin.”

“I believe the best compromise is balancing low bleeding, high efficacy…and clinical endpoint should be our bottom line.”

Dr. Padgett: “I vehemently oppose this. If the major risk of VTE [venus thromboembolism] is PE, and if 90% of the PE originate from deep vein thrombosis, and if therefore we reduce the DVT [deep vein thromobosis] rate, perhaps we can reduce the PE rate and underlying fatalities associated with this.”

“Why thromboembolic events? It’s the Virchow’s triad [hypercoagulation at top, stasis and endothelial damage at bottom].The thesis of my opponent has been that the optimal way to prevent VTE and its complications is to use anticoagulants addressing the hypercoaguable aspect of this triad. There are better and safer alternatives to this.”

“Strategies to reduce VTE events are largely driven towards chemoprophylaxis. Why? Money. The basis of this has been the recommendations of the ACCP; the grades of recommendations have been based upon methodologic strength and the clarity of perceived risk and benefit.”

“Current ACCP guidelines: low molecular weight Heparin, Fondaparinux, and adjusted dose Warfarin with a target INR of 2.5; recommendations are against aspirin, low dose Heparin and intermittent pneumatic compression solely as an agent. ACCP guidelines are sponsored by big pharma, the investigators are all consultants, and they downplay the risks of anticoagulation.”

“Exhibit A: a meta-analysis of potent anticoagulants—a study performed at our institution—over 28, 000 patients looking at all cause mortality. They were grouped into potent anticoagulants: group A had low molecular weight Heparin, oral anti-thrombin agents, etc; group B was the HSS protocol which combined spinal epidural, aspirin, and pneumatic compression; group C was the Warfarin group. The results that the highest all cause mortality and the highest rate of non-fatal PE occurred in groups A and C, with the lowest rates occurring in group B.”

“More importantly is exhibit B…the failure of the ACCP article that was submitted by Robert Barrack and coauthors. The authors switched from using their standard Warfarin techniques for DVT prevention to the use of the ACCP guidelines using Lovenox. The intended protocol was approximately a 10 day course for total hips and knees with an intention to treat 1, 500 patients. After less than 300 patients were enrolled, 9% of the patients presented with major complications: a readmission DVT rate of 3.8%, a 5% readmission rate, and a 3.4% reoperation rate for wound drainage. The study was terminated by the IRB [Institutional Review Board].”

“If limb torsion is associated with restriction of blood flow and decreased blood flow leads to stasis and stasis leads to thrombosis, then why not mechanical compression. DVT prevention using mechanical devices has been studied in total hips and knees, and it has a systemic effect by releasing endothelial derived relaxing factors and urokinases, and has a systemic endogenous fibrilytic effect.”

“The advantages of mechanical compression: nearly complication free, it’s safe, and time worn appears to be related to the effectiveness. Disadvantages: applied often after surgery, worn only in the hospital, and compliance is an issue. ActiveCare, the CECT System—Continuous Enhanced Circulation Therapy—it’s miniature, portable, battery powered, applied at the time of surgery and the patients can go home with it. It’s triggered with inspiration cycle to maximize venous return.”

“We did a multicenter randomized trial that we published this year in the Journal of Bone and Joint Surgery (JBJS). We looked at the hypothesis of superiority, and the efficacy and safety of the device compared to Enoxaparin. We looked at a consecutive series of total hips that were performed unilateral. In the CECT arm the device was applied in the OR, surgery was performed, and patients received an aspirin per day, skin checks, and follow up at 10-14 days with a three month clinical follow up. In the Lovenox arm there were no compression devices; Lovenox was administered BID [twice a day], and we evaluated the patients at 10-14 days (sutures out, Doppler study, both lower extremities) and a three month clinical follow up.”

“We used no general anesthesia, but we did avoid the profound hypotension that we actually prefer at HSS, so mean arterial pressure was >60; Intravenous Patient-Controlled Analgesia for pain. We monitored major and minor bleeding, looking at drops in hemoglobin, rehospitalization, as well as fatalities. There were 411 patients consented. We found no difference in the distribution of DVT by either the Lovenox group or the compression device, as well as the incidence of PE. The bleeding indices tended to be lower in the compression device. Most significant was the major bleeding events: none in the compression device, minor bleeds were less than 25%, however in the Lovenox arm there were 6% major bleed and 31% minor bleed. Compliance rate: mean use was for 11 days (intended use of the device was 10-14 days). But we could not demonstrate relationship between DVT and the use of the device.”

“The object of total hip: perform it well, make it safe, and reduce the risks. We clearly demonstrated efficacy between the two modalities; we demonstrated the indisputable safety of this device in regards to the risk of postoperative bleeding after total hip.”

Moderator MacDonald: “So Vinny…is Doug crazy?”

Dr. Pellegrini: “The paper that was the lead article in the JBJS earlier this year was not powered to determine efficacy—only to determine safety. Nowhere under the sun can we have 200 patients in each group and determine a statistically significant difference in an event that occurs less than 1% of the time. That study was supported by a commercial entity and was designed to prove safety. I’m excited by the device, but that paper doesn’t help me get there. Another point: there are three Level 1 trials in the literature—prospective, randomized studies—of chemoprophylaxis versus pneumatic compression full length of leg, that show higher proximal clot rates with pneumatic compression alone.”

Dr. Padgett: “Most of the prior studies on intermittent pneumatic compression were done during the hospital period where patients actually stay in the institution, which is approximately three days. It’s probably unlikely that these days it is sufficient to do the trick. Also, if the initiating event occurs at the time of surgery you might say that use of a pneumatic compression device intraoperatively is the way to go. You’re right that our study was not powered enough to demonstrate the efficacy; we did demonstrate, however, and it was powered strong enough for the safety. But the biggest issue now is safety.”

Moderator MacDonald: “Thank you, gentlemen.”

Please visit www.CCJR.com to register for the 2012 CCJR Winter Meeting, December 12 – 15 in Orlando, Florida.

“You may now view CCJR meeting content on your mobile device on the CCJR MobileTM App. Please scan the QR code to download from iTunes.”