CCOHTA. No. 27 Jan 2004

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1 No. 27 Jan 2004 Before CCOHTA decides to undertake a health technology assessment, a pre-assessment of the literature is performed. Pre-assessments are based on a limited literature search; they are not extensive, systematic reviews of the literature. They are provided here as a quick guide to important, current assessment information on this topic. Readers are cautioned that the pre-assessments have not been externally peer reviewed. Introduction Venous insufficiency (VI) is a chronic condition of incompetent venous circulation, in which the veins do not adequately return blood from the lower limbs back to the heart. This condition usually results from deep vein thrombosis (DVT) or from damage to or the congenital absence of venous valves. VI induces the development of new thrombi in the veins. It typically affects the lower extremities and commonly results in pain; edema; changes in skin colour; or chronic and recurrent skin ulcers in the affected leg. According to previous studies, about 3% to 11% of adults have skin changes and edema as a result of chronic VI. 1 In the United States, about 400,000 to 500,000 out of five million people who show evidence of chronic VI have or will develop a venous leg ulcer. 2,3 Severe cases are associated with recurrent hospitalization, medical expenses, disability or fatal pulmonary embolism. Thus, prevention of the re-occurrence of VI is as important as treatment for existing disorders. External pneumatic compression (EPC) therapy is used to reduce venous stasis by compressing the superficial veins and forcing blood into the deep veins, which then return it to the heart. EPC differs from previous compression therapy in that it involves the use of air as a compression medium. EPC devices are sleeve- or boot-shaped chambers that fill with air and electrical pumps with gauges that provide intermittent compression to the lower extremities. EPC therapy is also known as intermittent pneumatic compression (IPC) therapy. It is mainly used in preventing DVT, but it also acts as an adjuvant therapy for skin ulcers and limb edema. The earliest comparative studies to evaluate its clinical effectiveness were conducted in the 1970s. Many studies show a favourable outcome in reducing venous stasis, though there are inconsistent results. Modifications have been made to IPC devices to enhance their functions. With the assistance of an attached heart monitor, the circulator boot, a boot-shaped pneumatic compression device, provides external pressure that simulates diastolic blood pressure. Compression is timed to coincide with end diastole and thus, to contribute to maximal venous emptying while prompting venous blood return to the heart. Research Questions 1. What is the evidence regarding the clinical effectiveness of EPC therapy for chronic VI compared with the standard treatment? 2. What is the optimal pressure for EPC therapy? 3. What are the contraindications and side effects of EPC therapy?

2 Assessment Process A search strategy for PubMed ( Nov 2003), The Cochrane Library (2003 Issue 4), web sites, clinical practice guidelines and clinical trials registries, according to the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) health technology assessment (HTA) checklist, was developed (Appendix 1). Experts/researchers consulted No experts were consulted during the pre-assessment. Summary of Findings 1. Primary studies: since 1976, 25 randomized controlled trials (RCTs) have been conducted to assess the clinical efficacy of EPC therapy for patients with VI. The trials done in the past 10 years are listed in Table 1. Table 1: Summary of findings from primary studies Author, year, Patients Intervention Results Conclusion design Ginzburg E, 2003, RCT patients received thromboprophylaxis after trauma IPC device versus low molecular weight heparin (LMWH) 2.7% developed DVT in IPC group, while 0.5% developed DVT in LMWH group; 4 patients in each group had major bleeding episodes Grieveson S, 2003, RCT 5 27 patients with ankle edema of venous origin Kiudelis M, 2002, RCT 6 54 patients undergoing elective laparoscopic fundoplications Flowpac pump versus elevation of lower limbs Leg bandages (LB), IPC or intermittent electric calf muscle stimulation (IECS) No significant differences observed in reduced edema between two groups Blood velocity in femoral vein was 20.1 cm/s in IPC group, 20.3 cm/s in IECS group and 23.9 cm/s in LB group IPC might be used safely and effectively for thromboprophylaxis in trauma patients Lower pressures with shorter inflation and deflation times more efficient than higher pressures and long inflation and deflation times IPC is more effective than IECS in reducing venous stasis

3 Maxwell GL, 2001, RCT postoperative gynecologic oncology patients Blanchard J, 1999, RCT patients underwent total knee Tamir L, 1999, RCT 9 Wautrecht, 1996, RCT 10 Westrich GH, 1996, RCT 48 patients after total knee 23 patients underwent brain tumour surgery 122 patients after total knee LMWH versus EPC LMWH versus IPC of foot EPC plus LMWH versus LMWH alone Graded compression stockings (GCS) versus GCS plus IPC Aspirin versus Aspirin plus pneumatic plantarcompression device 2 patients in LMWH group and 1 patient in EPC group diagnosed with DVT; frequency of bleeding complications similar between two groups 26.7% of patients in LMWH group and 64.6% of patients in IPC group developed DVT; 1 patient in LMWH group had severe bleeding Lower limb swelling and pain significantly reduced for EPC group in relation to LMWH group 40% of patients in GCS group and 0% in GCS plus IPC group developed DVT 59% of patients in Aspirin group and 27% of patients in EPC group developed DVT; patients with compression device had less edema than those who used Aspirin alone LMWH and EPC are similarly effective in postoperative prophylaxis of thromboembolism; both modalities are reasonable choices for prophylaxis in this patient population LMWH is superior to IPC of foot for thromboprophylaxis after total knee EPC therapy is important prophylactic addition to antithrombotic treatment in overcoming hazardous clinical implications of venous stasis GCS combined with IPC more effective than GCS alone in preventing postoperative DVT in this patient population Study confirmed safety and efficacy of EPC plus Aspirin compared with Aspirin alone and supports use of mechanical compression for prophylaxis against DVT and for reduction of edema in study population

4 Goldhaber SZ, 1995, RCT patients after coronary artery bypass surgery Lieberman JR, 231 patients 1994, RCT 12 after total hip arthroplasties with use of hypotensive epidural anesthesia McCulloch JM, 1994, RCT patients with chronic venous ulcers Bradley JG, 1993, RCT patients after total hip GCS plus IPC versus GCS EPC plus Aspirin versus Aspirin IPC plus Unna s boot plus local wound care versus Unna s boot plus local wound care IPC plus standard therapy versus standard therapy DVT was diagnosed in 19% of patients in IPC plus GCS group and in 22% of patients in GCS group, but difference was not significant 6% of patients in EPC plus Aspirin group had DVT, while 8% of patients in Aspirin group had DVT; difference was not significant Healing rate: 0.15 cm 2 /day in IPC group, compared with 0.08 cm 2 /day in control group; difference was significant Incidence of DVT was 6.6% in pumped group and 27.27% in nonpumped group; result was significant Addition of IPC did not add significant incremental benefit to GCS alone for DVT prophylaxis in study population Combination of hypotensive epidural anesthesia and Aspirin is effective prophylaxis against DVT in study population IPC is beneficial in management of VI ulcers Chemical prophylaxis plus IPC reduce incidence of thromboembolic complications further than chemical prophylaxis alone

5 2. Systematic reviews and meta-analysis: five systematic reviews regarding the efficacy of EPC therapy were identified. Table 2: Summary of findings from systematic reviews Author, year Study design Results Authors conclusions (country) Berliner E, 2003 (US) 15 Systematic review on 91 articles, 7 of which contained relevant clinical trials; medical interventions were pneumatic compression therapy versus compression stockings, bandages, or Unna s boot; included articles were searched before March 8, 2001 Results from follow-up studies indicated improvements of signs and symptoms of venous edema; results from RCTs showed that symptoms improved in treatment group compared to control group, but in some trials, difference was not significant Several studies showed significant improvement with use of pneumatic compression devices on chronic leg ulcers that had not healed after use of other methods; long-term use of pneumatic compression devices at home may be alternative to other compression therapies on chronic VI and leg ulcers Mani R, 2003 (UK) 16 Cochrane review on effect of IPC on venous leg ulcer healing and quality of life, included RCTs searched until end of January 2001 One trial found increased ulcer healing with IPC plus compression than with compression alone; two trials found no evidence of benefit for IPC plus compression compared with compression alone; Further trials required to determine whether IPC increases healing of venous leg ulcers Freedman KB, Meta-analysis of 2000 (US) 17 efficacy and safety of agents used for thromboembolic prophylaxis in patients undergoing total hip ; 52 RCTs from January 1996 to May 1998 included one trial found no difference between IPC and compression bandages alone Risk of DVT was 20.7% for EPC, while it was 48.5% for placebo; compared with placebo (1.51%), EPC was associated with significantly lower risk of pulmonary embolism (0.26%) Best prophylactic agent in terms of efficacy and safety was warfarin, followed by pneumatic compression

6 Westrich GH, Meta-analysis to 2000 (US) 18 assess efficacy of 4 regimes for thromboembolic prophylaxis after total knee ; 23 RCTs done between January 1980 and December 1997 included Palfreyman SJ, 1998 (UK) 19 Systematic review on compression therapy of venous leg ulcers; among 8 trials identified, 2 RCTs compared pneumatic compression with compression stockings or Unna s boot Incidence of DVT (17%) and asymptomatic pulmonary embolism (6.3%) were lower in EPC group than in other groups More patients healed in treatment arm of study with pneumatic compression, pool odds ratios for total number of ulcers healed : 8.45, 95% CI (0.627, ). EPC had lowest incidence of thromboembolism and is acceptable for prophylaxis in total knee No benefit found for IPC therapy when results from trials were pooled; probably due to small sample size of 2 RCTs, and heterogeneity between them EPC reduces the risk of DVT for patients who cannot walk due to trauma, joint surgery or neurosurgery. There is still limited evidence, however, supporting the effect of EPC on the healing of venous ulcers and other disorders resulting from chronic VI. Conclusion There is a large potential patient population who could use this treatment. Although several systematic reviews were identified in the preliminary literature search, the most recent RCTs found in these reviews were done in Since then, more RCTs and other studies have been performed to evaluate the safety and efficacy of EPC devices. An evidencebased assessment would be timely. References 1. Nicolaides AN. Investigation of chronic venous insufficiency: a consensus statement. Circulation 2000;102(20):E Available: (accessed 2003 Nov 26). 2. Dalen JE, Paraskos JA, Ockene IS, Alpert JS, Hirsh J. Venous thromboembolism. Scope of the problem. Chest 1986;89(5 Suppl):370S-3S. 3. Coon WW, Willis PW, Keller JB. Venous thromboembolism and other venous disease in the Tecumseh community health study. Circulation 1973;48(4): Ginzburg E, Cohn SM, Lopez J, Jackowski J, Brown M, Hameed SM. Randomized clinical trial of intermittent pneumatic compression and low molecular weight heparin in trauma. Br J Surg 2003;90(11): Grieveson S. Intermittent pneumatic compression pump settings for the optimum reduction of oedema. J Tissue Viability 2003;13(3):98-100, 102, 104.

7 6. Kiudelis M, Endzinas Z, Mickevicius A, Pundzius J. Venous stasis and deep vein thrombosis prophylaxis during laparoscopic fundoplication [in German]. Zentralbl Chir 2002;127(11): Maxwell GL, Synan I, Dodge R, Carroll B, Clarke-Pearson DL. Pneumatic compression versus low molecular weight heparin in gynecologic oncology surgery: a randomized trial. Obstet Gynecol 2001;98(6): Blanchard J, Meuwly JY, Leyvraz PF, Miron MJ, Bounameaux H, Hoffmeyer P, et al. Prevention of deepvein thrombosis after total knee replacement. Randomised comparison between a low-molecular-weight heparin (nadroparin) and mechanical prophylaxis with a foot-pump system. J Bone Joint Surg Br 1999;81(4): Tamir L, Hendel D, Neyman C, Eshkenazi AU, Ben Zvi Y, Zomer R. Sequential foot compression reduces lower limb swelling and pain after total knee. J Arthroplasty 1999;14(3): Wautrecht JC, Macquaire V, Vandesteene A, Daoud N, Golzarian J, Capel P, et al. Prevention of deep vein thrombosis in neurosurgical patients with brain tumors: a controlled, randomized study comparing graded compression stockings alone and with intermittent sequential compression. Correlation with preand postoperative fibrinolysis. Preliminary results. Int Angiol 1996;15(3 Suppl 1): Goldhaber SZ, Hirsch DR, MacDougall RC, Polak JF, Creager MA, Cohn LH. Prevention of venous thrombosis after coronary artery bypass surgery (a randomized trial comparing two mechanical prophylaxis strategies). Am J Cardiol 1995;76(14): Lieberman JR, Huo MM, Hanway J, Salvati EA, Sculco TP, Sharrock NE. The prevalence of deep venous thrombosis after total hip with hypotensive epidural anesthesia. J Bone Joint Surg Am 1994;76(3): McCulloch JM, Marler KC, Neal MB, Phifer TJ. Intermittent pneumatic compression improves venous ulcer healing. Adv Wound Care 1994;7(4):22-4, Bradley JG, Krugener GH, Jager HJ. The effectiveness of intermittent plantar venous compression in prevention of deep venous thrombosis after total hip. J Arthroplasty 1993;8(1): Berliner E, Ozbilgin B, Zarin DA. A systematic review of pneumatic compression for treatment of chronic venous insufficiency and venous ulcers. J Vasc Surg 2003;37(3): Mani R, Vowden K, Nelson EA. Intermittent pneumatic compression for treating venous leg ulcers [Cochrane Review]. In: The Cochrane Library, Issue 4. Oxford: Update Software; Freedman KB, Brookenthal KR, Fitzgerald RH, Williams S, Lonner JH. A meta-analysis of thromboembolic prophylaxis following elective total hip. J Bone Joint Surg Am 2000;82- A(7): Westrich GH, Haas SB, Mosca P, Peterson M. Meta-analysis of thromboembolic prophylaxis after total knee. J Bone Joint Surg Br 2000;82(6): Palfreyman SJ, Lochiel R, Michaels JA. A systematic review of compression therapy for venous leg ulcers. Vasc Med 1998;3(4):

8 Pre-assessment Search Appendix 1 Databases Limits Hits Keywords MEDLINE (Pubmed) to 11 Nov 2003 Human circulator boot*[all fields] OR enddiastolic pneumatic compression boot*[all fields] OR Pneumatic Boot*[all fields] OR Pneumatic compression[all fields] AND 2. Venous [MeSH] OR venous insufficienc*[title/abstract] OR Venous Thrombosis[MeSH] OR deep venous thrombosis[title/abstract] OR DVT[title/abstract] OR Varicose Veins[MeSH] OR varicose vein[title/abstract] OR varicose veins[title/abstract] OR Dermatitis[MeSH] OR Stasis dermatitis[title/abstract] OR Leg Ulcer[MeSH] OR leg ulcer[title/abstract] OR leg ulcers[title/abstract] OR foot ulcer[title/abstract] OR foot ulcers[title/abstract] OR venous ulcer[title/abstract] OR venous Cochrane Library 2003 Issue 4 ulcers[title/abstract] ((circulator next boot*) or (end-diastolic next pneumatic next compression next boot*) or (pneumatic next boot*) or (pneumatic next compression)) AND 2. ((venous next insufficienc*) or (deep next venous next thrombosis) or dvt or (varicose next vein) or (varicose next veins) or (stasis next dermatitis) or (leg next ulcer) or (leg next ulcers) or (foot next ulcer) or (foot next ulcers) or (venous next ulcer) or (venous next ulcers)) OR VENOUS INSUFFICIENCY explode tree 1 (MeSH) OR VENOUS THROMBOSIS explode tree 1 (MeSH) OR VARICOSE VEINS explode tree 1 (MeSH) OR DERMATITIS explode tree 1 (MeSH) OR LEG ULCER explode tree 1 (MeSH)

9 Search of HTA, near- HTA websites for published, in-progress, planned reports. Search of trial registers. As per CCOHTA HTA Checklist