Chronic Thromboembolic Pulmonary Hypertention CTEPH

Transcription

1 Chronic Thromboembolic Pulmonary Hypertention CTEPH Medical Management Otto Schoch, Prof. Dr. Klinik für Pneumologie und Schlafmedizin Kantonsspital St.Gallen

2 CTEPH: Medical Management Diagnostic aspects / risk factors Evidence for specific drug therapy Patient management recommendations Supportive therapy

3 A history of PE is common in CTEPH CTEPH occurs in ~0.5 4% after pulmonary embolism > CH: Input Study results pending Latent phase between PE and CTEPH symptoms Previous PE confirmed for approximately 75% of CTEPH patients Link between venous thromboembolic disease history and CTEPH PE not necessary for diagnosi: No history of PE in some patients Undiagnosed PE may be a factor in patients with no history of PE > Lifelong anticoagulation is recommended in all patients with CTEPH

4 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Eur Respir J 2015; 46:

5 Independent risk factors for CTEPH n=687 patients at three European centers offering PEA between Risk factor Adjusted odds ratio 95% CI, p value Previous VTE , <0.001 Recurrent VTE , <0.001 Thyroid hormone replacement , <0.001 Malignancy , Antiphospholipid antibodies/lupus anticoagulant , Ventriculo-atrial shunt or infected pacemaker , <0.001 Splenectomy , CI, confidence interval; PEA, pulmonary endarterectomy; VTE, venous thromboembolism. Bonderman D et al. Eur Respir J 2009;33:

6 Diagnostic pitfalls Screening PH with CT angiogram potentially misses CTEPH 1 Screening for CTEPH is not common practice In a PH registry, 43% of PAH patients diagnosed without V/Q scanning 2 Patients with CTEPH can present without history of DVT or PE 3 Failure to refer to a specialist center may result in a patient being wrongly assessed as inoperable 1 All patients with suspected CTEPH should be referred to a specialist center for confirmation of diagnosis, assessment of operability, and optimal treatment 1. Jenkins D et al. Eur Respir Rev 2012;21: McLaughlin V et al. Chest 2010;138:351A. 3. Pepke-Zaba J et al. Circulation 2011;124:

7 Surgery not possible in all CTEPH patients Surgery not possible in 20 40% of patients 1,2 Recent CTEPH registry, 36% (n=247) of patients inoperable 1 Distal or inaccessible thromboembolism 48% Comorbidities 13% Imbalance between increased PVR and 10% amount of accessible occlusions PVR >1500 dyn sec cm 5 2% Age 2% Other reason 23% Of those patients considered operable, 38 refused surgery 1 1. Pepke-Zaba J et al. Circulation 2011;124: Mayer E et al. J Thorac Cardiovasc Surg 2011;141:

8 Operated, N=404 Non operated, N=275 Cumulative Survival Lausanne 2016 / CTEPH Medical Management Figure 1a Time to death from date of diagnosis Int. CTEPH Registry 1 : KM survival estimates of Kaplan Meier estim ates All patients enrolled, N = 679 operated and non-operated patients p=< (log rank test) Cumulative Survival patients at risk at the end of the time period % 91% 89% 88% baseline Operated p=< (log rank 30 test) Non-operated PAP (mmhg) 48 (17 80) 45 (14 81) Months from Diagnosis CI (L/min/m 2 ) 2.2 ( ) 2.3 ( ) 0.20 Operated, N=404 Non operated, N=275 PVR (dyn s cm 5 ) 728 ( ) 676 ( ) 79% % (86%) (58%) 0.00 patients at risk at the end of the time period Months from Diagnosis Delcroix M, et al. Circulation. 2016; 133:

9 Yerly P, Prella M, Aubert J-D SMW 2016; 146:w14305 Hoeper Eur Respir Rev 2015; 24: Prostacyclins: 1 RCT: inhaled iloprost 2002, n=203: unchanged PVR, + 6MWT Open label case series with inconsistent results ERAs: Bosentan: next slide Maxitentan: MERIT (10/2016) NO pathway: PDE-5 inhibitors: RCT n=19, 6MWT neg, PVR +, FC + Riociguat CHEST-1 / CHEST-2

10 Prostacyclins

11 Bosentan

12 Bosentan for CTEPH: Negative RCT 2008 BOCTEPH 2007: 16 Pts, open label, +54m in 6MWD (6mths) S.Ulrich et. al. SMW 2007;137: BENEFIT 2008: 140 Pts, RCT, +4m in 6MWT: Negative Study Jais et al. J Am Coll Cardiol 2008; 52:

13 13 Ghofrani HA, et al. N Engl J Med 2013;369: Countries where patients were recruited

14 Study design n=261 Analysis of primary and secondary endpoints at Week 16 Randomization multiple CHEST-1 CHEST-2 Titration 8 weeks Maintenance 8 weeks 8 weeks 2 1 Riociguat up to 2.5 mg tid Placebo Sham titration Titrate up to 2.5 mg tid Long-term open-label phase at chronic dose up to 2.5 mg 24-week blinded phase Ghofrani HA, et al. N Engl J Med 2013;369:

15 CHEST titration strategy Dose was titrated every 2 weeks according to the BP measured at trough before intake of the morning dose 95 mmhg: increased dose mmhg: maintained dose <90 mmhg without symptoms of hypotension: reduced dose <90 mmhg with symptoms of hypotension: treatment discontinued for 24 hours and 2.5 mg tid restarted at a 0.5 mg lower dose 1.0 mg tid 2 weeks 1.5 mg tid 2 weeks 2.0 mg tid 2 weeks 2 weeks 2.5 mg tid 2.0 mg tid 1.5 mg tid 1.0 mg tid 0.5 mg tid Optimal dose to be achieved 15

16 CHEST baseline characteristics balanced across randomized groups Characteristic Riociguat (n=173) Placebo (n=88) Mean age, years Female, % Mean PVR a, dyn s cm mpap a, mmhg Mean 6MWD, m WHO FC I/II/III/IV, % 2/32/62/5 0/28/68/2 b Inoperable/persistent, % 70/30 77/23 a All PVRs and mpaps measured. b One patient with missing data at baseline. 6MWD, 6-minute walking distance; mpap, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance; WHO FC, World Health Organization functional class. Ghofrani HA, et al. N Engl J Med 2013;369:319-29

17 Mean change from baseline in 6MWD (m) Lausanne 2016 / CTEPH Medical Management Primary endpoint (6MWD) achieved Placebo-corrected treatment effect = 46 m (95% CI: m; p<0.0001) n=168 n=88 n=167 n=87 Riociguat Placebo * n=162 n=86 Observed Imputed Week 6MWD, 6-minute walking distance. Last visit = last observed value (not including follow-up) for patients who completed the study or withdrew, except imputed worst value (zero) in case of death or clinical worsening without a termination visit or a measurement at that termination visit. n=158 n=157 n=84 n=82 n=159 * n=83 * n=173 n=88 Ghofrani HA, et al. N Engl J Med 2013;369:

18 Consistent and robust improvement in secondary endpoints Parameter Riociguat vs placebo; p value PVR < NT-proBNP < WHO FC Time to clinical worsening a Borg dyspnea score a EQ-5D a < LPH a a Hierarchical testing. EQ-5D, EuroQol Group 5-Dimension Self-Report Questionnaire; LPH, Living with Pulmonary Hypertension Questionnaire; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PVR, pulmonary vascular resistance; WHO FC, World Health Organization functional class. Ghofrani HA, et al. N Engl J Med 2013;369:

19 Improvement of functional class and reduced rate of clinical worsening Significant functional class improvement (p=0.0026) 6MWD, 6-minute walking distance; FC, functional class. Riociguat Clinical worsening Riociguat Placebo Improved, % Stable, % Deteriorated, % 5 7 Placebo Number of patients with clinical worsening, n (%) 4 (2.3) 5 (5.7) Hospitalization due to PH 0 1 (1.1) Start of new PH treatment 2 (1.2) 1 (1.1) Decrease in 6MWD due to PH 1 (0.6) 2 (2.3) Persistent worsening of FC due to PH 0 1 (1.1) Death 2 (1.2) 3 (3.4) Ghofrani HA, et al. N Engl J Med 2013;369:

20 Mean change from baseline in 6MWD All patients received riociguat up to 2.5 mg tid in the long-term extension. Data shown are observed values. Simonneau G et al. Eur Respir J 2014;44(Suppl.58):1802.

21 Fibrosis Vasoconstriction Proliferation Inflammation Ghofrani et. al. CHEST 2016

22 Pulmonary hypertension (International classification) GROUP 1 PAH GROUP 2 Left-heart related GROUP 3 Lung/hypoxia related GROUP 4 CTEPH GROUP 5 Other Epoprostenol Treprostinil Iloprost No approved drug No approved drug Riociguat approved* No approved drug Bosentan Ambrisentan Sildenafil Tadalafil Macitentan Riociguat *In US, Canada, EU, and Switzerland Galiè N et al. Eur Heart J 2009;30:

23 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary Hypertension Eur Respir J 2015; 46:

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25 CTEPH is not PAH 1 4 CTEPH PAH Common pathobiologic link: endothelial dysfunction/no depletion Common symptoms: dyspnea, fatigue, weakness, syncope Etiology Risk factors Diagnosis Treatment After PE: Embolism may not have resolved Etiology uncertain if no history of PE PE, infected surgical cardiac shunt or pacemaker, splenectomy, antiphospholipid antibodies, high levels of factor VIII, abnormal fibrinolytic response Segmental perfusion defects in V/Q scan; diagnostic work-up including pulmonary angiography, CT / MR angiography PEA with DHCA for operable patients Licensed medical therapy Abnormal proliferation of endothelium and smooth muscle in vessel walls Genetic mutation, certain drugs/toxins, HIV, connective tissue disorders, congenital heart disease No segmental perfusion defects in V/Q scan; RHC Medical treatments targeting dysfunctional pathways in endothelial cells DHCA, deep hypothermic circulatory arrest; HIV, human immunodeficiency virus; NO, nitric oxide; PE, pulmonary embolism; PEA, pulmonary endarterectomy; RHC, right 1. Humbert M. heart Eur catheterization Respir V/Q, Rev ventilation/perfusion. 2010;19: Galiè N et al. Eur Heart J 2009;30: Keogh AM et al. J Am Coll Cardiol 2009;54:S Kim NH et al. J Am Coll Cardiol 2013;62:D92 9.

26 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary Hypertension Eur Respir J 2015; 46:

27 A small proportion (<10%) of patients received additional PH medications in CHEST-2 Therapy, n (%) Inoperable CTEPH Persistent/recurrent CTEPH Start of CHEST-2 n=172 n=65 Riociguat monotherapy 172 (100) 65 (100) 1 year n=122 n=35 Riociguat monotherapy 113 (93) 32 (91) Combination therapy overall 9 (7) 3 (9) Endothelin RA 6 (5) 2 (6) Prostanoids 3 (2) 1 (3) Hoeper MM et al. Am J Resp Crit Care Med 2014;189:A2459.

28 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary Hypertension Eur Respir J 2015; 46:

29 European Heart Journal (2015) 36, N= 23, CTEPH 7 Pts, 3 period cross-over, 1 week 3L of nocturnal O2 vs placebo vs acetazolamide

30 European Heart Journal (2016) 37, N= 87, CTEPH 26 Pts

31 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary Hypertension Eur Respir J 2015; 46: