Comparison of the efficacy and safety of thrombectomy devices in acute stroke : a network meta-analysis of randomized trials

2017 ◽  
Vol 10 (8) ◽  
pp. 729-734 ◽  
Author(s):  
Hamidreza Saber ◽  
Gary B Rajah ◽  
Riyad Y Kherallah ◽  
Ashutosh P Jadhav ◽  
Sandra Narayanan
Keyword(s):  
Meta Analysis ◽  
Credible Interval ◽  
Functional Independence ◽  
Stent Retriever ◽  
First Line ◽  
Level Data ◽  
Efficacy Outcome ◽  
Safety Outcomes ◽  
Symptomatic Intracranial Hemorrhage ◽  
Mr Clean

IntroductionMechanical thrombectomy (MT) is increasingly used for large-vessel occlusions (LVO), but randomized clinical trial (RCT) level data with regard to differences in clinical outcomes of MT devices are limited. We conducted a network meta-analysis (NMA) that enables comparison of modern MT devices (Trevo, Solitaire, Aspiration) and strategies (stent retriever vs aspiration) across trials.MethodsRelevant RCTs were identified by a systematic review. The efficacy outcome was 90-day functional independence (modified Rankin Scale (mRS) score 0–2). Safety outcomes were 90-day catastrophic outcome (mRS 5–6) and symptomatic intracranial hemorrhage (sICH). Fixed-effect Bayesian NMA was performed to calculate risk estimates and the rank probabilities.ResultsIn a NMA of six relevant RCTs (SWIFT, TREVO2, EXTEND-IA, SWIFT-PRIME, REVASCAT, THERAPY; total of 871 patients, 472 Solitaire vs medical-only, 108 Aspiration vs medical-only, 178 Trevo vs Merci, and 113 Solitaire vs Merci) with medical-only arm as the reference, Trevo had the greatest functional independence (OR 4.14, 95% credible interval (CrI) 1.41–11.80; top rank probability 92%) followed by Solitaire (OR 2.55, 95% CrI 1.75–3.74; top rank probability 72%). Solitaire and Aspiration devices had the greatest top rank probability with respect to low sICH and catastrophic outcomes (76% and 91%, respectively), but without significant differences between each other. In a separate network of seven RCTs (MR-CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME, REVASCAT, THERAPY, ASTER; 1737 patients), first-line stent retriever was associated with a higher top rank probability of functional independence than aspiration (95% vs 54%), with comparable safety outcomes.ConclusionsThese findings suggest that Trevo and Solitaire devices are associated with a greater likelihood of functional independence whereas Solitaire and Aspiration devices appear to be safer.

SOFIA catheter for direct aspiration of large vessel occlusion stroke: A single-center cohort and meta-analysis

2021 ◽  
pp. 159101992110053
Author(s):  
Federico Bolognini ◽  
Pablo A Lebedinsky ◽  
Mariano Musacchio ◽  
Mariette Delaitre ◽  
Abdoulaye M Traoré ◽  
...  
Keyword(s):  
Rescue Therapy ◽  
Meta Analysis ◽  
Functional Independence ◽  
Large Vessel ◽  
Study Cohort ◽  
Large Vessel Occlusion ◽  
First Line ◽  
Vessel Occlusion ◽  
Global Rate ◽  
Symptomatic Intracranial Hemorrhage

Background and Purpose Direct aspiration (DA) using large-bore distal aspiration catheters is an established strategy for the endovascular thrombectomy (EVT) of large-vessel occlusion stroke (LVOS). However, the performance of individual catheters like SOFIA has yet to be examined. Methods We present a cohort of 144 consecutive patients treated with first-line DA and SOFIA 6 F Plus catheter for LVOS. We also conducted a systematic review of the literature searching multiple databases for reports on thrombectomy with DA and SOFIA catheters and performed a meta-analysis of recanalization, safety, and clinical outcomes. Results In the study cohort a successful recanalization (mTICI 2b-3) rate of 75.7% was achieved with DA alone, the global rate for functional independence (90-day mRS 0-2) was 40.3%. For the metanalysis we selected nine articles that included a total of 758 patients treated with first-line thrombectomy with the SOFIA catheters. The mTICI 2b-3 rate was 71.6% (95%CI, 66.3-76.5%) while a rescue stent-retriever was used in 24.1% (95%CI, 17.7-31.9%) of cases. The overall mTICI2b-3 rate after DA and rescue therapy was 88.9% (95%CI, 82.6-93.1%). We found a pooled estimate of 45.6% (95%CI, 38.6-52.8%) for functional independence, a mortality within 90 days of 19% (95%CI, 14.1-25.0%) and a rate of 5.8% (95%CI, 4.2-8.0%) of symptomatic intracranial hemorrhage. Conclusion The DA approach for LVOS with the SOFIA catheters is highly effective with an efficacy and safety profile comparable to those found in contemporary thrombectomy trials and observational studies that use other devices or approaches.

First-line contact aspiration versus first-line stent retriever for acute posterior circulation strokes: an updated meta-analysis

2021 ◽  
pp. neurintsurg-2021-017497
Author(s):  
Gengfan Ye ◽  
Xuebin Wen ◽  
Hongcai Wang ◽  
Chengfeng Sun ◽  
Zhihao Pan ◽  
...  
Keyword(s):  
Observational Studies ◽  
Meta Analysis ◽  
Functional Independence ◽  
Posterior Circulation ◽  
Stent Retriever ◽  
First Line ◽  
Random Effects Models ◽  
First Pass

BackgroundBoth stent retriever (SR) and contact aspiration (CA) are widely used as first-line strategies for acute posterior circulation strokes (PCS). However, it is still unclear how CA and SR compare as the first-line treatment of acute PCS. Several new studies have been published recently, so we aimed to perform an updated meta-analysis.MethodsThe meta-analysis was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement. Random-effects models were performed to pool the outcomes and the value of I2 was calculated to assess the heterogeneity.ResultsTen observational studies with 1189 patients were included, among whom 492 received first-line CA and 697 received first-line SR. The pooled results revealed that first-line CA could achieve a significantly higher proportion of modified Thrombolysis In Cerebral Infarction (mTICI) 2b/3 (OR 1.90, 95% CI 1.33 to 2.71, I2=0%), mTICI 3 (OR 1.95, 95% CI 1.15 to 3.31, I2=59.6%), first-pass effect (OR 2.91, 95% CI 1.51 to 5.58, I2=0%), lower incidence of new-territory embolic events (OR 0.20, 95% CI 0.05 to 0.83, I2=0%), and shorter procedure time (mean difference −29.4 min, 95% CI −46.8 to −12.0 min, I2=62.8%) compared with first-line SR. At 90-day follow-up, patients subjected to first-line CA showed a higher functional independence (modified Rankin Scale score 0–2; OR 1.38, 95% CI 1.01 to 1.87, I2=23.5%) and a lower mortality (OR 0.71, 95% CI 0.50 to 1.00, p=0.050, I2=0%) than those subjected to first-line SR.ConclusionsThis meta-analysis suggests that the first-line CA strategy could achieve better recanalization and clinical outcomes for acute PCS than first-line SR. Limited by the quality of included studies, this conclusion should be drawn with caution.

EXPRESS: Stent Retriever Alone vs. Aspiration and Stent-Retriever Combination in Large Vessel Occlusion Stroke: A Matched Analysis

2021 ◽  
pp. 174749302110192
Author(s):  
Mahmoud H Mohammaden ◽  
Diogo C. Haussen ◽  
Leonardo Pisani ◽  
Alhamza Al-Bayati ◽  
Aaron Anderson ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Functional Independence ◽  
Stent Retriever ◽  
Sensitivity Analyses ◽  
First Line ◽  
Anterior Circulation ◽  
Vessel Occlusion ◽  
Guide Catheter ◽  
First Pass ◽  
Combined Technique

Background Three randomized clinical trials have reported similar safety and efficacy for contact aspiration (CA) and Stent-retriever (SR) thrombectomy. Aim We aimed to determine whether the Combined Technique (SR+CA) was superior to SR alone as first-line thrombectomy strategy in a patient cohort where balloon-guide catheter was universally used. Methods A prospectively maintained mechanical thrombectomy database from January 2018-December 2019 was reviewed. Patients were included if they had anterior circulation proximal occlusion ischemic stroke (intracranial ICA or MCA-M1/M2 segments) and underwent SR alone thrombectomy or SR+CA as first-line therapy. The primary outcome was the first-pass effect (FPE) (mTICI2c-3). Secondary outcomes included modified FPE (mTICI2b-3), successful reperfusion (mTICI2b-3) prior to and after any rescue strategy, and 90-day functional independence (mRS ≤2). Safety outcomes included rate of parenchymal hematoma (PH) type-2 and 90-day mortality. Sensitivity analyses were performed after dividing the overall cohort according to first-line modality into two matched groups. Results A total of 420 patients were included in the analysis (mean age 64.4 years; median baseline NIHSS 16[11-21]). As compared to first-line SR alone, first-line SR+CA resulted in similar rates of FPE (53% vs. 51%,aOR 1.122, 95%CI[0.745-1.691],p=0.58), mFPE (63% vs. 60.4%,aOR1.250, 95%CI[0.782-2.00],p=0.35), final successful reperfusion (97.6% vs. 98%,p=0.75) and higher chances of successful reperfusion prior to any rescue strategy (81.8% vs. 72.5%,aOR 2.033, 95%CI[1.209-3.419],p=0.007). Functional outcome and safety measures were comparable between both groups. Likewise, the matched analysis (148 patient-pairs) demonstrated comparable results for all clinical and angiographic outcomes except for significantly higher rates of successful reperfusion prior to any rescue strategies with the first-line SR+CA treatment (81.8% vs. 73.6%,aOR 1.881, 95%CI[1.039-3.405],p=0.037). Conclusions Our findings reinforce the findings of ASTER-2 trial in that the first-line thrombectomy with a Combined Technique did not result in increased rates of first-pass reperfusion or better clinical outcomes. However, addition of contact aspiration after initial SR failure might be beneficial in achieving earlier reperfusion.

Abstract TP12: Comparison of 3D Stent Retriever to Solitaire in Patients with Small Ischemic Cores: An Analysis of the Penumbra 3D Trial

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Adnan Siddiqui ◽  
Donald Frei ◽  
Albert J Yoo ◽  
Ghita Soulimani ◽  
Hope Buell ◽  
...  
Keyword(s):  
Functional Outcomes ◽  
Meta Analysis ◽  
Analysis Data ◽  
Functional Independence ◽  
Stent Retriever ◽  
The Novel ◽  
Inclusion Criteria ◽  
Aspiration System ◽  
Randomized Controlled ◽  
Scale 8

Introduction: A recent meta-analysis of four randomized controlled trials (RCTs) concluded that mechanical thrombectomy using Solitaire for large vessel ischemic stroke was effective with significantly reduced disability. Hypothesis: Our hypothesis was that treatment with the Penumbra Aspiration System and the novel 3D Stent Retriever would demonstrate similar angiographic and functional outcomes compared to use of Solitaire. Methods: The 3D trial was a RCT to compare the safety and effectiveness of the 3D Stent Retriever when used with the Penumbra Aspiration System (3D/PS) compared to the PS alone. Inclusion criteria for the 3D RCT included presentation with NIH Stroke Scale ≥ 8 and refractory to or not eligible for IV rtPA. Analysis compared reperfusion to mTICI 2b or 3 and functional independence (mRS 0-2 at 90 days) in a 3D Trial cohort with ASPECTS 8-10 vs the meta-analysis data reported by Campbell et al ( Stroke 2016). Results: One hundred four (104) of 198 patients met analysis criteria. Baseline ASPECTS (median [IQR]) were similar between the 3D Trial ASPECTS 8-10 cohort (3D/PS, PS, combined: 9 [8,10]) and Campbell group (9 [7,10]). Substantial reperfusion (mTICI 2b or 3) was experienced in 84.6% (44/52) of 3D/PS and 75.0% (39/52) of PS alone cases, similar to the Campbell group (76.6%). When both arms were pooled, results (79.8%) were also similar to Campbell. With regards to functional independence, both 3D cohorts and pooled trial results showed similar rates compared with Campbell (Figure). Conclusions: The novel 3D Stent Retriever + Penumbra System and the Penumbra Aspiration System alone showed similar reperfusion and functional outcomes compared to Solitaire.

scholarly journals Long-Term Outcomes of Mechanical Thrombectomy for Stroke: A Meta-Analysis

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
David J. McCarthy ◽  
Anthony Diaz ◽  
Dallas L. Sheinberg ◽  
Brian Snelling ◽  
Evan M. Luther ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Endovascular Therapy ◽  
Mechanical Thrombectomy ◽  
Meta Analysis ◽  
Functional Independence ◽  
Long Term Outcomes ◽  
Long Term Follow Up ◽  
Mr Clean

Mechanical thrombectomy (MT) has become the standard treatment for large vessel occlusion (LVO) in acute ischemic stroke (AIS). Few studies have investigated long-term outcomes for AIS treated with MT. Therefore, a pooled meta-analysis using data from randomized clinical trials (RCT) was performed to assess for long-term clinical outcomes. A systematic literature search was conducted on 27 September 2017, by searching the English literature in the Cochrane Library, MEDLINE, and Embase for RCTs investigating long-term outcomes (greater than standard 3-month timepoint) of endovascular intervention versus medical management for patients with AIS. The study was carried out according to PRISMA guidelines and random effects analysis was carried out to account for heterogeneity. Three trials were included: IMS III, MR CLEAN, and REVASCAT, comprising a total of 1,362 patients. Long-term clinical outcomes were available for 1-year follow-up in IMS III and REVASCAT and at 2 years in MR CLEAN. Functional independence at long-term follow-up favored endovascular stroke intervention (OR 1.51; p = 0.02). When stratified by LVO inclusion criteria, greater endovascular functional independence benefits were observed (OR 1.85; p = 0.0005). There was a significant difference between the 2 arms in favor of endovascular therapy for the quality of life at long-term follow-up (mean difference 0.11; p = 0.0002). No difference in mortality at long-term follow-up was observed (OR 0.82; p = 0.12). We conclude that endovascular therapy results in favorable outcomes at long-term follow-up for patients with acute ischemic stroke compared to standard medical treatment alone and that the 90-day timepoint offers a fair representation of the long-term outcomes.

scholarly journals Mechanical Thrombectomy in Acute Ischemic Stroke: A Meta-analysis of Stent Retrievers Versus Direct Aspiration Versus a Combined Approach

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Pavlos Texakalidis ◽  
Stefanos Giannopoulos ◽  
Theofilos Karasavvidis ◽  
Leonardo Rangel-Castilla ◽  
Dennis J Rivet ◽  
...  
Keyword(s):  
Mechanical Thrombectomy ◽  
Meta Analysis ◽  
Stent Retriever ◽  
Combined Approach ◽  
First Line ◽  
Symptomatic Intracerebral Hemorrhage ◽  
Rescue Treatment ◽  
Combined Use ◽  
Stent Retrievers ◽  
Event Rates

Abstract INTRODUCTION Recent randomized control trials (RCTs) established that mechanical thrombectomy is superior to medical therapy for patients with stroke. Stent retriever thrombectomy, direct aspiration and combined use of a stent retriever and aspiration have been alternatively used.The aim of this study was to compare the safety and efficacy profile of the different mechanical thrombectomy strategies. METHODS This study was performed according to the PRISMA guidelines. A random-effects model meta-analysis was conducted. RESULTS In all 21 studies with a total of 3059 patients were included. No differences were identified between the stent retriever and aspiration group in terms of modified thrombolysis in cerebral infarction (mTICI) 2b/3, mTICI 3 recanalization rates and favorable outcome (mRS = 2). Adverse event rates including 90-d mortality, symptomatic intracerebral hemorrhage (sICH), subarachnoid hemorrhage (SAH), parenchymal hematoma, new territory emboli, arterial dissection and perforation were similar between the stent retriever and direct aspiration group. Use of the stent retriever was associated with a higher risk of vasospasm (OR:2.59; 95% CI: 1.00-6.74; I2:0%) compared to direct aspiration. When compared with the direct aspiration group, the subgroup of patients who underwent mechanical thrombectomy with the combined approach as a first-line strategy had a higher likelihood of successful mTICI 2b/3 (OR: 1.76; 95% CI:1.23-2.52; I2: 5.5%) and mTICI 3 recanalization (OR: 2.29; 95% CI: 1.08-4.88; I2: 58%) although with a higher risk of SAH (OR: 4.33; 95% CI: 1.15-16.32; I2: -). In addition, patients who had thrombectomy with the combined approach as a rescue treatment after failure of first-line aspiration were at a significantly higher risk of sICH (OR: 3.49; 95% CI: 1.20-10.19; I2: 21.7%). CONCLUSION Stent retriever thrombectomy and direct aspiration were equally safe and effective. When compared with direct aspiration, the combined use of a stent retriever and aspiration as a first-line strategy was associated with higher mTICI 2b/3 and mTICI 3 recanalization rates although with a higher risk of 24-hr SAH.

Abstract WP18: Benefits of M2 Thrombectomy in Arise 2 - Analysis of Revascularization in Ischemic Stroke With Embotrap

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Ana Paula Narata ◽  
Aymeric Amelot ◽  
Osama Zaidat ◽  
Jeffrey Saver ◽  
Hormozd Bozorgchami ◽  
...  
Keyword(s):  
Distal Segment ◽  
Functional Independence ◽  
Similar Efficacy ◽  
Stent Retriever ◽  
Inclusion Criteria ◽  
Small Vessels ◽  
First Pass ◽  
Symptomatic Intracranial Hemorrhage ◽  
Target Locations ◽  
Study Inclusion

Introduction: Patients with proximal (M1) and more distal occlusions (M2) of the middle cerebral artery (MCA) from the ARISE II Study were assessed in order to determine risks and efficacy of revascularization with the EmboTrap device, which has a 5 mm diameter, in small vessels. Methods: Data from the ARISE II Study concerning MCA occlusions were separated into 2 groups: M1 occlusion and M2 occlusion (proximal, median, distal segment). From the ARISE II Study, inclusion criteria were NIHSS score ≥ 8 and ≤ 25, ASPECT ≥ 6. Comparison of the 2 groups was performed in order to evaluate M2 revascularization with EmboTrap device. Results: M1 occlusion was present in 126 patients and M2 occlusions in 57 patients. M2 occlusions were distal in 35.1%. Substantial reperfusion within 3 passes (TICI 2b-3) was similar for both target locations, 79.3% for M1 and 78.9% for M2 (P=0.29). First pass substantial reperfusion was also similar, 43.6% for M1 versus 40.3% for M2 (p=0.75). Symptomatic intracranial hemorrhage was observed in 4.7% of patients in M1 and 3.5% in M2 (p=0.66). Functional independence at 90 days (mRS 0-2) was achieved in 67.5% of patients with M1 occlusions and 70.2% with M2 occlusions (p=0.320). Conclusions: Revascularization of the M2 segment of MCA with a 3 or 4 mm-stent retriever was previously evaluated and was considered safe and efficient. In this study, we analyzed patients with M2 occlusions and treated with a 5 mm stent retriever EmboTrap that showed similar efficacy and safety compared to M1 occlusions. Use of the same device for proximal and more distal occlusions can have economic and technical advantages.

Endovascular treatment for calcified cerebral emboli in patients with acute ischemic stroke

2021 ◽  
pp. 1-11
Author(s):  
Agnetha A. E. Bruggeman ◽  
Manon Kappelhof ◽  
Nerea Arrarte Terreros ◽  
Manon L. Tolhuisen ◽  
Praneeta R. Konduri ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
The Netherlands ◽  
Endovascular Treatment ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Functional Independence ◽  
First Line ◽  
Multicenter Randomized Controlled Trial ◽  
Intravenous Alteplase ◽  
Mr Clean

OBJECTIVE Calcified cerebral emboli (CCE) are a rare cause of acute ischemic stroke. The authors aimed to assess the association of CCE with functional outcome, successful reperfusion, and mortality. Furthermore, they aimed to assess the effectiveness of intravenous alteplase treatment and endovascular treatment (EVT), as well as the best first-line EVT approach in patients with CCE. METHODS The Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry is a prospective, observational multicenter registry of patients treated with EVT for acute ischemic stroke in 16 intervention hospitals in the Netherlands. The association of CCE with functional outcome, reperfusion, and mortality was evaluated using logistic regression models. Univariable comparisons were made to determine the effectiveness of intravenous alteplase treatment and the best first-line EVT approach in CCE patients. RESULTS The study included 3077 patients from the MR CLEAN Registry. Fifty-five patients (1.8%) had CCE. CCE were not significantly associated with worse functional outcome (adjusted common OR 0.71, 95% CI 0.44–1.15), and 29% of CCE patients achieved functional independence. An extended Thrombolysis in Cerebral Infarction score ≥ 2B was significantly less often achieved in CCE patients compared to non-CCE patients (adjusted OR [aOR] 0.52, 95% CI 0.28–0.97). Symptomatic intracranial hemorrhage occurred in 8 CCE patients (15%) vs 171 of 3022 non-CCE patients (6%; p = 0.01). The median improvement on the National Institutes of Health Stroke Scale (NIHSS) was 2 in CCE patients versus 4 in non-CCE patients (p = 0.008). CCE were not significantly associated with mortality (aOR 1.16, 95% CI 0.64–2.12). Intravenous alteplase use in CCE patients was not associated with functional outcome or reperfusion. In CCE patients with successful reperfusion, stent retrievers were more often used as the primary treatment device (p = 0.04). CONCLUSIONS While patients with CCE had significantly lower reperfusion rates and less improvement on the NIHSS after EVT, CCE were not significantly associated with worse functional outcome or higher mortality rates. Therefore, EVT should still be considered in this specific group of patients.

scholarly journals Efficacy and safety of long-acting β-agonist/long-acting muscarinic antagonist combinations in COPD: a network meta-analysis

Thorax ◽  
2015 ◽  
Vol 71 (1) ◽  
pp. 15-25 ◽  
Author(s):  
Yuji Oba ◽  
Siva T Sarva ◽  
Sofia Dias
Keyword(s):  
Lung Function ◽  
Meta Analysis ◽  
Credible Interval ◽  
Severe Exacerbation ◽  
Efficacy And Safety ◽  
Muscarinic Antagonist ◽  
Safety Outcomes ◽  
Randomised Control Trials ◽  
St George's Respiratory Questionnaire ◽  
Long Acting

BackgroundThe place of long-acting β agonist/long-acting muscarinic antagonist (LABA/LAMA) combinations in stable patients with COPD is not well defined. The purpose of this study was to systematically review the efficacy and safety of LABA/LAMA combinations.MethodsSeveral databases and manufacturers’ websites were searched for relevant clinical trials. Randomised control trials, at least 12 weeks duration, comparing a LABA/LAMA combination with placebo and/or monotherapy were included. The data were pooled using a network as well as a traditional direct comparison meta-analysis.ResultsTwenty-three trials with a total of 27 172 patients were included in the analysis. LABA/LAMA combinations were associated with a greater improvement in lung function, St. George's Respiratory Questionnaire (SGRQ) score, and Transitional Dyspnoea Index (TDI) than monotherapies. LABA/LAMA combinations were associated with a significantly greater proportion of SGRQ and TDI responders than monotherapies (OR 1.23 (95% credible interval (CrI) 1.06–1.39), OR 1.34 (95% CrI 1.19–1.50) versus LABAs and OR 1.24 (95% CrI 1.11–1.36), OR 1.31 (95% CrI 1.18–1.46) versus LAMAs, respectively) and fewer moderate-to-severe exacerbations compared with LABAs (HR 0.82 (95% CrI 0.73–0.93)), but not when compared with LAMAs (HR 0.92 (95% CrI 0.84–1.00)). There were no statistically significant differences associated with LABA/LAMA combinations compared with monotherapies in safety outcomes as well as in severe exacerbations.ConclusionsThe combination therapy was the most effective strategy in improving lung function, quality of life, symptom scores and moderate-to-severe exacerbation rates, and had similar effects on safety outcomes and severe exacerbations as compared with monotherapies.

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