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: 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.
Treatment of hyperlipidaemia
Lipid Lowering Drugs www.freelivedoctor.com
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
Endemic Hyperlipidemias <ul><li>66% UK population have a Total cholesterol >5.2 mmol/L </li></ul><ul><li>Reflects high dietary fat, obesity and genotype </li></ul><ul><li>Secondary causes should be excluded* but explains only a minority of cases </li></ul>* Liver or biliary disease, hypothyroidism, diabetes, nephrotic syndrome or drug-induced (etretinate, HAART, thiazides, OC, glucocorticoids, -blockade and ciclosporin) www.freelivedoctor.com
Management Strategy <ul><li>Who to treat? </li></ul><ul><ul><li>Primary – 10 yr risk of event 30% </li></ul></ul><ul><ul><li>Secondary - Established IHD or CVD </li></ul></ul><ul><li>What degree of hyperlipidemia should trigger intervention? </li></ul><ul><ul><li>Total cholesterol > 5mmol/L (or LDL >3) </li></ul></ul><ul><li>What are the specific interventions </li></ul><ul><ul><li>Correct secondary causes – if possible </li></ul></ul><ul><ul><li>Dietary modification – in all subjects </li></ul></ul><ul><ul><li>Drug Rx – for vast majority a statin </li></ul></ul>www.freelivedoctor.com
Dietary Intervention <ul><li>Step II diet has <30% of calories as fat, <7% as saturated fat and <200mg cholesterol/day. </li></ul><ul><li>Can achieve a fall in LDL-C of 8-15% … but long-term compliance a problem. </li></ul><ul><li>Has useful 2ary benefits </li></ul><ul><ul><li>Weight reduction </li></ul></ul><ul><ul><li>BP reduction </li></ul></ul><ul><ul><li>Reduced insulin resistance </li></ul></ul><ul><ul><li>Improve intake vitamins & fresh fruit/vegetables (folate and antioxidants) </li></ul></ul>www.freelivedoctor.com
General points about Statins <ul><li>They competitively and potently inhibit HMG-CoA reductase (in nM range) leading to 2ary upregulation of surface LDL receptors </li></ul><ul><li>They have short half-lives (~2 hours except atorvastatin at 14h) but effective with once daily administration </li></ul><ul><li>All have slightly higher efficacy if given at night </li></ul><ul><li>All except pravastatin are metabolised through CYP enzymes in the liver (usually 3A4) which is the source of important interactions </li></ul><ul><li>Major side effects – hepatitis (stop if ALT rises > 3x ULN) and myositis </li></ul>www.freelivedoctor.com
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  3806 7.4 BAS -13/2 -7 -19 NR AFCAPS/TexCAPS  6605 4.8 Lovastatin -25/6 NR -40 -33 WOSCOPS  6595 4.9 Pravastatin -26/5 -22 -31 -37 HHS  4081 5 Gemfibrozil -10/10 0 -34 NR Secondary prevention CDP  1119 15 Niacin -10/NA -11 NR NR 4S  4444 5.4 Simvastatin -35/8 -30 -34 -34 CARE  4159 5 Pravastatin -28/2 -9 -24 -27 LIPID  9014 6 Pravastatin -25/6 -22 -24 -20 PostCABG  1351 4.3 + 3a Lovastatin -40/4 -35 -31 -30 VA-HIT  2531 5.1 Gemfibrozil 0/6 -11 -22 -9 BIP  3090 6.2 Bezafibrate -7/18 +6 -11 -4 POSCH  838 14.7 Surgery -38/4 -25 -40 -69
ELIGIBILITY: MRC/BHF Heart Protection Study (HPS)* <ul><li>Increased risk of CHD death due to prior disease: </li></ul><ul><li>Myocardial infarction or other coronary heart disease; </li></ul><ul><li>Occlusive disease of non-coronary arteries; or </li></ul><ul><li>Diabetes mellitus or treated hypertension </li></ul><ul><li>Age 40-80 years </li></ul><ul><li>Total cholesterol 3.5 mmol/l ( 135mg/dl) </li></ul><ul><li>Statin or vitamins not considered clearly indicated or contraindicated by patient’s own doctors </li></ul><ul><li>* Lancet 2002;360:7-22 </li></ul>www.freelivedoctor.com
PRIOR DISEASE at BASELINE www.freelivedoctor.com
TOTAL & LDL CHOLESTEROL terciles at BASELINE www.freelivedoctor.com
SIMVASTATIN: Main conclusions <ul><li>After allowance for non-compliance, 40mg daily simvastatin safely reduces the risk of heart attack, of stroke, and of revascularisation by about one-third </li></ul><ul><li>5 years of statin treatment typically prevents these “major vascular events” in about: </li></ul><ul><li>100 of every 1000 people with previous MI </li></ul><ul><li> 80 " " " other CHD </li></ul><ul><li> 70 " " " cerebrovascular disease </li></ul><ul><li> 70 " " " other arterial disease </li></ul><ul><li> 70 " " " diabetes (age 40+) </li></ul><ul><li>irrespective of cholesterol level (or age, or sex, or other treatments) </li></ul>www.freelivedoctor.com
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
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
Are the effects of Statins solely explained by reduction in cholesterol ? <ul><li>Atherosclerosis can be viewed as an inflammatory process </li></ul><ul><li>Statins could affect inflammatory process by </li></ul><ul><ul><li>2ary effect on LDL uptake by macrophages (as source of CRP) </li></ul></ul><ul><ul><li>1ary effect on the acute phase-response </li></ul></ul><ul><li>Both scenarios suggest an exclusive focus on cholesterol reduction may be misplaced </li></ul>
Cardiovascular Risk Prediction: the role of hs-CRP (1) <ul><li>Women’s Health Survey – long term effects of ASA & vit E </li></ul><ul><li>Baseline samples from 27,939 patients </li></ul><ul><li>Mean age 55. 25% had HT, 12% smoked, 45% on HRT & 2.5% had DM </li></ul><ul><li>Followed for mean of 8 years </li></ul><ul><li>Endpoint of MI, stroke, revascularization of CV death </li></ul>Ridker et al , NEJM 2002;347:1557
Cardiovascular Risk Prediction: the role of hs-CRP (2) <ul><li>CRP provides additional risk prediction to that provided by Framingham risk assessor across all LDL-C groups. </li></ul>
Statins have an Effect on Inflammatory Markers such as CRP <ul><li>CHEST study (Heart 2003;5:2-7) – in 80 dyslipidaemic patients statins (atorva, simva and pravastatin) reduced CRP at 1 week with further falls up to 12 weeks. Fall in CRP correlated closely with the fall in LDL-cholesterol </li></ul><ul><li>PRINCE study (JAMA 2001;286:9) – primary prevention study of 1702 subjects randomised to placebo or 40mg prava and CRP followed to 24 weeks. Prava reduced CRP by 17% </li></ul><ul><li>Atheroscleosis 2003;166:129 – 186 Type2 DM patients randomised to placebo or 10/80mg atorvastatin. Atorva reduced CRP by 15 & 47% without significant effect on plasma IL-6 </li></ul>
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
Current Unresolved Issues on the Use of Statins <ul><li>For secondary prevention we should treat all patients with established IHD but … </li></ul><ul><ul><li>How soon after an event should they be started? </li></ul></ul><ul><ul><li>Is dose-titration versus LDL-chol still appropriate? </li></ul></ul><ul><ul><li>Should we simply put all patients on a high dose of a statin without titration in keeping with HPS? </li></ul></ul><ul><li>For primary prevention is the current threshold of 30% risk over 10 years too stringent? </li></ul>
Fibrates <ul><li> FA oxidation in muscle and liver and lipogenesis in the liver </li></ul><ul><li>Most effective at reducing VLDL (TG); smaller in LDL-chol but useful in HDL-chol </li></ul><ul><li>Act as PPAR ligands (cf glitazones) - reduced expression of Apo C11 is key to VLDL catabolism </li></ul><ul><li>Main side effects </li></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><ul><li>1-2% increase in the incidence of gallstones </li></ul></ul><ul><li>Important interactions </li></ul><ul><ul><li>increased risk of myositis on a statin </li></ul></ul><ul><ul><li>reduction in dose requirements (~30%) for patients on warfarin </li></ul></ul>
Nicotinic Acid <ul><li>1ary effect is reduced FA mobilization from the periphery hepatic VLDL synthesis </li></ul><ul><li>Is the agent with largest impact on HDL, and the only agent that lowers Lp(a) (by ~ 30%) </li></ul><ul><li>Usually employed in combination with fibrate, resin or statin – this avoids side effects of higher doses </li></ul><ul><li>Major side effects </li></ul><ul><ul><li>Flushing – prostaglandin mediated </li></ul></ul><ul><ul><li>Skin drying & GI intolerance </li></ul></ul>
Anion-Exchange Resins <ul><li>Sequester bile acids (BA) in the gut hence blocking enterohepatic cycling of BA e.g. cholestyramine and colestipol </li></ul><ul><li>2ary effect on cholesterol synthesis actually VLDL and hyperTG may limit use </li></ul><ul><li>Usually used in combination with a statin </li></ul><ul><li>Major side effect – not palatable and constipate </li></ul><ul><li>Important interactions – bind polar drugs such as warfarin, digoxin, thyroxine and statins give 1 hr before resin </li></ul>
‘ Super’ Statins <ul><li>New ‘Superstatins’ </li></ul><ul><ul><li>Rosuvastatin launched 2003, Pitavastatin expected 2005 </li></ul></ul><ul><li>‘ Super’ is an exaggeration </li></ul><ul><li>Do we really need them? </li></ul><ul><ul><li>No doubt that reduction in ischaemic end-points is a class-effect </li></ul></ul><ul><ul><li>Proven safety should probably be the major concern following cerivastatin withdrawal </li></ul></ul><ul><ul><li>Older statins going generic i.e. costs likely to fall </li></ul></ul>
Does the intensity of Lipid reduction matter? <ul><li>PROVE IT-TIMI 22 Trial (NEJM 2004; 350:1495) </li></ul><ul><li>designed as a non-inferiority study of the two agents </li></ul><ul><li>4162 patients within 10 days of an ACS were randomized to pravastatin 40mg/d or atorvastatin 80mg/d </li></ul><ul><li>followed up for mean of 24 months </li></ul><ul><li>Atorvastatin limb produced a 16% reduction in primary end point events </li></ul><ul><li>LDL-cholesterol was 1.6 mmol/l vs 2.46 in pravastatin limb </li></ul>Note early separation of event curves vs. 12-18 m delay in 2ary prevention trials – does this still reflect differences in the pleiotropic actions of the 2 statins?
The Z phase of the A to Z Trial: intense vs leisurely simvastatin, SS <ul><li>Patients with ACS randomised to either SS 40mg/d for 1/12 then 80mg/d OR placebo for 4/12 then SS 20mg/d </li></ul><ul><li>No difference in 1ary end point (composite CV death, non-fatal MI, ACS or need for revasc) in first 4/12 </li></ul><ul><li>Differences only obvious after 6-8/12 </li></ul><ul><li>Only 10 episodes of myopathy (9 in intense limb) </li></ul>
Newer Therapies - Ezetimibe <ul><li>Novel inhibitor of intestinal cholesterol transporter (? SR-B1) </li></ul><ul><li>Rapidly metabolised to glucuronide (EZEG) – which has 400x the potency of EZE and prolongs action by enterohepatic cycling </li></ul><ul><li>No important adverse effects OR significant drug interactions </li></ul><ul><li>Effective in mild/moderate HC as monotherapy or in combination with statins for moderate/severe HC where it acts synergistically </li></ul><ul><li>Unlike resins does not raise TG - actually falls and again synergism with a statin </li></ul>www.freelivedoctor.com
Emerging Therapy - Torcetrapib <ul><li>Novel inhibitor of cholesteryl ester transfer protein, (CETP), that is normally responsible for transfer of these esters from HDL to Apo-B1 => fall in HDL-cholesterol content and particle size. </li></ul>NEJM 2004;350:1505 <ul><li>small rise in HDL with atorvastatin 20mg/d </li></ul><ul><li>much larger and dose-dependent rise with Torcetrapib </li></ul>www.freelivedoctor.com
Important points <ul><li>Hyperlipidemia is common and a major risk factor for IHD and stroke </li></ul><ul><li>Intervention with a statin is highly effective and can reduce risk by ~ 1/3 rd </li></ul><ul><li>Statins are safe but still under prescribed even to high risk groups (e.g. diabetics) </li></ul><ul><li>HPS has still to impact on guidelines and clarification needed on the dogma of dose-titration </li></ul><ul><li>Prescription of statins is likely to expand substantially driven by appearance of generics and OTC sales? </li></ul>www.freelivedoctor.com