Testing for V LEIDEN and FII 20210G>A mutations

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1 Testing for V LEIDEN and FII 20210G>A mutations September 2006 Department of Medical and Surgical Procedures Assessment 2 avenue du Stade de France Saint-Denis La Plaine CEDEX Tel. : Fax : http :// N SIRET : Code APE : 751 C

2 THE TEAM The report on which this summary is based was prepared by Céline Moty-Monnereau, MD PhD (HAS project manager). The full report is available in French on the HAS website. Documentary research at HAS was carried out by Christine Devaud with the help of Renée Cardoso, under the supervision of Frédérique Pages, PhD. The draft report was peer reviewed by: - Martine Alhenc-Gelas, MD, at the request of Professor Anne-Marie Fischer, MD, Haematology laboratory, Georges-Pompidou hospital, Paris; - Jacqueline Conard, MD, Biological haematology department, Hôtel-Dieu hospital, Paris. The final report was validated by the HAS Committee for the Assessment of Diagnostic and Therapeutic procedures in September Contact details Phone: (+33) Fax: (+33) contact.seap@has-sante.fr Department of Medical and Surgical Procedures Assessment Head of department, Sun Hae Lee-Robin, MD Deputy head, Denis Jean David, PhD - 2 -

3 SUMMARY 1. Introduction Thrombophilia refers to abnormalities of haemostasis which predispose to thrombosis or a clinical tendency to thrombosis (deep vein thrombosis and pulmonary embolism). These abnormalities may be linked to the presence of certain mutations, such as the Factor V Leiden mutation (FV Leiden) and the g.20210g>a mutation in the prothrombin gene (FII 20210G>A). The observed prevalence of the FV Leiden mutation in the general population is about 3 5%, and the estimated prevalence of the FII 20210G>A mutation about 2 4%. Three tests are used to identify these two hereditary risk factors for thrombophilia and to help classify patients according to risk of thrombosis: - the activated protein C (APC) resistance test which is a functional biological assay used to screen for FV Leiden; the result, if positive, is confirmed by the genetic test, - a genetic test for FV Leiden, - a genetic test for FII 20210G>A. There are no functional biological tests to screen for this mutation. The genetic tests differentiate between homozygotes and heterozygotes. These three tests are currently not reimbursed in France. The APC test is included in the American, Australian, and Belgian health insurance schedules. The genetic tests are also included in these three health insurance schedules as well as in the Quebec schedule, under the non-specific section of testing for these mutations (Only in the Australian schedule, is the genetic test for FV Leiden named). At the request of the French National Health Executive, the Haute Autorité de Santé has assessed the expected benefit of these tests in order to give an opinion on their inclusion in the NABM 1 (revised "Haemostasis section). 2. Assessment method The HAS method for assessing expected or actual benefit of procedures is based on a review of the literature and expert opinion (members of the NABM committee and consulted experts in this instance). The main medical databases (Medline, Cochrane Library, Cochrane Library, National Guideline Clearinghouse and HTA Database) were searched for guidelines, meta-analyses and literature reviews over the period January 1999 to July 2005 for diagnostic studies and over the period January 1995 to July 2005 for epidemiological and health economics data. Article selection criteria - practice guidelines - prospective and retrospective case series measuring the performance of the APC resistance test. - studies measuring the impact on morbidity and on the health care system. 1 NABM: French Health Insurance Schedule of reimbursed biological procedures - 3 -

4 Of the 234 articles retrieved in the literature search, 35 were selected for analysis, and 13 were cited in the report : 5 studies of diagnostic performance, 7 practice guidelines including 1 published in 2006 (after the literature review), and 1 study measuring impact. 3. Results of the literature review Indications According to 7 practice guidelines based on expert opinion, the indications for the tests can be divided into two categories depending upon whether they do or do not relate to obstetrics: (i) Outside of pregnancy, the tests are used to investigate the cause of the following, particularly in patients under 50 years of age: - unexplained or recurrent deep vein thrombosis, - unexplained or recurrent pulmonary embolism. (ii) In pregnant women, they are used to investigate the cause of a venous thromboembolism in patients - with a proven family history of venous thromboembolism, - with a personal history of venous thromboembolism. Diagnostic performance The genetic tests are the reference diagnostic methods. The sensitivity and specificity of the APC test is given in Table 1. Table 1. Sensitivity and specificity of the APC test (5 studies) Test sample Undiluted plasma Studies (N) 1 Patients (N) 498 Sensitivity (%) 100* 68 Specificity (%) Immunochromeassay with a factor VIII-based assay After dilution in factor V deficient plasma * (all patients) 95.5 (liver dysfunction) 68.8 (lupus anticoagulant present) * Positivity thresholds were defined a posteriori in 3 studies for a 100% sensitivity. Safety and complications of the procedures There are no specific safety problems as the tests are performed on a blood sample. Conditions of use One guideline specifies that the indication for the tests should be discussed jointly by the clinician and haematologist. Genetic testing of individuals for medical purposes is regulated by the French Public Health Code: section III of the new legislative section (articles L to L ) and section III of the new regulatory section (articles R to R )

5 The tests should be carried out in accordance with good laboratory practice (GBEA) 2. One guideline states that each laboratory should specify the test used and the range of normal values for the APC test. Contribution to the treatment strategy The results of the tests may be used in certain indications to adjust a patient s treatment to prevent the occurrence or recurrence of venous thromboembolism (anticoagulant therapy, adjustment of dose and duration of anticoagulant therapy, etc). The risk of haemorrhage associated with anticoagulant therapy should be taken into account. These treatments are defined in 4 guidelines based on levels of evidence ranging from expert opinion to randomized clinical trials. They do not depend on the presence of the FV Leiden mutation or FII 20210G>A mutation. The impact of the tests on morbidity and mortality was assessed in the EPCOT cohort study 3 (including France) of the venous thromboembolism recurrence rate in patients with a family history of thrombophilia, who may or may not have received long-term anticoagulant therapy. After a mean follow-up of 5.6 years, the annual recurrence rate was 5.0% (CI 95% [ ]) in the untreated group (44/180) compared with 1.1% (CI 95% [ ]) in the treated group (7/124). There are no published data on the impact of these tests on the healthcare system or on public health programmes in France (no health economics data). 4. Position of the working group Positions of the NABM committee in 2003 According to the NABM committee, these tests are part of the workup for venous thromboembolism (study of predictive factors). Genetic testing of individuals for medical purposes is regulated by the French Public Health Code: section III of the new legislative section (articles L to L ) and section III of the new regulatory section (articles R to R ). Only licensed laboratories and authorized practitioners may carry out these tests. Specific rules apply to children under 18 years and to asymptomatic patients. The NABM committee voted in favour of including these tests on their list. Position of experts consulted in 2006 According to the experts contacted during the final stages of the report, the tests should be prescribed after discussion between the clinician (gynaecologist, vascular physician, etc.) and a haematologist, in specialist centres if possible. The experts stressed that, in France, there is no agreement on the use of the APC test for diagnosis. In theory, the genetic test identifying and characterising the FV Leiden mutation (homozygote or heterozygote) is only performed after a positive result in the APC resistance test. However, in practice, laboratories authorised to carry out genetic tests perform the genetic test immediately, without first performing the APC resistance test which carries a risk of false negative results. Besides, the APC resistance tests available on the market have heterogenous diagnostic performance. 2 GBEA: Guide de bonne exécution des analyses de biologie médicale 3 EPCOT: European Prospective Cohort on Thrombophilia - 5 -

6 5. Conclusion Diagnostic benefit These tests represent a benefit for the diagnosis of risk factors for recurrent venous thromboembolism. They meet a diagnostic need. - APC resistance test: This test is used to detect the FV Leiden mutation and may be performed by non-hospital laboratories. A positive result automatically leads up to a confirmatory genetic test for the mutation. However, the laboratories authorised to carry out genetic testing prefer to genetically test for the mutation immediately because of the risk of false negatives with the APC test. - Genetic tests: These tests identify the FV Leiden and FII 20210G>A mutations and specify whether they are homozygote or heterozygote. They may be carried out by authorised laboratories only. The indications for and place in the treatment strategy of these three laboratory tests were established by 7 guidelines based on expert opinion. The tests are effective and do not pose safety problems. Genetic testing of individuals for medical purposes is regulated by the French Public Health Code: section III of the new legislative section (articles L to L ) and section III of the new regulatory section (articles R to R ). Benefit in patient management In some cases, testing for the FV Leiden and FII 20210G>A mutations during workup for haemostasis can help adjust preventive and curative treatment (anticoagulant therapy). The tests have a positive impact on morbidity and mortality according to a European cohort study in patients with a family history of thrombophilia, which reported a higher recurrence rate for venous thromboembolism in untreated than treated patients. However, no published data have confirmed these findings. Additional data on benefits and risks are thus needed. Benefit to public health There are no published data on the impact of these tests on the healthcare system and public health programmes in France. Conclusion The expected benefit of the APC resistance test is insufficient because the tests available on the market have heterogeneous diagnostic performance. The test is not appropriate as a screening method. It is superseded by the genetic test for the FV Leiden mutation. The expected benefit of the genetic tests for the FV Leiden and FII 20210G>A mutations is considered to be sufficient. The improvement in expected benefit provided by the genetic tests is not known as: thrombophilia is a multifactorial disease; treatment methods are not specific for the presence of these mutations; there are no impact measures for morbidity and mortality for all the indications for these tests; the tests concern genetic characteristics. HAS opinion on the use of the APC resistance test to detect the FV Leiden mutation could be re-examined if a list of the APC resistance tests with good diagnostic performance were available. Drawing up such a list is the responsibility of the French Health Products Safety Agency (AFSSAPS) which has been informed by HAS of the need