Cundiff David K, Agutter Paul S, Malone P Colm, Pezzullo John C
Theoretical Medicine and Biology Group, 26 Castle Hill, Glossop, Derbyshire SK13 7RR, UK.
Theor Biol Med Model. 2010 Aug 11;7:31. doi: 10.1186/1742-4682-7-31.
Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S. Food and Drug Administration began requiring randomized controlled clinical trials (RCTs) showing efficacy, so efficacy trials were never required for FDA approval. In clinical trials of 'high VTE risk' surgical patients before the 1980s, anticoagulant prophylaxis was clearly beneficial (fatal pulmonary emboli (FPE) without anticoagulants = 0.99%, FPE with anticoagulants = 0.31%). However, observational studies and RCTs of 'high VTE risk' surgical patients from the 1980s until 2010 show that FPE deaths without anticoagulants are about one-fourth the rate that occurs during prophylaxis with anticoagulants (FPE without anticoagulants = 0.023%, FPE while receiving anticoagulant prophylaxis = 0.10%). Additionally, an FPE rate of about 0.012% (35/28,400) in patients receiving prophylactic anticoagulants can be attributed to 'rebound hypercoagulation' in the two months after stopping anticoagulants. Alternatives to anticoagulant prophylaxis should be explored.
The literature concerning dietary influences on VTE incidence was reviewed. Hypotheses concerning the etiology of VTE were critiqued in relationship to the rationale for dietary versus anticoagulant approaches to prophylaxis and treatment.Epidemiological evidence suggests that a diet with ample fruits and vegetables and little meat may substantially reduce the risk of VTE; vegetarian, vegan, or Mediterranean diets favorably affect serum markers of hemostasis and inflammation. The valve cusp hypoxia hypothesis of DVT/VTE etiology is consistent with the development of VTE being affected directly or indirectly by diet. However, it is less consistent with the rationale of using anticoagulants as VTE prophylaxis. For both prophylaxis and treatment of VTE, we propose RCTs comparing standard anticoagulation with low VTE risk diets, and we discuss the statistical considerations for an example of such a trial.
Because of (a) the risks of biochemical anticoagulation as anti-VTE prophylaxis or treatment, (b) the lack of placebo-controlled efficacy data supporting anticoagulant treatment of VTE, (c) dramatically reduced hospital-acquired FPE incidence in surgical patients without anticoagulant prophylaxis from 1980 - 2010 relative to the 1960s and 1970s, and (d) evidence that VTE incidence and outcomes may be influenced by diet, randomized controlled non-inferiority clinical trials are proposed to compare standard anticoagulant treatment with potentially low VTE risk diets. We call upon the U. S. National Institutes of Health and the U.K. National Institute for Health and Clinical Excellence to design and fund those trials.
使用抗凝剂预防和治疗静脉血栓栓塞症（VTE：深静脉血栓形成（DVT）和肺栓塞（PE））均与严重出血及致命性出血的重大风险相关。自1962年美国食品药品监督管理局开始要求提供显示疗效的随机对照临床试验（RCT）之前，VTE的抗凝治疗在美国就是标准治疗方法，因此FDA批准从未要求进行疗效试验。在20世纪80年代之前的“高VTE风险”手术患者的临床试验中，抗凝预防显然是有益的（未使用抗凝剂时致命性肺栓塞（FPE）发生率 = 0.99%，使用抗凝剂时FPE发生率 = 0.31%）。然而，20世纪80年代至2010年期间对“高VTE风险”手术患者的观察性研究和RCT表明，未使用抗凝剂时的FPE死亡发生率约为使用抗凝剂预防时发生率的四分之一（未使用抗凝剂时FPE发生率 = 0.023%，接受抗凝预防时FPE发生率 = 0.10%）。此外，接受预防性抗凝治疗的患者中约0.012%（35/28,400）的FPE发生率可归因于停用抗凝剂后两个月内的“反弹性高凝状态”。应探索抗凝预防的替代方法。
回顾了有关饮食对VTE发生率影响的文献。就饮食与抗凝方法在预防和治疗方面的基本原理，对有关VTE病因的假设进行了批判。流行病学证据表明，富含水果和蔬菜且肉类较少的饮食可能会大幅降低VTE风险；素食、纯素食或地中海饮食对止血和炎症的血清标志物有有利影响。DVT/VTE病因的瓣膜尖缺氧假说与VTE的发生直接或间接受饮食影响是一致的。然而，这与使用抗凝剂作为VTE预防的基本原理不太一致。对于VTE的预防和治疗，我们建议进行RCT，比较标准抗凝治疗与低VTE风险饮食，并讨论此类试验示例的统计学考量。
由于（a）生化抗凝作为VTE预防或治疗存在风险，（b）缺乏支持VTE抗凝治疗的安慰剂对照疗效数据，（c）与20世纪60年代和70年代相比，1980 - 2010年期间未进行抗凝预防的手术患者中，医院获得性FPE发生率大幅降低，以及（d）有证据表明VTE发生率和结局可能受饮食影响，因此建议进行随机对照非劣效性临床试验，以比较标准抗凝治疗与潜在低VTE风险饮食。我们呼吁美国国立卫生研究院和英国国家卫生与临床优化研究所设计并资助这些试验。
