Il ruolo del trombo venoso residuo

Transcription

1 Il ruolo del trombo venoso residuo Alessandra Malato, MD, PhD Ca5edra ed U.O. di Ematologia con trapianto Policlinico Universitario di Palermo

2 Topics Residual vein thrombosis (RVT) as a marker for assessing the individual risk of recurrence RVT to establish duration of anticoagulation after an episode of DVT Controversies of current systematic reviews on RVT New horizons for RVT

3 Residual Vein Thrombosis Residual Venous Thrombosis (RVT): vein clot persistence over?me (> 50% of the vein lumen) Detected by venous ultra sonography (C US) in one or more segments of the lower limbs Shown to be an independent risk factor for VTE recurrence (idiopathic or provoked) RVT indica?ves for an con?nuous, underlying hypercoagulable state since recurrences may occur in the controlateral leg or other sites (but correla?ons with thrombophilia has not been proven so far) *Siragusa S et al. Thromb Haemost 1993;69:1435 Piovella F et al. Haematologica 2002;87(5): Prandoni P et al. Ann Intern Med 2002;137:955

4 Detec<on of Residual Vein Thrombosis (RVT)* κ (95% CI ) RVT + RVT Before Vein Compression Clot Clot During Compression Clot Clot *Siragusa S et al. Blood 2008; 112: Thrombus occupying > 40% of the vein diameter Thrombus occupying < 40% of the vein diameter

5 Topics Residual vein thrombosis (RVT) as a marker for assessing the individual risk of recurrence RVT to establish duration of anticoagulation after an episode of DVT Controversies of current systematic reviews on RVT New horizons for RVT

6 Study Publcation Study design Patient enrollement Outcome assessment Duration of followup Cosmi 2010 Full article Post hoc RCT Multi centre Prospective consecutive Blinded cental adjudication committee 1.8 Prandoni 2009 Full article Multi centre RCT Prospective consecutive Blinded indipendent adjudication committee 2.75 Siragusa 2008 Full article Multi centre RCT Prospective consecutive Blinded cental adjudication committee 2.0 Cosmi 2005 Full article Single centre cohort study Rodger 2008 Piovella 2002 Full article Full article Multi centre Cohort stdy Cohort study Prospective consecutive Prospective consecutive Prospective consecutive Blinded repeating CUS Indipendently adjudicated by blinded physicians nr 1.0

7 Residual vein obstruction as a predictor for recurrent thromboembolic events after a first unprovoked episode:data from the REVERSE cohort study Gregoire LE GAL et al Journal Thrombosis and Haemostasis march 2011

8 Study design

9 Cumula<ve incidence of recurrent VTE according to baseline CUS results Nessuna correlazione tra CUS e recidiva, tu[avia CUS eseguita dopo TAO prolungata

10 Topics Residual vein thrombosis (RVT) as a marker for assessing the individual risk of recurrence RVT to establish duration of anticoagulation after an episode of DVT Controversies of current systematic reviews on RVT New horizons for RVT

11 Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study Sergio Siragusa, Alessandra Malato, Raffaela Anastasio, Valeria Cigna,Glauco Milio,Corrado Amato, Mario Bellisi,Maria Teresa Attanzio, Oreste Cormaci,Massimo Pellegrino, Alberto Dolce,Alessandra Casuccio,Guido Bajardi and Guglielmo Mariani BLOOD 2008;112:511-15

12 Pre-study Study period Group A1 Index DVT 3 mo. C-US RVT yes no R Legend: RVT (residual vein thrombosis) C-US (compression ultrasonography) Group A2 Group B 12 mo. 24 mo. OAT No therapy A1 indicates patients with RVT who continued OAT for 12 months (in total); A2 indicates patients with RVT randomized to stop OAT after 3 months; B indicates patients without RVT who stopped OAT after 3 months.

13 Recurrent VTE accordingly to RVT status (n. 92) (n. 78) (n. 88) Outcomes, person-year % Group A1 Group A2 Group B Recurrent VTE 10.1% 15.2% 0.63% Major bleeding 1.1% 0.53% 0 NCT

14 Conclusions of Dacus Study The DACUS Study have shown that: Presence of RVT requires at least 1 year of OA Absence of RVT, instead, identifies patients at low risk for recurrent trombotic events that may withhold OA after 3 months after the index DVT However, the safety of such approach needs further confirmation

15 Extended Dacus: Ra<onale and Objec<ve of the study Ra<onale: To evaluate the advantage of a RVT based management a^er DVT of the lower limbs in pa?ents with idiopathic DVT Objec<ve: Prospec?ve study to evaluate the efficacy and safety of withholding VKA in pa?ents with idiopathic DVT and without RVT, 3 months a^er the index thrombo?c episode while con?nuing an?coagula?on for 15 to 21 months in those with RVT (according to physician s/pa?ent s preferences)

16 Study Design 0 m. 3 mo. 18 mo. 24 mo. 36 mo. Index DVT Yes RVT Pos. Group RVT* Baseline C US 3 mo. C US No RVT Neg. Group VKA Stop VKA /Follow up *Siragusa S et al. Blood 2008; 112: 511 5

17 Pa<ents and Methods (I) Inclusion criteria: Pa?ents with a first episode of idiopathic proximal DVT were eligible a^er 3 months VKA treatment (target Interna?onal Normalised Ra?o [INR] 2.5, range ). Idiopathic DVT was defined as an episode occurring in apparently healthy individuals without evident risk factors, such as surgery, trauma, immobiliza?on or previous acute medical illness

18 Pa<ents and Methods (II) Exclusion criteria: Ac?ve cancer Limited life expectancy An?phospholipid an?body syndrome Known thrombophilic states (deficiencies of An?thrombin, Protein C and S, homozygosity for the FV Leiden or F II G20210A muta?ons or combined heterozygosity for the same) Severe liver disease and/or renal failure Those who lived too far from the recrui?ng center

19 Results Of the 603 VTE pa?ents diagnosed as of October 2006, 15 were excluded because did not agree to par?cipate in the study and 38 because of the presence of an exclusion criterion. Two pa?ents were lost to follow up. A total of 548 pa?ents were included in the study. RVT was absent in 164/548 pa?ents (29.9%); present in the remaining 384 (70.1%). Among the la[er cohort, excluding those who had recurrent events during treatment (27), 207 individuals received 18 months and 150 received 24 months of VKA treatment.

20 Kaplan Meier curves of recurrent VTE aper VKA suspension 24 months 18 months

21 Conclusions of Extended Dacus This study indicates that the absence of RVT a^er a short an?coagula?on course (3 months) is associated to a very low risk for recurrence even in pa?ents with idiopathic DVT A VTE pa?ent cohort bearing a substan?ally different risk of relapse (RVT present) needs an?coagula?on extended to two years We therefore iden?fied an individual parameter that allows to decide VKA dura?on at the ini?al?me of an?coagula?on

22 Residual Vein Thrombosis for Assessing the Op<mal Dura<on of Low Molecular Weight Heparin in Cancer Pa<ents with Deep Vein Thrombosis of the Lower Limbs: the Cancer DACUS Study (NCT ) Sergio Siragusa for the Cancer DACUS Inves?gators Oral Session ASH 2010

23 Background We do not know whether RVT is effec?ve in pa?ents at high risk (cancer pa?ents) and treated with LMWH instead of VKA

24 Study Hypothesis To test the hypothesis that RVT may be used for establishing the dura?on of LMWH in cancer pa?ents, we performed a randomized study in pa?ents with a first episode of cancer related symptoma?c DVT of the lower limbs Cancer related DVT was intended as a venous thrombosis that occurred in pa?ents with ac?ve cancer or those in whom a cancer was diagnosed in the previous six months from the thrombo?c event

25 Pa<ents and Methods (I) Inclusion criteria: Cancer pa?ents with a first episode of Compression Ultra Sonography (C US) detected proximal DVT and treated for 6 months with Low Molecular Weight Heparin (LMWH), administered at full dose (Nadroparine 97 UI an? FXa/Kg twice daily) in the first month and then reduced by 25% in the following 5 months

26 Pa<ents and Methods (II) Exclusion criteria: Presence of diseases requiring an?coagula?on (atrial fibrilla?on, severe thrombophilia, etc) Life expectancy < 1 year History of previous DVT or PE Pregnancy Inability to a[end follow up Unwillingness to partecipate Severe renal or hepa?c insufficiency

27 Pre-study Study period Group A1 Index DVT 6 mo. C-US RVT yes no R Legend: RVT (residual vein thrombosis) C-US (compression ultrasonography) Group A2 Group B 12 mo. 24 mo. LMWH No therapy A1 indicates patients with RVT who continued LMWH for 12 months (in total); A2 indicates patients with RVT randomized to stop LMWH after 6 months; B indicates patients without RVT who stopped LMWH after 6 months.

28 Results Pa?ents and treatment groups: Over a period of 36 months, 409 pa?ents were evaluated; 62 were excluded (refusal, need for con?nuing an?coagula?on, etc). In total, 347 were included in the study RVT was detected in 242 (69.7%) pa?ents; they were randomized to con?nue (119 pa?ents) (group A1) or to stop LMWH (123 pa?ents) (group A2). RVT was absent in 105/347 (30.3%) pa?ents (group B)

29 Baseline pa<ent characteris<cs Group A1 (n.119) Group A2 (n.123) Group B (n.105) P value Female sex, n (%) 53 (44.5) 59 (47.9) 52 (49.5) Age, mean + SD (y) 58.2 ± ± ± Total dura?on of FU, (y) Mean follow up, (y) 1.2 ± ± ± Type of cancer: Gastrointes?nal, % Genitourinary, % Breast, % Lung, % Haematologic, % Advanced cancer, %

30 Study Outcomes (I) Outcomes Group A1 (n.119) Group A2 (n.123) Group B (n.105) P value Recurrences, n/total (%) 17/119 (14.2) 27/123 (21.9) 3/105 (2.8) A1vsB A2vsB A1vsA2 Recurrences, n/100 person-year (%) 17/54.75 (31.0) 27/60.33 (44.7) 3/48.92 (6.1) Type of recurrent VTE DVT DVT + PE Isolated PE Controlateral 9 (52.9) 6 (35.3) 2 (11.7) 4 (23.5) 19 (70.3) 7 (25.9) 1 (3.7) 7 (25.9) 2 (66.6) 1 (33.3) 0 1 (33.3) Major bleeding, n/total (%) 5/119 (4.2) 2/123 (1.6) 2/105 (1.9) Major bleeding n/100 person-yr (%) 5/50.17 (9.9) 2/66.83 (2.9) 2/46.75 (4.2) 0.390

31 Study Outcomes (II) The adjusted HR between group A1 versus RVT nega?ve group (B) was 4.54 (CI ; P =.028). The adjusted HR (Group A2 vs A1) was 1.58 (95% confidence interval [CI], ; P = 0.145). These HR were maintained even when adjusted for age and sex Overall, 89 (25.6%) pa?ents died due to cancer progression a^er a median follow up of 12.2 months

32 Kaplan Meier curve for recurrent VTE in the three groups Cumula?ve Recurrent thrombosis LMWH Pre study Group B (No RVT, No LMWH) Group A1 (RVT, Yes LMWH) Group A2 (RVT, No LMWH) P 0.08 P

33 Conclusions (I) Absence of RVT iden?fies DVT cancer pa?ents at low risk for recurrent thrombo?c events (about 1/3 of pa?ents who completed 6 months of LMWH) In pa?ents with RVT, the recurrence rate was high and relapses occurred soon a^er LMWH suspension, sugges?ng that RVT posi?ve pa?ents need of a longer treatment

34 Conclusions (II) Advantages of RVT over D dimer assessment are of being insensi?ve to inflammatory status of the cancer and of being performed without interrup?ng an?coagula?on

35 Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients With Deep Venous Thrombosis Paolo Prandoni for the AESOPUS Investigators* Annals of Internal Medicine 2009

36 Interven<ons Patients were randomly assigned to: -Fixed duration anticoagulation (no further anticoagulation for secondary thrombosis and an extra 3 months for unprovoked thrombosis) or -Flexible-duration, ultrasonography-guided anticoagulation (no further anticoagulation in patients with recanalized veins and continued anticoagulation in all other patients for up to 9 months for secondary DVT and up to 21 months for unprovoked thrombosis). For the primary outcome assessment, 530 patients completed the trial.

37 Results Overall, 46 (17.2%) of 268 patients allocated to fixed duration anticoagulation and 32 (11.9%) of 270 patients allocated to flexible-duration anticoagulation developed recurrent VTE (adjusted hazard ratio [HR], 0.64 [95% CI, 0.39 to 0.99]). For patients with unprovoked DVT, the adjusted HR was 0.61 (CI, 0.36 to 1.02) and 0.81 (CI, 0.32 to 2.06) for those with secondary DVT. Major bleeding occurred in 2 (0.7%) patients in the fixed-duration group and 4 (1.5%) patients in the flexible-duration group (P 0.67).

38 Cumula<ve incidence of recurrent VTE

39 Topics Residual vein thrombosis (RVT) as a marker for assessing the individual risk of recurrence RVT to establish duration of anticoagulation after an episode of DVT Controversies of current systematic reviews on RVT New horizons for RVT

40 Residual vein obstruction as a predictive factor for recurrent thromboembolic events in patients with proximal deep vein thrombosis:a systematic review Melanie Tan, Inge C.M.Mos, Frederikus A. Klos and Menno Huisman British Journal of Haematology 2011

41 Results The literature search revealed 1227 studies of which 818 studies were unique; 803 studies were excluded after review of title and abstract and 14 studies were identified for more detailed evaluation. Finally, 11 studies [including two abstracts (Siragusa, 2009, 2008) and two letters (Cosmi et al, 2005b; Poli et al, 2008)] were left for inclusion in this systematic review (Piovella et al, 2002; Prandoni et al, 2002, 2009; Cosmi et al, 2005a,b, 2010; Poli et al, 2008; Rodger et al, 2008; Siragusa, 2008, 2009; Siragusa et al, 2008).

42 Conclusions Residual thrombosis was positively correlated with recurrent VTE. Large heterogeneity was present, due to differences in study population, timing and the differences in method of measuring residual thrombosis. The effect was more pronounced in patients with malignancy or was dependent on the criteria used. This systematic review shows a positive relationship between residual thrombosis and recurrent VTE during follow up.

43 Residual vein obstruction to predict the risk of recurrent thromboembolic events in patients with proximal deep vein thrombosis: a systematic review Mark Carrier, Mark Rodger, Philip S Wells, Marc Righini and Gregoire Le Gal Journal Thrombosis and Haemostasis 2011, in press

44 Results A total of 1347 citations were identified by our literature search and 34 articles were deemed potentially eligible. Fourteen articles were included in the review (9 studies were cohort studies) that included patients with DVT who had a assessment for RVO using compression ultrasonography. Overall, the presence of RVO is not associated with an increased risk of recurrent VTE (OR: 1.24, 95% CI: 0.9 to 1.7) in patients with unprovoked DVT that stopped oral anticoagulation therapy at the time of RVO assessment. However, RVO was significantly associated with recurrent VTE in patients with any (unprovoked and provoked) DVT: OR 1.5 (95% CI: 1.1 to 2.0).

45 Conclusions Residual vein obstruction was associated with a modest increased risk of recurrent VTE in patients with DVT (unprovoked and provoked). However, RVO does not seem to be a predictor of recurrent VTE in patients with unprovoked DVT following anticoagulation discontinuation. Further prospective studies are needed to assess the role of RVO in patients with unprovoked DVT.

46 Topics Residual vein thrombosis (RVT) as a marker for assessing the individual risk of recurrence RVT to establish duration of anticoagulation after an episode of DVT Controversies of current systematic reviews on RVT New horizons for RVT

47 Cancer Related Venous Thrombosis: Residual Vein Thrombosis Improves Screening for Occult Cancer Siragusa S et al Oral session ASH 2007

48 Background (I) Patients with symptomatic idiopathic Deep Vein Thrombosis (DVT) and apparently cancer-free have an approximate 10% incidence of subsequent cancer in the next 3 years* A clinical advantages of extensive screening for occult cancer in patients with idiopathic Deep Vein Thrombosis (DVT) is still debated since this approach improves early detection of cancer but not cancerrelated mortality** Prandoni et al. NEJM 2003;348: **Piccioli A et al. JTH 2004;2:884 9, Monreal M et al. JTH 2004;2:876 81

49 Background (II) We have demonstrated that patients with Residual Vein Thrombosis (RVT), 3 months after DVT, have a high risk for cancer in the subsequent 2 years *Siragusa et al. Blood 2005;106(11):OC262

50 Rationale of the study At the present it is unknown whether RVT assessment may be used to select patients, with idiopathic DVT, who require screening for occult cancer

51 Study Design Cohort A * RVT present Clinical surveillance for cancer Index DVT 3 mo. C-US 12 mo. F.U. 24 mo. F.U. *Period

52 Study Design Cohort B * Extensive screening for occult cancer** Clinical surveillance for cancer RVT present Index DVT 3 mo. C-US *Period mo. F.U. 24 mo. F.U. **Ultrasound and/or CT scan of the abdomen and pelvis, gastroscopy, colonoscopy or sigmoidoscopy, hemoccult, sputum cytology and tumor markers

53 Results Over a period of 6 years, 397 patients were considered eligible for the analysis; 52 of them were excluded because of an evidence for cancer between index DVT and RVT determination 345 patients were included in the analysis: first cohort included 213 patients (Group A, period ), second cohort 132 (Group B, period ) Clinical characteristics between groups were homogenous

54 Results (I) During the follow-up, 8.4% of patients developed overt cancer in group A; in group B, 8.3% of patients had diagnosed cancer at the moment of extensive screening while one new case (0.7%) occurred during the follow-up The sensitivity of this approach was 91.6% (95% confidence intervals )

55 Cancer-related mortality was 6.5% in group A and 3.0% in group B

56 Conclusions and clinical impact of the Study RVT-based screening for occult cancer improves patients management. In those without RVT, extensive screening for cancer may be not indicated since the risk for new overt cancer is low over time (6/318, [1.8%]) In patients with RVT, our approach improves early detection of occult cancer and may reduce cancer-related mortality Large randomized clinical trial should confirm benefit/risks of such approach

57 Università degli Studi di Palermo

58 Ematologia Policlinico Universitario di Palermo How we detect RVT Residual Venous Thrombosis (RVT): vein clot during compression Rate of compression: persistence over time evaluation of vein diameter 15 mm 10 mm Detected by venous ultra-sonography before ad during Shown to be an independent risk factor for VTE compression. recurrence* Thrombus burden > 40% RVT indicatives for an continuous, underlying hypercoagulable state since recurrences may occur in the controlateral leg or other sites ofdvt RVT This holds for both idiopathic andpresence provoked κ [95%CI ]

59 Outcomes in the subgroups RVT Posi<ve Group (384) RVT Nega<ve Group (164) 18 months of VKA (207) 24 months of VKA (150) Subgroup n. of events/total (%) n. of events/100 person year n. of events/total (%) n. of events/100 person year N of events/total (%) n of events/100 person year Sex Male Female 23/111 (20.7) 14/96 (14.6) 23/98.8 (23.3) 14/88.0 (15.9) 7/81 (8.6) 3/69 (4.3) 7/76.3 (9.2) 3/67.3 (4.4) 2/87 (2.3) 0/77 (0) 2/85.9 (2.3) 0/77 (0) Age < 65 y 65 y 19/130 (14.6) 18/77 (23.4) 28/119.3 (23.5) 29/67.5 (42.9) 3/96 (3.1) 7/54 (12.9) 6/94.6 (6.3) 11/49.0 (22.4) 0/110 (0.90) 2/54 (3.7) 0/110 (0) 2/52.9 (3.8)

60 Rela<ve Risks aper VKA suspension Focusing the analysis on the free of therapy follow up, the Rela?ve Risk (RR) of developing recurrent VTE was: 2.68 ( ) between pa?ents who received 18 vs 24 month of VKA ( ) between those who received VKA for 18 months vs. RVT nega?ve group 5.47 ( ) between pa?ents treated for 24 months vs. RVT nega?ve group

61 Type of recurrent VTE Outcomes RVT Pos. Group (n= 384) RVT Neg. Group (n=164) Isolated DVT DVT + PE Isolated PE Controlateral 8 2 0