- Email: [email protected]
Catheter-directed thrombolysis for acute deep vein thrombosis – Authors' reply
Correspondence
the incidence of post-thrombotic syndrome in Enden and colleagues’ study, we calculate an expected absolute risk reduction in CDT patients of 4%, owing to better compliance with compression stocking use. Furthermore, more CDT patients than non-CDT patients had goodquality anticoagulant treatment at both follow-up points. Oral anticoagulant treatment that achieves an international normalised ratio within the therapeutic range reduces the risk of post-thrombotic syndrome by 63% compared with patients who spend more than 50% of time beneath the therapeutic range.4 Unfortunately, time in therapeutic range was not reported in Enden and colleagues’ trial and was not accounted for in examining the effect of CDT on postthrombotic syndrome. The CDT strategy, with its more intense treatment and hospital admission, does seem to improve outcome. However, this might not be the effect of additional thrombolysis. Instead, it could be due to more intense initial patient support, which results in more awareness of the relevance of treatment compliance. We feel that taking treatment compliance into account is important before coming to conclusions about the effect of thrombolysis on post-thrombotic syndrome and before exposing patients to costly and invasive procedures. We declare that we have no conflicts of interest.
Inge M van Schouwenburg, Hilde A M Kooistra, Nic J G M Veeger, *Karina Meijer [email protected] Division of Hemostasis and Thrombosis, Department of Hematology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands (IMvS, HAMK, NJGMV, KM); and Trial Coordination Center, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands (NJGMV) 1
1786
Enden T, Haig Y, KlØw NE, et al, on behalf of the CaVenT Study Group. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012; 379: 31–38.
2
3
4
Brandjes DP, Buller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349: 759–62. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004; 141: 249–56. van Dongen CJ, Prandoni P, Frulla M, Marchiori A, Prins MH, Hutten BA. Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome. J Thromb Haemost 2005; 3: 939–42.
Tone Enden and colleagues, in their CaVenT trial,1 explore the interesting hypothesis of catheter-directed thrombolysis (CDT) in the prevention of post-thrombotic syndrome. We have several comments. In the Introduction section, reference to the updated Cochrane review2 as suggesting a benefit of systemic thrombolysis in prevention of post-thrombotic syndrome comes with the caveat that the only study with a Jadad score of greater than 3 showed no benefit.3 The CaVenT trial was done in four specialised centres, and hence the outcomes might be very different elsewhere. Additionally there might have been a learning curve for optimum results with CDT; hence it would be interesting to have a comparison of those who entered the trial earlier versus those who entered later. Enden and colleagues do not present the bleeding rates (if any) for the control group, and hence a number needed to harm is not available. Also, the rate of stent placement and its association with outcomes would have been interesting, especially in view of scant evidence available on the topic.4 The limitations of the open-label design might have manifested with an obvious greater adherence to oral anticoagulation in the CDT group at 6 months. Finally, Enden and colleagues imply a cost effectiveness with CDT, citing the cost associated with post-thrombotic syndrome;5 however, it would be interesting to assess the expense associated with CDT and
other indirect costs associated with the longer hospital stay necessary. We declare that we have no conflicts of interest.
*Saurav Chatterjee, Abhishek Sharma [email protected] Maimonides Medical Center, Brooklyn, NY 11220, USA 1
2
3
4
5
Enden T, Haig Y, Kløw NE, et al, on behalf of the CaVenT Study Group. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012; 379: 31–38. Watson LI, Armon MP. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev 2004; 4: CD002783. Arnesen H, Hoiseth A, Ly B. Streptokinase or heparin in the treatment of deep vein thrombosis: follow-up results of a prospective study. Acta Medica Scand 1982; 211: 65–68. Vedantham S. Endovascular procedures in the management of DVT. Hematology Am Soc Hematol Educ Program 2011; 2011: 156–61. Bergqvist D, Jendteg S, Johansen L, Persson U, Odegaard K. Cost of long-term complications of deep venous thrombosis of the lower extremities: an analysis of a defined patient population in Sweden. Ann Intern Med 1997; 126: 454–57.
Authors’ reply Both sets of correspondents raise an issue about whether the noted absolute reduction in post-thrombotic syndrome of 14·4% in patients treated with additional catheter-directed thrombolysis (CDT) could be attributed to the thrombolytic treatment alone, since a higher proportion of these patients reported daily wear of elastic compression stockings and had international normalised ratios within the therapeutic range. We agree that the non-significant tendency to better compliance could be attributable to the inherent risk of bias of this open-label randomised controlled trial, and relevance to the noted effect size cannot be ruled out. However, we think the effect on postthrombotic syndrome cannot be simplified as suggested by Inge van Schouwenburg and colleagues. First, the two landmark studies on the use of elastic compression stockings1,2 reported on patients with any level of proximal deep vein thrombosis (DVT) from the popliteal vein and up, whereas our patients had a high proximal www.thelancet.com Vol 379 May 12, 2012
Correspondence
www.thelancet.com Vol 379 May 12, 2012
estimate of the complication rates including numbers needed to harm. Details of the technical aspects of the CDT procedures including adjunctive balloon angioplasty and stent insertion will be presented in a subsequent paper and were not included in this report, which focused on the clinically relevant outcomes. Finally, we are currently doing an economic evaluation of CDT. We declare that we have no conflicts of interest.
Tone Enden, Nils-Einar Kløw, *Per Morten Sandset [email protected] Departments of Haematology and Radiology, Oslo University Hospital, Oslo, Norway (TE); Department of Radiology, Oslo University Hospital, Oslo, Norway (N-EK); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (N-EK, PMS); Department of Haematology, Oslo University Hospital, Oslo, Norway (PMS); and Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Box 4950 Nydalen, 0424 Oslo, Norway (PMS) 1
2
3
4
5
Brandjes DP, Buller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349: 759–62. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004; 141: 249–56. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149: 698–707. van Dongen CJ, Prandoni P, Frulla M, Marchiori A, Prins MH, Hutten BA. Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome. J Thromb Haemost 2005; 3: 939–42. Kahn SR, Kearon C, Julian JA, et al. Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis. J Thromb Haemost 2005; 3: 718–23.
First, once prophylaxis was discontinued at 6 months, transmission risk returned to the same as without prophylaxis. This finding implies that infant prophylaxis needs to be extended for a further 6 months, as per the WHO recommendation to breastfeed for 12 months.2,3 Second, prophylaxis was not efficacious in preventing infection in exposed infants whose mothers had low CD4 cell counts but were not receiving antiretroviral therapy (ART). This finding indicates the importance not only of prompt initiation of ART for eligible mothers, but also the ensuring of close CD4 monitoring for those with initial high CD4 counts. These issues pose new questions. What is the efficacy and safety of the infant nevirapine regimen over 12 months? Will health workers and caregivers be able to give correct doses of nevirapine to infants for a long period of time, with dose adjustment according to infants’ age? To what extent can we provide regular CD4 assessments to mothers and start ART promptly? These questions need to be answered, especially in the context of a resource-limited setting. Translation of scientific evidence into an effective field operation is not always straightforward. With these unanswered questions remaining, careful consideration and close observation is required for the field implementation of extended prophylaxis for infants. We declare that we have no conflicts of interest.
Nevirapine prophylaxis during breastfeeding
*Naoko Ishikawa, Shinsuke Miyano, Izukanzi Sikazwe
The HPTN 046 trial (Jan 21, p 221)1 provides further evidence of the efficacy and safety of infant nevirapine prophylaxis during 6 months of exclusive breastfeeding, especially for infants born to women with CD4 cell counts of 350 cells/μL or more. However, it also reveals two important aspects that require further attention.
Bureau of International Medical Cooperation, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, Japan (NI, SM); and Zambia Ministry of Health, University of Maryland, Institute of Human Virology, Lusaka, Zambia (IS)
[email protected]
1
Abbie Trayler-Smith/Panos
DVT from mid-thigh level and up. Hence our patients are likely to have had a higher risk of post-thrombotic syndrome,3 which is reflected in the relatively high frequency of this event noted in CaVenT. Hence, the effect size in the studies of elastic compression stockings does not necessarily apply to our study. Additional issues to consider when inferring from these studies are their open design (both) and the non-validated definition of postthrombotic syndrome in one.1 Second, although an association between anticoagulation quality and post-thrombotic syndrome was shown in one study,4 no association was found in a similar one.5 In both studies, anticoagulation was given for 3 months initially and the effect on post-thrombotic syndrome might be mediated through an increased rate of recurrent venous thrombosis due to suboptimum anticoagulation therapy. We agree that time in the therapeutic range would have been a better indicator of anticoagulation quality. Finally, both elastic compression stockings and CDT are treatments that are unlikely to be well assessed in a double-blind trial design. In response to Saurav Chatterjee and Abhishek Sharma, it is our opinion that one regional centre doing the procedures might have done better overall than the others. By tradition in Norway, CDT is done by interventional vascular radiologists, although currently there is no formal training for subspecialties within radiology. CDT was established at all four interventional centres for several years before the CaVenT study, and we did not look into team or individual performance, but agree that there is a learning curve for interventions in general and that possible differences could have been assessed as a substudy. Safety was a secondary outcome, but no bleeding complications were noted in the control group in the acute phase. The sample size would need to be larger to obtain a robust
Coovadia HM, Brown ER, Fowler MG, et al. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 379: 221–28.
1787
the incidence of post-thrombotic syndrome in Enden and colleagues’ study, we calculate an expected absolute risk reduction in CDT patients of 4%, owing to better compliance with compression stocking use. Furthermore, more CDT patients than non-CDT patients had goodquality anticoagulant treatment at both follow-up points. Oral anticoagulant treatment that achieves an international normalised ratio within the therapeutic range reduces the risk of post-thrombotic syndrome by 63% compared with patients who spend more than 50% of time beneath the therapeutic range.4 Unfortunately, time in therapeutic range was not reported in Enden and colleagues’ trial and was not accounted for in examining the effect of CDT on postthrombotic syndrome. The CDT strategy, with its more intense treatment and hospital admission, does seem to improve outcome. However, this might not be the effect of additional thrombolysis. Instead, it could be due to more intense initial patient support, which results in more awareness of the relevance of treatment compliance. We feel that taking treatment compliance into account is important before coming to conclusions about the effect of thrombolysis on post-thrombotic syndrome and before exposing patients to costly and invasive procedures. We declare that we have no conflicts of interest.
Inge M van Schouwenburg, Hilde A M Kooistra, Nic J G M Veeger, *Karina Meijer [email protected] Division of Hemostasis and Thrombosis, Department of Hematology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands (IMvS, HAMK, NJGMV, KM); and Trial Coordination Center, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands (NJGMV) 1
1786
Enden T, Haig Y, KlØw NE, et al, on behalf of the CaVenT Study Group. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012; 379: 31–38.
2
3
4
Brandjes DP, Buller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349: 759–62. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004; 141: 249–56. van Dongen CJ, Prandoni P, Frulla M, Marchiori A, Prins MH, Hutten BA. Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome. J Thromb Haemost 2005; 3: 939–42.
Tone Enden and colleagues, in their CaVenT trial,1 explore the interesting hypothesis of catheter-directed thrombolysis (CDT) in the prevention of post-thrombotic syndrome. We have several comments. In the Introduction section, reference to the updated Cochrane review2 as suggesting a benefit of systemic thrombolysis in prevention of post-thrombotic syndrome comes with the caveat that the only study with a Jadad score of greater than 3 showed no benefit.3 The CaVenT trial was done in four specialised centres, and hence the outcomes might be very different elsewhere. Additionally there might have been a learning curve for optimum results with CDT; hence it would be interesting to have a comparison of those who entered the trial earlier versus those who entered later. Enden and colleagues do not present the bleeding rates (if any) for the control group, and hence a number needed to harm is not available. Also, the rate of stent placement and its association with outcomes would have been interesting, especially in view of scant evidence available on the topic.4 The limitations of the open-label design might have manifested with an obvious greater adherence to oral anticoagulation in the CDT group at 6 months. Finally, Enden and colleagues imply a cost effectiveness with CDT, citing the cost associated with post-thrombotic syndrome;5 however, it would be interesting to assess the expense associated with CDT and
other indirect costs associated with the longer hospital stay necessary. We declare that we have no conflicts of interest.
*Saurav Chatterjee, Abhishek Sharma [email protected] Maimonides Medical Center, Brooklyn, NY 11220, USA 1
2
3
4
5
Enden T, Haig Y, Kløw NE, et al, on behalf of the CaVenT Study Group. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012; 379: 31–38. Watson LI, Armon MP. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev 2004; 4: CD002783. Arnesen H, Hoiseth A, Ly B. Streptokinase or heparin in the treatment of deep vein thrombosis: follow-up results of a prospective study. Acta Medica Scand 1982; 211: 65–68. Vedantham S. Endovascular procedures in the management of DVT. Hematology Am Soc Hematol Educ Program 2011; 2011: 156–61. Bergqvist D, Jendteg S, Johansen L, Persson U, Odegaard K. Cost of long-term complications of deep venous thrombosis of the lower extremities: an analysis of a defined patient population in Sweden. Ann Intern Med 1997; 126: 454–57.
Authors’ reply Both sets of correspondents raise an issue about whether the noted absolute reduction in post-thrombotic syndrome of 14·4% in patients treated with additional catheter-directed thrombolysis (CDT) could be attributed to the thrombolytic treatment alone, since a higher proportion of these patients reported daily wear of elastic compression stockings and had international normalised ratios within the therapeutic range. We agree that the non-significant tendency to better compliance could be attributable to the inherent risk of bias of this open-label randomised controlled trial, and relevance to the noted effect size cannot be ruled out. However, we think the effect on postthrombotic syndrome cannot be simplified as suggested by Inge van Schouwenburg and colleagues. First, the two landmark studies on the use of elastic compression stockings1,2 reported on patients with any level of proximal deep vein thrombosis (DVT) from the popliteal vein and up, whereas our patients had a high proximal www.thelancet.com Vol 379 May 12, 2012
Correspondence
www.thelancet.com Vol 379 May 12, 2012
estimate of the complication rates including numbers needed to harm. Details of the technical aspects of the CDT procedures including adjunctive balloon angioplasty and stent insertion will be presented in a subsequent paper and were not included in this report, which focused on the clinically relevant outcomes. Finally, we are currently doing an economic evaluation of CDT. We declare that we have no conflicts of interest.
Tone Enden, Nils-Einar Kløw, *Per Morten Sandset [email protected] Departments of Haematology and Radiology, Oslo University Hospital, Oslo, Norway (TE); Department of Radiology, Oslo University Hospital, Oslo, Norway (N-EK); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (N-EK, PMS); Department of Haematology, Oslo University Hospital, Oslo, Norway (PMS); and Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Box 4950 Nydalen, 0424 Oslo, Norway (PMS) 1
2
3
4
5
Brandjes DP, Buller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349: 759–62. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004; 141: 249–56. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149: 698–707. van Dongen CJ, Prandoni P, Frulla M, Marchiori A, Prins MH, Hutten BA. Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome. J Thromb Haemost 2005; 3: 939–42. Kahn SR, Kearon C, Julian JA, et al. Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis. J Thromb Haemost 2005; 3: 718–23.
First, once prophylaxis was discontinued at 6 months, transmission risk returned to the same as without prophylaxis. This finding implies that infant prophylaxis needs to be extended for a further 6 months, as per the WHO recommendation to breastfeed for 12 months.2,3 Second, prophylaxis was not efficacious in preventing infection in exposed infants whose mothers had low CD4 cell counts but were not receiving antiretroviral therapy (ART). This finding indicates the importance not only of prompt initiation of ART for eligible mothers, but also the ensuring of close CD4 monitoring for those with initial high CD4 counts. These issues pose new questions. What is the efficacy and safety of the infant nevirapine regimen over 12 months? Will health workers and caregivers be able to give correct doses of nevirapine to infants for a long period of time, with dose adjustment according to infants’ age? To what extent can we provide regular CD4 assessments to mothers and start ART promptly? These questions need to be answered, especially in the context of a resource-limited setting. Translation of scientific evidence into an effective field operation is not always straightforward. With these unanswered questions remaining, careful consideration and close observation is required for the field implementation of extended prophylaxis for infants. We declare that we have no conflicts of interest.
Nevirapine prophylaxis during breastfeeding
*Naoko Ishikawa, Shinsuke Miyano, Izukanzi Sikazwe
The HPTN 046 trial (Jan 21, p 221)1 provides further evidence of the efficacy and safety of infant nevirapine prophylaxis during 6 months of exclusive breastfeeding, especially for infants born to women with CD4 cell counts of 350 cells/μL or more. However, it also reveals two important aspects that require further attention.
Bureau of International Medical Cooperation, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, Japan (NI, SM); and Zambia Ministry of Health, University of Maryland, Institute of Human Virology, Lusaka, Zambia (IS)
[email protected]
1
Abbie Trayler-Smith/Panos
DVT from mid-thigh level and up. Hence our patients are likely to have had a higher risk of post-thrombotic syndrome,3 which is reflected in the relatively high frequency of this event noted in CaVenT. Hence, the effect size in the studies of elastic compression stockings does not necessarily apply to our study. Additional issues to consider when inferring from these studies are their open design (both) and the non-validated definition of postthrombotic syndrome in one.1 Second, although an association between anticoagulation quality and post-thrombotic syndrome was shown in one study,4 no association was found in a similar one.5 In both studies, anticoagulation was given for 3 months initially and the effect on post-thrombotic syndrome might be mediated through an increased rate of recurrent venous thrombosis due to suboptimum anticoagulation therapy. We agree that time in the therapeutic range would have been a better indicator of anticoagulation quality. Finally, both elastic compression stockings and CDT are treatments that are unlikely to be well assessed in a double-blind trial design. In response to Saurav Chatterjee and Abhishek Sharma, it is our opinion that one regional centre doing the procedures might have done better overall than the others. By tradition in Norway, CDT is done by interventional vascular radiologists, although currently there is no formal training for subspecialties within radiology. CDT was established at all four interventional centres for several years before the CaVenT study, and we did not look into team or individual performance, but agree that there is a learning curve for interventions in general and that possible differences could have been assessed as a substudy. Safety was a secondary outcome, but no bleeding complications were noted in the control group in the acute phase. The sample size would need to be larger to obtain a robust
Coovadia HM, Brown ER, Fowler MG, et al. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 379: 221–28.
1787