Abstract
Background
Combination therapy (CT) for patients with pulmonary arterial hypertension (PAH) has
been recommended for many years, despite weak evidence of efficacy over monotherapy
(MT). A previous meta-analysis comparing CT vs MT with pulmonary vasodilators failed
to demonstrate a clear reduction in clinical worsening events.
Methods
We searched for relevant articles in PubMed, EMBASE, the Cochrane Database, and clinicaltrials.gov; we also manually searched review articles and conference abstracts from 1980-December
2015. Target articles were double-blinded studies of 2 or more pulmonary vasodilators
given in combination vs monotherapy for treatment of patients with PAH. The principal
outcome of interest was “combined clinical worsening” (CCW) events (including but
not limited to death or hospitalization). Data on physiological outcomes were also
explored. Meta-analysis was performed using the DerSimonian and Laird random-effects
model.
Results
We extracted data from 18 randomized controlled trials (RCTs) (N = 4162). CT was associated
with a significant 38% reduction of risk of CCW (15 RCTs: n = 3906; risk ratio [RR],
0.62; 95% confidence interval [CI], 0.50-0.77). This reduction in risk was driven
by a reduction in nonfatal end points (12 RCTs: n = 2611; RR, 0.56; 95% CI, 0.40-0.78)
and not by a reduction of mortality (12 RCTs: n = 2717; RR, 0.79; 95% CI, 0.53-1.17).
CT was also associated with improvement in 6-minute walking distance (10 RCTs: n =
1553; weighted mean difference [WMD], +23.0 m; 95% CI, 15.9-30.1), improved functional
class (9 RCTs: n = 1737; RR, 1.26; 95% CI, 1.05-1.51), and beneficial effects on pulmonary
hemodynamics such as cardiac index (WMD, +0.35 L/min/m; 95% CI, 0.14-0.56).
Conclusions
In this highly comprehensive meta-analysis, CT reduces the risk of CCW events in patients
with PAH and brings physiological improvement.
Résumé
Introduction
Le traitement combiné (TC) chez les patients atteints d’hypertension artérielle pulmonaire
(HAP) est recommandé depuis plusieurs années en dépit de la faiblesse des preuves
sur l’efficacité par rapport à la monothérapie (MT). Une méta-analyse précédente qui
comparait le TC vs la MT par vasodilatateurs pulmonaires n’a pas démontré de réduction nette des événements
de détérioration clinique.
Méthodes
Nous avons recherché des articles pertinents dans les banques de données PubMed, EMBASE,
Cochrane et clinicaltrials.gov; nous avons également recherché manuellement des articles de revues et des résumés
de conférences de 1980 à décembre 2015. Les articles cibles constituaient des études
à double insu sur 2 vasodilatateurs pulmonaires ou plus donnés en combinaison vs en monothérapie pour traiter des patients atteints d’HAP. Le critère d’intérêt principal
était les événements de « détérioration clinique combinée » (DCC) (y compris, sans
toutefois s’y limiter, le décès ou l’hospitalisation). Nous avons également étudié
les données sur les résultats physiologiques. Nous avons réalisé la méta-analyse à
l’aide du modèle à effets aléatoires selon DerSimonian et Laird.
Résultats
Nous avons extrait les données de 18 essais cliniques aléatoires (ECA) (n = 4162).
Le TC était associé à une réduction significative du risque de DCC de 38 % (15 ECA
: n = 3906; risque relatif [RR], 0,62; intervalle de confiance [IC] à 95 %, 0,50-0,77).
Cette réduction de risque était attribuable à une réduction des critères d’évaluation
non fatals (12 ECA : n = 2611; RR, 0,56; IC à 95 %, 0,40-0,78) et non à une réduction
de la mortalité (12 ECA : n = 2717; RR, 0,79; IC à 95 %, 0,53-1,17). Le TC était également
associé à l’amélioration de la distance de marche en 6 minutes (10 ECA : n = 1553;
différence moyenne pondérée [DMP], +23,0 m; IC à 95 %, 15,9-30,1), à l’amélioration
de la classification fonctionnelle (9 ECA : n = 1737; RR, 1,26; IC à 95 %, 1,05-1,51),
et aux effets bénéfiques sur l’hémodynamique pulmonaire tels que l’index cardiaque
(DMP, +0,35 l/min/m; IC à 95 %, 0,14-0,56).
Conclusions
Dans le cadre de cette méta-analyse vraiment complète, le TC réduit le risque d’événements
de DCC chez les patients atteints d’HAP et apporte une amélioration physiologique.
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Article info
Publication history
Published online: March 16, 2016
Accepted:
March 8,
2016
Received:
February 27,
2016
Footnotes
See page 1528 for disclosure information.
Identification
Copyright
© 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
