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Rory Collins - One of the best experts on this subject based on the ideXlab platform.
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impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection study
European Heart Journal, 2013Co-Authors: Jemma C Hopewell, Robert Clarke, Sarah Parish, Mark Lathrop, Jane Armitage, Alison Offer, Emma Link, Rory CollinsAbstract:Aims Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response. Methods and results A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1 , and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE , and SLCO1B1 . The largest and most significant effects were with LPA and APOE , but were only 2–3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response. Conclusions Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.
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lipids and lipoproteins and risk of different vascular events in the mrc bhf Heart Protection study
Circulation, 2012Co-Authors: Sarah Parish, Jemma C Hopewell, Robert Clarke, Jane Armitage, Alison Offer, Michael Hill, James D Otvos, Rory CollinsAbstract:Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...
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Lipids and Lipoproteins and Risk of Different Vascular Events in the MRC/BHF Heart Protection Study
Circulation, 2012Co-Authors: Sarah Parish, Jemma C Hopewell, Robert Clarke, Jane Armitage, Alison Offer, Michael Hill, James D Otvos, Rory CollinsAbstract:Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...
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no impact of kif6 genotype on vascular risk and statin response among 18 348 randomized patients in the Heart Protection study
Journal of the American College of Cardiology, 2011Co-Authors: Jemma C Hopewell, J. Armitage, Louise Bowman, Jörg Hager, Robert Clarke, Sarah Parish, Mark Lathrop, Rory CollinsAbstract:Objectives The aim of this study was to test the effects of the KIF6 Trp719Arg polymorphism (rs20455) on vascular risk and response to statin therapy in 18,348 participants from the Heart Protection Study. Background There have been claims that noncarriers of the KIF6 719Arg variant receive little benefit from statin therapy. Screening for this genetic variant is now being used to influence statin use. Methods Participants received 40 mg simvastatin daily for 4 to 6 weeks before being randomly allocated 40 mg simvastatin daily or placebo for 5 years. Major coronary event was pre-defined as coronary death or nonfatal myocardial infarction, and major vascular event was pre-defined as major coronary event plus revascularization or stroke. Results The KIF6 genotype was not significantly associated, among placebo-allocated participants, with the risks of incident major vascular events, major coronary events, revascularizations, or strokes. Overall, 40 mg simvastatin daily produced a 42% reduction in low-density lipoprotein cholesterol, which did not differ significantly by KIF6 719Arg carrier status (p = 0.51). Proportional reductions in the risk of major vascular events with statin therapy were similar (interaction p = 0.70) and highly significant across KIF6 genotypes: 23% (95% confidence interval: 16% to 29%; p = 5.3 × 10−10) in carriers (Arg/Arg or Trp/Arg), and 24% (95% confidence interval: 17% to 31%; p = 4.6 × 10−9) in noncarriers (Trp/Trp). A similar lack of interaction was observed for major coronary events, revascularizations, and strokes considered separately. Conclusions Statin therapy significantly reduces the incidence of coronary and other major vascular events to a similar extent, irrespective of KIF6 genotype. Consequently, the use of KIF6 genotyping to guide statin therapy is not warranted. (Heart Protection Study; ISRCTN48489393)
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lipoprotein a genetic variants associated with coronary and peripheral vascular disease but not with stroke risk in the Heart Protection study
Circulation-cardiovascular Genetics, 2011Co-Authors: Jemma C Hopewell, Jörg Hager, Robert Clarke, Sarah Parish, Mark Lathrop, Jane Armitage, Rory CollinsAbstract:Background—Genetic studies have identified 2 single-nucleotide polymorphisms (SNPs) at the LPA locus (rs3798220 and rs10455872) that are strongly and independently related to lipoprotein(a) levels and to coronary disease risk, but their relevance for other atherothrombotic disease is uncertain. Methods and Results—These 2 LPA SNPs were examined together as an LPA genotype score for associations with vascular outcomes among participants in the Heart Protection Study. The LPA score was examined first in 12 236 participants with prevalent vascular disease (9277 coronary disease cases, and 1326 ischemic stroke and 2011 peripheral vascular disease cases with no history of coronary disease) and 3687 vascular disease-free controls and, subsequently, in 3251 participants who had incident major vascular events during follow-up (2106 coronary disease, 507 ischemic stroke, and 707 peripheral vascular disease events). For prevalent disease, the LPA score was strongly associated with coronary disease (odds ratio [OR] ...
Jane Armitage - One of the best experts on this subject based on the ideXlab platform.
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Serious Adverse Effects of Extended-Release Niacin/Laropiprant: Results From the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial
Clinical therapeutics, 2019Co-Authors: Richard Haynes, Jemma C Hopewell, Sarah Parish, Elsa Valdes-marquez, Fang Chen, Martin J Landray, Jane ArmitageAbstract:Abstract Purpose The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial of patients at high risk of vascular disease found that adding extended-release niacin-laropiprant to intensive statin-based LDL-lowering therapy had no benefit on cardiovascular outcomes. However, the trial also identified previously unrecognized serious adverse effects (including new-onset diabetes, bleeding, and infection). Our objective was to explore the safety profile of niacin-laropiprant and examine whether any patients were at lower (or higher) risk of its adverse effects. Methods HPS2-THRIVE was a randomized, double-blind trial of niacin-laropiprant (2000/40 mg/d) versus placebo among 25,673 patients at high risk of vascular disease. Information on all serious adverse events was collected during a median of 3.9 years of study treatment. Effects of niacin-laropiprant on new-onset diabetes, disturbances of diabetes control, bleeding, infection, and gastrointestinal upset were estimated by (1) time after randomization, (2) severity, (3) baseline characteristics, (4) baseline risk of the adverse event of interest, and (5) risk of major vascular event. Findings The hazard ratio (HR) for new-onset diabetes with niacin/laropiprant was 1.32 (95% CI, 1.16–1.51; P Implications Practitioners or patients considering the use of niacin (in addition to, or instead of, a statin) despite the lack of evidence of cardiovascular benefits (at least when added to effective statin therapy) should take account of the significant risks of these serious adverse effects when making such decisions. ClinicalTrials.gov identifier: NCT00461630.
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impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection study
European Heart Journal, 2013Co-Authors: Jemma C Hopewell, Robert Clarke, Sarah Parish, Mark Lathrop, Jane Armitage, Alison Offer, Emma Link, Rory CollinsAbstract:Aims Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response. Methods and results A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1 , and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE , and SLCO1B1 . The largest and most significant effects were with LPA and APOE , but were only 2–3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response. Conclusions Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.
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Does the Benefit from Statin Therapy Extend Beyond 5 Years?
Current Atherosclerosis Reports, 2013Co-Authors: Richard Bulbulia, Jane ArmitageAbstract:Large randomized trials have shown that lowering the concentration of LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, with further benefit emerging during each year of treatment allocation. But, limited evidence is available about the long-term efficacy and safety of statin treatment. Long-term follow-up of surviving trial participants allows direct assessment of the benefits (and any hazards) of a sustained reduction in LDL cholesterol concentration during the post-trial period. Post-trial follow-up of several large statin trials (of which the Heart Protection Study was the largest) confirms that the substantial absolute benefits and cost-effectiveness of statin therapy were, in fact, underestimated in previous analyses restricted to the “in-trial” periods of randomized studies. Reassuringly, no adverse effects on cancer incidence or non-vascular mortality emerged during the extended follow-up of the Heart Protection Study. These findings support the prompt initiation and long-term continuation of statin therapy in individuals at increased vascular risk.
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lipids and lipoproteins and risk of different vascular events in the mrc bhf Heart Protection study
Circulation, 2012Co-Authors: Sarah Parish, Jemma C Hopewell, Robert Clarke, Jane Armitage, Alison Offer, Michael Hill, James D Otvos, Rory CollinsAbstract:Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...
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Lipids and Lipoproteins and Risk of Different Vascular Events in the MRC/BHF Heart Protection Study
Circulation, 2012Co-Authors: Sarah Parish, Jemma C Hopewell, Robert Clarke, Jane Armitage, Alison Offer, Michael Hill, James D Otvos, Rory CollinsAbstract:Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...
Jemma C Hopewell - One of the best experts on this subject based on the ideXlab platform.
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Serious Adverse Effects of Extended-Release Niacin/Laropiprant: Results From the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial
Clinical therapeutics, 2019Co-Authors: Richard Haynes, Jemma C Hopewell, Sarah Parish, Elsa Valdes-marquez, Fang Chen, Martin J Landray, Jane ArmitageAbstract:Abstract Purpose The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial of patients at high risk of vascular disease found that adding extended-release niacin-laropiprant to intensive statin-based LDL-lowering therapy had no benefit on cardiovascular outcomes. However, the trial also identified previously unrecognized serious adverse effects (including new-onset diabetes, bleeding, and infection). Our objective was to explore the safety profile of niacin-laropiprant and examine whether any patients were at lower (or higher) risk of its adverse effects. Methods HPS2-THRIVE was a randomized, double-blind trial of niacin-laropiprant (2000/40 mg/d) versus placebo among 25,673 patients at high risk of vascular disease. Information on all serious adverse events was collected during a median of 3.9 years of study treatment. Effects of niacin-laropiprant on new-onset diabetes, disturbances of diabetes control, bleeding, infection, and gastrointestinal upset were estimated by (1) time after randomization, (2) severity, (3) baseline characteristics, (4) baseline risk of the adverse event of interest, and (5) risk of major vascular event. Findings The hazard ratio (HR) for new-onset diabetes with niacin/laropiprant was 1.32 (95% CI, 1.16–1.51; P Implications Practitioners or patients considering the use of niacin (in addition to, or instead of, a statin) despite the lack of evidence of cardiovascular benefits (at least when added to effective statin therapy) should take account of the significant risks of these serious adverse effects when making such decisions. ClinicalTrials.gov identifier: NCT00461630.
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impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection study
European Heart Journal, 2013Co-Authors: Jemma C Hopewell, Robert Clarke, Sarah Parish, Mark Lathrop, Jane Armitage, Alison Offer, Emma Link, Rory CollinsAbstract:Aims Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response. Methods and results A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1 , and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE , and SLCO1B1 . The largest and most significant effects were with LPA and APOE , but were only 2–3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response. Conclusions Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.
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lipids and lipoproteins and risk of different vascular events in the mrc bhf Heart Protection study
Circulation, 2012Co-Authors: Sarah Parish, Jemma C Hopewell, Robert Clarke, Jane Armitage, Alison Offer, Michael Hill, James D Otvos, Rory CollinsAbstract:Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...
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Lipids and Lipoproteins and Risk of Different Vascular Events in the MRC/BHF Heart Protection Study
Circulation, 2012Co-Authors: Sarah Parish, Jemma C Hopewell, Robert Clarke, Jane Armitage, Alison Offer, Michael Hill, James D Otvos, Rory CollinsAbstract:Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...
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no impact of kif6 genotype on vascular risk and statin response among 18 348 randomized patients in the Heart Protection study
Journal of the American College of Cardiology, 2011Co-Authors: Jemma C Hopewell, J. Armitage, Louise Bowman, Jörg Hager, Robert Clarke, Sarah Parish, Mark Lathrop, Rory CollinsAbstract:Objectives The aim of this study was to test the effects of the KIF6 Trp719Arg polymorphism (rs20455) on vascular risk and response to statin therapy in 18,348 participants from the Heart Protection Study. Background There have been claims that noncarriers of the KIF6 719Arg variant receive little benefit from statin therapy. Screening for this genetic variant is now being used to influence statin use. Methods Participants received 40 mg simvastatin daily for 4 to 6 weeks before being randomly allocated 40 mg simvastatin daily or placebo for 5 years. Major coronary event was pre-defined as coronary death or nonfatal myocardial infarction, and major vascular event was pre-defined as major coronary event plus revascularization or stroke. Results The KIF6 genotype was not significantly associated, among placebo-allocated participants, with the risks of incident major vascular events, major coronary events, revascularizations, or strokes. Overall, 40 mg simvastatin daily produced a 42% reduction in low-density lipoprotein cholesterol, which did not differ significantly by KIF6 719Arg carrier status (p = 0.51). Proportional reductions in the risk of major vascular events with statin therapy were similar (interaction p = 0.70) and highly significant across KIF6 genotypes: 23% (95% confidence interval: 16% to 29%; p = 5.3 × 10−10) in carriers (Arg/Arg or Trp/Arg), and 24% (95% confidence interval: 17% to 31%; p = 4.6 × 10−9) in noncarriers (Trp/Trp). A similar lack of interaction was observed for major coronary events, revascularizations, and strokes considered separately. Conclusions Statin therapy significantly reduces the incidence of coronary and other major vascular events to a similar extent, irrespective of KIF6 genotype. Consequently, the use of KIF6 genotyping to guide statin therapy is not warranted. (Heart Protection Study; ISRCTN48489393)
Sarah Parish - One of the best experts on this subject based on the ideXlab platform.
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Serious Adverse Effects of Extended-Release Niacin/Laropiprant: Results From the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial
Clinical therapeutics, 2019Co-Authors: Richard Haynes, Jemma C Hopewell, Sarah Parish, Elsa Valdes-marquez, Fang Chen, Martin J Landray, Jane ArmitageAbstract:Abstract Purpose The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial of patients at high risk of vascular disease found that adding extended-release niacin-laropiprant to intensive statin-based LDL-lowering therapy had no benefit on cardiovascular outcomes. However, the trial also identified previously unrecognized serious adverse effects (including new-onset diabetes, bleeding, and infection). Our objective was to explore the safety profile of niacin-laropiprant and examine whether any patients were at lower (or higher) risk of its adverse effects. Methods HPS2-THRIVE was a randomized, double-blind trial of niacin-laropiprant (2000/40 mg/d) versus placebo among 25,673 patients at high risk of vascular disease. Information on all serious adverse events was collected during a median of 3.9 years of study treatment. Effects of niacin-laropiprant on new-onset diabetes, disturbances of diabetes control, bleeding, infection, and gastrointestinal upset were estimated by (1) time after randomization, (2) severity, (3) baseline characteristics, (4) baseline risk of the adverse event of interest, and (5) risk of major vascular event. Findings The hazard ratio (HR) for new-onset diabetes with niacin/laropiprant was 1.32 (95% CI, 1.16–1.51; P Implications Practitioners or patients considering the use of niacin (in addition to, or instead of, a statin) despite the lack of evidence of cardiovascular benefits (at least when added to effective statin therapy) should take account of the significant risks of these serious adverse effects when making such decisions. ClinicalTrials.gov identifier: NCT00461630.
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impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection study
European Heart Journal, 2013Co-Authors: Jemma C Hopewell, Robert Clarke, Sarah Parish, Mark Lathrop, Jane Armitage, Alison Offer, Emma Link, Rory CollinsAbstract:Aims Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response. Methods and results A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1 , and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE , and SLCO1B1 . The largest and most significant effects were with LPA and APOE , but were only 2–3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response. Conclusions Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.
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lipids and lipoproteins and risk of different vascular events in the mrc bhf Heart Protection study
Circulation, 2012Co-Authors: Sarah Parish, Jemma C Hopewell, Robert Clarke, Jane Armitage, Alison Offer, Michael Hill, James D Otvos, Rory CollinsAbstract:Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...
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Lipids and Lipoproteins and Risk of Different Vascular Events in the MRC/BHF Heart Protection Study
Circulation, 2012Co-Authors: Sarah Parish, Jemma C Hopewell, Robert Clarke, Jane Armitage, Alison Offer, Michael Hill, James D Otvos, Rory CollinsAbstract:Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...
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no impact of kif6 genotype on vascular risk and statin response among 18 348 randomized patients in the Heart Protection study
Journal of the American College of Cardiology, 2011Co-Authors: Jemma C Hopewell, J. Armitage, Louise Bowman, Jörg Hager, Robert Clarke, Sarah Parish, Mark Lathrop, Rory CollinsAbstract:Objectives The aim of this study was to test the effects of the KIF6 Trp719Arg polymorphism (rs20455) on vascular risk and response to statin therapy in 18,348 participants from the Heart Protection Study. Background There have been claims that noncarriers of the KIF6 719Arg variant receive little benefit from statin therapy. Screening for this genetic variant is now being used to influence statin use. Methods Participants received 40 mg simvastatin daily for 4 to 6 weeks before being randomly allocated 40 mg simvastatin daily or placebo for 5 years. Major coronary event was pre-defined as coronary death or nonfatal myocardial infarction, and major vascular event was pre-defined as major coronary event plus revascularization or stroke. Results The KIF6 genotype was not significantly associated, among placebo-allocated participants, with the risks of incident major vascular events, major coronary events, revascularizations, or strokes. Overall, 40 mg simvastatin daily produced a 42% reduction in low-density lipoprotein cholesterol, which did not differ significantly by KIF6 719Arg carrier status (p = 0.51). Proportional reductions in the risk of major vascular events with statin therapy were similar (interaction p = 0.70) and highly significant across KIF6 genotypes: 23% (95% confidence interval: 16% to 29%; p = 5.3 × 10−10) in carriers (Arg/Arg or Trp/Arg), and 24% (95% confidence interval: 17% to 31%; p = 4.6 × 10−9) in noncarriers (Trp/Trp). A similar lack of interaction was observed for major coronary events, revascularizations, and strokes considered separately. Conclusions Statin therapy significantly reduces the incidence of coronary and other major vascular events to a similar extent, irrespective of KIF6 genotype. Consequently, the use of KIF6 genotyping to guide statin therapy is not warranted. (Heart Protection Study; ISRCTN48489393)
Robert Clarke - One of the best experts on this subject based on the ideXlab platform.
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impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection study
European Heart Journal, 2013Co-Authors: Jemma C Hopewell, Robert Clarke, Sarah Parish, Mark Lathrop, Jane Armitage, Alison Offer, Emma Link, Rory CollinsAbstract:Aims Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response. Methods and results A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1 , and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE , and SLCO1B1 . The largest and most significant effects were with LPA and APOE , but were only 2–3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response. Conclusions Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.
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lipids and lipoproteins and risk of different vascular events in the mrc bhf Heart Protection study
Circulation, 2012Co-Authors: Sarah Parish, Jemma C Hopewell, Robert Clarke, Jane Armitage, Alison Offer, Michael Hill, James D Otvos, Rory CollinsAbstract:Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...
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Lipids and Lipoproteins and Risk of Different Vascular Events in the MRC/BHF Heart Protection Study
Circulation, 2012Co-Authors: Sarah Parish, Jemma C Hopewell, Robert Clarke, Jane Armitage, Alison Offer, Michael Hill, James D Otvos, Rory CollinsAbstract:Background—Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Methods and Results—Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A1, and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16–1.34) for LDL cholesterol, 1.22 (95% CI, 1.14–1.32) for non–HDL cholesterol, 1.23 (95% CI, 1.15–1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16–1.35) for LDL particle number. Given the total LDL ...
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no impact of kif6 genotype on vascular risk and statin response among 18 348 randomized patients in the Heart Protection study
Journal of the American College of Cardiology, 2011Co-Authors: Jemma C Hopewell, J. Armitage, Louise Bowman, Jörg Hager, Robert Clarke, Sarah Parish, Mark Lathrop, Rory CollinsAbstract:Objectives The aim of this study was to test the effects of the KIF6 Trp719Arg polymorphism (rs20455) on vascular risk and response to statin therapy in 18,348 participants from the Heart Protection Study. Background There have been claims that noncarriers of the KIF6 719Arg variant receive little benefit from statin therapy. Screening for this genetic variant is now being used to influence statin use. Methods Participants received 40 mg simvastatin daily for 4 to 6 weeks before being randomly allocated 40 mg simvastatin daily or placebo for 5 years. Major coronary event was pre-defined as coronary death or nonfatal myocardial infarction, and major vascular event was pre-defined as major coronary event plus revascularization or stroke. Results The KIF6 genotype was not significantly associated, among placebo-allocated participants, with the risks of incident major vascular events, major coronary events, revascularizations, or strokes. Overall, 40 mg simvastatin daily produced a 42% reduction in low-density lipoprotein cholesterol, which did not differ significantly by KIF6 719Arg carrier status (p = 0.51). Proportional reductions in the risk of major vascular events with statin therapy were similar (interaction p = 0.70) and highly significant across KIF6 genotypes: 23% (95% confidence interval: 16% to 29%; p = 5.3 × 10−10) in carriers (Arg/Arg or Trp/Arg), and 24% (95% confidence interval: 17% to 31%; p = 4.6 × 10−9) in noncarriers (Trp/Trp). A similar lack of interaction was observed for major coronary events, revascularizations, and strokes considered separately. Conclusions Statin therapy significantly reduces the incidence of coronary and other major vascular events to a similar extent, irrespective of KIF6 genotype. Consequently, the use of KIF6 genotyping to guide statin therapy is not warranted. (Heart Protection Study; ISRCTN48489393)
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lipoprotein a genetic variants associated with coronary and peripheral vascular disease but not with stroke risk in the Heart Protection study
Circulation-cardiovascular Genetics, 2011Co-Authors: Jemma C Hopewell, Jörg Hager, Robert Clarke, Sarah Parish, Mark Lathrop, Jane Armitage, Rory CollinsAbstract:Background—Genetic studies have identified 2 single-nucleotide polymorphisms (SNPs) at the LPA locus (rs3798220 and rs10455872) that are strongly and independently related to lipoprotein(a) levels and to coronary disease risk, but their relevance for other atherothrombotic disease is uncertain. Methods and Results—These 2 LPA SNPs were examined together as an LPA genotype score for associations with vascular outcomes among participants in the Heart Protection Study. The LPA score was examined first in 12 236 participants with prevalent vascular disease (9277 coronary disease cases, and 1326 ischemic stroke and 2011 peripheral vascular disease cases with no history of coronary disease) and 3687 vascular disease-free controls and, subsequently, in 3251 participants who had incident major vascular events during follow-up (2106 coronary disease, 507 ischemic stroke, and 707 peripheral vascular disease events). For prevalent disease, the LPA score was strongly associated with coronary disease (odds ratio [OR] ...
