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Association of Optimal Combination Drug Treatment with Obesity Status among Recent Ischemic Stroke Patients: Results of the Vitamin Intervention for Stroke Prevention (VISP) Trial.

ABSTRACT: One explanation for the 'obesity paradox', where obese patients seem to have better cardiovascular outcomes than lean patients, is that obese patients display an identifiable high cardiovascular risk phenotype that may lead to receiving or seeking earlier/more aggressive treatment.We analyzed a clinical trial dataset comprising 3643 recent (<120 days) ischemic stroke patients followed up for 2 years. Subjects were categorized as lean (body mass index [BMI], <25 kg/m2, n=1,006), overweight (25-29.9 kg/m2, n=1,493), or obese (?30 kg/m2, n=1,144). Subjects were classified as level 0 to III depending on the number of secondary prevention prescriptions divided by the number of potentially indicated drugs (0=none of the indicated medications and III=all indicated medications as optimal combination drug treatment [OCT]). Independent associations between each BMI category and stroke/myocardial infarction/vascular death (major vascular events [MVEs]) and all-cause death were assessed.MVEs occurred in 17.4% of lean, 16.1% of overweight, and 17.1% of obese patients; death occurred in 7.3%, 5.5%, and 5.1%, respectively. Individuals with a higher BMI status received more OCT (45.8%, 51.7%, and 55.3%, respectively; P<0.001). In the lean patient group, multivariable adjusted Cox analyses, showed that compared with levels 0-I, level II and level III were linked to lower risk of MVEs (hazard ratio [HR] 0.55; 95% confidence interval [CI]: 0.32-0.95 and HR 0.48; 95% CI: 0.28-0.83, respectively) and death (0.44; 0.21-0.96 and 0.23; 0.10-0.54, respectively).OCT for secondary prevention after an ischemic stroke is less frequent in lean (vs. obese) subjects, but when implemented is related to significantly better clinical outcomes.

SUBMITTER: Park JH

PROVIDER: S-EPMC5466287 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other

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Association of Optimal Combination Drug Treatment with Obesity Status among Recent Ischemic Stroke Patients: Results of the Vitamin Intervention for Stroke Prevention (VISP) Trial.

Park Jong-Ho JH Lee Juneyoung J Ovbiagele Bruce B

Journal of stroke 20170531 2

<h4>Background and purpose</h4>One explanation for the 'obesity paradox', where obese patients seem to have better cardiovascular outcomes than lean patients, is that obese patients display an identifiable high cardiovascular risk phenotype that may lead to receiving or seeking earlier/more aggressive treatment.<h4>Methods</h4>We analyzed a clinical trial dataset comprising 3643 recent (<120 days) ischemic stroke patients followed up for 2 years. Subjects were categorized as lean (body mass inde ...[more]

PMID: 28592783

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Project description:BackgroundB vitamins play an important role in homocysteine metabolism, with vitamin deficiencies resulting in increased levels of homocysteine and increased risk for stroke. We performed a genome-wide association study (GWAS) in 2,100 stroke patients from the Vitamin Intervention for Stroke Prevention (VISP) trial, a clinical trial designed to determine whether the daily intake of high-dose folic acid, vitamins B6, and B12 reduce recurrent cerebral infarction.MethodsExtensive quality control (QC) measures resulted in a total of 737,081 SNPs for analysis. Genome-wide association analyses for baseline quantitative measures of folate, Vitamins B12, and B6 were completed using linear regression approaches, implemented in PLINK.ResultsSix associations met or exceeded genome-wide significance (P ≤ 5 × 10(-08)). For baseline Vitamin B12, the strongest association was observed with a non-synonymous SNP (nsSNP) located in the CUBN gene (P = 1.76 × 10(-13)). Two additional CUBN intronic SNPs demonstrated strong associations with B12 (P = 2.92 × 10(-10) and 4.11 × 10(-10)), while a second nsSNP, located in the TCN1 gene, also reached genome-wide significance (P = 5.14 × 10(-11)). For baseline measures of Vitamin B6, we identified genome-wide significant associations for SNPs at the ALPL locus (rs1697421; P = 7.06 × 10(-10) and rs1780316; P = 2.25 × 10(-08)). In addition to the six genome-wide significant associations, nine SNPs (two for Vitamin B6, six for Vitamin B12, and one for folate measures) provided suggestive evidence for association (P ≤ 10(-07)).ConclusionOur GWAS study has identified six genome-wide significant associations, nine suggestive associations, and successfully replicated 5 of 16 SNPs previously reported to be associated with measures of B vitamins. The six genome-wide significant associations are located in gene regions that have shown previous associations with measures of B vitamins; however, four of the nine suggestive associations represent novel finding and warrant further investigation in additional populations.

Project description:<p>The VISP trial (PI Jim Toole, M.D., Wake Forest University School of Medicine) was a multi-center, double-blind, randomized, controlled clinical trial that enrolled patients aged 35 or older with Hcy levels above the 25th percentile at screening and a non-disabling cerebral infarction (NDCI) within 120 days of randomization [Toole, 2002]. The trial was designed to determine if daily intake of a multivitamin tablet with high dose folic acid, vitamin B6 and vitamin B12 reduced recurrent cerebral infarction (primary endpoint), and nonfatal myocardial infarction (MI) or mortality (secondary endpoints). Subjects were randomly assigned to receive daily doses of the high-dose formulation (n=1,827), containing 25mg pyridoxine (B6), 0.4mg cobalamin (B12), and 2.5mg folic acid; or the low-dose formulation (n=1,853), containing 200µg pyridoxine, 6 µg cobalamin and 20µg folic acid. Enrollment in VISP began in August 1997, and was completed in December 2001, with 3,680 participants enrolled.</p> <p>Within the trial, 2,164 participants from 46 clinic sites provided DNA and agreed for it to be shared for use in a genetic subset study of VISP. This study is part of the Genomics and Randomized Trials Network (GARNET, <a href="http://www.garnetstudy.org" target="_blank">http://www.garnetstudy.org</a>) funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to stroke through large-scale genome-wide association studies of treatment response in randomized clinical trials. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington.</p> <p>The data of the VISP trial will be released to dbGaP users in several segments; the current segment, version 1 (phs000343.v1.p1), consists of n=4 phenotype datasets, and all raw, cleaned and imputed genotype data.</p> <p>Toole, J. F. (2002). Vitamin intervention for stroke prevention. J Neurol Sci, 203-204, 121-4. PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/12417369" target="_blank">12417369</a>.</p>

Dataset Information

Association of Optimal Combination Drug Treatment with Obesity Status among Recent Ischemic Stroke Patients: Results of the Vitamin Intervention for Stroke Prevention (VISP) Trial.

Publications

Association of Optimal Combination Drug Treatment with Obesity Status among Recent Ischemic Stroke Patients: Results of the Vitamin Intervention for Stroke Prevention (VISP) Trial.

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