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ALL YOU NEED TO KNOW ABOUT LIPIDS BUT WERE AFRAID TO ASK!

ALL YOU NEED TO KNOW ABOUT LIPIDS BUT WERE AFRAID TO ASK!. Dr. Pat Twomey, Consultant Chemical Pathologist The Ipswich Hospital. CHEMICAL PATHOLOGIST. Clinical activity Currently Lipid/Cardiovascular Risk Clinic Nutrition Obesity Metabolic Previously Diabetes Clinics

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ALL YOU NEED TO KNOW ABOUT LIPIDS BUT WERE AFRAID TO ASK!

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  1. ALL YOU NEED TO KNOW ABOUT LIPIDS BUT WERE AFRAID TO ASK! Dr. Pat Twomey, Consultant Chemical Pathologist The Ipswich Hospital

  2. CHEMICAL PATHOLOGIST • Clinical activity • Currently • Lipid/Cardiovascular Risk Clinic • Nutrition • Obesity • Metabolic • Previously • Diabetes Clinics • Endocrinology Clinics

  3. CHEMICAL PATHOLOGIST • Laboratory Interpretation • GMS2 and training changes increase this • Laboratory Management • Utilisation of laboratory tests • Laboratory organisation • Quality • Research (if I am lucky)

  4. CHEMICAL PATHOLOGIST • Trained in • Cork • Dublin • Edinburgh

  5. THE STONE OF ELOQUENCE • Blarney Castle is famous for its stone, which is traditionally believed to have the power to bestow eloquence on all those who kiss it.

  6. THE BRITISH ISLES

  7. THE BRITISH ISLES ADJUSTED FOR I.Q.

  8. THE BRITISH ISLES ADJUSTED FOR I.Q.

  9. DISCLOSURE1 • Shares – None • Advisory Boards • AstraZeneca • Novartis • Presentations • Abbot • AstraZeneca • Bayer • Fournier • Glaxo Smith Kline • Merck • MSD • Novartis • Pfizer • Roche • Takeda 1. Pharmaceutical Companies

  10. THE STONE OF ELOQUENCE • Blarney Castle is famous for its stone, which is traditionally believed to have the power to bestow eloquence on all those who kiss it. • Questions at anytime.

  11. Lipids • What are they? • Name some lipids? • Why are they important?

  12. Turbidity • What is it? • What causes it? • What wavelengths are involved? • Are all assays affected at these wavelengths?

  13. Interfering spectra Absorbance NADH Turbidity Hemolysis Icterus 340415450510 570 600 700 800 Wavelength (nm)

  14. CVD Risk factors • What are they?

  15. Serum Cholesterol Levels in Men* Framingham Heart Study 40 MI No MI 30 % Population 20 10 0 150 200 250 300 350 400 450 (mg/dl) (mmol/L) 3.9 5.2 6.5 7.8 9.1 10.3 11.6 Serum cholesterol *During first 16 years of study: Entry ages 30–40 years Adapted from Castelli WP Can J Cardiol 1988;4(suppl A):5A-10A.

  16. Increased HDL and Reduced CHD Incidence Framingham Study (mmol/L) (5.7) (4.1) (2.6) 3 LDL 220 mg/dl LDL 160 mg/dl LDL 100 mg/dl 2 Relative risk of CHD 1 0 25 0.65 35 0.90 45 1.16 55 1.42 65 1.68 75 1.94 85 2.20 (mg/dl) (mmol/L) HDL Adapted from Kannel WB. Status of risk factors and their consideration in antihypertensive therapy. Am J Cardiol 1987;59:80A-90A.

  17. Copenhagen Male Study Relative Risk for Ischemic Heart Disease (IHD) during 8 Years according to Level of Fasting Triglycerides Adjusted for: Age LDL-C HDL-C Alcohol use Tobacco Physical activity BMI SBP/DBP HTN NIDDM Glycosuria Low social class 4 3 P <.001 Relative risk of IHD 2 2.2 P <.05 1.5 1 1.0 0 (mmol/L) (mg/dl) 0.88 (0.44–1.09) 78 1.33 (1.10–1.59) 117 2.45 (1.60–22.4) 217 TG level (thirds) Adapted from Jeppesen J et al Circulation 1998;97:1029-1036.

  18. Lipoproteins • Name as many lipoproteins as you can?

  19. Lipoproteins • LDL • HDL • Chylomicrons • Chylomicron remnants • VLDL • IDL (VLDL remnants) • Lp (a)

  20. Lipoproteins • Where do they come from?

  21. C-II HDL Metabolism and Atherosclerosis Chylomicron Chylomicron Remnant B Intestine LPL B E B B C-II LPL C-II HL B LPL E Oxidation LRP IDL E LDLr LDL CD36SR-A VLDL SR-BI CholesterolPool Lipids CETP A-I Liver A-I LCAT ABC1 HDL-R Kidney NascentHDL Arterial WallMacrophage HDL Courtesy of HB Brewer Jr, MD

  22. Lipoprotein Treatment Priorities • Total cholesterol (LDL cholesterol) • HDL cholesterol • Triglycerides

  23. UKPDS: Major Identified Risk Factors • LDL cholesterol • Diastolic blood pressure • Smoking • HDL cholesterol • HbA1C Adapted from Turner RC et al BMJ 1998;316:823-828.

  24. Cost Effectiveness • ‘in determining health policy, cost effectiveness rather than the cost of drugs is of pivotal importance. It is clear that treatment of the elderly and those at highest risk is more cost effective’ Joint British Recommendations Dec 1998

  25. Number of individuals needed to be treated (NNT) to prevent a coronary event versus underlying CHD risk* 50 WOSCOPS all 40 30 WOSCOPShigh risk NNT 20 4 S 10 Primaryprevention Primaryprevention(high risk) Secondaryprevention 0 0 1 2 3 4 5 6 % CHD event rate/year *Data taken from several recent clinical trials.

  26. CHD Mortality in Type 2 Diabetics 100 80 60 40 20 0 Non-diabetic, no MI (n=1304) Type 2, no MI (n=890) Non-diabetic, MI (n=69) Type 2, MI (n=169) % Survival 0 1 2 3 4 5 6 7 8 Years Adapted from Haffner SM et al (East-West Study in Finland) New Engl J Med 1998;339:229-234.

  27. 2o causes of dyslipidaemia • Obesity • Diabetes Mellitus • Alcohol abuse • Liver disease • Renal disease • Hypothyroidism • Medication

  28. Why rule out 2o causes? • Good medicine - treat the cause, not the resulting condition • Increased side effects, e.g., hypothyroidism and statins

  29. How low should we go?

  30. Lipid Management in Clinical Practice What Is an Appropriate Therapeutic Target for LDL Cholesterol? 0 LRC-CPPT (cholestyramine) 20 CARE (pravastatin) WOSCOPS (pravastatin) % Reduction in risk ofcardiac endpoints 40 4S (simvastatin) ? 70 ? 10 13 26 35 50 60 % LDL-C reduction LRC-CPPT = Lipid Research Clinics–Coronary Primary Prevention Trial; CARE = Cholesterol and Recurrent Events; WOSCOPS = West of Scotland Coronary Prevention Study; 4S = Scandinavian Simvastatin Survival Study

  31. Lipids • ‘at least to an LDL cholesterol less than 3.0 mmol/L (total cholesterol less than 5.0 mmol/L)’ in established CHD • ‘Patients who fail to reach this target should be referred to a specialist clinic’ Joint British Recommendations Dec 1998

  32. Lipids - rechecking • 3 months after dietary advice • 4 - 6 weeks after drug initiation/change in dosage

  33. QUESTIONS • Do high risk populations achieve similar benefit irrespective of starting cholesterol (or LDL-C) concentrations? • Is there benefit from starting statins immediately post-event rather than waiting until 3-6 months as in 4S, CARE etc.? • Do high risk populations achieve extra benefit from intensive cholesterol (or LDL-C) lowering?

  34. HPS: VASCULAR EVENT by PRIOR LIPID LEVELS Baseline STATIN PLACEBO Risk ratio and 95% CI feature (10269) (10267) STATIN better STATIN worse LDL (mmol/l) < 3.0 (116 mg/dl) 602 761 c  2 3.0 < 3.5 483 655 Het = 3.0 2  3.5 (135 mg/dl) 957 1190 Total cholesterol (mmol/l) <5.0 (193 mg/dl) 361 476 c  5.0 < 6.0 746 965 2 Het = 0.5 2  6.0 (232 mg/dl) 935 1165 ALL PATIENTS 2042 2606 24% SE 2.6 reduction (19.9%) (25.4%) (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 MRC/BHF Heart Protection Study. Lancet 2002;360:7-22.

  35. Lipid Lowering and Recent Statin Trials • MIRACL • REVERSAL • PROVE IT – TIMI 22

  36. Acute coronary event No history of CAD Unstable CAD Stable CAD 4 mo AFCAPS / TexCAPS/WOSCOPS MIRACL t=0 CARE/LIPID 3 mo 4S 6 mo Randomization:24–96 h Randomization:>6 mo Randomization:CARE - 3–20 moLIPID - 3–36 mo Primary prevention Secondary prevention MIRACL: Addressed a Research Gap Schwartz GG et al. Am J Cardiol 1998;81:578–581.

  37. Hospitalisationforunstable anginaor non-Q-wave MI n=3,086 Randomised 24-96 hours after admission Placebo Atorvastatin 80 mg 16 weeks Assessments conducted at weeks 0, 2, 6 and 16 MIRACL - Study Design Study Hypothesis: Lipid lowering with atorvastatin 80mg started within 24 - 96 hours of hospitalisation following diagnosis of unstable angina or non-Q-wave acute MI, reduces early recurrent ischaemic events. Schwartz GG et al. JAMA 2001; 285(13)1711-1718

  38. Lipids at Randomisation and Study End Baseline End of study Mean of both groups % Change Atorvastatin vs. placebo mmol/L Total cholesterol 5.3 -34% LDL cholesterol 3.2 -52% (1.9mmol/L) HDL cholesterol 1.2 +1.6% Triglycerides 2.0 -25% Schwartz GG et al. JAMA 2001; 285(13)1711-1718

  39. Placebo 17.4% 15 14.8% Atorvastatin 10 Cumulative incidence (%) • Time to first occurrence of: • Death • Nonfatal MI • Resuscitated cardiac arrest • Worsening angina with objective evidence of ischaemia requiring rehospitalisation Relative Risk = 0.84(0.70-1.00), p=0.048 5 0 0 4 8 12 16 Time since randomisation (weeks) Relative Event Rate Reduction in Primary Endpoint Schwartz GG et al. JAMA 2001; 285(13)1711-1718

  40. REVERSAL 657 CHD Patients Atorvastatin 80mg Pravastatin 40mg 253 patients with IVUS at baseline and 18 months 249 patients with IVUS at baseline and 18 months • Randomised, double blind multicentre trial performed at 34 community and tertiary care centres in the United States • Primary endpoint: % change in Coronary Plaque Volume by IVUS Nissen SE et al. JAMA 2004; 291(9)1071-1080

  41. Patient Population • Inclusion criteria: • Patients aged 30-75 years requiring diagnostic coronary angiography for a clinical indication • LDL-cholesterol between 3.2 mmol/L and 5.4 mmol/L • Angiographic inclusion criteria: • Angiographic evidence of CHD defined as ≥ 1 lesion with ≥ 20% reduction in lumen diameter in any coronary artery • ≤ 50% reduction in lumen diameter of the left main coronary artery • The vessel undergoing IVUS evaluation (the ‘target’ vessel) should have ≤ 50% stenosis throughout a segment of minimum length of 30 mm Nissen SE et al. JAMA 2004; 291(9)1071-1080

  42. Intravascular Ultrasound (IVUS) Nissen SE et al. JAMA 2004; 291(9)1071-1080

  43. % Change from Baseline in Lipid Parameters Triglycerides HDL-cholesterol Total cholesterol LDL-cholesterol 10 2.9 5.6 0 -6.8 -10 Change from baseline (%) -20 -18.4 -20.0* Pravastatin -25.2 -30 Atorvastatin -34.1* -40 -46.3* -50 2.04mmol/L *P<.001 Nissen SE et al. JAMA 2004; 291(9)1071-1080

  44. Pravastatin Atorvastatin Percent Change in Total Atheroma Volume 3.5 Progression (p=0.001*) 3 % Change in Total Atheroma Volume 2.7 2.5 p = 0.02† 2 1.5 1 0.5 0 -0.4 -0.5 No change (p=0.98*) -1 * vs baseline † between groups Nissen SE et al. JAMA 2004; 291(9)1071-1080

  45. Comparative Adverse Events Nissen SE et al. JAMA 2004; 291(9)1071-1080

  46. Study Limitations • The REVERSAL study was not powered to assess differences in clinical events • Morbidity and mortality endpoints are always the preferred efficacy measures in clinical trials • However, comparison of two statins in a conventional events trial would require approximately 10,000 patients and 5-6 years follow-up • Furthermore, previous trials have demonstrated a relationship between atherosclerosis progression and vascular events Nissen SE et al. JAMA 2004; 291(9)1071-1080

  47. PROVE IT – TIMI 22 Rationale • Are statins effective in reducing cardiac events when started early after an acute coronary syndrome (ACS)? • Do the benefits of “intensive” LDL-C lowering to ~1.8mmol/L with 80mg atorvastatin achieve a greater reduction in clinical events than “standard” LDL-C lowering to ~2.6mmol/L with 40mg pravastatin? (Pravastatin Or Atorvastatin Evaluation and Infection Therapy - Thrombolysis in Myocardial Infarction 22) Cannon CP et al. NEJM 2004; 350(9):15

  48. PROVE IT – TIMI 22: Study Design 4,162 patients with an Acute Coronary Syndrome < 10 days ASA + Standard Medical Therapy • Randomised, double blind study • 349 sites in 8 countries • Designed as a non - inferiority trial Standard Therapy (Pravastatin 40 mg) Intensive Therapy (Atorvastatin 80 mg) 2x2 Factorial: Gatifloxacin vs. placebo • Primary Endpoint: Death, MI, Documented UA requiring hospitalisation, • Revascularisation (>30 days after randomisation), and Stroke Duration: Mean 2 year follow-up (> 925 events) Cannon CP et al. NEJM 2004; 350(9):15

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