Where are we now in the longterm. of PAH and CTEPH? Hits and misses of medical treatment. Hap Farber Boston University School of Medicine, Boston, USA

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1 Where are we now in the longterm management of PAH and CTEPH? Hits and misses of medical treatment Hap Farber Boston University School of Medicine, Boston, USA Monday, 28 September ERS International Congress 2015

2 Disclosures Honoraria: Actelion, Bayer HealthCare, Gilead Consultancy: Actelion, Bayer HealthCare, Bristol Myers Squibb, Gilead, Ikaria, United Therapeutics Research grants: Gilead, United Therapeutics

3 Long-term management of PH Issues in CTEPH Issues in PAH

4 Pulmonary hypertension is classified into five main categories, based on etiology Pulmonary hypertension (ESC/ERS classification 2015) GROUP 1 PAH Idiopathic (IPAH) Heritable (BMPR2 and other mutations) Drug- and toxininduced Associated with other conditions (APAH) WHO Group 1 Pulmonary venoocclusive disease Pulmonary capillary hemangiomatosis WHO Group 1 Persistent pulmonary hypertension of the newborn (PPHN) GROUP 2 Left-heart related Left ventricular systolic dysfunction Left ventricular diastolic dysfunction Valvular disease Congenital/acquired left heart inflow/ outflow tract obstruction and congenital cardiomyopathies Congenital/acquired pulmonary veins stenosis GROUP 3 Lung/hypoxia related Chronic obstructive pulmonary disease Interstitial lung disease Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental lung diseases GROUP 4 CTEPH and other PA obstructions Chronic thromboembolic pulmonary hypertension Other pulmonary artery obstructions GROUP 5 Unclear multifactorial Hematological disorders Systemic disorders Metabolic disorders Others BMPR2, bone morphogenetic protein 2. Galie N et al. Eur Heart J 2015: doi: /eurheartj/ehv317.

5 A complete diagnostic work-up for PH should always be performed to ensure the correct diagnosis is made Symptoms, signs, history suggestive of PH High or intermediate Echocardiographic probability of PH Low Consider left heart disease and lung diseases by symptoms, signs, risk factors, ECG, PFT + DLCO, chest radiograph and HRCT, arterial blood gases Consider other causes and/or follow-up No signs of severe PH/RV dysfunction Treat underlying disease Yes Diagnosis of left heart diseases or lung diseases confirmed? No V/Q scan a Mismatched perfusion defects? PAH likely Specific diagnostic tests Yes Copyright protected content. Signs of severe PH/RV dysfunction Refer to PH expert center Please view original content Refer to PH expert in center the following reference: Galiè CTEPH possible? N et al. Eur Heart J 2015:doi: /eurheart/ehv317 Yes RHC CT pulmonary angiography, mpap 25 mmhg, PWAP RHC +/- pulmonary angiography 15 mmhg, PVR >3 Wood units Differential diagnosis is important because CTD CHD the prognosis Drugs - toxin and treatment Portopulmonary approaches HIV Schistosomiasis vary for different PH groups No a CT pulmonary angiography alone may miss diagnosis of CTEPH. Heritable PVOD/PCH Idiopathic PVOD/PCH Idiopathic PAH Heritable PAH CHD, congenital heart disease; CT, computed tomography; CTD, connective tissue disease; DLCO, diffusion capacity of the lung for carbon dioxide; ECG, electrocardiogram; HIV, human immunodeficiency virus; HRCT, high-resolution computed tomography; mpap, mean pulmonary arterial pressure; PAWP, pulmonary artery wedge pressure; PFT, pulmonary function tests; PVOD/PCH, pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis; PVR, pulmonary vascular resistance; RHC, right heart catheterization; RV, right ventricular, V/Q, ventilation/perfusion. Galiè N et al. Eur Heart J 2015:doi: /eurheart/ehv317.

6 ESC/ERS 2015 diagnostic guidelines for CTEPH The presentation of CTEPH is non-specific and often subtle; 1 3 CTEPH should be suspected in any PE survivors with persistent dyspnea 3 IIaC* Diagnosis based on presence of precapillary PH (mpap 25 mmhg; PAWP 15 mmhg; PVR >2 WU) in patients with multiple chronic/organized occlusive thrombi/emboli persisting after effective anticoagulation for minimum of three months 3 IC V/Q scan is first-line imaging modality in screening CTEPH IC CTPA alone cannot exclude CTEPH 3 If symptoms, echocardiographic and V/Q scan results are compatible with CTEPH, patient should be referred to center with expertise in surgical PEA IIaC CTPA and RHC ± PA required for diagnostic confirmation 3 IC *Indicates class and level of evidence. CTPA, computed tomographic pulmonary angiography; mpap; mean pulmonary arterial pressure; PA. pulmonary angiography; PAWP, pulmonary arterial wedge pressure; PE, pulmonary embolism; PEA, pulmonary endarterectomy; PVR, pulmonary vascular resistance; RHC, right heart catheterization; V/Q, ventilation/perfusion; WU, Wood units. 1. Jenkins D et al. Eur Respir Rev 2012;21: Hoeper MM et al. Circulation 2006;113: Galiè N et al. Eur Heart J 2015: doi: /eurheartj/ehv317.

7 Issues in CTEPH Underdiagnosis or misdiagnosis results in many patients with CTEPH being overlooked for potentially curative treatment with PEA 1,2 Late diagnosis contributes to poor prognosis 3 Widespread use of PAH-targeted medical therapies in CTEPH No robust evidence to support the efficacy of unapproved therapies in patients with inoperable CTEPH and persistent/recurrent CTEPH post-pea Only riociguat has proven efficacy in these indications, based on robust evidence from the CHEST studies 4,5 PEA, pulmonary endarterectomy. 1. Jenkins D et al. Eur Respir Rev 2012;21: Panduranga P, Mukhaini M. Ann Thorac Med 2011;6: Olsson KM et al. Dtsch Arztebl Int 2014;111: Ghofrani HA et al. N Engl J Med 2013;369: Simonneau G et al. Eur Respir J 2014;44(Suppl.58):1802.

8 CTEPH: Pathophysiological similarities with PAH Controversy whether in situ thrombosis or embolic phenomenon responsible for CTEPH 1 Microscopic similarities between CTEPH and forms of PAH, including plexogenic lesions 2,3 Difficult to distinguish whether CTEPH leads to vasculopathic pathology of PAH, or PAH leads to CTEPH 4 1. Peacock A et al. Proc Am Thorac Soc 2006; Pepke-Zaba J et al. Eur Respir J 2013;41: Yi ES et al. Am J Respir Crit Care Med 2000;162: Berger G et al. IMAJ 2011;13:

9 Acute PE: Role in CTEPH? PE prevalence and associated mortality ~600,000 cases in US/year; up to 200,000 deaths/year 1 Without treatment, mortality 30%; accurate diagnosis and appropriate treatment reduces mortality to 2 8% 2,3 Proportion of patients with PE-associated CTEPH Unclear why some patients with PE develop CTEPH 2 Most patients return to baseline functional status and normal hemodynamics Occurrence is not precisely known: % of patients after acute PE 4 Thus, ~ ,600 CTEPH patients in US annually Not all patients with CTEPH have a history of PE/DVT 5 DVT, deep vein thrombosis; PE, pulmonary embolism. 1. Tapson V et al. Proc Am Thorac Soc 2006;3: Fedullo P et al. Am J Respir Crit Care Med 2011;183: Vuylsteke A. PH and RV failure. In Cardiovascular Critical Care, Griffiths M, Cordingley J, Price S (Eds). Wiley-Blackwell 2010; pp Lang I. Eur Respir Rev 2015;24: Humbert M. Eur Respir Rev 2010;19:59 63.

10 Proportion of population (%) V/Q scan is underutilized as a screening modality Follow-up testing for PH in PE survivors is inadequate 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0 PE cases from national health claims database covering 70 million lives 1 55% 90% a 7% 16% 47% 87% a Comprising those listed on X-axis: CTPA, computed tomographic pulmonary angiography; Echo, echocardiography; PA, pulmonary angiogram; QuERI, Quality Enhancement Research Initiative; RHC; right heart catheterization; V/Q, ventilation/perfusion. 1. Channick RN et al. Am J Respir Crit Care Med 2015;191:A McLaughlin VV et al. Chest 2013;143: Zhang C et al. CJNMMI 2013;33: % 34% All patients (n=7,068) PH subset (n=538) 1% 4% 0% 2% Any test V/Q scan Echo CTPA scan RHC PA (1-year incidence of PH = 7.6%) V/Q scan performed during PH diagnostic workup in separate US QuERI database: % (n=433) in academic center 48.7% (n=353) in community center

11 Proportion of population (%) V/Q scan is underutilized as a screening modality Follow-up testing for PH in PE survivors is inadequate Utility as a screening modality 3 V/Q scan Multidetector CTPA 100% 90% 80% 70% 60% 50% 40% PE cases from national health claims database covering 70 million lives 1 55% 90% Sensitivity (%) % Accuracy (%) % % 16% 10% 7% 1% 4% 0% 2% Negative predictive 0% 0 value a (%) Any test V/Q scan Echo CTPA scan RHC PA 47% 87% a Comprising those listed on X-axis: CTPA, computed tomographic pulmonary angiography; Echo, echocardiography; PA, pulmonary angiogram; QuERI, Quality Enhancement Research Initiative; RHC; right heart catheterization; V/Q, ventilation/perfusion. 1. Channick RN et al. Am J Respir Crit Care Med 2015;191:A McLaughlin VV et al. Chest 2013;143: Zhang C et al. CJNMMI 2013;33: % All patients (n=7,068) PH subset (n=538) Specificity (%) (1-year incidence of PH = 7.6%) V/Q scan performed during PH diagnostic workup in separate US QuERI database: % (n=433) in academic center 48.7% (n=353) in community center

12 Treatment algorithm for CTEPH Diagnosis confirmed by CTEPH expert center Lifelong anticoagulation IC Operability assessment by a multidisciplinary CTEPH team Acceptable risk:benefit ratio Technically operable Technically non-operable Copyright protected content. Please view original content in the following reference: Non-acceptable Galiè N et al. Eur Heart risk:benefit J 2015:doi: /eurheart/ehv317 ratio a IB Targeted medical therapy Pulmonary endarterectomy Persistent symptomatic PH Consider BPA in expert center b Consider lung transplantation a Technically operable patients with non-acceptable risk/benefit ratio can be considered also for BPA. b In some centers medical therapy and BPA are initiated concurrently. Persistent severe symptomatic PH IIbC BPA, balloon pulmonary angioplasty. Galiè N et al. Eur Heart J 2015:doi: /eurheart/ehv317.

13 Do you currently use riociguat in treating CTEPH? 1. Yes 2. No 3. I do not treat CTEPH patients, I refer them VOTE NOW!

14 Summary: CTEPH Optimizing treatment for patients with CTEPH or PAH demands a correct diagnosis 1 CTEPH should be suspected in any PE survivors with persistent dyspnea Referral to expert centers for assessment by MDT team is essential to ensure patients are provided with the best available care V/Q scan is recommended screening modality to rule out CTEPH 1 CTPA and RHC ± PA required for diagnostic confirmation PEA is recommended, potentially curative treatment for CTEPH 1 Riociguat is the only approved medical treatment recommended (IB) for inoperable CTEPH and persistent/recurrent CTEPH post-pea 1,2 CTPA, computed tomography pulmonary angiography; MDT, multidisciplinary team; PA, pulmonary angiogram; PEA, pulmonary endarterectomy; RHC, right heart catheterization; V/Q, ventilation/perfusion. 1. Galiè N et al. Eur Heart J 2015: doi: /eurheartj/ehv Bayer HealthCare. Adempas Summary of Product Characteristics. July 2015.

15 Long-term management of PH Issues in CTEPH Issues in PAH

16 Issues in PAH Many patients do not achieve treatment goals, 1 requiring escalation or change of therapy Which treatment regimen? Monotherapy Dual combination therapy Triple combination therapy When and how? Upfront Inefficacy, treatment Add-on failure, adverse events Transition Which drugs, and in what order? 1. Badesch DB et al. Chest 2010;137:

17 Treatment algorithm for PAH Treatmentnaïve patient PAH confirmed by expert center General measures Supportive therapy CCB therapy Vasoreactive Acute vasoreactivity test (IPAH/HPAH/DPAH only) Non-vasoreactive Low or intermediate risk (WHO FC II III) a High risk (WHO FC IV) a Initial monotherapy b Initial oral combination b Initial oral combination including i.v. PCA c Patient already on treatment Copyright protected content. Please view original content in the following reference: Galiè N et al. Eur Heart J 2015:doi: /eurheart/ehv317 Inadequate clinical response Double or triple sequential combination Consider referral for lung transplantation Inadequate clinical response Consider listing for lung transplantation d a Some WHO-FC III patients may be considered high risk. b Initial combination with ambrisentan+tadalafil has proven to be superior to initial monotherapy with ambrisentan or tadalafil in delaying clinical failure. c Intravenous epoprostenol should be prioritized as it has reduced 3-month mortality in high-risk PAH patients also as monotherapy. d Consider also balloon atrial septostomy. CCB, calcium channel blocker; DPAH, drug-induced pulmonary arterial hypertension; HPAH, hereditary pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; i.v., intravenous; PCA, prostacyclin analog; WHO FC, World Health Organization functional class. Galiè N et al. Eur Heart J 2015:doi: /eurheart/ehv317.

18 ESC/ERS 2015 recommendations for monotherapy in PAH Copyright protected content. Please view original content in the following reference: Galiè N et al. Eur Heart J 2015:doi: /eurheart/ehv317 APAH, associated pulmonary arterial hypertension; EMA, European Medicines Agency; IP, prostacyclin receptor; IPAH, idiopathic pulmonary arterial hypertension; RCT, randomized controlled trial; s.c., subcutaneous; WHO FC, World Health Organization functional class. Galiè N et al. Eur Heart J 2015:doi: /eurheart/ehv317.

19 ESC/ERS 2015 recommendations for upfront and sequential combination therapy in PAH Upfront Sequential Copyright protected content. Please view original content in the following reference: Galiè N et al. Eur Heart J 2015:doi: /eurheart/ehv317 Consideration: Dose adjustments and potential side effects may be simpler to manage with sequential administration of combination partners a Class of recommendation. b Level of evidence. c Supporting references. d Time to clinical worsening as RCT primary endpoint, or drugs reducing all-cause mortality. e No EMA approval at time of publication. EMA, European Medicines Agency; ERA, endothelin receptor antagonist; i.v. intravenous; PDE5i, phosphodiesterase type 5 inhibitor; s.c. subcutaneous; WHO FC, World Health Organization functional class. Galiè N et al. Eur Heart J 2015:doi: /eurheart/ehv317.

20 What do the majority of your PAH patients receive? 1. Monotherapy 2. Dual combination therapy (upfront or sequential combination) 3. Triple combination therapy (upfront or sequential combination) 4. I refer my PAH patients VOTE NOW!

21 Proportion of patients c (%) REVEAL: Majority of patients with PAH receive dual combination therapy 100% Monotherapy Dual combination a Triple combination b 80% 48% of patients (n=2438) were receiving monotherapy at time of study enrollment 60% 40% 20% 0% % 24.4% 18.5% 17.1% 16.1% 11.1% 7.4% 7.5% 4.8% 5.8% 0.9% 3.0% ERA* PDE5 inhibitor* i.v./s.c. prostacyclin* Inhaled prostacyclin* Enrollment prior to approval of riociguat in 2014 *Percentages for each drug class add up to proportion of patients receiving that class in total population, e.g. 47% of patients received ERA. a Combination with one oral therapy or one prostanoid; b Combination with more than one other therapy; c Proportion of overall population. Oral therapy defined as bosentan, sildenafil, ambrisentan, sitaxsentan, or tadalafil. ERA, endothelin receptor antagonist; i.v., intravenous; PDE5, phosphodiesterase type 5; s.c., subcutaneous. Badesch DB et al. Chest 2010;137;

22 AMBITION: Ambrisentan + tadalafil upfront combination therapy improved time to clinical worsening vs monotherapy 1 Proportion of patients event-free (%) year 88.9% 75.5% Combination therapy Pooled monotherapy* 2 years 79.7% Copyright protected content. 63.2% Please view original content in the following reference: Galiè N et al. Eur Respir J 2014;44(Suppl 58): years 67.6% 56.1% Time (weeks) Additional observations: Earlier initiation of upfront ambrisentan + tadalafil (WHO FC II) is more effective than later initiation (WHO FC III) vs monotherapy 2 *Pooled ambrisentan and tadalafil monotherapy arms of study. WHO FC, World Health Organization functional class. 1. Galiè G et al. Eur Respir J 2014;44(Suppl 58): Frost A et al. Am J Respir Crit Care Med 2015;191:A4781.

23 Upfront triple combination therapy in PAH was favorable in a small study population Retrospective pilot study of bosentan + sildenafil + i.v. epoprostenol Copyright protected content. Please view original content in the following reference: Sitbon O et al. Eur Respir J 2014;43: Improvements (p<0.01) in 6MWD and hemodynamics after 4 months therapy in 18 out of 19 patients who initiated the regimen Solid squares represent mean; boxes and diamonds represent SD; whiskers represent range. Enrollment between Dec 2007 and July 2012; observational period ended in July Final follow-up: time-point of complete evaluation including right heart catheterization. 6MWD, 6-minute walking distance; i.v., intravenous; PAP, pulmonary arterial pressure; PVR pulmonary vascular resistance. Sitbon O et al. Eur Respir J 2014;43:

24 Riociguat: a PH-targeted therapy with proven long-term efficacy in both PAH and CTEPH Class sgc stimulator Prostanoid ERA PDE5 inhibitor a Not currently approved. by European Medicines Agency. Drug Riociguat Epoprostenol Treprostinil Iloprost Selexipag a Bosentan Ambrisentan Macitentan Sildenafil Tadalafil ERA, endothelin receptor antagonist; PDE5, phosphodiesterase type 5; sgc, soluble guanylate cyclase. Randomized pivotal clinical trials in specific PH groups 1. Ghofrani HA et al. N Engl J Med 2013;369: Rubin LJ et al. Eur Respir J 2015 May;45: Simonneau G et al. Eur Respir J 2014;44(Suppl.58):P Ghofrani HA et al. N Engl J Med 2013;369: Simonneau G et al. Eur Respir J 2015 ;45: Simonneau G et al. Eur Respir J 2014;44(Suppl.58):P Barst RJ et al. N Engl J Med 1996;334: Simonneau G et al. Am J Respir Crit Care Med 2002;165: Olschewski H et al. N Engl J Med 2002;347: McLaughlin VV et al. J Am Coll Cardiol 2015;65(10S):A Rubin LJ et al. N Engl J Med 2002;346: Jaïs X et al. J Am Coll Cardiol 2008;52: Galiè N et al. Circulation 2008;117: GlaxoSmithKline. AMBER I. Available at: (accessed Aug 2015). 15. Pulido T et al. N Engl J Med 2013;369: Actelion. MERIT-1. Available at: (accessed Aug 2015). 17. Galiè N et al. N Engl J Med : Galiè N et al. Circulation 2009;119: PAH PATENT-1 and Barst (1996) 7 Simonneau (2002) 8 AIR 9 CTEPH CHEST-1 and GRIPHON 10 BREATHE-1 11 ARIES-1 and SERAPHIN 15 SUPER-1 17 PHIRST 18 BENEFiT 12 completed AMBER I 14 recruiting MERIT-1 16 = Met primary endpoint = Failed to meet primary endpoint

25 Summary: PAH Many patients with PAH do not achieve treatment goals, requiring escalation or change of therapy: Increase dose or transition Combination of two or more drugs Referral to expert centers for assessment by MDT team is essential to ensure patients are provided with the best available care Initial monotherapy is recommended in treatment naïve, low or intermediate risk patients in WHO FC II III Combination therapy is an attractive option for patients in WHO FC II IV: Upfront dual therapy in WHO FC II III Triple therapy in WHO FC III IV Sequential add-on dual or triple therapy in patients with inadequate treatment response to initial approaches MDT, multidisciplinary team; WHO FC, World Health Organization functional class. Galiè N et al. Eur Heart J 2015: doi: /eurheartj/ehv317.

26 Thanks