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Background: Despite using identical evidence to support practice guidelines for lipid-lowering treatment in primary prevention of cardiovascular disease (CVD), it is unclear to what extent the 2018 American Heart Association/American College of Cardiology/Multisociety, 2016 US Preventive Services Task Force (USPSTF), 2020 Department of Veterans Affairs/Department of Defense, 2021 Canadian Cardiovascular Society, and 2019 European Society of Cardiology/European Atherosclerosis Society guidelines differ in grading and assigning levels of evidence and classes of recommendations (LOE/class) at a population level.Methods: We included 7262 participants, aged 45 to 75 years, without history of CVD from the prospective population-based Rotterdam Study. Per guideline, proportions of the population recommended statin therapy by LOE/class, sensitivity and specificity for CVD events, and numbers needed to treat at 10 years were calculated.Results: Mean age was 61.1 (SD 6.9) years; 58.2% were women. American Heart Association/American College of Cardiology/Multisociety, USPSTF, Department of Veterans Affairs/Department of Defense, Canadian Cardiovascular Society, and European Society of Cardiology/European Atherosclerosis Society strongly recommended statin initiation in respective 59.4%, 40.2%, 45.2%, 73.7%, and 42.1% of the eligible population based on high-quality evidence. Sensitivity for CVD events for treatment recommendations supported with strong LOE/class was 86.3% for American Heart Association/American College of Cardiology/Multisociety (IA or IB), 69.4% for USPSTF (USPSTF-B), 74.5% for Department of Veterans Affairs/Department of Defense (strong for), 93.3% for Canadian Cardiovascular Society (strong), and 66.6% for European Society of Cardiology/European Atherosclerosis Society (IA). Specificity was highest for the USPSTF at 45.3% and lowest for European Society of Cardiology/European Atherosclerosis Society at 10.0%. Estimated numbers needed to treat at 10 years for those with the strongest LOE/class were ranging from 20 to 26 for moderate-intensity and 12 to 16 for high-intensity statins.Conclusions: Sensitivity, specificity, and numbers needed to treat at 10 years for assigned LOE/class varied greatly among 5 CVD prevention guidelines. The level of variability seems to be driven by differences in how the evidence is graded and translated into LOE/class underlying the treatment recommendations by different professional societies. Efforts towards harmonizing evidence grading systems for clinical guidelines in primary prevention of CVD may reduce ambiguity and reinforce updated evidence-based recommendations. [ABSTRACT FROM AUTHOR]

It is generally believed that pharmacologic prophylaxis for venous thromboembolism (VTE) is underused. However, previous studies have not shown associations between increased prophylaxis administration and reductions in VTE. We here investigated prophylaxis administration and VTE incidence among trauma patients at our facility to determine whether to further increase prophylaxis administration after implementation of a standardized monitoring protocol. Univariate analyses and regression models were used to evaluate the protocol's effect on VTE, identify clinical factors associated with VTE and with receiving prophylaxis, and identify over- or under-prophylaxed patients. A final prophylaxis rate of 71.2% was achieved, an increase from the 40.8% reported by the Trauma Quality Improvement Program in 2015, with no accompanying reduction in VTE (1.5% pre and postintervention). Factors that identified patients at lower probability of receiving prophylaxis were those that increased bleeding risk: severe head injuries (odds ratio [OR] 5 0.13) and preexisting bleeding (OR5 0.69) and renal/kidney (OR 50.46) disorders. A large group of patients was both at increased odds of receiving prophylaxis and at low risk of VTE, representing a group that may be considered for nonpharmacologic options. Examination of current prophylaxis practices and identification of underuse or overuse is beneficial before expending effort to increase prophylaxis administration to reduce VTE. [ABSTRACT FROM AUTHOR]

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 (Pinteraction 0.087 for HR; Pheterogeneity 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 (Pinteraction=0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative (Pinteraction=0.04) and absolute VTE reduction (Pheterogeneity=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. [ABSTRACT FROM AUTHOR]

Multiple recent pharmacological clinical trials in neuropathic pain have failed to show beneficial effect of drugs with previously demonstrated efficacy, and estimates of drug efficacy seems to have decreased with accumulation of newer trials. However, this has not been systematically assessed. Here, we analyze time-dependent changes in estimated treatment effect size in pharmacological trials together with factors that may contribute to decreases in estimated effect size. This study is a secondary analysis of data from a previous published NeuPSIG systematic review and meta-analysis, updated to include studies published up till March 2017. We included double-blind, randomized, placebo-controlled trials examining the effect of drugs for which we had made strong or weak recommendations for use in neuropathic pain in the previously published review. As the primary outcome, we used an aggregated number needed to treat for 50% pain reduction (alternatively 30% pain reduction or moderate pain relief). Analyses involved 128 trials. Number needed to treat values increased from around 2 to 4 in trials published between 1982 and 1999 to much higher (less effective) values in studies published from 2010 onwards. Several factors that changed over time, such as larger study size, longer study duration, and more studies reporting 50% or 30% pain reduction, correlated with the decrease in estimated drug effect sizes. This suggests that issues related to the design, outcomes, and reporting have contributed to changes in the estimation of treatment effects. These factors are important to consider in design and interpretation of individual study data and in systematic reviews and meta-analyses. [ABSTRACT FROM AUTHOR]

Abstract: Randomized, double-blind, placebo-controlled trials on neuropathic pain treatment are accumulating, so an updated review of the available evidence is needed. Studies were identified using MEDLINE and EMBASE searches. Numbers needed to treat (NNT) and numbers needed to harm (NNH) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions. One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients. [ABSTRACT FROM AUTHOR]

Abstract: Understanding a change score is indispensable for interpretation of results from clinical studies. One way of determining the relevance of change scores is through the use of transition questions that assesses patients’ retrospective perception of treatment effect. Unfortunately, results from studies using transition questions are difficult to compare since wording of questions and definitions of important improvements vary between studies. The objectives of this study were to determine the consequence of using different transition questions on pain and disability measures and make proposals for a standardised use of such questions. Two hundred and thirty-three patients with low back pain and/or leg pain were recruited. Participants were followed over an 8-week period and randomised to two groups receiving a 7- (TQ1) and 15-point (TQ2) transition question, respectively, in addition to a numeric rating scale evaluating the importance of the perceived change. Four external criteria were generated using both stringent and less stringent standards to dichotomise patients. Discrimination was determined using area under the receiver operating characteristic curve (ROCauc) and responsiveness using standardised response mean (SRM). Results demonstrated small variations in ROCauc across the external criteria for all outcome measures. 7% more patients were classified as improved in the group receiving the 15-point TQ compared to the 7-point TQ (stringent standard). SRMs were higher for the retrospective TQs in primary sector patients compared to the serial measures with no difference between TQ1 and TQ2. On the basis of our findings we have outlined a proposal for a standardised use of transition questions. [Copyright &y& Elsevier]

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 <0.50, surgical LER, and longer target lesion length were associated with increased risk of ALI. Incident ALI was associated with subsequent all-cause mortality (hazard ratio [HR], 2.59 [95% CI, 1.98-3.39]) and major amputation (HR, 24.87 [95% CI, 18.68-33.12]). Rivaroxaban reduced ALI relative to placebo by 33% (absolute risk reduction, 2.6% at 3 years; HR, 0.67 [95% CI, 0.55-0.82]; 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.

The article offers insight on the association of shared decision making with the increased cardiovascular mortality and morbidity. Topics discussed include an overview of preventive medications, the increased population of cardiovascular patients' morbidity and mortality, and the existing trend in shared decision making in relation to the issue.

Physicians are legally and ethically compelled to present their patients with available evidence on the potentially beneficial and harmful effects of a proposed medical or surgical treatment. This, however, is only half the story. It does not offer the patient a clear view of the pros and cons of one treatment option versus another, or even versus no treatment at all. Explicitly stating the number of patients who will not benefit from the proposed treatment, in combination with the risk of a complication, may better inform patients and help them determine and express their treatment preference. This may also help standardize the informed consent procedure.

Study Design: Single blinded, randomized clinical trial for the evaluation of lumbosacral orthoses (LSOs) in the management of lower back pain (LBP)., Objective: To evaluate the effects of two types of LSOs on self-rated disability in patients with LBP., Summary of Background Data: LSOs are commonly used for the management of LBP, but their effectiveness may vary because of design. An inextensible LSO (iLSO) reduces trunk motion and increases trunk stiffness, whereas an extensible LSO (eLSO) does not., Methods: A total of 98 participants with LBP were randomized to 3 groups: (1) standard care (SC) group, which included medication and physical therapy (n = 29), (2) SC with eLSO (eLSO group) (n = 32), and (3) SC with iLSO (iLSO group) (n = 37). Outcome measures were evaluated before and after 2 weeks of treatment: modified Oswestry Disability Index (ODI), Patient Specific Activity Scale, pain ratings, and Fear Avoidance Beliefs Questionnaire., Results: There were no statistically significant differences between groups at baseline. Compared with the SC alone, iLSO group showed greater improvement on the ODI scores (P = 0.01) but not the eLSO group. The ODI scores improved by a mean of 2.4 (95% confidence interval [CI], 2.2-7.1), 8.1 (95% CI, 2.8-13.4), and 14.0 (95% CI, 8.2-19.8) points for SC, eLSO, and iLSO groups, respectively. Individuals wearing the iLSO had 4.7 times higher odds of achieving 50% or greater improvement in the ODI scores than those assigned to SC (95% CI, 1.2-18.5, P = 0.03). Both the eLSO and iLSO groups had a greater improvement in the Patient Specific Activity Scale scores than the SC group (P = .05 and P = 0.01, respectively), but the change did not meet the minimal clinically important difference. Pain ratings improved for all 3 groups, with no statistical difference between them. Finally, no significant differences across groups were found for the Fear Avoidance Beliefs Questionnaire., Conclusion: An iLSO led to greater improvement in ODI scores than SC and an eLSO. We surmise that the likely mechanism responsible for this difference in outcome was the added trunk stiffness and motion restriction by the iLSO., Level of Evidence: 2.

Purpose: Gait retraining, comprising biofeedback and/or an exercise intervention, might reduce the risk of musculoskeletal conditions. The purpose was to examine the effect of a gait-retraining program on medial tibial stress syndrome incidence during a 26-wk basic military training regimen., Methods: A total of 450 British Army recruits volunteered. On the basis of a baseline plantar pressure variable (mean foot balance during the first 10% of stance), participants classified as at risk of developing medial tibial stress syndrome (n = 166) were randomly allocated to an intervention (n = 83) or control (n = 83) group. The intervention involved supervised gait retraining, including exercises to increase neuromuscular control and flexibility (three sessions per week) and biofeedback enabling internalization of the foot balance variable (one session per week). Both groups continued with the usual military training regimen. Diagnoses of medial tibial stress syndrome over the 26-wk regimen were made by physicians blinded to the group assignment. Data were modeled in a survival analysis using Cox regression, adjusting for baseline foot balance and time to peak heel rotation., Results: The intervention was associated with a substantially reduced instantaneous relative risk of medial tibial stress syndrome versus control, with an adjusted HR of 0.25 (95% confidence interval, 0.05-0.53). The number needed to treat to observe one additional injury-free recruit in intervention versus control at 20 wk was 14 (11 to 23) participants. Baseline foot balance was a nonspecific predictor of injury, with an HR per 2 SD increment of 5.2 (1.6 to 53.6)., Conclusions: The intervention was effective in reducing incidence of medial tibial stress syndrome in an at-risk military sample.

Background: In this manuscript we will present several evidence-based medicine concepts and tools that can be helpful to the clinician seeking answers to clinical questions. The clinical scenario used to demonstrate these concepts is one of the substantial current controversy in pediatric orthopaedics, that is the efficacy of bracing in adolescent idiopathic scoliosis. We hope to provide some important information about how to search and interpret the current literature on bracing but also to discuss the concepts related to "surrogate outcomes" and the "number needed to treat," which we believe are increasingly important in this era of evidence-based medicine., Methods: We performed a structured literature review of scoliosis bracing and also a separate analysis of the number needed to treat (NNT) for preventing surgery in adolescent idiopathic scoliosis., Results: Bracing for idiopathic scoliosis significantly reduces the rate of curve progression more than 6 degrees. However, the applicability of the 6-degree surrogate outcome compared with a more important outcome such as progression to surgery is doubtful. Bracing may decrease the risk of progression to surgery although the confidence intervals are large. The NNT for routine scoliosis bracing is about 9 patients for each surgery prevented. The NNT for patients highly compliant with bracing is about 4. We caution that these NNTs are derived from nonrandomized cohorts, and the true values from quality randomized controlled studies may be substantially different. There is no evidence for any particular brace over another although rigid bracing seems better than SpineCor bracing from 1 small randomized controlled study., Conclusions: Systematic reviews support bracing's ability to prevent curve progression of 6 degrees but not for preventing surgery. Analysis of a patient cohort does support bracing's ability to prevent surgery with NNT of 9 for all patients and 4 for highly compliant patients., Level of Evidence: Systematic review-therapeutic level 2. Cohort analysis-therapeutic level 2.