Anti-inflammatory Treatment and Cardiovascular Outcomes: Results of Clinical Trials.
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ABSTRACT:
SUBMITTER: Lorenzatti AJ
PROVIDER: S-EPMC8086421 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Conclusive data about cardiovascular toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) are sparse. We hypothesized that regular NSAID use is associated with increased risk for cardiovascular events in postmenopausal women, and that this association is stronger with greater cyclooxygenase (cox)-2 when compared with cox-1 inhibition.Postmenopausal women enrolled in the Women's Health Initiative were classified as regular users or nonusers of nonaspirin NSAIDs. Cox regression examined NSAID use as a time-varying covariate and its association with the primary outcome of total cardiovascular disease defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary analyses considered the association of selective cox-2 inhibitors (eg, celecoxib), nonselective agents with cox-2>cox-1 inhibition (eg, naproxen), and nonselective agents with cox-1>cox-2 inhibition (eg, ibuprofen) with the primary outcome. Overall, 160 801 participants were available for analysis (mean follow-up, 11.2 years). Regular NSAID use at some point in time was reported by 53 142 participants. Regular NSAID use was associated with an increased hazard for cardiovascular events versus no NSAID use (hazard ratio [HR], 1.10; 95% confidence interval, 1.06-1.15; P<0.001). Selective cox-2 inhibitors were associated with a modest increased hazard for cardiovascular events (hazard ratio, 1.13; 1.04-1.23; P=0.004 and celecoxib only: HR, 1.13; 1.01-1.27; P=0.031). Among aspirin users, concomitant selective cox-2 inhibitor use was no longer associated with increased hazard for cardiovascular events. There was an increased risk for agents with cox-2>cox-1 inhibition (HR, 1.17; 1.10-1.24; P<0.001 and naproxen only: HR, 1.22; 1.12-1.34; P<0.001). This harmful association remained among concomitant aspirin users. We did not observe a risk elevation for agents with cox-1>cox-2 inhibition (HR, 1.01; 0.95-1.07; P=0.884 and ibuprofen only: HR, 1.00; 0.93-1.07; P=0.996).Regular use of selective cox-2 inhibitors and nonselective NSAIDs with cox-2>cox-1 inhibition showed a modestly increased hazard for cardiovascular events. Nonselective agents with cox-1>cox-2 inhibition were not associated with increased cardiovascular risk.www.clinicaltrials.gov. Unique identifier: NCT00000611.
| S-EPMC4151243 | biostudies-literature
Project description:BackgroundThe cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD).ObjectiveTo determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH.MethodsCombined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged ≥65 years for TRUST (n=737) and ≥80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age.ResultsThe median [IQR] age was 75.0 [69.7-81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38± SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 ± 3.3 mIU/L in the placebo group, compared with 3.66 ± 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 μg. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41-1.25]), atrial fibrillation (HR 0.69 [0.32-1.52]), or heart failure (0.41 [0.13-1.35]), or all-cause mortality (HR 1.28 [0.54-3.03]), irrespective of history of CVD and age.ConclusionTreatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age.Clinical trial registration[ClinicalTrials.gov], identifier [NCT01660126] (TRUST); Netherlands Trial Register: NTR3851 (IEMO80+).
| S-EPMC8173189 | biostudies-literature
Project description:The prevalence of type 2 diabetes is catalyzing a pandemic in kidney disease, with ensuing cardiovascular complications. The effort to identify antidiabetic agents capable of promoting benefits that go beyond the bounds of glucose control has produced remarkable outcomes in recent cardiovascular outcomes trials in patients with type 2 diabetes mellitus, many of whom have diabetic kidney disease. Two novel antidiabetic drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), improve cardiovascular outcomes in different ways, with SGLT2is reducing the risk of heart failure and cardiovascular death and GLP-1 RAs being associated with reduced risk of myocardial infarction and cardiovascular death. Further mechanistic studies and additional cardiovascular outcome trials are ongoing and are expected to determine whether these benefits are a result of class effect, as well as to delineate optimum timing for intervention and population target.
| S-EPMC6336216 | biostudies-literature
Project description:Background Survival and health status (eg, symptoms and quality of life) are key outcomes in clinical trials of heart failure treatment. However, health status can only be recorded on survivors, potentially biasing treatment effect estimates when there is differential survival across treatment groups. Joint modeling of survival and health status can address this bias. Methods and Results We analyzed patient-level data from the PARTNER 1B trial (Placement of Aortic Transcatheter Valves) of transcatheter aortic valve replacement versus standard care. Health status was quantified with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 1, 6, and 12 months. We compared hazard ratios for survival and mean differences in KCCQ scores at 12 months using several models: the original growth curve model for KCCQ scores (ignoring death), separate Bayesian models for survival and KCCQ scores, and a Bayesian joint longitudinal-survival model fit to either 12 or 30 months of survival follow-up. The benefit of transcatheter aortic valve replacement on 12-month KCCQ scores was greatest in the joint-model fit to all survival data (mean difference, 33.7 points; 95% credible intervals [CrI], 24.2-42.4), followed by the joint-model fit to 12 months of survival follow-up (32.3 points; 95% CrI, 22.5-41.5), a Bayesian model without integrating death (30.4 points; 95% CrI, 21.4-39.3), and the original growth curve model (26.0 points; 95% CI, 18.7-33.3). At 12 months, the survival benefit of transcatheter aortic valve replacement was also greater in the joint model (hazard ratio, 0.50; 95% CrI, 0.32-0.73) than in the nonjoint Bayesian model (0.54; 95% CrI, 0.37-0.75) or the original Kaplan-Meier estimate (0.55; 95% CI, 0.40-0.74). Conclusions In patients with severe symptomatic aortic stenosis and prohibitive surgical risk, the estimated benefits of transcatheter aortic valve replacement on survival and health status compared with standard care were greater in joint Bayesian models than other approaches.
| S-EPMC6579042 | biostudies-literature
Project description:Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti-cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven randomised controlled trials (RCTs) involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD)=0.40, 95% confidence interval (CI), 0.22-0.59). Anti-tumour necrosis factor drugs were most commonly studied (five RCTs); SMD=0.33 (95% CI; 0.06-0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD=0.19 (95% CI, 0.00-0.37) and 0.51 (95% CI, 0.34-0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (P=0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.
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Project description:The randomized, double-blind, cardiovascular outcomes trials LEADER (NCT01179048) and SUSTAIN 6 (NCT01720446) showed cardiovascular risk reduction in patients with type 2 diabetes treated with liraglutide and semaglutide, respectively, compared with placebo. This post hoc analysis examined the impact of microvascular disease at baseline on cardiovascular outcomes in these trials, and the efficacy of liraglutide (1.8 mg) and once-weekly semaglutide (0.5-1.0 mg) in patients with and without microvascular disease. In total, 9340 patients from LEADER and 3297 patients from SUSTAIN 6 were included in this analysis; of these, 5761 and 2356 had a history of microvascular disease at baseline and 3835 and 1640 had a history of both microvascular and macrovascular disease, respectively. Patients with microvascular disease were shown to have an increased risk of major adverse cardiovascular events compared with patients without microvascular disease (hazard ratio [95% confidence interval] in LEADER: 1.15 [1.03; 1.29], P =?.0136; SUSTAIN 6: 1.56 [1.14; 2.17], P =?.0064). Liraglutide and semaglutide consistently reduced cardiovascular risk in patients with and without microvascular disease.
| S-EPMC7689837 | biostudies-literature
Project description:During a recent Food and Drug Administration workshop on clinical trials to evaluate new TB drugs, questions were raised regarding the use of bacteriologic endpoints such as treatment failure and relapse as measures of improvement in health status and long term outcome after treatment. FDA scientists asked how patients' clinical signs and symptoms changed during therapy, noting that while such information is usually collected during clinical trials, it is not often reported. We analyzed data from an international phase 3 TB treatment trial that included systematic assessments of symptoms. The percentage of subjects with self-reported symptoms at baseline ranged from 30% for dyspnea to 81% for cough, with 51% reporting fever. During therapy, fever, sweats, and dyspnea decreased most rapidly, with near resolution by the end of therapy. Chest pain and cough resolved more slowly; 13% of subjects reported cough at six months. Symptom resolution during treatment did not differ between those who relapsed and those who did not. Among those with microbiological relapse, symptoms returned with significant increases in the proportion with fever, cough, and chest pain. At the time of relapse, cough was the most frequent symptom, occurring in 75% of subjects who relapsed but only 12% of those who did not. Our data support the continued use of bacteriologic endpoints based on sputum culture as surrogate measures of the relief of symptoms, improvement in health status and favorable long term treatment outcome in TB drug trials.
| S-EPMC3215825 | biostudies-literature
Project description:BackgroundWhether or not toxicity predicts clinical outcomes has long been a question regarding cancer treatments. While prior studies have focused on specific cancers, therapies, and toxicities, no comprehensive evidence exists on whether treatment toxicity predicts favorable outcomes.MethodsWe abstracted treatment toxicity and clinical outcome data from a sample of phase III oncology randomized clinical trials (n = 99 trials). We investigated whether treatments with relatively greater toxicity compared with their controls had relatively higher, lower, or equivocal rates of clinical efficacy, measured by progression-free survival (PFS) and overall survival (OS). Several toxicities were assessed (all grades, grades III/IV, cutaneous rash, gastrointestinal toxicity, and myelosuppression).ResultsToxicity and efficacy were greater among treatments than controls (e.g. 3.5 instances of all-grade toxicity per patient in treatment arms versus 2.8 instances in controls, P < 0.001; mean PFS of 9.1 months across treatment arms versus 7.1 months across controls, P < 0.001; mean OS of 18.6 months across treatment arms versus 16.9 months across controls, P < 0.001). Across trials, greater relative treatment toxicity was strongly associated with greater PFS in treatments versus controls (P < 0.001), but not OS (P = 0.44). Although higher relative rates of myelosuppression and cutaneous rash among treatments were not associated with greater treatment efficacy, greater relative gastrointestinal toxicity among treatments was associated with greater relative PFS compared with controls (P = 0.007).ConclusionAcross trials, treatments with relatively greater all-grade toxicity compared with controls are associated with relatively greater PFS but not OS.
| S-EPMC4207731 | biostudies-literature
Project description:Patient-reported outcomes (PROs) are reports of a person's health status that provide a global perspective of patient well-being. PROs can be classified into 4 primary domains: global, mental, physical, and social health. In this descriptive review, we focus on how PROs can be used in cardiac clinical trials, with an emphasis on cardiac surgical trials for patients with coronary heart disease and heart failure. We also highlight ongoing challenges and provide specific suggestions and novel opportunities to advance cardiac clinical trials. Current challenges include the long-term measurement of PROs in clinical trials beyond 1 year, inconsistency in the choice of the outcome measures among studies, and the lack of measurement of PROs across multiple domains. Opportunities for advancement include measuring PROs using consumer health informatics tools, including returning information back to participants in formats that they can understand using visualization. Future opportunities include quantifying cohort-specific minimal clinically important differences for PROs.
| S-EPMC8487900 | biostudies-literature
Project description:AimsThese recommendations aim to improve care for patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk in Central and Eastern Europe. Cardiovascular disease (CVD) and/or chronic kidney disease (CKD) are major interdependent comorbidities in patients with T2D, accounting for 50% of mortality. Following recent CV outcomes trial (CVOT) results, including those from EMPA-REG OUTCOME®, LEADER®, SUSTAIN™-6 and, most recently, the CANVAS study, it is essential to develop regional expert consensus recommendations to aid physicians in interpreting these newest data to clinical practice.MethodsThe Central and Eastern European Diabetes Expert Group (CEEDEG) followed a Delphi method to develop treatment algorithms to aid physicians in the clinical management of patients with T2D at high CV risk.ResultsIn light of the latest CVOT results, and in particular the EMPA-REG OUTCOME® and LEADER® trials, the diagnosis, assessment, treatment choice and monitoring of patients with T2D and established CVD and/or CKD have been considered together with existing guidelines and presented in two reference algorithms. In addition, adherence, special prescribing considerations and a proposed multidisciplinary management approach have been discussed and are presented with the proposed algorithms.ConclusionsThe latest available high-level evidence on glucose-lowering drugs has enabled CEEDEG to develop practical consensus recommendations for patients with established CVD and/or CKD. These recommendations represent an update to international and country-level guidelines used for these patients, with the aim of providing a resource not only to endocrinologists, but to cardiologists, nephrologists and primary care physicians in the region.
| S-EPMC5654048 | biostudies-literature