ASH 2011: Clinically relevant highlights regarding venous thromboembolism and anticoagulation

The annual meeting of the American Society of Hematology took place Dec. 10 to 13 in San Diego.

I thought only one abstract was clinical practice-changing — abstract #543, titled “Aspirin after oral anticoagulants for prevention of recurrence in patients with unprovoked venous thromboembolism: the WARFASA study.”

I was surprised and disappointed that it had not been chosen as one of the six abstracts for the plenary session. I consider it important enough.

Below, I briefly discuss the abstracts that I thought were the most interesting and clinically relevant on thrombosis and anticoagulation.

It is, of course, important to bear in mind that these are just abstracts, not peer-reviewed full publications. Thus, interpretation of the presented data is limited.

Benefits of aspirin therapy

Aspirin prevents recurrent VTE

Summary: Fascinating news: In patients with a history of unprovoked venous thromboembolism (VTE) treated for 6 to 18 months with warfarin, subsequent aspirin was much more effective than placebo in preventing recurrent VTE (abstract #543).

Details: There has been some evidence over the years that aspirin protects against VTE, but the effect observed has been mild. The WARFASA study investigated patients with a history of unprovoked VTE, enrolling them after they had been treated with warfarin for 6 to 18 months.

They were then randomly assigned to aspirin 100 mg/day or placebo and followed for an average of 2 years. The study had a double blind design. Primary endpoints were symptomatic VTE and fatal pulmonary embolism.

Of the 403 patients enrolled, 205 received aspirin and 198 received placebo.

Recurrent VTE occurred in 11% of patients treated with placebo and in 5.9% of patients on aspirin. Aspirin led to a 40% risk reduction. The incidence of major bleeding and clinically relevant nonmajor bleeding was similar in both treatment groups.

Perspective: The study findings are remarkable: Aspirin can prevent some deep vein thrombosis and pulmonary embolism, with no detectable increase in significant bleeding.

Consequences for my practice: Does this study change my clinical practice? Yes. I used to tell patients with unprovoked VTE who came off warfarin after treatment for an appropriate length of time (often 3 to 6 months) that there was no strong reason to take aspirin. I will now tell them that, once they stop warfarin, it is worthwhile to take aspirin long term. What dose will I recommend? I will tell the patient that, here in the United States — where we do not have 100 mg tablet sizes — either a baby aspirin (81 mg) or an adult aspirin (325 mg) would be appropriate.

Would I recommend that patients who are on long-term warfarin now stop warfarin and switch to aspirin instead? No, clearly not. Warfarin is much more effective than aspirin, and aspirin is not a replacement for warfarin.

Limitations of this study need to be highlighted: (A) It has not yet been published in a peer-reviewed journal; and (B) a follow-up study is needed to see whether the results can be confirmed.

New oral anticoagulants

Dabigatran in acute VTE

Summary: A relevant phase 3 study was presented (abstract #205). Maybe this study will lead to FDA approval of dabigatran (Pradaxa, Boehringer Ingelheim) for the VTE indication.

Details: At present, dabigatran is FDA-approved in the United States for atrial fibrillation but not for VTE.

The large RECOVER I trial had shown that dabigatran and warfarin taken for 6 months for acute VTE were equally effective in preventing recurrent VTE and were equally safe.

The FDA mandated a follow-up study before considering approval of the drug. The RECOVER II trial now presented was a replica study — a large phase 3, randomized, double blind trial of 2,568 patients with acute VTE, 1,279 of whom were randomly assigned to dabigatran and 1,289 to warfarin.

As in RECOVER I, dabigatran was not given right away, but only after 5 to 11 days of low–molecular-weight heparin (LMWH) or heparin therapy. The dabigatran dose was 150 mg twice daily. The length of treatment was 6 months.

Stephan Moll

Recurrent symptomatic VTE occurred in 2.4% of patients on dabigatran, compared with 2.2% of patients in the warfarin arm.

Conclusions: (A) Dabigatran and warfarin were equally effective; and (B) there was no difference in major bleeding between the two groups.

Perspective: This study provides confirmatory results that dabigatran can be used (off label at this point) for the treatment of patients with deep vein thrombosis (DVT) and pulmonary embolism. However, it has not been shown that dabigatran can be used immediately upon the diagnosis of VTE. Initial therapy with LMWH, fondaparinux or unfractionated heparin is still needed for a week or so.

I think these study results may lead to FDA approval of the drug for the DVT and PE indication.

Do I prescribe dabigatran off label for patients with DVT and PE, even though it is not yet FDA approved for that indication? I do not rush into it. I prefer to wait to see what the FDA decides on the DVT and PE indication after review of all of the data. However, if a patient poorly tolerates warfarin, has significantly fluctuating INRs or has a strong preference to switch from warfarin, I discuss a switch to dabigatran even now. And if the patient is fully educated, understands that we would be using the drug in a non-FDA approved indication and still wants to change, I consider prescribing it for DVT and/or PE. However, my general preference is to see clinical experience with the drug gained in the approved indication before I use it off label.

Bleeding management with new oral anticoagulants

Summary: No data on this topic helpful for patient management were presented. Clinical strategies as to how to manage major and life-threatening bleeding on dabigatran have recently been published by ASH, Clot Connect and others.

Details: Abstract #2316 showed that in a rat-tail bleeding model, non-activated and activated prothrombin complex concentrates and recombinant Factor VIIa reversed the dabigatran-induced bleeding, although the coagulation test prolongations did not correct.

Abstract #1252 showed that in ex vivo plasma spiking studies, coagulation test prolongations induced by the new, non–FDA-approved oral anticoagulant edoxaban (Daiichi Sankyo) were reversible.

Perspective: No conclusions from these ex vivo and animal studies can be drawn that would help with clinical decision-making in patients with major bleeding on one of the new oral anticoagulants.

Monitoring dabigatran or rivaroxaban

Summary: Data on two monitoring tests were presented.

The Hemoclot test, a dilute thrombin clotting time test, appears to be useful in monitoring dabigatran (abstract #2307, published Jan. 6 in Blood Coagulation & Fibrinolysis).

The prothrombinase-induced clotting test (PiCT) may be useful for monitoring of dabigatran, rivaroxaban (Xarelto, Janssen Pharmaceuticals) or apixaban (Bristol-Myers Squibb/Pfizer; abstract #3363).

However, neither test is widely available in routine clinical practice.

Details: In case of bleeding or thrombosis in the patient on dabigatran or rivaroxaban, the clinician may want to have available a monitoring test to determine whether a patient is supra- or sub-therapeutic on the anticoagulant drug. In addition, before a major surgery that has a high risk for bleeding, a physician may want to make sure that no residual drug is circulating in the patient.

Limited published data exist as to which coagulation test is best used to determine drug overdose or residual levels of anticoagulant.

Perspective: At this time, for dabigatran monitoring, the ecarin clotting time (not widely available either) and maybe the activated partial thromboplastin time and thrombin time (limited availability) may be the most useful tests to obtain, depending on the purpose of testing. For determination of rivaroxaban overdose or residual circulating drug activity, prothrombin time may be most suitable. However, more data on the performance of coagulation tests in patients on dabigatran or rivaroxaban are needed, performed on plasma samples from patients on these drugs rather than from ex vivo plasma spiking studies.

Length of anticoagulation in VTE

Should family history of VTE influence length of anticoagulation in a patient with first unprovoked VTE?

Summary: No, at least based on the study explained in abstract #2299, although it was limited by relatively small numbers of relatives with VTE.

Details: Many physicians assume that a strong family history of VTE indicates that a patient who has had VTE is at high risk of recurrence if he or she comes off anticoagulation. However, it is not known whether that is true.

This abstract presented data from a large multicenter prospective study in which 669 patients with unprovoked VTE were enrolled. Detailed family histories were obtained. Findings and conclusions were that a family history of VTE is not a predictor for recurrent VTE and should, therefore, not be used to determine length of anticoagulation therapy.

Perspective: The findings are interesting, but I would not use them for clinical decision making at this point given the small sample size in this study and the abstract nature of this publication.

How to predict which patients with unprovoked VTE need long-term anticoagulation.

Summary: This abstract (#544) showed that the D-dimer, Age, Sex, Hormones (DASH) score can separate patients with unprovoked VTE into those with a low risk of recurrence, in whom anticoagulation can be discontinued after a few months of treatment, and those who should be on long-term anticoagulation because of a high risk of recurrence. However, at this point, I would not use the DASH score for clinical decision-making.

Details: The authors performed a meta-analysis of seven prospective studies of patients with unprovoked DVT who had been treated for at least 3 months with vitamin K antagonists and determined what characteristics were indicators of a high risk of recurrent VTE.

Main predictors of recurrence were abnormal D-dimer after stopping anticoagulation, age younger than 50 years, male gender and VTE not associated with hormonal therapy. A predictive recurrence score was then created — the DASH score — with the following points:

l+2 for abnormal post-anticoagulation D-dimer

l+1 for age<50 years

l+1 for male gender

l–2 for hormone use

The annual recurrence rate was 3.1% for DASH score of 1 or less; 6.4% for DASH score of 2; and 12.3% for score of at least 3.

As the risk of recurrence is low with a DASH score of 1 or less, these are patients with unprovoked VTE in whom long-term anticoagulation is not needed. These account for about 50% of patients with unprovoked VTE.

Perspective: At this point I would not use the DASH score for clinical decision-making.

The DASH score needs to be validated. In addition, a discrepancy with another existing scoring system — the HERDOO-2 score (also not validated) — needs to be resolved.

The discrepancy is that in the DASH score, a younger age (≤ 50 years) is a predictor of recurrence, whereas in the HERDOO-2 score, older age (≥ 70 years) predicts a higher risk of recurrence. So, it is not clear at this point whether it is worse to be young or old when it comes to VTE recurrence risk.

Cancer and VTE

VTE prevention with LMWH in outpatient cancer patients receiving chemotherapy

Summary: The once-daily subcutaneous ultra-LMWH semuloparin, given for VTE prophylaxis in cancer patients receiving chemotherapy, decreases the occurrence of symptomatic VTE without increasing major bleeding. The benefit is particularly seen in patients at moderate and high risk for VTE as assessed by the Khorana score.

Details: The phase 3 SAVE-ONCO trial investigated once-daily ultra-LMWH semuloparin — an investigational agent manufactured by Sanofi — vs. placebo for VTE prevention in cancer patients receiving chemotherapy.

In the trial, 3,212 patients were randomly assigned and treated for a median of 3.5 months. Patients’ baseline VTE risk was assessed by the Khorana score to determine which risk category of patients may benefit most from VTE prophylaxis.

Primary endpoint was symptomatic VTE or VTE-related death. In the overall study population, the primary endpoint occurred in 1.2% of patients compared with 3.4% of the placebo-treated patients. A reduction of VTE occurrence with semuloparin was seen in all VTE risk groups, particularly — to no surprise — in the high-risk VTE patients. In the high-risk group, 1.5% of patients assigned to semuloparin had VTE vs. 5.4% of patients assigned to placebo.

How long should cancer patients with VTE due to major surgery be treated?

Summary: It is recommended by ASCO, the American College of Chest Physicians and the National Comprehensive Cancer Network guidelines that cancer patients with DVT or pulmonary embolism should be treated with anticoagulants “indefinitely or until the cancer is resolved.”

However, it is not known whether cancer patients with major surgery-associated VTE truly have a high risk of recurrent VTE that would justify long-term anticoagulation therapy.

Details: This was a single-center cohort study (abstract #3342).

Of 220 cancer patients with symptomatic VTE, 42 underwent major surgery within 3 months of the diagnosis of VTE and, thus, were classified as having had surgery-associated VTE. Most of these patients were treated with anticoagulation for only 6 months, whereas the other VTE patients remained on longer-term anticoagulation.

The risk for recurrent VTE was much lower in the surgery-associated VTE patients than in the nonsurgical cancer patients: 2.8% vs. 11.3% at 6 months, 3% vs. 16.2% at 1 year and 9.3% vs. 27.5% at 2 years. Thus, clearly, the risk for recurrent VTE was lower in the surgery-associated VTE cancer patients. However, whether the risk is low enough to warrant time-limited anticoagulation for 3 or 6 months only is not clear at this point.

Other studies of interest

Subsegmental pulmonary embolism: Is it really a pulmonary embolism? Is it clinically relevant? Should we anticoagulate?

Summary: A patient who is said to have “isolated subsegmental pulmonary embolism” by CT angiography may actually not have a pulmonary embolism. There is only moderate agreement in CT angiography interpretation between radiologists when it comes to such pulmonary embolisms.

In addition, it is not clear whether patients with isolated subsegmental pulmonary embolism benefit from anticoagulant therapy — the risk–benefit ratio is unclear.

Details: Seventy patients who had presented with suspected pulmonary embolism and had been diagnosed by CT angiography with isolated subsegmental pulmonary embolism were retrospectively studied.

The CT angiography images were reviewed by a blinded thoracic radiologist. In only 44% of the cases, the radiologist agreed with the original diagnosis.

Of the 70 patients, 26% did not receive anticoagulation and none had a recurrent VTE during 3 months of follow-up. One of the patients who received anticoagulation had a major bleed.

Are progestin contraceptives safe from a VTE point of view?

Summary: Progestin-only oral formulations used for contraception do not appear to increase the risk for VTE, but injectable progestins do.

Details: A review of the published literature identified seven studies investigating the risk for VTE associated with various progestin-only contraceptives (abstract #3344).

A table in the abstract lists the seven studies, the study designs, the drug formulations and the adjusted RR for VTE. The overall risk for VTE with injectable progestins was 2.67 (95% CI, 1.29-5.53) compared with those not taking hormonal contraceptives, whereas oral progestin-only contraceptives did not increase the VTE risk (RR=0.87; 95% CI, 0.53-1.42).

For more information:

• American Society of Hematology. 2011 Clinical practice guide on anticoagulant dosing and management of anticoagulant-associated bleeding complications in adults. Available at: www.hematology.org/Practice/Guidelines/2934.aspx. Accessed Jan. 10, 2012.
• Clot Connect. 2011. Pradaxa (dabigatran) – hospital guideline. Available at: http://professionalsblog.clotconnect.org/2011/04/26/pradaxa-dabigatran-hospital-guideline/. Accessed Jan. 10, 2012.
• Khorana A. Blood. 2008;111:4902-4907.
• Schulman S. N Engl J Med. 2009;361:2342-2352.
• Stangier J. Blood Coagul Fibrinolysis. 2012;epub ahead of print.
• The following were presented at the 53rd Annual Meeting of the American Society of Hematology; Dec. 10-13, 2011; San Diego.
• Becattini C. Abstract #543.
• Delluc A. Abstract #3342.
• Gauthier K. Abstract #2299.
• Halim AB. Abstract #1252.
• Hoppensteadt, D. Abstract #3363.
• Kimpton M. Abstract #714.
• Mantha S. Abstract #3344.
• Schulman S. Abstract #205.
• Stangier J. Abstract #2307.
• Tosetto A. Abstract #544.
• van Ryn J. Abstract #2316.