Mixed Treatment Comparison Research Articles

Supraglottic airway devices as a strategy for unassisted tracheal intubation: A network meta-analysis.

We aimed to compare the effectiveness of supraglottic airway devices as a strategy for unassisted tracheal intubation. Accordingly, we searched the OVID-MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, KoreaMed, and Google Scholar databases to identify all relevant randomized controlled trials (RCTs) on supraglottic airway devices as a strategy for tracheal intubation published until May 2017. The primary outcome was the overall success rate of intubation by the intention to treat (ITT) strategy. The secondary outcomes of the study were the overall success rate of tracheal intubation by the per protocol (PP) strategy and the success rate of tracheal intubation at first attempt by ITT and PP. We conducted a network meta-analysis with a mixed-treatment comparison method to combine direct and indirect comparisons among supraglottic airway devices. Of 1396 identified references, 16 RCTs (2014 patients) evaluated unassisted intubation with supraglottic airway devices. Patients were grouped according to the type of device used: LMA-CTrach, LMA-Fastrach, Air-Q, i-gel, CobraPLA, Ambu-Aura, or single-use LMA devices. Based on the surface under the cumulative ranking curve, the three best supraglottic airway devices for use as a strategy for unassisted tracheal intubation were LMA-CTrach (which included video-assisted tracheal tube guidance), single-use LMA-Fastrach, and LMA-Fastrach. LMA-Fastrach showed a higher success rate of intubation than did i-gel, CobraPLA, Air-Q, and Ambu-Aura. However, this study was limited by the small number of eligible RCTs. Therefore, well-designed RCTs performed on large patient populations are required to increase the confidence of the results.

Evaluating the cost-effectiveness of secukinumab in moderate-to-severe psoriasis: a Japanese perspective

Aim: To evaluate the cost-effectiveness of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, compared to other clinically used biologics (adalimumab, infliximab, and ustekinumab) in Japan for the treatment of moderate-to-severe psoriasis from the healthcare system (total costs) and patient co-payment (using different frequencies of drug purchase) perspectives.Methods: A decision-tree (first year)/Markov model (subsequent years), with an annual cycle, was developed. The model adopted a 5-year time horizon. Efficacy inputs were obtained from a mixed-treatment comparison analysis, and other model inputs were collected from published literature and local Japanese sources. Model outcomes included quality-adjusted life years (QALYs) and an incremental cost-effectiveness ratio (ICER) in terms of cost per QALY gained. The annual discounting rate of 2% was applied to both costs and outcomes.Results: Results for the healthcare system perspective showed that secukinumab had the highest number of quality-adjusted life years (QALYs) (4.07) vs other biologics, dominated ustekinumab and infliximab, and the ICER of secukinumab compared to adalimumab was ¥8,418,222/QALY gained. In the patient co-payment perspective with the monthly purchase of drugs, ustekinumab had the lowest co-payment cost, followed by infliximab, adalimumab, and secukinumab. In the patient co-payment perspective with a once every 3 months purchase of secukinumab and adalimumab, the co-payment costs of secukinumab, adalimumab, and ustekinumab became comparable, and infliximab had the highest co-payment cost.Limitations: Only short-term efficacy data was modeled, as there was a lack of data on long-term outcomes. Treatment sequencing was restricted to first-line biologic treatment. Drop-out rates for comparators were assumed to be equivalent to secukinumab in the absence of available data.Conclusions: Secukinumab is a cost-efficient treatment for moderate-to-severe psoriasis, providing greater health outcomes to patients at lower total costs compared to infliximab and ustekinumab, as well as comparable patient co-payment relative to other biologic treatments.

PSS31 - COST PER RESPONDER OF SECUKINUMAB COMPARED TO OTHER BIOLOGICS IN MODERATE-TO-SEVERE PLAQUE PSORIASIS FROM THE PRIVATE PAYER PERSPECTIVE IN BRAZIL

To estimate the cost per Psoriasis Area and Severity Index (PASI) ≥90 responder of secukinumab as first biologic treatment compared with adalimumab, etanercept, infliximab and ustekinumab over 16 and 52 weeks, and cost per sustained response in 16-week responders up to 52 weeks from the perspective of the Brazilian private healthcare system. A 52-week decision-tree model reflecting response to treatment, defined as PASI reduction of <50%, 50%-74%, 75%-89% and ≥90% was developed. Non-responders patients (PASI<75 at 16 weeks) and patients that discontinued treatment due to other reasons (e.g. adverse events, dropouts) were switched to standard of care. Clinical data inputs of PASI distribution at 4, 8, 12, 16 and 52 weeks were derived from a mixed treatment comparison comparing the biologics to placebo. Annual drug costs were based on the respective ex-factory prices and the number of doses required for 52 weeks. Sensitivity analysis was performed to evaluate the uncertainties of the model. Over 16 weeks, the cost per PASI ≥90 responder of secukinumab (BRL 65,353) was lower than most biologics, except for ustekinumab (BRL 56,638). Secukinumab had the lowest cost per PASI ≥90 responder over 52 weeks (BRL 151,415) compared with ustekinumab (BRL 156,744), adalimumab (BRL 248,203), infliximab (BRL 255,713) and etanercept (BRL 278,183). Likewise, secukinumab had the lowest cost per sustained 52-week PASI ≥90 responder (BRL 82,535) compared with other biologic treatments (range from BRL 98,643 to BRL 136,026). Sensitivity analysis confirmed the favorable results of secukinumab. Secukinumab as first biologic treatment of adults with moderate-to-severe psoriasis is cost-effective, with a lower cost per PASI ≥90 responder compared with other biologic treatments in Brazil from private payer perspective.

PMS5 - A NETWORK META-ANALYSIS TO EVALUATE THE EFFICACY OF BARICITINIB AND OTHER TREATMENTS OF RHEUMATOID ARTHRITIS IN PATIENTS WHO ARE INADEQUATE RESPONDERS TO METHOTREXATE

To assess the comparative effectiveness of baricitinib (BARI) 4-mg (background MTX) (oral, JAK 1/2 inhibitor) and other targeted synthetic/biologic disease modifying anti-rheumatic drugs in moderate-to-severe rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX-IR). A systematic literature review (SLR) of randomized controlled trials (RCTs-Phase 3) of interventions of interest was conducted (1999 to 2017) in Medline, Medline In-Process, Embase, Biosciences Information Service, the Cochrane Library, and trials registers. Network meta-analyses (NMAs) of RCTs reporting the American College of Rheumatology (ACR) response data were conducted using Bayesian mixed-treatment comparisons. Here we present main results for the 24-week (+/-4) timepoint (fixed effects simultaneous models). 24 trials met the SLR inclusion criteria. Analyses, using BARI RA-BEAM trial data, showed BARI 4-mg (background MTX) to be more effective than adalimumab (ADA) 40-mg (EOW) (Odds Ratio 1.33; 95%-Credible Interval 1.01-1.75), abatacept (ABA) 10-mg (IV/4weeks) (OR 1.47; 95%-CrI 1.02-2.13), infliximab (IFX) 3-mg (IV/8weeks) (OR 1.61; 95%-CrI 1.12-2.27) for ACR20. While no differences were found on ACR50, BARI 4-mg (background MTX) was found to be more effective than ADA 40-mg (OR 1.39; 95%-CrI 1.02-1.89), ABA 10-mg (OR 1.85; 95%-CrI 1.09-3.23), rituximab (RTX) 1000-mg (OR 2.38; 95%-CrI 1.10-5.00) and 2000-mg (OR 2.44; 95%-CrI 1.04-5.56) for ACR70. Bari 4 mg (background MTX) showed better results versus etanercept monotherapy (50mg/week or 25mg/biweekly) (OR 2.27; 95%-CrI 1.04-5.26) for ACR20, and RTX 1000-mg monotherapy for ACR20/ACR70 (OR 1.82; 95%-CrI 1.02-3.13)/(OR 2.70; 95%-CrI 1.04-7.14), respectively. Sensitivity analysis that included 10 additional trials with up to 20% of patients with prior biologic use allowed comparison versus tofacitinib (TOFA), showing BARI 4-mg (background MTX) to be more effective than TOFA 5-mg (BID) monotherapy for ACR20 (OR 1.92; 95%-CrI 1.32-2.86). The comparative analyses support BARI as an efficacious treatment option for moderate-to-severe RA patients with inadequate response to MTX.

Dose response of sodium glucose cotransporter-2 inhibitors in relation to urinary tract infections: a systematic review and network meta-analysis of randomized controlled trials.

The sodium glucose cotransporter-2 (SGLT2) inhibitors are a novel group of drugs for treatment of type 2 diabetes mellitus. We investigated whether there is a dose-response relation between SGLT2 inhibitors and urinary tract infections (UTIs) in patients with type 2 diabetes, relative to other diabetes therapies or placebo. We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) of SGLT2 inhibitors in patients with type 2 diabetes. We searched 6 databases and the reference lists of key papers. We included studies with placebo or active antidiabetic comparators that reported the outcome of UTI, and established thresholds for high and low doses of SGLT2 inhibitors. We used a random-effects model to estimate the pooled effect estimates and 95% credible intervals. We screened 2418 citations and included 105 references for studies of 8 unique SGLT2 inhibitors, representing 60 082 individuals (with a total of 4348 UTIs). Most mixed-treatment comparisons showed no significant difference in risk of UTI, with the exception of high-dose dapagliflozin (≥ 10 mg) compared with placebo (odds ratio [OR] 1.30, 95% credible interval 1.09-1.57), with active comparators (OR 1.44, 95% credible interval 1.15-1.79), with empagliflozin at both low (OR 1.30, 95% credible interval 1.04-1.60) and high (OR 1.39, 95% credible interval 1.12-1.72) doses, and with low-dose ertugliflozin (OR 1.43, 95% credible interval 1.01-2.01). When the analysis was restricted to RCTs with a low risk of bias, the results were nonsignificant. Current RCT evidence does not suggest a dose-response relation between most SGLT2 inhibitors and UTIs, with the exception of dapagliflozin. Further research is needed to quantify the relation between SGLT2 inhibitors and more serious infections. PROSPERO registration no. CRD42016038715.

Safety and efficacy of switching from unfractionated heparin to bivalirudin during primary percutaneous coronary intervention.

To evaluate the safety and efficacy of switching to bivalirudin during primary percutaneous coronary intervention (PCI) for patients who received preprocedure unfractionated heparin (UFH). Current guidelines favor bivalirudin for primary PCI in patients at high risk of bleeding, particularly when femoral access is used. However, patients with ST-segment elevation myocardial infarction frequently receive UFH before arrival in the catheterization laboratory. Scientific databases and websites were searched for randomized controlled trials. Patients were divided into those who received heparin with or without glycoprotein IIb/IIIa inhibitors (heparin group); those switched to bivalirudin during primary PCI from preprocedure UFH (switch group); and those who received bivalirudin without preprocedure UFH (Biv-alone group). Both traditional pairwise meta-analyses using moderator analyses and network meta-analyses using mixed-treatment comparison models were performed. Data from five trials including13,547 patients were analyzed. In mixed-comparison models, switching to bivalirudin during primary PCI was associated with lower rates for all-cause mortality and major adverse cardiovascular events (MACEs) compared to the other strategies. Rates for all-cause mortality, MACEs, and net adverse clinical events (NACEs) were similar for the heparin and Biv-alone groups. Switching strategies was also associated with lower major bleeding rates compared to heparin alone. Similarly, in a standard pairwise model, both the switch and Biv-alone groups were associated with decreased bleeding risk compared to the heparin group. However, only the switch strategy was associated with decreased all-cause mortality (RR, 0.47; 95% CI, 0.30-0.75; P = 0.001), MACE (RR, 0.67; 95% CI, 0.49-0.91; P = 0.012), and NACE (RR, 0.61; 95% CI, 0.41-0.92; P = 0.019) compared with heparin alone. During primary PCI, use of bivalirudin for those receiving preprocedure UFH was associated decreased rates for major bleeding, NACEs, MACEs, and all-cause mortality compared to heparin +/- GPI. This strategy was also associated with decreased rates for MACEs and all-cause mortality compared to bivalirudin alone without preprocedure UFH.

Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis.

Second and third generation AEDs have been directly compared to controlled-release carbamazepine (CBZ-CR) as initial monotherapy for new-onset focal epilepsy. Conversely, no head-to-head trials have been performed. The aim of this study was to estimate the comparative efficacy and tolerability of the antiepileptic monotherapies in adults with newly diagnosed focal epilepsy through a network meta-analysis (NMA). Randomized, double-blinded, parallel group, monotherapy studies comparing any AED to CBZ-CR in adults with newly diagnosed untreated epilepsy with focal-onset seizures was identified. The outcome measures were the seizure freedom for 6 and 12months, the occurrence of treatment-emergent adverse events (TEAEs), and the treatment withdrawal due to TEAEs. Mixed treatment comparisons were conducted by a Bayesian NMA using the Markov chain Monte Carlo methods. Effect sizes were calculated as odds ratios (ORs) with 95% credible intervals (CrIs). Four trials were included involving 2856 participants, 1445 for CBZ-CR and 1411 for the comparative AEDs. Monotherapy AEDs compared to CBR-CR were levetiracetam (LEV), zonisamide (ZNS), lacosamide (LCM), and eslicarbazepine acetate (ESL). There were no statistical differences in the 6- and 12-month seizure freedom and TEAEs occurrence between LEV, ZNS, LCM, ESL, and CBZ-CR In the analysis of drug withdrawal due to TEAEs, LCM treatment was associated with a significantly lower discontinuation rate than CBZ-CR (OR 0.659, 95% CrI 0.428-0.950). LEV, ZNS, LCM, and ESL are effective initial monotherapy treatments in adult patients with newly diagnosed focal epilepsy and represent suitable alternatives to CBZ-CR.

Frontline treatment for transplant-eligible multiple myeloma: A 6474 patients network meta-analysis.

Autologous transplantation continues to be the cornerstone of younger and fit multiple myeloma patients. It is known that frontline induction therapy before transplantation can influence post-transplant results. Therefore, best frontline treatment for transplant-eligible patients should be based on best available evidence to guide therapy. Furthermore, until now due to data scarcity, it was not possible to thoroughly compare lenalidomide to other regimens in this setting. We performed a systematic review and network (mixed treatment comparison) meta-analysis of 21 clinical trial publications, enrolling 6474 patients and comparing 11 different treatment frontline setting regimens regarding survival, response, and safety outcomes. OS analysis showed superiority of CRD (cyclophosphamide-lenalidomide-dexamethasone) over TD-based (thalidomide-dexamethasone, HR=0.76,0.62-0.90), VAD-based (HR=0.71,0.52-0.90), and Z-Dex (idarubicin-dexamethasone, HR=0.37,0.17-0.76) regimens. Concerning PFS, VTD (bortezomib-thalidomide-dexametasone) showed superior results when compared with TD-based (HR=0.66,0.51-0.84), VAD-based (HR=0.61,0.46-0.82), Z-Dex (HR=0.42,0.22-0.78), and high dose dexamethasone (Dex, HR=0.62,0.41-0.90) regimens. Bortezomib/thalidomide regimens were not superior to lenalidomide, considering these outcomes. Also, concerning complete and overall response, VTD ranked first among other regimens, showing clear superiority over thalidomide-only containing protocols. Safety outcome evaluated infectious, cardiac, gastrointestinal, neurological, thrombotic, and hematological grade 3 to 4 adverse events. Risk of thrombotic events was higher with TAD (thalidomide-doxorubicin-dexamethasone), neurological with PAD (bortezomib-doxorubicin-dexamethasone), infectious with Dex, hematological with Z-Dex, gastrointestinal with VTD, and cardiac with PAD regimens. Our study endorses current recommendations on combined immunomodulatory drugs and proteasome inhibitors frontline regimens (in triplets) in transplant-eligible multiple myeloma patients, but also formally demonstrates the favorable performance of lenalidomide in overall and progression-free survival, when compared with bortezomib/thalidomide protocols.

Which Antimicrobial Agent is Likely to be the Best for Treating Clostridium difficile Infections? A Bayesian Network Meta-Analysis of Randomized Clinical Trials.

Vancomycin, metronidazole, fidaxomicin, teicoplanin, fusidic acid and bacitracin have been recommended for the treatment of Clostridium difficile infections (CDI). We conducted a Bayesian network meta-analysis comparing all the antimicrobial agents used in CDI. Electronic databases were searched for randomized controlled trials comparing antimicrobial agents used for CDI. Risk of bias was assessed. Random effects model was used to derive the mixed treatment comparison estimates. Odds ratio with 95% confidence intervals was used as effect estimate. Seventeen studies were included in this meta-analysis. Teicoplanin was observed to perform better than vancomycin, metronidazole, fusidic acid and bacitracin to achieve the symptomatic cure. Teicoplanin was also associated with higher rates of bacteriological cure than vancomycin and metronidazole. Fidaxomicin is associated with significantly higher rates of symptomatic cure than vancomycin, bacitracin and metronidazole and is similar to teicoplanin. To conclude, teicoplanin and fidaxomicin have been observed to perform better than other antimicrobials for the treatment of CDI. We recommend conducting high quality randomized controlled clinical trials evaluating teicoplanin and fidaxomicin with other standard interventions for the management of CDI.

Network meta-analysis of antiplatelet therapy following coronary artery bypass grafting (CABG): none versus one versus two antiplatelet agents.

Numerous agents have been trialed following coronary artery bypass grafting (CABG) to maintain long-term graft patency. While clear evidence exists for the use of aspirin in maintaining graft patency, the role of dual-antiplatelet therapy in CABG patients is not as well established. This network meta-analysis aimed to compare the short-term post-CABG graft patency outcomes for patients with none, one or two antiplatelet agents. Electronic databases were queried for randomized controlled trials comparing CABG graft patency rates at three months and beyond using various antiplatelet agents or placebo. Drug and graft patency data were compared using a mixed treatment comparison under a Bayesian hierarchical framework. A random-effects consistency model was applied. Direct and indirect comparisons were made between drugs and used to determine the relative efficacy for graft patency. The literature search identified 16 papers fulfilling the inclusion criteria, including a total of 3,133 patients with an average of 2.43 [95% confidence interval (CI): 2.20-2.66] grafts per patient. Graft types were incompletely reported, however, saphenous vein grafts (SVGs) were predominantly used [where specifically reported: 4,490 SVG, 1,226 internal mammary artery (IMA) grafts]. In all, five different agents and placebo in various regimens were compared by results of angiographic follow-up conducted at a mean of 10.4 months (95% CI: 9.28-11.5 months). Compared to placebo, aspirin alone [odds ratio (OR) 1.9; 95% credible interval (CrI): 1.3-2.8], aspirin + dipyridamole (OR 1.9; 95% CrI: 1.3-2.6), aspirin + clopidogrel (OR 2.9; 95% CrI: 1.5-5.7) and aspirin + ticagrelor (OR 3.8; 95% CrI: 1.2-13.0) significantly improved graft patency. When compared to aspirin monotherapy, aspirin + clopidogrel (OR 1.6; 95% CrI: 0.86-2.7) and aspirin + ticagrelor (OR 2.0; 95% CrI: 0.69-6.3) had OR that suggested a trend favoring patency compared to aspirin monotherapy, however, these results did not reach significance. Sub-group analysis of SVG graft patency was unable to reach significance (only eight studies with six treatment comparisons were evaluated). Secondary endpoints of death, bleeding, myocardial infarction and cerebrovascular accident were incompletely reported and were pooled but not compared between drug treatment arms. Aspirin monotherapy and dual antiplatelet therapy (DAPT) provided significant all-graft patency benefit compared to placebo at three months and beyond. A trend existed for DAPT to improve graft patency compared to aspirin, although this did not reach statistical significance. Further randomized controlled studies comparing aspirin monotherapy to DAPT are required to determine the utility of DAPT in CABG patients for maintaining graft patency.

First-line treatment strategies for newly diagnosed chronic myeloid leukemia: a network meta-analysis.

ObjectivesWith bosutinib proven to be available for frontline treatment, there are currently four frontline treatments as well as an additional strategy with high-dose imatinib for newly diagnosed chronic myeloid leukemia (CML). Due to the lack of direct comparison of high-dose imatinib, dasatinib, nilotinib, and bosutinib, we summarized the evidence to indirectly compare the efficacy among these treatment options.MethodsIn total, 14 randomized clinical trials including 5,630 patients were analyzed by direct and mixed-treatment comparisons. Outcomes assessed were the following: complete cytogenetic response at 12 months; major molecular response at 12, 24, and 36 months; deep molecular response at 12, 24, 36, and 60 months; early molecular response at 3 months; progression-free survival (PFS); overall survival (OS); and Grade 3 or 4 adverse events (AEs).ResultsThe Bayesian network meta-analysis demonstrated that high-dose imatinib was less effective than all new-generation tyrosine kinase inhibitors and had a higher probability of Grade 3 or 4 AEs. For molecular response, 300 mg of nilotinib was likely to be the preferred frontline treatment, as demonstrated by higher response rates and faster, deeper, and longer molecular response. For PFS and OS, there were high likelihoods (79% and 74%, respectively) that 400 mg of nilotinib was the preferred option. For AEs, standard-dose imatinib has the highest probability (65%) of being the most favorable toxicity profile.ConclusionConsidering the efficacy and toxicity profile, it is not recommended to use high-dose imatinib for treatment. This analysis also showed that nilotinib has the highest probability to become the preferred frontline agents for treating CML.

PSS8 - Cost Per-Responder Analysis of Secukinumab Compared to Other Biologics for Treatment of Moderate to Severe Psoriasis Patients in Saudi Arabia

Secukinumab 300 mg, a fully human interleukin-17A antibody, has demonstrated superior and sustained efficacy in treatment of adults with moderate to severe psoriasis over other biologic treatments. The analysis compared the cost per responder of secukinumab (SEC) as first-line biologic treatment versus adalimumab (ADA), etanercept (ETN), infliximab (INF), ustekinumab (UST) and placebo. A 52-week decision-tree model reflecting response to treatment defined as Psoriasis Area Severity Index (PASI) reduction of ≥90%, from a mixed-treatment comparison, led into a Markov model to evaluate the cost per response for each treatment. Responders (PASI≥90) at week 16 continued the initial treatment. Non-responders and drop-outs were switched to standard of care. Analyses were conducted for responders at week 16, week 52 and for sustained responders between weeks 16 and 52, from a Saudi Arabian perspective over a 1-year time horizon. Costs for each treatment included the drug and resource costs, obtained from the Saudi Food and Drug Authority website and national sources respectively, for 2018. No discount was applied. SEC 300 mg had the lowest cost per PASI≥90 responder at 52 weeks (SAR148,952), compared with UST (SAR166,923), INF (SAR175,876), ADA (SAR198,825) or ETN (SAR228,029). Likewise, SEC had the lowest cost per sustained 52-week PASI≥90 responder (SAR80,648) and ADA the highest (SAR105,023). At week 16, cost per PASI≥90 responder was lower for SEC (SAR64,326) versus ADA (SAR 86,785), ETN (SAR115,804) and INF (SAR86,160) except UST (SAR61,035). Sensitivity analysis supported the robustness of the results. Secukinumab as first-line biologic treatment of adults with moderate to severe psoriasis has the lowest cost per PASI≥90 responder compared with other biologic treatments in Saudi Arabia over 1 year.

The safety and efficacy of endobronchialvalve therapy in patients with advanced heterogeneous emphysema versus standard medical care: A meta-analysis.

BackgroundEndobronchial valves had been utilized for many years to treat patients with advanced emphysema, despite unfavorable results. In this meta-analysis, we aimed to assess the efficacy and safety of the use of endobronchial valves in patients with heterogeneous advanced emphysema.MethodsWe performed systematic database searches to identify clinical trials that met all our inclusion criteria. Direct-comparison and mixed-treatment-comparison (MTC) meta-analyses were conducted to estimate the mean difference or odds ratio of outcomes. Each outcome was analyzed with Review Manager 5 statistical software.ResultsEight prospective clinical trials assessing this therapy were retrieved, with a total of 744 patients. Outcomes, including the forced expiratory volume in 1 second (FEV1), 6-minute walk test (6MWT), and St. George's Respiratory Questionnaire (SGRQ), were analyzed, and the odds ratio of reported complications related to endobronchial valve therapy was calculated. Significant improvement in the mean difference of FEV1 (5.61 [4.42, 6.80]), 6MWT (25.75 [12.30, 39.20]), and SGRQ (−10.96 [−13.88, −8.05]) was observed after endobronchial valve treatment. Moreover, the rate of adverse events related to endobronchial valves was low.ConclusionsEndobronchial valve treatment offers benefits in terms of lung function and quality of life. Endobronchial valve treatment is feasible and safe for patients with advanced heterogeneous emphysema, especially those with no evidence of collateral ventilation.

Drugs for treating severe hypertension in pregnancy: a network meta-analysis and trial sequential analysis of randomized clinical trials.

Several antihypertensive drugs are used in the treatment of severe hypertension in pregnancy. The present study is a network meta-analysis comparing the efficacy and safety of these drugs. Electronic databases were searched for randomized clinical trials comparing drugs used in the treatment of severe hypertension in pregnancy. The number of women achieving the target blood pressure (BP) was the primary outcome. Doses required and time taken for achieving the target BP, failure rate, and incidences of maternal tachycardia, palpitation, hypotension, headache, and neonatal death and stillbirth were the secondary outcomes. Mixed treatment comparison pooled estimates were generated using a random-effects model. Odds ratios for the categorical and mean difference for the numerical outcomes were the effect estimates. Fifty-one studies were included in the systematic review and 46 in the meta-analysis. No significant differences in the number of patients achieving target BP was observed between any of the drugs. Diazoxide [-15 (-20.6, -9.4)], nicardipine [-11.8 (-22.3, -1.2)], nifedipine/celastrol [-19.3 (-27.4, -11.1)], nifedipine/vitamin D [-17.1 (-25.7, -9.7)], nifedipine/resveratrol [-13.9 (-22.6, -5.2)] and glyceryl trinitrate [-33.8 (-36.7, -31)] were observed to achieve the target BP (in minutes) more rapidly than hydralazine. Nifedipine required fewer doses than hydralazine for achieving the target BP. Glyceryl trinitrate and labetalol were associated with fewer incidences of tachycardia and palpitation respectively than hydralazine. Trial sequential analysis concluded adequate evidence for hydralazine and nifedipine compared with labetalol. Moderate quality of evidence was observed for direct comparison estimate between labetalol and hydralazine but was either low or very low for other comparisons. The present evidence suggests similar efficacy between nifedipine, hydralazine and labetalol in the treatment of severe hypertension in pregnancy. Subtle differences may exist in their safety profile. The evidence is inadequate for other drugs.

Update in Cardiovascular Safety of Glucagon-Like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes—A Mixed Treatment Comparison Meta-analysis of Randomized Controlled Trials

Background: The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) was recently published. Thus, we here present a mixed treatment comparison meta-analysis (MTC) of major randomized clinical trials to determine Glucagon like peptide 1 (GLP-1) receptor agonists’ effects on CV outcomes in patients with T2DM. Methods: A comprehensive, systematic review was conducted using Embase and MEDLINE databases. Studies were included in the MTC meta-analysis if they were (1) RCTs and (2) evaluated the effects of one of the GLP-1 agonists vs. placebo on CV outcomes as their primary endpoint. The primary outcomes were CV death, nonfatal MI, and nonfatal stroke. Hospitalization for HF was evaluated as a secondary endpoint. Results: A total of 202 publications were identified and reviewed, of which 198 were excluded based on study design or relevance to the research question. A total of 4 trials, including 33,457 patients, met the eligibility criteria and were retained analysis. The pairwise meta-analysis showed a 13% reduction in death from cardiovascular causes in patients who received GLP-1 agonists vs. those who received placebo (RR 0.87, 95% CI: 0.78-0.96, I2=0%, P=0.592). The NMA showed no differences among all the interventions, with liraglutide the preferred agent (53%) followed by semaglutide (18%). The pairwise meta-analysis showed no significant reduction in non-fatal MI events between the two groups (RR 0.95, 95% CI: 0.86-1.04, I2=19.5%, P=0.293). Like the pairwise meta-analysis, the NMA results showed no reduction in non-fatal MI events with semaglutide as the preferred agent (66%), followed by liraglutide (19%). Conclusion: GLP-1 therapy was associated with a significant reduction in CV death. However, GLP-1 agonists seem to have a safety profile comparable to placebo in terms of reducing non-fatal MI, non-fatal stroke events, and rates of HF hospitalization. Disclosure O. Alfayez: None. M.S. Al Yami: None. R. Alsheikh: None.

Pharmacological interventions for premature ejaculation: a mixed-treatment comparison network meta-analysis of randomized clinical trials.

Premature ejaculation (PE) is the most common sexual dysfunction in men. The present study is a network meta-analysis of drugs used for treating PE. Electronic databases were searched for randomized controlled trials comparing medical interventions with either placebo or with other active drugs in patients with PE. Inverse variance heterogeneity model was used for mixed-treatment comparisons. Intravaginal ejaculatory latency time (IELT) and adverse events were the main outcome measures. A total of 44 studies were included in the meta-analysis. Dapoxetine 30 and 60 mg, tadalafil, sildenafil, paroxetine with sildenafil, topical lidocaine, dapoxetine 30 mg with mirodenafil, vardenafil, fluoxetine, and tadalafil, pindolol with paroxetine, tramadol, topical lidocaine with tadalafil, paroxetine with tadalafil, and topical eutectic mixture of local anesthetics were associated with a significant increase in IELT. Similarly, dapoxetine 60 mg, venlafaxine, fluoxetine, tramadol at 25, 50, and 100 mg, and combined fluoxetine and tadalafil were associated with an increased risk of adverse events. Dapoxetine 30 mg has a high likelihood of being the "best" in the interventional pool. Dapoxetine at 30 mg could be used as the first-line agent in the management of PE.

Efficacy and safety of iron chelators in thalassemia and sickle cell disease: a multiple treatment comparison network meta-analysis and trial sequential analysis

ABSTRACTBackground: To compare the efficacy and safety of desferrioxamine (DFO), deferiprone (DFP), deferasirox (DFX) and silymarin in patients with either thalassemia or sickle cell disorder through network meta-analysis.Methods: Electronic databases were searched for appropriate randomized clinical trials comparing iron chelators in patients with iron overload. Random effects model was used to generate direct, indirect and mixed treatment comparison pooled estimates for the following outcomes: serum ferritin, liver iron concentration (LIC), changes in serum ferritin, mortality, urine iron excretion, adverse events, neutropenia, agranulocytosis and number of patients withdrawing the chelating therapy.Results: Thirty-two clinical trials were included in the meta-analysis. DFX/DFO was associated with better serum ferritin levels compared to DFO, DFX, DFO/Silymarin and DFP/DFO. DFX/DFO also lower LIC significantly compared to DFO. DFP/DFO was associated with higher LVEF, low risk of adverse events and reduced end of serum ferritin compared to DFO. Combination of silymarin with either DFP or DFX was observed with reduced end of treatment serum ferritin compared to using either of the drugs alone. DFP was observed with better effects in sickle cell disease. The strength of evidence was very low for most of the comparisons.Conclusion: Relative estimates between the individual iron chelators have been established. However, this evidence should be considered preliminary and may change with the results of future head-to-head clinical trials.

Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis.

Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies. We systematically reviewed PubMed, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness Results: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: -0.89 to -0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: -0.97 to -0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: -3.96 to -0.75). Memantine was effective for negative symptoms (standardised mean difference: -0.56 95% confidence interval: -0.93 to -0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and Ginkgo biloba showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise meta-analyses. On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality.

PSS11 - Cost Per Responder of Secukinumab Compared to Other Biologics in Moderate-To-Severe Plaque Psoriasis in Brazil

To estimate the cost per Psoriasis Area and Severity Index (PASI) ≥90 responder of secukinumab as first biologic treatment compared with adalimumab, etanercept, infliximab and ustekinumab over 16 and 52 weeks, and cost per sustained response in 16-week responders over 52 weeks from the perspective of the Brazilian Unified Health System (SUS). A 52-week decision-tree model reflecting response to treatment, defined as PASI reduction of <50%, 50%-74%, 75%-89%, and ≥90%. Sustained response was defined as response (PASI≥75) at 16 weeks and maintained at week 52. Non-responders and patients that discontinued treatment due to other reasons (e.g. adverse events, dropouts) were switched to standard of care. Clinical data inputs of PASI distribution at 4, 8, 12, 16 and 52 weeks were derived from the mixed treatment comparison comparing the biologics to placebo. Drug costs were estimated using the public price approved by Ministry of Health and the number of doses required for 52 weeks. Sensitivity analysis was performed to evaluate the impact of including 20% discount on the comparator prices. Secukinumab had the lowest cost per PASI ≥90 responder over 16 weeks (BRL 13,816) compared with adalimumab (BRL 19,313), ustekinumab (BRL 22,482), etanercept (BRL 27,931) and infliximab (BRL 31,475). Over 52 weeks, costs per PASI ≥90 responder ranged from BRL 31,949 (secukinumab) to BRL 62,414 (infliximab). Likewise, secukinumab had the lowest cost per sustained 52-week PASI ≥90 responder (BRL 17,244) compared with other biologic treatments (BRL 23,775 – BRL 38,562). Sensitivity analysis confirmed the base case results. The cost per PASI ≥90 responder was consistently lower for secukinumab compared with other biologic treatments from SUS perspective.

PRS2 - Systematic Review and Network Meta-Analysis of Approved Medicines for the Treatment of Idiopathic Pulmonary Fibrosis

To perform a systematic review and network meta-analysis (NMA) to access the efficacy and tolerability of two of the most recently approved treatments for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, in adult-patients with IPF. A review was conducted up to September 2017. Randomized controlled trials selection (from CENTRAL, MEDLINE, Embase), data extraction, risk of bias analysis and GRADE assessment were carried out by two authors separately. Direct estimates were calculated using standard pairwise meta-analysis. A Bayesian mixed treatment comparison approach, for NMA estimates with 95% credible intervals, was used to compare pirfenidone and nintedanib. Odds ratios (OR) and number needed to treat for an additional beneficial outcome (NNTB) or an additional negative outcome (NNTH) were also calculated. 10 randomized controlled trials were included. Both drugs showed a positive effect on percentage of FVC decline ≥10% (pirfenidone OR 0.54 (95% CI 0.37-0.80), NNTB 9 (95% CI 7-22); nintedanib OR 0.59 (95% CI 0.41-0.84), NNTB 9 (95% CI 6-23) both with moderate risk of bias). The network meta-analysis did not show any differences when comparing pirfenidone and nintedanib regarding FVC decline (OR 0.91 (95% CrI 0.45-2.03) with low quality of the indirect estimate) or dropouts (OR 0.75 (95% CrI 0.33-1.27) with low quality of the indirect estimate). Nintedanib showed an effect on dropouts OR 1.61 (1.13-2.28) and NNTH 14 (8 - 61) with low quality of the risk of bias assessment. Additionally, there were no differences when comparing the two treatments either to placebo or to each other with respect to acute exacerbations, mortality and serious adverse events. Based on RCTs of 12 month duration in patients with IPF, positive effects were noticed on FVC decline for both treatments and on dropouts for nintedanib. No significant differences were noted between the two treatments regarding any of the outcomes.