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Lipid-Lowering Trials Are Not Representative of Patients Managed in Clinical Practice: A Systematic Review and Meta-Analysis of Exclusion Criteria.

ABSTRACT: Background Randomized clinical trials (RCTs) might not be representative of the real-world population because of unreasonable exclusion criteria. We sought to determine which groups of patients are excluded from RCTs that included lipid-lowering therapy. Methods and Results We retrieved all trials from the Cholesterol Treatment Trialists Collaboration and systematically searched for large (≥1000 participants) lipid-lowering therapy RCTs, defined as statins, ezetimibe, and PCSK9 inhibitors. We predefined groups: older adults (>70 or >75 years), women, non-Whites, chronic kidney failure, heart failure, immunosuppression, cancer, dementia, treated thyroid disease, chronic obstructive pulmonary disease, mental illness, atrial fibrillation, multimorbidity (≥2 chronic diseases), and polypharmacy. We counted the number of RCTs excluding patients of the predefined groups and meta-analyzed the prevalence of included patients to obtain pooled estimates with a random-effects model. We included 42 RCTs (298 605 patients). Eighty-one percent of trials excluded patients with severe and 76% those with moderate kidney failure. Seventy-one percent of trials excluded groups of women, 64% excluded patients with moderate to severe heart failure, 64% those with immunosuppressant conditions, 48% those with cancer, 29% those with dementia, and 29% of trials excluded older adults. The pooled prevalence for patients >70 years of age was 25% (95% CI, 0%-49%), 11% (3%-18%) for >75 years of age, and 51% (38%-63%) for multimorbidity. Conclusions The majority of lipid-lowering therapy trials excluded patients with common diseases, such as moderate-to-severe kidney disease or heart failure or with immunosuppression. Underrepresenting certain populations, including women and older adults, might lead to limited transportability of study results and uncertainty on possible side-effects and efficacy in these groups. Future trials should promote diversity in the recruitment strategies and improve equity in cardiovascular research. Registration URL: ClinicalTrials.gov; Unique Identifier: CRD42021253909.

SUBMITTER: Aeschbacher-Germann M

PROVIDER: S-EPMC9973576 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Lipid-Lowering Trials Are Not Representative of Patients Managed in Clinical Practice: A Systematic Review and Meta-Analysis of Exclusion Criteria.

Aeschbacher-Germann Martina M Kaiser Nathalie N Speierer Alexandre A Blum Manuel R MR Bauer Douglas C DC Del Giovane Cinzia C Aujesky Drahomir D Gencer Baris B Rodondi Nicolas N Moutzouri Elisavet E

Journal of the American Heart Association 20221224 1

Background Randomized clinical trials (RCTs) might not be representative of the real-world population because of unreasonable exclusion criteria. We sought to determine which groups of patients are excluded from RCTs that included lipid-lowering therapy. Methods and Results We retrieved all trials from the Cholesterol Treatment Trialists Collaboration and systematically searched for large (≥1000 participants) lipid-lowering therapy RCTs, defined as statins, ezetimibe, and PCSK9 inhibitors. We pr ...[more]

PMID: 36565207

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Project description:BackgroundRandomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events.MethodsWe performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters.ResultsA total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non-high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non-high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76-0.82; P<0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76-0.85; P<0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75-0.94; P=0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76-0.83; P<0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81-1.006; P=0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91-0.95]; P<0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89-1.03]).ConclusionsIn randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.

Project description:ObjectiveTotal knee arthroplasty (TKA) rehabilitation trials use exclusion criteria, which may limit their generalizability in practice. We investigated whether patients seen in routine practice who meet common exclusion criteria recover differently from TKA compared to research-eligible patients. We hypothesized that research-ineligible patients would demonstrate poorer average postoperative function and slower rate of functional recovery compared to research-eligible patients.MethodsPatient characteristics and exclusion criteria were extracted and summarized from trials included in the three most recent systematic reviews of TKA rehabilitation. Trial participant characteristics were compared to a clinical dataset of patient outcomes collected in routine TKA rehabilitation. Where possible, individual exclusion criterion from the trials were applied to the clinical dataset to determine "eligible" and "ineligible" groups for research participation. Postoperative functional outcomes including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Timed Up and Go (TUG) were compared between "eligible" and "ineligible" groups using mixed effects models.Results2,528 participants from 27 trials were compared to 474 patients from the clinical dataset. Research participants were older, with lower Body Mass Index than patients in the clinical dataset. Many patients in the clinical dataset would be "ineligible" for research participation based upon common exclusion criteria from the trials. Differences were observed in average postoperative functioning between some "eligible" and "ineligible" groups in the clinical dataset. However, no differences were observed in functional recovery rate between groups, except for patients with diabetes whose TUG recovered more slowly than their "eligible" counterparts.ConclusionsMany patients in the clinical dataset were "ineligible" for research participation based upon common TKA rehabilitation trial exclusion criteria. However, the postoperative recovery rate did not differ between "eligible" and "ineligible" groups based on individual exclusion criterion-except for individuals with diabetes. This suggests that both clinical and research populations may recover similarly from TKA.

Project description:BackgroundKuding tea (KT), traditional tea material and widely used in China, has been found to have lipid-lowering effect in clinical and experimental studies. However, there has been no systematic review of the evidence on this subject.MethodsEight electronic databases were searched from database inception until September 2021 for relevant randomized controlled trials (RCTs). We used the Cochrane Reviewer's Handbook to assess the quality of the included studies. Weighted mean difference (WMD) and 95% confidence interval (CI) were used to measure the pooled effect size by random-effects model. Funnel plot, Egger regression test, and the Begg's test was used to assess publication bias.ResultsEight RCTs involving 716 patients were included in our meta-analysis. Comparing with the control group, KT group reduced serum total cholesterol (TC) levels (WMD: -0.56 mmol/L; 95% CI: -0.64, -0.47; I2 = 56.56%; P = 0.00), triglyceride (TG) levels (WMD: -0.30 mmol/L; 95% CI: -0.35, -0.24; I 2 = 88.60%; P = 0.00), and low-density lipoprotein cholesterol (LDL-C) levels (WMD: -0.29 mmol/L; 95% CI: -0.37, -0.21; I2 = 89.43%; P = 0.00), but no significant effects on high-density lipoprotein cholesterol (HDL-C) (WMD: 0.07 mmol/L; 95% CI: -0.02, 0.16; I 2 = 93.92%; P = 0.12). The results of sensitivity analysis were not altered after removing each study in turn. Subgroup analyses showed that KT intervention period was the source of heterogeneity. Following analysis, results revealed that long-term (>4 weeks and ≤8 weeks) use of KT increased HDL-C levels (WMD: 0.19; 95% CI: 0.13, 0.25). In addition, both the sensitivity analysis and subgroup analysis showed that our results were robust. No potentially significant publication bias was found from the funnel plot, Begg-Mazumdar correlation test and Egger regression test.ConclusionKT supplementation can effectively improve lipid profile and KT is a promising approach to reduce blood lipid level in patients with metabolic disorders.Systematic review registration[www.crd.york.ac.uk/prospero], identifier [CRD42020221850].

Project description:BackgroundDyslipidaemia is a major risk factor for coronary heart disease (CHD). Danhong and Huangqi injections, two traditional Chinese medicine prescriptions, have been widely studied regarding their lipid-lowering properties. However, the results were inconsistent and inconclusive. Thus, we conducted this meta-analysis of clinical controlled trials to clarify the lipid-lowering effects of Danhong and Huangqi injections.MethodsThe databases including PubMed, Google Scholar, Web of Science, Cochrane Library, Wanfang Database, CNKI and VIP were searched. The following information was obtained from each study: first author, age, gender, ethnicity, health condition, treatment dose, treatment duration, sample size, mean and standard deviation or standard error of lipid variables before and after treatment. The changes in lipid levels from pre- to post-treatment were calculated and compared between the control groups and the treatment groups in this meta-analysis.ResultsForty-four studies (5021 subjects) and 7 studies (542 subjects) were respectively identified for Danhong and Huangqi injections. Compared with the control groups, Danhong injection yielded a significant reduction in triglycerides (TG) [standardized mean difference (SMD) = - 0.76, 95% confidence interval (CI) = (- 0.91, - 0.61), P < 0.001], total cholesterol (TC) [SMD = - 1.29, 95% CI = (- 1.56, - 1.03), P < 0.001] and low-density lipoprotein cholesterol (LDL-C) [SMD = - 0.76, 95% CI = (- 0.93, - 0.59), P < 0.001], and a significant elevation in high-density lipoprotein cholesterol (HDL-C) [SMD = 0.70, 95% CI = (0.41, 0.98), P < 0.001]. Regarding Huangqi injection, it yielded a significant reduction in TC [SMD = - 1.13, 95% CI = (- 2.09, - 0.16), P = 0.02] and marginally in TG [SMD = - 1.27, 95% CI = (- 2.53, 0.00), P = 0.05] comparing with the control groups.ConclusionsDanhong injection can effectively decrease the plasma levels of TG, TC and LDL-C, and increase HDL-C levels. Huangqi injection also has significant effects on TG and TC reduction, but not as powerful as Danhong injection.

Dataset Information

Lipid-Lowering Trials Are Not Representative of Patients Managed in Clinical Practice: A Systematic Review and Meta-Analysis of Exclusion Criteria.

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Lipid-Lowering Trials Are Not Representative of Patients Managed in Clinical Practice: A Systematic Review and Meta-Analysis of Exclusion Criteria.

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