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Controversial issues in dyslipidemia management

Controversial issues in dyslipidemia management. By Ashraf Reda,MD Menoufiya university. ACS Regression of plaque Aggressive lipid lowering Guide lines Which statin to which pt.?. ACS Regression of plaque Aggressive lipid lowering Guide lines Which statin to which pt.?.

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Controversial issues in dyslipidemia management

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  1. Controversial issues in dyslipidemia management By Ashraf Reda,MD Menoufiya university

  2. ACS • Regression of plaque • Aggressive lipid lowering • Guide lines • Which statin to which pt.?

  3. ACS • Regression of plaque • Aggressive lipid lowering • Guide lines • Which statin to which pt.?

  4. ACS:PROVE-IT TIMI 22 4162 Pts With ACS 80mg Atorvastatin 40mg Pravastatin Mean follow up:24 months 95 mg/dl (2.46 mmol/l) 62 mg/dl (1.6 mmol/l) LDL 1ry end points 26.3% 22.4% 16%RRR (p0.005)

  5. ACS: A to Z trial • 2265 Pts with ACS receiving 40 mg/d of simvastatin for 1 month • followed by 80 mg/d thereafter • 2232 Pts with ACS patients receiving placebo for 4 months • followed by 20 mg/d of simvastatin ------------------------------------------------------------------------------ 6-24 months follow up Placebo-Simva (20)gr. Simva only(40/80) gr. Median LDL 1 month 8 months 122mg/dl 77mg/dl 68 mg/dl 63mg/dl --------------------------------------------------------------------------------------------------------------- [HR], 0.89; 95% [CI] 0.76-1.04; P =.14). 1ry EPs 343(16.7%) 309(14.4%) CVD 109(5.4%) 83(4.1%) HR, 0.75; 95% CI, 0.57 -1.00; P =.05) Myopathy occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin , and in 1 patient receiving placebo (P =.02).

  6. Is It due to Difference in LDL reduction or Different in anti inflammatory effect ?

  7. Statin effect and baseline CRP Evidence of an anti-inflammatory effect of statins Patients (n = 2,924) with ≥70% stenosis in ≥1 coronary artery average of 2.4 years after discharged on a statin prescription. .No early statin benefit .Survival curves separated after >2 years .improved survival .Curve separation:3months .Improved survival .Curve separation:1week CRP: <1.2 1.2 to 1.7 >1.7 mg/dl), Joseph B. Muhlestein, a,b,*, Jeffrey L. Anderson, a,b, Benjamin D. Horne, a, John F. Carlquist, a,b, Tami L. Bair, a, T.Jared Bunch, a, Robert R. Pearson,

  8. Treating to dual targets Investigators also further stratified patients based on levels of CRP and LDL cholesterol: LDL cholesterol >70 mg/dL and CRP >2.0 mg/L. LDL cholesterol >70 mg/dL and CRP <2.0 mg/L. II LDL cholesterol <70 mg/dL and CRP >2.0 mg/L. LDL cholesterol <70 mg/dL and CRP <2.0 mg/L. "Even with the most aggressive statin that we have used to date, 56% of patients still did not make it to the dual target,"

  9. What can we do to patient with LDL reaching the goal But wit persistently high CRP?

  10. ACS • Regression of plaque • Aggressive lipid lowering • Guide lines • Which statin to which pt.?

  11. Decrease the progression • Prevent progression • Regression • 0r is it the plaque stabilization?

  12. Main 1ry and 2ry end-point results of REVERSAL ----------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------- Nissen SE et al. JAMA 2004; 291:1071-1080. The effect on clinical out come?

  13. REVERSAL: Cholesterol levels and percent change Symptomatic CAD Pts with LDL: 125-210mg/dl ------------------------------------------------------------------------------------------ --------------------------------------------------------------------------------------- Nissen SE et al. JAMA 2004; 291:1071-1080.

  14. Simvastatin and plaque regression after 6 months of MRI-monitored therapy. 27 patients (treated with simvastatin 20 to 80 mg daily) (MRI) for aortic atherosclerotic plaque (AP) before and after 6 months of therapy AP volume was reduced from 3.3+/-0.1.4 to 2.9+/-1.4 cm3 at 6 months (P<0.02) luminal volume increase was less accentuated (from 12.0+/-3.9 to 12.2+/-3.7 cm3, P<0.06). LDL cholesterol decreased by 23% (from 125+/-32 to 97+/-27 mg/dL, P<0.05) in 6 months. ?LDL or CRP Circulation. 2004 Oct 19;110(16):2336-41. Lima JA, Desai MY, Steen H, Warren WP, Gautam S, Lai S.

  15. CRP reductions in REVERSAL Final LDL-C , mg/dL 110.4(25.2%) 78.9(-46.3%) Reduction of CRP May be related to the magnitude of LDL reduction Nissen SE et al. JAMA 2004; 291:1071-1080.

  16. ACS • Regression of plaque • Aggressive lipid lowering • Guide lines • Which statin to which pt.?

  17. Lower Cholesterol Levels Associated With Lower CHD Risk The Framingham Heart Study 150 125 100 CHD Incidence per 1000 75 50 25 0 265-294  204 205-234 235-264  295 Serum Cholesterol (mg/100 mL) Castelli WP. Am J Med. 1984;76:4-12.

  18. Relation of Serum Cholesterol to CHD Mortality The MRFIT Study 4 3.42 3 Mortality Relative Risk 2 2.21 1.73 1 n = 356,222 (35-57 yrs) 1.29 1 0 < 182 182-202 203-220 221-244 > 244 Serum Cholesterol (mg/dL) Stamler J, et al. JAMA. 1986;256:2823-2828.

  19. Increased Relative Risk of CHD Associated With Increasing LDL Levels ARIC Study Men 4.50 2.85 Relative Risk of CHD 1.80 Adjusted for age and race 12-year follow-up n = 5432 1.15 0.75 2.35 2.85 3.35 3.85 4.35 4.85 (mmol/L) 91 110 130 149 168 188 (mg/dL) LDL Cholesterol Adapted from Sharrett AR, et al. Circulation. 2001;104:1108-1113.

  20. ACS • Regression of plaque • Aggressive lipid lowering • Guide lines • Which statin to which pt.?

  21. New Features of ATP III • Modifications of Lipid Targets: • MAIN TARGET: LDL <100 mg/dL • HDL <40 mg/dL considered low (instead of 35 mg/dL) • Triglycerides >200 mg/dL considered to be high • Focus on Multiple Risk Factors: • Diabetes (without CHD) raised to the level of CHD equivalent • Support for Implementation: • Recommends complete lipoprotein profile (TC, LDL, HDL & TG) as preferred initial test NCEP-ATP III = National Cholesterol Education Program-Adult Treatment Panel III Expert Panel JAMA 2001;285(19):2486-2497; Wood D et al Atherosclerosis 1998;140:199-270; Sempos CT et al JAMA 1993;269(23):3009-3014; Pearson TA et al Arch Intern Med 2000;160:459-467

  22. LDL Cholesterol Goals for Therapeutic Lifestyle Changes (TLC) and Drug Therapy According to NCEP ATP III LDL-C Level for Consideration of Drug Therapy (mg/dL) LDL-C Level for Initiation of TLC (mg/dL) LDL-C Goal (mg/dL) Risk Category CHD or CHD Risk Equivalents (10-y risk > 20%) < 100  100 • 130 (100-129: drug optional) 2 + Risk Factors (10-y risk  20%) < 130  130 10-y risk 10%-20%:  130 10-y risk < 10%:  160 < 160  160  190 (160-189: LDL-C-lowering drug optional) 0-1 Risk Factor NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  23. Previous guidelines set the upper limit of normal according to the risk: 160, 130, 100 But They didn’t tell us how low should we go?

  24. Changes in the guide lines LDL 100 is not enough Moderate risk 2-3 RFs High risk Diabetic ------------------------------------------------------------------------------------------------------------ Treatment when > 130 Optional 100-129 Trigger is 130 ATPIII NCEP update Target<130 ----------------------------------------------------------------------------------------------------------- Target <130 Optional<100 Trigger is 100 Treatment when >100 Aim: 30-40% reduction ------------------------------------------------------------------------------------------------------------- Goal still <100, optional goal <70mg/dl Waiting for: TNT, SEARCH and IDEAL (aggressive lowering in stable Pts)

  25. Lipid profile among patients with ACS incardiology dep. Menoufiya university No % Mean (mg/dl) TC < 200mg/dl 25/40 62.5 160.3 Mean BNP 943.2 (N: up to 350) TC > 200mg/dl 15/40 37.5 238.9 Mean BNP 1376 TGs < 200 32/40 80 137.2 Mean BNP 988 TGs > 200 8/40 20 254 Mean BNP 1599.7 Data from file: Reda et al 2003

  26. Waiting for the big trials Treating to New Targets (TNT) trial(Atorva80 Vs Atorva 10) + 10000 CHD patients and should be completed in December 2004. In this trial, patients are treated to different goals to compare the conventional NCEP guideline of an LDL cholesterol goal of less than 100 mg/dL with a more aggressive LDL cholesterol goal of less than 75 mg/dL. The Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine with Simvastatin and Folic Acid/Vitamin B12(SEARCH) (Simva 20 Vs Simva 80) Compares the intensity of lipid lowering, rather than specific goals, in 12000 subjects who have had a prior MI. The Incremental Decrease in Endpoints through Aggressive Lipid Lowering(IDEAL) trial (Atorva 80 Vs Simva 20 or Simva 40) 7600-patient, investigating whether additional clinical benefits can be achieved by greater percentage reductions in LDL-cholesterol levels in patients with existing CHD.

  27. ACS • Regression of plaque • Aggressive lipid lowering • Guide lines • Which statin to which pt.?

  28. Should our targets differ? • ACS: • Chronic stable CAD • High LDL • Low HDL • RACE

  29. Pravastatin: Primary prevention (WOSCOPE) Secondary prevention (CARE, LIPID) Combination therapy Fluvastatin: PCI&ACS (LIPS) Diabetes & low HDL High Apo-B & small LDL Combination therapy Simvastatin High risk & Diabetes (HPS) Secondary prevention (4S) ACS (A to Z) Atorvastatin: ACS (MIRACLE, PROVEIT) Hypertension Decrease CRP (PROVE-IT, REVERSAL) Diabetes (CARDS)

  30. ACS • Regression of plaque • Aggressive lipid lowering • Guide lines • Which statin to which pt.?

  31. Thank you

  32. LDL and non-HDL cholesterol Patients with 0-1 risk factor (n=163) Patients with >2 risk factors (n=340) Patients with CHD or CHD risk equivalents (n=728) Patients with triglycerides >200 mg/dL who achieved ATP III LDL cholesterol goal (%) 78 71 52 Patients with triglycerides >200 mg/dL who achieved ATP III LDL cholesterol and non-HDL goals (%) 64 52 27 Percent of patients who achieved their LDL and non-HDL cholesterol goals Davidson MH, et al. Drugs Affecting Lipid Metabolism 2004 meeting; Oct 24-27, 2004; Venice, Italy; Abstract 204.

  33. Lipoprotein subclasses by race and gender

  34. What about HDL?

  35. 3,5 3 85 55 25 2,5 2 Relative Risk 1,5 1 0,5 0 100 160 220 LDL mg/dL Framingham Study:Relative Risk for CHD Impact of High LDL and Low HDL Kannel WB AJC 1983: 52: 9B -12B

  36. ARBITER-2: Niacin added to statin therapy slows atherosclerotic progression CAD pts with Low HDL And LDL at goal with statin N=167 One year: Statin+Niacin Vs Statin + Placebo LDL<89&HDL<45 with statin therapy HDL:39 47(21%) No significant progression in IMT Compared to the placebo group 2004 American Heart Association (AHA) Scientific Sessions, lead investigator Dr Allen Taylor

  37. Fluvastatin increases HDL cholesterol in type 2 diabetic patients Fluvastatin N=50 Atorvastatin N=50 Bevilacqua M et al. Drugs Affecting Lipid Metabolism 2004 meeting; October 24-27, 2004; Venice, Italy; Abstract 184.

  38. Percent change in study end points *Indicates primary end point Farnier M et al. Drugs Affecting Lipid Metabolism 2004 meeting; October 24-27, 2004; Venice, Italy.

  39. CETP inhibitors Kuivenhoven JA. Drugs Affecting Lipid Metabolism 2004 meeting; October 24-27, 2004; Venice, Italy.

  40. Side effects

  41. Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S). Death and cancer incidence in the original treatment groups ( median total follow-up time of 10.4 years) Simva Placebo RR 0.85 ,95% CI 0.74-0.97, p=0.02 No of deaths: 414 468 0.76 [0.64-0.90], p=0.0018 Coronary mortality 238 300 0.81 [0.60-1.08], p=0.14 Cancer death 85 100 0.88 [0.73-1.05], p=0.15 Incident cancer 227 248 Strandberg TE, Pyorala K, Cook TJ, Wilhelmsen L, Faergeman O, Thorgeirsson G, Pedersen TR, Kjekshus J; 4S Group.

  42. Genetic risk factors for statin myopathy found; coenzyme Q10, carnitine supplements might help the American College of Rheumatology 2004

  43. Absence of interaction between atorvastatin or other statins and clopidogrel: results from the interaction study. All patients (n = 75) received 325 mg of aspirin daily for at least 1 week and 300 mg of clopidogrel immediately prior to stent implantation atorvastatin (n = 25), any other statin (n = 25), or no statin (n = 25) for at least 30 days prior to stenting conventional aggregometry, rapid analyzers, and flow cytometry comparison of platelet biomarkers 4 and 24 • Statins in general, and atorvastatin in particular, do not affect the ability of clopidogrel to inhibit platelet function. • statins may inhibit platelets directly via yet unknown mechanism(s) possibly related to the regulation of the PAR-1 thrombin receptors Arch Intern Med. 2004 Oct 11;164(18):2051-7 Serebruany VL, Midei MG, Malinin AI, Oshrine BR, Lowry DR, Sane DC, Tanguay JF, Steinhubl SR, Berger PB,

  44. Stopping statins in the short-term is okay for stable patientsOct 13, 2004 • ACS: Abrupt discontinuation increase the risk • Chronic stable condition: Up to 6 weeks my not be risky Dr Mary P McGowan (New England Heart Institute, Manchester, NH) and colleagues from the Treating to New Target (TNT)

  45. Scientific Board Directors Prof. Dr. Ikram Sadek. Prof. Dr. Abdel Fattah Ferer. Prof. Dr. Samir Abdel Kader. Prof. Dr. Helmy Bakr. Prof. Dr. Saeid Shalaby. Prof. Dr. Ahmed Abdel Moneim. Prof. Dr. Abdulla Moustafa. Prof. Dr. Osama Sanad.

  46. Conference Guest Faculty (Chairpersons & Speakers are ordered alphabetically) Abdallah Abou Hashem Zagazig Abdallah Moustafa Menoufiya Abdel Moneim Ibrahim Cairo Adel Allam Al Azhar Adel El Banna NHI Adel El Etreby Ain Shams Ahmed Abdel Moneim Banha Ahmed Nassar Ain Shams Ahmed Shafie Amar Zagazig Aliaa Abdel Fattah Cairo Aly Ramzy Ain Shams Amany Serag Menoufiya Amr Serag Tanta Amr Zaki Alexandria Ashraf Ragab Cairo Ashraf Reda Menoufiya Ayman Abu El Magd Al Azhar Galal El Saied Cairo Hala Mahfouz Menoufiya Hany Ragui NHI Helmi Bakr Mansoura Hesham El Ashmawy Alexandria Hesham Hassan Menoufiya Hossam Kandil Cairo Ibtehag Hamdy Alexandria Ihab Abdel Fattah Menoufiya Ihab Attia Ain Shams Ikram Sadek Tanta Kawkab Khedr Alexandria Khairy Abd El Dayem Ain Shams Khaled Sorour Cairo Mahmoud Hassanein Alexandria May Salama Tanta Medhat El Ashmawy Tanta Mohamed Ashraf Cairo

  47. Mohamed Awad Taher Ain Shams Mohamed El Noomany Menoufiya Mohamed El Seteiha Tanta Mohamed Gamal Assiut Mohamed Hamed Badr Tanta Mohamed Sobhy Alexandria Mohamed Wafaii Zagazik Mohsen Ibrahim Cairo Mokhtar Gomaa Al Azhar Moustafa El Sayed Al Azhar Moustafa Nawar Alexandria Nabil El Kafrawy Menoufiya Nasser Rasmy Cairo Nesim Shaaban Tanta Omar Awwad Ain Shams Ossama Abd El Aziz Tanta Ossama Sanad Banha Ramez Guindy Ain Shams Ramzi El Mawardi Ain Shams Rania Gaber Tanta Saeid El Malah Menoufiya Saied Khaled Ain Shams Saied Shalaby Menoufiya Sameh Zaghloul Cairo Samir Abdel Kader Assiut Samir Rafla Alexandria Sherif El Beltagui Alexandria Sherif El Tobgi Cairo Sherif Mokhtar Cairo Taher El Kadi NHI Tarek Helmy Cairo Tarek Zaki Ain Shams Wagdy Ayad Alexandria Wagdy Galal Ain Shams

  48. Cairo: 13 Ain shams: 12 Menoufiya: 10 Alex: 10 Tanta: 9 Alazhar: 4 Zagazig: 3 NHI: 3 Banha: 2 Assuite: 2 Mansoura: 1 Military: 1

  49. Lipidology Plenary- 1 Chairperson(s) Mahmoud Hassanein, Alex 16:30-18:30Ossama Abd El Aziz, Tanta Samir Abdel Kader, Assiut Wagdy Ayad, Alex 16:30-16:55 Statin and ACS: When?, how and for whom ? Mohamed Wafaii Zagazig 17:00-17:25 The pleotropic effects of statin: Do they really matter? Omar Awad Ain Shams 17:30-17:55 Controversial issues in Dyslipidemia Ashraf Reda Menoufiya 18:00-18:25 HDL: The Forgotten target Ihab Attia Ain Shams

  50. Action- 1 19:00 - 20:00 Case Presentation & Panel Discussion 19:00-19:30 Case1: Aorto osteal restenotic lesion: Management of unexpected procedural complications Mohamed Ashraf Cairo Panelist(s): Ihab Abdel Fattah, Menoufiya Amr Zaki, Alexandria Mohamed Sobhy, Alexandria Tarek Zaki, Ain Shams 19:30 - 20:00 Case 2: Coronary intervention in a diabetic patients Hossam Kandil Cairo Panelist(s): Adel El Banna, Ain Shams Mohamed El Seteiha, Tanta Sherif El Tobgi, Cairo Nabil El Kafrawy, Menoufiya

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