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Objective The aim of this study was to examine the effectiveness of a real-world, population-scaled, school-based physical activity (PA) intervention that provided two to three additional physical education lessons per week to children aged 6 to 14 years in Slovenia. Methods More than 34,000 participants from over 200 schools were compared with a similar number of nonparticipants from the same schools. Generalized estimating equations were used to estimate the effects of differing levels of exposure to the intervention (i.e., from 1–5 years) on BMI in children with normal weight, overweight, or obesity at baseline. Results BMI was lower in the intervention group, irrespective of participation duration or baseline weight status. The difference in BMI increased with the program duration, with maximal effects being seen after 3 to 4 years of participation, and was consistently larger for children with obesity (peaking at 1.4 kg/m2 [95% CI: 1.0–1.9] for girls with obesity and peaking at 0.9 kg/m2 [95% CI: 0.6–1.3] for boys with obesity). The program started to become effective at reversing obesity after 3 years, whereas the lowest numbers needed to treat (NNTs) were observed after 5 years (NNTs = 17 for girls and 12 for boys). Conclusions The population-scaled, school-based PA intervention was effective in preventing and treating obesity. The effects were the greatest in children initially presenting with obesity, such that the program was able to benefit children needing support the most.

Healthcare professionals frequently communicate the benefits of treatments as a relative risk reduction (RRR) in the likelihood of an event occurring. Here we evaluated whether presenting the benefits of osteoporosis treatment as a RRR in fractures compared with an absolute risk reduction (ARR) changed the patient’s attitudes towards accepting treatment. We surveyed 160 individuals attending a specialised osteoporosis clinic for face-to-face consultations between May 2018 and Jan 2021. They were presented with information on RRR for the treatment being considered followed by ARR and after each question were asked about how likely they would be to start treatment on a 5-point scale (1 = very likely, 5 = very unlikely). Participants were less likely to accept treatment when it was presented as ARR (mean score 2.02 vs. 2.67, p p r − 0.32, 95% CI − 0.46 to − 0.17, p ≤ 0.001). Whilst presentation of data as ARR more accurately reflects individual benefit and helps facilitate shared decision-making, clinicians should be aware that this will lead to a proportion of patients with lower fracture risk declining treatment for osteoporosis.

Background: Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a thrombotic event associated with amputation, disability, and mortality. Previous lower extremity revascularization (LER) is associated with increased ALI risk in chronic PAD. However, the pattern of risk, clinical correlates, and outcomes after ALI early after LER are not well-studied, and effective therapies to reduce ALI post-LER are lacking. Methods: The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD; rNCT02504216) randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of low-dose aspirin. The primary outcome was a composite of ALI, major amputation of vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. ALI was prospectively ascertained and adjudicated by a blinded committee. The cumulative incidence of ALI was calculated using Kaplan-Meier estimates, and Cox proportional hazards models were used to generate hazard ratios and associated CIs. Analyses were performed as intention-to-treat. Results: Among 6564 patients followed for a median of 2.3 years, 382 (5.8%) had a total of 508 ALI events. In placebo patients, the 3-year cumulative incidence of ALI was 7.8%. After multivariable modeling, previous LER, baseline ankle-brachial index P =0.0001), with benefit starting early (HR, 0.45 [95% CI, 0.24–0.85]; P =0.0068 at 30 days). Benefit was present for severe ALI (associated with death, amputation, or prolonged hospitalization and intensive care unit stay, HR, 0.58 [95% CI, 0.40–0.83]; P =0.003) and regardless of LER type (surgical versus endovascular revascularization, P interaction=0.42) or clopidogrel use ( P interaction=0.59). Conclusions: After LER for symptomatic PAD, ALI is frequent, particularly early after LER, and is associated with poor prognosis. Low-dose rivaroxaban plus aspirin reduces ALI after LER, including ALI events associated with the most severe outcomes. The benefit of rivaroxaban for ALI appears early, continues over time, and is consistent regardless of revascularization approach or clopidogrel use.

Interpreting study results is an essential component of decision-making. Both laypeople and healthcare professionals often misinterpret treatment effects that are presented as relative risk reduction. Therefore, we developed and piloted a web-based tool to teach the difference between relative and absolute risk reductions. This project follows the UKMRC-guidance for complex interventions. The tool was developed based on adult learning and design theories. This was followed by a qualitative feasibility study focusing on acceptance, applicability, and comprehensibility with healthcare professionals and laypersons. We conducted think-aloud and semi-structured interviews and analysed them using qualitative content analysis. In addition, we explored calculation skills. Between January 2020 and April 2021, we conducted 22 interviews with 8 laypeople and 14 healthcare professionals from different settings. Overall, the tool proved to be feasible and relevant. With regard to comprehension, we observed an awareness of the interpretation of risk reduction, presented therapy effects were questioned more critically, and the influence of relative effects was recognized. Nevertheless, there were comprehension problems in some of the participants, especially with calculations in connection with low mathematical skills. The tool can be used to improve the interpretation of risk reductions in various target groups and to supplement existing educational programs.

We used the method proposed by Schneider et al. Theor Biol Med Model 2011;8:27, to clarify how the radiation-induced secondary cancer incidence rate changes in patients after proton craniospinal irradiation (CSI) without and with vertebral-body-sparing (VBS). Eight patients aged 3–15 years who underwent proton CSI were enrolled in the study. For each case, two types of plan without and with VBS in the target were compared. The prescribed doses were assumed to be 23.4 Gy relative biological effectiveness (RBE) and 36 Gy (RBE). Using the dose–volume histograms of the two plans, the lifetime attributable risk (LAR) was calculated by both methods for each patient based on the dose data calculated using an XiO-M treatment planning system. Eight organs were analyzed as follows: lung, colon, stomach, small intestine, liver, bladder, thyroid and bone. When the prescribed dose used was 23.4 Gy (RBE), the average LAR differences and the average number needed to treat (NNT) between proton CSI without and with VBS were 4.04 and 24.8, respectively, whereas the average LAR difference and the average NNT were larger at 8.65 and 11.6, respectively, when the prescribed dose of 36 Gy (RBE) was used. The LAR for radiation-induced secondary cancer was significantly lower in proton CSI with VBS than without VBS in pediatric patients, especially for the colon, lung, stomach and thyroid. The results of this study could serve as reference data when considering how much of vertebral bodies should be included when performing proton CSI according to age in clinical settings.

Several terms are used to describe changes in PROM scores in relation to treatments. Whether the change is small, large, or relevant is defined in different ways, yet these change scores are used to recommend or oppose treatments. They are also used to calculate the necessary number of patients for a study. This article offers a theoretical explanation behind the terms responsiveness, minimal important difference (MID), minimal important change (MIC), minimal relevant difference (MIREDIF), and threshold of clinical importance. It also gives instructions on how these and the optimal number of patients for a study are calculated. Responses to two domains of the Knee Injury and Osteoarthritis Outcome Score (KOOS), before and 1 year after reconstruction of the anterior cruciate ligament of 164 patients, are used to illustrate the calculations. This paper presents the most common methods used to calculate and interpret MID. Results vary substantially across domains, patient location on the scale, and health conditions. The optimal number of patients depends on the minimal relevant difference (MIREDIF), the standard error of the measure (SEM), the desired statistical power for the measurement, and the responsiveness of the measurement instrument (the PROM). There is often uncertainty surrounding the calculation and interpretation of responsiveness, MID, and MIREDIF, as these concepts are complex. When MID is used to evaluate research results, authors should specify how the MID was calculated, and its relevance for the study population. These measures should only be used after thorough consideration to justify healthcare decisions.

The number needed to treat (NNT) is a widely used measure of the potential impact of a treatment or intervention, but it is often calculated and discussed in ways which oversimplify critical issues. Specifically, the NNT itself depends on the population under study and the specific form that "treatment" would take in that population. We discuss how understanding the difference between the effect of removing a harmful exposure and the effect of deploying a specific intervention to remove that harmful exposure can affect the calculation and interpretation of an NNT. Our discussion extends a previously described framework distinguishing exposure effects from population intervention effects.

Objective The objective of this study was to present ways to graphically represent a number needed to treat (NNT) in (network) meta-analysis (NMA). Study Design and Setting A barrier to using NNT in NMA when an odds ratio (OR) or risk ratio (RR) is used is the determination of a single control event rate (CER). We discuss approaches to calculate a CER, and illustrate six graphical methods for NNT from NMA. We illustrate the graphical approaches using an NMA of cognitive enhancers for Alzheimer's dementia. Results The NNT calculation using a relative effect measure, such as OR and RR, requires a CER value, but different CERs, including mean CER across studies, pooled CER in meta-analysis, and expert opinion-based CER may result in different NNTs. An NNT from NMA can be presented in a bar plot, Cates plot, or forest plot for a single outcome, and a bubble plot, scatterplot, or rank-heat plot for ≥2 outcomes. Each plot is associated with different properties and can serve different needs. Conclusion Caution is needed in NNT interpretation, as considerations such as selection of effect size and CER, and CER assumption across multiple comparisons, may impact NNT and decision-making. The proposed graphs are helpful to interpret NNTs calculated from (network) meta-analyses.

Chronic obstructive pulmonary disease (COPD) is defined based on a reduced ratio of forced expiratory volume in one second (FEV1 ) to forced vital capacity (FVC) on spirometry. However, within this definition, there is significant heterogeneity of pathophysiological processes that lead to airflow obstruction and variation in phenotypic manifestations across patients. Current pharmacological treatments are based on large randomised clinical trials that apply to an "average" patient. Precision health enables tailoring of treatment for each individual patient by taking into account their unique characteristics. The number needed to treat (NNT) metric is often used to define implementation of precision health for specific interventions, with common endpoints requiring an NNT ≤ 5 to achieve precision therapy. Higher NNTs may be acceptable for rare but important endpoints such as mortality. Long-acting muscarinic antagonists and inhaled corticosteroids, which are commonly used in COPD, have 1-year treatment NNTs between 15 and 20 for exacerbation prevention in unselected patients with COPD. Subgroup identification using biomarkers or clinical traits may enable precision health. For example, NNT for inhaled corticosteroids is 9 in patients with a blood eosinophil count ≥ 300 cells/μL and 8 for long-acting muscarinic antagonists in patients with a body mass index ≤ 20 kg/m2 . Lung volume reduction surgery is associated with an NNT of 6 for survival over 5 years in patients with upper lobe-predominant disease and low exercise capacity (whereas the NNT is 245 when no bioimaging or exercise markers are used). Continuous domiciliary oxygen therapy (for at least 15 hours/day) has an NNT of 5 for survival over 5 years in patients with resting hypoxemia (PaO2

Introduction: Substantial paradigm shifts have been recently registered in metastatic renal cell carcinoma (mRCC), with combination therapies including immunotherapy showing unprecedented results. We performed number needed to treat (NNT) and number needed to harm (NNH) analyses to evaluate these approaches in mRCC.Areas covered: Clinical data of mRCC patients enrolled in four phase III trials were collected. The rates at 6, 12, 18, and 24 months for overall survival (OS), duration of response (DoR), and progression-free survival (PFS) were considered. At 6 months, the number of patients that should be treated to prevent one death with sunitinib was 20 for both pembrolizumab-lenvatinib or axitinib, 14 for nivolumab-cabozantinib, and 50 for nivolumab-ipilimumab. NNT was 100 (at 6 months) or >100 (at 12 and 18 months) for nivolumab-ipilimumab. The combinations reported peculiar and not superimposable safety profiles at the NNH analysis.Expert opinion: Although our results should be interpreted with caution, the analysis provides useful insight into the increasingly compelling interpretation of clinical trials. Immune combinations present clinically meaningful differences in terms of efficacy, with some treatments reporting different results at the NNT and the NNH analyses.

Background Postoperative pain is common and may be severe. Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, may reduce the incidence and severity of opioid-induced adverse events (AEs). Objectives To assess the analgesic efficacy and adverse effects of single-dose intravenous ketorolac, compared with placebo or an active comparator, for moderate to severe postoperative pain in adults. Search methods We searched the following databases without language restrictions: CENTRAL, MEDLINE, Embase and LILACS on 20 April 2020. We checked clinical trials registers and reference lists of retrieved articles for additional studies. Selection criteria Randomized double-blind trials that compared a single postoperative dose of intravenous ketorolac with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery. Data collection and analysis We used standard methodological procedures expected by Cochrane. Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a four- and six-hour period. Our secondary outcomes were time to and number of participants using rescue medication; withdrawals due to lack of efficacy, adverse events (AEs), and for any other cause; and number of participants experiencing any AE, serious AEs (SAEs), and NSAID-related or opioid-related AEs. For subgroup analysis, we planned to analyze different doses of parenteral ketorolac separately and to analyze results based on the type of surgery performed. We assessed the certainty of evidence using GRADE. Main results We included 12 studies, involving 1905 participants undergoing various surgeries (pelvic/abdominal, dental, and orthopedic), with 17 to 83 participants receiving intravenous ketorolac in each study. Mean study population ages ranged from 22.5 years to 67.4 years. Most studies administered a dose of ketorolac of 30 mg; one study assessed 15 mg, and another administered 60 mg. Most studies had an unclear risk of bias for some domains, particularly allocation concealment and blinding, and a high risk of bias due to small sample size. The overall certainty of evidence for each outcome ranged from very low to moderate. Reasons for downgrading certainty included serious study limitations, inconsistency and imprecision. Ketorolac versus placebo Very low-certainty evidence from eight studies (658 participants) suggests that ketorolac results in a large increase in the number of participants achieving at least 50% pain relief over four hours compared to placebo, but the evidence is very uncertain (risk ratio (RR) 2.81, 95% confidence interval (CI) 1.80 to 4.37). The number needed to treat for one additional participant to benefit (NNTB) was 2.4 (95% CI 1.8 to 3.7). Low-certainty evidence from 10 studies (914 participants) demonstrates that ketorolac may result in a large increase in the number of participants achieving at least 50% pain relief over six hours compared to placebo (RR 3.26, 95% CI 1.93 to 5.51). The NNTB was 2.5 (95% CI 1.9 to 3.7). Among secondary outcomes, for time to rescue medication, moderate-certainty evidence comparing intravenous ketorolac versus placebo demonstrated a mean median of 271 minutes for ketorolac versus 104 minutes for placebo (6 studies, 633 participants). For the number of participants using rescue medication, very low-certainty evidence from five studies (417 participants) compared ketorolac with placebo. The RR was 0.60 (95% CI 0.36 to 1.00), that is, it did not demonstrate a difference between groups. Ketorolac probably results in a slight increase in total adverse event rates compared with placebo (74% versus 65%; 8 studies, 810 participants; RR 1.09, 95% CI 1.00 to 1.19; number needed to treat for an additional harmful event (NNTH) 16.7, 95% CI 8.3 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from eight studies (703 participants) did not demonstrate a difference in rates between ketorolac and placebo (RR 0.62, 95% CI 0.13 to 3.03). Ketorolac versus NSAIDs Ketorolac was compared to parecoxib in four studies and diclofenac in two studies. For our primary outcome, over both four and six hours there was no evidence of a difference between intravenous ketorolac and another NSAID (low-certainty and moderate-certainty evidence, respectively). Over four hours, four studies (337 participants) produced an RR of 1.04 (95% CI 0.89 to 1.21) and over six hours, six studies (603 participants) produced an RR of 1.06 (95% CI 0.95 to 1.19). For time to rescue medication, low-certainty evidence from four studies (427 participants) suggested that participants receiving ketorolac waited an extra 35 minutes (mean median 331 minutes versus 296 minutes). For the number of participants using rescue medication, very low-certainty evidence from three studies (260 participants) compared ketorolac with another NSAID. The RR was 0.90 (95% CI 0.58 to 1.40), that is, there may be little or no difference between groups. Ketorolac probably results in a slight increase in total adverse event rates compared with another NSAID (76% versus 68%, 5 studies, 516 participants; RR 1.11, 95% CI 1.00 to 1.23; NNTH 12.5, 95% CI 6.7 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from five studies (530 participants) did not demonstrate a difference in rates between ketorolac and another NSAID (RR 3.18, 95% CI 0.13 to 76.99). Only one of the five studies reported a single serious AE. Authors' conclusions The amount and certainty of evidence for the use of intravenous ketorolac as a treatment for postoperative pain varies across efficacy and safety outcomes and amongst comparators, from very low to moderate. The available evidence indicates that postoperative intravenous ketorolac administration may offer substantial pain relief for most patients, but further research may impact this estimate. Adverse events appear to occur at a slightly higher rate in comparison to placebo and to other NSAIDs. Insufficient information is available to assess whether intravenous ketorolac has a different rate of gastrointestinal or surgical-site bleeding, renal dysfunction, or cardiovascular events versus other NSAIDs. There was a lack of studies in cardiovascular surgeries and in elderly populations who may be at increased risk for adverse events.

We thank Lawrence and colleagues1 for their interest in our work,2 about which they raised some comments as the need of expressing results in absolute rather than relative risks. As they appropriately mentioned in their correspondence, absolute risk is an important parameter for the estimation of the effect of an intervention and must sometimes be preferred to relative risk. However, when discussing with health professionals and policymakers, using absolute risk reductions, expressed as percentages, may incorrectly lead to an intervention being considered unnecessary. As example, what would be the point of reducing by 30% the occurrence of an event affecting 2% of the population? This is exactly what we were confronted to with the COVID-19 pandemic, when policymakers were criticised for putting in place measures to reduce individual freedoms, which were considered excessive in relation to the …

Importance Dapagliflozin has been shown to reduce the risk of cardiovascular death or worsening heart failure (HF) in patients with chronic HF and reduced ejection fraction (HFrEF). However, clinical inertia often underlies deferred initiation of effective therapies. Objective To examine timing of onset of clinical benefit with dapagliflozin and magnitude as a function of proximity to prior HF hospitalization. Design, Setting, and Participants This is a secondary analysis of a completed multinational trial. The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure trial was a double-blind, placebo-controlled randomized clinical trial of dapagliflozin in patients with chronic HFrEF (n = 4744). From February 2017 to August 2018, the study enrolled patients in New York Heart Association classes II through IV and with left ventricular ejection fraction of 40% or less; the median (range) follow-up time was 18.2 (0-27.8) months. Hazard ratios (HRs) were calculated for the primary efficacy outcome with dapagliflozin vs placebo by time following randomization. Efficacy and safety of dapagliflozin were assessed according to the timing of the most recent HF hospitalization prior to trial enrollment. Exposures None. Main Outcomes and Measures Composite of cardiovascular death or worsening HF. Results A total of 4744 patients were included (1109 women [23.4%]; mean [SD] age, 66.3 [10.9] years). The reduction in the primary outcome with dapagliflozin was rapidly apparent, with a sustained statistically significant benefit by 28 days after randomization (HR at 28 days, 0.51 [95% CI, 0.28-0.94];P = .03). A total of 2251 patients (47.4%) had been previously hospitalized for HF, and 1301 (27.4%) had been hospitalized within 12 months prior to enrollment. Among patients treated with placebo, there was a stepwise gradient of risk for the primary outcome according to timing of most recent HF hospitalization, with 2-year Kaplan-Meier rates of 21.1%, 25.3%, and 33.8% (adjustedP = .003) for patients with a prior HF hospitalization never, more than 12 months ago, and 12 or fewer months ago, respectively. Across these subgroups, dapagliflozin reduced the relative risk of the primary outcome by 16% (HR, 0.84 [95% CI, 0.69-1.01]), 27% (HR, 0.73 [95% CI, 0.54-0.99]), and 36% (HR, 0.64 [95% CI, 0.51-0.80]), respectively (P = .07 for trend). Accordingly, patients with a more recent HF hospitalization tended to experience greater absolute risk reductions with dapagliflozin at 2 years: 2.1% (95% CI, −1.9% to 6.1%), 4.1% (95% CI, −3.6% to 11.7%), and 9.9% (95% CI, 3.3%-16.5%), respectively (P = .05 for trend). Conclusions and Relevance In this study, treatment with dapagliflozin was associated with rapid reduction in the risk of cardiovascular death or worsening HF, with a sustained statistically significant benefit emerging very early after randomization. Patients with a more recent HF hospitalization were at particularly high risk and experienced greater relative and absolute risk reductions with dapagliflozin. Trial Registration ClinicalTrials.gov IdentifierNCT03036124

Importance Patient-reported outcomes are increasingly used as end points in clinical trials, assessments in clinical care, and tools for population health, with an increasing role in quality assessment. For patients with coronary artery disease, the Seattle Angina Questionnaire (SAQ) has emerged as the most commonly used measure of disease-specific health status to quantify patients’ symptoms of angina and the extent to which their angina affects their functioning and quality of life. This review explains how to interpret the SAQ and describes the construction and face validity of the SAQ, focusing on aligning scores and changes in scores with clinical constructs. Observations The SAQ asks questions similar to those an experienced clinician would ask of a patient with stable ischemic heart disease. Therefore, SAQ scores can be aligned with clinical constructs (eg, scores on the SAQ angina frequency scale of 0-30 points indicate daily angina, 31-60 points indicate weekly angina, 61-99 points indicate monthly angina, and 100 points indicate no angina), and changes in scores can be described by aligning them with changes in question responses. After clinical thresholds are defined, it is important for clinical trials to not simply report mean differences between treatment arms but to also report the distributions of patients who have had clinically important benefits so that a number needed to treat can be generated. Conclusions and Relevance The widespread use of the SAQ is a consequence of its well-established validity, reproducibility, prognostic importance, and sensitivity to clinical change. Nevertheless, interpreting the SAQ can be challenging because of lack of familiarity with the clinical importance of its domains, either cross-sectionally or longitudinally. This review provides an overview of the interpretability of the SAQ as a foundation for its use as an end point in clinical trials, a tool to support more patient-centered care, and a means of facilitating population health strategies to provide a better foundation for the integration of patient experiences with clinical care.

OBJECTIVES: To prevent the future development of insomnia in at-risk adolescents. METHODS: A randomized controlled trial comparing 4 weekly insomnia prevention program with a nonactive control group. Subjects were assessed at baseline, postintervention, and 6 and 12 months after intervention. Assessors were blinded to the randomization. Analyses were conducted on the basis of the intention-to-treat principles. RESULTS: A total of 242 adolescents with family history of insomnia and subthreshold insomnia symptoms were randomly assigned to an intervention group (n = 121; mean age = 14.7 ± 1.8; female: 51.2%) or control group (n = 121; mean age = 15.0 ± 1.7; female: 62.0%). There was a lower incidence rate of insomnia disorder (both acute and chronic) in the intervention group compared with the control group (5.8% vs 20.7%; P = .002; number needed to treat = 6.7; hazard ratio = 0.29; 95% confidence interval: 0.12–0.66; P = .003) over the 12-month follow-up. The intervention group had decreased insomnia symptoms (P = .03) and reduced vulnerability to stress-related insomnia (P = .03) at postintervention and throughout the 12-month follow-up. Decreased daytime sleepiness (P = .04), better sleep hygiene practices (P = .02), and increased total sleep time (P = .05) were observed at postintervention. The intervention group also reported fewer depressive symptoms at 12-month follow-up (P = .02) compared with the control group. CONCLUSIONS: A brief cognitive behavioral program is effective in preventing the onset of insomnia and improving the vulnerability factors and functioning outcomes.

Objective Clinical trials typically report antiepileptic drug efficacy by evaluating reduction in monthly convulsive seizure frequency (MCSF) through group response (active versus placebo). Although useful for regulatory purposes, population statistics do not easily translate into clinical practice, where treatment decisions are made on an individual-patient basis. Responder analyses help bridge this gap by showing proportions of patients who achieved various MCSF improvement levels. Deriving numbers needed to treat (NNTs) to achieve clinically desirable response levels can further inform individual decision-making. We calculated the NNT with fenfluramine to achieve “clinically meaningful” (≥50%) or “profound” (≥75%) MCSF reductions in patients with Dravet syndrome (DS). Methods NNT to achieve ≥50% or ≥75% MCSF reduction was assessed using longitudinal data from two phase 3 studies for adjunctive fenfluramine in DS patients aged 2–18 years. NNT was calculated: 1/((Experimental-Responder Rate)−(Control-Responder Rate)). Results In Study 1, NNTs to achieve ≥50% and ≥75% MCSF reduction were 1.8 and 2.1 at 0.7 mg/kg/day fenfluramine. In Study 2, these NNTs were 2.0 and 3.1, respectively. These results were seen as early as Weeks 6–7 and were sustained through Weeks 14–15. Interpretation For every two to three patients with DS treated with fenfluramine in these trials, one patient achieved ≥50% or ≥75% MCSF reduction, respectively, compared with placebo (large treatment effect size; Cohen’s d≈0.8). Responder analyses and NNTs can aid in clinical decision-making by offering clinically important information that is complementary to the population mean data on the chance of an individual patient achieving meaningful levels of MCSF improvement. (NCT02682927/NCT02826863, NCT02926898)

Background There is currently insufficient evidence to support the use of lipid-lowering drug treatment (LLT) for primary prevention of cardiovascular disease (CVD) in the elderly. Objectives We examined the relationship of early initiation of LLT with short- and long-term all-cause and CVD mortality in persons older than 65 years in this post hoc study from the Second Australian National Blood Pressure study (ANBP2). Methods This was an in- and post-trial observational study. About 4257 hypertensive participants aged 65 to 84 years within Australian family practices were randomized to an angiotensin-converting enzyme inhibitor or a diuretic treatment group. After excluding participants with a prior history of CVD, the cohort was stratified into "LLT" and "no LLT" subgroups based on LLT status at randomization. Results At randomization, the participants had a mean age of 72 years, average blood pressure of 168/91 mm Hg and estimated 5-year CVD risk of 18.7 ± 8.3%. In the overall study population, the association of LLT with long-term (11-years) all-cause and non-CVD mortality was significant (hazard ratio [HR] 0.78 [95% confidence interval {CI} 0.66–0.92, P = .003] and HR 0.70 [95% CI 0.54–0.90, P = .006], respectively). Magnitudes of the association of LLT with long-term mortality and the association with short-term mortality were similar; however, no statistically significant association with short-term mortality was observed. In the subgroup analysis by baseline 5-year CVD risk, LLT participants in the highest risk tertile had a substantially lower relative risk for short-term all-cause mortality (HR 0.31, 95% CI 0.13–0.71, P for interaction .02) compared to those with lower estimated CVD risk. All analyses were adjusted for baseline and in-trial characteristics. Conclusion Our study showed a strong association between LLT and reduced long-term all-cause mortality. Thus, our findings support recommendations of the use of LLT in patients over 65 years, particularly those with high CVD risk who were more likely to obtain additional benefits in the short term. The findings also suggested that mortality benefits of LLT for the elderly may take longer to become evident.

The recent results of Cardiovascular Outcomes Trials (CVOTs) in type 2 diabetes have clearly established the cardiovascular (CV) safety or even the benefit of two therapeutic classes, Glucagon-Like Peptide-1 receptor agonists (GLP-1 RA) and Sodium-Glucose Co-Transporter-2 inhibitors (SGLT-2i). Publication of the latest CVOTs for these therapeutic classes also led to an update of ESC guidelines and ADA/EASD consensus report in 2019, which considers using GLP-1 RA or SGLT-2i with proven cardiovascular benefit early in the management of type 2 diabetic patient with established cardiovascular disease (CVD) or at high risk of atherosclerotic CVD. The main beneficial results of these time-to event studies are supported by conventional statistical measures attesting the effectiveness of GLP-1 RA or SGLT2i on cardiovascular events (absolute risk, absolute risk difference, relative risk, relative risk reduction, odds ratio, hazard ratio). In addition, another measure whose clinical meaning appears to be easier, the Number Needed to Treat (NNT), is often mentioned while discussing the results of CVOTs, in order to estimating the clinical utility of each drug or sometimes trying to establish a power ranking. While the value of the measure is admittedly of interest, the subtleties of its computation in time-to-event studies are little known. We provide in this article a clear and practical explanation on NNT computation methods that should be used in order to estimate its value, according to the type of study design and variables available to describe the event of interest, in any randomized controlled trial. More specifically, a focus is made on time-to-event studies of which CVOTs are part, first to describe in detail an appropriate and adjusted method of NNT computation and second to help properly interpreting NNTs with the example of CVOTs conducted with GLP-1 RA and SGLT-2i. We particularly discuss the risk of misunderstanding of NNT values in CVOTs when some specific parameters inherent in each study are not taken into account, and the following risk of erroneous comparison between NNTs across studies. The present paper highlights the importance of understanding rightfully NNTs from CVOTs and their clinical impact to get the full picture of a drug’s effectiveness.

When we treat a patient, we are guided by the ethical principle of beneficence: to do good for them. How often do we achieve that goal? The best available data on interventions tested in randomized trials suggest that, even for medications that are efficacious on a population level, our

Background: Current guidelines for the primary prevention of atherosclerotic cardiovascular disease are based on the estimation of a predicted 10-year cardiovascular disease risk and the average relative risk reduction estimates from statin trials. In the clinical setting, however, decision-making is better informed by the expected benefit for the individual patient, which is typically lacking. Consequently, a personalized statin benefit approach based on absolute risk reduction over 10 years (ARR10 benefit threshold ≥2.3%) has been proposed as a novel approach. However, how this benefit threshold relates with coronary plaque burden in asymptomatic individuals with low/intermediate cardiovascular disease risk is unknown. Aims: In this study, we compared the predicted ARR10 obtained in each individual with plaque burden detected by coronary computed tomography angiography. Methods and Results: Plaque burden (segment volume score, segment stenosis score, and segment involvement score) was assessed in prospectively recruited asymptomatic subjects (n = 70; 52% male; median age 56 years [interquartile range 51–64 years]) with low/intermediate Framingham risk score (< 20%). The expected ARR10 with statin in the entire cohort was 2.7% (1.5–4.6%) with a corresponding number needed to treat over 10 years of 36 (22–63). In subjects with an ARR10 benefit threshold ≥2.3% (vs. < 2.3%), plaque burden was significantly higher (p = 0.02). Conclusion: These findings suggest that individuals with higher coronary plaque burden are more likely to get greater benefit from statin therapy even among asymptomatic individuals with low cardiovascular risk.

ObjectiveOur aim was to describe the efficacy and tolerability of pimavanserin, a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP), using the metrics of number needed to treat (NNT) and number needed to harm (NNH).MethodsCategorical efficacy and tolerability data were extracted from the clinical trial databases of the double-blind placebo-controlled studies of pimavanserin in persons with PDP. NNT and NNH values were calculated with their respective 95% confidence intervals. The likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response versus discontinuation because of an adverse event.ResultsNNT values for pimavanserin 34 mg/d versus placebo for several definitions of clinical response are 10, and/or are not statistically significant, and/or show an advantage for pimavanserin over placebo (such as for postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times more likely to result in clinical response (as measured by a ≥3 point decrease from baseline on the Scale for the Assessment of Positive Symptoms adapted for Parkinson’s disease) versus discontinuation due to an adverse event.ConclusionsUsing the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for the treatment of PDP appears to have a compelling benefit/risk profile.

The aim of this study was to compare the public health impact of introducing 2 Herpes Zoster (HZ) vaccines, Zoster Vaccine Live (ZVL) versus a non-live adjuvanted subunit candidate vaccine (HZ/su), in the German population aged 50+ years split into 3 age cohorts, i.e. 50–59, 60–69 and 70+ years, respectively. A multi-cohort static Markov model was developed following age cohorts over their lifetime. Demographic data were obtained from the German federal statistical office. HZ incidence and the proportion of HZ individuals developing post-herpetic neuralgia (PHN) were derived from German specific sources. Age-specific vaccine efficacy and waning rates were based on published clinical trial data. Vaccine coverage for both vaccines was assumed to be 40%, with compliance of the second dose of the HZ/su vaccine of 70%. Sensitivity analyses were performed to assess the robustness of the results. It was estimated that, over the remaining lifetime since vaccination, the HZ/su vaccine would reduce the number of HZ cases by 725,233, 533,162 and 486,794 in the 3 age cohorts, respectively, compared with 198,477, 196,000 and 104,640, using ZVL. The number needed to vaccinate (NNV) to prevent one HZ case ranged from 8 to 11 using the HZ/su vaccine compared with 20 to 50 using ZVL. Corresponding NNV to prevent one PHN case ranged from 39 to 53 using the HZ/su vaccine compared with 94 to 198 using ZVL. Due to the higher, sustained vaccine efficacy, the candidate HZ/su vaccine demonstrated superior public health impact compared with ZVL.

Nowadays, guidelines are derived from the findings of randomized controlled therapeutic trials. However, an overall significant P value does not exclude that some patients may be harmed by or will not respond to the therapeutic agent being studied. Trials in patients with a low risk of events and/or a limited chance of providing significant differences in therapeutic effects require a large patient population to demonstrate a beneficial effect. Composite efficacy endpoints are often employed to obviate the need for a large patient population when low rates of events or limited therapeutic efficacy are anticipated. Results of randomized controlled therapeutic trials are commonly expressed in terms of relative risk reduction, whereas absolute risk reduction allows the calculation of the "number needed to treat" to prevent an adverse outcome. The number needed to treat is a far more clinically relevant variable than relative risk reduction. The clinician's mission is to match treatment to patient with the goal of achieving optimal therapeutic response. Drug-safety monitoring is also of major importance to avoid exposing patients to irreversible adverse effects. Unfortunately, drug-safety monitoring is often overlooked in routine clinical practice. Finally, the lack of long-term therapeutic data (>5-10 years) is an unsolved dilemma, as most trials are limited to a duration of a few months or years.

KEY POINTS After concluding that a randomized controlled trial (RCT) is both internally and externally valid, consumers of evidence may want to consider an intervention’s overall importance compared with other interventions or health technologies. Such an exercise contributes to our perception of

Background Surgical patients incur preventable harm from cognitive and judgment errors made under time constraints and uncertainty regarding patients’ diagnoses and predicted response to treatment. Decision analysis and techniques of reinforcement learning theoretically can mitigate these challenges but are poorly understood and rarely used clinically. This review seeks to promote an understanding of decision analysis and reinforcement learning by describing their use in the context of surgical decision-making. Methods Cochrane, EMBASE, and PubMed databases were searched from their inception to June 2019. Included were 41 articles about cognitive and diagnostic errors, decision-making, decision analysis, and machine-learning. The articles were assimilated into relevant categories according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. Results Requirements for time-consuming manual data entry and crude representations of individual patients and clinical context compromise many traditional decision-support tools. Decision analysis methods for calculating probability thresholds can inform population-based recommendations that jointly consider risks, benefits, costs, and patient values but lack precision for individual patient-centered decisions. Reinforcement learning, a machine-learning method that mimics human learning, can use a large set of patient-specific input data to identify actions yielding the greatest probability of achieving a goal. This methodology follows a sequence of events with uncertain conditions, offering potential advantages for personalized, patient-centered decision-making. Clinical application would require secure integration of multiple data sources and attention to ethical considerations regarding liability for errors and individual patient preferences. Conclusion Traditional decision-support tools are ill-equipped to accommodate time constraints and uncertainty regarding diagnoses and the predicted response to treatment, both of which often impair surgical decision-making. Decision analysis and reinforcement learning have the potential to play complementary roles in delivering high-value surgical care through sound judgment and optimal decision-making.

Objective:In this study, we used the concept of organ-equivalent dose (OED) to evaluate the excess absolute risk (EAR) for secondary cancer in various organs after radiation treatment for breast cancer.Methods:Using CT data set of 12 patients, we generated three different whole-breast radiation treatment plans using 50 Gy in 2 Gy fractions: three-dimensional conformal radiotherapy with a field-in-field (FinF) technique, intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT). The OEDs were calculated from differential dose–volume histograms on the basis of the “linear–exponential,” “plateau,” and “full mechanistic” dose–response models. Secondary cancer risks of the contralateral breast (CB), contralateral lung (CL), and ipsilateral lung (IL) were estimated and compared.Results:The lowest EARs for the CB, CL, and IL were achieved with FinF, which reduced the EARs by 77%, 88%, and 56% relative to those with IMRT, and by 77%, 84%, and 58% relative to those with VMAT, respectively. The secondary cancer risk for FinF was significantly lower than those of IMRT and VMAT. OED-based secondary cancer risks for CB and IL were similar when IMRT and VMAT were used, but the risk for CL was statistically lower when VMAT was used.Conclusion:The overall estimation of EAR indicated that the radiation-induced cancer risk of breast radiation therapy was lower with FinF than with IMRT and VMAT. Therefore, when secondary cancer risk is a major concern, FinF is considered to be the preferred treatment option in irradiation of whole-breast.Advances in knowledge:Secondary malignancy estimation after breast radiotherapy is becoming an important subject for comparative treatment planning.When secondary cancer risk a major concern, FinF technique is considered the preferred treatment option in whole breast patients.

BACKGROUND: The presence of oesophageal varices is associated with the risk of upper gastrointestinal bleeding. Endoscopic variceal ligation is used to prevent this occurrence but the ligation procedure may be associated with complications. OBJECTIVES: To assess the beneficial and harmful effects of band ligation versus no intervention for primary prevention of upper gastrointestinal bleeding in adults with cirrhosis and oesophageal varices. SEARCH METHODS: We combined searches in the Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 9 February 2019. SELECTION CRITERIA: We included randomised clinical trials comparing band ligation verus no intervention regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms. Included participants had cirrhosis and oesophageal varices with no previous history of variceal bleeding. DATA COLLECTION AND ANALYSIS: Three review authors extracted data independently. The primary outcome measures were all‐cause mortality, upper gastrointestinal bleeding, and serious adverse events. We undertook meta‐analyses and presented results using risk ratios (RRs) with 95% confidence intervals (CIs) and I(2) values as a marker of heterogeneity. In addition, we calculated the number needed to treat to benefit (NNTTB) for the primary outcomes . We assessed bias control using the Cochrane Hepato‐Biliary domains; determined the certainty of the evidence using GRADE; and conducted sensitivity analyses including Trial Sequential Analysis. MAIN RESULTS: Six randomised clinical trials involving 637 participants fulfilled our inclusion criteria. One of the trials included an additional small number of participants (< 10% of the total) with non‐cirrhotic portal hypertension/portal vein block. We classified one trial as at low risk of bias for the outcome, mortality and high risk of bias for the remaining outcomes; the five remaining trials were at high risk of bias for all outcomes. We downgraded the evidence to moderate certainty due to the bias risk. We gathered data on all primary outcomes from all trials. Seventy‐one of 320 participants allocated to band ligation compared to 129 of 317 participants allocated to no intervention died (RR 0.55, 95% CI 0.43 to 0.70; I(2) = 0%; NNTTB = 6 persons). In addition, band ligation was associated with reduced risks of upper gastrointestinal bleeding (RR 0.44, 95% CI 0.28 to 0.72; 6 trials, 637 participants; I(2) = 61%; NNTTB = 5 persons), serious adverse events (RR 0.55, 95% CI 0.43 to 0.70; 6 trials, 637 participants; I(2) = 44%; NNTTB = 4 persons), and variceal bleeding (RR 0.43, 95% CI 0.27 to 0.69; 6 trials, 637 participants; I² = 56%; NNTTB = 5 persons). The non‐serious adverse events reported in association with band ligation included oesophageal ulceration, dysphagia, odynophagia, retrosternal and throat pain, heartburn, and fever, and in the one trial involving participants with either small or large varices, the incidence of non‐serious side effects in the banding group was much higher in those with small varices, namely ulcers: small versus large varices 30.5% versus 8.7%; heartburn 39.2% versus 17.4%. No trials reported on health‐related quality of life. Two trials did not receive support from pharmaceutical companies; the remaining four trials did not provide information on this issue. AUTHORS' CONCLUSIONS: This review found moderate‐certainty evidence that, in patients with cirrhosis, band ligation of oesophageal varices reduces mortality, upper gastrointestinal bleeding, variceal bleeding, and serious adverse events compared to no intervention. It is unlikely that further trials of band ligation versus no intervention would be considered ethical.

Given limited resources, schools are encouraged to consider not only what works, but also at what cost. Cost-effectiveness analysis offers a formal methodology to conceptualize and calculate the ratio of the costs to implement an intervention to its effects (i.e., incremental cost-effectiveness ratios). This study used the ingredients method to analyze secondary data from a randomized controlled trial (N = 537 fourth- and fifth-grade students) to calculate the cost-effectiveness of a classwide math intervention, and provides an overview of cost-effectiveness analysis for readers unfamiliar with the formal methodology. For fourth-graders, the incremental cost-effectiveness ratio was $169.07, indicating it cost $169.07 per student for a 1 standard deviation increase in scaled scores on the state assessment. For fifth-graders, there was no statistically significant effect on the state assessment, but there were improvements in curriculum-based measurement (CBM) scores with incremental cost-effectiveness ratios ranging from $65.08 to $469.12, depending on the type of CBM probe and implementation context. Additionally, using number-needed-to-treat (i.e., the number of participants who must be provided with the intervention to prevent one failure on the state assessment), the cost was $126.90 to prevent failure on the state assessment for one fourth-grade student receiving special education services or for one student who scored below the 25th percentile on the prior year's state assessment. Implications and directions for future research are discussed.

Background Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occurs during autumn or winter and remits in spring. The prevalence of SAD ranges from 1.5% to 9%, depending on latitude. The predictable seasonal aspect of SAD provides a promising opportunity for prevention. This review - one of four reviews on efficacy and safety of interventions to prevent SAD - focuses on second-generation antidepressants (SGAs). Objectives To assess the efficacy and safety of second-generation antidepressants (in comparison with other SGAs, placebo, light therapy, melatonin or agomelatine, psychological therapies or lifestyle interventions) in preventing SAD and improving patient-centred outcomes among adults with a history of SAD. Search methods A search of the Specialised Register of the Cochrane Depression, Anxiety and Neuorosis Review Group (CCDANCTR) included all years to 11 August 2015. The CCDANCTR contains reports of randomised controlled trials derived from EMBASE (1974 to date), MEDLINE (1950 to date), PsycINFO (1967 to date) and the Cochrane Central Register of Controlled Trials (CENTRAL). Furthermore, we searched the Cumulative Index to Nursing and Allied Health Literature, Web of Knowledge, The Cochrane Library and the Allied and Complementary Medicine Database (to 26 May 2014). We also conducted a grey literature search and handsearched the reference lists of included studies and pertinent review articles. Selection criteria For efficacy, we included randomised controlled trials on adults with a history of winter-type SAD who were free of symptoms at the beginning of the study. For adverse events, we planned to include non-randomised studies. Eligible studies compared an SGA versus another SGA, placebo, light therapy, psychological therapy, melatonin, agomelatine or lifestyle changes. We also intended to compare SGAs in combination with any of the comparator interventions versus the same comparator intervention as monotherapy. Data collection and analysis Two review authors screened abstracts and full-text publications and assigned risk of bias ratings based on the Cochrane 'Risk of bias' tool. We resolved disagreements by consensus or by consultation with a third party. Two review authors independently extracted data and assessed risk of bias of included studies. When data were sufficient, we conducted random-effects (Mantel-Haenszel) meta-analyses. We assessed statistical heterogeneity by calculating the Chi2 statistic and the Cochran Q. We used the I2 statistic to estimate the magnitude of heterogeneity and examined potential sources of heterogeneity using sensitivity analysis or analysis of subgroups. We assessed publication bias by using funnel plots. However, given the small number of component studies in our meta-analyses, these tests have low sensitivity to detect publication bias. We rated the strength of the evidence using the system developed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group. Main results We identified 2986 citations after de-duplication of search results and excluded 2895 records during title and abstract reviews. We assessed 91 full-text papers for inclusion in the review, of which four publications (on three RCTs) providing data from 1100 people met eligibility criteria for this review. All three RCTs had methodological limitations due to high attrition rates. Overall moderate-quality evidence indicates that bupropion XL is an efficacious intervention for prevention of recurrence of depressive episodes in patients with a history of SAD (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.44 to 0.72; three RCTs, 1100 participants). However, bupropion XL leads to greater risk of headaches (moderate-quality evidence), insomnia and nausea (both low-quality evidence) when compared with placebo. Numbers needed to treat for additional beneficial outcomes (NNTBs) vary by baseline risks. For a population with a yearly recurrence rate of 30%, the NNTB is 8 (95% CI 6 to 12). For populations with yearly recurrence rates of 40% and 50%, NNTBs are 6 (95% CI 5 to 9) and 5 (95% CI 4 to 7), respectively. We could find no studies on other SGAs and no studies comparing SGAs with other interventions of interest such as light therapy, psychological therapies, melatonin or agomelatine. Authors' conclusions Available evidence indicates that bupropion XL is an effective intervention for prevention of recurrence of SAD. Nevertheless, even in a high-risk population, four of five patients will not benefit from preventive treatment with bupropion XL and will be at risk for harm. Clinicians need to discuss with patients advantages and disadvantages of preventive SGA treatment and might want to consider offering other potentially efficacious interventions, which might confer lower risk of adverse events. Given the lack of comparative evidence, the decision for or against initiating preventive treatment of SAD and the treatment selected should be strongly based on patient preferences. Future researchers need to assess the effectiveness and risk of harms of SGAs other than bupropion for prevention of SAD. Investigators also need to compare benefits and harms of pharmacological and non-pharmacological interventions.

Background: An aging population combined with an increased colorectal cancer (CRC) incidence in the older population will increase its prevalence in the elderly, questioning how many years of life are lost (YLLs) in these patients. Patients and methods: Data from 32,568 Dutch CRC patients ≥ 80years were used to estimate the number of YLLs after diagnosis, using a reference age-, sex- and year-of-onset-matched cohort derived from national life tables. YLLs were additionally adjusted by comorbidities. Number needed to treat (NNT) was used as measure of surgical effect size. Results: Surgery was applied in 74.9% of patients leading to 1.3 YLLs, being superior in 86.1% of cases with respect to alternative therapies (YLLs 4.8years) and resulting in a number of two patients needed to operate to achieve one positive outcome. YLLs and NNTs depended on CRC stage, patient’ age and comorbidities. For Stage I–II patients in the best clinical conditions (80–85years without comorbidities), YLLs increased up to 4.1years after surgery and up to 8.8years without surgery (NNT 3). For Stage III patients, the NNT of surgery varied between 2 when they were in the best clinical conditions and 4 when they were older with high comorbidities. In Stage IV patients, the NNT ranged between 6 and 31. Conclusions: YLLs represents a novel approach to evaluate CRC prognosis. Stage I–III surgical patients can have a life expectancy similar to that of general population, being the NNT of surgery reasonably small compared with alternatives. Personalized comorbidity data are needed to confirm present findings.

Relative risk reduction and absolute risk reduction measures in the evaluation of clinical trial data are poorly understood by health professionals and the public. The absence of reported absolute risk reduction in COVID-19 vaccine clinical trials can lead to outcome reporting bias that affects the interpretation of vaccine efficacy. The present article uses clinical epidemiologic tools to critically appraise reports of efficacy in Pfzier/BioNTech and Moderna COVID-19 mRNA vaccine clinical trials. Based on data reported by the manufacturer for Pfzier/BioNTech vaccine BNT162b2, this critical appraisal shows: relative risk reduction, 95.1%; 95% CI, 90.0% to 97.6%; p = 0.016; absolute risk reduction, 0.7%; 95% CI, 0.59% to 0.83%; p < 0.000. For the Moderna vaccine mRNA-1273, the appraisal shows: relative risk reduction, 94.1%; 95% CI, 89.1% to 96.8%; p = 0.004; absolute risk reduction, 1.1%; 95% CI, 0.97% to 1.32%; p < 0.000. Unreported absolute risk reduction measures of 0.7% and 1.1% for the Pfzier/BioNTech and Moderna vaccines, respectively, are very much lower than the reported relative risk reduction measures. Reporting absolute risk reduction measures is essential to prevent outcome reporting bias in evaluation of COVID-19 vaccine efficacy.

Faced with rising healthcare costs, state Medicaid programs need short-term, easily calculated budgetary estimates for new drugs, accounting for medical cost offsets due to clinical advantages. To estimate the budgetary impact of direct-acting oral anticoagulants (DOACs) compared with warfarin, an older, lower-cost vitamin K antagonist, on 12-month Medicaid expenditures for nonvalvular atrial fibrillation (NVAF) using number needed to treat (NNT). Medicaid utilization files, 2009 through second quarter 2015, were used to estimate OAC cost accounting for generic/brand statutory minimum (13/23%) and assumed maximum (13/50%) manufacturer rebates. NNTs were calculated from clinical trial reports to estimate avoided medical events for a hypothetical population of 500,000 enrollees (approximate NVAF prevalence × Medicaid enrollment) under two DOAC market share scenarios: 2015 actual and 50% increase. Medical service costs were based on published sources. Costs were inflation-adjusted (2015 US$). From 2009–2015, OAC reimbursement per claim increased by 173 and 279% under maximum and minimum rebate scenarios, respectively, while DOAC market share increased from 0 to 21%. Compared with a warfarin-only counterfactual, counts of ischemic strokes, intracranial hemorrhages, and systemic embolisms declined by 36, 280, and 111, respectively; counts of gastrointestinal hemorrhages increased by 794. Avoided events and reduced monitoring, respectively, offset 3–5% and 15–24% of increased drug cost. Net of offsets, DOAC-related cost increases were US$258–US$464 per patient per year (PPPY) in 2015 and US$309–US$579 PPPY after market share increase. Avoided medical events offset a small portion of DOAC-related drug cost increase. NNT-based calculations provide a transparent source of budgetary-impact information for new medications.

Background Assessed by number needed to treat (NNT) to prevent one event, it was previously shown that for those at similar atherosclerotic cardiovascular disease (CVD) risk, the benefit accruing from treating people with higher cholesterol levels with statins is greater than for those with lower levels. Method By estimating NNT from both the absolute atherosclerotic cardiovascular risk and the pre-treatment low density lipoprotein cholesterol (LDL-C) concentration, recent recommendations for fixed dose high and moderate intensity statin treatment in the primary and secondary prevention of CVD were compared with cholesterol-lowering therapy aimed at a target LDL-C. Results We report that the USA and UK recommendations to employ a fixed dose of atorvastatin 20 mg daily for primary prevention will produce good results in people with low cholesterol levels, but are a disadvantage for those with higher levels who benefit more from a therapeutic target and statin dose titration and, where necessary, adjunctive cholesterol-lowering therapy to achieve this target. The higher dose of atorvastatin 80 mg daily with no target recommended for secondary prevention is generally more effective than aiming for a LDL-C goal except in people with particularly high cholesterol. Conclusion For optimum clinical effectiveness, initial LDL-C concentration must be considered in deciding whether a target will allow a greater decrease in LDL-C and thus a lower NNT than a fixed dose regimen. Individual variation in the LDL-C response to statins also makes post-treatment cholesterol measurement essential.

Background Despite topiramate's ability to reduce heavy drinking, its adverse effects may limit its clinical utility. Method To evaluate the risks and benefits of topiramate, we reanalyzed data from a completed trial of the medication in 138 heavy drinkers whose goal was to reduce their drinking to safe levels. We used the number of patients who had no heavy drinking days during the last 4 weeks of treatment to calculate topiramate's number needed to treat (NNT). To balance the risks and benefits of topiramate, we adjusted the NNT using 2 different levels of adverse event severity: moderate or greater (NNT-AEmod+) and severe or greater (NNT-AEsev+). This measure helps to guide the clinical use of topiramate in heavy drinkers by incorporating both its beneficial and adverse effects in a single measure. Because a polymorphism (rs2832407) in the gene encoding a kainate receptor subunit appears to moderate topiramate's effects in heavy drinkers, we repeated the analyses based on rs2832407 genotype (C-homozygote vs A-allele carrier) in the European American subsample (n = 122). Results Overall, the NNT for topiramate was 5.29, the NNT-AEmod+ was 7.52, and the NNT-AEsev+ was 6.12. Among European Americans with the rs2832407*CC genotype, the NNT was 2.28, the NNT-AEmod+ was 2.63, and the NNT-AEsev+ was 2.56. In contrast, for rs2832407*A-allele carriers, the NNT was 180.00, the NNT-AEmod+ was 322.16, and the NNT-AEsev+ was 217.45. Conclusions In this sample of heavy drinkers, topiramate had a clinically important treatment effect that was most evident in European Americans with the rs2832407*CC genotype. In that group, in particular, it had a robust treatment effect, even when adjusted for adverse events. Trial registration ClinicalTrials.gov identifier: NCT00626925.

Many patient-relevant outcomes, particularly quality of life measures such as pain or function, are routinely measured on a continuous scale. However, the interpretation of continuous outcomes is difficult, particularly when considering application to clinical practice and shared decision-making. Making matters worse is the frequent existence of multiple scales for any given construct. Therefore, quantitative syntheses of literature must find a way to combine different scales into a ‘common language’, and the most frequently used and longest-standing method to do so is the standardised mean difference. Unfortunately, the standardised mean difference is even more difficult to interpret clinically. However, there are validated methods to make these measures easier to understand and apply clinically. This analysis explores these issues and offers a resource to help make these continuous measures more clinically useful.

Background There is evidence that implantable cardioverter-defibrillator (ICD) for primary prevention in people with an ischaemic cardiomyopathy improves survival rate. The evidence supporting this intervention in people with non-ischaemic cardiomyopathy is not as definitive, with the recently published DANISH trial finding no improvement in survival rate. A systematic review of all eligible studies was needed to evaluate the benefits and harms of using ICDs for primary prevention in people with non-ischaemic cardiomyopathy. Objectives To evaluate the benefits and harms of using compared to not using ICD for primary prevention in people with non-ischaemic cardiomyopathy receiving optimal medical therapy. Search methods We searched CENTRAL, MEDLINE, Embase, and the Web of Science Core Collection on 10 October 2018. For ongoing or unpublished clinical trials, we searched the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the ISRCTN registry. To identify economic evaluation studies, we conducted a separate search to 31 March 2015 of the NHS Economic Evaluation Database, and from March 2015 to October 2018 on MEDLINE and Embase. Selection criteria We included randomised controlled trials involving adults with chronic non-ischaemic cardiomyopathy due to a left ventricular systolic dysfunction with an ejection fraction of 35% or less (New York Heart Association (NYHA) type I-IV). Participants in the intervention arm should have received ICD in addition to optimal medical therapy, while those in the control arm received optimal medical therapy alone. We included studies with cardiac resynchronisation therapy when it was appropriately balanced in the experimental and control groups. Data collection and analysis The primary outcomes were all-cause mortality, cardiovascular mortality, sudden cardiac death, and adverse events associated with the intervention. The secondary outcomes were non-cardiovascular death, health-related quality of life, hospitalisation for heart failure, first ICD-related hospitalisation, and cost. We abstracted the log (hazard ratio) and its variance from trial reports for time-to-event survival data. We extracted the raw data necessary to calculate the risk ratio. We summarised data on quality of life and cost-effectiveness narratively. We assessed the certainty of evidence for all outcomes using GRADE. Main results We identified six eligible randomised trials with a total of 3128 participants. The use of ICD plus optimal medical therapy versus optimal medical therapy alone decreases the risk of all-cause mortality (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.66 to 0.92; participants = 3128; studies = 6; high-certainty evidence). An average of 24 patients need to be treated with ICD to prevent one additional death from any cause (number needed to treat for an additional beneficial outcome (NNTB) = 24). Individuals younger than 65 derive more benefit than individuals older than 65 (HR 0.51, 95% CI 0.29 to 0.91; participants = 348; studies = 1) (NNTB = 10). When added to medical therapy, ICDs probably decrease cardiovascular mortality compared to not adding them (risk ratio (RR) 0.75, 95% CI 0.46 to 1.21; participants = 1781; studies = 4; moderate-certainty evidence) (possibility of both plausible benefit and no effect). Implantable cardioverter-defibrillator was also found to decrease sudden cardiac deaths (HR 0.45, 95% CI 0.29 to 0.70; participants = 1677; studies = 3; high-certainty evidence). An average of 25 patients need to be treated with an ICD to prevent one additional sudden cardiac death (NNTB = 25). We found that ICDs probably increase adverse events (possibility of both plausible harm and benefit), but likely have little or no effect on non-cardiovascular mortality (RR 1.17, 95% CI 0.81 to 1.68; participants = 1781; studies = 4; moderate-certainty evidence) (possibility of both plausible benefit and no effect). Finally, using ICD therapy probably has little or no effect on quality of life, however shocks from the device cause a deterioration in quality of life. No study reported the outcome of first ICD-related hospitalisations. Authors' conclusions The use of ICD in addition to medical therapy in people with non-ischaemic cardiomyopathy decreases all-cause mortality and sudden cardiac deaths and probably decreases mortality from cardiovascular causes compared to medical therapy alone. Their use probably increases the risk for adverse events. However, these devices come at a high cost, and shocks from ICDs cause a deterioration in quality of life.

N/a.

Background This article on choosing the target difference for a randomised controlled trial (RCT) and undertaking and reporting the sample size calculation has been dual published in the BMJ and BMC Trials journals. A key step in the design of a RCT is the estimation of the number of participants needed in the study. The most common approach is to specify a target difference between the treatments for the primary outcome and then calculate the required sample size. The sample size is chosen to ensure that the trial will have a high probability (adequate statistical power) of detecting a target difference between the treatments should one exist. The sample size has many implications for the conduct and interpretation of the study. Despite the critical role that the target difference has in the design of a RCT, the way in which it is determined has received little attention. In this article, we summarise the key considerations and messages from new guidance for researchers and funders on specifying the target difference, and undertaking and reporting a RCT sample size calculation. Methods The DELTA2 (Difference ELicitation in TriAls) project comprised five major components: systematic literature reviews of recent methodological developments (stage 1) and existing funder guidance (stage 2); a Delphi study (stage 3); a two-day consensus meeting bringing together researchers, funders and patient representatives (stage 4); and the preparation and dissemination of a guidance document (stage 5). Results and Discussion The key messages from the DELTA2 guidance on specifying the target difference are presented. Recommendations for specifying the target difference and the subsequent reporting of the sample size calculation are provided.

According to current guidelines prophylactic implantable cardioverter-defibrillator (ICD) therapy is recommended in patients with significantly impaired left ventricular systolic function. However, the recently published DANISH trial did not find a significantly lower long-term rate of death from any cause compared with usual clinical care in patients with non-ischemic cardiomyopathy. We investigated whether registry data from a multi-center ‘real-life’ registry on patients with non-ischemic cardiomyopathy are similar to this trial. The German Device Registry (DEVICE) is a nationwide, prospective registry with one-year follow-up investigating 5451 patients receiving device implantations in 50 German centers. The present analysis of DEVICE focused on patients with non-ischemic cardiomyopathy and a left ventricular ejection fraction ≤35% who received a prophylactic ICD. Out of 779 patients with symptomatic heart failure and nonischemic cardiomyopathy, 33.1% received a single chamber ICD (VVI), while 11.0% were implanted with a dual-chamber ICD (DDD), and 55.8% received a defibrillator system for cardiac resynchronization therapy. Median follow-up was 16.1 months. 90.7% were alive at follow-up, 9.3% had died during this period. Overall mortality after one year was 5.4%. Overall mortality one year after implantation was significantly increased in patients 68 years and older(7.9%) as compared to younger patients (59–68 years: 2.5%; < 59 years: 3.8%; p

Background The majority of people with epilepsy have a good prognosis, and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCT) of zonisamide, used as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant antiepileptic drug. This is an updated version of the Cochrane review previously published in 2013. Objectives To evaluate the efficacy and tolerability of zonisamide, when used as an add-on treatment for people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs. Search methods For this update, on 4 September 2017, we searched the Cochrane Epilepsy Group Specialised Register, Cochrane Register of Studies Online, MEDLINE Ovid, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform ICTRP. We searched SCOPUS on 13 February 2013, but this is no longer necessary, because RCTs and quasi-RCTs in Embase are now included in CENTRAL. In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing or unpublished studies. Selection criteria Randomised controlled trials, in which add-on zonisamide was compared with placebo or another antiepileptic drug in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs. Data collection and analysis Two review authors independently selected trials for inclusion, extracted data, assessed for risk of bias using the Cochrane 'Risk of bias' tool, and assessed the quality of the evidence, using the GRADE approach. The primary outcome was at least a 50% reduction in total seizure frequency; the secondary outcomes were (1) tolerability; and (2) adverse effects. We used an intention-to-treat approach for our primary analyses. We estimated summary risk ratios (RRs) for each outcome. We displayed a summary of the estimates of effects and quality of the evidence for each outcome in a 'Summary of findings' table. Main results We included eight studies (1636 participants). The overall RR with 95% confidence interval (CI) for at least a 50% reduction in seizure frequency compared to placebo for 300 mg to 500 mg/day of zonisamide was 1.90 (95% CI 1.63 to 2.22; 7 trials, 1371 participants; moderate-quality evidence). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 mg to 500 mg/day) was 1.86 (95% CI 1.60 to 2.17; 7 trials, 1429 participants; moderate-quality evidence). The number needed to treat for an additional beneficial outcome was six (95% CI 4.1 to 6.8) for this outcome. Two trials provided evidence of a dose-response relationship for this outcome. The RR for treatment withdrawal for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.59 (95% CI 1.18 to 2.13; 6 trials, 1099 participants; moderate-quality evidence), and for 100 mg to 500 mg/day was 1.44 (95% CI 1.08 to 1.93; 6 trials, 1156 participants; moderate-quality evidence). The number needed to treat for an additional harmful outcome was 15 (95% CI 9.3 to 36.7). The CIs of the following adverse effects indicated that they were significantly associated with zonisamide: ataxia RR 3.85 (99% CI 1.36 to 10.93; 4 trials, 734 participants; low-quality evidence); somnolence RR 1.52 (99% CI 1.00 to 2.31; 8 trials, 1636 participants; moderate-quality evidence); agitation RR 2.35 (99% CI 1.05 to 5.27; 4 trials, 598 participants; low-quality evidence); and anorexia RR 2.74 (99% CI 1.64 to 4.60; 6 trials, 1181 participants; low-quality evidence).Across the eight studies, we rated risk of bias domains at low or unclear risk of bias apart from two studies which we rated at high risk of attrition bias. Five of the eight studies were sponsored by the drug companies that produced zonisamide. Authors' conclusions When used as an add-on treatment in people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs, moderate-quality evidence found that zonisamide was more successful than placebo at reducing the frequency of seizures by at least 50%. We were unable to identify minimum effective and maximum tolerated doses. The included trials evaluated a maximum stable-dose phase of 18 weeks, so results cannot be used to confirm longer periods of efficacy in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.

Psoriasis is a chronic inflammatory skin disease with an estimated prevalence in Spain of 2.3% of the population. Approximately 30% of patients have moderate-to-severe forms. Treatment with biologic agents is proving to be a step forward in the management of the disease, although these treatments are very expensive. The objective of this study was to determine the efficiency, in terms of cost per number needed to treat (NNT), of the biologic drugs available in Spain for the treatment of moderate to severe plaque psoriasis.NNT data were obtained from a network meta-analysis that included all randomized clinical trials of biologic drugs sold in Spain. The cost of each treatment was calculated based on the approved dosage for the first year of treatment, as indicated in the Summary of Product Characteristics. These data were used to calculate the cost per NNT of the drugs for various PASI scores (75, 90, and 100). A sensitivity analysis was performed taking into consideration only the PASI-response measurement time (after 10, 12, or 16 weeks, depending on the drug).The order of efficiency, from most to least efficient, in the case of a PASI 75 response was ixekizumabustekinumab 45mgustekinumab 90mgsecukinumabinfliximabetanerceptadalimumab. The order for PASI 90 was ixekizumabsecukinumabustekinumab 45mgustekinumab 90mginfliximabadalimumabetanercept. The order for PASI 100 was ixekizumabsecukinumabinfliximabustekinumab 90mgustekinumab 45mgadalimumabetanercept. The sensitivity analysis showed some changes in the order, depending on the response-assessment period.The findings show a link between the efficacy of the biologic therapies available in Spain for the treatment of moderate-to-severe plaque psoriasis and their efficiency. Ixekizumab had the lowest cost per NNT for all PASI-response scores (75, 90, and 100) during the first year of treatment.

Background Panic disorder is characterised by repeated, unexpected panic attacks, which represent a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes, and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. It is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, the National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology consider antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Several classes of antidepressants have been studied and compared, but it is still unclear which antidepressants have a more or less favourable profile in terms of effectiveness and acceptability in the treatment of this condition. Objectives To assess the effects of antidepressants for panic disorder in adults, specifically: 1. to determine the efficacy of antidepressants in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison to placebo; 2. to review the acceptability of antidepressants in panic disorder, with or without agoraphobia, in comparison with placebo; and 3. to investigate the adverse effects of antidepressants in panic disorder, with or without agoraphobia, including the general prevalence of adverse effects, compared to placebo. Search methods We searched the Cochrane Common Mental Disorders' (CCMD) Specialised Register, and CENTRAL, MEDLINE, EMBASE and PsycINFO up to May 2017. We handsearched reference lists of relevant papers and previous systematic reviews. Selection criteria All double-blind, randomised, controlled trials (RCTs) allocating adults with panic disorder to antidepressants or placebo. Data collection and analysis Two review authors independently checked eligibility and extracted data using a standard form. We entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details and settings. Primary outcomes included failure to respond, measured by a range of response scales, and treatment acceptability, measured by total number of dropouts for any reason. Secondary outcomes included failure to remit, panic symptom scales, frequency of panic attacks, agoraphobia, general anxiety, depression, social functioning, quality of life and patient satisfaction, measured by various scales as defined in individual studies. We used GRADE to assess the quality of the evidence for each outcome Main results Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias. We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo. Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference. When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference. Authors' conclusions The identified studies comprehensively address the objectives of the present review. Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants. The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review. Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes. Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.