Meta-Analysis of Monotherapy Versus Combination Therapy for Pulmonary Arterial Hypertension

doi:10.1016/j.amjcard.2011.06.021

The American Journal of Cardiology

Volume 108, Issue 8, 15 October 2011, Pages 1177-1182

https://doi.org/10.1016/j.amjcard.2011.06.021 Get rights and content

Previous studies comparing combination therapy (CT) of pulmonary vasodilators to monotherapy (MT) in patients with pulmonary arterial hypertension (PAH) report conflicting results as to whether CT is more efficacious than MT. We systematically searched the Cochrane Library, EMBASE, and MEDLINE databases for randomized controlled trials comparing CT to MT for patients with PAH. Data were pooled using the DerSimonian–Laird random-effects model. Six randomized controlled trials including 729 patients met our inclusion criteria. Follow-up ranged from 12 to 16 weeks. Compared to MT, CT resulted in a modest increase in 6-minute walk distance at the end of follow-up (weighted mean difference 25.2 m, 95% confidence interval [CI] 13.3 to 37.2). CT did not decrease mortality (risk ratio [RR] 0.42, 95% CI 0.08 to 2.25), admissions for worsening PAH (RR 0.72, 95% CI 0.36 to 1.44), or escalation of therapy (RR 0.36, 95% CI 0.09 to 1.39) and did not improve New York Heart Association functional class (RR 1.32, 95% CI 0.38 to 4.5) compared to MT. Incidence of study-drug discontinuation was similar between groups (RR 0.89, 95% CI 0.53 to 1.48). CT did not decrease the combined end point of mortality, admission for worsening PAH, lung transplantation, or escalation of PAH therapy (RR 0.42, 95% CI 0.17 to 1.04). In conclusion, this meta-analysis suggests that in PAH CT does not offer an advantage over MT apart from modestly increasing exercise capacity. However, given the paucity of good-quality data, more studies are required to define the efficacy of CT in this population before establishing final guidelines.

Section snippets

Methods

We searched MEDLINE, EMBASE, and the Cochrane Library from 1980 through January 2011. Search terms were designed to provide maximum sensitivity in detecting therapeutic trials in PAH. The search terms were “([prostanoid or epoprostenol or prostacyclin or Flolan or iloprost or Ventavis or Remodulin or treprostinil] or [‘endothelin receptor antagonist’ or bosentan or Tracleer or sitaxsentan or Thelin or ambrisentan or Volibris] or [‘phosphodiesterase 5 inhibitor’ or sildenafil or Viagra or

Results

Our database search identified 5,222 studies after removal of duplicate studies (Figure 1). No further articles were retrieved by manual searching. After reviewing title and abstracts to exclude irrelevant articles, 70 studies were reviewed in detail. Of these, 64 were rejected (11 narrative reviews or editorials, 34 uncontrolled case series/observational studies, 18 single-case reports). One RCT (Pulmonary Arterial Hypertension and Response to Tadalafil [PHIRST-1] study comparing tadalafil to

Discussion

We performed a meta-analysis of 6 RCTs of CT versus MT for treating patients with PAH. The clinical worsening end points examined were death, admission to hospital, transplantation and escalation of PAH therapy, a combined end point of these events (death, admission, transplantation, and treatment escalation), and change in 6MWD. In the entire meta-analysis of clinical worsening events (alone and combined) CT did not have a statistically significant beneficial effect. 6MWD did increase

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Cited by (55)

Efficacy and safety of sequential combination therapy for pulmonary arterial hypertension: A meta-analysis of Randomized-Controlled Trials
2022, Pulmonary Pharmacology and Therapeutics
Previous meta-analyses of pulmonary arterial hypertension (PAH) combination therapy pooled sequential and initial combination together, which might threaten their authenticity and clinical significance for the difference between two strategies.
PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sequential combination therapy (SCT) with background therapy (BT) in PAH patients. Raw data were extracted to calculate risk ratio (RR) or weighted mean difference (WMD) for predefined efficacy and safety outcomes. Mantel-Haenszel fixed or random effects model was used based on heterogeneity.
17 RCTs involving 4343 patients (97.2% of patients with WHO-FC II-III) were included. SCT decreased clinical worsening (RR 0.66, 95% CI 0.58 to 0.76), nonfatal clinical worsening (RR 0.61, 95% CI 0.52 to 0.71), functional class (decrease of 28% in the portion of patients with WHO-FC worsening and increase of 33% in the portion of patients with WHO-FC improvement), and increased 6-min walk distance (WMD 17.68 m, 95% CI 10.16 to 25.20), but didn't reduce mortality, lung transplantation, admission to hospital, and treatment escalation compared with BT. Although any adverse event and serious adverse event were similar between SCT and BT, SCT increased all-cause treatment discontinuation (RR 1.49, 95% CI 1.30 to 1.71) and drug-related treatment discontinuation (RR 2.30, 95% CI 1.86 to 2.84) with higher incidence of headache, flushing, nausea, diarrhoea and jaw pain.
For WHO-FC II-III PAH patients who have established BT, our study reinforced the recommendation of SCT to improve clinical worsening, functional status, and exercise capacity, although with higher incidence of side-effects and withdrawal.
Efficacy and tolerability of pharmacological interventions for pulmonary arterial hypertension: A network meta-analysis
2018, Pulmonary Pharmacology and Therapeutics
This network meta-analysis (NMA) is designed to compare the efficacy and tolerability of various therapies and combinations for pulmonary arterial hypertension (PAH).
We conducted a systematic search in databases PubMed, Embase, and Cochrane Library. Treatment efficacy and tolerability were compared by synthesizing direct and indirect evidence. The surface under the curve ranking area was utilized to rank multiple interventions.
A total of 43 randomized clinical trials were included in our NMA. With regard to efficacy outcomes, including 6 min walking distance (6MWD), functional class amelioration (FCA), death, clinical worsening (CW), pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), cardiac index (CI), and mean right atrial pressure (mRAP), endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitor (PDE-5Is), ERA combined with PDE-5Is (EAP), and prostacyclin analogs (PGI) combined with ERA (PAE) performed better than others. Meanwhile PAP and PGE demonstrated better than others in tolerability. Overall, EAP and PAE showed good efficacy and were well-tolerated among all therapies.
Overall, we recommend EAP as the optimal choice for patients with PAH in clinical practice and PAE as suboptimal in view of their desirable performance in efficacy. Most of the combination therapies performed better than monotherapies.
Combination Therapy for Pulmonary Arterial Hypertension: A Systematic Review and Meta-analysis
2016, Canadian Journal of Cardiology
Citation Excerpt :
The relative benefits of sequential vs upfront CT have not yet been formally tested in a clinical trial. Another source of heterogeneity in the studies was the definition of the CCW end point, which has become prominent only in the past few years.10,11 All recent trials included death, hospitalization, treatment escalation, transplantation, and septostomy in the CCW definition, along with a general “clinical worsening” event.
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.
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.
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).
In this highly comprehensive meta-analysis, CT reduces the risk of CCW events in patients with PAH and brings physiological improvement.
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.
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.
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).
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.
Time to consider death in clinical trials for PAH
2016, The Lancet Respiratory Medicine
Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension: A Meta-analysis of Randomized Controlled Trials
2016, Chest
Citation Excerpt :
When the clinical response is considered inadequate, combination therapy is considered.2 Previous meta-analyses of the efficacy of combination therapy vs monotherapy concluded that combination therapy can improve clinical outcomes but has no proven effect on mortality.6,46 Our meta-analysis RCTs reinforced earlier results by including recently published RCTs.
Previous meta-analyses of pulmonary arterial hypertension (PAH)-specific therapy for PAH pooled PAH-specific combination therapy and monotherapy. This flaw may threaten the authenticity of their findings.
PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials that evaluated any PAH-specific medications in the treatment of PAH. We calculated ORs with 95% CIs for dichotomous data and standardized mean differences for continuous data.
In total, 35 randomized controlled trials involving 6,702 patients were included. In monotherapy vs placebo/conventional therapy, significance was obtained in mortality reduction (OR, 0.50 [95% CI, 0.33 to 0.76]; P = .001), 6-min walk test (mean difference, 31.10 m [95% CI, 25.40 to 36.80]; P < .00001), New York Heart Association/World Health Organization functional class (OR, 2.48 [95% CI, 1.51 to 4.07]; P = .0003), and hemodynamic status based on mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and incidence of withdrawal due to adverse effects. In combination therapy vs monotherapy, significance was reached for the 6-min walk test (mean difference, 19.96 m [95% CI, 15.35 to 24.57]; P < .00001), functional class (OR, 1.65 [95% CI, 1.20 to 2.28]; P = .002), hemodynamic status, and incidence of withdrawal due to adverse effects (OR, 2.01 [95% CI, 1.54 to 2.61]; P < .00001) but not for mortality reduction (OR, 0.98 [95% CI, 0.57 to 1.68]; P = .94).
Our meta-analysis revealed that PAH-specific monotherapy could improve mortality, exercise capacity, functional class, and hemodynamic status compared with placebo or conventional therapy. However, combination therapy could further improve exercise capacity, functional class, and hemodynamic status compared with monotherapy, but it had no proven effect on mortality. Combination therapy had a much higher incidence of withdrawal due to adverse effects than monotherapy.
Combination therapy versus monotherapy for pulmonary arterial hypertension: A meta-analysis
2016, The Lancet Respiratory Medicine
Citation Excerpt :
15 trials investigated the effect of sequential add-on PAH-specific combination therapies,11–14,29–31,33–40 while two assessed the effect of upfront combination therapy,10,32 compared with PAH-specific monotherapy in adult patients with PAH (table 1). The 15 sequential add-on trials assessed the additional effect of oral or inhaled prostaglandins (n=5),11,12,14,37,38 phosphodiesterase-5 inhibitors (n=4),13,31,33,39 endothelin receptor antagonists (n=3),34,35,40 soluble guanylate cyclase stimulators (n=1),29 and a selective prostacyclin receptor agonist (n=2).30,36 The two upfront therapy trials assessed the combination of an endothelin receptor antagonist with either intravenous prostaglandins (n=1),10 or a phosphodiesterase type 5 inhibitor (n=1).32
Several randomised controlled studies and a previous meta-analysis have reported conflicting results regarding the effect of combined targeted therapy compared with monotherapy for pulmonary arterial hypertension (PAH). We did a systematic review and meta-analysis to assess the effects of a combination of PAH-specific therapies compared with monotherapy on predefined clinical worsening in PAH.
We searched MEDLINE, Embase, and the Cochrane Library for reports published from Jan 1, 1990, to May 31, 2015, of prospective randomised controlled trials of at least 12 weeks that assessed a combination of PAH-specific therapies (upfront and sequential add-on) compared with background PAH-specific monotherapy in patients older than 12 years. We extracted data from the reports, and assessed the primary outcome of risk of clinical worsening, as defined a priori in each trial, using the Mantel-Haenszel method based on a fixed-effects model.
Of 2017 studies that we identified from our search, we included 17 (4095 patients) in our analysis. 15 studies assessed clinical worsening and were included in the primary analysis. Combined therapy was associated with significant risk reduction for clinical worsening compared with monotherapy (combined therapy 17% [332 of 1940 patients] vs monotherapy 28% [517 of 1862 patients], risk ratio [RR] 0·65 [95% CI 0·58–0·72], p<0·00001). We noted no heterogeneity between the studies (I²=18%, p_homogeneity=0·25). A publication bias was suggested by the results of an Egger test (t=–2·3982, p=0·031), but when we excluded the four studies with the highest SEs, the RR for clinical worsening was identical (0·65 [95% CI 0·58–0·73], p<0·00001).
In our analysis, combined therapy for PAH was associated with a significant reduction in clinical worsening compared with monotherapy. However, our study was limited by the variable definition of clinical worsening among the trials and possible publication bias. Because many patients still had clinical worsening with combination therapy, identification of innovative therapeutic targets for PAH is thus urgently needed.
None.

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: This work was funded by the Bank of Montreal Center for the Study of Heart Disease in Women at the Jewish General Hospital, Montreal, Quebec, Canada. Dr. Fox is supported by the William and Ida Pencer Family Foundation at the Jewish General Hospital, Montreal, Quebec, Canada and the American Fellowship Program for Medicine in Israel, Boston, Massachusetts. Dr. Shimony is supported by the Azrieli Fellowship Fund Montreal, Quebec, Canada and the American Fellowship Program for Medicine in Israel.

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MiscellaneousMeta-Analysis of Monotherapy Versus Combination Therapy for Pulmonary Arterial Hypertension

Section snippets

Methods

Results

Discussion

Am Heart J

J Am Coll Cardiol

Control Clin Trials

Control Clin Trials

J Heart Lung Transplant

Circulation

A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension

N Engl J Med

Bosentan therapy for pulmonary arterial hypertension

N Engl J Med

Sildenafil citrate therapy for pulmonary arterial hypertension

N Engl J Med

Pharmacologic principles for combination therapy

Proc Am Thorac Soc

Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial

Ann Intern Med

Miscellaneous
Meta-Analysis of Monotherapy Versus Combination Therapy for Pulmonary Arterial Hypertension