Update on the Treatment of Pulmonary Arterial Hypertension

Fernandes, Caio J.; Calderaro, Daniela; Assad, Ana Paula Luppino; Salibe-Filho, William; Kato-Morinaga, Luciana Tamie; Hoette, Susana; Piloto, Bruna; Castro, Marcela Araújo; Lisboa, Roberta Pontes; Silva, Taysa Antonia Felix da; Martins, Murillo de Araújo; Alves-Jr, Jose L.; Jardim, Carlos; Terra-Filho, Mario; Souza, Rogerio de

doi:10.36660/abc.20200702

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Review Article • Arq. Bras. Cardiol. 117 (4) • Oct 2021 • https://doi.org/10.36660/abc.20200702 copy

Update on the Treatment of Pulmonary Arterial Hypertension

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

In the last decades, important advances have been made in the treatment of pulmonary arterial hypertension (PAH), a severe, progressive, incurable, and potentially fatal disease. For an adequate therapy, correct hemodynamic diagnosis and etiology classification are fundamental. Many etiologies – rheumatic disease, portal hypertension, congenital heart diseases, schistosomiasis – require specific measures, in addition to drug therapy for PAH. The specific therapy for PAH is based on medications that act on three pathophysiological pathways – prostacyclin, endothelin, and nitric oxide pathways. These drugs have multiple presentations (oral, intravenous, subcutaneous, and inhaled) and have changed the history of PAH. This review presents an overview of drug therapy strategies and different forms and peculiarities of PAH.

Pulmonary Arterial Hypertension; Pulmonary Hypertension; Diagnosis; Therapeutics

1. Pulmonary arterial hypertension (PAH)
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drug- or toxin-induced PAH
1.4 PAH 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
1.5 Calcium channel blocker responders
1.6 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
1.7 Persistent pulmonary hypertension of the newborn
2. Pulmonary hypertension (PH) due to left heart disease
2.1 Heart failure with preserved ejection fraction
2.2 Heart failure with reduced ejection fraction
2.3 Valvular heart disease
2.4 Congenital or acquired heart diseases leading to post-capillary pulmonary hypertension
3. Pulmonary hypertension due to pulmonary disease and/or hypoxia
3.1 Obstructive lung disease
3.2 Restrictive lung disease
3.3 Other lung diseases with mixed obstructive/restrictive pattern
3.4 Hypoxia without structural lung disease
3.5 Developmental lung diseases
4. Pulmonary hypertension due to pulmonary artery obstruction
4.1 Pulmonary hypertension due to chronic pulmonary thromboembolism
4.2 Other pulmonary artery obstructions
5. Pulmonary hypertension with multifactorial and/or unknown mechanisms
5.1 Hematological diseases: chronic hemolytic anemia, myeloproliferative disorders
5.2 Systemic and metabolic diseases: pulmonary Langerhans cell histiocytosis, Gaucher’s disease, glycogen storage disease, neurofibromatosis and sarcoidosis
5.3 Others: fibrosing mediastinitis, chronic renal failure, with or without hemodialysis
5.4 Complex congenital heart diseases

Drugs	Posology	Administration route	Common side effects	Pathway	Reference
Iloprost	2,5-5 mcg 6-9x day	Inhaled	Cough Local irritation	PGI₂	³⁴
Selexipag	200-1600 mcg 2x day	Oral	Headache Diarrhea	PGI₂	³⁵
Ambrisentan	5-10 mg 1 x day	Oral	Anemia Edema	ET1	⁴⁰
Bosentan	62,5-125 mg 2x day	Oral	Anemia Hepatotoxicity	ET1	³⁸
Macitentan	10 mg 1x day	Oral	Anemia Hepatotoxicity Edema	ET1	³⁹
Sildenafil	20-80 mg 3x day	Oral	Headache	NO	⁴³
Riociguat	0,5-2,5 mg 3x day	Oral	Headache Hypotension	NO	⁴⁵

Prognostic determinants	One-year mortality (estimated)

	Low risk < 5%	Intermediate risk 5-10%	High risk > 10%
Clinical signs of right ventricular failure	Absent	Absent	Present
Progression of symptoms	None	Slow	Fast
Syncope	None	Occasionally*	Repeatedly **
WHO FC	I, II	III	IV
6M-WD	> 440 m	165-440 m	< 165 m
Cardiopulmonary exercise test	Peak VO₂> 15 mL/min/Kg (>65% predicted ) VE/VCO₂slope < 36	Peak VO₂11–15 mL/min/Kg (35-65% predicted) VE/VCO₂slope 36–44.9	Peak VO₂< 11mL/min/Kg (<35% predicted) VE/VCO₂≥ 45
NT-proBNP plasma levels	BNP < 50 ng/l NT-proBNP < 300 ng/mL	BNP 50–300 ng/l NT-proBNP 300–1,400 ng/L	BNP > 300 ng/L NT-proBNP > 1,400 ng/L
Imaging tests (ECHO, chest magnetic resonance)	Right atrial area < 18 cm² Absence of pericardial effusion	Right atrial area 18–26 cm² Absent or minimal pericardial effusion	Right atrial area > 26 cm² Presence of pericardial effusion
Hemodynamic parameters	Right atrial pressure < 8 mmHg CI ≥ 2.5 L/min/m² ScvO₂> 65%	Right atrial pressure 8–14 mmHg CI 2.0–2.4 L/min/m² ScvO₂60–65%	Right atrial pressure > 14 mmHg CI < 2.0 L/min/m² ScvO2 < 60%

	Risk factors	Screening
SS	Long term disease Telangiectasias Anti-centromere Reduced DLCO or FVC/DLCO>1.6	-Annually in asymptomatic patients Echocardiogram ± biomarkers/ PFT or DETECT algorithm BNP/NTproBNP and PFT ± ECHO
LES	Serositis Antibodies: Antiphospholipid, RNP and Ro	In symptomatic patients only

	Immunosuppression (IS)	Specific therapy
SS	Not recommended	According to risk stratification
SEL functional class I/II	CCP and GCT for six months	If PH continues after IS
SEL functional class III/IV	CCP and GCT plus specific therapy	Associated with IS, according to risk stratification
MCTD functional class I/II	CCP and GCT for six months	If PH continues after IS
MCTD functional class III/IV	CCP and GCT plus specific therapy	Associated with IS, according to risk stratification

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E-mail: revista@cardiol.br

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[1] Mailing Address: Caio J. Fernandes • Unidade de Circulação Pulmonar - Divisão de Pneumologia – Incor - Faculdade de Medicina da Universidade de São Paulo - Av. Dr. Enéas de Carvalho Aguiar, 44. Postal Code 05403-000, São Paulo, SP - Brazil E-mail: cjcfernandes@yahoo.com.br