Prevention of VTE Sequelae: Post-thrombotic Syndrome and Chronic Thromboembolic Pulmonary Hypertension

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1 Prevention of VTE Sequelae: Post-thrombotic Syndrome and Chronic Thromboembolic Pulmonary Hypertension Susan R. Kahn MD MSc Professor of Medicine, McGill University Director, Jewish General Hospital Centre of Excellence in Thrombosis and Anticoagulation Care Montréal, Canada Thrombosis and Hemostasis Societies of North America 2018 San Diego, CA, March 8-10, 2018

2 Prevention of post-thrombotic syndrome (PTS)

3 Post-thrombotic syndrome (PTS) Occurs in 20-50% of DVT patients (severe in 5-10% of patients), in spite of receiving optimal anticoagulant therapy Costly to society Impairs QOL, causes disability and suffering to patients Prandoni 1996; Kahn 2008; Kahn 2015

4 Clinical images of PTS

5 Risk factors (RF) for PTS 1. Those apparent at the time of DVT diagnosis 2. Those related to the treatment of acute DVT 3. Those apparent during follow-up after DVT

6 RF apparent at time of DVT diagnosis Risk factor DVT location Previous ipsilateral DVT Elevated body mass index (BMI > 30) Older age Pre-existing primary venous insufficiency (e.g. varicose veins) Magnitude of risk 2-3 fold risk after proximal DVT (especially iliac or common femoral vein) than distal (calf) DVT. 2-3 fold risk More than 2-fold risk risk from 30% to 3-fold. Up to 2-fold risk Little to no effect on the risk of developing PTS: Male vs. female; provoked vs. unprovoked DVT; genetic thrombophilia Galanaud JP et al. J Vasc Surg Venous Lymphat Disord Rabinovich A et al. J Vasc Surg Venous Lymphat Disord Kahn SR et al. Circulation 2014

7 J Thromb Haemost 2018 High risk predictors at baseline: 1 point: Iliac vein DVT 2 points: BMI >35 1 point: Villalta score 9-14 at baseline 2 points: Villalta score >14 at baseline Score of >4: 6-fold risk of PTS SOX-PTS index will be validated in ATTRACT study cohort

8 RF related to the treatment of acute DVT Risk factor Quality of oral anticoagulation with vitamin K antagonists (VKA) Choice of anticoagulant to treat DVT: DOAC vs. LMWH vs. VKA Thrombolysis to treat DVT (preventive?) Magnitude of risk 2-3 fold risk if level subtherapeutic INR >50% time during first 3 months of VKA treatment Not known if use of DOAC to treat DVT influences risk of PTS, vs. treatment with LMWH or VKA Metaanalysis suggests use of LMWH monotherapy to treat DVT may risk of PTS, compared to treatment with LMWH for 5-7 days followed by VKA To discuss later in talk Galanaud JP et al. J Vasc Surg Venous Lymphat Disord Hull & Townshend, Thromb Haemost 2013 Cheung YW et al. Thromb Haemost. 2016

9 RF apparent during follow-up after DVT Risk factor Ipsilateral DVT recurrence Persistent venous symptoms and signs 1 month after acute DVT Residual thrombosis on ultrasound 3-6 months after acute DVT Magnitude of risk 4-6-fold risk (via damaging compromised venous valves or aggravating venous outflow obstruction) risk of subsequent PTS in graded fashion (may be a marker of persistent inflammation or venous outflow obstruction) 1.5 to 2-fold risk Persistent elevation of D-dimer in weeks to months after DVT Modest risk factor Kahn SR et al. Annals Intern Med 2008 Rabinovich A et al. J Vasc Surg Venous Lymphat Disord Galanaud JP et al. J Vasc Surg Venous Lymphat Disord. 2016

10 Preventing PTS Prevent the initial DVT Improve systematic use of thromboprophylaxis in patients at risk for VTE (high-risk patients, high-risk settings) Prevent ipsilateral DVT recurrence Optimize treatment of initial DVT (ensure appropriate duration and intensity of anticoagulation) Ensure good quality of anticoagulation for DVT During 1 st 3 months, INR<2 more than 50% of time: 2-3-fold risk PTS (van Dongen, JTH 2005; Chitsike JTH 2012) Choice of anticoagulant Data insufficient to make specific recommendations re: VKA vs. DOAC vs. LMWH monotherapy on risk of developing PTS

11 Additional approaches to preventing PTS Elastic compression stockings (ECS)? Catheter directed thrombolysis (CDT)?

12 Do ECS prevent PTS? 2 older open-label RCTs reported that wearing mm Hg knee-high ECS for at least 2 years after proximal DVT reduced the risk of PTS by ½ (Brandjes 1997; Prandoni 2004) HOWEVER More recently, a large multicenter, placebo-controlled RCT of 803 patients with proximal DVT showed no benefit of mm Hg knee-high ECS, worn for two years, to 1) prevent PTS; 2) reduce recurrent VTE; or 3) improve quality of life (SOX Trial; Kahn Lancet 2014)

13 SOX Trial results: Primary outcome (ITT analysis) Active ECS (n=409) Placebo ECS (n=394) Hazard Ratio (95% CI) PTS (Ginsberg criteria) 44 Cumulative Incidence * 14.2% 37 Cumulative incidence 12.7% 1.13 (0.73, 1.76) p=0.58 SOX Trial. Kahn SR et al, Lancet 2014

14 SOX Trial results: Secondary outcomes Active ECS (n=409) Placebo ECS (n=394) Hazard Ratio (95% CI) PTS (Villalta criteria) Villalta score 5 at or after 6 month visit 176 Cumulative incidence 52.6% 168 Cumulative incidence 52.3% 1.0 ( ) p=0.96 Follow up, days SOX Trial. Kahn SR et al, Lancet 2014

15 ACCP 2016 Kearon et al, Chest 2016

16 2 recent ECS trials None designed to assess if ECS started at time of DVT diagnosis prevents PTS OCTAVIA study, 518 patients (BMJ 2016) All patients wore ECS for 1 year after prox DVT If free of PTS at 1 year, randomized to continue for 1 more year, or stop ECS IDEAL study, 865 patient (Lancet Haem 2017) All patients wore ECS for 6 mos. after prox DVT If free of PTS at 6 mos., randomized to continue for 18 more mos., or tailor continued use according to Villalta score

17 Mol GC et al. BMJ 2016 Results Developed PTS in 2 nd year after DVT % (95%CI) Stop ECS after 1 year (n=256) 19.9% (16%-24%) Continue ECS for total of 2 years (n=262) 13.0% (9.9%-17%) Difference, % (95% CI) 6.9% (0.6%, 12.3%) Adj HR 1.6 (1.0, 2.5) QOL did not differ between groups 1 year not non-inferior to 2 years Suggests if one has worn ECS for 1 year after DVT and have not developed PTS, may be benefit to continuing for 2 years, compare to stopping after 1 year.

18 IDEAL Study results Individualized duration ECS non-inferior to standard 2 years duration 66% in intervention group able to stop wearing stockings before 2 years ten Cate-Hoek A, Lancet Haematol 2017

19 How I use ECS Do I prescribe ECS for 2 years or longer to all my proximal DVT patients? No. ECS hard to apply, uncomfortable, expensive, must be replaced every few months. Many patients don t wear them in real life, especially if no symptoms Not clear if ECS prevents vs. palliates PTS à may be as effective, more convenient (and achieve better compliance) to start using ECS at time of PTS onset Based on current state of evidence: I prescribe mm Hg or mm Hg below-knee ECS to patients who have residual leg pain or swelling after proximal or distal DVT I continue them for as long as the patient derives symptomatic benefit or is able to tolerate them. Contraindications: symptomatic claudication due to PAD, allergy to material

20 Thrombolysis to prevent PTS Anticoagulant drugs do not eliminate thrombus Endogenous fibrinolysis slow and often incomplete Could immediate thrombus removal at time of acute DVT open veins, save venous valves, and prevent PTS?

21 ATTRACT Trial Acute venous Thrombosis Thrombus Removal with Adjunctive Catheter- Directed Thrombolysis Hypothesis PCDT will reduce future PTS by 33% (30% to 20%, assessed from 6 to 24 months) Patients randomized to PCDT vs. no PCDT; all patients received AC and ECS Not blinded: Healthcare providers, patients Blinded: Randomization; outcome assessors

22 Patients studied Proximal DVT ( femoral) 691 common femoral or iliac 57% not common femoral or iliac 43% Age 53 yrs Males 62 % Symptoms 6 days Exclusions: <16 and >75 yrs; symptoms 14 d; high bleeding risk; cancer

23 Study Outcomes Primary: PTS (Villalta Scale 5, 6-24m) Secondary: Many Short & Long-term

24 PCDT Used Initial PCDT Infuse-First 58% Single Session 38% AngioJet (22%) Trellis (15%) Adjunctive (88%) Baloon maceration 62% Baloon venoplasty 62% AngioJet 61% Stent 28% Aspiration 21% Trellis 5%

25 Short-Term Results Outcome PCDT n=336 No-PCDT n=355 P Value Major Bleeding (10 d)* 1.7% 0.3% Any Bleeding (10 d) 4.5% 1.7% Leg Pain (10 d) Leg Pain (30 d) Leg Swelling (10 d) Leg Swelling (30 d) Recurrent VTE (10d) 1.8% 1.1% 0.5

26 Long-Term Results Outcome (24 months) PCDT n=336 No-PCDT n=355 P Value Any PTS 47% 48% 0.56 Recurrent VTE 13% 8% 0.09 Generic QOL (SF-36 PCS) Venous QOL (VEINES) Moderate/Severe PTS 18% 24% MS-PTS: IF-DVT 18% 28% MS-PTS: FP-DVT 17% 18%

27 Conclusions PCDT Does not prevent PTS May reduce the severity of PTS Increases bleeding Modestly reduces acute symptoms

28 ACCP 2012 and 2016 recommendations Use of CDT requires substantial resources and expertise. Patients who are most likely to benefit have iliofemoral DVT, symptoms <14 days, good functional status, life expectancy > 1 year, and low risk of bleeding. Kearon C et al, Chest 2012, Chest 2016 Because the balance of risks and benefits is uncertain, anticoagulant therapy alone is an acceptable alternative to CDT in all patients with acute DVT who do not have impending venous gangrene.

29 CTEPH (Chronic Thromboembolic Pulmonary Hypertension)

30 Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Overview Late complication of Pulmonary Embolism (PE): - 1-4% of patients after acute PE cases/million (general population) More common cause of pulmonary hypertension (PH) than idiopathic pulmonary arterial hypertension If untreated: life-threatening disease with poor prognosis leading to death (refractory RV failure) within a few years

31 How does CTEPH develop after PE? (current pathophysiology concept) (Infection, inflammation, immunity, genetics, in situ thrombosis) Acute PE CTEPH 1. Incomplete resolution and organisation of thrombus 2. Development of fibrotic stenoses/occlusions 3. Adaptative vascular remodelling of resistance vessels Lang IM, Eur Respir J. 2013; 41 ( )

32 Clinical Features of CTEPH Progressive dyspnea and exercise intolerance Clinical presentation of CTEPH may mimic acute PE or other conditions (asthma, physical deconditioning, older age, interstitial lung disease, CAD, or psychogenic dyspnea) Non-specific presentation and, early in its natural history, subtle physical examination findings Fernandes T, Thromb Res. 2018

33 How often does CTEPH develop after PE? Recent meta-analysis 16 studies (4047 pts) Type of PE All comers with symptomatic PE Survivors* of symptomatic PE Survivors* of Symptomatic PE, no major comorbidities Non-objective diagnostic criteria Number of studies CTEPH Incidence % (95% CI) 2 studies 0.56% ( ) 4 studies 3.2% ( ) 9 studies 2.8% ( ) 12 studies 6.3% ( ) * Only patients that were alive after an initial treatment period of 6 months Ende-Verhaar YM, Eur Respir J. 2017; 49 (1-11)

34 Occurrence of CTEPH: Known risk factors

35 Demographic or medical factors associated with occurrence of CTEPH (none modifiable) Age > 60 Previous splenectomy Antiphospholipid antibodies Increased levels of lipoprotein(a) Hypothyroidism, thyroid replacement therapy Non-O blood groups Malignancy Known chronic inflammatory conditions (osteomyelitis, inflammatory bowel disease, infected intravascular devices) Fernandes T, Thromb Res. 2018

36 Risk factors related to initial PE (some modifiable) Acute PE: up to 25% of CTEPH patients have no known documented history of PE Characteristics of the initial episode of acute PE: unprovoked PE (OR 4.1) recurrent PE (OR 3.2) larger initial perfusion defects RV dysfunction at diagnosis delay in PE diagnosis persistent PH after therapy with a PAsP > 50 mm Hg Fernandes T, Thromb Res Ende-Verhaar YM, Eur Respir J. 2017

37 Prevention

38 Prevention of CTEPH Modality Methods Data Thrombolysis of acute PE AC therapy duration DOAC vs. warfarin New therapeutic targets Urokinase, streptokinase, Tenecteplase Extended anticoagulant therapy for at least 24 months Pharmacokinetics and antithrombotic effect, Safety None identified Not effective Unknown No data available No data available

39 Thrombolysis of acute PE for prevention of CTEPH Thrombolysis of acute PE is associated with significantly lower PA pressure and vascular resistance compared to those initially treated with heparin alone. Evidence based on two small RCTs 40 patients (Sharma GV, N Engl J Med. 1980) 23 patients (Sharma GV, Vasc Med 2000) Pesavento R, Expert Rev Cardiovasc Ther. 2015; 13 ( )

40 Thrombolysis of acute PE for the prevention of CTEPH PEITHO trial: Most recent long-term results Outcome (Median 37.8 months) T n=144 No-T n=146 P Value CTEPH 2.1% 3.2% 0.79 Residual PH and/or RV dysfunction 44.1% 36.6% 0.20 Konstantinides SV, J Am Coll Cardiol. 2017; 69 ( )

41 Treatment Options

42 Treatment options: Overview In patients with established CTEPH: Surgery Endovascular interventions Medical treatment Lung transplant in highly selected patients Time to diagnosis is a key factor in selection of treatment options!!!

43 Curative Treatment: Pulmonary Endarterectomy (PEA) Surgical procedure Mechanical removal of the proximal fibrous pulmonary artery obstruction Treatment of choice for patients with CTEPH Early diagnosis and treatment are crucial to improve the prognosis: up to 30% of CTEPH patients are already inoperable at time of diagnosis Complications Short-term: postoperative residual PH (up to 40% of operated patients) and mortality (<5%) Long-term: recurrent CTEPH, survival rates (> 90% at 1 year, 89% at 3 years and >70% at 10 years), residual PH. Hoeper MM, Lancet Respir Med 2014; 2 ( ) Galiè N, Eur Respir J. 2015; 46 ( ) Delcroix M, Circulation 2016; 133 ( )

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45 Pulmonary Endarterectomy (PEA) Advantages Best therapeutic option 1. Relevant improvement in symptoms in majority of patients 2. Almost complete normalization of most important hemodynamic parameters; only potentially curative treatment option for early-stage CTEPH Hybrid intervention: PEA and BPA promising Balloon Pulmonary Angioplasty (BPA) performed in highly selected patients after unsuccessful PEA or for late recurrent CTEPH after PEA Disadvantages Assessment of operability is a complex task 1. Multidisciplinary, devoted team (expert surgeons, radiologists, anesthesiologists, cardiologists, pulmonologists, internists) 2. Expert surgical centre, performing at least 20 PEAs per year with mortality rate < 10%. Surgical procedure is complex Highly specialized training level and complex protocols of postoperative care. Galiè N, Eur Respir J. 2015; 46 ( ) - Wiedenroth CB, J Heart Lung Transplant 2016; 35 ( )

46 Medical therapy as an alternative effective treatment Recommended in symptomatic patients with persistent or recurrent CTEPH after surgery and in those considered inoperable Life-long anticoagulation is recommended, once the diagnosis of CTEPH is established for the prevention of in situ thrombosis and recurrent VTE: VKA (well known), DOAC as the first choice treatment (No RCT data available) Alternatives to anticoagulant therapy: IVC filters sometimes used in patients with clots in known location: e.g. lower limbs, pelvic region Usual supportive therapy for heart or respiratory failure is also recommended to reduce arterial PH: prostacyclin analogues, endothelin receptor antagonists, PDE-5 inhibitors, riociguat Galiè N, Eur Respir J. 2015; 46 ( ) Kearon C, Chest 2016; 149 ( )

47 Palliative treatment: Balloon pulmonary angioplasty (BPA) For patients with technically non-operable and unfavourable risk-benefit ratio for PEA, (+/- residual lesions, recurrent/ residual PH after PEA). Used in association with medical therapy or PEA Complications: reperfusion pulm edemea; +/- PA injury with hemorrhage due to artery rupture or dissection, wire perforation, high-pressure perfusion haemoptysis. Disadvantages: Multiple sessions are required to treat all lesions (usually at intervals of one or more weeks). Potential adverse effects from repeated exposure to radiation and contrast media. Feinstein JA, Circulation 2001;103 (10-13) - Taniguchi Y, EuroIntervention 2014;10 ( ) Roik M, Int J Cardiol 2016; 203 ( ) - Ogo T, Eur J Radiol 2017; 89 ( )

48 End-stage treatment option: Lung transplantation Bilateral lung or heart/lung transplantation in highly selected young patients for whom no other therapeutic option is available. Effectiveness: data are lacking and an indirect comparison with other treatment options might be inappropriate. Threshold for unrecoverable RV systolic dysfunction and/or LV diastolic dysfunction is unknown. Disadvantages: delays in referral, shortage of organ donors (length of waiting time), limited success (survival rates: 52 75% at 5 years and 45 66% at 10 years) Galiè N, Eur Respir J. 2015; 46 ( )

49 Areas for Future Research Better understanding of underlying pathology of CTEPH Better characterization of true incidence of CTEPH Better identification of risk factors and predictors Assess efficacy and safety of hybrid intervention and novel molecules in operable and non-operable patients Assess the potential preventive role of DOAC Identify new therapeutic and preventive targets