Number Needed To Harm Research Articles

Investigating the association of mechanical restraint with somatic harmful outcomes: national register-based study.

Coercive measures to manage disruptive or violent behaviour are accepted as standard practice in mental healthcare, but systematic knowledge of potentially harmful outcomes is insufficient. To examine the association of mechanical restraint with several predefined somatic harmful outcomes. We conducted a population-based, observational cohort study linking data from the Danish national registers from 2007 to 2019. The primary analyses investigated the association of mechanical restraint with somatic adverse events, using panel regression analyses (within-individual analysis) to account for repeated exposures and outcomes. Secondary between-group analyses were performed with a control group exposed to types of coercion other than mechanical restraint. The study population comprised 13 022 individuals. We report a statistically significant association of mechanical restraint with thromboembolic events (relative risk 4.377, number needed to harm (NNH) 8231), pneumonia (relative risk 5.470, NNH 3945), injuries (relative risk 2.286, NNH 3240) and all-cause death (relative risk 5.540, NNH 4043) within 30 days after mechanical restraint. Estimates from the between-group analyses (comparing the exposed group with a control group of 22 643 individuals) were non-significant or indicated increased baseline risk in the control group. A positive dose-response analysis for cardiac arrest, injury and death supported a causative role of mechanical restraint in the reported associations. Although the observed absolute risk increases were small, the derived relative risks were non-negligible considering that less restrictive interventions are available. Clinicians and decision makers should be aware of the excess risk in future decisions on the use of mechanical restraint versus alternative interventions.

Risk-Benefit Analysis of Novel Treatments for Patients with Generalized Myasthenia Gravis.

This study used network meta-analysis (NMA) to inform and compare the number needed to treat (NNT), number needed to harm (NNH), and cost per improved outcome (CPIO) associated with more recently approved treatments for anti-acetylcholine receptor antibody-positive (anti-AChR Ab+) generalized myasthenia gravis (gMG). Clinical trials of neonatal Fc receptor (FcRn) inhibitors, efgartigimod intravenous (IV) and rozanolixizumab, and complement inhibitors, ravulizumab and zilucoplan, versus placebo (with background conventional treatment) were included in the primary NMA to compare efficacy and safety outcomes. The outputs from the NMAs were used to estimate NNT and NNH of each treatment versus placebo. CPIO (2024 USD) was estimated for a≥3- or≥5-point reduction from baseline in Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores. Sensitivity analyses were performed adding efgartigimod PH20 subcutaneous (SC) and eculizumab to the NMA. Efgartigimod IV had the lowest NNT versus placebo for achieving a≥3- and≥5-point reduction in QMG, as well as a≥5-point reduction in MG-ADL, whereas rozanolixizumab had the lowest NNT for a≥3-point reduction in MG-ADL. The NNH versus placebo was similar across comparator treatments. Efgartigimod IV had the lowest CPIO among all treatments for all assessed efficacy outcomes. Sensitivity analyses yielded results consistent with primary analysis and indicated that efgartigimod PH20 SC had comparable NNT and CPIO values to efgartigimod IV, whereas eculizumab had comparable NNT and higher CPIO values compared to other complement inhibitors. FcRn inhibitors and complement inhibitors assessed in this study all demonstrated clinical benefit in terms of NNT as well as an acceptable safety profile in terms of NNH. Within the limitations of this meta-analysis, efgartigimod was associated with a favorable benefit-risk profile as well as a better economic value compared to ravulizumab, rozanolixizumab, and zilucoplan as treatments for anti-AChR Ab+gMG.

Effects of beta blockers on outcome in patients with PAH with and without comorbid conditions: a Multicenter Prospective Cohort Study (BNP-PL)

Abstract Background The current guidelines do not recommend the use of beta-blockers (BB) in patients with pulmonary arterial hypertension (PAH) unless necessitated by comorbidities. However, the evidence regarding the role of BB in PAH is contradictory. This study investigates the effects of BB on clinical outcomes in patients newly diagnosed with PAH, stratified by the presence of cardiovascular comorbidities that justify their use. Methods We analyzed data from 806 patients newly diagnosed with PAH, who were prospectively enrolled from March 1, 2018, to August 31, 2023, in the multicentre registry, Database of Pulmonary Hypertension in the Polish population (BNP-PL). The primary endpoints were all-cause mortality and a composite of hospitalization due to right heart exacerbation, syncope, or death. The follow-up period for these patients extended until August 31, 2023. Comorbidities in the study group that indicated the need for BB therapy included hypertension, significant arrhythmia, and coronary artery disease. In the Cox regression analysis, the association between BB use and the predefined endpoints was adjusted for age, baseline European Society of Cardiology risk score, and upfront therapy. Results Among the 806 patients, BBs were administered to 469 (58.2%) at the time of PAH diagnosis. In the entire cohort, BB therapy was linked to increased all-cause mortality (29.6% vs 21.4%; p=0.005, Fig 1.A) and a higher incidence of the composite endpoint (34.1% vs 22.6%; p<0.0001, Fig 1.B). The Number Needed to Harm (NNH) for BB treatment, regarding mortality and the composite endpoint, were 12.1 and 8.7, respectively. In patients without comorbidities, BB use significantly raised the risk of both all-cause mortality (Hazard Ratio [HR] 1.81, 95% Confidence Interval [CI]: 1.01-3.15) and the composite endpoint (HR 1.85, 95% CI 1.09-3.14), after adjustments for age, baseline three-strata PAH mortality risk, and upfront therapy. However, in patients with at least one comorbidity, BB therapy showed a neutral effect on both outcomes. Across the whole group, the use of nonselective BB was associated with a higher risk of the composite endpoint (HR 1.78, 95% CI 1.13-2.82, p=0.01) compared to selective β1 agents, although this did not extend to all-cause mortality (HR 1.34, 95% CI 0.79-2.25, p=0.28). Conclusion BBs, particularly nonselective, pose significant risks in patients with PAH who lack comorbidities that justify their use.

Skin injury: Associations with variables related to perfusion and pressure.

Skin injuries are a major healthcare problem that are not well understood or prevented in the critically ill, suggesting that underappreciated variables are contributing. This pilot study tested the hypothesis that perfusion-related factors contribute to skin injuries diagnosed as hospital-acquired pressure injuries (HAPIs). A total of 533 adult patients were followed over 2574 critical care days (mean age 62.4, standard deviation (SD) 14.3 years, mean body mass index 30.4 (SD 7.4) kg/m2, 36.4% female). This was a secondary analysis of prospective, non-randomised clinical data from an intensive care unit at a large urban teaching hospital. Factors related to perfusion, specifically two or more infusions of vasopressors/inotropes, temporary mechanical circulatory support (MCS), extracorporeal membrane oxygenation, and durable MCS, were analysed to determine whether they were more strongly associated with HAPIs than immobility due to prolonged mechanical ventilation (>72 h) or operating room time (>6 h). Patients diagnosed with a HAPI had a statistically significant higher risk of being exposed to variables related to perfusion and immobility (P < 0.05 for each variable). Perfusion-related variables, except durable MCS, had a larger effect on skin breakdown (number needed to harm (NNH) 4-10) than immobility-associated variables (NNH 12-17). The finding that perfusion-related variables predicted HAPIs may warrant consideration of alternative diagnoses, such as skin failure due to impaired perfusion as a pathophysiological process that occurs concurrently with multisystem organ failure. Differentiation of skin injuries primarily from circulatory malfunction, rather than external pressure, may guide the development of more effective treatment and prevention protocols. This pilot study suggests that the contribution of perfusion to skin injuries should be explored further.

Adjunctive cariprazine for the treatment of major depressive disorder: Number needed to treat, number needed to harm, and likelihood to be helped or harmed

BackgroundThe number needed to treat (NNT) for efficacy and number needed to harm (NNH) for tolerability/safety were evaluated for adjunctive cariprazine in major depressive disorder (MDD). MethodsData were extracted from five randomized, double-blind, placebo-controlled trials of adjunctive cariprazine in MDD. NNTs (response, remission, severity shift) and NNHs (discontinuations due to adverse events [AEs], AEs, laboratory shifts) were determined in dose groupings; likelihood to be helped/harmed (LHH) was calculated. ResultsNNTs (95 % CI) for adjunctive cariprazine versus placebo were statistically significant at week 6/early termination for Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥ 50 % response (doses ≥1 mg/d = 12 [9–21]; 1–2 mg/d = 12 [8–25]; 2–4.5 mg/d = 14 [9–43]) and other response/remission outcomes. NNHs for cariprazine versus placebo were generally ≥10 for AEs that were statistically significant; an apparent dose-response was seen for akathisia (lower dose = 24 [17–43]; higher dose = 9 [7–11]). LHHs were ≥ 1 (acceptable benefit/harm ratio) for MADRS total score response versus most important cariprazine AEs in most dose groupings. For response versus discontinuation because of an AE, adjunctive cariprazine 1–2 mg/d had a more favorable response/tolerability profile in indirect comparison with other approved atypical antipsychotics. LimitationsPost hoc analysis; indirect comparisons. ConclusionsPatients receiving adjunctive cariprazine encountered benefits more often than harm; NNT values at week 6/ET were statistically significant versus placebo on response/remission outcomes across dose groupings from the 5 pooled studies. Adjunctive cariprazine was well tolerated; NNH values versus placebo were generally >10, with better akathisia tolerability in the lower-dose range.

Comparison of Sitting versus Nonsitting Position for the Resection of Brain Metastases in the Posterior Fossa in a Contemporary Cohort.

For surgery of brain metastases, good immediate postoperative functional outcome is of utmost importance. Improved functional status can enable further oncologic therapies and adverse events might delay them. Pros and cons of either sitting or prone positioning for resective surgery of the posterior fossa are debated, but contemporary data on direct postoperative outcome are rare. The aim of our study was to compare the functional outcome and adverse events of surgery for brain metastases in the sitting versus the nonsitting position in the direct postoperative setting. We retrospectively compared surgery of metastases located in the posterior fossa over a 3-year period in two level-A neurosurgical centers. Center 1 performed surgery exclusively in the sitting, while center 2 performed surgery only in the nonsitting position. Worse functional outcome (Karnofsky performance scale) and functional deterioration were seen in the "sitting" group. We found significantly more "sitting" patients to deteriorate to a KPS score of ≤60%. In this study, treating patients with brain metastases in the sitting position resulted in a number needed to harm (NNH) of 2.3 and was associated with worse outcome and more adverse events. Therefore, we recommend the nonsitting position for surgery of brain metastases of the posterior fossa.

Thirty-day risk of digoxin toxicity among older adults co-prescribed trimethoprim-sulfamethoxazole versus amoxicillin: A population-based cohort study.

Trimethoprim-sulfamethoxazole (TMP-SMX) may increase digoxin concentration, a medication with a narrow therapeutic index. Small changes in digoxin concentration could predispose individuals to the risk of toxicity. To characterize the risk of digoxin toxicity in older adults taking digoxin following co-prescription of TMP-SMX compared with co-prescription of amoxicillin. Retrospective population-based cohort study in Ontario, Canada (2002-2020) using linked health care data. Participants comprised 47,961 older adults taking digoxin (58% women; median age 80 years [interquartile range 74-86]) who were newly treated with TMP-SMX (n = 10,273) compared with those newly treated with amoxicillin (n = 37,688). Co-prescription of TMP-SMX versus amoxicillin in older adults concurrently taking digoxin. The primary outcome was a hospital encounter (i.e., hospital admission or emergency department visit) with digoxin toxicity within 30 days of the antibiotic prescription. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. The number needed to harm (NNH) was calculated as 1/RD. A hospital encounter with digoxin toxicity occurred in 49/10,273 (0.48%) patients treated with TMP-SMX versus 32/37,688 (0.08%) in those treated with amoxicillin (weighted RR, 5.71 [95% confidence interval (CI), 3.19 to 10.24]; weighted RD, 0.39% [95% CI, 0.25% to 0.53%]; NNH 256 [95% CI, 233 to 400]). In older adults taking digoxin, the 30-day risk of a hospital encounter with digoxin toxicity was nearly 6 times higher in those co-prescribed TMP-SMX versus amoxicillin, although the absolute risk difference was low (0.4%). Physicians should prescribe an alternative antibiotic when clinically appropriate. If TMP-SMX must be co-prescribed with digoxin (if the benefit is believed to outweigh the risk), digoxin should be dose-reduced on an individual basis.

A Risk-Difference Meta-Analysis for the Prophylactic Treatments of Chronic Migraine.

Chronic migraine (CM) imposes significant personal, societal, and financial burdens, historically lacking specific prophylactic treatments. Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) represent a novel, mechanism-based, and migraine-specific prophylactic approach. Four mAbs, namely, erenumab, fremanezumab, galcanezumab, and eptinezumab, have been marketed, although head-to-head trials with standard anti-migraine treatments are absent. This study aimed to compare the efficacy and safety of anti-CGRP mAbs with standard anti-migraine treatments using a cross-trial indirect model of the absolute risk difference (ARD) of a 50% responder rate, in order to express the final results in terms of the number needed to treat (NNT) and number needed to harm (NNH). Phase 3 and 2b randomized controlled trials (RCTs) for CM prophylaxis were searched in the MEDLINE and CENTRAL databases with specific inclusion and exclusion criteria. The ARD between groups for the percentage of trial participants who reported a 50% reduction in monthly migraine days and the differences in the number of adverse events (AEs), serious adverse events (SAEs), and participants who withdrew from each RCT were calculated, and subsequently, the NNT and NNH were calculated for each one of the outcome measures. In total, eight RCTs were considered eligible. A similar efficacy and safety have been demonstrated among CGRP mAbs and all standard CM treatments. The results of the ARD for the total number of studies concerning efficacy, total adverse events, serious adverse events, and dropout from the RCTs ranged from -0.688 (95% confidence interval (CI): -0.821-(-0.513)) to -0.018 (95% CI: -0.044-(0.007)), from 0.032 (95% CI: -0.041, 0.104) to -0.380 (95% CI: -0.589, -0.126), from -0.025 (95% CI: -0.046, -0.006) to 0.014 (95% CI: -0.015, 0.42), from 0.048 (95% CI: -0.112, 0.014) to 0.232 (95% CI: -0.016, 0.458) correspondingly. All anti-CGRP mAbs showed a roughly equal statistically significant ARD and similar NNTs, ranging from 5 to 8, while the ARD of onbotulinum toxin A (oBTA) was not significant with an NNT 56. The two studies of topiramate showed contradictory results, the one significant while the other not, with NNTs 2 and 22, respectively. All four anti-CGRP mAbs showed an invariably high efficacy among their studies, in terms of the ARD and its derivative measure of NNT, in contrast to oBTA, while in topiramate, the results are contradictory between the two studies.

Equivalent mortality after operation with sliding hip screw or intramedullary nail for trochanteric AO/OTA A1 and A2 fractures reported in the Norwegian Hip Fracture Register 2008 to 2020.

This study aimed to compare mortality in trochanteric AO/OTA A1 and A2 fractures treated with an intramedullary nail (IMN) or sliding hip screw (SHS). The primary endpoint was 30-day mortality, with secondary endpoints at 0 to 1, 2 to 7, 8 to 30, 90, and 365 days. We analyzed data from 26,393 patients with trochanteric AO/OTA A1 and A2 fractures treated with IMNs (n = 9,095) or SHSs (n = 17,298) in the Norwegian Hip Fracture Register (January 2008 to December 2020). Exclusions were made for patients aged < 60 years, pathological fractures, pre-2008 operations, contralateral hip fractures, fractures other than trochanteric A1/A2, and treatments other than IMNs or SHSs. Kaplan-Meier and Cox regression analyses adjusted for type of fracture, age, sex, cognitive impairment, American Society of Anesthesiologists (ASA) grade, and time period were conducted, along with calculations for number needed to harm (NNH). In unadjusted analyses, there was no significant difference between IMN and SHS patient survival at 30 days (91.8% vs 91.1%; p = 0.083) or 90 days (85.4% vs 84.5%; p = 0.065), but higher one-year survival for IMNs (74.5% vs 73.3%; p = 0.031) compared with SHSs. After adjustments, no significant difference in 30-day mortality was found (hazard rate ratio (HRR) 0.94 (95% confidence interval (CI) 0.86 to 1.02(; p = 0.146). IMNs exhibited higher mortality at 0 to 1 days (HRR 1.63 (95% CI 1.13 to 2.34); p = 0.009) compared with SHSs, with a NNH of 556, but lower mortality at 8 to 30 days (HRR 0.89 (95% CI 0.80 to 1.00); p = 0.043). No differences were observed in mortality at 2 to 7 days (HRR 0.94 (95% CI 0.79 to 1.11); p = 0.434), 90 days (HRR 0.95 (95% CI 0.89 to 1.02); p = 0.177), or 365 days (HRR 0.97 (95% CI 0.92 to 1.02); p = 0.192). This study found no difference in 30-day mortality between IMNs and SHSs. However, IMNs were associated with a higher mortality at 0 to 1 days and a marginally lower mortality at 8 to 30 days compared with SHSs. The observed differences in mortality were small and should probably not guide choice of treatment.

Daridorexant for patients with chronic insomnia disorder: number needed to treat, number needed to harm, and likelihood to be helped or harmed

ABSTRACT Objectives Appraise the evidence for daridorexant 50 mg and 25 mg versus placebo when treating chronic insomnia disorder in terms of number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Methods NNT, NNH, and LHH were calculated from a 3-month pivotal Phase 3 study (N = 930; randomized 1:1:1 to daridorexant 50 mg, daridorexant 25 mg, or placebo once nightly). Wakefulness after sleep onset, latency to persistent sleep, self-reported total sleep time, Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), and Insomnia Severity Index were used for the NNT efficacy analysis. NNH safety analysis was performed using rates of adverse events (AEs) occurring in >1% of the participants in any arm. LHH was assessed for all NNT estimates, contrasting them with NNH estimates for somnolence, headache, and fatigue AEs. Results NNT estimates for daridorexant 50 mg versus placebo were <10 for clinically meaningful thresholds across all outcomes. NNT estimates for daridorexant 25 mg versus placebo were not as robust as those observed for daridorexant 50 mg, with many values exceeding 10. NNH estimates for daridorexant 50 mg and 25 mg versus placebo did not show a statistically significant treatment difference except for falls, where NNH was negative for the daridorexant 50 mg group (−44 [95% CI −328; −21]; rate of falls was greater with placebo than for daridorexant 50 mg). All LHH ratios at Months 1 and 3 were >1 (except for daridorexant 25 mg for the IDSIQ alert/cognition domain), indicating that patients were more likely to respond to daridorexant 50 mg and 25 mg than to experience an AE of somnolence, headache, or fatigue. Conclusion Daridorexant 50 mg and 25 mg have a favorable benefit–risk ratio over 3 months. Daridorexant 50 mg demonstrated more robust (lower) NNT estimates versus placebo than daridorexant 25 mg.

The influence of perioperative enoxaparin on bleeding after TORS oropharyngectomy.

Perioperative enoxaparin is often avoided in patients undergoing transoral robotic (TORS) oropharyngectomy. Our goal was to quantify the risk of postoperative hemorrhage (POH) in patients receiving enoxaparin after TORS oropharyngectomy. This was a retrospective database cohort study set up in 89 separate healthcare organizations. The TriNetX electronic database was queried for patients with OPSCC who underwent TORS oropharyngectomy. Propensity-score matching was used to create two cohorts, one receiving and one not receiving perioperative enoxaparin. Outcome measures were the POH rate within 1day of surgery ("primary") and POH rate within 2-30days of surgery ("secondary"). 1109 patients undergoing TORS for OPSCC were identified, 400 of which received perioperative enoxaparin. One-to-one propensity score matching resulted in 310 patients per cohort. After matching, the primary POH rates between patients receiving and not receiving enoxaparin were 3.23% for both cohorts (OR 1.000, 95% CI 0.410 to 2.438). The secondary POH rates between those receiving and not receiving enoxaparin were 5.47% vs. 3.54% (OR 1.577, 95% CI 0.726 to 3.424). The number needed to harm (NNH) with perioperative enoxaparin use for secondary POH after TORS was 53; no difference was found in primary POH rates. While not statistically significant, the use of perioperative enoxaparin after TORS is associated with increased odds of secondary POH with a NNH of 53; no difference was found in rates of primary POH. For patients undergoing TORS, enoxaparin use requires careful weighing of the risks and benefits.

Comparison of Dual Antiplatelet Therapies for Minor, Nondisabling, Acute Ischemic Stroke: A Bayesian Network Meta-Analysis.

Dual antiplatelet therapy (DAPT) appears to be an effective treatment option for minor (nondisabling) acute ischemic stroke. This conclusion is based on trials that include both transient ischemic attack (TIA) and minor stroke; however, these 2 conditions may differ. To compare DAPT regimens specifically for minor stroke. PubMed was searched for randomized clinical trials published up to November 4, 2023. Search terms strategy included TIA, transient ischemic attack, minor stroke, or moderate stroke, with the filter randomized controlled trial. Unpublished data on minor stroke were sourced from authors and/or institutions. Trials testing DAPT within the first 24 hours of a minor stroke (defined as a National Institutes of Health Stroke Scale score ≤5) were included by consensus. Of 1508 studies screened, 6 (0.3%) initially met inclusion criteria and were reviewed. The study was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by multiple observers. Bayesian fixed-effect network meta-analysis was conducted. Secondary analysis performed for high-risk TIA alone. Treatments were ranked using a probability measure called surface under the cumulative rank curve (SUCRA). The primary outcome was subsequent ischemic stroke at 90 days. Secondary outcomes included major hemorrhage, mortality, and hemorrhagic stroke. The number needed to treat (NNT) and number needed to harm (NNH) were obtained. Five trials were included that described 28 148 patients, of whom 22 203 (78.9%) had a minor stroke. Of these, 13 995 (63.0%) were in DAPT groups and 8208 (37.0%) in aspirin (acetylsalicylic acid) groups. Aspirin and ticagrelor had a 94% probability of being the superior treatment for minor stroke (SUCRA, 0.94) for the primary outcome. Both aspirin and ticagrelor (NNT, 40; 95% CI, 31-64) and aspirin and clopidogrel (NNT, 58; 95% CI, 39-136) were superior to aspirin alone in the prevention of recurrent ischemic stroke at 90 days. Both treatments had higher rates of major hemorrhage than aspirin alone (NNH for aspirin and ticagrelor, 284; 95% CI, 108-1715 vs NNH for aspirin and clopidogrel, 330; 95% CI, 118-3430), but neither had increased risk of hemorrhagic stroke or death. For high-risk TIA, ticagrelor and aspirin had a 60% probability (SUCRA, 0.60) and clopidogrel and aspirin had a 40% probability (SUCRA 0.40) of being a superior treatment; neither was optimum, but both were superior to aspirin alone for the primary outcome. These findings suggest that DAPT with aspirin and ticagrelor has higher probability of being the superior treatment among patients with minor stroke when presence of CYP2C19 loss-of-function alleles has not been excluded. For patients with TIA, the superiority of aspirin and ticagrelor vs aspirin and clopidogrel was not demonstrated.

Efficacy and Safety of Combination Therapy with Low-Dose Rivaroxaban in Patients with Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objectives: To review the evidence on the effectiveness and safety of low-dose-rivaroxaban 2.5 mg twice daily (LDR) in patients with coronary artery disease (CAD) and/or peripheral artery disease (PAD) taking antiplatelets. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Efficacy endpoints were cardiovascular events (CVEs), myocardial infarction, stroke, all-cause, and cardiovascular death. Any, major, fatal bleeding, and intracranial hemorrhage (ICH) were safety endpoints. Numbers needed to treat (NNT), and numbers needed to harm (NNH) were also calculated. Results: Seven RCTs were included with 45,836 patients: 34,276 with CAD and 11,560 with PAD. Overall, 4247 CVEs and 3082 bleedings were registered. LDR in association with either any antiplatelet drug or aspirin (ASA) alone reduced the risk of CVEs (hazard ratio [HR] 0.86, 95% confidence interval [95%CI] 0.78-0.94) and ischemic stroke (HR 0.68, 95%CI 0.55-0.84). LDR + ASA increased the risk of major bleeding (HR 1.71, 95%CI 1.38-2.11) but no excess of fatal bleeding or ICH was found. The NNT to prevent one CVE for LDR + ASA was 63 (43-103) and the NNH to cause major bleeding was 107 (77-193). Conclusions: The combination of LDR with either antiplatelet drugs or low-dose aspirin reduces CVEs and ischemic stroke in patients with CAD/PAD. There was an increased risk of major bleeding but no excess of fatal or ICH was found. LDR seems to have a favorable net clinical benefit compared to ASA treatment alone.

Prioritizing patients for hip fracture surgery: the role of frailty and cardiac risk.

The number of patients with hip fractures continues to rise as the average age of the population increases. Optimizing outcomes in this cohort is predicated on timely operative repair. The aim of this study was to determine if patients with hip fractures who are frail or have a higher cardiac risk suffer from an increased risk of in-hospital mortality when surgery is postponed >24 h. All patients registered in the 2013-2021 TQIP dataset who were ≥65 years old and underwent surgical fixation of an isolated hip fracture caused by a ground-level fall were included. Adjustment for confounding was performed using inverse probability weighting (IPW) while stratifying for frailty with the Orthopedic Frailty Score (OFS) and cardiac risk using the Revised Cardiac Risk Index (RCRI). The outcome was presented as the absolute risk difference in in-hospital mortality. A total of 254,400 patients were included. After IPW, all confounders were balanced. A delay in surgery was associated with an increased risk of in-hospital mortality across all strata, and, as the degree of frailty and cardiac risk increased, so too did the risk of mortality. In patients with OFS ≥4, delaying surgery >24 h was associated with a 2.33 percentage point increase in the absolute mortality rate (95% CI: 0.57-4.09, p = 0.010), resulting in a number needed to harm (NNH) of 43. Furthermore, the absolute risk of mortality increased by 4.65 percentage points in patients with RCRI ≥4 who had their surgery delayed >24 h (95% CI: 0.90-8.40, p = 0.015), resulting in a NNH of 22. For patients with OFS 0 and RCRI 0, the corresponding NNHs when delaying surgery >24 h were 345 and 333, respectively. Delaying surgery beyond 24 h from admission increases the risk of mortality for all geriatric hip fracture patients. The magnitude of the negative impact increases with the patient's level of cardiac risk and frailty. Operative intervention should not be delayed based on frailty or cardiac risk.

Impact of Alcohol Consumption on Breast Cancer Incidence and Mortality: The Women's Health Study.

Background: Alcohol intake is associated with breast cancer (BC) risk, but estimates of greatest public health relevance have not been quantified in large studies with long duration. Materials and Methods: In this prospective cohort study of 39,811 women (median 25 years follow-up), we examined the association between alcohol consumption and BC incidence and mortality with adjusted hazard ratios (HRs), cubic splines, absolute risks, number needed to harm (NNH), and population-attributable fractions. Results: We documented 2,830 cases of BC, including 237 BC deaths. Each additional alcoholic drink/day was associated with a 10% higher rate (HR = 1.10, 95% confidence intervals [CIs]: 1.04-1.16) of total BC in a linear manner (p = 0.0004). The higher rate was apparent for estrogen receptor (ER)+ (HR = 1.12, 95% CI: 1.06-1.18) but not ER- tumors (HR = 0.95, 95% CI: 0.82-1.10), with a statistically significant difference between these associations (p = 0.03). We constructed models comparing BC incidence among 100,000 women followed for 10 years. Compared to a scenario where all women rarely or never consumed alcohol, we expect 63.79 (95% CI: 58.35-69.24) more cases (NNH = 1,567) had all women consumed alcohol at least monthly and 278.66 (95% CI: 268.70-288.62) more cases (NNH = 358) had all women consumed >1 drink/day. Approximately 4.1% of BC cases were attributable to consumption exceeding one drink/month. Conclusion: Alcohol consumption is associated with a linear dose-response increase in BC incidence even within recommended limits of up to one alcoholic drink/day, at least for ER+ tumors. Our estimates of risk differences, attributable fraction, and NNH quantify the burden that alcohol consumption imposes on women in the general population. ClinicalTrials.gov Identifier: NCT00000479.

Incremental Risk of Adverse Events with Oral Janus Kinase Inhibitor Use in Atopic Dermatitis and Other Indications: A Systematic Review and Meta-Analysis

Introduction: The number of treatment opportunities for patients with moderate-severe atopic dermatitis (AD) is increasing, however with varying treatment safety profiles. The safety profile of oral JAKis remains a concern because of their ubiquitous mechanism of action inhibiting many cytokines. Safety warnings for these products have combined data across indications, making it difficult to assess risk for specific populations.&#x0D; Objective: We aimed to estimate the incremental risk of pre-specified adverse events (AEs) per patient-year (PY) of oral JAKi compared with standard of care (SoC), incl. topical corticosteroids, biologic agents, and other treatments, among those with AD or with other diagnoses.&#x0D; Methods: A systematic literature review was conducted on 17 preselected AEs based on randomized controlled trials of oral JAKis.&#x0D; Meta-analyses (MA) estimated the incidence rate difference (IRD) for each AE between oral JAKis and SoC, both in AD and non-AD populations. Number needed to harm (NNH) was calculated as the inverse of the IRD for each AE. &#x0D; Results: We identified 82 studies, including 19 in AD population, for use in the MA.&#x0D; In the AD population, the estimated NNH in PY for acne was 5, indicating 1 additional acne event for every 5 patients treated with oral JAKis vs SoC per year. Moreover, the NNH was 33 for herpes zoster, 62 for anemia, 94 for serious adverse events (SAEs), and 452 for malignancies. In the non-AD population, the NNH was 52 for HZ, 56 for hyperlipidemia, 58 for SAEs, 113 for anemia, 153 for acne, and 254 for malignancies.&#x0D; Conclusions: The MA identified an increased risk with oral JAKis compared with SoC for multiple AEs, spanning from less to more severe AE, including malignancies in both AD and non-AD populations. As safety risks are observed in both the AD and non-AD populations, the use of oral JAKis should be carefully considered.

Regular use of paracetamol and risk of liver cancer: a prospective cohort study

BackgroundParacetamol induces hepatotoxicity and subsequent liver injury, which may increase the risk of liver cancer, but epidemiological evidence remains unclear. We conducted this study to evaluate the association between paracetamol use and the risk of liver cancer.MethodsThis prospective study included 464,244 participants free of cancer diagnosis from the UK Biobank. Incident liver cancer was identified through linkage to cancer and death registries and the National Health Service Central Register using the International Classification of Diseases (ICD)-10 codes (C22). An overlap-weighted Cox proportional hazards model was utilized to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of liver cancer associated with paracetamol use. The number needed to harm (NNH) was calculated at 10 years of follow-up.ResultsDuring a median of 12.6 years of follow-up, 627 cases of liver cancer were identified. Paracetamol users had a 28% higher risk of liver cancer than nonusers (HR 1.28, 95% CI 1.06–1.54). This association was robust in several sensitivity analyses and subgroup analyses, and the quantitative bias analysis indicated that the result remains sturdy to unmeasured confounding factors (E-value 1.88, lower 95% CI 1.31). The NNH was 1106.4 at the 10 years of follow-up.ConclusionThe regular use of paracetamol was associated with a higher risk of liver cancer. Physicians should be cautious when prescribing paracetamol, and it is recommended to assess the potential risk of liver cancer to personalize the use of paracetamol.

Comparative profiles of lubiprostone, linaclotide, and elobixibat for chronic constipation: a systematic literature review with meta-analysis and number needed to treat/harm

ObjectiveTo comprehensively evaluate the efficacy, safety, patient symptoms, and quality-of-life (QoL) of lubiprostone, linaclotide, and elobixibat as treatment for chronic constipation (CC).DesignSystematic literature review (SLR) and meta-analysis (MA). Literature searches were conducted on PubMed and Embase using the Ovid platform.MethodsSLR including randomized controlled trials (RCTs) and observational studies was conducted to identify the overall efficacy and safety of lubiprostone, linaclotide, and elobixibat. Thereafter, MA was performed using only RCTs. The number needed to treat (NNT) and number needed to harm (NNH) analyses were additionally conducted.Primary and secondary outcome measures The primary outcome was efficacy regarding change in spontaneous bowel movements. Secondary outcomes included safety, constipation-related symptoms, and QoL.ResultsTwenty-four studies met the inclusion criteria for the SLR: 17 RCTs, 4 observational studies, and 3 single-arm trials. Feasibility assessment for the MA resulted in 14 studies available for safety data analysis, and 8 available for efficacy analysis, respectively. Three drugs showed similar efficacy in the MA and NNT analysis. However, the NNH analysis revealed distinct safety profiles: lubiprostone, linaclotide, and elobixibat were linked to the highest risk of nausea, diarrhea, and abdominal pain, respectively.ConclusionThe current study provides an updated overview of the efficacy, safety, patient symptoms, and QoL of the three drugs with different mechanisms of action for CC treatment.The findings could help physicians adopt an individualized approach for treating patients with CC in clinical practice.

Atractylodes macrocephala-Paeonia lactiflora Class Formula for the Treatment of Irritable Bowel Syndrome: A Systematic Review With Meta-Analysis and Trial Sequential Analysis.

Previous meta-analyses suggested that Chinese herbal medicine (CHM) is effective for irritable bowel syndrome (IBS). Formulas with Atractylodes macrocephala and Paeonia lactiflora as the core pairs have been widely used by traditional Chinese medicine (TCM) practitioners for the treatment of IBS. We aimed to examine the efficacy and safety of the Atractylodes macrocephala-Paeonia lactiflora class formula (A-P CHM) for IBS through a meta-analysis and trial-sequential analysis (TSA). The protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023439087. We searched seven databases for data up to May 23, 2023. The primary outcome was global IBS symptom relief. The secondary outcomes included theIBS severity scoring system (IBS-SSS) score and treatment-related adverse events. The relative ratio (RR) (dichotomous variables), the standardized mean difference (SMD) (continuous variables), the number needed to treat (NNT), the number needed to harm (NNH), and the required information size (RIS) were calculated. Twenty-four eligible articles with 3,768 participants were included. Thirteen trials were at low risk of bias (RoB). Compared with placebo or Western medication, A-P CHM was associated with a significantly higher proportion of relief of global IBS symptoms. The TSA analysis verified the primary outcome. For the secondary outcome, the A-P CHM IBS-SSS score was lower than Western medication or placebo at the end of the treatment, which was further confirmed by the TSA analysis. We asserted that A-P CHM might be a potential candidate for patients with IBS, especially for IBS-D. It may provide a theoretical basis for future optimization of irritable bowel syndrome with diarrhea (IBS-D) herbal formulas. The overall certainty of the evidence was not high; more tightly designed randomized controlled trials (RCTs) are required in the future.

Association of Central Nervous System-Affecting Medications With Occurrence and Short-Term Mortality of Traumatic Brain Injury.

The use of medications commonly prescribed after traumatic brain injury (TBI) has been little studied before TBI. This study examined the association between the use of medications that affect the central nervous system (CNS) and the occurrence and short-term mortality of TBI. Mandatory Finnish registries were used to identify TBI admissions, fatal TBIs, and drug purchases during 2005-2018. Patients with TBI were 1:1 matched to nontrauma control patients to investigate the association between medications and the occurrence of TBI and 30-day mortality after TBI. Number needed to harm (NNH) was calculated for all medications. The cohort included 59 606 patients with TBI and a similar number of control patients. CNS-affecting drugs were more common in patients with TBI than in controls [odds ratio = 2.07 (2.02-2.13), P < .001)]. Benzodiazepines were the most common type of medications in patients with TBI (17%) and in controls (11%). The lowest NNH for the occurrence of TBI was associated with benzodiazepines (15.4), selective serotonin uptake inhibitors (18.5), and second-generation antipsychotics (25.8). Eight percent of the patients with TBI died within 30 days. The highest hazard ratios (HR) and lowest NNHs associated with short-term mortality were observed with strong opioids [HR = 1.41 (1.26-1.59), NNH = 33.1], second-generation antipsychotics [HR = 1.36 (1.23-1.50), NNH = 37.1], and atypical antidepressants [HR = 1.17 (1.04-1.31), NNH = 77.7]. Thirty-seven percent of patients with TBI used at least 1 CNS-affecting drug. This proportion was significantly higher than in the control population (24%). The highest risk and lowest NNH for short-term mortality were observed with strong opioids, second-generation antipsychotics, and atypical antidepressants. The current risks underscore the importance of weighing the benefits and risks before prescribing CNS-affecting drugs in patients at risk of head injury.