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- Gupta, A., et al.
(författare)
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Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase
- 2017
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Ingår i: Lancet. - : Elsevier BV. - 0140-6736. ; 389:10088, s. 2473-2481
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Tidskriftsartikel (refereegranskat)abstract
- Background In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. Methods In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40-79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6.5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment-and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. Results The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3.3 years (IQR 2.7-3.7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] nonusers), with a median follow-up of 2.3 years (2.2-2.4). During the blinded phase, muscle-related AEs (298 [2.03% per annum] vs 283 [2.00% per annum]; hazard ratio 1.03 [95% CI 0.88-1.21]; p= 0.72) and erectile dysfunction (272 [1.86% per annum] vs 302 [2.14% per annum]; 0.88 [0.75-1.04]; p= 0.13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1.00% per annum] vs 210 [1.46% per annum]; 0.69 [0.56-0.85]; p= 0.0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0.20% per annum] vs 32 [0.22% per annum]; 0.94 [057-1.54]; p= 0.81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1.87%] per annum vs 392 [1.51%] per annum; 1.23 [1.08-1.41]; p= 0.002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1.26% per annum] vs 124 [1.00% per annum]; 1.41 [1.10-1.79]; p= 0.006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8.69% per annum] vs 831 [7.45% per annum]; 1.17 [1.06-1.29]; p= 0.001) and blood and lymphatic system disorders (114 [0.88% per annum] vs 80 [0.64% per annum]; 1.40 [1.04-1.88]; p= 0.03), which were reported more commonly by statin users than by non-users. Interpretation These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. C1, 2013, Heart of the matter part 2-cholesterol drug war
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| 53. |
- Gupta, A. K., et al.
(författare)
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Metabolic syndrome, independent of its components, is a risk factor for stroke and death but not for coronary heart disease among hypertensive patients in the ASCOT-BPLA
- 2010
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Ingår i: Diabetes Care. - 0149-5992. ; 33:7, s. 1647-1651
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate whether in hypertensive patients the risk of cardiovascular disease is greater in association with the metabolic syndrome (MetS) or the sum of its individual components. RESEARCH DESIGN AND METHODS: Cox regression analysis models were developed to assess the influence of age, sex, ethnicity, and the individual components of MetS on risk associated with the MetS (using several definitions) of coronary outcomes, stroke, and all-cause mortality. RESULTS: MetS was significantly associated with coronary outcomes, stroke, and all-cause mortality after adjusting for age, sex, and ethnicity. However, when the model was further adjusted for the individual components, MetS was associated with significantly increased risk of stroke (hazard ratio 1.34 [95% CI 1.07-1.68]) and all-cause mortality (1.35 [1.16-1.58]) but not coronary outcomes (fatal coronary heart disease plus nonfatal myocardial infarction 1.16 [0.95-1.43] and total coronary events 1.06 [0.91-1.24]). CONCLUSIONS: MetS, independent of its individual components, is associated with increased risk of stroke and all-cause mortality but not coronary outcomes.
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| 54. |
- Johnson, Toby, et al.
(författare)
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Blood Pressure Loci Identified with a Gene-Centric Array.
- 2011
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 1537-6605 .- 0002-9297. ; 89:6, s. 688-700
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Tidskriftsartikel (refereegranskat)abstract
- Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56× 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56× 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
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