Overcoming Barriers to Drug Development in Children with CKD.

Like all sick children, children with CKD need access to safe and effective medicines that have been formulated and examined specifically for them. Despite legislation in the United States and the European Union that either mandates or incentivizes programs for children, conducting trials to advance the treatment of children continues to prove to be a challenge for drug developers. This is also the case for drug development in children with CKD, where trials face challenges in recruitment and completion and where there remains a substantial time lag between initial approval of a medicinal product for use in adults and completion of studies that result in the addition of pediatric-specific labeling for the same indication. The Kidney Health Initiative commissioned a workgroup of diverse stakeholders ( https://khi.asn-online.org/projects/project.aspx?ID=61 ), including participants from the Food and Drug Administration and the European Medicines Agency, to think carefully through the challenges in drug development for children with CKD and how to overcome them. This article provides an overview of the regulatory frameworks in the United States and the European Union that govern pediatric drug development, the current landscape of drug development and approval for children with CKD, the challenges in conduct and execution of these drug trials, and the progress that has been made to facilitate drug development for children with CKD.

Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent α-thalassaemia or ß-thalassaemia: an open-label, multicentre, phase 2 study.

BACKGROUND: Patients with non-transfusion-dependent thalassaemia (NTDT), although they do not require regular blood transfusions for survival, can still accrue a heavy burden of comorbidities. No approved disease-modifying therapies exist for these patients. We aimed to investigate the safety and efficacy of mitapivat (Agios Pharmaceuticals, Cambridge, MA, USA), a pyruvate kinase activator, in adults with non-transfusion-dependent (NTD) α-thalassaemia or NTD ß-thalassaemia. METHODS: In this open-label, multicentre, phase 2 study, patients were recruited from four academic clinical study sites in Oakland, CA, and Boston, MA, USA; Toronto, ON, Canada; and London, UK. Patients were eligible if they were aged 18 years or older, with NTDT (including ß-thalassaemia with or without α-globin gene mutations, haemoglobin E ß-thalassaemia, or α-thalassaemia), and a baseline haemoglobin concentration of 10·0 g/dL or lower. During a 24-week core period, mitapivat was administered orally at 50 mg twice daily for the first 6 weeks followed by an escalation to 100 mg twice daily for 18 weeks thereafter. The primary endpoint was haemoglobin response (a ≥1·0 g/dL increase in haemoglobin concentration from baseline at one or more assessments between weeks 4 and 12). Efficacy and safety were assessed in the full analysis set (ie, all patients who received at least one dose of study drug). This study is registered with ClinicalTrials.gov, NCT03692052, and is closed to accrual. FINDINGS: Between Dec 28, 2018, and Feb 6, 2020, 27 patients were screened, of whom 20 were enrolled (15 [75%] with ß-thalassaemia and five [25%] with α-thalassaemia) and received mitapivat. The median age of patients was 44 years (IQR 35-56), 15 (75%) of 20 patients were female, five (25%) were male, and ten (50%) identified as Asian. 16 (80% [90% CI 60-93]) of 20 patients had a haemoglobin response (p<0·0001), five (100%) of five with α-thalassaemia and 11 (73%) of 15 with ß-thalassaemia. 17 (85%) patients had a treatment-emergent adverse event, and 13 had a treatment-emergent event that was considered to be treatment related. One serious treatment-emergent adverse event occurred (grade 3 renal impairment), which was considered unrelated to study drug, resulting in discontinuation of treatment. The most commonly reported treatment-emergent adverse events were initial insomnia (ten [50%] patients), dizziness (six [30%]), and headache (five [25%]). No patients died during the 24-week core period. INTERPRETATION: These efficacy and safety results support the continued investigation of mitapivat for the treatment of both α-thalassaemia and ß-thalassaemia. FUNDING: Agios Pharmaceuticals.

Results of the BfR MEAL Study: The food type has a stronger impact on calcium, potassium and phosphorus levels than factors such as seasonality, regionality and type of production.

The BfR MEAL Study aims to provide representative levels of chemical substances in foods consumed by the population in Germany for dietary exposure assessment. Calcium, potassium and phosphorus (Ca, K, P) are essential to obtain physiological functions in humans. Levels were investigated in 356 foods. Foods were purchased representatively, prepared as typically consumed and pooled before analysis. High mean levels were found in milk, dairy products, legumes, nuts, oilseeds and spices as well as chia seeds (Ca, K, P), chewing gum (Ca) and cocoa powder (K). Different levels comparing organically and conventionally produced foods were determined among others in cereal cracker (puffed), olives and tofu. Higher K levels were found in fried compared to boiled potatoes. Similar P levels were mainly found in regionally and seasonally sampled foods. These data provide a substantially improved basis to address dietary exposure assessment of the population in Germany for Ca, K and P.

Effect of ferric citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis-dependent chronic kidney disease: path analyses.

BACKGROUND: Among patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and iron-deficiency anemia (IDA), ferric citrate increases hemoglobin and iron parameters and reduces serum phosphate and fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone. We conducted post hoc analyses of a phase 3 trial to explore associations between iron replacement, serum phosphate changes and FGF23 regulation. METHODS: We employed multivariable regression and longitudinal mixed-effects models to identify and confirm, respectively, whether baseline demographic and laboratory variables were associated with ferric citrate-induced changes in serum phosphate or FGF23 concentrations. We employed path analyses to determine whether changes in FGF23 concentrations were mediated via changes in serum phosphate and/or transferrin saturation (TSAT). RESULTS: We analyzed a total of 117 and 115 ferric citrate-treated and placebo-treated patients, respectively. At 16 weeks, ferric citrate significantly reduced serum phosphate versus placebo (P = 0.006) only among patients with elevated baseline serum phosphate (≥4.5 mg/dL) and did not reduce serum phosphate among patients with baseline serum phosphate within the population reference range. Ferric citrate reduced intact FGF23 and C-terminal FGF23 partially via changes in TSAT (for C-terminal FGF23) and serum phosphate (for intact FGF23) and partially via unknown/unmeasured mechanisms. CONCLUSIONS: Ferric citrate reduced serum FGF23 concentrations (partially via effects on serum phosphate and iron balance) and did not reduce serum phosphate among patients with baseline serum phosphate concentrations within the population reference range.

Usefulness of Oral Ferric Citrate in Patients With Iron-Deficiency Anemia and Chronic Kidney Disease With or Without Heart Failure.

Patients with chronic inflammatory conditions including chronic kidney disease (CKD) and heart failure (HF) are undertreated with iron-deficiency anemia (IDA). Progressive inflammation and reduced iron transport associated with CKD and HF may reduce the efficacy of oral iron therapy. Oral ferric citrate improves anemia markers in CKD, but its effects in patients with CKD and concomitant HF have not been described. Patients with CKD not on dialysis and IDA from a phase 2 and 3 trial were treated with ferric citrate (n = 190) or placebo (n = 188); patients with HF were identified from medical histories. Hemoglobin response was defined as a ≥10.0-g/L increase in hemoglobin. Changes in hemoglobin, transferrin saturation, ferritin, and serum phosphate from baseline to week 12 and the incidence of adverse events potentially related to HF were evaluated. HF was reported in 22% (n = 81) of patients. The proportion of patients with hemoglobin response to ferric citrate treatment did not significantly differ in patients with and without HF (43% vs 49%, respectively; p = 0.47); changes from baseline in hemoglobin, iron parameters, and serum phosphate were similar. Adverse events potentially related to HF were noted more frequently in patients with HF (ferric citrate, 23%; placebo, 17%) versus those without HF (ferric citrate, 12%; placebo, 11%). In conclusion, these results indicate a potential role for ferric citrate in the treatment of IDA in patients with CKD not on dialysis and concomitant HF.

Safety and efficacy of ferric citrate in patients with nondialysis-dependent chronic kidney disease.

Two randomized, placebo-controlled trials conducted in patients with nondialysis-dependent (NDD) chronic kidney disease (CKD), iron deficiency anemia, and normal or elevated serum phosphorus demonstrated that ferric citrate (FC) significantly increased hemoglobin and decreased serum phosphate concentrations. Pooling these trial results could provide a more robust evaluation of the safety and efficacy of FC in this population. We pooled results of a phase 2 (n = 149) and 3 trial (n = 233) of patients randomized and treated for up to 12 and 16 weeks, respectively. The starting dose in both trials was three 1-g (elemental iron 210 mg) tablets/day with food, up to 12 tablets/day. Doses were titrated in the phase 2 and 3 trials to lower serum phosphate concentrations to a target range (0.97-1.13 mmol/L) and to achieve a ≥10-g/L hemoglobin increase, respectively. Safety was assessed in all patients who received ≥1 dose of FC (n = 190) and placebo (n = 188). Treatment-emergent adverse events (AEs) were reported in 143 of 190 (75.3%) FC-treated and 116 of 188 (61.7%) placebo-treated patients; gastrointestinal AEs were the most frequent (94 [49.5%] vs. 52 [27.7%], respectively). Specific events reported in >5% of patients (FC vs. placebo, respectively) included discolored feces (41 [21.6%] vs. 0 [0.0%]), diarrhea (39 [20.5%] vs. 23 [12.2%]), constipation (35 [18.4%] vs. 19 [10.1%]), and nausea (18 [9.5%] vs. 8 [4.3%]). Twenty FC-treated (10.5%) and 21 placebo-treated patients (11.2%) experienced a serious AE. Two patients (1.1%) died in each group. A pooled efficacy assessment demonstrated a consistent hemoglobin rise and modest serum phosphate decline, with few excursions below the normal range. When used for treatment of patients with NDD-CKD, FC contributes to gastrointestinal AEs at higher rates than placebo, while simultaneously correcting two of the principal metabolic manifestations of CKD (iron deficiency anemia and relative hyperphosphatemia).

Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia.

Iron deficiency anemia is common and consequential in nondialysis-dependent CKD (NDD-CKD). Efficacy and tolerability of conventional oral iron supplements are mixed; intravenous iron administration associates with finite but important risks. We conducted a randomized double-blind clinical trial in adults with NDD-CKD and iron deficiency anemia to compare the safety and efficacy of oral ferric citrate (n=117) and placebo (n=115). The primary end point was the proportion of patients who achieved a ≥1.0 g/dl increase in hemoglobin at any time during a 16-week randomized period. Patients who completed the 16-week period could also participate in an 8-week open-label extension period. Significantly more patients randomized to ferric citrate achieved the primary end point (61 [52.1%] versus 22 [19.1%] with placebo; P<0.001). All secondary end points reached statistical significance in the ferric citrate group, including the mean relative change in hemoglobin (0.84 g/dl; 95% confidence interval, 0.58 to 1.10 g/dl; P<0.001) and the proportion of patients who achieved a sustained increase in hemoglobin (≥0.75 g/dl over any 4-week period during the randomized trial; 57 [48.7%] versus 17 [14.8%] with placebo; P<0.001). Rates of serious adverse events were similar in the ferric citrate (12.0%) and placebo groups (11.2%). Gastrointestinal disorders were the most common adverse events, with diarrhea reported in 24 (20.5%) and 19 (16.4%) and constipation in 22 (18.8%) and 15 (12.9%) patients treated with ferric citrate and placebo, respectively. Overall, in patients with NDD-CKD, we found oral ferric citrate to be a safe and efficacious treatment for iron deficiency anemia.

Closing the gap between evidence and practice in chronic kidney disease.

There are major gaps between our growing knowledge of effective treatments for chronic kidney disease (CKD), and the delivery of evidence-based therapies to populations around the world. Although there remains a need for new, effective therapies, current evidence suggests that many patients with CKD are yet to fully realize the benefits of blood pressure-lowering drugs (with and without reducing proteinuria with renin-angiotensin system blockade), wider use of statins to reduce atherosclerotic cardiovascular disease events, and better glycemic control in both type 1 and type 2 diabetes. There are many barriers to optimizing evidence-based nephrology care around the world, including access to health care, affordability of treatments, consumer attitudes and circumstances, the dissemination of appropriate knowledge, the availability of expertise and structural impediments in the delivery of health care. Further investment in implementation science that addresses the major barriers to effective care in a cost-effective manner could yield both local and global benefits.

Action plan for optimizing the design of clinical trials in chronic kidney disease.

High-quality clinical trials are the cornerstone of evidence-based prevention and treatment of a disease, but nephrology has a strikingly weak base of such trials. Building the evidence base to improve outcomes for people with a kidney disease, therefore, requires both greater quantity and quality of clinical trials. To address these issues, we propose that we aim to enroll 30% of people with chronic kidney disease in trials by 2030. Goal 1: Strongly encourage and promote the conduct of clinical trials in people with chronic kidney disease to increase the number of clinical trials conducted. Goal 2: Optimize the design of clinical trials in people with chronic kidney disease. Goal 3: Increase the capacity for conducting clinical trials in people with chronic kidney disease.

Recommendations for kidney disease guideline updating: a report by the KDIGO Methods Committee.

Updating rather than de novo guideline development now accounts for the majority of guideline activities for many guideline development organizations, including Kidney Disease: Improving Global Outcomes (KDIGO), an international kidney disease guideline development entity that has produced guidelines on kidney diseases since 2008. Increasingly, guideline developers are moving away from updating at fixed intervals in favor of more flexible approaches that use periodic expert assessment of guideline currency (with or without an updated systematic review) to determine the need for updating. Determining the need for guideline updating in an efficient, transparent, and timely manner is challenging, and updating of systematic reviews and guidelines is labor intensive. Ideally, guidelines should be updated dynamically when new evidence indicates a need for a substantive change in the guideline based on a priori criteria. This dynamic updating (sometimes referred to as a living guideline model) can be facilitated with the use of integrated electronic platforms that allow updating of specific recommendations. This report summarizes consensus-based recommendations from a panel of guideline methodology professionals on how to keep KDIGO guidelines up to date.

Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients.

BACKGROUND: Modern immunosuppressive regimens after kidney transplantation usually use a combination of two or three agents of different classes to prevent rejection and maintain graft function. Most frequently, calcineurin-inhibitors (CNI) are combined with corticosteroids and a proliferation-inhibitor, either azathioprine (AZA) or mycophenolic acid (MPA). MPA has largely replaced AZA as a first line agent in primary immunosuppression, as MPA is believed to be of stronger immunosuppressive potency than AZA. However, treatment with MPA is more costly, which calls for a comprehensive assessment of the comparative effects of the two drugs. OBJECTIVES: This review of randomised controlled trials (RCTs) aimed to look at the benefits and harms of MPA versus AZA in primary immunosuppressive regimens after kidney transplantation. Both agents were compared regarding their efficacy for maintaining graft and patient survival, prevention of acute rejection, maintaining graft function, and their safety, including infections, malignancies and other adverse events. Furthermore, we investigated potential effect modifiers, such as transplantation era and the concomitant immunosuppressive regimen in detail. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register (to 21 September 2015) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: All RCTs about MPA versus AZA in primary immunosuppression after kidney transplantation were included, without restriction on language or publication type. DATA COLLECTION AND ANALYSIS: Two authors independently determined study eligibility, assessed risk of bias and extracted data from each study. Statistical analyses were performed using the random-effects model and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included 23 studies (94 reports) that involved 3301 participants. All studies tested mycophenolate mofetil (MMF), an MPA, and 22 studies reported at least one outcome relevant for this review. Assessment of methodological quality indicated that important information on factors used to judge susceptibility for bias was infrequently and inconsistently reported.MMF treatment reduced the risk for graft loss including death (RR 0.82, 95% CI 0.67 to 1.0) and for death-censored graft loss (RR 0.78, 95% CI 0.62 to 0.99, P < 0.05). No statistically significant difference for MMF versus AZA treatment was found for all-cause mortality (16 studies, 2987 participants: RR 0.95, 95% CI 0.70 to 1.29). The risk for any acute rejection (22 studies, 3301 participants: RR 0.65, 95% CI 0.57 to 0.73, P < 0.01), biopsy-proven acute rejection (12 studies, 2696 participants: RR 0.59, 95% CI 0.52 to 0.68) and antibody-treated acute rejection (15 studies, 2914 participants: RR 0.48, 95% CI 0.36 to 0.65, P < 0.01) were reduced in MMF treated patients. Meta-regression analyses suggested that the magnitude of risk reduction of acute rejection may be dependent on the control rate (relative risk reduction (RRR) 0.34, 95% CI 0.10 to 1.09, P = 0.08), AZA dose (RRR 1.01, 95% CI 1.00 to 1.01, P = 0.10) and the use of cyclosporin A micro-emulsion (RRR 1.27, 95% CI 0.98 to 1.65, P = 0.07). Pooled analyses failed to show a significant and meaningful difference between MMF and AZA in kidney function measures.Data on malignancies and infections were sparse, except for cytomegalovirus (CMV) infections. The risk for CMV viraemia/syndrome (13 studies, 2880 participants: RR 1.06, 95% CI 0.85 to 1.32) was not statistically significantly different between MMF and AZA treated patients, whereas the likelihood of tissue-invasive CMV disease was greater with MMF therapy (7 studies, 1510 participants: RR 1.70, 95% CI 1.10 to 2.61). Adverse event profiles varied: gastrointestinal symptoms were more likely in MMF treated patients and thrombocytopenia and elevated liver enzymes were more common in AZA treatment. AUTHORS' CONCLUSIONS: MMF was superior to AZA for improvement of graft survival and prevention of acute rejection after kidney transplantation. These benefits must be weighed against potential harms such as tissue-invasive CMV disease. However, assessment of the evidence on safety outcomes was limited due to rare events in the observation periods of the studies (e.g. malignancies) and inconsistent reporting and definitions (e.g. infections, adverse events). Thus, balancing benefits and harms of the two drugs remains a major task of the transplant physician to decide which agent the individual patient should be started on.

Adverse events following implantable cardioverter defibrillator implantation: a systematic review.

PURPOSE: Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death, but patients need to be counseled about potential harms. We summarized the evidence on adverse events from ICDs with a focus on ICD use for primary prevention of sudden cardiac death. METHODS: We searched MEDLINE and Cochrane Central Register of Controlled Trials from 2002 through 2012 for reports of adverse events from ICDs implanted for primary prevention or mixed indications (primary and secondary prevention). Studies had to have ≥500 patients and specify patient numerators and denominators. RESULTS: Data from 35 independent cohorts reported in 53 articles were included. Reports from one registry provided high quality evidence on adverse events during hospitalization for ICD implantation. Adverse events ranged from 2.8 to 3.6%. Serious adverse events ranged from 1.2 to 1.4%. The most frequent serious adverse events were pneumothorax (0.4-0.5%) and cardiac arrest (0.3%). The quality of the evidence for long-term adverse events was low. Frequency of adverse events post-hospitalization was variable, as was follow-up: device-related complications <0.1-6.4% (2-49 months), lead-related complications <0.1-3.9% (1.5-40 months), infection 0.2-3.7% (1.5-49 months), and thrombosis 0.2-2.9% (1.5-49 months). Evidence for inappropriate shock was of moderate quality with 3-21% of patients experiencing at least one inappropriate shock during 1 to 5 years of follow-up. LIMITATIONS: The limitation of the evidence reviewed in this study is low quality evidence for adverse events post-hospitalization. Evidence is predominantly from mixed primary and secondary prevention populations. CONCLUSIONS: In-hospital adverse events after ICD implantation are infrequent. The estimates for long-term adverse events are uncertain. Up to one-fifth of patients receive inappropriate shocks.

Performance of creatinine-based GFR estimating equations in solid-organ transplant recipients.

BACKGROUND: Accurate assessment of kidney function is important for the management of solid-organ transplant recipients. In other clinical populations, glomerular filtration rate (GFR) most commonly is estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine or the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. The accuracy of these equations compared with other GFR estimating equations in transplant recipients has not been carefully studied. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: Solid-organ transplant recipients longer than 6 months posttransplantation from 5 clinical populations (N=3,622, including recipients of kidney [53%], liver [35%], and other or multiple organs [12%]). INDEX TEST: Estimated GFR (eGFR) using creatinine-based GFR estimating equations identified from a systematic review of the literature. Performance of the CKD-EPI creatinine and the MDRD Study equations was compared with alternative equations. REFERENCE TEST: Measured GFR (mGFR) from urinary clearance of iothalamate or plasma clearance of iohexol. MEASUREMENTS: Error (difference between mGFR and eGFR) expressed as P30 (proportion of absolute percent error <30%) and mean absolute error. RESULTS: We identified 26 GFR estimating equations. Mean mGFR was 55.1±22.7 (SD) mL/min/1.73 m(2). P30 and mean absolute error for the CKD-EPI and the MDRD Study equations were 78.9% (99.6% CI, 76.9%-80.8%) for both and 10.6 (99.6% CI, 10.1-11.1) versus 11.0 (99.6% CI, 10.5-11.5) mL/min/1.73 m(2), respectively; these equations were more accurate than any of the alternative equations (P <0.001 for all pairwise comparisons for both measures). They performed better than or as well as the alternative equations in most subgroups defined by demographic and clinical characteristics, including type of transplanted organ. LIMITATIONS: Study population included few nonwhites and people with solid-organ transplants other than liver and kidneys. CONCLUSIONS: The CKD-EPI creatinine and the MDRD Study equations perform better than the alternative creatinine-based estimating equations in solid-organ transplant recipients. They can be used for clinical management.

Prognostic differences of the Mini Nutritional Assessment short form and long form in relation to 1-year functional decline and mortality in community-dwelling older adults receiving home care.

OBJECTIVES: To compare the prognostic value of the revised Mini Nutritional Assessment short form (MNA-SF) classification with that of the long form (MNA-LF) in relation to mortality and functional change in community-dwelling older adults receiving home care in Germany. DESIGN: Multicenter, 1-year prospective observational study. SETTING: Community. PARTICIPANTS: Older adults (≥ 65) receiving home care (n = 309). MEASUREMENTS: Nutritional status (well nourished, at risk of malnutrition, malnourished) was classified using the MNA-SF and MNA-LF at baseline. Functional status was determined according to the Barthel Index of activities of daily living (ADLs) at baseline and after 1 year. Hazard ratios (HRs) and 95% confidence intervals (CIs) of mortality were calculated for MNA-SF and MNA-LF categories using stepwise Cox regression analyses. Repeated-measurements analysis of covariance was used to examine changes in ADL scores over time for MNA-SF and MNA-LF categories. RESULTS: MNA-SF classified 15% of the sample as malnourished and 41% as being at risk of malnutrition, whereas the MNA-LF classified 14% and 58%, respectively. During the follow-up year, 15% of participants died. The estimated hazard ratios (HR) for 1-year mortality were lower for MNA-SF than for MNA-LF categories (at risk of malnutrition: HR = 2.21, 95% confidence interval (CI) = 1.02-4.75 vs HR = 5.05, 95% CI = 1.53-16.58; malnourished: HR = 3.27, 95% CI = 1.34-8.02 vs HR = 8.75, 95% CI = 2.45-31.18). For MNA-SF categories, no differences in functional change were found. According to the MNA-LF, ADL decline tended to be greater in those at risk of malnutrition (7.1 ± 10.1 points) than in those who were well nourished (3.7 ± 10.1 points) and malnourished (4.9 ± 10.1 points). CONCLUSION: In this sample of older adults receiving home care, the MNA-LF was superior to the MNA-SF in predicting mortality and differentiating functional decline during 1 year of follow-up.

Effectiveness of implantable cardioverter defibrillators for primary prevention of sudden cardiac death in subgroups a systematic review.

BACKGROUND: Previous systematic reviews of implantable cardioverter defibrillators (ICDs) used for primary prevention of sudden cardiac death (SCD) concluded that ICDs are less effective in women and the elderly. PURPOSE: To examine ICD effectiveness for primary prevention of SCD across subgroups by sex, age, New York Heart Association class, left ventricular ejection fraction, heart failure, left bundle branch block, QRS interval, time since myocardial infarction, blood urea nitrogen level, and diabetes. DATA SOURCES: MEDLINE and the Cochrane Central Register of Controlled Trials through 3 September 2013 with no language restriction. STUDY SELECTION: Researchers screened articles for studies comparing ICD versus no ICD for primary prevention. DATA EXTRACTION: Data were extracted about study design, patients, interventions, mortality and SCD outcomes, subgroup characteristics, and subgroup effects. Quality of subgroup analyses was determined by consensus. Relative odds ratios comparing subgroup effects were calculated, and random-effects model meta-analyses were conducted on these ratios. DATA SYNTHESIS: Meta-analysis of 14 studies showed a decrease in deaths and SCDs due to ICD treatment. Ten studies provided subgroup analyses. Nine studies compared ICD versus no ICD, whereas one compared cardiac resynchronization therapy plus a defibrillator versus no ICD. Within-study interaction tests and across-study meta-analyses yielded weak evidence that did not show differences for all-cause mortality in subgroups by sex, age, and QRS interval. The evidence was indeterminate for other evaluated subgroups because of a paucity of data. LIMITATION: Many subgroup analyses were underpowered, which may have resulted in false-negative findings. CONCLUSION: Weak evidence fails to show differences for all-cause mortality in subgroups of sex, age, and QRS interval. Evidence is indeterminate for all-cause mortality in the other subgroups and for SCD. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Fluorescence in situ hybridization testing for the diagnosis of high-grade cervical abnormalities: a systematic review.

OBJECTIVE: We examined the diagnostic performance of fluorescence in situ hybridization (FISH) tests on cervical cytology for precancerous lesions or cancer on cervical histology. MATERIALS AND METHODS: A search was conducted in MEDLINE, the Cochrane Central Register of Controlled Trials, and Scopus through September 3, 2013. Eleven studies examined FISH tests for telomerase RNA component gene (TERC), myelocytomatosis oncogene (MYC), or human papillomavirus (HPV) type 16 or 18 in samples exhibiting atypical squamous cells of unknown significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). None examined HPV-positive, cytologically normal samples. We extracted data on the sensitivity and specificity for high-grade cervical intraepithelial neoplasia (CIN 2+ or CIN 3+). RESULTS: Fluorescence in situ hybridization test probes and thresholds varied across studies. Included populations were convenience samples. Only 1 study testing for TERC specified HPV status. In meta-analysis, FISH for TERC in LSIL (9 studies, 1,082 cases) had a summary sensitivity of 0.76 (95% confidence interval = 0.63-0.85) and a summary specificity of 0.78 (95% confidence interval = 0.57-0.91) for CIN 2+. Fluorescence in situ hybridization for TERC in ASC-US (3 studies, 839 cases) showed sensitivities ranging from 0.75 to 1.00 and specificities from 0.87 to 0.93 for CIN 2+. For CIN 3+, sensitivity and specificity appeared similar, although a small number of studies preclude firm conclusions. For FISH tests for HPV, we found only few studies with small sample sizes. CONCLUSIONS: The evidence on FISH testing is limited given the small number of studies for each cytology subgroup and the lack of studies in well-defined screening contexts stratifying participants by HPV status.

A framework for crafting clinical practice guidelines that are relevant to the care and management of people with multimorbidity.

Many patients of all ages have multiple conditions, yet clinicians often lack explicit guidance on how to approach clinical decision-making for such people. Most recommendations from clinical practice guidelines (CPGs) focus on the management of single diseases, and may be harmful or impractical for patients with multimorbidity. A major barrier to the development of guidance for people with multimorbidity stems from the fact that the evidence underlying CPGs derives from studies predominantly focused on the management of a single disease. In this paper, the investigators from the Improving Guidelines for Multimorbid Patients Study Group present consensus-based recommendations for guideline developers to make guidelines more useful for the care of people with multimorbidity. In an iterative process informed by review of key literature and experience, we drafted a list of issues and possible approaches for addressing important coexisting conditions in each step of the guideline development process, with a focus on considering relevant interactions between the conditions, their treatments and their outcomes. The recommended approaches address consideration of coexisting conditions at all major steps in CPG development, from nominating and scoping the topic, commissioning the work group, refining key questions, ranking importance of outcomes, conducting systematic reviews, assessing quality of evidence and applicability, summarizing benefits and harms, to formulating recommendations and grading their strength. The list of issues and recommendations was reviewed and refined iteratively by stakeholders. This framework acknowledges the challenges faced by CPG developers who must make complex judgments in the absence of high-quality or direct evidence. These recommendations require validation through implementation, evaluation and refinement.