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Rapid Responses: Rapid Responses published:
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With no known risk factors for recurrence
- Anil Kumar Chawla (10 February 2007)
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The site of DVT
- GAMAL B ALFITORI (15 February 2007)
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One year follow up not enough
- Anil K Chawla (15 February 2007)
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Potentially biased assessment of bleeding with 6 versus 3 months of anticoagulation for venous thromboembolism
- Clive Kearon (16 February 2007)
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Optimal duration for anticoagulation in VTE
- Nosa A Akporehwe, Kerstin A Akporehwe (19 February 2007)
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The study is underpowered and cases are poorly representative of those commonly entountered in clinical practice
- Luca Puccetti (22 February 2007)
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How long the anticoagulation therapy?
- Fulvio Pomero, Christian Bracco, Giobatta Cavallero, Luigi Fenoglio (23 February 2007)
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Anticoagulation beyond 3 months in idiopathic venous thromboembolism
- Diana C Ferreira, Gustavo L B Costa, Leonardo C Paixão, Reginaldo A Valacio (10 March 2007)
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Duration of Anticoagulation Therapy
- Sameer Chadha, Shikha Mehta, Medical Student , Maulana Azad Medical College, New Delhi ,India (12 March 2007)
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D-dimers can be a better guide for the length of anticoagulation
- Mohammed A M SIDDIQUI (29 March 2007)
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Physician vs GP management of venous thrombosis
- Andrew Mahony, Stephen Wilson (3 April 2007)
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Methodological issues keep the 3 versus 6 month treatment debate unresolved
- Amit Patel (5 April 2007)
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Anil Kumar Chawla, Senior Consultant in Medicne Ibra Hospital, POBox3, PC413, Ibra, Oman
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The online front page of the journal in its brief three lines of the summary of the article states, " For patients with known risk factors for recurrence......". But actually the authors conclusion states,"For patients in the UK with Deep Vein thrombosis or pulmonary embolism and no known risk factors of recurrence......" Now the'no' in the authors summary of this article is all too important and makes all the difference in the conclusions and relevance of this study. It might be a typographical omission and needs to be set right at the earliest and no added to the front page summary of the article. Thanks Competing interests: None declared |
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GAMAL B ALFITORI, SENIOR SHO-Haematology Prince Charles Hospital,CF47 9DT
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This is a good study which might have an influence on the current practice. There was no mention in the study of the site of DVT (proximal/distal).In many centres, distal DVT is systematically screened for and treated by anticoagulants, I wonder if there were any patients with distal DVT included in the trial, as this may has had a significant influence on the results of the study e.g. The recurrence and extension rates as well as the fatal outcomes. Competing interests: None declared |
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Anil K Chawla, Senior Consultant Ibra Hospital, POBox3, PC413, Ibra, Oman
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There are many a risk factors which are not immediately known and of which DVT may be the first presenting feature, for example Protein C and S deficiency, antithrombin III deficiency, Anti phospholipid syndrome etc. The second episode of DVT may occur more than an year later. To decide about long term requirement of anticoagulation, a patient with no obvious or known risk factors should be tested for these defects after a month or so of stopping anticoagulation given for the first episode of DVT. And then if none were found, patient may go without prolonged anticoagulation. Another study-(1)has shown that those patients who one month after the end of three month's anticoagulation had high D dimer results, were at a higher risk of developing recurrent events and in them anticoagualtion should be carried on for a longer period. So the authors conclusions of short term anticoagulation should be seen in the light of these observations.Thanks. (1)Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped.Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S.Thromb Haemost. 2002 Jan;87(1):7-12. Competing interests: None declared |
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Clive Kearon, Prosessor of Medicine McMaster University, Henderson Hospital, 711 Concession St., Hamilton, Ontario, Canada, L8V 1C3
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Dear Sir/Madam, Campbell and colleagues reported that 6 months of anticoagulant therapy was associated with a statistically significant increase in major episodes of bleeding compared with 3 months of therapy (8 versus 0 episodes), but this may be misleading.(1) Three of the episodes occurred in the first three months of treatment and, as all patients were receiving anticoagulant therapy for the first three months, this difference (3 versus 0 episodes) should reflect chance rather than a true difference in the risk of bleeding between the two treatment groups. Five of the episodes occurred during months 4 to 6 of anticoagulant therapy. However, bleeding does not appear to have been assessed, or at least is not reported, in the 3-month group during months 4 to 6 of the study. Consequently, from the current report, it is not possible to assess the degree to which extending anticoagulant therapy from 3 to 6 months increases bleeding. If the frequency of major bleeding in the 3-month group during months 4 to 6 of the trial is known, this data should be presented and assurances should be given that the 3-month group (who had stopped anticoagulants) was monitored for bleeding with the same intensity as the patients in the 6-month group (who remained on anticoagulants). In this study, one of the criteria for classifying a bleeding episode as major was that the clinician decided to stop anticoagulant therapy. This decision is subjective, is likely to be influenced by knowledge of whether patients have already completed 3 months of treatment, and cannot be applied to the 3-month group during months 4 to 6 of the study. A description of the 8 bleeding episodes, including the criteria for classifying each as major, would be helpful. Lastly, as this group of investigators was among the first to identify that unprovoked VTE (also termed “idiopathic” or “no evident cause”) is associated with a much higher risk of recurrent VTE after stopping anticoagulant therapy than VTE that was provoked by a temporary risk factor, it is surprising that findings in these two subgroups are not presented.(2) Reference List (1) Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HG, Williamson IJ. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. Br Med J. 2007. (2) Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet. 1992;340:873-76. Competing interests: None declared |
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Nosa A Akporehwe, Locum Consultant Physician in Rehabilitation Medicine James Cook University Hospital Middlesbrough TS4 3BW, Kerstin A Akporehwe
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We read with keen interest this very welcomed study which aim to establish the optimal duration for effective anticoagulation in VTE conditions [1]. It is undoubtedly a question every clinician want answered in the management of this preventable but potentially lethal condition. Nevertheless, it would also be pertinent to point out certain issues arising from this study namely, 1. The use of multiple imaging techniques e.g. ultrasound or venographic methods would have in no small measure confounded the diagnosis of DVT, even in one centre especially if no clear cut criteria was given for the radiological diagnosis of DVT. Except of course this was done but space precluded same. The use of for instance Doppler ultrasound across the board may have helped reduce this significant confounding factor. 2. For instance there was no distinction made between proximal and distal DVT and patients with 'suspected DVT' as opposed to objectively confirmed DVT were also accepted in the trial.It remains unclear how DVT resolution, recurrence, extension was judged : clinical or radiological ? Objective judgement can only be derived from the latter which appears not to be the case even if it were in a minority of participants. In one study, only 42% with DVT detected by objective criteria was associated with symptoms [2] 3. Relating to haemorrage, it would be interesting to know if other medications like Aspirin, Clopidogrel, NSAID or alcohol were being concurrenttly taken in those who actually experienced haemorrage as an adverse event in both groups. Reference 1. Campbell A, Bentley DP, Prescott RJ, Routledge PA, Shetty HGM, Williamson IJ. Anticoagulation for three months versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ 2007;0:bmj.39098.583356.55v1 2. Girard P, Musset D, Parent F, Maitre S, Phlippoteau C, Simmonneau G. High prevalence of detectable deep vein thrombosis in patients with acute pulmonary embolism. Chest.1999;116:903-908. Competing interests: The 1st author has received grants from within the NHS and pharmarceutical industry for an ongoing research which amongst others aim to estabblish the incidence of DVT in lower limb amputees |
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Luca Puccetti, MD, President Promed Galileo Medical Society
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Dear Sir/Madam The study of Campbell and collegues (1) launchs an important message as far as the duration of anticoagulant therapy after a deep vein thrombosis or pulmonary embolism is concerned. Since the message is important the study must be compliant with strict methodological issues. Predetermined primary adverse outcomes were defined to be: death from deep vein thrombosis or pulmonary embolism, failure during treatment (failure to resolve, extension, recurrence during treatment), recurrence after the end of treatment, and major haemorrhage during treatment. Patients experiencing any of the above were grouped together under the heading of "adverse outcome," and this combined index has been reported as a further point of comparison between the groups. Therefore the primary end point has not been clearly established and, consequently, the sample size has not been well defined. The Authors state that the sample size has been calculated with an alpha .05 and beta .20 regarding differences between recurrence rates (is this the primary, pre-specified end point?) of 6% and 9%. The amount of cases enrolled is far distant from these requirements, particularly if the primary end point were mortality, therefore the study is largely underpowered and it is inadequate to test such an hypothesis. It should be concluded that, regretting for difficulties in ethical committees decisions and problems in randomization to different heparins, the study is unconclusive for lack of an adequate sample size and the conclusions are unproven. But several other issues must be addressed, most of them have been already discussed in other rapid reponses to the article. First of all the Authors excluded a series of conditions well known to be important risk factors for recurrence, therefore the subjects enrolled in the study fit relatively rare situations in common clinical practice and therefore it should be stressed that the conclusions , if any, must be strictly confined to these subjects. Little details are given of the characteristics of the two groups, particularly as far as the site of DVT, the risk for bleeding and the sensibility and accuracy of the survellaince between the groups in regard of this latter adverse event are concerned. It could be argued that the 3 episodes of bleeding occurred in the first 3 months of the study, all developed in the 6-months group, indicate a baseline higher risk for bleeding in the 6-months group in comparison with the 3-months group; in fact, while the two groups have been controlled for the confounding factors for thrombosis they have not been controlled for the factors increasing the risk of bleeding. (1) Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HG, Williamson IJ. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. Br Med J. 2007. Competing interests: None declared |
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Fulvio Pomero, medical doctor Internal Medicine, Ospedale Santa Croce e Carle, Cuneo, via Michele Coppino 26, 12100, Christian Bracco, Giobatta Cavallero, Luigi Fenoglio
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Dear Sir, the study by Campbell et al. has shown that three months of therapy with vitamin K antagonist are sufficient in patients with deep venous thrombosis or pulmonary embolism without permanent risk factors, while six months of treatment increase risk of major bleeding without a reduction in adverse outcome as result of DVT or PE (1) . Although this seems interesting , we think that some doubts are rightful . First, population of the study is too heterogeneous, because includes patients with idiopathic deep venous thrombosis (42% and 47%) and patients with deep venous thrombosis linked to transient risk factors (58 and 53%). In a prospective cohort study of 1996, Prandoni et al. have shown that the presence of transient risk factors, such as surgery or recent trauma, was associated with a decreased risk of recurrent thromboembolism (hazard ratios, 0.4 and 0.5, respectively) (2). These and other results provide further support for the inference that treatment for 3 months is sufficient in patients with a first episode of DVT secondary to a transient risk factor, but that is not sufficient in patients with idiopathic dvt (3). Second, we dose not agree the choice of the therapeutic target for INR (INR from 2 to 3.5) The target INR should be 2.0 to 3.0. Target INRs above 3.0 were previously shown by Kearon et al. to result in more bleeding, without any benefit in the prevention of recurrent thrombotic episodes, while lowering the INR results in more recurrences with no advantage in terms of the risk of bleeding (4-5) . In a recent randomized trial Crowther et al compared standard-intensity warfarin therapy (INR, 2.0 to 3.0) with high-intensity warfarin therapy (INR, 3.1 to 4.0) for the prevention of recurrent thromboembolism in patients with very high risk of recurrence (persistently positive antiphospholipid antibodies and a history of thromboembolism) showing that high-intensity warfarin therapy did not provide improved antithrombotic protection (6). We think that the choice for correct length of anticoagulant is possible only trough an accurate risk stratification for recurrence of thromboembolism and for bleeding. According to a recent work by Palareti et al., a modern therapy approach considers also residual deep venous thrombosis and also value of d-dimer at the end of therapy, to accurately define risk profile in every patient (7-8) . Bibliography 1. Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HGM, Williamson IJ. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ 2007 Feb 8 2. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125:1–7. 3. Buller HL, Agnelli G, Hull RD, Hyers TM, Prons MH, Raskpb GE et al. Antithrombotic therapy for venous thromboembolic disease. The seventh ACCP Conference on Antithrombotic and Thrombolytic therapy. Chest 2004; 126: 401-28S. 4. Hull R, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982;307:1676-81. 5. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of lowintensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349:631-9. 6. Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003; 349:1133–1138 7. Prandoni P, Lensing AW, Prins H, Bernardi E, Marchiori A, Bagattella P, Frulla M, Morena L, Tormene D, Piccioli A, Simioni P, Antonio Girolami A. Residual Venous Thrombosis as a Predictive Factor of Recurrent Venous Thromboembolism. Ann Intern Med. 2002;137:955-960. 8. Palareti G, Cosmi B, Legnani C, et al. D-dimer Testing to Determine the duration of anticoagulation theraphy N Engl J Med 2006 ; 355: 1780-1789. Competing interests: None declared |
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Diana C Ferreira, senior resident Hospital Municipal Odilon Behrens, Belo Horizonte, MG, Brazil, CEP 30210-780, Gustavo L B Costa, Leonardo C Paixão, Reginaldo A Valacio
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Dear Sir, Campbel and colleagues suggest that extending anticoagulation beyond 3 months in British patients with venous thromboembolism (VTE) is too much trouble (and risk) for nothing(1)! That could be good news for us, as we strive to run a busy anticoagulation clinic at a teaching hospital on the other side of the Atlantic - and of the Equator -, and to our patients. In their way along the narrow lane that certainly has bleeding on one side, thrombosis on the other side seemed to justify the troubles with INR monitoring, adjustments and adaptations. We wondered if their conclusions would apply to our patients “in whom there are no persistent risk factors”, i.e., those with idiopatic VTE and those with transient risk factors, two very different groups as far as risk of recurrence is concerned(2). Among the patients included in analysis, idiopathic VTE was present in nearly half of the patients (underlying causes were “not evident” in 42% of patients in the three month group and in 47% of those in the six month group). Overall, recurrence rate was around 8%, much lower than that of 19,4% observed in a previsouly published cohort of British patients with “unprovoked VTE”(3). In that study, being idiopathic was much better in predicting risk of recurrence than any detected thrombophilia. In Canada, Kearon and colleagues had to stop their trial earlier than planned, as extending anticoagulation beyond 6 months in idiopatic VTE patients had a dramatic and highly significant impact on the risk of recurrence (27,4 % versus 1,3% per patient-year - NNT 3,83) but not on the risk of bleeding (0 versus 3,8% per patient-year)(2). More recently, an Italian trial(4) demonstrated that in patients with idiopatic VTE and high levels of D- dimer extended anticoagulation made an important and significant difference in recurrence rates (15% versus 2,9%; NNT 8,33). These and other “evidence for substantial benefit”(5) has recently led the American College of Physicians and the American Academy of Family Physicians to recommend extended-duration therapy for idiopathic VTE(6). We were also concerned that highly selected patients with idiopathic VTE and VTE with transient risk factors were included in Campbel’s multicentre trial. Of notice, it took more than 3 years (September 1999 to December 2002) for 46 British hospitals to recruit 810 patients. It would be interesting to know from how many potential candidates volunteers were selected and how representative recruited patients were. Tips from the exclusion criteria may allow us to figure it out. Patients were excluded: 1) on the basis of easily recognizable severity, defined as requirement for thrombolysis or embolectomy. 2) if they had any of a long list of risk factors for recurrence, including several medical conditions, immobility and thrombophilias; 3) if they had “requirement for long term anticoagulation”, defined by each physicians’ discretion, not based on risk factors, VTE in the preceding 3 years or anticipated immobility, already included in the former group. Further, studies of equivalence are always problematic. Potential sources of bias may not be apparent. For instance, as more than two thirds of patients in both groups had deep venous thrombosis (DVT) only, slightly different proportions of patients with proximal and distal DVT could mean different prognosis from the start(7). Additionally, the fact that 3 out of 8 adverse events happened during the initial 3 months (all in the six month group) has to be taken into account. An issue of debate, randomisation at the end of the three months of anticoagulation is probably more relevant to answer the clinical question of whether the intervention “prolong” or the control “not to prolong” are different in terms of benefits and harm. Curiously, out of 810 patients who entered the study, 27 in the three month and 34 in the six month group were eventually excluded from analysis, due to previously unnoticed exclusion criteria. Unbalances in the time in therapeutic range, which is very difficult to measure, may also have occurred, despite the fact that “good anticoagulation” (INR between 2,0 and 3,5 on at least two thirds of the occasions) was similar in both groups, around 55-60%. References: 1. Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HG, Williamson IJ. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ 2007; doi:10.1136/bmj.39098.583356.55. 2. Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, et al. A comparison of three months of anticoagulation with extended anticoagulation for first episode of idiopathic venous thromboembolism. N Engl Med 1999;340:901-7. 3. Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003;362(9383):523-6. 4. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, et al. D-dimer testing to determine the duration of anticoagulation. N Engl J Med 2006;355:1780-9. 5. Ost D, Tepper J, Mihara H, Lander O, Heinzer R, Fein A. Duration of anticoagulation following venous thromboembolism: a metaanalysis. JAMA 2005;294:706-15. 6. Segal JB, Streiff MB, Hoffman LV, Thornton K, Bass EB. Management of venous thromboembolism: a systematic review for a practice guideline. Ann Intern Med 2007;146:211-22. 7. Seinturier C, Bosson JL, Colonna M, Imbert B, Carpentier PH. Site and clinical outcome of deep vein thrombosis of the lower limbs: an epidemiological study. J Thromb Haemost 2005;3:1362-7. Competing interests: None declared |
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Sameer Chadha, Medical Student Maulana Azad Medical College, New Delhi, India, Shikha Mehta, Medical Student , Maulana Azad Medical College, New Delhi ,India
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Patients with Pulmonary Embolism following surgery or trauma ordinarily have a low rate of recurrence after a total duration of 6 months of anticoagulation therapy. While the patients with idiopathic Pulmoary Embolism the recurrence rate is very high after the cessation of the anti-coagulation. The PREVENT trial established anti- coagulation with warfarin for Six months with a target INR of 2.0 to 3.0 followed by indefinte duration of anti- coagulation with low intensiy warfarin, target INR of 1.5 to 2.0 Competing interests: None declared |
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Mohammed A M SIDDIQUI, SHO Acute Medicine Bishop Auckland General Hospital, DL14 6AD
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D-dimers represent fibrinolysis either current or very recent. Would it not be useful to assess level of D-dimer at 3 month interval and decide about duration of anticoagulation. Those with persistently high levels of D-dimers should continue to have anticoagulation for further 3 months. Moreover warfarin per se doesn’t cause bleeding unless there is some damage either by inappropriate co-prescription or over the counter use of NSAIDs and to assume that it is due to increased duration of the treatment would be inappropriate. I think in such circumstances D-dimers would be a better guide in determining the duration of anticoagulation and this should be assessed in detail through large studies. Competing interests: None declared |
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Andrew Mahony, Medical Registrar St Vincent's Hospital, Sydney 2010, Stephen Wilson
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Campbell et al. have demonstrated the benefits of anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism in a hospital population (1). The introduction of Low Molecular Weight Heparin (LMWH) has placed general practitioners at the forefront of the management of these conditions. In the Australian health system patients with a first deep venous thrombosis (DVT) may have little contact with a physician other than a brief visit to the emergency department for assessment and investigation. In fact DVT is listed as an avoidable admission by the New South Wales Government(2). As an example St Vincents Hospital is one of the busiest emergency departments in Sydney and admitted only 12 DVTs (Diagnostic Related Group F63B) to hospital during the year 05/06. Campbells study also included patients with recent surgery which constituted 11% of the study population. It would be interesting to know what proportion of this group had below knee DVTs and may have been more appropriate for even shorter periods of anticoagulation with LMWH. This approach has been implemented successfully in orthopaedic programs and avoids Warfarin entirely for most patients with below knee non propogating DVTs (3). 1.Campbell I, Bentley D, Prescott R, Routledge P, Shetty H, Williamson I. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomized trial. BMJ 2007;334;674-. 2.Premiers Department.State Plan.New South Wales Government 2006:78 3.O’Reilly R, Burgess I, Zicat B. The prevalence of venous thromboembolism after hip and knee replacement surgery. Medical Journal of Australia 2005;182,4;154-159. Competing interests: None declared |
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Amit Patel, Academic Clinical Fellow & Specialist Registrar in Haematology Imperial College London & Hammersmith Hospitals NHS Trust, Charing Cross Hospital, London, W6 8RF
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I read the multi-centre prospective randomised control study on non- severe idiopathic deep venous thrombosis (DVT) and pulmonary embolus (PE) in patients without another indication for anticoagulation with great interest.[1] With only 749 patients, it is inadequately powered[1] and the presented data on equivalence of death, treatment failure or recurrence, and composite outcome cannot be confidently concluded. The two groups may not have been adequately balanced. The 6 month group had slightly more severe cases, with an excess of men (57 versus 50%) with pulmonary embolus alone (32% versus 27%). A variety of imaging modalities were used for diagnosis with ranked categories of confidence, and the DVT sites were not disclosed. No group comparison of this crucial data is presented. Significantly increased non-fatal haemorrhage in the six month group (p = 0.008) is misleading as three of the eight cases occurred in the first three months. Their grade of anticoagulation control is also unclear. Only 55% of study patients at three months had an INR within target range two thirds of the time, with 18% of the 4-6 month cohort lost to follow-up. The INR range of 2-3.5 is rather wide for a first idiopathic DVT/PE and current recommendations suggest specification of an exact target INR rather than a range to improve anticoagulation control. It is not clear whether patients were tested for the prothrombin (20210 G to A) mutation described in 1996[2] or for beta-2 glycoprotein-1 antibodies. Studies suggest this mutation is present in around 2% in the general population[3] and it increases the risk of deep venous thrombosis by a factor of 3-4 in heterozygotes, and higher in homozygotes. The updated 2006 diagnostic criteria for antiphospholipid syndrome advocate beta-2 glycoprotein-1 antibody measurement[4] as they are more specific for the syndrome and maybe the only positive test in around 10% of cases. With follow-up of only one year, presentation of other features of the syndrome maybe missed. Both factors may unbalance the two groups and account for some the treatment failures and recurrences. The prospective randomised controlled PROLONG study indicated raised d-dimer level one month after discontinuation of anticoagulation predicted a higher risk of thrombosis recurrence,[5] justifying re-initiation of anticoagulation. Studies are ongoing examining d-dimer level during initial anticoagulation, preventing early recurrence on cessation of therapy. This may prove helpful in risk stratifying high risk groups and inform length of treatment. References [1] Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HGM, Williamson IJ. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ 2007;334:674 [2] Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698-3703. [3] Rosendaal FR, Doggen CJ, Zivelin A, Arruda VR, Aiach M, Siscovick DS, Hillarp A, Watzke HH, Bernardi F, Cumming AM, Preston FE, Reitsma PH. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998;79:706-8. [4] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. [5] Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, IorioA, Pengo V, Ghirarduzzi A, Pattacini C, Testa S, Lensing AWE, Tripodi A. D-Dimer Testing to Determine the Duration of Anticoagulation Therapy. N Engl J Med 2006;355:1780-9. Competing interests: None declared |
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