Correspondence
I declare no competing interests.
David Shaw [email protected] Institute for Biomedical Ethics, University of Basel, CH-4056 Basel, Switzerland 1
Shaw D. The right to participate in high-risk research. Lancet 2014; 383: 1009–11.
Compression stockings to prevent postthrombotic syndrome
post-thrombotic syndrome: heparin, a drug discovered a century ago by Jay McLean (in 1916), which revolutionised deep-vein thrombosis prognosis.4 Moreover, a well-conducted anticoagulation treatment has also been associated with a decreased rate of post-thrombotic syndrome. Therefore, the results of the SOX trial should not be “leaving doctors empty handed”,2 but should rather reinforce their role in offering a high-quality anticoagulant treatment to their patients. An ongoing international placebocontrolled trial should assess more precisely the effect of heparin on the natural history of post-thrombotic syndrome after a distal deep-vein thrombosis (NCT00539058). The effect of new oral anticoagulants on the prevention of post-thrombotic syndrome is another important issue.5 We declare no competing interests.
In their SOX trial (March 8, p 880),1 Susan Kahn and colleagues did not report any benefit of elastic compression stockings in preventing post-thrombotic syndrome. According to Arina ten Cate-Hoek,2 this unexpected result “could have an important effect on daily practice, leaving doctors empty handed”.2 In 1946, in The Lancet, Swedish surgeon Gunnar Bauer reported on the effectiveness of heparin on long-term sequelae of deep-vein thrombosis.3 In the absence of anticoagulants, 5 years after an objectively confirmed “late” (ie, proximal) deep-vein thrombosis, all patients developed venous insufficiency and 20% a venous leg ulcer. Heparin reduced by 78·9% the risk of developing signs of post-thrombotic syndrome after deep-vein thrombosis.3 Interestingly, Bauer’s reported prevalence of post-thrombotic syndrome at 3 years in patients treated with heparin (up to 26·3%) did not differ substantially from the prevalence of post-thrombotic syndrome reported in contemporary cohorts. We therefore believe that doctors already have a very, although not fully, effective treatment to prevent www.thelancet.com Vol 384 July 12, 2014
*Jean-Philippe Galanaud, Marc Righini, Isabelle Quéré [email protected] Department of Internal Medicine and Clinical Investigation Centre, University Hospital Saint Eloi, Montpellier 34295, France (J-P G, IQ); and Vascular Medicine Unit, Geneva University Hospital, Geneva, Switzerland (MR) 1
2
3
4
5
Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent postthrombotic syndrome: a randomised placebocontrolled trial. Lancet 2014; 383: 880–88. Ten Cate-Hoek AJ. Elastic compression stockings—is there any benefit? Lancet 2014; 383: 851–53. Bauer G. Thrombosis; early diagnosis and abortive treatment with heparin. Lancet 1946; 247: 447–54. Galanaud JP, Laroche JP, Righini M. The history and historical treatments of deep vein thrombosis. J Thromb Haemost 2013; 11: 402–11. Prandoni P. Healthcare burden associated with the post-thrombotic syndrome and potential impact of the new oral anticoagulants. Eur J Haematol 2012; 88: 185–94.
The SOX trial is the largest study so far of elastic compression stockings to prevent post-thrombotic syndrome.1 The post-thrombotic syndrome incidence using Ginsberg’s criteria was the primary endpoint and the Villalta’s criteria the secondary. Thus, the signs and symptoms of post-thrombotic syndrome were
left to the discretion of the observer with no quantitative measurement or use of CEAP (Clinical, Etiological, Anatomical, and Pathophysiological) classification. The results were not reported at 2 years as planned, but rather were a cumulative incidence of post-thrombotic syndrome from 6 to 24 months. There was no difference for both endpoints, with 2-year data for the primary outcome available in only 45·5% of patients, and for the secondary endpoint in 27% of patients. This study1 contradicts previous findings.2–4 The design and execution of this trial, including the timing of application of elastic compression stockings, the application itself, and definition and evaluation of compliance, seem inappropriate. Patients were randomised at a mean of 4·7 days from the time of deep venous thrombosis, and elastic compression stockings were applied within the first 2 weeks of diagnosis. What was the mean time from diagnosis to elastic compression stockings application? Optimum management in this acute phase is crucial for early symptom relief, recurrence, and late outcome. This has clearly been shown for adequate anticoagulation treatment,5 but also for compression and immediate mobilisation. 6 Compression and walking exercises reduce pain and swelling immediately, and symptoms diminish after 1 week.6 The aim of continuing wearing elastic compression stockings is to maintain this effect—this could be crucial because the patient might recognise the immediate benefit from using elastic compression stockings and therefore overall compliance would be improved. Sizing was based on leg measurements and elastic compression stockings were sent to patients without provision of proper training. Most patients are unable to apply stockings without specific instruments or training, especially
Life In View/Science Photo Library
that non-autonomous participants are identified, and as Malmqvist states, many potential participants are capable of fully understanding the risks and benefits of research. Malmqvist’s and Hunter’s arguments do not undermine the case for a right to participate in high-risk research.
129
Correspondence
with 30–40 mm Hg compression. Although patients might have been given some instructions on how to wear the stockings, they were not helped by a professional to assess adequate application at randomisation or during follow-up. In clinical practice, patients are trained and assessed for adequate elastic compression stockings fitting. Most experienced compression stockings fitters would not be comfortable if they were not able to check fitting, and the risk of inadequate fitting is quite high. Compliance was assessed by asking patients whether they used compression stockings. Frequent use (defined as 3 or more days/week) showed no difference in the cumulative incidence of post-thrombotic syndrome. Although Susan Kahn and colleagues1 state that this was also the case in daily users, no data are provided. It is difficult to establish the actual time of use by asking patients at 6-month intervals and basing the results on them remembering. Additionally, patients often exaggerate their use of compression therapy. Therefore, this approach is not an accurate measure of compliance. Compliance after 2 years was low, with only 55·6% of patients using compression stockings for 3 or more days per week. Previous studies showing a benefit from the use of compression stockings had a compliance of about 90%.3 Moreover, in the evaluation of patient and investigator blindness, 59% and 87%, respectively, provided either the wrong answer or were uncertain of the type of elastic compression stockings. This finding also suggests that patients did not wear their stockings. We declare no competing interests.
*Nicos Labropoulos, Antonios P Gasparis, Joseph A Caprini, Hugo Partsch Stony Brook Medical Center, Stony Brook, NY 11794, USA (NL, APG); University of Chicago, Pritzker School of Medicine, Chicago, IL, USA (JAC); and Medical University of Vienna, Vienna, Austria (HP)
130
1
2
3
4
5
6
Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet 2014; 383: 880–88. Giannoukas AD, Labropoulos N, Michaels JA. Compression with or without early ambulation in the prevention of post-thrombotic syndrome: a systematic review. Eur J Vasc Endovasc Surg 2006; 32: 217–21. Brandjes DPM, Buller HR, Heijboer H, Hulsman MV, de Rijk M, Jagt H. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349: 759–62. Ten Cate-Hoek AJ, Ten Cate H, Tordoir J, Hamulyák K, Prins MH. Individually tailored duration of elastic compression therapy in relation to incidence of the postthrombotic syndrome. J Vasc Surg 2010; 52: 132–38. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986; 315: 1109–14. Partsch H, Kaulich M, Mayer W. Immediate mobilisation in acute vein thrombosis reduces post-thrombotic syndrome. Int Angiol 2004; 23: 206–12.
Authors’ reply We agree with Jean-Philippe Galanaud and colleagues’ comments about the need to investigate the role of new oral anticoagulants for the prevention of post-thrombotic syndrome. Nicos Labropoulos and colleagues claim that inappropriate endpoints were used in the SOX trial.1 There is no consensus gold standard for diagnosis or longitudinal follow-up of post-thrombotic syndrome. The CEAP classification is not specific for post-thrombotic syndrome and post-thrombotic syndrome-related symptoms and signs do not correlate reliably with vein anatomy or function. We purposely chose endpoints that more accurately reflect patient-important outcomes. Accordingly, based on high inter-rater reliability, validity, and responsiveness, the Villalta post-thrombotic syndrome scale is recommended to diagnose post-thrombotic syndrome, rate its severity,2,3 and has been used in previous similar trials.4 As in previous studies of elastic compression stockings to prevent postthrombotic syndrome,4,5 we reported the cumulative incidence of postthrombotic syndrome during study
follow-up. This is a standard approach for any survival analysis; the numbers at risk account for censoring of patients who developed the outcome, died, or withdrew before 2 years. Regarding timing of elastic compression stockings initiation, patients were randomised a mean of 4·7 days after deep-vein thrombosis diagnosis and study stockings were shipped to patients within 24–48 h of randomisation. Thus, on average, elastic compression stockings use began sooner after deep-vein thrombosis diagnosis in the SOX trial than in two previous trials that reported benefit of stockings to prevent post-thrombotic syndrome.4,5 We p r o v i d e d d e t a i l s o f stockings-related training of research nurses and study patients in the appendix.1 In-person demonstrations and instructions were provided to patients at randomisation and at each study visit, with further reinforcement by phone on days 14 and 60. Labropoulos and colleagues also question our assessment of compliance. To our knowledge, there is no other reasonable way to assess stocking use other than asking the patient. Since our trial required daily use of a device for a 2-year period, we think that compliance was very good, and better than in clinical practice.6 As reported in our paper, a planned per-protocol analysis of frequent stockings users did not show benefit of stockings; neither did a post-hoc analysis restricted to daily stockings users (HR 0·72, p=0·46). Although patients in our study had a first proximal deep-vein thrombosis and thus no previous experience with elastic compression stockings, 41% of patients in the active stocking group versus 17% in the placebo group correctly guessed their treatment assignment. Although more unblinding therefore occurred in the active elastic compression stockings group, we might expect this to exaggerate a favourable response to elastic compression stockings. www.thelancet.com Vol 384 July 12, 2014
I declare no competing interests.
David Shaw [email protected] Institute for Biomedical Ethics, University of Basel, CH-4056 Basel, Switzerland 1
Shaw D. The right to participate in high-risk research. Lancet 2014; 383: 1009–11.
Compression stockings to prevent postthrombotic syndrome
post-thrombotic syndrome: heparin, a drug discovered a century ago by Jay McLean (in 1916), which revolutionised deep-vein thrombosis prognosis.4 Moreover, a well-conducted anticoagulation treatment has also been associated with a decreased rate of post-thrombotic syndrome. Therefore, the results of the SOX trial should not be “leaving doctors empty handed”,2 but should rather reinforce their role in offering a high-quality anticoagulant treatment to their patients. An ongoing international placebocontrolled trial should assess more precisely the effect of heparin on the natural history of post-thrombotic syndrome after a distal deep-vein thrombosis (NCT00539058). The effect of new oral anticoagulants on the prevention of post-thrombotic syndrome is another important issue.5 We declare no competing interests.
In their SOX trial (March 8, p 880),1 Susan Kahn and colleagues did not report any benefit of elastic compression stockings in preventing post-thrombotic syndrome. According to Arina ten Cate-Hoek,2 this unexpected result “could have an important effect on daily practice, leaving doctors empty handed”.2 In 1946, in The Lancet, Swedish surgeon Gunnar Bauer reported on the effectiveness of heparin on long-term sequelae of deep-vein thrombosis.3 In the absence of anticoagulants, 5 years after an objectively confirmed “late” (ie, proximal) deep-vein thrombosis, all patients developed venous insufficiency and 20% a venous leg ulcer. Heparin reduced by 78·9% the risk of developing signs of post-thrombotic syndrome after deep-vein thrombosis.3 Interestingly, Bauer’s reported prevalence of post-thrombotic syndrome at 3 years in patients treated with heparin (up to 26·3%) did not differ substantially from the prevalence of post-thrombotic syndrome reported in contemporary cohorts. We therefore believe that doctors already have a very, although not fully, effective treatment to prevent www.thelancet.com Vol 384 July 12, 2014
*Jean-Philippe Galanaud, Marc Righini, Isabelle Quéré [email protected] Department of Internal Medicine and Clinical Investigation Centre, University Hospital Saint Eloi, Montpellier 34295, France (J-P G, IQ); and Vascular Medicine Unit, Geneva University Hospital, Geneva, Switzerland (MR) 1
2
3
4
5
Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent postthrombotic syndrome: a randomised placebocontrolled trial. Lancet 2014; 383: 880–88. Ten Cate-Hoek AJ. Elastic compression stockings—is there any benefit? Lancet 2014; 383: 851–53. Bauer G. Thrombosis; early diagnosis and abortive treatment with heparin. Lancet 1946; 247: 447–54. Galanaud JP, Laroche JP, Righini M. The history and historical treatments of deep vein thrombosis. J Thromb Haemost 2013; 11: 402–11. Prandoni P. Healthcare burden associated with the post-thrombotic syndrome and potential impact of the new oral anticoagulants. Eur J Haematol 2012; 88: 185–94.
The SOX trial is the largest study so far of elastic compression stockings to prevent post-thrombotic syndrome.1 The post-thrombotic syndrome incidence using Ginsberg’s criteria was the primary endpoint and the Villalta’s criteria the secondary. Thus, the signs and symptoms of post-thrombotic syndrome were
left to the discretion of the observer with no quantitative measurement or use of CEAP (Clinical, Etiological, Anatomical, and Pathophysiological) classification. The results were not reported at 2 years as planned, but rather were a cumulative incidence of post-thrombotic syndrome from 6 to 24 months. There was no difference for both endpoints, with 2-year data for the primary outcome available in only 45·5% of patients, and for the secondary endpoint in 27% of patients. This study1 contradicts previous findings.2–4 The design and execution of this trial, including the timing of application of elastic compression stockings, the application itself, and definition and evaluation of compliance, seem inappropriate. Patients were randomised at a mean of 4·7 days from the time of deep venous thrombosis, and elastic compression stockings were applied within the first 2 weeks of diagnosis. What was the mean time from diagnosis to elastic compression stockings application? Optimum management in this acute phase is crucial for early symptom relief, recurrence, and late outcome. This has clearly been shown for adequate anticoagulation treatment,5 but also for compression and immediate mobilisation. 6 Compression and walking exercises reduce pain and swelling immediately, and symptoms diminish after 1 week.6 The aim of continuing wearing elastic compression stockings is to maintain this effect—this could be crucial because the patient might recognise the immediate benefit from using elastic compression stockings and therefore overall compliance would be improved. Sizing was based on leg measurements and elastic compression stockings were sent to patients without provision of proper training. Most patients are unable to apply stockings without specific instruments or training, especially
Life In View/Science Photo Library
that non-autonomous participants are identified, and as Malmqvist states, many potential participants are capable of fully understanding the risks and benefits of research. Malmqvist’s and Hunter’s arguments do not undermine the case for a right to participate in high-risk research.
129
Correspondence
with 30–40 mm Hg compression. Although patients might have been given some instructions on how to wear the stockings, they were not helped by a professional to assess adequate application at randomisation or during follow-up. In clinical practice, patients are trained and assessed for adequate elastic compression stockings fitting. Most experienced compression stockings fitters would not be comfortable if they were not able to check fitting, and the risk of inadequate fitting is quite high. Compliance was assessed by asking patients whether they used compression stockings. Frequent use (defined as 3 or more days/week) showed no difference in the cumulative incidence of post-thrombotic syndrome. Although Susan Kahn and colleagues1 state that this was also the case in daily users, no data are provided. It is difficult to establish the actual time of use by asking patients at 6-month intervals and basing the results on them remembering. Additionally, patients often exaggerate their use of compression therapy. Therefore, this approach is not an accurate measure of compliance. Compliance after 2 years was low, with only 55·6% of patients using compression stockings for 3 or more days per week. Previous studies showing a benefit from the use of compression stockings had a compliance of about 90%.3 Moreover, in the evaluation of patient and investigator blindness, 59% and 87%, respectively, provided either the wrong answer or were uncertain of the type of elastic compression stockings. This finding also suggests that patients did not wear their stockings. We declare no competing interests.
*Nicos Labropoulos, Antonios P Gasparis, Joseph A Caprini, Hugo Partsch Stony Brook Medical Center, Stony Brook, NY 11794, USA (NL, APG); University of Chicago, Pritzker School of Medicine, Chicago, IL, USA (JAC); and Medical University of Vienna, Vienna, Austria (HP)
130
1
2
3
4
5
6
Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet 2014; 383: 880–88. Giannoukas AD, Labropoulos N, Michaels JA. Compression with or without early ambulation in the prevention of post-thrombotic syndrome: a systematic review. Eur J Vasc Endovasc Surg 2006; 32: 217–21. Brandjes DPM, Buller HR, Heijboer H, Hulsman MV, de Rijk M, Jagt H. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349: 759–62. Ten Cate-Hoek AJ, Ten Cate H, Tordoir J, Hamulyák K, Prins MH. Individually tailored duration of elastic compression therapy in relation to incidence of the postthrombotic syndrome. J Vasc Surg 2010; 52: 132–38. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986; 315: 1109–14. Partsch H, Kaulich M, Mayer W. Immediate mobilisation in acute vein thrombosis reduces post-thrombotic syndrome. Int Angiol 2004; 23: 206–12.
Authors’ reply We agree with Jean-Philippe Galanaud and colleagues’ comments about the need to investigate the role of new oral anticoagulants for the prevention of post-thrombotic syndrome. Nicos Labropoulos and colleagues claim that inappropriate endpoints were used in the SOX trial.1 There is no consensus gold standard for diagnosis or longitudinal follow-up of post-thrombotic syndrome. The CEAP classification is not specific for post-thrombotic syndrome and post-thrombotic syndrome-related symptoms and signs do not correlate reliably with vein anatomy or function. We purposely chose endpoints that more accurately reflect patient-important outcomes. Accordingly, based on high inter-rater reliability, validity, and responsiveness, the Villalta post-thrombotic syndrome scale is recommended to diagnose post-thrombotic syndrome, rate its severity,2,3 and has been used in previous similar trials.4 As in previous studies of elastic compression stockings to prevent postthrombotic syndrome,4,5 we reported the cumulative incidence of postthrombotic syndrome during study
follow-up. This is a standard approach for any survival analysis; the numbers at risk account for censoring of patients who developed the outcome, died, or withdrew before 2 years. Regarding timing of elastic compression stockings initiation, patients were randomised a mean of 4·7 days after deep-vein thrombosis diagnosis and study stockings were shipped to patients within 24–48 h of randomisation. Thus, on average, elastic compression stockings use began sooner after deep-vein thrombosis diagnosis in the SOX trial than in two previous trials that reported benefit of stockings to prevent post-thrombotic syndrome.4,5 We p r o v i d e d d e t a i l s o f stockings-related training of research nurses and study patients in the appendix.1 In-person demonstrations and instructions were provided to patients at randomisation and at each study visit, with further reinforcement by phone on days 14 and 60. Labropoulos and colleagues also question our assessment of compliance. To our knowledge, there is no other reasonable way to assess stocking use other than asking the patient. Since our trial required daily use of a device for a 2-year period, we think that compliance was very good, and better than in clinical practice.6 As reported in our paper, a planned per-protocol analysis of frequent stockings users did not show benefit of stockings; neither did a post-hoc analysis restricted to daily stockings users (HR 0·72, p=0·46). Although patients in our study had a first proximal deep-vein thrombosis and thus no previous experience with elastic compression stockings, 41% of patients in the active stocking group versus 17% in the placebo group correctly guessed their treatment assignment. Although more unblinding therefore occurred in the active elastic compression stockings group, we might expect this to exaggerate a favourable response to elastic compression stockings. www.thelancet.com Vol 384 July 12, 2014
