Randomized Controlled Trials Data Research Articles

Clinical efficacy and safety of high-flow nasal cannula (HFNC) in acute hypoxaemic patients with COVID-19: a protocol for a systematic review and meta-analysis

IntroductionWhen COVID-19 patients develop hypoxaemic respiratory failure, they often undergo early intubation. Such a potentially aerosol-generating approach places caregivers at increased risk of contracting COVID-19. This protocol aims to evaluate...

Preventing all-cause hospitalizations in type 2 diabetes with sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: A narrative review and proposed clinical approach.

Patients with type 2 diabetes (T2D) are at increased risk for hospital admissions, and acute hospitalizations are associated with a worse prognosis. However, outcomes related to all‐cause hospital admissions (ACHAs) were often overlooked in trials that demonstrated the cardiovascular and kidney benefits of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs). This review includes a contemporary literature summary of emerging data regarding the effects of SGLT2 inhibitors and GLP‐1RAs on ACHAs. The role of SGLT2 inhibitors in preventing ACHAs was shown in exploratory investigations of several randomized controlled trials (RCTs) and was further supported by real‐world evidence (RWE). However, the association between GLP‐1RA use and lower ACHA risk was mainly shown through RWE, with minimal available RCT data. We also discuss the advantages and challenges of studying ACHAs. Finally, we propose an easily memorized (“ABCDE” acronym) clinical approach to evaluating T2D status and treatment in admitted patients, as they transition from hospital to community care. This systematic approach may assist clinicians in recognizing possible pitfalls in T2D management, thereby preventing subsequent hospitalizations and improving patient prognoses. While acute admission can sometimes be perceived as a management failure, it should also be viewed as an opportunity to take action to prevent the next hospitalization.

Evaluation of HIV treatment outcomes with reduced frequency of clinical encounters and antiretroviral treatment refills: A systematic review and meta-analysis.

BackgroundGlobal HIV treatment programs have sought to lengthen the interval between clinical encounters for people living with HIV (PLWH) who are established on antiretroviral treatment (ART) to reduce the burden of seeking care and to decongest health facilities. The overall effect of reduced visit frequency on HIV treatment outcomes is however unknown. We conducted a systematic review and meta-analysis to evaluate the effect of implementation strategies that reduce the frequency of clinical appointments and ART refills for PLWH established on ART.Methods and findingsWe searched databases​ between 1 January 2010 and 9 November 2021 to identify randomized controlled trials (RCTs) and observational studies that compared reduced (6- to 12-monthly) clinical consultation or ART refill appointment frequency to 3- to 6-monthly appointments for patients established on ART. We assessed methodological quality and real-world relevance, and used Mantel–Haenszel methods to generate pooled risk ratios (RRs) with 95% confidence intervals for retention, viral suppression, and mortality. We evaluated heterogeneity quantitatively and qualitatively, and overall evidence certainty using GRADE. Searches yielded 3,955 records, resulting in 10 studies (6 RCTs, 3 observational studies, and 1 study contributing observational and RCT data) representing 15 intervention arms with 33,599 adults (≥16 years) in 8 sub-Saharan African countries. Reduced frequency clinical consultations occurred at health facilities, while reduced frequency ART refills were delivered through facility or community pharmacies and adherence groups. Studies were highly pragmatic, except for some study settings and resources used in RCTs. Among studies comparing reduced clinical consultation frequency (6- or 12-monthly) to 3-monthly consultations, there appeared to be no difference in retention (RR 1.01, 95% CI 0.97–1.04, p = 0.682, 8 studies, low certainty), and this finding was consistent across 6- and 12-monthly consultation intervals and delivery strategies. Viral suppression effect estimates were markedly influenced by under-ascertainment of viral load outcomes in intervention arms, resulting in inconclusive evidence. There was similarly insufficient evidence to draw conclusions on mortality (RR 1.12, 95% CI 0.75–1.66, p = 0.592, 6 studies, very low certainty). For ART refill frequency, there appeared to be little to no difference in retention (RR 1.01, 95% CI 0.98–1.06, p = 0.473, 4 RCTs, moderate certainty) or mortality (RR 1.45, 95% CI 0.63–3.35, p = 0.382, 4 RCTs, low certainty) between 6-monthly and 3-monthly visits. Similar to the analysis for clinical consultations, although viral suppression appeared to be better in 3-monthly arms, effect estimates were markedly influence by under-ascertainment of viral load outcomes in intervention arms, resulting in overall inclusive evidence. This systematic review was limited by the small number of studies available to compare 12- versus 6-monthly clinical consultations, insufficient data to compare implementation strategies, and lack of evidence for children, key populations, and low- and middle-income countries outside of sub-Saharan Africa.ConclusionsBased on this synthesis, extending clinical consultation intervals to 6 or 12 months and ART dispensing intervals to 6 months appears to result in similar retention to 3-month intervals, with less robust conclusions for viral suppression and mortality. Future research should ensure complete viral load outcome ascertainment, as well as explore mechanisms of effect, outcomes in other populations, and optimum delivery and monitoring strategies to ensure widespread applicability of reduced frequency visits across settings.

Analysing outcome variables with floor effects due to censoring: a simulation study with longitudinal trial data

ackground: Randomised controlled trials (RCTs) are the gold standard to estimate treatment effects. When patients receive effective treatment over time they may reach the limit of a certain measurement scale. This phenomenon is known as censoring and lead to skewed distributions of the outcome variable with an excess of either low (floor effect) or high values (ceiling effect). Applying traditional methods such as linear mixed models to analyse this kind of longitudinal RCT data may result in bias of the regression parameters. To deal with floor effects due to censoring, a tobit mixed model can be used. The objective of this study was to compare the results of longitudinal linear mixed model analyses with longitudinal tobit mixed model analyses.Methods: First, a simulation study was performed in which several situations of RCTs with floor effects were simulated. Second, data from an empirical RCT was analysed with both methods.Results: Although all analyses underestimated the intervention effects, the tobit mixed model performed much better than the linear mixed model in handling floor effects. However, with an increasing number of follow-up measurements in combination with a strong floor effect estimates from the tobit mixed model were also not accurate.Conclusion: tobit mixed model analysis should be used to estimate treatments effects in longitudinal RCTs with floor effects due to censoring.

Minimally invasive mitral valve surgery versus conventional sternotomy mitral valve surgery: A systematic review and meta-analysis of 119 studies.

Whether minimally invasive mitral valve surgery (MMVS) leads to better outcomes remains unclear. We conducted a systematic review and meta-analysis comparing various MMVS approaches with conventional sternotomy. We searched Cochrane CENTRAL, MEDLINE, EMBASE, ClinicalTrials. gov, and the ISRCTN Register for studies comparing minimally invasive approach (thoracotomy, port access, partial sternotomy, or robotic) with median sternotomy for mitral valve surgery. We performed title and abstract, full-text screening, and data extraction independently and in duplicate. We pooled data using random effect models. Quality assessment was performed using validated tools. Certainty of evidence was established using the GRADE framework. One hundred and nineteenstudies (n = 38,106) met eligibility criteria: eight randomized controlled trials (RCTs) and 111 observational studies. MMVS was associated with fewer days in hospital (RCT: MD: -2.2 days, 95% CI, [-3.7 to -0.8]; observational: MD:-2.4 days, 95% CI, [-2.7 to -2.1]). Observational studies suggested that MMVS reduced transfusion requirements with fewer units transfused per patient (MD: -1.2; 95% CI, [-1.6 to -0.9]) and fewer patients transfused (RR, 0.7; 95% CI, [0.6-0.7]). Observational data also suggested lower mortality with MMVS (RR, 0.6; 95% CI, [0.5-0.7], p < .001, I2 = 0%), but this was not corroborated by RCT data. The risk of postoperative mitral regurgitation (≥2+ or requiring re-intervention) did not differ between the two groups. MMVS may be associated with shorter length of hospital stay with no significant difference in short-term morbidity and mortality. There is a paucity of high-quality data on the long-term outcomes of MMVS when compared with conventional sternotomy.

Toward higher import substitution: does quality governance matter for uptake and pricing of improved local rice in Ghana?

PurposeProduct quality standardization is the solution to market collapses due to quality-insensitive pricing regimes prevalent in West African (WA) rice value chains. However, access to local rice that is differentiated by quality standards is limited. This paper explores feasibility of quality standardization of local rice and evaluates how its price–quality connecting effect depends on retailer characters/reactions.Design/methodology/approachThis study uses panel data from a wholesale randomized control trial (RCT) and three surveys of 135 rice retailers in Ghana.FindingsImproved local food value chains and access to quality differentiated products are impactful entry points for import substitution policies. The strength of interretailer competition, retail infrastructure and wholesaler activities matter for a stronger connection of prices and quality, given uptake of quality-standardized local rice.Research limitations/implicationsAccess to quality-differentiated local rice can be increased via private and third-party certification. This addresses the prevailing inefficient pricing and its related problems. The positive impacts of such access would be magnified by designing quality certification interventions to elicit regular-frequent purchases by retailers and target retailers with adequate retail infrastructure in high competition areas. However, this study only explored profitability and opportunities for strategic behavior as the behavioral basis for quality-sensitive pricing. Other impact mechanisms could be explored in further research that includes consumer data.Originality/valueDespite their difficulty and limited use in value chains studies, RCT and panel data methods are used. This study is the first to empirically analyze feasibility of introducing product standardization, a missing institution in the WA local rice markets.

Selection and outcome of implantable cardioverter-defibrillator patients with and without cardiac resynchronization therapy: Comparison of 4384 patients from the German Device Registry to randomized controlled trials.

Registry data add important information to randomized controlled trials (RCT) on real-life aspects of implantable cardioverter-defibrillator (ICD) patients with and without cardiac resynchronization therapy (CRT-D). This analysis of the prospectively conducted German Device Registry aims at comparing mortality rates, comorbidities, complication rates to results from RCT. The German Device registry (DEVICE) prospectively collected data on ICD and CRT-D first implantations from 50 German centres. Demographic data, details on cardiac disease, electrocardiogram (ECG), medication, and data about procedure, complications, and hospital stay were stored in electronic case report forms. One year after device implantation patients were contacted for follow-up. DEVICE included n = 4384 first ICD/CRT-D implantations (29.3% CRT-D devices). We found a strong adherence to guidelines with over 90% of patients being on ß-blocker and ACE-inhibitor medication and adequate QRS width in the majority of CRT-D patients. Patients receiving a CRT-D were older (67.6 ± 11.0 years vs. 63.9 ± 13.4 years, p < .001) and had lower ejection fractions (mean 25% vs. 30%, p < .001) compared to ICD patients. Dilated cardiomyopathy was the predominant underlying heart disease in CRT-D (53.3%), coronary artery disease in ICD patients (64.7%). Compared to RCT our DEVICE patients had more comorbidities (17.9% chronic kidney disease [CKD]) and higher 1-year mortality rates (10.7% ICD group, 12.3% CRT group). In multivariate analysis, CKD patients had an almost 2-fold higher risk of 1-year mortality. Despite relevant limitations of registry data, DEVICE highlights important differences between RCT and real-world registry data and the impact of comorbidities on mortality of ICD and CRT-D recipients.

Regional trends of minimally invasive radical hysterectomy for cervical cancer and exploration of perioperative outcomes

IntroductionRadical hysterectomy (RH) with bilateral pelvic lymph node dissection is the standard treatment for early stage cervical cancer which can be performed either by an abdominal or a minimally invasive (MIS) approach. In 2018, Ramirez et al. presented their randomized-controlled trial data which demonstrated that patients who were treated with minimally invasive surgical (MIS) radical hysterectomy (RH) had higher rates of locoregional disease recurrence and lower rates of overall survival when compared to patients treated with an abdominal approach. The objective of this study is to examine the trends in management of patients diagnosed with cervical cancer in New York State (NYS) and to analyze their perioperative outcomes. MethodsUsing the Statewide Planning and Research Cooperative System (SPARCS) Database, patients undergoing RH for early stage cervical cancer in NYS between the years of 2007–2015 were identified and categorized based on surgical approach. Demographic information was collected and multivariable regression was conducted to assess the impact of hysterectomy approach on perioperative outcomes. ResultsIn NYS, 5575 patients were treated with RH for early stage cervical cancer with 3257 (58.4%) treated by abdominal RH and 2318 (41.6%) treated with MIS RH. Between the years of 2007 and 2015, patients diagnosed with cervical cancer treated with MIS RH increased from 25.7% to 48.3% respectively. Surgeons performing MIS RH were more likely to be younger (average age 47.1 vs 49.2, p < 0.001) and have less time elapsed from their fellowship graduation (20.37 vs 22.64 years, p < 0.001). Patients who saw high volume doctors (OR 1.95, CI 1.65–2.31) and were seen in high volume facilities (OR 1.40, CI 1.18–1.65) were more likely to undergo MIS RH compared to abdominal RH. Patients who underwent MIS RH were more likely to be discharged home as opposed to acute rehab or nursing facility, when compared to patients treated with abdominal RH (98.5 vs 94.2% p < 0.001). When analyzing perioperativce outcomes, patient undergoing MIS RH had a 85% decrease in length of hospital stay compared to abdominal RH, a 40% reduction in 30-day readmission rates, and a 10% reduction in hospital costs respectively. DiscussionIn our study period, between the years of 2007 and 2015, the number of cervical cancer cases treated with MIS RH increased from 25.7% to 48.3%. MIS techniques led to a reduction in length of hospital stay, patient readmission rates, and hospital costs. Based on recent data from Ramirez et al., preliminary data demonstrated decrease in MIS RH for treatment of cervical cancer after presentation of the LACC trial and our data confirmed these reported trends in NYS. With this change in surgical practice, there will be associated changes in perioperative outcomes. Moreover, for patients diagnosed with cervical cancer with microscopic disease or previous treatment with an excisions procedure, MIS approach should be considered for improvement in perioperative outcomes as long as oncologic outcomes are not compromised.

OP34 Efficacy and safety of advanced induction and maintenance therapies in patients with moderately to severely active Ulcerative Colitis: An indirect treatment comparison using Bayesian network meta-analysis

Abstract Background The therapeutic armamentarium to treat adult patients with moderately to severely active ulcerative colitis (UC) continues to evolve. With this rapid innovation, the comparative efficacy and safety of more recent advanced therapies remain unknown. Methods Bayesian network meta-analysis was used to indirectly compare the efficacy and safety of advanced therapies for induction (6–10 weeks) and maintenance (44–54 weeks post-induction response) in adults with moderately-to-severely active UC. Efficacy was assessed separately in bio-naïve and bio-exposed populations by clinical remission (Full Mayo score [FM] of ≤2 with no subscore &amp;gt;1), clinical response (decrease from baseline in FM ≥3 points and ≥30% with decrease in rectal bleeding score [RBS] of ≥1 or absolute RBS ≤1) and endoscopic improvement (endoscopic score ≤1); ad hoc analyses were conducted on upadacitinib (UPA) RCT data to produce FM outcomes. Safety was assessed by discontinuation due to adverse events (AEs), serious AEs, and serious infections. Induction therapies included UPA 45 mg, adalimumab 160/80 mg, filgotinib 100 and 200 mg, golimumab 200/100 mg, infliximab 10 and 5 mg/kg, ozanimod 0.92 mg, tofacitinib 10 mg, ustekinumab (UST) 6 mg/kg, and vedolizumab (VED) 300 mg. The maintenance analysis included low and high maintenance doses of these therapies. Phase 3 randomized controlled trials (RCTs) were identified via systematic literature review. Random effects models were used to account for expected heterogeneity in endpoints and study design. Guidelines from the National Institute for Health and Care Excellence were followed. Results Out of 31 RCTs identified, 23 were included (18 for induction and 14 for maintenance). Odds ratios vs. placebo (PBO), numbers needed to treat/harm, and surface under the cumulative ranking curve estimates are presented for efficacy in bio-naïve (Table 1) and bio-exposed (Table 2) populations and for safety in overall populations (Table 4). Intent-to-treat rates of maintenance efficacy outcomes adjusted by the likelihood of induction response show UPA to be consistently the most efficacious therapy (Table 3). There were no significant differences in serious AEs or serious infections for any advanced therapy vs PBO. For discontinuation due to AEs, only UPA had significantly lower odds vs PBO after induction, while UST and VED had significantly lower odds vs PBO after maintenance (Table 4). Conclusion In patients with moderately-to-severely active UC, UPA 45 mg induction and 30 mg maintenance appear more efficacious than other advanced therapies/PBO at inducing and maintaining clinical response, clinical remission, and endoscopic response, with no greater safety assessments vs PBO, over 1-year.

The Effect and Safety of Iguratimod Combined With Methotrexate on Rheumatoid Arthritis: A Systematic Review and Meta-Analysis Based on a Randomized Controlled Trial.

Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease with inflammatory synovitis. Iguratimod (IGU) combined with methotrexate (MTX) therapy may have better efficacy and safety. Methods: First, we searched randomized controlled trials (RCTs) of IGU + MTX in the treatment of RA through literature databases (such as PubMed, Corkland Library, CNKI, etc.) and then conducted RCT quality assessment and data extraction. Finally, we used RevMan 5.3 for meta-analysis, STATA 15.0 for publication bias assessment, and GRADE tool for the evidence quality assessment of primary outcomes. This systematic review and meta-analysis were registered in PROSPERO (CRD42021220780). Results: This systematic review and meta-analysis included 31 RCTs involving 2,776 patients. Compared with MTX alone, the ACR20, ACR50, and ACR70 of IGU + MTX are higher, while DAS28 is lower [ACR20: (RR 1.55, 95% CI 1.14–2.13, p = 0.006); ACR50: (RR 2.04, 95% CI 1.57–2.65, p < 0.00001); ACR70: (RR 2.19, 95% CI 1.44–3.34, p = 0.00003); DAS28: (weighted mean difference (WMD) −1.65, 95% CI −2.39 to −0.91, p < 0.0001)]. Compared with MTX + leflunomide, IGU + MTX has no significant difference in improving ACR20, ACR50, ACR70, but IGU + MTX improves DAS28 more significantly [ACR20: (RR 1.09, 95% CI 0.79–1.89, p = 0.59); ACR50: (RR 1.07, 95% CI 0.64–1.78, p = 0.81); ACR70: (RR 1.17, 95% CI 0.44–3.10, p = 0.76); DAS28: (WMD −0.40, 95% CI −0.42 to −0.38, p < 0.0001)]. Compared with the MTX + tripterygium subgroup and MTX-only subgroup, the incidence of adverse events of the IGU + MTX group is of no statistical significance [MTX only: (RR 0.99, 95% CI 0.87–1.13, p = 0.90); MTX + Tripterygium: (RR 0.73, 95% CI 0.29–1.85, p = 0.50)]. However, compared with MTX + leflunomide, the incidence of adverse events in the IGU + MTX group was lower (RR 0.74, 95% CI 0.62–0.88, p = 0.0009). The quality of ACR70 was high; the quality of adverse events and ACR50 test was moderate. Conclusion: Compared with conventional therapy, IGU + MTX may be a safer and more effective therapy for RA patients. When the intervention method is (IGU 25 mg Bid, MTX 10–25 mg once a week), and the intervention lasts for at least 12 weeks, the curative effect may be achieved without obvious adverse events.

The effect of psychotherapy on anxiety, depression, and quality of life in patients with diabetic retinopathy: A protocol for systematic review and network meta-analysis.

Background:Diabetic retinopathy (DR) is one of the common microvascular complications in diabetic patients, which is characterized by progressive development and often leads to irreversible visual impairment. More seriously, DR patients suffer great psychological stress due to impaired visual function and reduced self-care ability such as anxiety and depression, which seriously affect the quality of life of patients. In recent years, various psychological therapies have been applied to alleviate anxiety, depression, and quality of life in DR patients, which have achieved positive results. However, the effectiveness and safety of different psychological therapies are unclear. This study aims to assess the effects of psychotherapy on anxiety, depression, and quality of life in DR patients through a network meta-analysis.Methods:All randomized controlled trials (RCTs) on the effects of psychotherapy on anxiety, depression, and quality of life in patients with DR published before 30 November 30, 2021, will be searched in the PubMed, EMBASE, Cochrane Register of Controlled Trials, Web of Science, Chinese Scientific Journal Database, China National Knowledge Infrastructure Database, Wanfang, and China Biomedical Literature Database. There will have no restrictions on publication status and language. Two researchers will be independently responsible for RCT screening, data extraction, and quality evaluation. All statistical analyses will be performed using Stata 14.0 and R 4.1.2.Results:The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.Conclusion:This study will provide comprehensive and reliable evidence-based references for elucidating the efficacy of psychotherapy on anxiety, depression, and quality of life in DR patients.Ethics and dissemination:Ethical approval was not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and shared on social media platforms.OSF Registration number:DOI 10.17605/OSF.IO/K8T27.

To Cement or Not to Cement: Have We Answered the Question?: Commentary on an article by Hasan R. Mohammad, MBChB, MRes(Dist), MRCS (Eng), DPhil(Oxon), et al.: "A Matched Comparison of the Long-Term Outcomes of Cemented and Cementless Total Knee Replacements, Based on Data from National Databases. An Analysis from the National Joint Registry of England, Wales, Northern Ireland and the

Commentary The debate regarding the optimal method of fixation in total knee arthroplasty (TKA) has continued for almost 40 years, beginning with case series and culminating recently with intermediate-term results from randomized controlled trials (RCTs). The ongoing interest in this debate is justified: TKA patients are getting younger, making implant longevity a priority; post-TKA dissatisfaction remains prevalent, leading to the question of whether implant fixation contributes to pain; and infection is still the most common reason for revision, prompting the desire to simplify surgery and reduce operative time. The popularity of cementless TKA has very recently increased, as reflected in the 2020 annual reports of the Australian Orthopaedic Association National Joint Replacement Registry and the American Joint Replacement Registry. Yet, to date, there have been few long-term (>10-year) large-scale studies that have investigated the clinical outcomes of cemented versus cementless TKA, while accounting for pertinent variables such as age, body mass index, and bone quality. Mohammad and colleagues have challenged this gap in the literature by conducting a rigorous propensity-score-matched cohort analysis of 22,477 patients treated with cementless TKA and 22,477 patients treated with cemented TKA from 2004 to 2018 with Great Britain’s National Joint Registry (NJR). This is the largest long-term matched analysis of TKA outcomes according to fixation type. Their results can be interpreted differently, depending on where your personal loyalties lie. Cement advocates will point out the lower overall implant survival rate, higher rate of reoperation (but not of component revision), and higher rate of revision for pain associated with cementless TKA. Cement cynics will stress the lower infection rate, lower overall reoperation rate, and lower aseptic loosening rate in patients <65 years of age associated with cementless TKA. Regardless of these differences, the study found that both fixation techniques exhibited a survival probability of >95%. Furthermore, historical concerns associated with cementless fixation, including early loosening and periprosthetic fractures, were not observed, nor were older designs associated with higher failure rates. Are the above results enough to encourage the masses to abandon cement in primary TKA? In isolation, probably not. However, the mounting evidence creates a compelling argument. Over the last 10 years, 6 separate RCTs comparing fixation techniques have found little difference in revision rates or survival1-6, at least in the short term. Does the internal consistency of each of these trials apply to your clinical practice? Not universally, but for a young patient who presents with good bone quality, mild/moderate deformity, and no predictors of poor postoperative pain coping, what strong argument exists against attempting cementless TKA? One may be able to point to the observation that cementless components tend to migrate more in the first 3 months to 2 years, but cemented components do so as well, sometimes even to a greater extent7. It is true that several important questions remain: what happens to the current RCT data at intermediate and long-term milestones? Are implant revisions easier with one type of fixation versus the other? Does fixation survival differ in mechanically versus kinematically aligned TKA? Is there an optimal porous surface coverage and keel/stem length that stands above other designs? Evidently, it will take more high-quality studies to answer all of these questions, but that should not necessarily stop surgeons from being selective in their clinical decisions. For now, it is clear that cement is certainly here to stay in primary TKA, especially in older, osteoporotic patients. However, we appear to be headed to what has already happened in hip arthroplasty—a recognition that a one-method-fits-all approach does not work for every patient. I congratulate the authors in helping us get one step closer to this reality.

An eHealth Intervention for Promoting COVID-19 Knowledge and Protective Behaviors and Reducing Pandemic Distress Among Sexual and Gender Minorities: Protocol for a Randomized Controlled Trial (#SafeHandsSafeHearts).

BackgroundExisting data on COVID-19 disparities among vulnerable populations portend excess risk for lesbian, gay, bisexual, transgender (LGBT) and other persons outside of heteronormative and cisgender identities (ie, LGBT+). Owing to adverse social determinants of health, including pervasive HIV and sexual stigma, harassment, violence, barriers in access to health care, and existing health and mental health disparities, sexual and gender minorities in India and Thailand are at disproportionate risk for SARS-CoV-2 infection and severe disease. Despite global health disparities among LGBT+ populations, there is a lack of coordinated, community-engaged interventions to address the expected excess burden of COVID-19 and public health–recommended protective measures.ObjectiveWe will implement a randomized controlled trial (RCT) to evaluate the effectiveness of a brief, peer-delivered eHealth intervention to increase COVID-19 knowledge and public health–recommended protective behaviors, and reduce psychological distress among LGBT+ people residing in Bangkok, Thailand, and Mumbai, India. Subsequent to the RCT, we will conduct exit interviews with purposively sampled subgroups, including those with no intervention effect.MethodsSafeHandsSafeHearts is a 2-site, parallel waitlist-controlled RCT to test the efficacy of a 3-session, peer counselor–delivered eHealth intervention based on motivational interviewing and psychoeducation. The study methods, online infrastructure, and content were pilot-tested with LGBT+ individuals in Toronto, Canada, before adaptation and rollout in the other contexts. The primary outcomes are COVID-19 knowledge (index based on US Centers for Disease Control and Prevention [CDC] items), protective behaviors (index based on World Health Organization and US CDC guidelines), depression (Patient Health Questionnaire-2), and anxiety (Generalized Anxiety Disorder-2). Secondary outcomes include loneliness, COVID-19 stress, and intended care-seeking. We will enroll 310 participants in each city aged 18 years and older. One-third of the participants will be cisgender gay, bisexual, and other men who have sex with men; one-third will be cisgender lesbian, bisexual, and other women who have sex with women; and one-third will be transfeminine, transmasculine, and gender nonbinary people. Participants will be equally stratified in the immediate intervention and waitlist control groups. Participants are mainly recruited from online social media accounts of community-based partner organizations. They can access the intervention on a computer, tablet, or mobile phone. SafeHandsSafeHearts involves 3 sessions delivered weekly over 3 successive weeks. Exit interviews will be conducted online with 3 subgroups (n=12 per group, n=36 in each city) of purposively selected participants to be informed by RCT outcomes and focal populations of concern.ResultsThe RCT was funded in 2020. The trials started recruitment as of August 1, 2021, and all RCT data collection will likely be completed by January 31, 2022.ConclusionsThe SafeHandsSafeHearts RCT will provide evidence about the effectiveness of a brief, peer-delivered eHealth intervention developed for LGBT+ populations amid the COVID-19 pandemic. If the intervention proves effective, it will provide a basis for future scale-up in India and Thailand, and other low- and middle-income countries.Trial RegistrationClinicalTrials.gov NCT04870723; https://clinicaltrials.gov/ct2/show/NCT04870723International Registered Report Identifier (IRRID)DERR1-10.2196/34381

Cost-Effectiveness of Adjuvant Immunotherapy With Cytokine-Induced Killer Cell for Hepatocellular Carcinoma Based on a Randomized Controlled Trial and Real-World Data.

BackgroundStudies using data from randomized controlled trials (RCTs) and real-world data (RWD) have suggested that adjuvant cytokine-induced killer (CIK) cell immunotherapy after curative treatment for hepatocellular carcinoma (HCC) prolongs recurrence-free survival (RFS) and overall survival (OS). However, the cost-effectiveness of CIK cell immunotherapy as an adjuvant therapy for HCC compared to no adjuvant therapy is uncertain.MethodsWe constructed a partitioned survival model to compare the expected costs, life-year (LY), and quality-adjusted life-year (QALY) of a hypothetical population of 10,000 patients between CIK cell immunotherapy and no adjuvant therapy groups. Patients with HCC aged 55 years who underwent a potentially curative treatment were simulated with the model over a 20-year time horizon, from a healthcare system perspective. To model the effectiveness, we used OS and RFS data from RCTs and RWD. We estimated the incremental cost-effectiveness ratios (ICERs) and performed extensive sensitivity analyses.ResultsBased on the RCT data, the CIK cell immunotherapy incrementally incurred a cost of $61,813, 2.07 LYs, and 1.87 QALYs per patient compared to no adjuvant therapy, and the estimated ICER was $33,077/QALY. Being less than the willingness-to-pay threshold of $50,000/QALY, CIK cell immunotherapy was cost-effective. Using the RWD, the ICER was estimated as $25,107/QALY, which is lower than that obtained using RCT. The time horizon and cost of productivity loss were the most influential factors on the ICER.ConclusionWe showed that receiving adjuvant CIK cell immunotherapy was more cost-effective than no adjuvant therapy in patients with HCC who underwent a potentially curative treatment, attributed to prolonged survival, reduced recurrence of HCC, and better prognosis of recurrence. Receiving CIK cell immunotherapy may be more cost-effective in real-world clinical practice.

Ginger for Migraine.

Many preclinical and clinical studies have examined the potential benefits of ginger extracts for a range of medical disorders. Ginger has been found to reduce both pain and nausea and has therefore also been studied in the context of migraine headache. One randomized controlled trial (RCT) found that ginger was no better than placebo for the prevention of migraine episodes. One meta-analysis (pooled N = 227) found that, relative to placebo, ginger was associated with a higher proportion of patients who were pain free 2 hours after treatment (risk ratio [RR], 1.79; 95% confidence interval [CI], 1.04-3.09; 2 RCTs). In this meta-analysis, relative to placebo, ginger reduced the risk of migraine-related nausea and vomiting (RR, 0.48; 95% CI, 0.30-0.77; 3 RCTs) and was not associated with an increased risk of adverse events (RR, 0.80; 95% CI, 0.46-1.41; 3 RCTs). No other RCT data are available. Such an evidence base is clearly too small for formal recommendations to be possible. It is suggested that raw ginger or proprietary ginger extracts may be useful as a home remedy for patients who experience an episode of migraine and who, for whatever reason, cannot take established first-line treatments for acute migraine. How ginger thus used compares with established treatments for migraine is presently unknown. Finally, it must be remembered that the chemical constituents of ginger will vary across source and extract; so, when an extract of ginger is studied, the findings of the study can be generalized only to that extract and, possibly, to other extracts with a similar composition.

Abstract 9758: Estimating Cardiovascular and Limb Benefits of Combined Contemporary Risk Reduction Therapies in Patients with Symptomatic Peripheral Artery Disease: An Analysis of Randomized Controlled Trials

Introduction: Individual randomized controlled trials (RCTs) have shown beneficial effects of low dose rivaroxaban and PCSK9 inhibition (PCSK9i) in addition to background aspirin and statin in patients with peripheral artery disease (PAD). However, the combined effect of these pharmacotherapies is not known. In this analysis of RCT data, we sought to estimate the combined effect of contemporary risk reduction therapies in patients with PAD. Methods: We used data from the COMPASS (n=4,129) and FOURIER (n=3,642) trials to estimate the combined effect of contemporary (aspirin, statin, low dose rivaroxaban and PCSK9i) versus standard therapy (aspirin and statin) in symptomatic PAD patients. The primary outcome was a composite of major adverse cardiovascular (MACE) or limb (MALE) events. Using the hazard rates for low dose rivaroxaban versus control and PCSK9i versus control from the two trials, we estimated the hazard rate for combined therapy by assuming that the treatment effects are approximately additive on the log hazard rate (no interaction between the two treatments). We then used an exponential model to simulate event-free survival and cumulative incidence functions, and hazard ratios (HRs) for the combined versus the standard therapy group. Results: Compared with standard therapy, combined contemporary pharmacotherapy estimated a 50% reduction in MACE or MALE (HR, 0.50; 95% confidence interval [CI], 0.36-0.70; P&lt;0.001). The 3-year cumulative incidence probability of MACE or MALE was 9.1% in the combined group and 15.4% in the standard therapy group ( Figure ). The hazards for MACE (HR, 0.52; 95% CI, 0.36-0.75; P=0.001) and MALE (HR, 0.35; 95% CI, 0.18-0.68; P=0.002) also favored combined contemporary therapy. Conclusions: Thoughtful incorporation of contemporary pharmacotherapies that include low dose rivaroxaban and PCSK9i in addition to aspirin and statin has the potential to substantially reduce cardiovascular and limb events in patients with PAD.

Pragmatic pharmacoeconomic analyses by using post-market adverse drug reaction reports: an illustration using infliximab, adalimumab, and the Canada vigilance adverse reaction database

BackgroundThe prediction of the real-world cost of adverse drug reactions (ADRs) has historically relied on the data from randomized controlled trials (RCT). However, trial conditions do not always reflect the real-world applications of pharmaceutical products; hence, they may not accurately portray the actual risks of ADRs associated with them. The objective of this study is two-fold: (a) demonstrate whether and how post-market and RCT ADR data could lead to different conclusions for a set of drugs of interest, and (b) evaluate the potential economic impact of the post-market ADRs associated with those drugs.MethodsWe selected two TNF-α inhibitor biologics, infliximab and adalimumab, and used the Canada Vigilance Adverse Reaction (CVAR) online database as a source of post-market ADR data. Adverse reaction data from RCTs were obtained from ClinicalTrials.gov. Direct healthcare costs associated with adverse reactions were obtained from Canadian Institute for Health Information (CIHI) or Interactive Health Data Application, Alberta. We calculated post-market ADR rates and compared them with those found in the randomized controlled trials of these two drugs. Using the post-market data, we estimated the costs associated with serious ADRs from three perspectives: patient, health system, and societal.ResultsFor both drugs, the post-market and RCT data exhibited significantly different adverse reaction rates for several different clinical outcomes. As a general trend, more serious adverse reactions, such as death, appeared to have a higher rate in post-market applications compared to the clinical trials. The estimated average annual economic burden of the severe adverse reaction outcomes ranged from $10 million to $20 million for infliximab and $6 million to $19 million for adalimumab.ConclusionsThe frequency and severity of post-market adverse reactions associated with pharmaceutical products may significantly differ from those detected in the clinical trials. Despite possible methodological differences, this is due to the fact that post-market data reflect the externalities of the real-world that are absent in RCTs. The economic burden of adverse reactions can be substantial, and the cost calculated using post-market data is better reflective of the cost of ADRs in the real-world.

The estimand framework and its application in substance use disorder clinical trials: a case study

ABSTRACT Relapse rates among individuals with substance use disorder (SUD) remain high and new treatment approaches are needed, which require evaluation in randomized controlled trials (RCTs). Measurement and interpretation challenges for SUD RCT data are often ignored or presented only in statistical analysis plans. Since different analytic approaches may result in different estimates and thus interpretations of the treatment effect, it is important to present this clearly throughout the trial. Inconsistencies between study analyses and objectives present further challenges for interpretation and cross-study comparisons. The recent International Council for Harmonization (ICH) addendum provides standardized language and a common framework for aligning trial objectives, design, conduct, and analysis. The framework focuses on estimands, which describe the treatment effect and link the trial objective with the scientific question and the analytic approach. The use of estimands offers SUD researchers and clinicians the opportunity to explicitly address events that affect measurement and interpretation at the outset of the trial. Furthermore, the use of standard terminology can lead to clearer interpretations of SUD trials and the treatments evaluated in SUD trials. Resources for understanding and applying estimands are needed to optimize the use of this new, helpful framework. This Perspective provides this resource for SUD researchers. Specifically, it highlights the relevance of estimands for SUD trials. Furthermore, it demonstrates how estimands can be used to develop clinically relevant analyses to address challenges in SUD trials. It also shows how a standardized framework can be employed to improve the interpretation and presentation of SUD study findings.

Propensity score methods for merging observational and experimental datasets.

We consider how to merge a limited amount of data from a randomized controlled trial (RCT) into a much larger set of data from an observational data base (ODB), to estimate an average causal treatment effect. Our methods are based on stratification. The strata are defined in terms of effect moderators as well as propensity scores estimated in the ODB. Data from the RCT are placed into the strata they would have occupied, had they been in the ODB instead. We assume that treatment differences are comparable in the two data sources. Our first "spiked-in" method simply inserts the RCT data into their corresponding ODB strata. We also consider a data-driven convex combination of the ODB and RCT treatment effect estimates within each stratum. Using the delta method and simulations, we identify a bias problem with the spiked-in estimator that is ameliorated by the convex combination estimator. We apply our methods to data from the Women's Health Initiative, a study of thousands of postmenopausal women which has both observational and experimental data on hormone therapy (HT). Using half of the RCT to define a gold standard, we find that a version of the spiked-in estimator yields lower-MSE estimates of the causal impact of HT on coronary heart disease than would be achieved using either a small RCT or the observational component on its own.

Catheter-associated bloodstream infection in patients with cancer: comparison of left- and right-sided insertions

There is limited research on the relationship between side of insertion of central venous catheter (CVAD) and bloodstream infection risk in patients with cancer. To conduct an exploratory analysis of data from a randomized control trial (RCT) and data from a prospective cohort study to compare infection rates for right- and left-sided insertions. The study populations were patients aged >14 years with cancer from two tertiary hospitals in Brisbane, Australia. The primary endpoint was catheter-associated bloodstream infection (CABSI) adjudicated by blinded assessors. For the RCT, randomized intention-to-treat comparisons were conducted between left- and right-side allocated insertion for early (≤14 days) and late (>14 days) infection using Cox proportional hazards regression. The RCT data were also combined with cohort study data collected from one of the hospitals prior to the RCT and non-randomized comparisons conducted between left- and right-sided insertions. In 634 randomly allocated CVADs there were 141 CABSIs. Analysis showed strong evidence of right-side allocated insertions having an increased risk of early infection by 2.5 times (95% confidence interval (CI): 1.3-4.7); however, there was no evidence of increased risk for late infection (hazard ratio: 1.06; 95% CI: 0.71-1.59). Results from analysis of the RCT and cohort study data combined (2786 CVADs and 385 CABSIs) were similar. There appears to be an increased risk of CABSI in patients with cancer for CVAD inserted into the right-side for around two weeks after line insertion. The mechanism underpinning the increased risk is unknown.