Control of Anticoagulation Subcommittee
July 12, 2003
09:00 to 17:30
Hall 8
The International Convention Center, Birmingham
Chairman: M. Greaves, UK
Co-chairs: H. Bounameaux, Switzerland; J. Harenberg, Germany; C. Kearon,
Canada;
M. Laposata, USA; F. R. Rosendaal, The Netherlands; S. Schulman, Sweden;
A. Tripodi, Italy; A.M.H.P. van den Besselaar, The Netherlands
Working Party on Duration of Anticoagulant Therapy
in Venous Thromboembolism
Chair: S Schulman/C Kearon
- Low Intensity Vitamin K Antagonists Revisited:
i. Summary of ELATE
C Kearon
The main results of the study, previously presented at the ASH meeting in
December 2002, were discussed, as well as additional results of subgroup analyses.
In summary ELATE was a randomised study of low intensity [INR target 1.5-1.9]
versus conventional intensity [INR 2.0-3.0] warfarin after conventional treatment
for a first unprovoked venous thromboembolism [VTE]. The frequency
of recurrent VTE was statistically significantly higher in the low intensity
treatment group with no significant difference between the groups in total
or major bleeds [major bleeds 1.1% vs 0.9% per patient year]. Dr Kearon
concluded that whilst standard intensity anticoagulation with warfarin is
very effective and the frequency of bleeds is low, the low intensity regimen
is less effective and does not reduce the frequency of bleeding.
In discussion Dr Bauer raised the issue of the low rate of bleeding complications
in the study [see commment below]. The validity of the stated INR measurements
was questioned from the floor. In response it was pointed out that whilst
no attempt was made in this study to standardise INR measurements between
centres the routine systems for quality assurance were in place and the results
should be generalisable to comparable patients receiving treatment for VTE.
ii. Extended low intensity oral anticoagulation
S Schulman
A non-randomised observational study previously reported in the Journal
of Haematology [2002; 3:311-4] was presented. 40 patients considered
to be at high risk of recurrent VTE and initially treated for around 12 months
with full dose warfarin were enrolled into a study of low intensity warfarin
[target INR 1.5-2.0] and followed for 120 patient years. The cohort
included some with antiphospholipid syndrome. There was no episode of
recurrent VTE, no major bleed and only 4 minor bleeds. Patient preference
was clearly in favour of the low intensity regimen.
iii. Summary of PREVENT
K Bauer
The results of the prevent trial [NEJM 2003; 348:1425-34] were reviewed.
Patients with VTE were recruited to a randomised study of low intensity warfarin
[INR target 1.5-2.0] versus placebo after 3 months of standard treatment with
oral anticoagulant. Subjects with cancer and known antiphospholipid syndrome
were excluded, although antiphospholipid antibodies were not actively sought.
The trial was terminated early after recruitment of 508 subjects. There
was a 64% reduction in recurrent VTE in the warfarin group and no difference
between the two arms in major bleeds. There was a 50% overall reduction
in risk of major outcomes [death, bleeding and recurrent VTE].
iv. Target INR in Antiphospholipid Syndrome
M Crowther
The results of the PAPRE study were presented. Dr Crowther first remarked
on retrospective observational data suggesting a need for high intensity oral
anticoagulant therapy in antiphospholipid syndrome [APS]. He also noted
a single prospective study of VTE in APS which contradicts this conclusion.
The aim of the PAPRE study was to obtain prospective data in this area.
In randomised double blind multicentre trial 114 subjects with previous
arterial or venous thrombosis were randomised to warfarin with an INR target
of 2.0-3.0 or 3.1-4.0. There were 8 recurrent events in the 114 recruited
subjects, with a hazard ratio for recurrence of 3.1 in favour of the lower
intensity regimen. There was no significant difference between the arms
in major bleeds nor in any bleeds.
I t was concluded that standard intensity warfarin is the appropriate treatment
in APS, but acknowledged that the study was of insufficient size to allow
meaningful subgroup analysis, for example of arterial versus venous thrombosis.
During discussion it was suggested that the results from previous, non-randomised
observational studies may have been confounded by selection bias and centre
bias, having largely involved tertiary referral centres.
- Alternatives to Coumarins
i. Coumarin or LMWH in cancer?
A Lee
The results of the CLOT study [NEJM 2003, 349:146-153] were described.
Subjects with cancer and VTE were randomised, after standard initial treatment
with heparin to warfarin, target INR 2.5, or Dalteparin 200u/kg for 1 month
then approximately 150u/kg. During follow-up there were significantly
fewer episodes of recurrent VTE and fewer bleeds in the Dalteparin than in
the oral anticoagulant arm. It was concluded that Dalteparin in the
doses used is preferable to standard intensity oral anticoagulation for prevention
of VTE recurrence in cancer.
ii. Summary of THRIVE III
S Schulman
In this randomised double blind trial subjects with VTE were entered after
6 months of standard therapy and randomised to Ximelagatran or placebo.
Recurrent VTE occurred during follow-up in 12.6% of the placebo arm and 2.8%
of the Ximelagatran arm [p<0.001]. There was no significant difference
in the occurrence of bleeding. A transient rise in serum ALT was noted
in 6% of subjects on Ximelagatran.
During discussion some concern was raised over the hepatic disturbance noted
and a note of caution advised with regard to conclusions about drug safety
at this point. In response it was emphasised that the effect was transient
in all cases
The low bleeding rate in the above trials was discussed. There was
general agreement to the suggestion that this is likely to result from the
selection process, whereby most bleeds would have occurred in those
susceptible during anticoagulant treatment prior to randomisation.
Summary and recommendations
Dr Kearon gave an overview on the above reports and some recommendations.
He emphasised that these latter reflected his personal views:
- The optimal intensity of oral anticoagulation long term after unprovoked
VTE is to a target INR of 2.5
- Ximelagatran is promising and may prove preferable to vitamin K antagonists
for this purpose
- For VTE in cancer LMWH is generally preferable to vitamin K antagonists
- In antiphospholipid syndrome with VTE the target INR should be 2.5.
In arterial thrombosis there is less certainty and INR 2.5 plus antiplatelet
therapy could be considered or target INR 3.5 without antiplatelet therapy.
It is acknowledged that others may regard low intensity warfarin to be preferable
for long term thromboprophylaxis for unprovoked VTE, and that the target INR
in antiphospholipid syndrome should be 2.5 until additional data become available.
The chairman has agreed to draft a consensus document combining recommendations
from the current and prior SSC meetings on intensity and duration of anticoagulant
therapy after VTE. Deadline October 2003.
The ECAA Steering Group and the Working Party on Near-patient
Testing and
Self-management of Oral Anticoagulant Control
Chair: T van den Besselaar/A Tripodi
1. Progress report on candidates
to replace RBT/90
A Tripodi
It was reported that there had been unexpected delays in publicising the
call for bids and that no submission for candidates had been made to date.
An announcement was to appear in the society’s journal shortly and a letter
had been sent to 9 manufacturers already. Of these 3 had declined involvement
and 6 responses are outstanding.
The working timetable is now:
Calibration [of no more than 3 candidates] May 2004
Statistical analyses December 2004
Choice of IRP July 2005
Submission to WHO October 2005
There was discussion on the need for use of glass-sealed ampoules and it
was agreed that their use is essential based on previous experience of deterioration
of material in rubber-closed vials.
2. Monitoring of the relationship
between RBT/90 and rTF/95
T van den Besselaar
It was reported that the overall mean ISI had been established originally
at 0.94 but that there had been a gradual rise to 0.99 in 2001. Reasons
for this were discussed, including changes in centres, technicians and preanalytical
variables and the inevitable use of different warfarin patients and normals
for plasma donation. The effect on the INR in the range 3-4.9 was shown
to be <10%, the generally accepted cut-off for ‘clinical significance’.
It was agreed that candidates for the replacement will be calibrated against
RBT/90, rTF/95 OBT/79 in order to minimise bias.
3. ECAA Normalisation and Standardisation
of Home PT Monitors, Final recommendations:
Simplified ISI calibration of CoaguChek and TAS monitors
T van den Besselaar
Two questions have been addressed:
Can whole blood samples be replaced by recalcified fresh plasma samples?
Can whole blood samples be replaced by lyophilised plasma samples?
Data from TAS and CoaguChek monitors were presented. For the latter
ISI using plasma compared to whole blood was acceptable, but not for TAS.
For the TAS a correction was introduced based on line of equivalence and showed
acceptable agreement, validated in 3 laboratories. A comparable result
was obtained with lyophilised plasma.
Quality control of CoaguChek and TAS monitors
A Tripodi
Sixty [artifically depleted and coumarin] plasmas were assigned INRs at
3 certifying centres and tested at 10 centres. INR between centres
differed considerably and subsets of 5 and 3 QA plasmas were shown to reflect
these differences adequately. It was also shown that these QA plasma
sets can detect outliers.
It was concluded that provision of these plasmas is a simple and practical
method for checking the INR results with individual point of care monitors.
They can be used on both TAS and CoaguChek monitors and could be made available
to anticoagulant clinics for periodic checks.
Technology implementation plan
J Jespersen
The progress so far was reviewed, including the development of a simplified
ISI calibration procedure, the possibility of and external QA scheme for monitors
and the validated use of lyophilised plasmas for QA.
In discussion Dr S Kitchen reminded the participants that a UK NEQAS scheme
had been active in this area for 7 years.
4. European Action on Anticoagulation.
Computer dosage clinical end-point study: First year report
L Poller
An update on progress was delivered. The study is based on previous
findings of a 19% improvement in time in range using the DAWN AC system.
The new study examines the effect on bleeding and thrombosis rates as well
as cost-effectiveness over a 4 year period. Both PARMA and DAWN systems
are included and 16,000 patient years of observation will accrue.
5. Draft SSC report on standardisation
of QC for near patient testing
S Kitchen
As an introduction the UK NEQAS near patient testing scheme was described.
The scheme has a high proportion of non-UK participants. 90% of around
100 centres which made full returns on the 8 samples distributed in 2001 obtained
the vast majority of results within consensus. Of the poor performers,
6 had INRs outwith consensus in 2 surveys, for example.
It was agreed that it should be possible to prepare guidelines on calibration
as well as QA and it may also be possible to consider other matters such as
regulatory issues and training. It was agreed that a draft would be
prepared by end of 2003.
6. Update on the use of the
INR in the USA: Information from the college of American Pathologists’ proficiency
testing programme.
JD Olson
An update on the use of INR and quality assurance issues in oral anticoagulant
control in the USA was delivered. Significant improvements in standardisation
of control were reported.
WHO Working Group on Unfractionated Heparin and Low
Molecular Weight Heparin / Working Party on Monitoring of Low Molecular Weight
Heparin
Chair: M Greaves
1. Progress on global
harmonisation of heparin assays
E Gray
It was reported that the proposal had been validated in drafting group laboratories
and had performed well. Plans were described for an international collaborative
study to assess the proposed anti-IIa chromogenic assay.
2. Progress on the 2nd
WHO standard for LMW heparin: Results of the international collaborative study
E Gray
Participants were reminded that stocks of the first IS for LMWH are depleted.
A pilot study, reported to the SSC in 2002, had allowed selection of 2 LMWH
as candidates for the main study. This study included 30 laboratories,
of various types, who returned data on results in anti-Xa and anti-II a assays.
The %GCV was <5% in the majority of laboratories for both and there had
been no sign of deterioration of samples after 1 year of storage. Based
on the slightly lower inter-laboratory variation in the anti-Xa assay with
‘sample B’, it was recommended that sample B [01/608] be adopted as the
Second International Standard for LMWH. A report on this work had
been submitted to the chairman of the SSC, Dr Rodeghiero, prior to the meeting.
3. Measurement of
thrombin generating potential
E
Gray
A multi-centre assessment of measurement of Endogenous Thrombin Potential
[ETP] using a continuous monitoring amidolytic technique was reported.
It was noted that interlaboratory variability was lower with use of automated
instruments and could also be improved by unification of methods, reagents
and substrates.
A proposal was made that Dr Gray should set up a working group to investigate
the possibility of developing a reference plasma. The proposal was agreed,
a report to be produced in time for the nect SSC meeting.
4. Anticoagulant
effects of LMWHs in surgical and interventional indications. Optimisation
of treatment
J Marmur
Data on the use of the activated clotting time [ACT] to monitor Dalteparin
during intravenous administration for interventional procedures were presented.
The need for monitoring for this type of clinical use was discussed and a
consensus view expressed that this may be desirable. The most appropriate
method was debated, with no clear consensus reached.
Working Party on Standardisation of Methods to
Determine Direct Thrombin Inhibitors.
Factor Xa inhibitors.
Chair: M Greaves
1. Laboratory monitoring of hirudin
therapy in heparin-induced thrombocytopenia.
T Lecompte
Data were presented suggesting that the APTT is not necessarily a good indicator
of overdosage. The need to establish the sensitivity of the reagent
used by testing on plasmas spiked with hirudin was identified. It was
acknowledged that there is a need for improvements in monitoring in this situation.
2. Proposal for the validation
of the determination of thrombin inhibitors in patients
J Harenberg
Earlier results, previously reported to the SSC by Dr Gray, were reviewed.
These indicated unacceptable variability between some assays, the anti-IIa
assay and wet Ecarin Clotting Time performing badly, for example.
The plans for the collaborative study on ex vivo samples, as the next step,
were reported. The proposed protocol was discussed and well received.
It was agreed that recruitment of participants would proceed, with an August
2003 deadline, and that the study would be carried out during the next 12
months.
3. Laboratory control
of oral and parenteral antithrombin agents. Assay methods and relevance to
therapeutic optimisation.
J Walenga
The use of the APTT for monitoring of Argatroban, Lepirudin and Bivalirudin
was reviewed. Differing responses in the assay to the different thrombin
inhibitors was noted, as well as variation with reagents. It was clear
that a target APTT of 2 to 2.5 would not be appropriate for all drugs.
The effect of Argatroban on prothrombin time/INR was demonstrated also.
4. Dosage optimisation
of new anticoagulants for surgical and interventional indications. Influence
of adjunctive therapies.
J Walenga
Data relating to monitoring were reviewed. In summary it was indicated
that the APTT may be an adequate method for low dose therapy and the ACT for
high dose. There is a need for standardisation of the ECT and also further
study of interactions in these assays of other drugs, such as glycoprotein
IIb/IIIa inhibitors, which may be used alongside.
There was a consensus view that whilst monitoring may not be essential during
routine use we need robust and validated methods for monitoring in specific
clinical situations. These might include treatment in the elderly, in
children and in adults of very low or high body mass index.
The subcommittee is supportive of further work in this area.
5. Monitoring of direct
and indirect factor Xa inhibitors. Influence of route of administration and
assay methods.
J Fareed
Data indicating major differences in the sensitivity of a range of tests
for monitoring of anti-Xa compounds were presented. Again the view was
expressed that there is a need for more standardisation in this area.
6. Influence of Xa inhibitors
on coagulation assays: the need for standardisation.
M Samama
The methods for monitoring of anti-Xa compounds were reviewed. A strong
argument was made against the expression of activity as anti-Xa [heparin]
units but for expression as gravimetric units. There was no dissent
from this point of view.
A study was proposed, to be carried out with Dr E Gray as co-investigator,
to determine optimal assay methods for Fondaparinux. There was general
approval for this proposal, the study to be carried out during the next 12
months.
Working Group on Calibrated Plasmas for ISI/INR Determination
Chair: T Barrowcliffe
Final report for discussion
T van den Besselaar
A final document entitled ‘Guidelines on preparation, certification and
use of certified plasmas for ISI calibration and INR determination’ was tabled
and reviewed. It was agreed that this could now be presented to the
chairman of SSC, Dr Rodeghiero.
Any Other Business
Dr Fareed made brief comments on his concerns regarding the emergence of
copycat versions of LMWHs. He distributed a document on this topic to
interested delegates.