Pulmonary hypertension

Anton Vonk Noordegraaf; Joanne A. Groeneveldt; Harm Jan Bogaard

doi:10.1183/16000617.0096-2015

Tables

TABLE 1

Updated classification of pulmonary hypertension (PH)

1 Pulmonary arterial hypertension

1.1 Idiopathic

1.2 Heritable

1.2.1 BMPR2 mutation

1.2.2 ALK1, ENG, SMAD9, CAV1 and KCNK3 mutation

1.2.3 Unknown

1.3 Drug and toxin induced

1.4 Associated with

1.4.1 Connective tissue disease

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart diseases

1.4.5 Schistosomiasis

1′ Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis

1′.1 Idiopathic

1′.2 Heritable

1′.2.1 EIF2AK4 mutation

1′.2.2 Other mutations

1′.3 Drug, toxin and radiation induced

1′.4 Associated with

1′.4.1 Connective tissue disease

1′.4.2 HIV infection

1″ Persistent PH of the newborn

2 PH due to left heart disease

2.1 Left ventricular systolic dysfunction

2.2 Left ventricular diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

3 PH due to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

3.4 Sleep disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

4 Chronic thromboembolic PH

5 PH with unclear multifactorial mechanisms

5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders and splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis and lymphangioleiomyomatosis

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease and thyroid disorders

5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure and segmental PH

BMPR: bone morphogenic protein receptor type II; ALK1: activin receptor-like kinase 1; ENG: endoglin; CAV1: caveolin-1; KCNK3: potassium channel, two pore domain subfamily K, member 3; EIF2AK4: eukaryotic translation initiation factor 2α kinase 4. Reproduced and modified from [1].

TABLE 2

Overview of clinical trials in pulmonary arterial hypertension (PAH) and chronic thromboembolic hypertension (CTEPH) in 2015

First author [ref.]	Therapy	Diagnosis	Patients n	Study design	Follow-up	Primary end-point(s)	Conclusion
Chen [9]	Pulmonary artery denervation	WHO group 1, 2 and 4	66	Phase II, non-randomised, open-label study	1 year	Haemodynamic, functional and clinical response	PADN procedure was associated with favourable 1-year outcomes
Khan [10]	Ranolazine 1000 mg twice daily	PAH	11	Phase I	3 months	Safety and tolerability	No major adverse events
Ruiter [11]	Intravenous iron	Iron-deficient iPAH	15	Open-label intervention study	12 weeks	Change in 6MWD	No significant increase in 6MWD
Hassoun [12]	Tadalafil 40 mg and ambrisentan 10 mg	SSc-PAH	24	Open-label, prospective clinical trial	36 weeks	Changes in PVR and RV mass	Significant decrease in PVR and RV mass
Galiè [13]	Tadalafil 40 mg and/or ambrisentan 10 mg	PAH NYHA II–III	500	Randomised, double-blind, phase 3–4 study	24 weeks	First event of clinical failure	HR for event of clinical failure was significantly reduced in combination therapy group compared to mono therapy groups
Ehlken [14]	Low-dose exercise training 4–7 days per week	PAH, CTEPH	87	Randomised controlled trial	15 weeks	Change in peak V′_O₂ per kg	Peak V′_O₂ per kg increased after low-dose exercise training
Frost [15]	Imatinib	PAH	78	Open-label extension study	Up to 204 weeks	Long-term safety and tolerability	SAEs and safety concerns preclude the use of imatinib in the treatment of PAH
Granton [16]	Endothelial NO synthase gene-enhanced progenitor cell therapy	PAH refractory to PAH therapy	7	Phase I, dose-escalating trial	6 months	Tolerability	Delivery of endothelial progenitor cells overexpressing endothelial NO synthase was tolerated haemodynamically in patients with PAH
McLaughlin [17]	Addition of bosentan/placebo to sildenafil	PAH patients on sildenafil therapy	334	Double-blind, event-driven trial	Mean±sd 39.7±22.6 months	Time to morbidity/mortality event	No significant effect of addition of bosentan to sildenafil on time to morbidity/mortality was observed
Speich [18]	Imatinib	PAH	15	Open-label, observational study	Median 37 months	Efficacy and tolerability	Long-term treatment with imatinib may improve functional class and quality of life The occurrence of 5% SDH per patient-year is concerning
Provencher [19]	Thermostable epoprostenol sodium versus epoprostenol sodium	PAH	16	Multicentre, open-label, single-arm study	4 weeks	HRQoL, ease of administration and change in dose from baseline	No significant improvement in HRQoL was measured Subjects preferred the thermostable product The products had similar safety and efficacy profiles
Galiè [20]	Riociguat and sildenafil	PAH patients on sildenafil therapy	17	Blinded, randomised controlled and extension study	12 weeks, thereafter extension	Change in supine SBP and safety	No difference in SBP was observed Potentially unfavourable safety signals with sildenafil plus riociguat were observed
Rubin [21]	Riociguat	PAH	396	Open-label extension study	Mean 95 weeks	Safety, tolerability and efficacy (6MWD, WHO functional class)	Long-term riociguat was well tolerated in patients with PAH Data support sustained efficacy on 6MWD and WHO functional class
Simonneau [22]	Riociguat	CTEPH or persistent PH after PEA	237	Open label extension study	Mean 83 weeks	Safety, tolerability and efficacy (6MWD, WHO functional class)	Long-term riociguat was well tolerated in patients with CTEPH Data support sustained efficacy on 6MWD and WHO functional class
Chin [23]	Treprostinil sodium	PAH	206	Open-label extension study	Up to 24 months	6MWD	Long-term therapy with inhaled treprostinil demonstrated persistent benefit for PAH patients who remained on therapy for up to 24 months
Sitbon [24]	Selexipag versus placebo	PAH	1156	Blinded, randomised controlled trial	Median 63.7 weeks (placebo), 70.7 weeks (selexipag)	Time-to-event, composite of death or a complication related to PAH	The risk for the primary composite end-point was significantly lower among patients on selexipag compared to patients on placebo

WHO: World Health Organisation; iPAH: idiopathic pulmonary arterial hypertension; SSc-PAH: systemic sclerosis-associated pulmonary arterial hypertension; NYHA: New York Heart Association functional class; PH: pulmonary hypertension; PEA: pulmonary endarterectomy; 6MWD: 6-min walk distance; PVR: pulmonary vascular resistance; RV: right ventricular; V′_O₂: oxygen uptake; HRQoL: health-related quality of life; SBP: systolic blood pressure; PADN: pulmonary artery denervation; HR: hazard ratio; SAE: serious adverse event; SDH: subdural haematoma.