Efficacy and safety of LDL‐lowering therapy among men and women: meta‐analysis of individual data from 174,000 participants in 27 randomised trials

Background There has been debate about whether statin therapy is as effective in women as men, especially for primary prevention. Methods Meta‐analyses were performed on data from 22 trials of statin therapy vs. control (n=134 537) and five trials of more intensive vs. less intensive statin therapy (n=39 612). Effects on major vascular events, major coronary events, stroke, coronary revascularisation and mortality were weighted per 1∙0 mmol/L reduction in LDL cholesterol and effects in men and women compared using a Cox model that adjusted for non‐gender differences. For subgroup analyses, 99% confidence intervals were used to make allowance for the multiplicity of comparisons. Findings Overall, 46675 (27%) of 174,149 randomised participants were women. Allocation to a statin had similar absolute effects on 1‐year lipid concentrations in both men and women (LDL cholesterol reduced by ~1∙1mmol/L in statin vs. control trials and ~0∙5mmol/L in more vs. less trials). The proportional reductions per 1∙0 mmol/L reduction in LDL cholesterol in major vascular events were similar in women (RR 0∙84, 99% CI 0∙78‐0∙91) and men (RR 0∙78, 99% CI 0∙75‐0∙81), both overall (adjusted p value for heterogeneity by gender=0∙33) and among those at <10% predicted 5‐year risk (adjusted heterogeneity p=0∙11). Likewise, the proportional reductions in major coronary events, coronary revascularisation and stroke did not differ by gender. Since there were similar proportional reductions in vascular mortality in women (RR 0∙92, 99% CI 0∙82‐1∙03) and men (RR 0∙87, 99% CI 0∙82‐0∙92) (adjusted heterogeneity p=0∙84), but no apparent effect on non‐vascular deaths in either sex, all‐cause mortality was reduced in both women (RR 0∙91, 99% CI 0∙84‐0∙99) and men (RR 0∙90, 99% CI 0∙86‐0∙95). Interpretation Other things being equal, statin therapy is of comparable effectiveness for the prevention of major vascular events in women as in men, even among those at low risk of vascular disease

Efficacy and safety of LDL‐lowering therapy among men and women: meta‐analysis of individual data from 174,000 participants in 27 randomised trials

Background There has been debate about whether statin therapy is as effective in women as men, especially for primary prevention. Methods Meta‐analyses were performed on data from 22 trials of statin therapy vs. control (n=134 537) and five trials of more intensive vs. less intensive statin therapy (n=39 612). Effects on major vascular events, major coronary events, stroke, coronary revascularisation and mortality were weighted per 1∙0 mmol/L reduction in LDL cholesterol and effects in men and women compared using a Cox model that adjusted for non‐gender differences. For subgroup analyses, 99% confidence intervals were used to make allowance for the multiplicity of comparisons. Findings Overall, 46675 (27%) of 174,149 randomised participants were women. Allocation to a statin had similar absolute effects on 1‐year lipid concentrations in both men and women (LDL cholesterol reduced by ~1∙1mmol/L in statin vs. control trials and ~0∙5mmol/L in more vs. less trials). The proportional reductions per 1∙0 mmol/L reduction in LDL cholesterol in major vascular events were similar in women (RR 0∙84, 99% CI 0∙78‐0∙91) and men (RR 0∙78, 99% CI 0∙75‐0∙81), both overall (adjusted p value for heterogeneity by gender=0∙33) and among those at <10% predicted 5‐year risk (adjusted heterogeneity p=0∙11). Likewise, the proportional reductions in major coronary events, coronary revascularisation and stroke did not differ by gender. Since there were similar proportional reductions in vascular mortality in women (RR 0∙92, 99% CI 0∙82‐1∙03) and men (RR 0∙87, 99% CI 0∙82‐0∙92) (adjusted heterogeneity p=0∙84), but no apparent effect on non‐vascular deaths in either sex, all‐cause mortality was reduced in both women (RR 0∙91, 99% CI 0∙84‐0∙99) and men (RR 0∙90, 99% CI 0∙86‐0∙95). Interpretation Other things being equal, statin therapy is of comparable effectiveness for the prevention of major vascular events in women as in men, even among those at low risk of vascular disease

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

OBJECTIVE: To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. DESIGN: Collaborative meta-analyses (systematic overviews). INCLUSION CRITERIA: Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen. STUDIES REVIEWED: 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens. MAIN OUTCOME MEASURE: "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death. RESULTS: Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000. CONCLUSIONS: Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed

Will availability of inhaled human insulin (Exubera (R)) improve management of type 2 diabetes? The design of the Real World trial

Background: Common deterrents to insulin therapy for both physicians and patients are the complexity and burden of daily injections. In January 2006, the first inhaled human insulin (INH, Exubera(R) (insulinhuman [ rDNA origin]) InhalationPowder) was approved for use in adult patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) in the United States and European Union. Results from the INH clinical trial program have shown comparable efficacy of INH to subcutaneous (SC) insulin and superior efficacy versus oral antidiabetic agents; thus providing effective glycemic control in adult patients with T2DM without the requirement for preprandial injections. However, because subjects in those trials were randomized to either INH or an alternative, the studies could not estimate the effect of INH on patient acceptance of insulin therapy. Therefore, traditional study designs cannot provide answers to important and practical questions regarding real world effectiveness, which is influenced by psychological and other access barriers.Methods: To overcome these limitations, the Real World Trial was designed to estimate the effect of the availability of INH as a treatment option for glycemic control. A total of approximately 700 patients from Canada, France, Germany, Italy, Spain, United Kingdom, and the United States with T2DM poorly controlled by oral agent therapy will be randomized to two different treatment settings. Patients and clinicians in both groups ( A & B) may choose from all licensed therapies for diabetes including SC insulin delivered by pens; INH will be an additional treatment option only available in Group A. The Real World Trial ( Protocol A2171018) has been registered with ClincalTrials. gov, registration id NCT00134147.Results: The primary outcome for the trial will be the difference in mean glycosylated hemoglobin (HbA(1c)) at 6 months between groups. The design was based on a preceding feasibility study examining the theoretical effects of inhaled insulin availability on treatment choice in 779 patients. In that study, patients were three times more likely to choose insulin therapy when inhaled insulin was available.Conclusion: Innovations in study designs may provide an opportunity to reveal unbiased answers to important treatment questions that are more relevant to prescribers, funding agencies, and healthcare policymakers

Current misconception 3: that subgroup-specific trial mortality results often provide a good basis for individualising patient care

Misconceptions and ill-founded theories can arise in all areas of science. However, the apparent accessibility of many epidemiology findings and popular interest in the subject can lead to additional misunderstandings. The article below is the third in an occasional series of short editorials highlighting some current misinterpretations of epidemiological findings. Invited authors will be given wide scope in judging the prevalence of the misconception under discussion. We hope that this series will prove instructive to cancer researchers in other disciplines as well as to students of epidemiology. Adrian L Harris and Leo Kinle

Twelve-year outcomes of watchful waiting versus surgery of mildly symptomatic or asymptomatic inguinal hernia in men aged 50 years and older: a randomised controlled trial

Background: Inguinal hernia belongs to the most common surgical pathology worldwide. Approximately, one third is asymptomatic. The value of watchful waiting (WW) in patients with asymptomatic or mildly symptomatic inguinal hernia has been established in a few randomised controlled trials (RCTs). The aim of this study was to assess long-term outcomes of a RCT comparing WW and elective surgery. Methods: In the original study, men aged ≥50 years with an asymptomatic or mildly symptomatic inguinal hernia were randomly assigned to WW or elective repair. In the present study, the primary outcome was the 12-year crossover rate to surgery, secondary outcomes were time-to-crossover, patient regret, pain, quality of life and incarceration. Dutch Trial Registry: NTR629. Findings: Out of 496 originally analysed patients, 488 (98.4%) were evaluable for chart review (WW: n = 258, surgery: n = 230), and 200 (41.0%) for telephone contact (WW: n = 106, surgery: n = 94) between November 2021 and March 2022 with a median 12 years follow-up (IQR 9–14). After 12 years, the estimated cumulative crossover rate to surgery was 64.2%, which was higher in mildly symptomatic than in asymptomatic patients (71.7% versus 60.4%, HR 1.451, 95% CI: 1.064–1.979). Time-to-crossover was longer in asymptomatic patients (50% after 6.0 years versus 2.0 years, p = 0.019). Patient regret was higher in the WW group (37.7 versus 18.0%, p = 0.002), as well as pain/discomfort (p = 0.031). Quality of life did not differ (p = 0.737). In the WW group, incarceration occurred in 10/255 patients (3.9%). Interpretation: During 12-year follow-up, most WW patients crossed over to surgery, significantly earlier with mildly symptomatic hernia. Considering the relatively low incarceration rate, WW might still be an option in asymptomatic patients with a clear preference and being well-informed about pros and cons. Funding: The initial trial was funded by the Netherlands Organisation for Health Research and Development (ZonMW). This long-term study did not receive funding

Enhanced clarity and holism: The outcome of implementing the ICF with an acute stroke multidisciplinary team in England

This article is made available through the Brunel Open Access Publishing Fund.Purpose: Although it is recommended that the ICF (International Classification of Functioning, Disability and Health) should be implemented to aid communication within multidisciplinary stroke services, there is no empirical evidence to demonstrate the outcomes of such implementation. Working with one stroke service, this project aimed to address this gap and sought to evaluate the outcomes of implementing an ICF-based clinical tool into practice. Method: Using an action research framework with mixed methods, data were collected from individual interviews, a focus group, questionnaires, email communications, minutes from relevant meetings and field notes. Thematic analysis was undertaken, using immersion and crystallisation, to define overall themes. Descriptive statistics were used to analyse quantitative data. Data from both sources were combined to create key findings. Results: Three findings were determined from the data analysis. The ICF (1) fosters communication within and beyond the multidisciplinary stroke team; (2) promotes holistic thinking; and (3) helps to clarify team roles. Conclusions: The ICF enhanced clarity of communication and team roles within the acute stroke multidisciplinary team as well as with other clinicians, patients and their relatives. In addition, the ICF challenged stroke clinicians to think holistically, thereby appropriately extending their domain of concern beyond their traditional remit. Implications for Rehabilitation: (1) The ICF is a globally accepted framework to describe functioning and is in use in a variety of clinical settings. Yet, the outcomes of using it in clinical practice have yet to be fully explored. (2) This study found that the ICF enhanced clarity of communication and team roles within an acute stroke multidisciplinary team and to others beyond the team, including clinicians, patients and their relatives. (3) Using the ICF also challenged clinicians to think holistically about patient needs following a stroke.The Elizabeth Casson Trus