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Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.

ABSTRACT: BACKGROUND:People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction. METHODS:In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4?mg vs. pravastatin 40?mg for 52?weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension Assay technology to determine the effects of statins on key atherosclerosis and CVD pathways among PWH. 225 participants had specimens available for biomarker analysis pre- and post-baseline. FINDINGS:The mean age was 49.5?±?8.0 (mean?±?SD), LDL-C 155?±?25?mg/dl and CD4 count 620?±?243 cell/mm3. Among all participants, three proteins significantly decreased: tissue factor pathway inhibitor [TFPI; t-statistic?=?-6.38, FDR p-value<0.0001], paraoxonase 3 [PON3; t-statistic?=?-4.64, FDR p-value?=?0.0003], and LDL-receptor [LDLR; t-statistic?=?-4.45, FDR p-value?=?0.0004]; and two proteins significantly increased galectin-4 [Gal-4; t-statistic?=?3.50, FDR p-value?=?0.01] and insulin-like growth factor binding protein 2 [IGFBP-2; t-statistic?=?3.21, FDR p-value?=?0.03]. The change in TFPI was significantly different between the pitavastatin and pravastatin groups. Among all participants, change in TFPI related to the change in LDL-C (r?=?0.43, P?

SUBMITTER: Toribio M

PROVIDER: S-EPMC6156703 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.

Toribio Mabel M Fitch Kathleen V KV Stone Lauren L Zanni Markella V MV Lo Janet J de Filippi Chris C Sponseller Craig A CA Lee Hang H Grundberg Ida I Thompson Melanie A MA Aberg Judith A JA Grinspoon Steven K SK

EBioMedicine 20180831

<h4>Background</h4>People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction.<h4>Methods</h4>In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4 mg vs. pravastatin 40 mg for 52 weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension A ...[more]

PMID: 30174281

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Project description:OBJECTIVES:This study sought to determine whether coronary artery calcium (CAC) could be used to optimize statin allocation among individuals for whom trial-based evidence supports efficacy of statin therapy. BACKGROUND:Recently, allocation of statins was proposed for primary prevention of atherosclerotic cardiovascular disease (ASCVD) based on proven efficacy from randomized controlled trials (RCTs) of statin therapy, a so-called trial-based approach. METHODS:The study used data from MESA (Multi-Ethnic Study of Atherosclerosis) with 5,600 men and women, 45 to 84 years of age, and free of clinical ASCVD, lipid-lowering therapy, or missing information for risk factors at baseline examination. RESULTS:During 10 years' follow-up, 354 ASCVD and 219 hard coronary heart disease (CHD) events occurred. Based on enrollment criteria for 7 RCTs of statin therapy in primary prevention, 73% of MESA participants (91% of those >55 years of age) were eligible for statin therapy according to a trial-based approach. Among those individuals, CAC = 0 was common (44%) and was associated with low rates of ASCVD and CHD (3.9 and 1.7, respectively, per 1,000 person-years). There was a graded increase in event rates with increasing CAC score, and in individuals with CAC >100 (27% of participants) the rates of ASCVD and CHD were 18.9 and 12.7, respectively. Consequently, the estimated number needed to treat (NNT) in 10 years to prevent 1 event varied greatly according to CAC score. For ASCVD events, the NNT was 87 for CAC = 0 and 19 for CAC >100. For CHD events, the NNT was 197 for CAC = 0 and 28 for CAC >100. CONCLUSIONS:Most MESA participants qualified for trial-based primary prevention with statins. Among the individuals for whom trial-based evidence supports efficacy of statin therapy, CAC = 0 and CAC >100 were common and associated with low and high cardiovascular risks, respectively. This information may guide shared decision making aimed at targeting evidence-based statins to those who are likely to benefit the most.

Project description:BACKGROUND:The prevalence of diabetes mellitus continues to inexorably rise in the United States and throughout the world. Lower limb amputations are a devastating comorbid complication of diabetes mellitus. Osteomyelitis increases the risk of amputation fourfold and commonly presages death. Antimicrobial therapy for diabetic foot osteomyelitis (DFO) varies greatly, indicating that high quality data are needed to inform clinical decision making. Several small trials have indicated that the addition of rifampin to backbone antimicrobial regimens for osteomyelitis outside the setting of the diabetic foot results in 28 to 42% higher cure rates. METHODS/DESIGN:This is a prospective, randomized, double-blind investigation of the addition of 6 weeks of rifampin, 600 mg daily, vs. matched placebo (riboflavin) to standard-of-care, backbone antimicrobial therapy for DFO. The study population are patients enrolled in Veteran Health Administration (VHA), ages ≥18 and ≤ 89 years with diabetes mellitus and definite or probable osteomyelitis of the foot for whom an extended course of oral or intravenous antibiotics is planned. The primary endpoint is amputation-free survival. The primary hypothesis is that using rifampin as adjunctive therapy will lower the hazard rate compared with the group that does not use rifampin as adjunctive therapy. The primary hypothesis will be tested by means of a two-sided log-rank test with a 5% significance level. The test has 90% power to detect a hazard ratio of 0.67 or lower with a total of 880 study participants followed on average for 1.8 years. DISCUSSION:VA INTREPID will test if a rifampin-adjunctive antibiotic regimen increases amputation-free survival in patients seeking care in the VHA with DFO. A positive finding and its adoption by clinicians would reduce lower extremity amputations and their associated physical and emotional impact and reduce mortality for Veterans and for the general population with diabetic foot osteomyelitis. Given that rifampin-adjunctive regimens are currently employed for therapy for the majority of DFO cases in Europe, and only in a small minority of cases in the United States, the trial results will impact therapeutic decisions, even if the null hypothesis is not rejected. TRIAL REGISTRATION:Registered January 6, 2017 at ClinicalTrials.gov, NCT03012529.

Dataset Information

Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.

Publications

Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.

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