Hoogervorst R, van Overhagen H, de Jong P A, Spiering W, de Borst G J, Veger H T C, Mairuhu A T A, Mali W P T M
Haga Hospital, HagaZiekenhuis, The Hague, The Netherlands.
UMC Utrecht, The Hague, The Netherlands.
CVIR Endovasc. 2022 Jun 6;5(1):26. doi: 10.1186/s42155-022-00298-y.
Pathologic studies have shown that in patients with critical limb threatening ischaemia (CLTI) medial arterial calcifications are frequently found and may be responsible for aggravating the disease. These extensive calcifitcations are found not only in arteries of the leg but also in the coronary arteries and the aorta. The progression of these calcifications is fast and they stiffen the vessel wall and may thus increase the cardiovascular risk. Reduction of progression of calcification may not only reduce the burden of CLTI but may also reduce the high residual cardiovascular risk. Medial calcifications have been halted by etidronate in other trials. Its potential to reduce the burden from peripheral vascular disease in CLTI and residual cardiovascular risk remains to be established.
This is an investigator-initiated multicenter, double blind, placebo-controlled, randomized trial comparing the effects of etidronate versus placebo in patients with CLTI. Subjects will be randomized to either treatment with etidronate for 12 months (cyclical 20 mg/kg for 2 weeks on and 10 weeks off) orally or placebo for 12 months (in a similar routine). The primary endpoint is the change in arterial calcification as quantified by CT-scan. Secondary endpoints are the number of amputations above and below the ankle, mortality, number of vascular interventions and quality of life.
Up to now, the inert end stage of vascular disease in patients with CLTI, has been considered calcification of vessel walls. We believe there is reason to reverse causation and hypothesize that calcification causes vascular disease. This reversal can be proven in a clinical trial if halting the calcification process improves the outcome of the patient. Therefore we use etidronate, a bisphosphate that has proven to stop the calcification in several rare monogenetic calcifying diseases. We aim to perform this mechanistic proof-of-concept study hopefully leading to a clinical outcome study later on.
病理研究表明，在严重肢体缺血（CLTI）患者中，常发现动脉中层钙化，这可能会加重病情。这些广泛的钙化不仅出现在腿部动脉，还出现在冠状动脉和主动脉。这些钙化进展迅速，会使血管壁变硬，从而可能增加心血管风险。减少钙化进展不仅可以减轻CLTI的负担，还可能降低高残留心血管风险。在其他试验中，依替膦酸钠已使中层钙化停止。其减轻CLTI患者外周血管疾病负担和残留心血管风险的潜力仍有待确定。
这是一项由研究者发起的多中心、双盲、安慰剂对照、随机试验，比较依替膦酸钠与安慰剂对CLTI患者的影响。受试者将被随机分为两组，一组口服依替膦酸钠治疗12个月（每2周20mg/kg，连续服用2周，停药10周），另一组口服安慰剂12个月（采用类似方案）。主要终点是通过CT扫描量化的动脉钙化变化。次要终点是踝关节以上和以下的截肢数量、死亡率、血管介入次数和生活质量。
到目前为止，CLTI患者血管疾病的惰性终末期一直被认为是血管壁钙化。我们认为有理由颠倒因果关系，并假设钙化导致血管疾病。如果停止钙化过程能改善患者的预后，那么这种因果关系的颠倒可以在临床试验中得到证实。因此，我们使用依替膦酸钠，一种双膦酸盐，已被证明能在几种罕见的单基因钙化疾病中阻止钙化。我们旨在进行这项机制性概念验证研究，有望随后开展临床结局研究。
