Update in Anticoagulation: Venous Thromboembolism Management and Atrial Fibrillation

At an industry-sponsored symposium held in conjunction with CHEST 2003, the annual meeting of the American College of Chest Physicians in Orlando, Florida, four leading clinicians discussed recent developments in the use of anticoagulants for treating patients with venous thromboembolism or atrial fibrillation.

This program was supported by an educational grant from AstraZeneca.

New Radiologic Techniques in the Diagnosis of Deep Vein Thrombosis and Pulmonary Embolism

“Ten years ago when pulmonary embolism was first diagnosed with HCT (helical computed tomography), it was obvious that there was little problem for CT to pick up large emboli, but it became clear that picking up small emboli was a big problem and this is what gave people a lot of hesitation about using HCT as an alternative method for diagnosing pulmonary embolism,” said Lawrence R. Goodman, MD, Professor of Diagnostic Radiology and Pulmonary Medicine
and Director of Thoracic Imaging at the Medical College of Wisconsin in Milwaukee, WI. Fortunately, advances in CT technology, as well as other diagnostic tools, have made it easier to diagnose pulmonary embolism (PE) and deep vein thrombosis (DVT).

Many of the patients who have PE or DVT go undetected. Furthermore, many patients with DVT have silent pulmonary emboli. Dr. Lopez-Beret, looking at 159 cases of proven DVT without any pulmonary symptoms, found that 41% had positive CTs for PE (J Vasc Surg 2001;33(3):515-521). Unfortunately, “It’s difficult for both the radiologist and clinician to get a handle on which patients to even study,” said Dr. Goodman. For those whose signs and symptoms suggest the need for testing, Dr. Goodman presented the audience with the algorithm used by the Medical College of Wisconsin. Basically, if the patient has only DVT symptoms, he/she is usually given an ultrasonogram. “To elaborate on that a little bit further, if the ultrasound is positive, patients get treated and it is up to the referring physician to decide whether or not a study for PE is indicated. If the ultrasound is negative, we stop, and if the ultrasound is equivocal, there may be additional testing,” said Dr. Goodman. If the patient has PE symptoms or PE + DVT symptoms, then a chest X-ray (CXR) is used for triage. “Those with a normal chest X-ray, or near normal chest X-ray, will go for a V/Q scan,” said Dr. Goodman. If the CXR is normal, the chances of a definitive V/Q scan is very high. Those with an abnormal chest CXR will go for CT studies of their legs and chest. If the CT scan is positive, the patient is treated. If the CT scan is negative, usually no treatment or further diagnostic imaging is performed.

Multi-detector CT
“The gold standard over all these years has been the pulmonary angiogram, and for central clots, big clots in the main, lobar, and segmental pulmonary art-eries, angiography is terrific,” said Dr. Goodman. Unfortunately, accuracy declines significantly with small vessels. Agreement between angiographers on the presence or absence of PE in subsegmental vessels is mediocre.

With the advent of multi-detector CT, accuracy has greatly improved. Initial helical CT used 5-mm collimation, required a 24-40 second breath hold to complete the study, and have sensitivities of 65-90%. The 16-channel multi-detector CT can perform 1.25 mm axial images of the whole chest in 7 seconds and provides sensitivities above 90% in most studies. Dr. Goodman compared the two methods by stating, “Ten years ago, everyone was complaining that CT wasn’t sensitive enough for the small emboli, but now they’re complaining that CT is too sensitive and we are seeing emboli that we may not want to know about. We must rethink how to handle very small PE when there is no evidence of DVT.”

Concluding Remarks
There is still debate as to how to deploy CT. Using a chest X-ray as a triage tool is simple and rational. Patients with abnormal chest X-rays are more likely to have an inconclusive V/Q scan and a multi-detector CT should be employed. Dr. Goodman acknowledged, “CT is expensive,” adding “but a V/Q scan, or a V/Q scan with an ultrasound, is more expensive than the CT combination.”

Treating and Preventing Venous Thromboembolism: New Data, New Approaches and Clinical Implications

Kenneth V. Leeper, Jr., MD, FCCP, Associate Professor of Medicine at the Emory University School of Medicine, Section Chief of Pulmonary and Critical Care Medicine at Crawford Long Hos-pital, and the Medical Director of Clinical Studies Center at the VA Medical Center in Atlanta, GA began his presentation with a list of the numerous guidelines for treatment of venous thromboembolism. Among them is the popular ACCP Guidelines (Table 1). Once this short -term treatment is completed, however, there is still a concern for recurrence of VTE. There have been a number of studies that have compared short- and long-term anticoagulation for recurrence of venous thromboembolism and Dr. Leeper briefly discussed 5 of the studies (N Engl J Med. 1995;332:1661-1665; N Engl J Med. 1999;340:901-907; N Engl J Med. 2001;345:165-169; Circulation. 2001;103:2453-2460; N Engl J Med. 1997;336:393-398). Overall, both treatments regimes lead to few major bleeding episodes while reducing risk of recurrence.

Long-term treatment with anticoagulants will reduce recurrence events of venous thromboembolism. Unfortun-ately, when treatment is discontinued, recurrence rates escalate rapidly. The current oral anticoagulants have many undesirable limitations for long-term therapy which include interactions with food and many other medications, and the requirement for regular laboratory monitoring. New anticoagulants are needed for long-term or indefinite therapy but they must have the advantages of infrequent monitoring and lack of food and/or drug interactions, as well as taken orally. Such a medication is ximelagatran, a direct thrombin inhibitor which interferes with thrombin which is the final step in the activation of the clotting pathway. Dr. Leeper said, “it has a rapid oral absorption and is biotransformed to its active metabolite melagatran, it is 80% renally excreted, the drug is not bound to plasma proteins like heparin and has a low potential for food and drug interactions. Therefore, it has clear advantages over heparin, and more importantly, there is no coagulation monitoring required and it has a fixed dosing” adding, “recent data has suggested that it may be very, very efficacious.”

THRIVE
Huisman et al. presented the THRIVE data last July at the ISTH meeting in England. In this long-term clinical trial over 2000 patients with acute DVT were randomized to receive ximelagatran (36 mg BID) or enoxaparin/warfarin. At the end of 6 months of treatment there were no significant differences between the two groups in regard to venous thrombolic events or bleeding events (Figure 1). “However, what was noted throughout the study was that there was a cumulative elevation in the liver function studies up to about 9%, and this occurred within the first three to six months of treatment with these patients and that after discontinuation of the drug, there was a decrease in the liver function abnormalities,” said Dr. Leeper. The clinical significance of the elevated serum levels of alanine aminotransferase in some patients on ximelagatran remains unclear.

In the second ximelagatran trial discussed by Dr. Leeper (THRIVE III), patients were randomized to receive ximelagatran (24 mg BID, n=612) or placebo (n=611) for 18 months. The estimated cumulative risk of VTE events were significantly reduced in the ximelagatran group (2.8%) compared to the placebo group (12.6%) without increasing the risk of bleeding (N Engl J Med. 2003;349:1713-1721). “I think that this agent definitely sort of fills the bill for the concerns that we have with the treatment of the venous thromboembolic events,” concluded Dr. Leeper.

Atrial Fibrillation Guidelines

“Atrial fibrillation is the most common of the arrhythmias that we face in the patients that we deal with. It accounts for about ten percent of patients hospitalized with arrhythmias, and this is really a problem that we’re seeing as patients age,” said Robert A. Balk, MD, FCCP, Director of the Pulmonary
and Critical Care Medicine at Rush-Presbyterian-St. Luke Medical Center in Chicago, IL.

Dr. Balk said there are several guidelines available, including ones published by the ACCP, ACC, AHA, and ESC. The guidelines categorize patients into low-, intermediate-, and high-risk patients based on age and cardiovascular history. A simplified version of these guidelines was developed by Gage et al. (JAMA. 2001;285:2864-2870) using a simple point system (i.e., higher the score, the higher the risk) with the acronym CHADS:

C – Recent congestive heart failure = 1 point
H – Hypertension = 1 point
A – Age > 75 = 1 point
D – Diabetes mellitus = 1 point
S – History of stroke or TIA = 2 points

Warfarin Underutilizaton
With the numerous guidelines available, it is still surprising that anticoagulant treatment remains poorly utilized. “Even when we do decide to use anticoagulants, it turns out more often than not we use it at the wrong dose or achieve inappropriate or non-therapeutic levels of the anticoagulant, and I think a lot of this is probably based on our fear of producing those dreaded complications of hemorrhage and bleeding,” acknowledged Dr. Balk. For example, a study by Go and Colleagues found that only 55% of patients who need wafarin treatment are getting wafarin treatment (Ann Intern Med. 1999;131:927-934). The key to reducing the risk of intercranial hemorrhage is to maintain an INR between 2 and 3. Analysis by Fulter et al. showed that the risk of intracranial bleeding only begins to increase when INR rises above 3.0 and risk of ischemia only increases when INR dips below 2.0 (J Am Coll Cardiol. 2001;38:1231-1266). Unfortunately, keeping patients in that small range of INR 2-3 can be difficult for the simple reason that most patients who have atrial fibrillation don’t appreciate that it is a serious abnormality and they are unaware that atrial fibrillation predisposes them to stroke. Such perceptions lead to poor compliance of both monitoring and treatment. In addition, many ‘at-risk’ patients do not receive any treatment at all. “What we are faced with is a real dilemma: we see that atrial fibrillation has the highest prevalence in the elderly,” concluded Dr. Balk, adding, “we’re now identifying a group of patients (the elderly) that are most likely to benefit from anticoagulation strategies, however they are, unfortunately, the least likely to receive anticoagulation strategy.” Dr. Balk ended his presentation stating that there is a great need for an easier, safer anticoagulation strategy which can prevent strokes in our patients who are at risk.

Emerging Anticoagulants for Atrial Fibrillation and Implications for Management in the Future INR Monitoring

Alan K. Jacobson, MD, Director of Cardiac Pacing and Director of the Anticoagulation Clinic at the Loma Linda VA Medical Center in Loma Linda, CA, expanded on Dr. Balk’s conclusion that the narrow therapeutic range needed to safely and effectively use warfarin makes it a highly underutilized treatment. Dr. Jacobson stated that one option to improve treatment safety and efficacy is to use point-of-care INR testing devices along with computerized patient follow-up systems in a professional anticoagulation clinic or home setting. Patients using these devices at home tend to test at a frequency of once a week rather than the traditional once a month. “You now have the potential for increased frequency of testing, so it’s a little bit easier to keep track and if a patient’s going to destabilize you find out in a much more timely manner,” stated Dr. Jacobson. By increasing the frequency of monitoring, studies have shown that once a week versus once a month INR monitoring can reduce the risk of thrombosis or major bleed by 87% (Jandula et al., J Thrombosis Haemostasis. (Suppl: Abstract P1954, July 2003). In addition to improvements in warafin monitoring, there are several new anticoagulants currently in clinical trials that may be as effective but safer and easier to monitor than warafin. Some of these newer medications were discussed by Dr. Jacobson.

Heparins
“Traditionally heparin and low molecular weight heparin have not had much of a role in the treatment of atrial fibrillation due to short duration of action and need for parenteral administration,” said Dr. Jacobson. However, two heparin-like compounds are in development (fondaparinux and idraparinux) which may be better candidates for long-term maintenance therapy. One trial with idraparinux is the AMADEUS trial which includes 5700 patients with atrial fibrillation being given 6-24 months of either idraparinux (once a week injectable) or traditional warfarin/vitamin K antagonist management. Results are not expected forseveral years.

Antiplatelets
Previous studies have shown that antiplatelet agents only cause a 20-25% reduction in risk of stroke but the recent development of clopidogrel, which is a more potent antiplatelet agent, may allow antiplatelets to be a more effective treatment option. Currently, trials are in development, including the ACTIVE W trial, comparing aspirin plus clopidogrel against warfarin, and the ACTIVE A trial, comparing aspirin plus clopidogrel against aspirin alone. As with the AMADEUS trial, these trials are just getting underway and results are not expected for several years, stated Dr. Jacobson.

Thrombin Inhibitors
One oral direct thrombin inhibitor in development is ximelagatran. The major clinical trials with ximelagatran are the SPORTIF trials. In the SPORTIF III trial, 3407 patients with nonvalvular atrial fibrillation and risk factors for stroke were involved in a multinational, open-label study to receive adjusted doses warfarin or fixed dose ximelagatran. Results of the SPORTIF III trial have recently been presented at the ESC in Vienna, Austria and published in Lancet (Lancet. 2003; 362:1691-1698). In this trial, both warfarin and ximelagatran had low rates of stroke with cumulative event rates (stroke and SEE) of 2.2% and 1.3%, respectively. In regard to bleeding episodes, event rates were also very low in both groups (Intracranial hemorrhage: warfarin 0.4%, ximelagatran 0.2%. Major bleeding: warfarin 1.8%, ximelagatran 1.3%). As in the other ximelagatran trials, serum alanine aminotransferase (ALT) levels were elevated in some patients in the ximelagatran group (6.3% of ximelagatran treated patients vs 0.8% of the warfarin treated patients).
In the SPORTIF V, warfarin and ximelagatran were compared in double blind randomized study (n=3922) and Dr. Jacobson said the preliminary results from the SPORTIF V trial will be presented at the American Heart Association annual meeting in Orlando, FL.

Concluding Remarks
The underutilization of anticoagulants in patients with atrial fibrillation should be reduced in the next few years. Key develops in both INR monitoring systems and in novel anticoagulant agents should greatly improve anticoagulant use, safety, and efficacy in these at-risk patients.