A cost analysis of the treatment of patients with post-thrombotic syndrome in Brazil

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1 Thrombosis Research (2006) 118, intl.elsevierhealth.com/journals/thre REGULAR ARTICLE A cost analysis of the treatment of patients with post-thrombotic syndrome in Brazil Eduardo Ramacciotti a, *, Marise Gomes a, Eduardo Toledo de Aguiar b, Jackson S. Caiafa c, Liberato Karaoglan de Moura d, Gilson R. Araújo e, Ana Truzzi f, Flavia Dietrich-Neto g on behalf of the CLE-PTS Investigators a Hospital e Maternidade Dr Cristóvão da Gama, Santo André, SP, Brazil b Hospital das Clinicas da USP, São Paulo, Brazil c Hospital Naval Marcílio Dias, Rio de Janeiro, Brazil d Hospital São Rafael, Salvado, Brazil e Hospital de Base de Brasília, Brasília, Brazil f sanofi-aventis, São Paulo, Brazil g sanofi-aventis, Bridgewater, NJ, United States Received 25 May 2005; received in revised form 24 November 2005; accepted 8 December 2005 Available online 18 January 2006 KEYWORDS Cost analysis; Deep vein thrombosis; Health economics; Post-thrombotic syndrome; Thromboprophylaxis Abstract Introduction: Post-thrombotic syndrome (PTS) occurs in 15 50% of patients with deep vein thrombosis (DVT), and is associated with substantial medical costs. This prospective observational study investigated the costs associated with the treatment of PTS in Brazil. Materials and methods: A total of 157 patients diagnosed with PTS and with a history of DVT were recruited from nine centers in Brazil. The costs of investigations and treatment for PTS over a 1-year follow-up period were analyzed. Ninety patients were available for this analysis. Results: Of the 90 patients, 17 had mild-to-moderate PTS, and 73 had severe PTS. The patients with severe PTS tended to undergo more investigations and hospitalizations for PTS than those with mild-to-moderate PTS, although the differences between the two groups did not reach statistical significance. The mean annual cost of treating PTS Abbreviations: DVT, deep vein thrombosis; LMWH, low molecular weight heparin; PTS, post-thrombotic syndrome; R$, Brazilian Reais; SD, standard deviation. * Corresponding author. Rua Rui Barbosa 333 apto 91, , Santo André, SP, Brazil. Tel.: ; fax: address: eramacciotti@yahoo.com (E. Ramacciotti) /$ - see front matter D 2005 Elsevier Ltd. All rights reserved. doi: /j.thromres

2 700 E. Ramacciotti et al. in Brazilian Reais was R$1214 (US$426) for mild-to-moderate PTS and R$3386 (US$1188) for severe PTS. The difference was mainly due to significantly higher hospitalization costs in patients with severe PTS (R$704/US$247 vs. R$0; p = 0.044). Conclusion: These results suggest that PTS imposes substantial demands on health care resources in Brazil. The implementation of effective thromboprophylactic strategies could significantly reduce the incidence of DVT, and hence of PTS, potentially resulting in significant cost savings. D 2005 Elsevier Ltd. All rights reserved. Approximately 15 50% of patients with symptomatic deep vein thrombosis (DVT) develop post-thrombotic syndrome (PTS) within 1 2 years [1 3]. The costs associated with treating PTS are about 75% of the economic costs associated with the management of primary DVT [4]. Moreover, 5 10% of patients with DVT develop severe PTS, which is associated with symptoms such as pain, ulceration, and swelling; these symptoms can markedly impair mobility, and in some cases ability to work [5,6],resulting in indirect economic costs due to lost productivity. The costs associated with the diagnosis and treatment of PTS are considerable. One study estimated the average lifetime cost of treatment to be US$4700 [4], while a further study estimated the annual costs of treating severe PTS in patients undergoing hip replacement surgery to be US$3817 during the first year and US$1677 in subsequent years [7]. There is thus a strong case for preventing the development of PTS. PTS can be averted by preventing DVT in high-risk patients and high-risk settings, which is recommended in current guidelines [8]. Prevention of idiopathic DVT or long-term anticoagulant therapy in patients with a first episode of DVT has been shown to reduce the risk of recurrent ipsilateral DVT, which is associated with an increased risk for PTS [1,9]. However, methods for preventing venous thromboembolism are required to be effective, safe and economically feasible, especially in a society with limited resources. The costs of treating avoidable PTS should therefore be an important component in economic evaluations of such therapies. This paper describes an observational study of the economic costs of treating PTS in Brazil. Materials and methods The study was a prospective observational study in patients enrolled in nine centers in Brazil between March 2000 and July The study was approved by the institutional review board and ethics committees at each study center. The cost analysis was conducted from the perspective of the Brazilian health care system. Patients Patients were eligible for inclusion in the study if they were aged 18 years or above, diagnosed with PTS, and had a documented history of DVT, or had been referred with DVT diagnosed elsewhere. DVT had been confirmed objectively by either duplex scan or venography. PTS was classified according to the criteria of Brandjes et al. (Table 1) [2]. All patients consented to provide information regarding their personal expenditure on materials and medications for PTS. Patients were excluded from the study if they had a history of DVT within 6 months prior to the study, or concomitant serious disease during the subsequent 6 months, or if they were likely to be lost to follow-up because of difficulties in traveling to the hospital (Fig. 1). PTS classification and all costs directly relating to the treatment of PTS were entered by the investigators on case report forms. Cost analysis Total medical costs directly relating to the treatment of PTS during a 1-year follow-up period were calculated by adding the costs of visits to clinics, wound dressings (simple or Unna s paste boot), examinations, hospitalizations and medications. Costs in Brazilian Reais (R$) were based on those published by the Brazilian Medical Association [21], and converted to US$ assuming an exchange rate of US$1/R$2.85 (October 2004). Statistical analysis Descriptive statistics (means, standard deviations, and ranges) were applied to continuous variables, while discrete variables were summarized in frequency tables [11]. For discrete variables, differences between groups were compared by chi-square tests, or by Fisher exact tests if at least 25% of cells had expected counts of less than 5 [11], while for continuous variables differences between groups were compared by Student s t-tests. For cost data, non-parametric Mann Whitney U tests were used

3 A cost analysis of the treatment of patients with post-thrombotic syndrome in Brazil 701 Table 1 Scoring system for PTS Subjective criteria Objective criteria Symptom Score Symptom Score Mild-to-moderate Spontaneous pain in calf 1 Calf circumference increased by 1 cm 1 PTS (scorez3) a Spontaneous pain in thigh 1 Ankle circumference increased by 1 cm 1 Pain in calf on standing/walking 1 Pigmentation 1 Pain in thigh on standing/walking 1 Venectasia 1 Edema of foot/calf 1 Newly formed varicosis 1 dheavinesst of leg 1 Phlebitis 1 Severe PTS (scorez4) Spontaneous pain and pain on 1 Calf circumference increased by 1 cm 1 standing/walking Edema of calf 1 Pigmentation, discoloration and venectasia 1 Impairment of daily activities 1 Venous ulcer 4 Reproduced with permission from Elsevier (The Lancet 1997;347: ) [2]. PTS, post-thrombotic syndrome. a Including one objective criterion. due to the high variability observed in these data [11]. A significance level of 5% was assumed for all tests. Results Patient characteristics A total of 157 patients were enrolled in the study, of which 67 were excluded from the analysis because they were lost to follow-up after the first visit to the clinic (Fig. 1). In the overall population, 32 (20.4%) had mild-to-moderate PTS, defined according to the criteria in Table 1, and 125 (79.6%) had severe PTS. Of the 90 patients included in the analysis, 17 (18.8%) had mild-to-moderate PTS and 73 (81.1%) had severe PTS. There were no significant differences in the demographic characteristics of the patients with mild-to-moderate or severe PTS (Table 2). The time since diagnosis of PTS was more than twice as high for patients with severe PTS (9.2 years) compared with those with mild-tomoderate PTS (4.3 years), although the sample size was not powered to show statistical significance (Table 2). Treatment of PTS During follow-up, patients with mild-to-moderate PTS had a mean of 4.9F3.4 consultations (range Figure 1 Study design. DVT, deep vein thrombosis; PTS, post-thrombotic syndrome.

4 702 Table ), whereas those with severe PTS had a mean of 6.1F4.4 (range 2 20); this difference was not statistically significant ( p = 0.332). The mean duration of follow-up was 10 months (range 14 days to 26 months) in patients with mild-to-moderate PTS, and 9.7 months (range 6 days to 27.5 months) for those with severe PTS ( p =0.527). The majority of patients did not use wound dressings. Two patients (11.8%) with mild-to-moderate PTS, and seven (9.6%) with severe PTS used simple dressings, while Unna s paste boots were used by three (17.6%) and 26 (35.6%) patients, respectively. Imaging tests for PTS were more common among patients with mild-to-moderate PTS than among those with severe PTS, whereas hospitalizations were more common for patients with severe PTS (Table 3), but the differences were not statistically significant. The number of days in hospital was higher for patients with severe PTS (Table 3). Cost analysis Costs associated with treating PTS are summarized in Fig. 2. The average annual cost per patient was R$1214 (US$426) for mild-to-moderate PTS, and R$3386 (US$1188) for severe PTS ( p =0.194). This difference was primarily due to significantly higher costs of hospitalization in patients with severe PTS (R$704/US$247 vs. R$0, p = 0.044). Discussion Patient characteristics Mild-to-moderate PTS (n =17) Severe PTS (n =73) Age (years) a 59.8F F16.2 Males/females 7/10 (41%/59%) 41/32 (56%/44%) Previous surgery 11 (64.7%) 52 (71.2%) Chronic disease 12 (70.6%) 51 (69.9%) Family history 1 (6.7%) 7 (9.5%) of DVT Time since PTS diagnosis (years) 4.3F F12.1 PTS, post-thrombotic syndrome. a Data are expressed as meanfsd. The results of this observational study show that the treatment of PTS imposes significant economic costs in Brazil, largely due to the need for hospitalization in patients with the most severe symptoms and greater use of wound dressings in these patients. These findings are consistent with those of other studies, which have shown that the management of PTS is associated with substantial medical costs [4,7]. The use of thromboprophylaxis to prevent DVT in high-risk patients is likely to reduce the risk of developing PTS [10]. Recurrent ipsilateral DVT, which has been shown to increase the risk of PTS by up to six-fold [1,5,12 14], has been identified as a risk factor for PTS. Moreover, even asymptomatic DVT can lead to PTS [15,16]. In patients who have had orthopedic surgery in the previous 2 4 years, PTS developed in 24% of patients with postoperative asymptomatic DVT [15]. Likewise, PTS developed in 27% of patients who were asymptomatic for DVT following hip replacement surgery [16]. A recent systematic review showed that in patients with asymptomatic DVT the overall relative risk of developing PTS was 1.58 (95% confidence interval ; p b ) compared with patients without DVT [17]. Current guidelines [8] recommend the use of low molecular weight heparins (LMWHs), elastic compression stockings, or both for the prevention of DVT in selected groups of patients according to the risk of thromboembolism. Following an episode of DVT, LMWH is recommended for the initial treatment of DVT and elastic compression stockings are recommended for the prevention of PTS [18]. Elastic compression stockings can improve tissue microcirculation and reduce edema by reducing venous hypertension and reflux, and are widely used in patients with DVT [19]. However, the effectiveness of this approach in preventing PTS is unclear: two studies found that the use of elastic stockings reduced the incidence of PTS in patients with established DVT by approximately 50% [2,20], whereas a third found no significant benefit [3]. Further studies into their efficacy in preventing PTS are needed. By contrast, LMWHs have consistently been shown to reduce the Table 3 PTS-related investigations, hospitalizations or surgery Mild-tomoderate PTS (n =17) E. Ramacciotti et al. Severe PTS (n =73) P value n (%) n (%) Imaging tests a 11 (64.7%) 37 (50.7%) b Duplex 10 (58.8%) 26 (35.6%) b ultrasonography Venography 1 (5.9%) 11 (15.1%) c Hospitalization 0 (0.0%) 15 (20.5%) c Mean number of F9.8 hospital days d Surgery 0 (0.0%) 11 (15.1%) c PTS, post-thrombotic syndrome. a Duplex ultrasonography and venography. b Chi-square test. c Fisher exact test. d Data available for 8 of the 15 severe PTS patients that were hospitalized.

5 A cost analysis of the treatment of patients with post-thrombotic syndrome in Brazil 703 p=0.035 Annual cost (R$) Consultations Mild-to-moderate PTS Severe PTS (83) (108) 37 (107) Simple wound dressings 48 (200) 945 (3143) Unna's paste boot 2292 (4369) Hospitalizations p= (0) 704 (1763) (489) (176) Medication/Examinations 1214 (3166) Total cost 3386 (5400) Figure 2 Annual cost of treating PTS per patient. PTS, post-thrombotic syndrome; R$, Brazilian Reais. risk of recurrent DVT in patients at various levels of risk [8], which is likely to reduce the risk of development of PTS [10]. The cost of a course of LMWH prophylaxis compares favorably with the costs for treating PTS as shown in this study. On average, a patient will require a 10-day course of LMWH prophylaxis to prevent DVT, which will cost approximately R$200 in Brazil (10 days at R$15 per dose and R$50 for application costs), whereas the cost of treating PTS in this study ranged from R$1214 to R$3386. This study is subject to certain limitations in that it was an observational study (as reflected in the wide variation in the number of consultations and duration of follow-up), and that 67 of 157 patients were lost to follow-up, thus limiting the statistical power of the study. There was no difference in the ratio of mild-to-moderate PTS versus severe PTS patients in the initial population and the study population, but perhaps severe PTS was easier to diagnose than mild-to-moderate PTS, thereby potentially leading to some selection bias in the inclusion of patients. Alternatively, it is likely that patients with severe PTS are more likely to seek medical attention compared with patients with mild-to-moderate PTS. This is further reflected in the relatively high percentage of patients with severe PTS in this study. Nevertheless, the results of this study suggest that PTS imposes substantial demands on health care resources in Brazil. This demand on health care resources is even more apparent when one takes into account the average life expectancy of the Brazilian population. According to the most recent census of the Brazilian Institute of Geography and Statistics [22], the average life expectancy of Brazilians aged years (the mean age of our patient population) is years, which will result in a substantial economic burden, although it should be noted that patients with PTS do not necessarily have the same life expectancy as the general Brazilian population. The implementation of effective thromboprophylactic strategies could significantly reduce the incidence of DVT, and hence of PTS, potentially resulting in significant cost savings. Acknowledgments This study was funded by an unrestricted educational grant from sanofi-aventis. References [1] Prandoni P, Lensing AW, Cogo A, Villalta S, Carta S, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1 7. [2] Brandjes DP, Bqller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349: [3] Ginsberg JS, Hirsh J, Julian J, Vander LaandeVries M, Magier B, MacKinnon B, et al. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med 2001;161: [4] Bergqvist D, Jendteg S, Johansen L, Persson U, Odegaard K. Cost of long-term complications of deep venous thrombosis

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