ASH guidelines on thrombophilia testing ‘could change practice’
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Thrombophilia is a known risk factor for venous thromboembolism, but the value of thrombophilia testing in guiding treatment decisions remains a topic of debate.
“Thrombophilia testing is a highly controversial area; there are very few guidelines or guidance documents due to the absence of high-level evidence,” Saskia Middeldorp, MD, PhD, full professor of medicine and head of the department of internal medicine at Radboud University medical center in Nijmegen, the Netherlands, told Healio. “American Society of Hematology decided that in our VTE guidelines, we cannot run away from this topic. It was more difficult than usual but, in the end, we succeeded.”
Middeldorp spoke with Healio about the challenge of drafting these guidelines, how the panel compiled the recommendations and the need for additional updates in the future.
Healio: How did you develop these guidelines?
Middeldorp: Ideally, we would use randomized trials in which a certain group of patients is tested and another group is not tested, so we can compare the outcomes. That would be the best type of evidence that we would use as the basis for certain recommendations. We were left, however, with observational evidence, so we applied a modeling approach where we looked at the population level — a thousand patients within a certain clinical scenario, for instance. What if we tested all those individuals and then developed a strategy based on the results of those tests? What would that do to that population?
The challenge was to obtain estimates of the effect of a certain strategy, for instance extending anticoagulant treatment in patients with thrombophilia, and stopping treatment in those with a negative test result. For this example, we took treatment effects of extended anticoagulation from other chapters [of the guidelines]. It could also be the effect of prophylaxis, or the effect of not taking oral contraceptives. So, there were quite a few aspects that we needed to put into that model in order to get these estimates.
Healio: Can you summarize some of the key recommendations you made?
Middeldorp: Thrombophilia is an important risk factor for a first episode of VTE, but it’s effect on recurrence is much less. There has been a dogma to be very, very conservative in determining who to test. Here is where our recommendations are novel, because using our approach, we came up with suggestions to test patients who have VTE provoked by nonsurgical risk factors. Those risk factors include pregnancy or the postpartum period, or VTE associated with the use of combined oral contraceptives. The suggestion in our (weak) recommendation is to extend anticoagulant treatment in thrombophilia-positive patients, and to stop it in those who do not have thrombophilia. That is one of those VTE populations for which, nowadays, people would say, “no, you’re not going to test,” but we suggest testing.
The other group of patients with VTE that we suggest to test are those with VTE in unusual sites, such as cerebral venous thrombosis and splanchnic vein thrombosis, but only if the standard treatment would be 3 to 6 months. This is where it gets complicated because the guidelines on how to treat a cerebral venous thrombosis or a splanchnic vein thrombosis are not all that clear in terms of how long to treat. So, we basically said, “If you are using a standard of care where you would treat indefinitely anyway, then don’t test. If you are considering stopping treatment, then test.” This sounds very strong, but again it is a weak recommendation. I know that these recommendations raise eyebrows.
For instance, say we have a 25-year-old pregnant woman with a clot; people would say it makes sense to test, because we’d want to know why, but we suggest extending treatment if she is found to have thrombophilia. This will likely lead to a lot of discussions and raise some eyebrows. However, it’s what the full panel came up with based on our model, but we should realize that these are weak recommendations based on low-quality evidence.
Healio: What else did the panel recommend?
Middeldorp: Because the majority of thrombophilia is inherited, we always have to deal with the family members of patients, who have a 50% chance of having the same thrombophilia. For individuals who have a brother, sister, mother, father or child with VTE and a known thrombophilic risk factor, we now suggest testing to provide thrombosis prophylaxis in situations with minor risk factors that would generally not justify prophylaxis.
Another important group is women with a family history of VTE. If there is a known high-risk thrombophilia in the family, we suggest testing for that specific thrombophilia, and if they are positive, we suggest avoiding the use of hormones and providing prophylaxis around pregnancy. That is something that is implicit in many guidance documents, but these documents never accounted for how many people we need to test and how many people need prophylaxis based on testing.
One final group of patients for whom we suggest testing are those with cancer who have a family history of thrombosis and are undergoing ambulatory cancer treatment. If they are at low or intermediate risk for VTE, the ASH cancer VTE guideline recommends against pharmacologic thromboprophylaxis. Based on our modeling approach, we recommend testing these people for thrombophilia. If they have thrombophilia, we suggest providing prophylaxis. This will result in a lot more testing because it means testing all patients with cancer undergoing ambulatory cancer treatment who have a positive family history of VTE. That’s something that is absolutely novel and could change practice to hopefully prevent many cancer-associated clots.
Healio: What do you expect to be the implications of these guidelines for clinical practice?
Middeldorp: Particularly for the VTE population and cases that are provoked by nonsurgical risk factors, the current guidelines could change practice. Nowadays, there is a reluctance to test because we have all learned that the risk for recurrence is only very mildly increased. Some people therefore criticize this and say, “Well, this includes a 70-year-old woman who has been in hospital with pneumonia and then gets clots, and I will not test her for thrombophilia.” I can relate to that, and it would be very nice if we would have more differential evidence on the risk for recurrence in such patients vs. in those with pregnancy-related or oral contraceptive-related clots. That is something we had to combine in our model because of the absence of granular data. So even if we do not have the trial, we would still benefit from having better observational data on risk.
For more information:
Saskia Middeldorp, MD, PhD, can be reached at Amsterdam UMC, De Boelelaan 1117 en 1118 1081 HV Amsterdam, Netherlands; email: saskia.middeldorp@radboudumc.nl.
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