Search

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: Circulating high-sensitivity cardiac troponin T (hsTnT) predominantly reflects myocardial injury, and higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction. Less is known about the prognostic significance of changes in hsTnT over time, the effects of dapagliflozin on clinical outcomes in relation to baseline hsTnT levels, and the effect of dapagliflozin on hsTnT levels. Methods: DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg daily) in patients with New York Heart Association class II to IV symptoms and left ventricular ejection fraction ≤40% (median follow-up, 18.2 months). hsTnT (Roche Diagnostics) was measured at baseline in 3112 patients and at 1 year in 2506 patients. The primary end point was adjudicated worsening heart failure or cardiovascular death. Clinical end points were analyzed according to baseline hsTnT and change in hsTnT from baseline to 1 year. Comparative treatment effects on clinical end points with dapagliflozin versus placebo were assessed by baseline hsTnT. The effect of dapagliflozin on hsTnT was explored. Results: Median baseline hsTnT concentration was 20.0 (25th–75th percentile, 13.7–30.2) ng/L. Over 1 year, 67.9% of patients had a ≥10% relative increase or decrease in hsTnT concentrations, and 43.5% had a ≥20% relative change. A stepwise gradient of higher risk for the primary end point was observed across increasing quartiles of baseline hsTnT concentration (adjusted hazard ratio Q4 versus Q1, 3.44 [95% CI, 2.46–4.82]). Relative and absolute increases in hsTnT over 1 year were associated with higher subsequent risk of the primary end point. The relative reduction in the primary end point with dapagliflozin was consistent across quartiles of baseline hsTnT ( P -interaction=0.55), but patients in the top quartile tended to have the greatest absolute risk reduction (absolute risk difference, 7.5% [95% CI, 1.0%–14.0%]). Dapagliflozin tended to attenuate the increase in hsTnT over time compared with placebo (relative least squares mean reduction, –3% [–6% to 0%]; P =0.076). Conclusions: Higher baseline hsTnT and greater increase in hsTnT over 1 year are associated with worse clinical outcomes. Dapagliflozin consistently reduced the risk of the primary end point, irrespective of baseline hsTnT levels. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03036124.

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.

Background Colorectal cancer (CRC) screening programs using fecal immunochemical test (FIT) have to choose a cut‐off value to decide which citizens to recall for colonoscopy. The evidence on the optimal cut‐off value is sparse and based on studies with a low number of cancer cases. Methods This observational study used data from the Danish Colorectal Cancer Screening Database. Sensitivity and specificity were estimated for various cut‐off values based on a large number of cancers. Traditionally optimal cut‐off values are found by weighting sensitivity and specificity equally. As this might result in too many unnecessary colonoscopies we also provide optimal cut‐off values for different weighting of sensitivity and specificity/number of needed colonoscopies to detect one cancer. Results Weighting sensitivity and specificity equally gives an optimal cut‐off value of 45 ng Hb/ml. This, however, means making 24 colonoscopies to detect one cancer. Weighting sensitivity lower and for example, aiming at making about 16 colonoscopies to detect one cancer, gives an optimal cut‐off value of 125 ng Hb/ml. Conclusions The optimal cut‐off value in an FIT population‐based screening program is 45 ng Hb/ml, when as traditionally sensitivity and specificity are weighted equally. If, however, 24 colonoscopies needed to detect one cancer is too huge a burden on the health care system and the participants, 80, 125, 175, and 350 ng Hb/ml are optimal cut‐off values when only 19/16/14/10 colonoscopies are accepted to find one cancer., If 24 colonoscopies needed to detect one cancer is acceptable for the health care system and the participants, the optimal cut‐off value in fecal immunochemical test screening is 45 ng Hb/ml. When only 19/16/14/10 colonoscopies are accepted to find one cancer, then, the optimal cut‐off value is 80/125/175/350 ng Hb/ml.

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.

Background: The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in subgroups with clinically and genetically defined risk. Methods: We performed a post hoc analysis of the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) were then combined in a meta-analysis to assess the class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Last, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab. Results: In FOURIER, the hazard ratio (HR) for VTE with evolocumab was 0.71 (95% CI, 0.50–1.00; P =0.05), with no effect in the 1st year (HR, 0.96 [95% CI, 0.57–1.62]) but a 46% reduction (HR, 0.54 [95% CI, 0.33–0.88]; P =0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR, 0.69 [95% CI, 0.53–0.90]; P =0.007). There was no relation between baseline low-density lipoprotein cholesterol levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline lipoprotein(a) (Lp[a]) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR, 0.52 [95% CI, 0.30–0.89]; P =0.017), whereas, in patients with lower baseline Lp(a) levels, evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk ( P interaction 0.087 for HR; P heterogeneity 0.037 for absolute risk reduction). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction ( P interaction =0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative ( P interaction =0.04) and absolute VTE reduction ( P heterogeneity =0.009) in comparison with those without high genetic risk. Conclusions: PCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given the ongoing development of potent Lp(a) inhibitors.

Luotettavin arvio hoidon tehosta saadaan meta-analyysistä, joka perustuu satunnaistettuihin hoitokokeisiin. ? Päätetapahtumanäytön tulisi olla potilaalle merkityksellistä, kuten ennalta- ehkäisevässä hoidossa vähenemä sairastavuudessa tai kuolleisuudessa, eikä pelkkä muutos tapahtumien riskiä kuvaavissa korvikemuuttujissa. ? Absoluuttisena vaikutuksena mitattuna ennaltaehkäisevästä hoidosta hyötyy todennäköisemmin suuremman kuin pienemmän sairastumisriskin potilas. publishedVersion

Melanoma is among the few cancers that demonstrate an increasing incidence over time. Simultaneously, this trend has been marked by an epidemiologic shift to earlier stage at diagnosis. Before 2011, treatment options were limited for patients with metastatic disease, and the median overall survival was less than 1 year. Since then, the field of melanoma therapeutics has undergone major changes. The use of anti–CTLA‐4 and anti‐PD1 immune checkpoint inhibitors and combination BRAF/MEK inhibitors for patients with BRAF V600 mutations has significantly extended survival and allowed some patients to remain in durable disease remission off therapy. It has now been confirmed that these classes of agents have a benefit for patients with stage III melanoma after surgical resection, and anti‐PD1 and BRAF/MEK inhibitors are standards of care in this setting. Some patients with stage II disease (lymph node‐negative; American Joint Committee on Cancer stage IIB and IIC) have worse melanoma‐specific survival relative to some patients with stage III disease. Given these results, expanding the population of patients who are considered for adjuvant therapy to include those with stage II melanoma has become a priority, and randomized phase 3 clinical trials are underway. Moving into the future, the validation of patient risk‐stratification and treatment‐benefit prediction models will be important to improve the number needed to treat and limit exposure to toxicity in the large population of patients with early stage melanoma., Adjuvant therapy has improved outcomes in patients with stage III melanoma and is being explored in those with stage II melanoma. Stage III data as well as risk‐stratification tools and clinical considerations for the lymph node‐negative population are reviewed.

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.

People in close contact with tuberculosis should have screening and appropriate management, as an opportunity for active case detection and prevention. However, implementation of tuberculosis contact screening and management is limited in high-burden settings. Behaviour change is needed across three levels of the healthcare system—policymakers, healthcare providers, and patients. To bridge the wide policy-practice gap, this study draws on the Consolidated Framework for Implementation Research, the Behaviour Change Wheel, and the RE-AIM model (Reach, Effectiveness, Adoption, Implementation, Maintenance) to respectively understand barriers, implement change, and evaluate process and outcome. This methods paper describes a mixed-methods intervention study in Eastern Indonesia. Quantitative data will be collected during baseline, intervention, and sustainability periods and analyzed using time series analysis. The primary outcome is the number of individuals completing tuberculosis preventive therapy by the end of the two-year intervention phase. Of an estimated 10,000 contacts during this period, we anticipate that a minimum of 416 will be found to have active TB or will complete preventive therapy. Qualitative data (semi-structured interviews, focus group discussions, and observations) will be collected from consenting healthcare providers, patients, and contacts. Activities to promote policy implementation include healthcare provider training, quarterly continuous quality improvement workshops, a social media discussion forum, and promotional materials. The Consolidated Framework for Implementation Research will be used to identify reasons for limited policy implementation at baseline. The Behaviour Change Wheel will be used to ensure that a suitable range of activities are implemented to facilitate change. The RE-AIM model will be used as the evaluation framework. Use of theoretical frameworks in combination can ensure a comprehensive understanding of, and robust response to, health policy underimplementation. The selected frameworks are highly applicable to this pragmatic intervention study, in a setting where End TB Strategy targets will not be met without substantial behavior change within health systems. Continuous quality improvement cycles will provide a way to engage staff and stakeholders in understanding local data to motivate behavior change. If successful, up to 500 people could be prevented from developing complications of tuberculosis through early case-finding or receiving preventive therapy over a two-year period. Australian New Zealand Clinical Trials Register 375803 .

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 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.

This cross-sectional study assesses the trends and characteristics of absolute measure reporting in highly cited medical journals from 2001 to 2019.

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: This work aimed to evaluate the efficacy and safety of routine tranexamic acid (TXA) use in elective orthopaedic lower limb joint replacement surgery. Methods: This retrospective cohort study included all primary hip or knee replacement procedures by a single surgeon over a 6-year period. TXA was introduced during the study period as part of an enhanced recovery after surgery strategy. Results: Of the 673 procedures, 446 cases (66.3%) received TXA. The median length of stay was 5 days (2-69) and 6 days (3-28) for the TXA and control groups, respectively (P < .001). Blood transfusion was required for 28 (6.3%) of the TXA cases versus 40 (17.6%) controls (P < .001). Complication rates were similar irrespective of TXA status. At multivariate analysis, TXA was significantly and independently associated with fewer blood transfusions (hazard ratio 0.309, 95% confidence interval: 0.168-0.568, P

The recently published Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial evaluated the hypothesis that rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary prevention. In India, stable cardiovascular disease occurs in a much younger age group relative to the rest of the world.Our critical analysis of COMPASS trial showed that the younger age group appeared to derive greater benefit from the rivaroxaban + aspirin combination (relative to aspirin alone) as seen with number needed to treat metrics as compared to the older age group. Keywords: Stable Coronary artery disease, Rivaroxaban, Young Indian Population, Likelihood of being helped and harmed

Background Previous meta-analyses of randomised controlled trials (RCTs) have suggested a reduction in parastomal hernias (PSH) with prophylactic mesh. However, concerns persist regarding variably supportive evidence and cost. We performed an updated systematic review and meta-analysis to inform a novel cost-effectiveness analysis. Methods The PubMed, EMBASE and Cochrane Centre Register of Controlled Trials databases were searched (February 2018). We included RCTs assessing mesh reinforcement during stoma formation. We assessed PSH rates, subsequent repair, complications and operative time. Odds ratios (OR) and numbers needed to treat (NNT) were generated on intention to treat (ITT) and per protocol (PP) bases. These then informed cost analysis using 2017 UK/USA reimbursement rates and stoma care costs. Results Eleven RCTs were included. Four hundred fifty-three patients were randomised to mesh (PP 412), with 454 controls (PP 413). Six studies used synthetic meshes, three composite and two biological (91.7% colostomies; 3.64% ileostomies, 4.63% not specified). Reductions were seen in the number of hernias detected clinically and on computed tomography scan. For the former, ITT OR was 0.23 (95% confidence interval 0.11–0.51; p = 0.0003; n = 11); NNT 4.17 (2.56–10.0), with fewer subsequent repairs: OR 0.29 (0.13–0.64; p = 0.002; n = 7; NNT16.7 (10.0–33.3). Reductions persisted for synthetic and composite meshes. Operative time was similar, with zero incidence of mesh infection/fistulation, and fewer peristomal complications. Synthetic mesh demonstrated a favourable cost profile, with composite approximately cost neutral, and biological incurring net costs. Conclusions Reinforcing elective stomas with mesh (primarily synthetic) reduces subsequent PSH rates, complications, repairs and saves money. We recommend that future RCTs compare mesh subtypes, techniques, and applicability to emergency stomas.

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.