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James J. Devlin - One of the best experts on this subject based on the ideXlab platform.
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providing patients with pharmacogenetic test results affects adherence to statin therapy results of the additional KIF6 risk offers better adherence to statins akrobats trial
Pharmacogenomics Journal, 2014Co-Authors: Scott L Charland, James J. Devlin, Barnabie C Agatep, Felix W. Frueh, V. Herrera, B Schrader, M Ryvkin, J Shabbeer, H R Superko, Eric J. StanekAbstract:Providing patients with pharmacogenetic test results affects adherence to statin therapy: results of the Additional KIF6 Risk Offers Better Adherence to Statins (AKROBATS) trial
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Cost Effectiveness of Targeted High-dose Atorvastatin Therapy Following Genotype Testing in Patients with Acute Coronary Syndrome
PharmacoEconomics, 2013Co-Authors: Anju Parthan, Lance A. Bare, Kevin Leahy, Amy K. O’sullivan, Olga A. Iakoubova, James J. Devlin, Milton C. WeinsteinAbstract:Background Results from the PROVE IT trial suggest that patients with acute coronary syndrome (ACS) treated with atorvastatin 80 mg/day (A80) have significantly lower rates of cardiovascular events compared with patients treated with pravastatin 40 mg/day (P40). In a genetic post hoc substudy of the PROVE IT trial, the rate of event reduction was greater in carriers of the Trp719Arg variant in kinesin family member 6 protein (KIF6) than in noncarriers. We assessed the cost effectiveness of testing for the KIF6 variant followed by targeted statin therapy (KIF6 Testing) versus not testing patients (No Test) and treating them with P40 or A80 in the USA from a payer perspective. Methods A Markov model was developed in which 2-year event rates from PROVE IT were extrapolated over a lifetime horizon. Costs and utilities were derived from published literature. All costs were in 2010 US dollars except the cost of A80, which was in 2012 US dollars because the generic formulation was available in 2012. Expected costs and quality-adjusted life-years (QALYs) were estimated for each strategy over a lifetime horizon. Results Lifetime costs were US$31,700; US$37,100 and US$41,300 for No Test P40, KIF6 Testing and No Test A80 strategies, respectively. The No Test A80 strategy was associated with more QALYs (9.71) than the KIF6 Testing (9.69) and No Test P40 (9.57) strategies. No Test A80 had an incremental cost-effectiveness ratio (ICER) of US$232,100 per QALY gained compared with KIF6 Testing. KIF6 Testing had an ICER of US$45,300 per QALY compared with No Test P40. Conclusions Testing ACS patients for KIF6 carrier status may be a cost-effective strategy at commonly accepted thresholds. Treating all patients with A80 is more expensive than treating patients on the basis of KIF6 results, but the modest gain in QALYs is achieved at a cost/QALY that is generally considered unacceptable compared with the KIF6 Testing strategy. Compared with treating all patients with P40, the KIF6 Testing strategy had an ICER below US$50,000 per QALY. The conclusions from this study are sensitive to the price of generic A80 and the effect on adherence of knowing KIF6 carrier status. The results were based on a post hoc substudy of the PROVE IT trial, which was not designed to test the effectiveness of KIF6 testing.
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Cost Effectiveness of Targeted High-dose Atorvastatin Therapy Following Genotype Testing in Patients with Acute Coronary Syndrome
PharmacoEconomics, 2013Co-Authors: Anju Parthan, Lance A. Bare, Kevin Leahy, Amy K. O’sullivan, Olga A. Iakoubova, James J. Devlin, Milton C. WeinsteinAbstract:Testing ACS patients for KIF6 carrier status may be a cost-effective strategy at commonly accepted thresholds. Treating all patients with A80 is more expensive than treating patients on the basis of KIF6 results, but the modest gain in QALYs is achieved at a cost/QALY that is generally considered unacceptable compared with the KIF6 Testing strategy. Compared with treating all patients with P40, the KIF6 Testing strategy had an ICER below US$50,000 per QALY. The conclusions from this study are sensitive to the price of generic A80 and the effect on adherence of knowing KIF6 carrier status. The results were based on a post hoc substudy of the PROVE IT trial, which was not designed to test the effectiveness of KIF6 testing. Copyright Springer International Publishing Switzerland 2013
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Abstract 290: Statin Adherence in Males and Females, and the Impact of Knowledge of a Genetic Test: Results from the AKROBATS Trial
Circulation-cardiovascular Quality and Outcomes, 2012Co-Authors: S.l. Charland, James J. Devlin, Robert Superko, Barnabie C Agatep, B.j. Schrader, Felix W. Frueh, V. Herrera, Miriam Ryvkin, Junaid Shabbeer, Eric J. StanekAbstract:Background A recent meta-analysis demonstrated that cardiovascular (CV) events and all-cause mortality are reduced in both sexes with statin therapy. Additionally, the Institute of Medicine and the American College of Cardiology advocate reporting of sex-specific CV treatment data. However, females are underrepresented in most CV clinical trials. We investigated the relationship between sex and other patient characteristics with regard to statin therapy adherence and persistence. Methods AKROBATS (NCT01068834) was a prospective, nonrandomized intervention trial of the effect on statin adherence and persistence of providing patients with information about KIF6 carrier status and their KIF6 test results. Eligible patients were ≥18 years old, new to statin therapy (none 6 months prior), and members of the same benefit plans. Controls and tested patients were matched for age, sex, prescription distribution channel, and number of chronic medications. The primary endpoint was statin adherence (proportion of days covered; PDC) at 6 months. Results The study included 1294 patients (582 males & 712 females) (Figure). There was no significant difference in beta blocker (22.3% vs 18.7%), calcium channel blocker (13.7% vs 16.0%), angiotensin-converting enzyme inhibitor, (22.9% vs 19.4%), or angiotensin receptor blocker (13.7% vs 14.2%) use in males compared with females. More females received diuretics (30.6% vs 19.6%) and aspirin/non-steroidal anti-inflammatory agents (16.3% vs 13.2%) than males, p KIF6 testing, distribution channel, number of chronic medications, statin out-of-pocket spend, and income. Independent of sex, more KIF6 -tested patients were adherent (PDC >0.80; OR 1.95, 95% CI 1.54 - 2.47, p Conclusions In this trial with a majority of females (55%), 6-month adherence and persistence to statin therapy did not vary by sex, and was significantly increased by individual knowledge of KIF6 test results in both males and females.
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The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study
BMC Cardiovascular Disorders, 2011Co-Authors: Dov Shiffman, Charles M. Rowland, James J. Devlin, Judy Z. Louie, Russell P Tracy, Mary Cushman, Ellen S O'meara, Bruce M PsatyAbstract:Background Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD) in prospective and case-control studies. A variant of KIF6 (719Arg) has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants) or a well-established non-genetic risk factor (C-reactive protein [CRP]) can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS)--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older. Methods Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC) and by net reclassification improvement (NRI). Results Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03) but not by NRI (NRI = 0.027, P = 0.32). Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02) and NRI (0.093, P = 0.008) in men, but not women (P ≥ 0.24). Conclusions While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.
Olga A. Iakoubova - One of the best experts on this subject based on the ideXlab platform.
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Cost Effectiveness of Targeted High-dose Atorvastatin Therapy Following Genotype Testing in Patients with Acute Coronary Syndrome
PharmacoEconomics, 2013Co-Authors: Anju Parthan, Lance A. Bare, Kevin Leahy, Amy K. O’sullivan, Olga A. Iakoubova, James J. Devlin, Milton C. WeinsteinAbstract:Background Results from the PROVE IT trial suggest that patients with acute coronary syndrome (ACS) treated with atorvastatin 80 mg/day (A80) have significantly lower rates of cardiovascular events compared with patients treated with pravastatin 40 mg/day (P40). In a genetic post hoc substudy of the PROVE IT trial, the rate of event reduction was greater in carriers of the Trp719Arg variant in kinesin family member 6 protein (KIF6) than in noncarriers. We assessed the cost effectiveness of testing for the KIF6 variant followed by targeted statin therapy (KIF6 Testing) versus not testing patients (No Test) and treating them with P40 or A80 in the USA from a payer perspective. Methods A Markov model was developed in which 2-year event rates from PROVE IT were extrapolated over a lifetime horizon. Costs and utilities were derived from published literature. All costs were in 2010 US dollars except the cost of A80, which was in 2012 US dollars because the generic formulation was available in 2012. Expected costs and quality-adjusted life-years (QALYs) were estimated for each strategy over a lifetime horizon. Results Lifetime costs were US$31,700; US$37,100 and US$41,300 for No Test P40, KIF6 Testing and No Test A80 strategies, respectively. The No Test A80 strategy was associated with more QALYs (9.71) than the KIF6 Testing (9.69) and No Test P40 (9.57) strategies. No Test A80 had an incremental cost-effectiveness ratio (ICER) of US$232,100 per QALY gained compared with KIF6 Testing. KIF6 Testing had an ICER of US$45,300 per QALY compared with No Test P40. Conclusions Testing ACS patients for KIF6 carrier status may be a cost-effective strategy at commonly accepted thresholds. Treating all patients with A80 is more expensive than treating patients on the basis of KIF6 results, but the modest gain in QALYs is achieved at a cost/QALY that is generally considered unacceptable compared with the KIF6 Testing strategy. Compared with treating all patients with P40, the KIF6 Testing strategy had an ICER below US$50,000 per QALY. The conclusions from this study are sensitive to the price of generic A80 and the effect on adherence of knowing KIF6 carrier status. The results were based on a post hoc substudy of the PROVE IT trial, which was not designed to test the effectiveness of KIF6 testing.
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Cost Effectiveness of Targeted High-dose Atorvastatin Therapy Following Genotype Testing in Patients with Acute Coronary Syndrome
PharmacoEconomics, 2013Co-Authors: Anju Parthan, Lance A. Bare, Kevin Leahy, Amy K. O’sullivan, Olga A. Iakoubova, James J. Devlin, Milton C. WeinsteinAbstract:Testing ACS patients for KIF6 carrier status may be a cost-effective strategy at commonly accepted thresholds. Treating all patients with A80 is more expensive than treating patients on the basis of KIF6 results, but the modest gain in QALYs is achieved at a cost/QALY that is generally considered unacceptable compared with the KIF6 Testing strategy. Compared with treating all patients with P40, the KIF6 Testing strategy had an ICER below US$50,000 per QALY. The conclusions from this study are sensitive to the price of generic A80 and the effect on adherence of knowing KIF6 carrier status. The results were based on a post hoc substudy of the PROVE IT trial, which was not designed to test the effectiveness of KIF6 testing. Copyright Springer International Publishing Switzerland 2013
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KIF6 polymorphism as a predictor of risk of coronary events and of clinical event reduction by statin therapy
American Journal of Cardiology, 2010Co-Authors: Yonghong Li, Olga A. Iakoubova, James J. Devlin, Dov Shiffman, Robert H Superko, James S ForresterAbstract:Evidence from multiple large prospective studies suggests that a common polymorphism that encodes an arginine (Arg)–to–tryptophan substitution at position 719 in the KIF6 gene is associated with coronary heart disease (CHD) and reduction in coronary events from statin therapy. Carriers of the 719Arg allele were at greater risk for primary and secondary CHD events, and statin therapy significantly reduced coronary events in 719Arg carriers but not in noncarriers. The number needed to treat to prevent a single CHD event ranged from 10 to 20 for 719Arg carriers, compared to >80 for noncarriers in the Cholesterol and Recurrent Events (CARE) study, the West of Scotland Coronary Prevention Study (WOSCOPS), the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT–TIMI22) study. In conclusion, assessment of 719Arg carrier status holds promise for stratification of coronary event risk and for selection of optimal therapy in primary and secondary CHD prevention.
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KIF6 trp719arg polymorphism and the effect of statin therapy in elderly patients results from the prosper study
European Journal of Preventive Cardiology, 2010Co-Authors: Olga A. Iakoubova, Carmen H. Tong, Michele Robertson, Charles M. Rowland, James J. Devlin, Joseph J. Catanese, Gerard J Blauw, J W Jukema, M B Murphy, Ian FordAbstract:Background Statin therapy has been found to substantially and significantly reduce coronary events in carriers of the KIF6 719Arg variant (rs20455) but not in noncarriers. We investigated whether, among the elderly, statin therapy also significantly reduced coronary events in carriers but not in noncarriers.Design and methods Among 5752 patients of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study, we assessed the effect of pravastatin, compared with placebo, on coronary events according to 719Arg carrier status using proportional hazards models.Results Since benefit from statin therapy in elderly patients has been primarily shown among those with prior vascular disease, we performed analyses in PROSPER patients with prior disease and found that pravastatin therapy significantly reduced events in 719Arg carriers [hazards ratio (HR): 0.66, 95% confidence interval (CI): 0.52–0.86] but not in noncarriers (HR: 0.94, 95% CI: 0.69–1.28), P= 0.09 for interaction between treatment and ca...
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effect of pravastatin therapy on coronary events in carriers of the KIF6 719arg allele from the cholesterol and recurrent events trial
American Journal of Cardiology, 2010Co-Authors: Dov Shiffman, Marc S. Sabatine, Todd G. Kirchgessner, Olga A. Iakoubova, James J. Devlin, Frank M Sacks, Hannia Campos, Judy Z. LouieAbstract:A previous genetic analysis of the Cholesterol and Recurrent Events (CARE) trial found that carriers of the 719Arg allele of the kinesin family member 6 gene ( KIF6 ) (rs20455), but not noncarriers, received significant event reduction from pravastatin therapy. However, that previous analysis of CARE included only Caucasian patients and was limited to the myocardial infarction components of the primary end point. Therefore, the aim of this study was to investigate whether pravastatin therapy reduced primary end point events in KIF6 719Arg carriers and noncarriers, separately, in the combined ethnic groups of CARE. The effect of pravastatin therapy on primary end point events (fatal coronary event or nonfatal myocardial infarction) was investigated in Cox regression models that adjusted for population structure using either self-reported ethnicity or the principal components of genetic heterogeneity. After adjustment for age, gender, and self-reported ethnicity, pravastatin therapy reduced events in carriers of KIF6 719Arg (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.49 to 0.83) but not in noncarriers (HR 1.01, 95% CI 0.69 to 1.45) (p for interaction = 0.049). After adjustment for age, gender, traditional risk factors, and principal components, pravastatin therapy reduced events in carriers of 719Arg (HR 0.64, 95% CI 0.49 to 0.85) but not in noncarriers (HR 0.90, 95% CI 0.62 to 1.32) (p for interaction = 0.14). In conclusion, in an analysis that included CARE patients of all ethnic groups, pravastatin therapy significantly and substantially reduced primary end point events in carriers of the KIF6 719Arg allele but not in noncarriers.
Charles M. Rowland - One of the best experts on this subject based on the ideXlab platform.
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KIF6 719Arg Genetic Variant and Risk for Thoracic Aortic Dissection
Aorta (Stamford Conn.), 2016Co-Authors: Olga Iakoubova, Carmen H. Tong, Charles M. Rowland, Joseph J. Catanese, May M. Luke, Maryann Tranquilli, John A. ElefteriadesAbstract:Carriers of the 719Arg variant in KIF6, compared with noncarriers, have been reported to be at greater risk for coronary heart disease (CHD) in six prospective studies. Because CHD, thoracic aortic dissection, and nondissection thoracic aortic aneurysm share some risk factors and aspects of pathophysiology, we investigated whether carriers of the 719Arg variant also have greater odds of thoracic aortic dissection or nondissected thoracic aortic aneurysm than noncarriers. We genotyped 140 thoracic aortic dissection cases, 497 nondissection thoracic aortic aneurysm cases, and 275 disease-free controls collected in the United States, Hungary, and Greece and investigated the association between KIF6 719Arg carrier status and thoracic aortic dissection, and between KIF6 719Arg carrier status and nondissection thoracic aortic aneurysm, using logistic regression models adjusted for age, sex, hypertension, smoking, and country. The odds of aortic dissection were two-fold greater in KIF6 719Arg carriers compared with noncarriers (odds ratio (OR) 2.14, 95% confidence interval (CI) 1.18-3.9). To account for the potential of concomitant CHD to confound the association between the KIF6 719Arg and thoracic aortic dissection, we repeated the analysis after removing subjects with concomitant CHD; the estimates for association of KIF6 719Arg carrier status remained essentially the same (OR 2.04, 95% CI 1.11-3.77). In contrast, KIF6 719Arg carrier status was not associated with risk for nondissection thoracic aortic aneurysm. We observed an association of the KIF6 719Arg genetic variant with thoracic aortic dissection in this multicenter case-control study. This association may enhance our management of patients with thoracic aortic disease.
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The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study
BMC Cardiovascular Disorders, 2011Co-Authors: Dov Shiffman, Charles M. Rowland, James J. Devlin, Judy Z. Louie, Russell P Tracy, Mary Cushman, Ellen S O'meara, Bruce M PsatyAbstract:Background Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD) in prospective and case-control studies. A variant of KIF6 (719Arg) has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants) or a well-established non-genetic risk factor (C-reactive protein [CRP]) can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS)--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older. Methods Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC) and by net reclassification improvement (NRI). Results Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03) but not by NRI (NRI = 0.027, P = 0.32). Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02) and NRI (0.093, P = 0.008) in men, but not women (P ≥ 0.24). Conclusions While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.
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the contribution of a 9p21 3 variant a KIF6 variant and c reactive protein to predicting risk of myocardial infarction in a prospective study
BMC Cardiovascular Disorders, 2011Co-Authors: Dov Shiffman, Charles M. Rowland, James J. Devlin, Judy Z. Louie, Ellen S Omeara, Russell P Tracy, Mary Cushman, Bruce M PsatyAbstract:Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD) in prospective and case-control studies. A variant of KIF6 (719Arg) has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants) or a well-established non-genetic risk factor (C-reactive protein [CRP]) can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS)--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older. Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC) and by net reclassification improvement (NRI). Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03) but not by NRI (NRI = 0.027, P = 0.32). Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02) and NRI (0.093, P = 0.008) in men, but not women (P ≥ 0.24). While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.
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Genetic variants in the KIF6 region and coronary event reduction from statin therapy
Human Genetics, 2011Co-Authors: Yonghong Li, Marc S. Sabatine, Carmen H. Tong, Ian Ford, Todd G. Kirchgessner, Christopher J. Packard, Michele Robertson, Charles M. Rowland, Lance A. Bare, James ShepherdAbstract:A single nucleotide polymorphism (SNP) in KIF6 , a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Cholesterol and Recurrent Events trial (CARE), 28 were associated with differential event reduction from statin therapy ( P _interaction
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genetic variants in the KIF6 region and coronary event reduction from statin therapy
Human Genetics, 2011Co-Authors: Yonghong Li, Marc S. Sabatine, Carmen H. Tong, Ian Ford, Todd G. Kirchgessner, Christopher J. Packard, Michele Robertson, Charles M. Rowland, Lance A. Bare, James ShepherdAbstract:A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associ- ated with diVerential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investi- gated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Choles- terol and Recurrent Events trial (CARE), 28 were associ- ated with diVerential event reduction from statin therapy (Pinteraction 0.4) in non-carriers. These three SNPs are in high linkage disequilibrium with one another (r 2 > 0.84). Functional studies of these variants may help to understand the role of KIF6 in the pathogenesis of CHD and diVerential response to statin therapy.
Lance A. Bare - One of the best experts on this subject based on the ideXlab platform.
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Cost Effectiveness of Targeted High-dose Atorvastatin Therapy Following Genotype Testing in Patients with Acute Coronary Syndrome
PharmacoEconomics, 2013Co-Authors: Anju Parthan, Lance A. Bare, Kevin Leahy, Amy K. O’sullivan, Olga A. Iakoubova, James J. Devlin, Milton C. WeinsteinAbstract:Background Results from the PROVE IT trial suggest that patients with acute coronary syndrome (ACS) treated with atorvastatin 80 mg/day (A80) have significantly lower rates of cardiovascular events compared with patients treated with pravastatin 40 mg/day (P40). In a genetic post hoc substudy of the PROVE IT trial, the rate of event reduction was greater in carriers of the Trp719Arg variant in kinesin family member 6 protein (KIF6) than in noncarriers. We assessed the cost effectiveness of testing for the KIF6 variant followed by targeted statin therapy (KIF6 Testing) versus not testing patients (No Test) and treating them with P40 or A80 in the USA from a payer perspective. Methods A Markov model was developed in which 2-year event rates from PROVE IT were extrapolated over a lifetime horizon. Costs and utilities were derived from published literature. All costs were in 2010 US dollars except the cost of A80, which was in 2012 US dollars because the generic formulation was available in 2012. Expected costs and quality-adjusted life-years (QALYs) were estimated for each strategy over a lifetime horizon. Results Lifetime costs were US$31,700; US$37,100 and US$41,300 for No Test P40, KIF6 Testing and No Test A80 strategies, respectively. The No Test A80 strategy was associated with more QALYs (9.71) than the KIF6 Testing (9.69) and No Test P40 (9.57) strategies. No Test A80 had an incremental cost-effectiveness ratio (ICER) of US$232,100 per QALY gained compared with KIF6 Testing. KIF6 Testing had an ICER of US$45,300 per QALY compared with No Test P40. Conclusions Testing ACS patients for KIF6 carrier status may be a cost-effective strategy at commonly accepted thresholds. Treating all patients with A80 is more expensive than treating patients on the basis of KIF6 results, but the modest gain in QALYs is achieved at a cost/QALY that is generally considered unacceptable compared with the KIF6 Testing strategy. Compared with treating all patients with P40, the KIF6 Testing strategy had an ICER below US$50,000 per QALY. The conclusions from this study are sensitive to the price of generic A80 and the effect on adherence of knowing KIF6 carrier status. The results were based on a post hoc substudy of the PROVE IT trial, which was not designed to test the effectiveness of KIF6 testing.
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Cost Effectiveness of Targeted High-dose Atorvastatin Therapy Following Genotype Testing in Patients with Acute Coronary Syndrome
PharmacoEconomics, 2013Co-Authors: Anju Parthan, Lance A. Bare, Kevin Leahy, Amy K. O’sullivan, Olga A. Iakoubova, James J. Devlin, Milton C. WeinsteinAbstract:Testing ACS patients for KIF6 carrier status may be a cost-effective strategy at commonly accepted thresholds. Treating all patients with A80 is more expensive than treating patients on the basis of KIF6 results, but the modest gain in QALYs is achieved at a cost/QALY that is generally considered unacceptable compared with the KIF6 Testing strategy. Compared with treating all patients with P40, the KIF6 Testing strategy had an ICER below US$50,000 per QALY. The conclusions from this study are sensitive to the price of generic A80 and the effect on adherence of knowing KIF6 carrier status. The results were based on a post hoc substudy of the PROVE IT trial, which was not designed to test the effectiveness of KIF6 testing. Copyright Springer International Publishing Switzerland 2013
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Genetic variants in the KIF6 region and coronary event reduction from statin therapy
Human Genetics, 2011Co-Authors: Yonghong Li, Marc S. Sabatine, Carmen H. Tong, Ian Ford, Todd G. Kirchgessner, Christopher J. Packard, Michele Robertson, Charles M. Rowland, Lance A. Bare, James ShepherdAbstract:A single nucleotide polymorphism (SNP) in KIF6 , a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Cholesterol and Recurrent Events trial (CARE), 28 were associated with differential event reduction from statin therapy ( P _interaction
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genetic variants in the KIF6 region and coronary event reduction from statin therapy
Human Genetics, 2011Co-Authors: Yonghong Li, Marc S. Sabatine, Carmen H. Tong, Ian Ford, Todd G. Kirchgessner, Christopher J. Packard, Michele Robertson, Charles M. Rowland, Lance A. Bare, James ShepherdAbstract:A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associ- ated with diVerential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investi- gated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Choles- terol and Recurrent Events trial (CARE), 28 were associ- ated with diVerential event reduction from statin therapy (Pinteraction 0.4) in non-carriers. These three SNPs are in high linkage disequilibrium with one another (r 2 > 0.84). Functional studies of these variants may help to understand the role of KIF6 in the pathogenesis of CHD and diVerential response to statin therapy.
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investigation of KIF6 trp719arg in a case control study of myocardial infarction a costa rican population
PLOS ONE, 2010Co-Authors: Lance A. Bare, Carmen H. Tong, Charles M. Rowland, James J. Devlin, Joseph J. Catanese, Edward A Ruiznarvaez, Andre R Arellano, Frank M Sacks, Hannia CamposAbstract:Background and Methodology: The 719Arg allele of KIF6 (rs20455) was associated with coronary events in Caucasian participants of five prospective studies. We investigated whether this KIF6 variant was associated with non-fatal myocardial infarction (MI) in a case-control study of an admixed population from the Central Valley of Costa Rica. Genotypes of the KIF6 variant were determined for 4,134 men and women. Cases (1,987) had survived a first MI; controls (2,147) had no history of MI and were matched to cases by age, sex, and area of residence. We tested the association between the KIF6 719Arg allele and non-fatal MI by conditional logistic regression and adjusted for admixture of founder populations. Principal Findings: Compared with the reference Trp/Trp homozygotes, KIF6 719Arg carriers were not at significantly higher risk for non-fatal MI in this study after adjustment for traditional risk factors or admixture (OR=1.12; 95%CI, 0.98–1.28). Heterozygotes of the KIF6 Trp719Arg variant were at increased risk of non-fatal MI: the adjusted odds ratio was 1.16 (95% confidence interval, 1.01–1.34), but this association would not be significant after a multiple testing correction. Conclusions/Significance: We found that carriers of the KIF6 719Arg allele were not at increased risk of non-fatal MI in a case-control study of Costa Ricans living in the Central Valley of Costa Rica.
Dov Shiffman - One of the best experts on this subject based on the ideXlab platform.
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The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study
BMC Cardiovascular Disorders, 2011Co-Authors: Dov Shiffman, Charles M. Rowland, James J. Devlin, Judy Z. Louie, Russell P Tracy, Mary Cushman, Ellen S O'meara, Bruce M PsatyAbstract:Background Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD) in prospective and case-control studies. A variant of KIF6 (719Arg) has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants) or a well-established non-genetic risk factor (C-reactive protein [CRP]) can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS)--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older. Methods Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC) and by net reclassification improvement (NRI). Results Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03) but not by NRI (NRI = 0.027, P = 0.32). Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02) and NRI (0.093, P = 0.008) in men, but not women (P ≥ 0.24). Conclusions While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.
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the contribution of a 9p21 3 variant a KIF6 variant and c reactive protein to predicting risk of myocardial infarction in a prospective study
BMC Cardiovascular Disorders, 2011Co-Authors: Dov Shiffman, Charles M. Rowland, James J. Devlin, Judy Z. Louie, Ellen S Omeara, Russell P Tracy, Mary Cushman, Bruce M PsatyAbstract:Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD) in prospective and case-control studies. A variant of KIF6 (719Arg) has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants) or a well-established non-genetic risk factor (C-reactive protein [CRP]) can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS)--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older. Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC) and by net reclassification improvement (NRI). Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03) but not by NRI (NRI = 0.027, P = 0.32). Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02) and NRI (0.093, P = 0.008) in men, but not women (P ≥ 0.24). While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.
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KIF6 polymorphism as a predictor of risk of coronary events and of clinical event reduction by statin therapy
American Journal of Cardiology, 2010Co-Authors: Yonghong Li, Olga A. Iakoubova, James J. Devlin, Dov Shiffman, Robert H Superko, James S ForresterAbstract:Evidence from multiple large prospective studies suggests that a common polymorphism that encodes an arginine (Arg)–to–tryptophan substitution at position 719 in the KIF6 gene is associated with coronary heart disease (CHD) and reduction in coronary events from statin therapy. Carriers of the 719Arg allele were at greater risk for primary and secondary CHD events, and statin therapy significantly reduced coronary events in 719Arg carriers but not in noncarriers. The number needed to treat to prevent a single CHD event ranged from 10 to 20 for 719Arg carriers, compared to >80 for noncarriers in the Cholesterol and Recurrent Events (CARE) study, the West of Scotland Coronary Prevention Study (WOSCOPS), the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT–TIMI22) study. In conclusion, assessment of 719Arg carrier status holds promise for stratification of coronary event risk and for selection of optimal therapy in primary and secondary CHD prevention.
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effect of pravastatin therapy on coronary events in carriers of the KIF6 719arg allele from the cholesterol and recurrent events trial
American Journal of Cardiology, 2010Co-Authors: Dov Shiffman, Marc S. Sabatine, Todd G. Kirchgessner, Olga A. Iakoubova, James J. Devlin, Frank M Sacks, Hannia Campos, Judy Z. LouieAbstract:A previous genetic analysis of the Cholesterol and Recurrent Events (CARE) trial found that carriers of the 719Arg allele of the kinesin family member 6 gene ( KIF6 ) (rs20455), but not noncarriers, received significant event reduction from pravastatin therapy. However, that previous analysis of CARE included only Caucasian patients and was limited to the myocardial infarction components of the primary end point. Therefore, the aim of this study was to investigate whether pravastatin therapy reduced primary end point events in KIF6 719Arg carriers and noncarriers, separately, in the combined ethnic groups of CARE. The effect of pravastatin therapy on primary end point events (fatal coronary event or nonfatal myocardial infarction) was investigated in Cox regression models that adjusted for population structure using either self-reported ethnicity or the principal components of genetic heterogeneity. After adjustment for age, gender, and self-reported ethnicity, pravastatin therapy reduced events in carriers of KIF6 719Arg (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.49 to 0.83) but not in noncarriers (HR 1.01, 95% CI 0.69 to 1.45) (p for interaction = 0.049). After adjustment for age, gender, traditional risk factors, and principal components, pravastatin therapy reduced events in carriers of 719Arg (HR 0.64, 95% CI 0.49 to 0.85) but not in noncarriers (HR 0.90, 95% CI 0.62 to 1.32) (p for interaction = 0.14). In conclusion, in an analysis that included CARE patients of all ethnic groups, pravastatin therapy significantly and substantially reduced primary end point events in carriers of the KIF6 719Arg allele but not in noncarriers.
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abstract 1259 the contribution of c reactive protein a KIF6 variant and a 9p21 variant to the prediction of myocardial infarction in the cardiovascular health study
Circulation, 2009Co-Authors: Dov Shiffman, Charles M. Rowland, James J. Devlin, Judy Z. Louie, Ellen S Omeara, Russell P Tracy, Mary Cushman, Bruce M PsatyAbstract:Background: Genetic and non-genetic risk markers might improve prediction of coronary events. A gene variant of KIF6 and several chromosome 9p21 variants were associated with increased risk of coronary heart disease (CHD) or myocardial infarction (MI) in large prospective studies. We asked if addition of genetic information ( KIF6, Trp719Arg or 9p21, rs10757274) or a well-established non-genetic risk marker (C-reactive protein [CRP]), can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS), a prospective observational study of cardiovascular disease in men and women aged 65 years or older. Methods: The predicted 10-year risk for MI of white participants of CHS was calculated by using FRS covariates in Cox models of incident MI for men (n=1495) and women (n=2156) separately. The coefficients for the FRS covariates were estimated using CHS data. Two methods were used to assess whether additional risk markers improved risk prediction: change in the area under the receiver operator characteristic curve (AUC) and net reclassification improvement (NRI), i.e ., using incident event information to determine if individuals were reclassified to more appropriate risk categories. Results: Among white participants, addition of plasma CRP level to the FRS did not improve the AUC (P>0.15) or NRI (P>0.19) in men or women (Table[⇓][1]). Similarly, addition of 9p21 information did not improve the AUC (P>0.35) or NRI (P>0.39). Addition of KIF6 719Arg carrier status to FRS improved the AUC in men (P=0.03) but not women (P=0.57); the NRI was not improved (P>0.32). Adding both CRP and KIF6 carrier status to the FRS improved both AUC (P=0.02) and NRI (P=0.008) in men but not women (P>0.24). Adding both CRP and 9p21 did not improve AUC or NRI (P>0.09 in men P>0.40 in women). Conclusion: While none of these risk markers individually or in combination improved risk prediction in women, KIF6 carrier status and CRP levels improved risk prediction among older men. ![Table][2] MI Risk Prediction in CHS [1]: #T1 [2]: pending:yes
