The Chairman welcomed the participants and outlined the program. As on the previous occasion the Subcommittee had been allocated two complete sessions. Draft recommendations were received from the Working Party on the Preparation and Use of Calibration Plasmas for INR Determination (T. Barrowcliffe, Chair) and on Low Molecular Weight Heparin (LMWH) Monitoring in infants from the Working Party on LMWH Monitoring (A. Giles, Chair).

The Chairman reported that the new Working Party had been established under the chairmanship of Dr. J. Hirsh. The membership comprises Drs. S. Shulman, C. Kearon, G. Agnelli and Dr. F.R. Rosendaal.

Dr. J. Hirsh:

The session addressed two unresolved issues in management of venous thromboembolism. These are: 1) the optimal duration of anticoagulant therapy for venous thromboembolism; and 2) the need for long-term anticoagulant prophylaxis in subjects with inherited thrombophilia.

The optimal duration of anticoagulation therapy in patients with venous thrombosis and pulmonary embolism is controversial. Three adequately designed studies have been performed, producing somewhat discrepant findings. Each of the senior authors of the studies (Drs. Kearon, Schulman and Agnelli) were invited to present the results of their studies and to present their views on the optimal duration of oral anticoagulant therapy in the following patient groups: proximal vein thrombosis without a provoking cause (idiopathic); proximal vein thrombosis after a reversible cause (secondary); idiopathic calf vein thrombosis; calf vein thrombosis after a provoking cause. The effect (if any) that the presence of associated inherited or acquired thrombophilia would have on this recommendation would also be considered.

For how long should the treatment with vitamin K antagonists be maintained?

(Dr. S. Schulman)

Recent prospective randomised studies on the optimum duration of oral anticoagulation with vitamin K antagonists after VTE have demonstrated that the probability of recurrence is reduced when the secondary prophylaxis is prolonged from four weeks to three months or from six weeks to six months or from six months to 27 months. The patient material and the duration of follow-up differed, however, between those trials. The reduced risk of recurrence is valid for almost all subgroups of patients except for those with the combination of a calf vein thrombosis and a temporary triggering risk factor, such as surgery. For those patients, a prolongation beyond six weeks of secondary prophylaxis is not of any benefit. For proximal deep vein thrombosis (DVT) or symptomatic pulmonary embolism (SPE) and a temporary trigger, a prolongation from six weeks to six months yields a significantly lower incidence of recurrence, but after three - four years this difference is not significant, and the optimal duration may be between three and six months. For those with an idiopathic or permanent triggering factor and any DVT or SPE, a prolongation from six weeks to six months confers a significant advantage regarding incidence of recurrences which remains even after six years. Even longer durations should be considered in patients with cardiolipin antibodies, due to a significantly higher probability of recurrence and a higher mortality due to all kinds of thrombotic events after cessation of anticoagulation at six months. The risk of recurrence is of the same magnitude in patients with proximal deep vein thrombosis or with symptomatic pulmonary embolism.

Patients with hereditary thrombophilia do not seem to run an increased risk of recurrence in case of heterozygous Factor V Leiden or prothrombin mutation. For the heterozygous forms of protein C, protein S, or antithrombin deficiency the risk of recurrence is at least 10% annually, which is twice that in patients without hereditary thrombophilia, and a prolongation beyond six months is warranted. For patients with hyperhomocysteinemia there is an increased risk of recurrence, but substitution with folate and vitamin B12 may provide a better benefit/risk ratio than vitamin K antagonists.

After the second event of VTE, prolongation of oral anticoagulation from six months to 48 months markedly reduces the rate of recurrence but with a trend toward more major hemorrhages in the latter group. Arguments against very long durations of conventional treatment with vitamin K antagonists aiming at an INR of 2.0-3.0, include the necessity of monitoring the prothrombin time with direct and indirect costs and the constant fear of interactions with other drugs or food products. This has to be weighed against the reduction or elimination of a risk of recurrence of about 5% per year after cessation of anticoagulation.

If lower intensity of anticoagulation (INR of 1.5-2.0) turns out to be safer regarding hemorrhages and more convenient by allowing for less frequent monitoring of prothrombin time, the recommendations for duration of anticoagulation will require revision.

Optimal duration of anticoagulant therapy for symptomatic venous thromboembolism: One perspective

(Dr. C. Kearon)

Six large, well-designed trials have recently been completed that have compared different durations of oral anticoagulation for the treatment of various categories of patients with venous thromboembolism (VTE). Their findings, in conjunction with those of a number of other prospective studies that have helped to identify risk factors for recurrent VTE and anticoagulant-related bleeding, have led to a better understanding of the optimal duration of therapy for individual patients with VTE. Current evidence suggests that three months of therapy is adequate for patients with VTE that was provoked by a major reversible risk factor such as surgery. Idiopathic VTE should be treated for a minimum of six months, and a longer duration of therapy (e.g., two years) is likely to be preferable. Patients with continuing (non-reversible) risk factors, such as cancer, should be treated until the risk factor resolves. Six months of therapy is reasonable for patients who do not fall clearly into one of these categories. The presence of an antiphospholipid antibody, deficiencies of protein C, protein S and antithrombin, homogeneity for Factor V Leiden, combined thrombophilic abnormalities; and a previous episode of idiopathic VTE, support longer durations of therapy within each category of patients. Conversely, a high risk of anticoagulant-related bleeding, isolated distal deep vein thrombosis, and patient preference support a shorter duration of anticoagulation, particularly in patients with idiopathic VTE (i.e., less than two years of therapy). Heterozygous Factor V Leiden appears to have little bearing on the optimal duration of anticoagulation

Dr. G. Agnelli presented results from a study, yet to be published, that compared the rates of recurrence of venous thromboembolism following treatment with oral anticoagulants for three months or 12 months after a first event.

Dr F.R. Rosendaal presented prospective data on thromboembolism from two studies. One, the European Prospective Cohort on Thrombophilia (EPCOT) Study includes patients from high risk families with familial thrombophilia (deficiencies of protein C, protein S, antithrombin, carriers of Factor V Leiden and of combined defects) from 11 European centers. The second study is the follow-up of a group of unselected consecutive patients with a first thrombosis, the Leiden Thrombophilia Study (LETS). In the EPCOT study 1,781 patients were followed for 4,838 patient-years. About half of them had not experienced thrombosis prior to entry in the cohort, while the other half had experienced on average 2.5 events prior to entry; again half of these patients received long-term anticoagulation. During follow-up 107 DVT/PE occurred. Annual risks were 0.9% for first events, and 3.8% for recurrences for those not receiving long-term anticoagulation, and 1.6% in those receiving long-term anticoagulation.

In the LETS 474 patients were followed for 2,784 patient-years and 81 recurrences occurred after the conclusion of three months of oral anticoagulation. The overall annual recurrence rate was 2.9%, varying from 1.9% in those without blood abnormalities [deficiencies of protein C, protein S, antithrombin, carriership of Factor V Leiden, Factor VIII levels 150IU/dl or hyperhomocysteinemia (>18.5m M/l)] to 4% in those with such abnormalities. The recurrent events were evenly distributed over time, i.e., there was not a particularly high risk following discontinuation of oral anticoagulation; in fact, over half of the recurrences occurred more than three years after the first event.

Dr. Rosendaal concluded that even in patients with familial thrombophilia from high-risk families, long-term anticoagulation is not warranted in asymptomatic patients; although the thrombotic risk is reduced in patients who have suffered prior thrombosis, it is uncertain if the benefits of such treatment would outweigh the risks. For consecutive patients with DVT, even those with blood abnormalities, these data do not suggest a benefit of extending the duration of anticoagulation beyond three months.

The Working Party will attempt to provide guidelines on the optimal duration of oral anticoagulant therapy.

The Chairman reported that a new Working Party has been established under the chairmanship of Prof. J. Harenberg to address issues relating to the monitoring of direct thrombin inhibitors. These are:

1. Methods to determine direct thrombin inhibitors:

2. Thrombin clotting time methods:

3. Antithrombin agents:

Dr. J. Fareed discussed monitoring issues related to the development of Factor Xa inhibitors. Currently, there are no guidelines for the monitoring of these agents. Since these agents are expected to enter into a fast-track clinical development in both the therapeutic and interventional indications, some recommendations for their monitoring are warranted. This presentation also provided comparative data on DX 9065a and a synthetic pentasaccharide SR-90107 in various laboratory assays.

The Subcommittee Chairman reported that despite detailed discussions there remained important and unresolved differences of opinion between Working Party members and, unfortunately, it had not proved possible to present any recommendations in respect of adult monitoring.

The membership expressed regret at this outcome and supported the view of the Subcommittee Chairman that in view of the importance of this subject the Working Party should continue its activities and attempt to present appropriate therapeutic guidelines.

Dr. P. Massicotte presented proposed guidelines on behalf of herself and Dr. Andrews. Critical issues for the use of LMWH in children include the age (or weight) dependancy of the pharmacokinetics of LMWHs with small infants having increased requirements per body weight. There is increased use of LMWH, rather than oral anticoagulants, for long-term therapy. This also has implications in respect of monitoring.

It is anticipated that in the very near future the guidelines will be forwarded to the Chairman of the Subcommittee for distribution to Subcommittee members.

Dr. A. Giles requested that he be allowed to stand down from the chairmanship of the Working Party on account of changed personal circumstances. He indicated that, if required, he would be willing to serve as a member of the Working Party. The Chairman accepted his request and thanked him on behalf of the Subcommittee for his active contribution.

Dr. Elaine Gray reported that two sets of heparinized plasmas, one set of ex-vivo patient plasma, and one set of in-vitro spiked plasma have been ampouled. Each set of plasma consists of a negative normal pooled plasma and three plasmas with varying concentrations of unfractionated heparin. A pilot study involving approximately ten laboratories will now be initiated and the results of the study will be reported at the next SSC meeting.

One of the proposals resulting from the June 1998 WHO/ISTH consultation on biological standardization of unfractionated heparin was to set up a Working Group on Biological Standardization for Unfractionated Heparin. The first remit of the working group is to review the methodology currently used for measurement of heparin biological activity. The first meeting of the group will be held in Geneva in September of this year, with a view of promoting harmonization of the USP and WHO standards for unfractionated heparin.

D. Yetsuka presented results of a study on the influence of thromboplastins of various ISIs on INR. This confirmed the advantages of thromboplastins with an ISI of approximately 1.0.

Dr. M. Johnston reported the results of a study that confirmed the greater precision and accuracy of thromboplastins with an ISI < 1.5.

Prof. J. Jespersen reported the results of an ECAA study that addressed the effect of sample size on fresh and lyophilized plasma thromboplastin ISI determination.

Dr. T. Barrowcliffe presented highlights from the draft guidelines on the preparation, calibration, and use of calibrated plasmas for INR determination.

It is anticipated that the draft guidelines will be forwarded to the Subcommittee Chairman in the very near future.

New Working Group on Near-Patient and Self-Management of Oral Anticoagulant Control

The Chairman announced the establishment of the new Working Group (Chair, F.E. Preston; Members: J. Ansell, T. van den Besselaar, S. Kitchen, G. Muller-Berghaus, G. Palareti.)

The aims of the Working Group are to address the issues arising out of the increased use of point-of-care testing devices for oral anticoagulant control with a view to publishing guidelines and recommendations.

Working Group members made the following presentations:

Prof. Muller-Beghaus: Patient self-testing of oral anticoagulation -- A new approach in controlling oral anticoagulant therapy.

Dr. T. van den Besselaar: Instrument calibration issues.

Dr. J. Ansell: Patient selection for patient self-testing.

Prof. G. Palareti: Dosing issues.

Dr. S. Kitchen: Quality control issues.

Prof. L. Poller presented details of an ECAA research study: Standardization of whole blood testing in home prothrombin time monitors.

Dr. Ginette Michaud, Chairperson, Workshop Steering Committee, US Food and Drug Administration, presented a report arising out of an International Workshop on the Standardization of Whole Coagulation Devices, held in Washington on August 13^th, 1999. The Workshop was sponsored jointly by the U.S. Food and Drug Administration Center for Devices and Radiological Health and the College of American Pathologists.

Participants at the Workshop were asked to establish the requirements of a project focused on standardizing the calibration of whole blood clotting devices.

Discussions centered on the PT, aPTT and ACT. There was a general consensus that the calibration issue required further study and that the magnitude of the problem needs to be better understood. Any effort to standardize the calibration of these assays should focus on the clinical impact of these tests and should not be driven exclusively by the correlation of test results between methods. Manufacturers would carry the primary responsibility for reliable calibration of their test systems. Standards would be specific to each assay type and clinical application.

The meeting closed at noon August 15^th, 1999.