Op-brhe130395 201..202

During the past 30 years, aPL have been demonstrated to be pathogenic [1], therefore aPL carriers should be considered at risk for clinical manifestations and managed accordingly. The problem of long-term primary prevention of thrombosis has puzzled physicians [2]. As we know from large cohorts of patients with aPL, the clinical consequences of thrombosis and its recurrence can be severe. The article by Cuadrado et al. [3] published in this issue reports on a randomized trial comparing the effect of low-dose aspirin (LDA) vs LDA plus low-intensity warfarin (LDA+W) in the primary prophylaxis of aPL carriers selected from patients with SLE and from women with pure obstetric APS. By following up 166 patients for nearly 4 years, this study is the largest and the most longlasting controlled trial for the primary prevention in aPL carriers ever published. Despite these strengths, the trial could not reach a definite conclusion. The authors identified some issues that limited the power of the trial. All points are important and need to be discussed as lessons to be learned in designing future studies. The first problem was the low recruitment rate. The novel and breakthrough combination therapy of LDA+W was unattractive and many patients refused to participate. We presume that aPL carriers did not feel motivated to comply with a drug regimen that carries the risk of bleeding and requires frequent blood sampling and lifestyle modifications. Therefore the first lesson to be learned is that drugs used in primary prophylaxis need to be acceptable to individuals who only carry a risk factor and do not generally perceive themselves as sick. A second problem was that the inclusion of low-risk patients may explain the lower than expected rate of thrombosis seen in the study. When the trial was designed, the relevance of the serological profile in risk stratification was not as clear as it is today. It is now well accepted that patients should be assessed for a complete aPL profile, including lupus anticoagulant (LA), aCL, and anti-b2-glycoprotein I antibodies [4]. A general consensus exists on the high-risk profile being characterized by positive LA, high IgG titre and triple positivity for aPL tests [5]. There is evidence that this group of aPL carriers are those who are at more risk of developing the first thromboembolic event [6]. Thus the second lesson to be learned is that a trial focusing on the primary thromboprophylaxis is more likely to be informative if only patients with a clinically significant aPL profile are enrolled. A third problem is the analysis of concomitant risk factors for thrombosis. The authors [3] reported that thrombosis occurred in all but one patient who carried such factors, even though none of these factors could be considered an independent predictor of the event. We are all aware that thrombosis is a multifactorial process, therefore the third lesson to be learned may be that the presence of concomitant vascular risk factors and/or a systemic autoimmune disease should be taken into consideration for risk stratification in any study dealing with the primary prophylaxis [5]. But this is only one aspect of the risk assessment: the other important aspect is the timely recognition of high-risk conditions. It is assumed in clinical practice that situations such as immobilization, puerperium and long-haul flights may trigger the thrombotic process by acting as a second hit [7]. The prophylaxis of these high-risk situations with low molecular weight heparin (LMWH) was demonstrated to be more efficacious than continuous prophylaxis with LDA in reducing thromboembolic events in a large prospective cohort [8]. As clinicians, our feeling is that proper management of high-risk situations may prevent most of these events. Therefore we believe that a study dealing with primary thromboprophylaxis should take this variable into account. As discussed, a crucial issue is the choice of medication. It must be acceptable to individuals who carry a risk factor. HCQ is a drug of interest [9], being generally well tolerated and not requiring any particular monitoring, with the exception of periodic eye examinations. Experimental data have shown the anti-inflammatory and anti-platelet activity of HCQ, possibly accounting for the protective effect of HCQ against thrombosis that was demonstrated in several studies [5]. Statins are also worth mentioning because they have been shown to be able to reverse the proinflammatory and procoagulant state induced by aPL [9]. Cuadrado et al. [3] did not find any benefit in patients who were taking HCQ or statins in addition to the trial medications. But the study was not focused on these aspects, and the number of patients on HCQ/statins may have been too low to see any difference. Turning to