Managing Antithrombic Therapy from Consensus Statement to Clinical Practice

Developing the New ATS VTE Treatment Guidelines: Striking an AppropriateBalance

There are currently guidelines for diagnosis and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) from the American Thoracic Society (ATS) and The American College of Chest Physicians (ACCP). Both are comprehensive and well-researched documents, but some important considerations are not adequately addressed.

“My conclusion is that diagnosis, therapy and prophylaxis of venous thromboembolic event (VTE) in the intensive care unit (ICU) might be addressed more comprehensively,” said Victor Tapson, MD, from Duke University Medical Center, Durham, NC. “Thromboembolism in the critically ill patient is complex. The management of massive PE, and preventing VTE in the critically ill patient are two of the main concerns. Proving or refuting suspected VTE can be difficult as well. Finally, because of the potential for bleeding that is frequently present in ICU patients, management of established VTE also requires careful consideration.”

Neither of the currently available statements adequately addresses issues pertaining to critically ill patients. Dr. Tapson feels this is one area that the ATS should focus on when discussing new guidelines. In addition, the ATS could concentrate on areas that are less emphasized by the ACCP.

Defining a Practical Approach for Treating VTE in Outpatients: Beyond the Guidelines

Roger Yusen, MD, MPH, Washington University School of Medicine, St. Louis, provided an overview of secondary prophylaxis treatment of DVT and PE.

There are a number of positive therapeutic aspects associated with low molecular weight heparins (LMWH) when compared to unfractionated heparin (UFH). Pharmacologically, the LMWHs are highly bioavailable and they have a rapid antithrombotic effect when given intravenously or subcutaneously. LMWHs have a predictable dose-response and weight-based dosing that does not typically need close monitoring. LMWHs have a long elimination half-life, allowing for once- or twice-a-day dosing.

Dr. Yusen presented data from a study of 432 people with proximal lower extremity DVT, randomized to either LMWH or UFH. Patients were assessed over three months for endpoints of recurrence, recurrent DVT/ PE, death and bleeding. LMWH and UFH treatment groups had statistically equivalent recurrence rates with trends favoring the LMWH. In addition, the patients receiving LMWH had a bleeding rate that was ten times lower and half the death rate seen in patients receiving UFH (Hull R, et al. NEJM 1992;326:975-82).

“What we have seen over and over is that the LMWHs are at least equivalent therapeutically to UFH in terms of efficacy and safety,” said Dr. Yusen. “Subcutaneous low molecular weight therapy given once or twice a day is as good as intravenous UFH for the treatment of DVT with or without PE.”

There have been similar results in research on PE. Dr. Yusen pointed to Simonneau, et al (NEJM 1997;37:663-9) where 612 patients were randomized to once-daily LMWH versus intravenous UFH. The combined endpoints of recurrent thromboembolism, bleeding and death were statistically equivalent between the groups.

Dr. Yusen next turned his attention to the treatment setting. He reviewed studies looking at low molecular weight heparin treatment in outpatient versus inpatient settings. A study by Levine and colleagues randomized 247 patients to low molecular weight heparin therapy, roughly half were treated completely in the outpatient setting. All but two of the 235 patients randomized to UFH were treated in the hospital (Levin et al. NEJM 1996;334: 677-81).

The recurrent VTE rates, major bleed rates and death rates were similar. However, there was a significant difference in length of stay (1.1 days for the LMWH group versus 6.5 days in UFH). Similar results found in the Koopman trial (NEJM 1996; 334:682-87) lead Dr. Yusen to suggest that outpatient-DVT therapy with subcutaneous LMWH appears to be as good as inpatient therapy with IV heparin.

Deciding on the setting for treatment is a judgment call. Those at high risk for recurrent VTE such as a previous history of VTE, multiple or large DVT/PE, or cancer should be considered for hospitalization if the goal is to avoid recurrences at home. Based on the current data, it is recommended that patients with symptoms of PE or poor cardiac reserve undergo treatment in a hospital setting. However, some studies have suggested that patients with uncomplicated PE may be safely treated in outpatient settings. More data are needed in this area. Patients at high risk for bleeding, such as those with guaiac positive stools and low platelet counts, may be poor candidates for outpatient treatment.

Low molecular weight heparins have an additional advantage.

“Treatment with LMWH may not only be better (clinically), but also it may be highly cost-effective, potentially even for inpatient therapy,” said Dr. Yusen.

Some practical aspects of LMWH outpatient therapy should be considered. Correct dosing is very important. Dose-rounding based on weight may cause confusion. Graduated syringes make it easier to find the appropriate dose for a given patient and enhances compliance. Multi-dose vials require careful withdrawal of the appropriate amount of drug into the syringe.

After determining a patient’s candidacy for outpatient therapy, “physicians need to understand the details of how to arrange for home therapy addressing issues such as how to dose the drug, how to order the drug and how to arrange for blood work and follow-up,” said Dr. Yusen.

Thromboprophylaxis in Medical Patients: Why Aren’t At-Risk Patients Being Treated?

Venous thromboembolic disease is the third most common disorder associated with thrombosis. For Dr. Alexander G.G. Turpie, McMaster University, Hamilton, Ontario, Canada it is incumbent on clinicians to consider preventing VTE in medical patients.

“A very interesting observation by Sam Goldhaber (Goldhaber S, et al. JAMA 1983;74:1023-1028) from the Framingham study was that about four times more medical patients die from PE than surgical patients,” he said. “Yet we focus on the prevention of thrombosis in postoperative settings, ignoring the medical patients.”

Dr. Turpie says there is no question risk is underestimated in medical patients. About one in four general medical patients will develop VTE. Two of the most common reasons for admission to the medical intensive care setting are congestive heart failure and acute respiratory failure. In these patients, 1 in 3 are at risk for venous thromboembolism.

Two types of medications are available for prophylaxis in this population, either LMWH or UFH. A meta-analysis of 8 randomized trials compared the various types of heparin available (Mismetti P, et al. Throm Haemost 2000;83:14-19). In their analysis 5,000 units of UFH given either twice or three times a day was compared versus all the usual once-a-day regimens of LMWH.

“The data is clear that anticoagulant therapy reduces the risk of venous thrombosis and pulmonary embolism in medical patients,” said Dr. Turpie. “We see a 50% reduction in the risk of VTE and about the same reduction for PE.”

The clinically important question then becomes, should practitioners use unfractionated or low molecular weight heparin? There are studies that demonstrate the effectiveness of the LMWHs in the prevention of thomboembolic disease.

The MEDENOX trial (Samama et al. NEJM 1999;341:793-800) compared 20 and 40 mg doses of enoxaparin against placebo. The 40 mg dose resulted in a reduction of 63% in the risk of all VTE and 64% reduction in proximal vein thrombosis. The 20 mg dose had no effect in medical patients.

“The data points to very similar risk reductions in patients with heart failure, respiratory failure and infections,” he said, “demonstrating clearly the beneficial effects of anticoagulant prophylaxis across a broad spectrum of medical patients.”

The other question becomes the relative efficacy of LMWH versus UFH. Data from four recent trials shows no statistical difference between enoxaparin and UFH in prophylaxis.

There is, however, a statistically significant lower risk of hemorrhagic complications in those receiving enoxaparin. “With all of that information, why is prophylaxis of medical patients underused?” asked Dr. Turpie. “Many clinicians are unaware of the level of risk. We are dealing with a heterogeneous population giving rise to the perception that it is difficult to risk-stratify medical patients.”

He proposed a three-category assessment model to guide physicians. The lowest risk patients are those with minor medical illnesses and few risk factors for thrombosis. Moderate-risk patients include medical illnesses involving the heart or lungs, cancer, inflammatory bowel disease, rheumatological disease, severe infections and those over the age of 70. Also in this category would be those with minor illnesses with thrombophilia or a history of venous thrombosis. The highest risk category includes those with lower limb paralysis or major medical illnesses with thrombophilia or a history of thombolic events.

“Considering that medical patients are at high risk for venous thromboembolism, prophylaxis is underused,” said Dr. Turpie. “We know that prophylaxis is effective, safe and results in cost savings.”

Thromboprophylaxis in Surgical Patients: Are Current Guidelines Appropriate?

In 2001, ACCP published guidelines to help direct physician decision-making regarding thromboprophylaxis in the surgical patient. Bruce Davidson, MD, MPH, the University of Washington School of Medicine in Seattle, has some concerns about their current usefulness.

“They were great for 1999 when consensus was actually reached. I do think it is time to incorporate some new data,” said Dr. Davidson.

Current recommendations for hip replacement include LMWH or warfarin with use of elastic stockings or pneumatic compression as needed for high-risk patients. At the time they were writing the guidelines, the authors were unwilling to recommend prolonged prophylaxis for total hip replacement.

Now, however, Dr. Davidson believes the data shows benefits for two drugs, enoxaparin and dalteparin, tested for prolonged prophylaxis after hip replacement.

Knee replacement guidelines suggest LMWH or warfarin, elastic stockings and intermittent pneumatic compression.

“There are zero studies showing any benefit for routinely administering prolonged LMWH or warfarin in knee replacement,” said Dr. Davidson. “This should be noted so we aren’t spending unnecessary money or subjecting patients to unneeded therapies.”

What about other orthopedic prophylaxis? Dr. Davidson said that low dose UFH and aspirin are specifically not recommended for use. He does not think that the data currently available allows any suggestions beyond that.

Warfarin is recommended, despite its venographic inferiority. This is related to what he calls the “cold fact” that many patients are unable to obtain LMWH after discharge due to cost or availability.

For pelvic gynecological surgery, the recommendations are based on risk. Those at highest risk (age over 40, myocardial infarction in the past, general surgical risk factors), and moderate risk (age greater than 40 and no other risk factors), should receive low dose UFH or LMWH with stockings or compression as the recommended treatment.

Data from Geerts and colleagues (Chest 2001;119:132S-175S) shows that 24% to 27% of patients develop DVT without prophylaxis. With the addition of low molecular weight heparin, the incidence decreases to 6%.

In general surgery, comparisons of LMWH and UFH found that LMWH appears to be better. One large study with the LMWH reviparin (World J Surg 1997;21:2-8) showed equivalence in prophylaxis but lower incidence of wound hematoma with the low molecular weight heparin.

Length of use is also an important aspect of decision-making. A recent article by Bergqvist et al. (NEJM 2002;346:975-980) looked at prolonged prophylaxis in patients undergoing surgery for abdominal or pelvic cancer. All patients were given enoxaparin for seven days.

They were randomized to either placebo or continuation of enoxaparin for an additional three weeks. Follow-up continued for three months. DVT dropped from 12% to 4.8% at the end of 7 days and the differences persisted at three months.

“With 7 days of prophylaxis, the incidence rate is going to be about 2.5%,” said Dr. Davidson. “We should consider increasing the duration of prophylaxis to 28 days for abdominal or pelvic cancer surgery patients.”

For intracranial surgery, the guidelines recommend low dose UFH or postoperative LMWH in combination with intermittent compression. In the Agnelli trial (NEJM 1998;339:80-85), the best results were found in patients who received compression and 40 mg of enoxaparin.

In trauma, low molecular weight heparin should be started as soon as there is control of hemorrhage. Intermittent compression or elastic stockings can be started early. “For cardiopulmonary bypass, there are no recommendations made and I think there should be,” said Davidson.

Ramos reported on 10-years’ experience in cardiopulmonary bypass patients. Combining medication and compression cut the incidence of pulmonary embolism in half from 2.8% with unfractionated heparin alone to 1.2% in the combination therapy (Chest 1996;109:82-5). Davidson thinks this is sufficient to recommend combined therapy.

Thrombolysis in VTE/SM

If prophylaxis does not succeed in preventing thromboembolic disease, the next step is treatment. In the view of Selim Arcasoy, MD, Columbia University College of Physicians and Surgeons, this step needs to be aggressive.

“There are two major reasons physicians need to be alert for pulmonary embolisms,” he said. “One is that it may account for approximately 15% of hospital in-patient deaths. The second is that it is a very common reason for malpractice lawsuits.”

Current ACCP recommendations suggest use of thrombolytic agents in patients with hemodynamically unstable PE or massive iliofemoral thrombosis at low risk for bleeding. But are these still appropriate?

The first study that attempted to address the advantages of thrombolysis in PE was the urokinase pulmonary embolism trial. It compared urokinase with heparin. (Urokinase Pulmonary Embolism Trial: Phase 1 Results, JAMA 1970;214:2163-72).

The researchers demonstrated faster hemodynamic, angiographic, and perfusion scan improvement in the first 24 hours with urokinase. Subsequently there have been 8 randomized studies with the majority showing that thrombolytic therapy leads to faster improvement initially with no significance difference in recurrence rates or mortality long-term. One small study of 8 patients in shock due to massive PE reported improved survival with thrombolysis.

“There have been several studies showing that right ventricular dysfunction (RVD) is an important prognostic indicator and is associated with a higher mortality rate,” said Dr. Arcasoy. “The question then becomes whether RVD should be an indication for thrombolytic therapy. Although thrombolytic therapy improves RV function faster than heparin, evidence of improved outcomes in normotensive patients in not conclusive.”

There have been 6 randomized studies looking at various regimens of streptokinase, urokinase and t-PA. The 2-hour t-PA regimen clearly results in more rapid clot lysis compared to the other two. However, using these agents in equivalent doses and delivered over the same time period, they appear to have the same effects. In addition, limited available data does not support the use of intrapulmonary thrombolytic therapy at usual doses, although local pharmacomechanical thrombolysis using low doses of agents may have a role, especially in patients with high bleeding risk.

In terms of optimum time window, thrombolytic therapy is most effective when administered immediately. However, some benefits extend up to 14 days after symptom onset.

“Thrombolytic therapy leads to much more and rapid improvement in pulmonary vascular obstruction and homodynamic abnormalities within the first 2 to 24 hours than treatment with anticoagulant alone. It has not been proven that this benefit translates into a reduction of morbidity or mortality,” said Dr. Arcasoy.

“In patients with shock due to massive PE, benefits of thrombolysis outweigh the risk of significant bleeding,” he continued. “In patients with small emboli and no hemodynamic disturbance, the risk of thrombolysis is clearly not warranted. Additional data is needed to determine whether thrombolysis reduces morbidity or mortality in patients with normal blood pressure and RVD. Until then, current ACCP consensus recommendations should be used.”