Subsequent Larger Trials Research Articles

Re-evaluating the role of pilot trials in informing effect and sample size estimates for full-scale trials: a meta-epidemiological study

BackgroundSome have argued that pilot trials have little value for informing the expected effect size of a subsequent large trial. This study aims to empirically evaluate the roles of pilot...

Sodium-Glucose Co-Transporter 2 Inhibitors as a Powerful Cardioprotective and Renoprotective Tool: Overview of Clinical Trials and Mechanisms

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been linked to beneficial effects on cardiovascular risk factors, blood pressure, body weight, and lipid profile, according to a substantial body of literature. Significant cardiac and renal benefits with the use of SGLT2 inhibitors have been shown in patients with type 2 diabetes, as well as in those with heart failure and/or chronic kidney disease (CKD), regardless of diabetes status, in subsequent large cardiovascular outcome trials. Thus, SGLT2 inhibitors have become a mainstay of therapy for type 2 diabetes in patients with established cardiovascular disease and CKD due to their benefits for the heart and kidneys. Based on data from randomized controlled trials and meta-analyses, this article attempts to present a thorough review of the mechanism of action, as well as the benefits of SGLT2 inhibitors for cardiac and renal protection. On the basis of a growing body of literature on diabetes and other conditions, clinical practice guidelines have been updated to suggest the use of SGLT2 inhibitors in specific patient populations. These modifications will also be concisely described, based on evidence-based medicine principles.

The long and short of showers: Effects of shower duration on behaviour, thermal comfort and soiling of organic growing-finishing pigs with access to outdoor runs

Showers can be used in the outdoor run to improve thermal comfort and provide environmental enrichment for growing-finishing pigs. Showers may also reduce ammonia emissions by preventing excessive soiling in summer. Few studies have addressed water cooling measures for pigs in systems with concrete outdoor runs, and none have considered the operation of showers outdoors. We therefore investigated the effect of showers in the outdoor run on pigs’ use of different pen areas, thermal comfort, and soiling of the pigs and the pen in multi-farm experiments in Austria and Switzerland. In a pilot experiment on three organic farms involving a total of 428 growing-finishing pigs in 15 groups with two to three assessment days each, we compared groups with access to showers to groups without showers. A subsequent larger trial (referred to as SHORT/LONG experiment) compared two different shower programmes (SHORT = 10-minutes; LONG = 30-minutes shower activation per hour), comprising a total of 472 pigs in 20 groups on three farms with six to seven assessment days each. The treatments SHORT and LONG were alternately applied with at least three replicates per farm. We assessed the pigs’ behaviour (activity, lying posture), respiratory rate and cleanliness as well as soiling of the pens on a group level. The pilot experiment revealed increased activity (p = 0.03) and reduced lateral lying (p = 0.08) in pigs with access to showers compared to pigs without, which supports the potential of showers to improve thermal comfort. In the SHORT/LONG experiment, we found interactions between treatment and outdoor temperature: The proportion of pigs under the shower (p < 0.01), lateral lying in the shower area (p = 0.01) and respiratory rate (p < 0.01) increased more with rising temperatures in treatment LONG than in SHORT. In both treatments, high temperatures increased the use of the outdoor run (p = 0.02) and the shower area (p < 0.001) as well as the soiling of pigs (p < 0.01), while at the same time reducing activity in the shower area (p = 0.02). Interestingly, fewer pigs were present in the shower area during and at the end of shower activation compared to the time before (p < 0.001), indicating avoidance of the water spray. This casts doubt on whether showers, apart from reducing heat stress, provide appropriate means to allow all aspects of species-specific thermoregulation. Our results suggest complex interactions between outdoor temperature, shower duration, pig behaviour, and soiling (with potential impact on ammonia emission), which require further investigation especially in open-air settings.

Targeted temperature management after out of hospital cardiac arrest: quo vadis?

Targeted temperature management (TTM) has become a cornerstone in the treatment of comatose post-cardiac arrest patients over the last two decades. Belief in the efficacy of this intervention for improving neurologically intact survival was based on two trials from 2002, one truly randomized-controlled and one small quasi-randomized trial, without clear confirmation of that finding. Subsequent large randomized trials reported no difference in outcomes between TTM at 33 vs. 36°C and no benefit of TTM at 33°C as compared with fever control alone. Given that these results may help shape post-cardiac arrest patient care, we sought to review the history and rationale as well as trial evidence for TTM, critically review the TTM2 trial, and highlight gaps in knowledge and research needs for the future. Finally, we provide contemporary guidance for the use of TTM in daily clinical practice.

Current Perspective on Menopause Hormone Therapy and Cardiovascular Risk

In past decades, there has a been a paradigm shift concerning menopause, hormone therapy (HT), and cardiovascular disease (CVD). While initial observational studies suggested hormone replacement to provide a cardioprotective benefit for all menopausal women, subsequent large randomized trials have not confirmed these benefits and furthermore brought to light the risks of HT with regard to CVD, venous thrombosis, and stroke. The goal of this review is to summarize current recommendations regarding HT as it pertains to cardiovascular risk. Menopause HT remains the most effective treatment for vasomotor symptoms. Guidelines now suggest benefits outweigh the risk for in women with bothersome vasomotor symptoms, when initiated in early menopause (within 10 years of symptom onset or age < 60 years) without contraindications. Consideration of cardiovascular risk is necessary. For women with a moderate atherosclerotic CVD risk score, or with CVD risk modifiers, a transdermal formulation is preferred. For patients with known CVD, non-hormonal alternatives should be trialed. Current evidence does not support the use of HT for primary or secondary prevention of CVD. Initiation of menopausal HT requires an individualized approach taking into account age of menopause, timing of initiation, vasomotor symptoms, and cardiovascular risk factors.

782. Clostridioides difficile environmental contamination in hospitalized patients with diarrhea: a pilot study

BackgroundThe relative contribution of Clostridioides difficile colonization or infection in contamination of the hospital environment is poorly understood.MethodsWe performed a prospective cohort study of patients with diarrhea who were tested for C. difficile infection via PCR and enzyme immunoassay (EIA) to compare C. difficile environmental contamination by test result. Patients were stratified into one of three cohorts: PCR-, PCR+/EIA+ or PCR+/EIA-. Environmental microbiological samples were taken within 24 hours of C. difficile cultures and again for two successive days for a total of three days. Patients were excluded if they had C. difficile infection in the past 6-weeks. Microbiological samples of surfaces were obtained with pre-moistened cellulose sponges from three locations (bathroom, adjacent to bed, and care areas) and processed using the stomacher technique. Ribotyping was completed on a subset of stool and environmental samples to measure concordance of isolates. CFU and recovery rates between arms were compared with a global ANOVA followed by pairwise comparisons using a Bonferroni adjustment.ResultsWe enrolled 41 patients between November 2019 and March 2020. 7 patients were PCR+/EIA+, 8 were PCR+/EIA- and 26 were PCR- (Table 1). A total of 347 individual and 116 room samples were obtained. PCR+/EIA+ patient rooms had a higher average room burden (435.6 CFU (95%CI: 178.0-694.0)) compared to PCR+/EIA- (83.5 (-9.1-175.0), p< 0.01) and PCR- rooms (17.1 (1.2-33.0), p< 0.01); PCR+/EIA- and PCR- rooms were similar (p=0.83). PCR+/EIA+ patient rooms had a higher recovery rate (61%) compared to PCR+/EIA- (36%, p=0.64), although not statistically significant, and PCR- rooms (16%, p< 0.01); PCR+/EIA- had a similar recovery rate to PCR- rooms (p=0.14) (Table 2). Of the rooms with both patient and environmental isolates, 79% of patient isolates had a concordant isolate recovered in the environment.Table 1 Table 2 ConclusionThe amount of environmental contamination of PCR+/EIA+ patients was higher than both PCR+/EIA- and PCR- patients, however, the recovery rate of PCR+/EIA+ patients was similar to PCR+/EIA- patients. Subsequent larger trials are needed to expand on this pilot data to determine the difference, if any, between environmental contamination levels of these patient populations.DisclosuresDavid J. Weber, MD, MPH, PDI (Consultant)

Failures and Successes in Pediatric Patients with Acute Myeloid Leukemia with First Relapse: A Large International Report on Current Treatment Strategies and Outcome

BACKGROUND: Children with high risk acute myeloid leukemia (AML) still experience consistently high rates of relapse. Survival after first relapse increased from 21% between 1987 and 1997 up to 39% in recent studies. However, since 2009, there have been no publications on subsequent large pediatric AML relapse trials. As the indications for HSCT during first-line treatment have been extended since then, the current survival of these patients at relapse remains unclear. Herein, we report outcome results from the BFM and COG study group, which represents the largest available dataset analyzed for post-relapse survival. PATIENTS AND METHODS: Pediatric patients with first relapse of AML (no Down syndrome, secondary leukemia or FAB M3) have been analyzed from two large study groups with patients from the United States, Canada, Australia, New Zealand, Germany, Austria, Czech Republic and Switzerland. Out of 1222 patients in the BFM cohort (AML-BFM study 2004, registry 2012 and study 2012), 350 experienced at least one relapse and 197 of those had a first relapse after closure of the last I-BFM relapse trial (04/2009 through 2017). Within the Children's Oncology Group (COG) Phase 3 trials (AAML0531 and AAML1031, n=2119) 852 pediatric patients suffered a relapse. Five-year probability of overall survival (pOS) and event-free survival (pEFS) were calculated according to Kaplan-Meier. EFS was calculated for the BFM cohort as time from relapse to the next event (second relapse, death, failure to achieve a second remission or secondary malignancy) or until last follow-up, while OS reflects the time from relapse until death or last follow-up. The Cox proportional hazards model was used for multivariate analysis of outcomes. Living patients were censored at last follow-up with a median follow-up after relapse of 4·2 years (BFM) and 4·8 years (COG). Data have been frozen at 03/27/2020 (BFM) and 03/31/2020 (COG). RESULTS: In the 197 patients with relapse after closure of the last BFM relapse trial (04/2009 through 2017) the pOS at 5 years was 42±4% (BFM). The 5-year pOS in patients relapsing after COG trials 2006-2018 was 35±2% (n=852). Patients experiencing a relapse between 2014 to 2017 had a pOS of 49±6% (BFM, n=78) and 40±3% (COG, n=333). Risk classification at initial diagnosis and a short time from diagnosis to relapse predicted a diminished survival probability in both cohorts (see Table 1). However, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival: Within the BFM dataset, a subgroup analysis in all patients receiving DNX-FLA (n=156) have been performed. Initial characteristics are comparable to the total cohort. Among these patients 147 were evaluable for response (7 excluded due to early death before evaluation, 2 for insufficient data). Eighty-nine (57%) achieved a CR (n=69) or CRp (n=20) and 52 (33%) no response. Overall survival was superior for patients with a CR/CRp (54±6% (CR/CRp) vs. 32±7% (No CR/CRp); p=0·0064), but long-term survival was still possible even with a poor re-induction response. Patients with a CRp had a comparable survival to those with a CR after a second re-induction (pOS 60±11% (CRp) vs. pOS 52±7% (CR); p=0·57). Patients with &amp;gt;5% leukemic blasts (n=32) had the lowest survival (pOS 27±9%). The 5-year pEFS for this cohort was 29±4% (pEFS 50±6% (CR) vs. pEFS 50±11% (CRp)). The analysis of post-relapse treatment showed that the vast majority of patients who survive had a HSCT following relapse. By landmark analysis, survival was significantly higher in patients with subsequent HSCT compared to that of non-transplanted patients (BFM: pOS 53±4%, n=154 vs. pOS 5±5%, n=21; p(Mantel-Byar)=0·0002). CONCLUSION: This is the largest report to date on post relapse survival in children with AML. Our analysis confirmed previously described risk factors for poor survival while also highlighting new findings contrary to established standards. Strikingly, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival at first relapse, thereby questioning the current value of the established International Working Group Criteria published by Cheson et al for response-evaluation in pediatric AML. As the international pediatric AML community embarks on collaborative efforts to evaluate new therapies in children with relapsed AML, a comprehensive review of post relapse survival is critical. Disclosures Bourquin: Servier: Other: Travel Support. Reinhardt:Novartis: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Internet-delivered acceptance and commitment therapy (iACT) for chronic pain-feasibility and preliminary effects in clinical and self-referred patients.

Acceptance and commitment therapy (ACT) is an evidence-based treatment to improve functioning and quality of life (QoL) for chronic pain patients, but outreach of this treatment is unsatisfactory. Internet-delivery has been shown to increase treatment access but there is limited evidence regarding feasibility and effectiveness of web-based ACT for chronic pain. The aim of the study was to evaluate and iterate a novel internet-delivered ACT program, iACT, in a clinical and a self-referred sample of chronic pain patients. The intervention was developed in close collaboration with patients. To enhance learning, content was organized in short episodes to promote daily engagement in treatment. In both the clinical and self-referred samples, three critical domains were evaluated: (I) feasibility (acceptability, practicality and usage); (II) preliminary efficacy on pain interference, psychological inflexibility, value orientation, QoL, pain intensity, anxiety, insomnia and depressive symptoms; and (III) potential treatment mechanisms. This was an open pilot study with two samples: 15 patients from a tertiary pain clinic and 24 self-referred chronic pain participants, recruited from October 2015 until January 2017. Data were collected via an online platform in free text and self-report measures, as well as through individual oral feedback. Group differences were analyzed with Chi square-, Mann-Whitney U- or t-test. Preliminary efficacy and treatment mechanism data were collected via self-report and analyzed with multilevel linear modeling for repeated measures. Feasibility: patient feedback guided modifications to refine the intervention and indicated that iACT was acceptable in both samples. User insights provided input for both immediate and future actions to improve feasibility. Comprehensiveness, workability and treatment credibility were adequate in both samples. Psychologists spent on average 13.5 minutes per week per clinical patient, and 8 minutes per self-referred patient (P=0.004). Recruitment rate was 24 times faster in the self-referred sample (24 patients in 1 month, compared to 15 patients in 15 months, P<0.001) and the median distance to the clinic was 40 km in the clinical sample, and 426 km in the self-referred sample (P<0.001). Preliminary effects: post-assessments were completed by 26 participants (67%). Significant effects of time were seen from pre- to post-treatment across all outcome variables. Within group effect sizes (Cohen's d) at post-treatment ranged from small to large: pain interference (d=0.64, P<0.001), psychological inflexibility (d=1.43, P<0.001), value progress (d=0.72, P<0.001), value obstruction (d=0.42, P<0.001), physical QoL (d=0.41, P=0.005), mental QoL (d=0.67, P=0.005), insomnia (d=0.31, P<0.001), depressive symptoms (d=0.47, P<0.001), pain intensity (d=0.78, P=0.001) and anxiety (d=0.46, P<0.001). Improvements were sustained at 1-year follow-up. Psychological inflexibility and value progress were found to be potential treatment mechanisms. The results from the present study suggests that iACT was feasible in both the clinical and the self-referred sample. Together with the positive preliminary results on all outcomes, the findings from this feasibility study pave the way for a subsequent large randomized efficacy trial.

Study protocol of coaching end-of-life palliative care for advanced heart failure patients and their family caregivers in rural appalachia: a randomized controlled trial

BackgroundHeart failure (HF) afflicts 6.5 million Americans with devastating consequences to patients and their family caregivers. Families are rarely prepared for worsening HF and are not informed about end-of-life and palliative care (EOLPC) conservative comfort options especially during the end stage. West Virginia (WV) has the highest rate of HF deaths in the U.S. where 14% of the population over 65 years have HF. Thus, there is a need to investigate a new family EOLPC intervention (FamPALcare), where nurses coach family-managed advanced HF care at home.MethodsThis study uses a randomized controlled trial (RCT) design stratified by gender to determine any differences in the FamPALcare HF patients and their family caregiver outcomes versus standard care group outcomes (N = 72). Aim 1 is to test the FamPALcare nursing care intervention with patients and family members managing home supportive EOLPC for advanced HF. Aim 2 is to assess implementation of the FamPALcare intervention and research procedures for subsequent clinical trials. Intervention group will receive routine standard care, plus 5-weekly FamPALcare intervention delivered by community-based nurses. The intervention sessions involve coaching patients and family caregivers in advanced HF home care and supporting EOLPC discussions based on patients’ preferences. Data are collected at baseline, 3, and 6 months. Recruitment is from sites affiliated with a large regional hospital in WV and community centers across the state.DiscussionThe outcomes of this clinical trial will result in new knowledge on coaching techniques for EOLPC and approaches to palliative and end-of-life rural home care. The HF population in WV will benefit from a reduction in suffering from the most common advanced HF symptoms, selecting their preferred EOLPC care options, determining their advance directives, and increasing skills and resources for advanced HF home care. The study will provide a long-term collaboration with rural community leaders, and collection of data on the implementation and research procedures for a subsequent large multi-site clinical trial of the FamPALcare intervention. Multidisciplinary students have opportunity to engage in the research process.Trial registrationClinicalTrials.gov NCT04153890, Registered on 4 November 2019

Chromoendoscopy versus autofluorescence imaging for neoplasia detection in patients with longstanding ulcerative colitis (FIND-UC): an international, multicentre, randomised controlled trial

Patients with longstanding ulcerative colitis undergo regular dysplasia surveillance because they have an increased colorectal cancer risk. Autofluorescence imaging and chromoendoscopy improve dysplasia detection. The aim of this study was to determine whether autofluorescence imaging should be further studied as an alternative method for dysplasia surveillance in patients with longstanding ulcerative colitis. This prospective, international, randomised controlled trial included patients from an ulcerative colitis-dysplasia surveillance cohort from five centres in the Netherlands and the UK. Eligible patients were aged 18 years or older who were undergoing dysplasia surveillance after being diagnosed with extensive colitis (Montreal E3) at least 8 years before study start or with left-sided colitis (Montreal E2) at least 15 years before study start. Randomisation (1:1) was minimised for a previous personal history of histologically proven dysplasia and concomitant primary sclerosing cholangitis. The coprimary outcomes were the proportion of patients in whom at least one dysplastic lesion was detected and the mean number of dysplastic lesions per patient. The relative dysplasia detection rate, calculated as the ratio of the detection rates by autofluorescence imaging and chromoendoscopy, needed to be more than 0·67 (using an 80% CI) for both primary outcomes to support a subsequent large non-inferiority trial. Outcomes were analysed on a per-protocol basis. The trial is registered at the Netherlands Trial Register, number NTR4062. Between Aug 1, 2013, and March 10, 2017, 210 patients undergoing colonoscopy surveillance for longstanding ulcerative colitis were randomised for inspection with either autofluorescence imaging (n=105) or chromoendoscopy (n=105). Dysplasia was detected in 13 (12%) patients by autofluorescence imaging and in 20 patients (19%) by chromoendoscopy. The relative dysplasia detection rate of autofluorescence imaging versus chromoendoscopy for the proportion of patients with ulcerative colitis with at least one dysplastic lesion was 0·65 (80% CI 0·43-0·99). The mean number of detected dysplastic lesions per patient was 0·13 (SD 0·37) for autofluorescence imaging and 0·37 (1·02) for chromoendoscopy (relative dysplasia detection rate 0·36, 80% CI 0·21-0·61). Adverse events were reported for two patients in the autofluorescence imaging group (one patient had intraprocedural mild bleeding, and one patient had abdominal pain) and for three patients in the chromoendoscopy group (two patients had intraprocedural mild bleeding, and one patient had perforation). Autofluorescence imaging did not meet criteria for proceeding to a large non-inferiority trial. Therefore, existing autofluorescence imaging technology should not be further investigated as an alternative dysplasia surveillance method. Olympus Europe and Olympus Keymed.

Cardiac\xa0output Optimisation following Liver Transplant (COLT) trial: study protocol for a\xa0feasibility\xa0 randomised controlled trial

BackgroundPatients with liver cirrhosis undergoing liver transplantation have a hyperdynamic circulation which persists into the early postoperative period making accurate assessment of fluid requirements challenging. Goal-directed fluid therapy (GDFT) has been shown to reduce morbidity and mortality in a number of surgery settings. The impact of GDFT in patients undergoing liver transplantation is unknown. A feasibility trial was designed to determine patient and clinician support for recruitment into a randomised controlled trial of GDFT following liver transplantation, adherence to a GDFT protocol, participant withdrawal, and to determine appropriate endpoints for a subsequent larger trial to evaluate the efficacy of GDFT in patients undergoing liver transplantation.MethodsThe Cardiac output Optimisation following Liver Transplant (COLT) trial is designed as a prospective, single-centre, randomised controlled study to assess the feasibility and safety of GDFT in liver transplantation for patients with cirrhosis. Consenting adults (aged between 18 and 80 years) with biopsy-proven liver cirrhosis who have been selected to undergo a first liver transplantation will be included in the trial and randomised into GDFT or standard care starting immediately after surgery and continuing for the first 12 h thereafter. Both groups will have cardiac output and stroke volume monitored using the FloTrac (EV1000) device. The intervention will consist of a protocolised GDFT approach to patient management, using stroke volume optimisation. The control group will receive standard care, without stroke volume and cardiac output measurement. After 12 h the patient’s fluid management will revert to standard of care. The primary endpoint of this study is feasibility. Secondary endpoints will include a safety assessment of the intervention, graft and patient survival, liver function, postoperative complications graded by Clavien-Dindo criteria, length of intensive care and hospital stay and quality of life across the intervention and control groups.DiscussionThere is a growing body of evidence that the use of perioperative GDFT in surgical patients can improve outcomes; however, signals of harm have also been detected. Patients with liver cirrhosis undergoing liver transplantation have markedly different cardiovascular physiology than general surgical patients. If GDFT is proven to be feasible and safe in this patient group, then a multicentre trial to demonstrate efficacy and cost-effectiveness will be required.Trial registrationInternational Standard Randomised Controlled Trial Registry, ID: ISRCTN10329248. Registered on 4 April 2016.

T-lymphocyte and glycemic status after vitamin D treatment in type 1 diabetes: A randomized controlled trial with sequential crossover.

Type 1 diabetes mellitus (T1D) is mediated by autoaggressive T effector cells with an underlying regulatory T-cell (Treg) defect. Vitamin D deficiency is highly prevalent in T1D, which can aggravate immune dysfunction. High-dose vitamin D treatment may enhance Tregs and improve metabolism in T1D patients. In a randomized double-blind placebo-controlled trial with crossover design, patients received either for 3 months cholecalciferol 4000 IU/d followed by 3 months placebo or the sequential alternative. Thirty-nine T1D patients (19 women and 20 men) completed the trial. Primary outcome was a change of Tregs, secondary HbA1C, and insulin demand. Effects were evaluated based on intra-individual changes between treatment and placebo periods for outcome measures. Exploratory analyses included vitamin D system variant genotyping and C-peptide measurements. Median 25(OH)D3 increased to 38.8 ng/ml with males showing a significantly stronger increase (p = .003). T-lymphocyte profiles did not change significantly (p > 2); however, the intra-individual change of Tregs between males and females was different with a significantly stronger increase in men (p = .017), as well as between genotypes of the vitamin D receptor (Apa, Taq, and Bsm: genotypes aa, TT, and bb; p = .004-0.015). Insulin demands declined significantly (p = .003-.039) and HbA1C improved (p < .001). Random C-peptide levels were low but rising (median, 0.125 ng/ml; range, 0.02-0.3) in 6 patients. No toxicity was observed. A daily vitamin D dose of 4000 IU for 3 months was well tolerated and enhanced Tregs in males. Glucometabolic control improved in all. Subsequent larger trials need to address ß-cell function and genotyping for individualized vitamin D doses.

Very large treatment effects in randomised trials as an empirical marker to indicate whether subsequent trials are necessary: meta-epidemiological assessment

Objective To examine whether a very large effect (VLE; defined as a relative risk of ≤0.2 or ≥5) in a randomised trial could be an empirical marker that subsequent trials...

Surrogate endpoints and competing risk of death in cardiac arrest research.

We urgently need new therapies to improve outcomes after cardiac arrest. Initial studies typically target surrogate endpoints, and these studies help to inform subsequent larger trials that are powered to measure more patient-orientated clinical outcomes such as survival. The competing risk of death and premature assessment of neurological prognosis pose significant challenges to measuring these surrogate endpoints after cardiac arrest.

When may systematic reviews and meta-analyses be considered reliable?

When may systematic reviews and meta-analyses be considered reliable?

What is wrong with meta-analysis? The importance of clinical heterogeneity in myocardial regeneration research

The author discusses the significance and potential pitfalls in performing a meta-analysis underscoring the importance of a usual forgotten issue in meta-analysis called clinical heterogeneity. Clinical heterogeneity can mislead results and misinform clinicians. Practical examples from the literature are given, and the results of meta-analyses are compared with the results of subsequent large randomised clinical trials addressing similar questions from a historical and contemporary point of view, highlighting clinical heterogeneity. The contemporary aspect culminates with the presentation of a meta-analysis evaluating myocardial cell regeneration with an emphasis in clinical heterogeneity, helping clinicians to understand the issue and better appraise future meta-analyses.

A New Look at an Old Therapy

DESPITE MAJOR ADVANCES IN THE CARE OF PAtients with acute coronary syndrome over the past 3 decades, rates of early morbidity and mortality associated with this condition remain unacceptably high. In the 1980s, the concept of administering glucose, insulin, and potassium (GIK) to patients with suspected myocardial ischemia garnered substantial interest in both the research and practice communities. The therapy is remarkably simple and available globally at a low cost—an especially attractive feature given the increasing incidence of cardiovascular disease in low-income countries. The results of several clinical trials of moderate size seemed to suggest a bright future for GIK therapy; however, a subsequent large pragmatic trial found no benefit, and discussion of the treatment subsided. Selker and colleagues, however, were not comfortable with the conventional wisdom that GIK should be retired from the therapeutic armamentarium. Stimulated both by the prodding of Apstein and by evidence from an animal model that the major effect of GIK was seen during the very early phase of coronary occlusion, the investigators were concerned that the therapy might have benefit but only if applied early, preferably within the first hour from onset of symptoms. They hypothesized that GIK therapy, if given early and prior to reperfusion, would reduce infarct size and lower mortality by preventing sudden arrhythmias. As reported in this issue of JAMA, Selker et al proposed an innovative study, the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) trial—funded by the National Heart, Lung, and Blood Institute (NHLBI)—and created a network to study GIK in the setting of emergency medical services. The IMMEDIATE trial was designed as a large pragmatic effectiveness trial with the primary goal of examining the effect of GIK on the rate of total mortality at 30 days and at 1 year. However, a combination of ambitious investigators and the particulars of the study mechanism combined caused the trial to fall far short of its enrollment goals. With support from the study’s data monitoring committee and from the NHLBI, the investigators reconfigured the trial to address a primary end point of progression to infarction. The more important end points (survival, cardiac arrest, and progression to heart failure) were designated as secondary end points, and in an interesting and unusual approach, these outcomes were examined with an overt statement that the 5 major secondary and 8 other secondary end points would be evaluated with an level of .05 for each hypothesis. By conventional criteria for multiple hypothesis testing, none of these tests would attain statistical significance. The cardiovascular community has been chastened by appealing biological hypotheses that were supported by secondary hypothesis testing that turned out to be random noise. The IMMEDIATE trial showed no effect of GIK on progression to infarction, but all major clinical end points trended in favor of treatment with GIK, as did infarct size in the small number of participants included in the mechanistic substudy. These results raise 4 questions that should be the subject of keen interest among the medical and public health communities. First, how should the trial findings be interpreted for practical purposes? The GIK therapy failed with regard to its primary end point, but there are tantalizing signs of benefit in more important secondary end points representing morbid and mortal disease outcomes. Given the massive amount of data from previous trials that on balance showed neither benefit nor significant risk, the clinical community is presented with a conundrum. Were previous trials flawed by late treatment with GIK that was given past the point when it can show benefit? Or was the IMMEDIATE trial a purely negative trial that exhausted its allotted statistical power with a negative primary question, rendering secondary trends of interest but of limited use in the quest to definitively decipher signal from random noise? There are no clear answers to these questions. There should be no rush to treatment, but more data are needed to answer the question definitively. Second, does the trial add new information that points toward the future use of this therapy? In an ideal scenario, this trial would be followed immediately with a definitive study, one that enrolled patients only within the first hour of symptom onset, with total mortality as the primary outcome. Such a trial probably could be done inexpensively, measuring the primary end point with a postcard or by harvesting electronic health records for vital status and symptoms of heart failure, depending on the environment. A rigorous meta-analysis of all previous data, specifically

β-Blockade in the perioperative management of the patient with cardiac disease undergoing non-cardiac surgery

The cardiology literature has suggested for decades that β-blockade protects patients with ischaemic heart disease. Extending this concept to perioperative patients initially produced promising results, with reductions in perioperative myocardial ischaemia and longer-term cardiovascular complications observed in several small randomized trials. However, subsequent larger trials have either shown no benefit or greater morbidity (especially stroke), despite reductions in cardiovascular events. Retrospective database analyses have confirmed or disputed these findings. Speciality societies, most importantly, the American Heart Association/American College of Cardiology Foundation, have promulgated guidelines for perioperative β-blockade, which have been revised, as the evidence has changed. While the European guidelines continue to emphasize perioperative β-blockade in high-risk patients, the American guidelines have reduced the strength and breadth of recommendations, focusing on haemodynamic titration. Future work will need to focus on identifying populations most likely to benefit or to be harmed, including pharmacogenetic analyses and distinctions between individual β-blockers.

Discontinuation of Dasatinib or Nilotinib in Chronic Myeloid Leukemia (CML) Patients (pts) with Stable Undetectable Bcr-Abl Transcripts: Results From the French CML Group (FILMC)

Abstract 604▪FN2▪This icon denotes a clinically relevant abstract Background:Imatinib, the first tyrosine kinase inhibitor (TKI) directed against the Bcr-Abl oncoprotein, has dramatically improved outcomes for pts with CML. Dasatinib and nilotinib, 2 highly potent second generation (2G)-TKI, have been historically licensed for the treatment of pts with resistance or intolerance to imatinib. They have recently received approval in the frontline setting in chronic phase (CP)-CML. Despite the outstanding efficacy of these drugs, their curative potential remains uncertain. Most TKI-treated pts retain residual leukemic cells detected by means of RTQ-PCR and termination of TKI therapy under such circumstances usually leads to disease relapse. Consequently, it is believed that most CML pts require a lifelong TKI treatment. On the contrary, stopping TKI may be envisaged in pts with stable undetectable molecular residual disease (UMRD), as suggested by recent results from the STop IMatinib trial (Mahon et al. Lancet Oncol. 2010), and our observation that dasatinib could be safely stopped in a pt with a stable UMRD suffering from drug-induced pleural effusion (Cony-Makhoul, et al. unpublished). Aims:We asked whether 2G-TKI could be ceased in CML pts with a stable UMRD. The primary objective of our work was to evaluate the risk of loosing major molecular responses (MMR: BCR-ABL/ABL internationally standardized (IS) ratio ≤ 0.1%) by 6 months. Methods:Pts aged at least 18 years with CP-CML and UMRD were proposed dasatinib or nilotinib discontinuation provided that (1) no prior progression to accelerated phase or blast crisis occurred (2) UMRD was sustained on continuing therapy. UMRD was defined by undetectable Bcr-Abl using internationally standardized RTQ-PCR testing performed in local laboratories, providing that at least 20 000 copies of the control gene had been amplified. After 2G-TKI discontinuation, Bcr-Abl transcripts were quantified monthly during the first 6 months and every 2 to 3 months thereafter. Dasatinib or nilotinib were advised to be re-introduced upon loss of MMR. Results:As of August 1, 2011, 25 pts agreed to stop therapy. The results presented here focus on the subgroup of 16 pts with a minimum follow-up (FU) of 6 months (median 15, range: 7–21). These were 9 females and 7 males, with a median age of 59 years (34-81). The Sokal risk group was low in 11/16 (68.75%), intermediate in 2/16 (12.5%), high in 1/16 (6.25%) and unknown in 2/16 (12.5%). Dasatinib (n=9) or nilotinib (n=7) had been administered owing to imatinib grade 2 hematologic or grade 2 to 4 non hematologic intolerance (n=13), secondary imatinib resistance (n=1) or as the frontline drug (n=1). At start of 2G-TKI, 1 pt was in CP, 1 had a complete hematologic response only, 2 had a partial cytogenetic response, 3 had a complete cytogenetic response but lacked MMR, 4 had a MMR with detectable Bcr-Abl transcripts and 5 had a UMRD. The median time on 2G-TKI therapy prior to discontinuation was 32 months (21-56). The median duration of sustained UMRD was 27 months (21-64).Subsequently, MMR was lost in 31.25% (5/16) pts after a median time off-therapy of 4 months (1-5). Treatment was restarted in 4 of these and in an additional pt without MMR loss but showing a detectable MRD on 2 consecutive assessments. Both MMR and UMRD were rapidly regained upon 2G-TKI re-introduction.Eleven pts remained off-therapy at the last follow-up after a median of 13 months (7-20), among which 10 with either a stable UMRD or weakly detectable Bcr-Abl transcripts on one or more occasions. Gender, age, Sokal risk group, type of 2G-TKI, total duration of continuous TKI treatment, duration of 2G-TKI therapy and of UMRD prior to treatment discontinuation did not markedly differ between pts who lost MMR and those with treatment-free persistent MMR but these results may be taken with caution due to the small size of our cohort. Conclusion:2G-TKI may be safely discontinued in CML pts with a long-lasting UMRD under strict molecular monitoring conditions. Importantly, the emergence of a low level of detectable residual disease below the MMR threshold after 2G-TKI withdrawal may not automatically herald CML relapse and may not preclude the possibility to remain treatment-free. A longer follow-up is required to ascertain whether CML will recur. Our study provides a reasonable basis for subsequent large scale prospective trials. Updated results based on a minimal 6 month-FU of the whole cohort will be presented. Disclosures:Rea:Novartis, BMS: Membership on an entity's Board of Directors or advisory committees. Nicolini:Norvartis Pharma France: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb France: Consultancy, Speakers Bureau. Tulliez:Novartis: clinical trial investigator. Guilhot:Novartis, BMS: Membership on an entity's Board of Directors or advisory committees. Mahon:Novartis, BMS: Membership on an entity's Board of Directors or advisory committees.

Cell-based therapy of the failing heart: a need to connect for proper electrical and contractile function

This editorial refers to ‘Skeletal myoblast implants induce minor propagation delays, but do not promote arrhythmias in the normal swine heart’ by J. Moreno et al. , on page 1637 Despite clear improvements in acute therapy and chronic management, myocardial infarction remains a severe threat to cardiac function.1,2 In contrast to other organs, the heart has only limited regeneration capacity. Therefore, most of the cardiomyocytes that die in the process of acute myocardial ischaemia are replaced by dysfunctional scar tissue. In this context, regeneration of infarcted areas of the heart via application of progenitors/stem cells is a fascinating prospect. Clinical observations suggested a beneficial effect of injecting bone marrow-derived cells into coronary arteries3–5 or skeletal myoblasts into hearts during open heart surgery6,7 in survivors of myocardial infarction with heart failure, resulting in a high expectation that regeneration of the left ventricle could be instigated by such ‘regenerative therapy'. Subsequent larger trials found modest or no effects after intracoronary injection of bone marrow-derived cells.8–10 Furthermore, careful clinical follow-up of patients … *Corresponding author. Tel: +49 251 8345185; fax: +49 251 8347864, Email: kirchhp{at}uni-muenster.de