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Treatment of hyperlipidaemia
- 1. Lipid Lowering Drugs www.freelivedoctor.com
- 2. Pathways of Lipid Transport & Inherited Hyperlipidemias Familial HyperTriGlyceridemia – LPL deficiency etc. RARE Familial Combined Hypertriglyceridemia – Polygenic. VERY COMMON (ApoB) Remnant Removcal Disease – ApoE deficiency. UNCOMMON Familial Hypoalphalipoproteinemia (Tangier’s Disease) – HDL low. RARE Familial Hyper- cholesterolemia – LDL receptor deficiency. COMMON. Heterozygotes ~1:500. X X = HMG-coA Reductase step – blocked by Statins www.freelivedoctor.com
- 7. Clinical Trials in Primary and Secondary Prevention of IHD LRC-CPPT = Lipid Research Clinics-Coronary Primary Prevention Trial; BAS = bile acid sequestrant; NR = not reported; AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; WOSCOPS = West of Scotland Coronary Prevention Study; HHS = Helsinki Heart Study; CDP = Coronary Drug Project; NA = not applicable; 4S = Scandinavian Simvastatin Survival Study; CARE = Cholesterol and Recurrent Events; LIPID = Long-Term Intervention with Pravastatin in Ischaemic Disease; PostCABG = Post Coronary Artery Bypass Graft Trial; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial; BIP = Bezafibrate Infarction Prevention Study; POSCH = Program on the Surgical Control of Hyperlipidemias. www.freelivedoctor.com Study No. of Patients Follow-up (yrs) Drug LDL/HDL Change (%) Total Mortality (%) CHD Death, Nonfatal MI (%) PTCA, Bypass (%) Primary prevention LRC-CPPT [4] 3806 7.4 BAS -13/2 -7 -19 NR AFCAPS/TexCAPS [14] 6605 4.8 Lovastatin -25/6 NR -40 -33 WOSCOPS [13] 6595 4.9 Pravastatin -26/5 -22 -31 -37 HHS [8] 4081 5 Gemfibrozil -10/10 0 -34 NR Secondary prevention CDP [7] 1119 15 Niacin -10/NA -11 NR NR 4S [12] 4444 5.4 Simvastatin -35/8 -30 -34 -34 CARE [11] 4159 5 Pravastatin -28/2 -9 -24 -27 LIPID [10] 9014 6 Pravastatin -25/6 -22 -24 -20 PostCABG [16] 1351 4.3 + 3a Lovastatin -40/4 -35 -31 -30 VA-HIT [9] 2531 5.1 Gemfibrozil 0/6 -11 -22 -9 BIP [5] 3090 6.2 Bezafibrate -7/18 +6 -11 -4 POSCH [6] 838 14.7 Surgery -38/4 -25 -40 -69
- 9. PRIOR DISEASE at BASELINE www.freelivedoctor.com
- 10. TOTAL & LDL CHOLESTEROL terciles at BASELINE www.freelivedoctor.com
- 11. SIMVASTATIN 40mg daily: Muscle symptoms www.freelivedoctor.com
- 12. SIMVASTATIN 40mg daily: Safety monitoring www.freelivedoctor.com
- 14. SIMVASTATIN: CORONARY EVENTS & REVASCULARISATION (10269) (10267) SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Major coronary event 357 574 Non-fatal MI 587 707 Coronary death (8.7%) (11.8%) 27% SE 4 reduction 898 1212 (2P<0.00001) CORONARY EVENTS Revascularisation 513 725 Coronary 450 532 Non-coronary (9.1%) (11.7%) 24% SE 4 reduction 939 1205 (2P<0.00001) REVASCULARISATIONS 0.4 0.6 0.8 1.0 1.2 1.4 www.freelivedoctor.com
- 15. SIMVASTATIN: MAJOR VASCULAR EVENTS (10269) (10267) SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Vascular event 898 1212 Major coronary 444 585 Any stroke 939 1205 Revascularisation (19.8%) (25.2%) 24% SE 3 reduction 2033 2585 (2P<0.00001) ANY OF ABOVE 0.4 0.6 0.8 1.0 1.2 1.4 www.freelivedoctor.com
- 16. 60(18) Benefit/1000 (SE): People suffering events (%) www.freelivedoctor.com SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR 0 1 2 3 4 5 6 0 5 10 15 20 25 30 Years of follow-up 5(3) 20(4) 35(5) SIMVASTATIN PLACEBO 46(5) 54(7)
- 17. SIMVASTATIN: MAJOR VASCULAR EVENT by LDL & TOTAL CHOLESTEROL (10269) (10267) SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Lipid levels at entry LDL cholesterol (mmol/l) 598 756 (17.6%) (22.2%) < 3.0 (116 mg/dl) 484 646 (19.0%) (25.7%) 3.0 < 3.5 951 1183 (22.0%) (27.2%) 3.5 (135 mg/dl) Total cholesterol (mmol/l) 360 472 (17.7%) (23.1%) < 5.0 (193 mg/dl) 744 964 (18.9%) (24.5%) 5.0 < 6.0 929 1149 (21.6%) (26.8%) > 6.0 (323 mg/dl) 24% SE 3 reduction (2P<0.00001) 2033 2585 (19.8%) (25.2%) ALL PATIENTS 0.4 0.6 0.8 1.0 1.2 1.4 www.freelivedoctor.com
- 19. Prospective Pravastatin Pooling Project: Coronary Event Rates in CARE and LIPID Patients with Baseline LDL-C <3.3mmol/L Coronary Event Rate (%) Sacks FM et al. Circulation 2002;105:1424-1428. <60 F M + — + — + — > 27 <27 <40 > 40 > 150 <150 Age Sex HTN Smoking DM BMI HDL-C TG ** * Pravastatin Placebo *p=.004 **p (interaction) =.005 > 60
- 20. Cumulative Coronary Event Rates in Diabetic and Nondiabetic Patients with Baseline LDL-C <3.3mmol/L Cumulative Risk of Coronary Event or Procedure (%) Years Follow-up Sacks FM et al. Circulation 2002;105:1424-1428. Placebo Diabetic Pravastatin Nondiabetic Pravastatin Diabetic Placebo Nondiabetic 0 1 2 3 4 6 7 5
- 25. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM): Statin Therapy Reduced Event Rate Event Rates [Mortality, MI] (%) 30-day Follow-up Period 0 1 2 3 4 7 5 Heeschen C et al. Circulation 2002;105:1446-1452. Statins discontinued No statins Statin continued
Notas del editor
- Notes: Eligibility for the study was guided chiefly by the &quot;uncertainty principle&quot;. Patients were informed at the start of the study that lowering cholesterol was already known to reduce the risk of heart attacks, but that most people among the range of volunteers recruited were not then receiving any kind of cholesterol-lowering treatment. Prior to randomisation, the patient's own doctor was provided with the patient's lipid profile and a summary of existing evidence about cholesterol-lowering therapy, and asked to indicate if -- in their view -- a statin was likely to be needed by the patient (in which case the patient would not be randomised). Subsequently, randomised participants and their doctors were encouraged to start a non-study statin if it was considered to have become indicated (e.g. because of emerging evidence from other trials or changes in the patient's medical condition).
- Notes: Patients included with a history of coronary heart disease were predominantly older individuals, women and those with average or below average cholesterol levels at entry to the study. Those with cerebrovascular disease had a history of a stroke, transient ischaemic attack or carotid artery surgery. Those with peripheral vascular disease had intermittent claudication or a history of aortic or peripheral revascularisation. Patients with diabetes had either type 1 or type 2 diabetes.
- Notes: Numbers are based on non-fasting lipid measurements taken at the initial visit prior to any lipid lowering therapy being taken. LDL cholesterol values were directly measured not calculated.
- Notes: Participants were asked about unexplained muscle pain or weakness at each follow-up. On average about 5% of participants reported such symptoms at each visit, but at no time during the study was there any significant difference between those allocated simvastatin or placebo. If participants stopped study medication the reasons for doing so were recorded.
- Notes: Numbers are of participants ever having values in the ranges shown. Participants were seen regularly at 4 month intervals during the first year and then six monthly during the study. A blood sample was taken at each visit and the liver enzyme alanine transaminase (ALT) routinely measured. In addition, if unexplained muscle pain or weakness was reported (or participants were taking non-study statin treatment as well as study simvastatin or placebo tablets) then creatine kinase (CK) was measured . In addition some CK values were reported by the managing doctor.
- Notes: none
- Notes: Similar proportional reductions in major coronary events, in strokes and in revascularisations yield a very definite effect on the first occurrence of any of these “major vascular events“. The extreme statistical significance of this reduction and the very large number of events and on which it is based, allows reliable assessment of the effects of treatment in various different circumstances.
- Notes: After the first year, there were highly significant reductions of about one quarter in the event rates during each separate year. This leads to continued divergence of the lines in this life-table plot of the effect of simvastatin on the incidence of a first major vascular event, which implies that benefits would increase with longer duration treatment and follow-up.
- Notes: Similar proportional reductions in risk of major vascular events are seen when participants are subdivided by baseline LDL or total cholesterol levels.
- Notes: none