Lipid lowering trials ppt

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collection of all important trials of lipid lowering druds

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  • there was early separation of the primary event curves. A post-hoc analysis showed that the reduction in MCEs was statistically significant within 6 months of randomization with rosuvastatin treatment (HR 0.62; 95% CI 0.40, 0.96; p=0.029). This significant treatment difference was continued throughout the trial.
  • Ischemic events occurred only in 13% in atorvastatingp when compared to 21% in the angioplasty gp.. A significant diference of 36%This was one trial that showed that in low risk pts with svd /dvd high dose statin even better than revascularisation. It Can delay or prevent the need for percutaneous revascularization.
  • There was a strong trend toward the reduction of major coronary event by 11% in high dose statin
  • Similarly there was 16% less relative reduction in high dose statin gp in the secondary outcomes (any coronary heart ds or any cardiovascular disease)
  • IN THE POST CABGS TRIAL , post bypass patients were randomised to receive either high dose statins with Lovastatin or the moderarate treatment and followed for 7.5 YRS
  • The primary endpoint occurred in 3.7% of pts treated with statin reload and in the 9.4% in the placebo arm; this difference is mostly driven by reduction in periprocedural myocardial infarction
  • Similar to REVERSAL trial, the ARBITER trial showed significant reduction of Carotid intima medial thickness with 80 mg of atrovastatin compared to 40 mg of pravastatin
  • In a metaanalysis of 18, 000 pts enrolled in various trials, the safety of the high dose of atorvastatin was conclusively established with an overall incidence of hepatic enzyme elevation of 1.43%, and only 4 patients with creatine kinase elevations 10 times the upper limit of normal
  • Lipid lowering trials ppt

    1. 1. LIPID LOWERING TRIALS DR.NAVIN AGRAWAL
    2. 2. INTRODUCTION  Earliest trials of lipid lowering with bile acid sequestrants  In 1971, Akira Endo, a Japanese reasoned that certain microorganisms may produce inhibitors of HMG CoA enzyme to defend themselves, as mevalonate is a precursor of many substances required by organisms for the maintenance of cell wall or cytoskeleton.  The first agent they identified was mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum.  Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs.  By 1978, Merck had isolated lovastatin (mevinolin, MK803) from the fungus Aspergillus terreus first marketed in 1987 as Mevacor.
    3. 3. Updated ATP III LDL-C Goals and Cutpoints for Therapy LDL-C (mg/dL) Initiation RISK FACTORS Level for Consideration Level for Cigarette smoking Risk Category TLC Drug Therapy  Hypertension (BP 140/90 mm HgGoal antihypertensive medication) or on CHD High risk: CHD or <100 100 100  Low HDL cholesterol (40 mg/dL), History of myocardial infarction <70) (<100: years of age; CHD history of premature CHD (CHD in male first-degree relative 55 consider drug (optional: Familyrisk equivalents CHD RISK EQUIVALENTS  Unstable angina options) (10-yr risk >20%) CHD in female first-degree relative 65 years of age)  Peripheral Arterial Disease  Stable angina Age:-men 45high risk: aortic aneurysm Moderately years; women 55 years. <130 130 130  Abdominal  Coronary artery procedures (angioplasty or bypass surgery) (100–129: consider drug 2+ risk factors (optional: <100)  Carotid artery significant myocardial ischemia. Evidence of clinicallydisease options) (10-yr risk 10–20%) ischemic attacks or stroke of carotid origin Transient  50% Moderate risk: obstruction of a carotid artery <130 130 160 2+ risk factors  Diabetes, (10-yr risk <10%) 2 risk factors with 10-year risk for hard CHD 20%. Lower risk: 0–1 risk factor <160 160 190 (160–189: LDL-C–lowering drug optional) Circulation 2004;110:227-239
    4. 4. 5-YEAR NNT VALUES FOR PRIMARY PREVENTION OF CVD Number Needed to Treat (5 years) 450 400 350 300 250 200 150 100 50 0 Ridker et al from the Jupiter study group
    5. 5. MAJOR STATIN TRIALS IN CAD Primary Prevention WOSCOPS AFCAPS/Tex CAPS ASCOT-LLA ALLHAT LLT CARDS ASPEN MEGA JUPITER Secondary Prevention 4S CARE LIPID GREACE TNT AVERT IDEAL ACS MIRACL PROVE IT-TIMI 22 A to Z (2004) STATIN STEMI ARMYDA-ACS ARMYDA-RECAPTURE
    6. 6. STATINS PRIMARY PREVENTION
    7. 7. WOSCOPS WEST OF SCOTLANDCORONARY PREVENTION STUDY 6995 MEN WITH NO CAD/ MEAN LDL 192 mg/ dL /F/U 5 YRS Primary Endpoint:-non fatal MI and CHD death 31% Risk Reduction 12 Pravastatin 40 mg 10 Placebo P=0.0001 8 Percent with 6 Events 4 2 0 0 1 2 3 4 5 6 Years in Study James Shepherd, et al, N Engl J Med 1995;333:1301-7
    8. 8. AFCAPS/TexCAPS AIR FORCE/TEXAS CORONARY ATHEROSCLEROSIS PREVENTIONSTUDY 5608 MEN,997 WOMEN,MEAN LDL 150//F/U 5.2 YRS Cumulative Incidence primary end point:-Fatal/Nonfatal MI, Sudden Cardiac Death, Unstable Angina 0.07 0.06 Placebo (n = 3301) Lovastatin (n = 3304) 37% risk reduction P < .001 0.05 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 >5 Years of Follow-up Downs JR, et al. JAMA. 1998;279:1615-1622.
    9. 9. CARDS THE COLLABORATIVE ATORVASTATIN DIABETES STUDY 2838 PATIENTS AGED 40-75 YRS WITH TYPE 2 DIABETES MELLITUS AND AT LEAST ONE OF: HYPERTENSION, RETINOPATHY, ALBUMINURIA, SMOKING. PRIMARY ENDPOINT: -ACS, REVASCULARIZATION, OR STROKE. MEDIAN F/U3.9 YEARS FOLLOW-UP,ATV 10 MG The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Atorvastatin reduced the death rate by 27%. ―The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld.‖ Colhoun HM et al. Lancet 2004;364:685-696.
    10. 10. JUPITER Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin • 17802 men>50 and women >60 yrs • LDL<130 • CRP>2 HAZARD RATIO • No CVD CAVEATS PRIMARY END POINT(1ST MACE):0.56 • No DM MI,STROKE,DEATH PATIENTS NOT INCLUDED 0.53 HIGH LDL AND LOW HS 1.9FROM CV CAUSE:• Median Follow Up CRPYrs HOSPITALIZATION:- 0.53 REVASCULARIZATION OR TRIAL STOPPED EARLY IN 2 YRS DEATH FROM ANYst Mace 0.80 • PrimaryEFFECTS OCCURING IN LATE THERAPY CANNOT BE RULED OUT ADVERSE End Point:- 1 CAUSE SMALL INCREASE IN BLOOD GLUCOSE AND HBAIC REPORTED From • Secondary End Point:-revasculariztion,hospitalisation Cv Cause,death From Any Cause • Randomized to rosuvastatin 20 mg vs placebo • Trial stopped early at 1.9 yrs of follow up Ridker PM et al NEJM 2008;2195
    11. 11. META ANALYSIS OF PRIMARY PREVENTION TRIALS  70 388 people, of whom 23 681 (34%) were women and 16 078 (23%) had diabetes mellitus. CAVEATS In patients without 4.1 years.  Mean follow-up was established cardiovascular disease but with cardiovascular risk factors, statin use was USE OF DIFFERENT TYPES AND DOSESsurvival and associated with significantlywith a significant risk improved OF STATINS Statin therapyRISKassociated DIFFERENT STUDIES DIFFERENT was PROFILE IN large in of major cardiovascular reduction reductions in the risk FOR DIFFERENT RISK BENEFITall cause mortality of 12%, in major coronary STRATIFIACTION events. GROUPS NOT DONE events of 30%, and in major cerebrovascular events of 19%.  No evidence of an increased risk of cancer was observed. J J Brugts et al BMJ 2009;338:b2376
    12. 12. STABLE CAD
    13. 13. 4S 4444 PTS WITH CAD,MEAN LDL 188MG DL/MEDIAN F/U 5.4 YRS/PLACEBO CONTROLLED PRIMARY ENDPOINT :-TOTAL MORTALITY Proportion Alive 1.00 0.95 0.90 0.85 Simvastatin Placebo 0.80 Log rank P = .0003 This improvement in survival is accounted for by the 42% reduction in the risk of coronary death. 0.00 0.0 1 2 3 4 5 6 Years Since Randomization Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.
    14. 14. CARE 4159 CAD PTS (3583 MEN/576 WOMEN)WITH MED LDL 139 /F U 5 YRS 15 Placebo Change in risk, 24% reduction P = 0.003 Incidence (%) Pravastatin(40 mg) 10 Nonfatal MI or CHD Death 5 0 0 1 2 3 Years 4 CABG ↓26% PCI ↓23% STROKE↓ 31% 5 TOTAL MI ↓25% FATAL MI ↓37% BENEFIT WOMEN>MEN ALL CAUSE MORTALITY DECREASED BY 9% Adapted from Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.
    15. 15. LIPID THE LONG TERM INTERVENTION WITH PRAVASTATIN IN ISCHAEMIC DISEASE(LIPID) STUDY 9014 CAD PTS ,RANDOMIZED TO PRVASTATIN 40G V/S PLACEBO F/U 6.1 YRS N Engl J Med 1998;339:1349-57
    16. 16. AVERT PRIMARY OUTCOME:-Ischemic Events 341 PTS ANGIOGRAPHICALLY DOCUMENTED CAD WITH EF>40% AND >4 MINUTES EXERCISE ON BRUCE RANDOMIZED TO HIGH DOSE STATIN/ANGIOPLASTY WITH STANDARD CARE/F / 18 MNTHS - 36% difference* 25 (P=0.048) CAVEATS 21% 20 SMALL NUMBER OF PATIENTS HIGH INCIDENCE OF CROSSOVER % of NUMBER OF EVENTS IN BOTH GROUPS WERE LESS 15 13% patients SHORT DURATION OF FOLLOW UP with an NOT APPLICABLE TO PATIENTS WITH HIGH RISK LESIONS OR TO 10 ischemic UNSTABLE PATIENTS event 5 0 Atorvastatin n=22 of 164 Angioplasty/UC n=37 of 177 Pitt B et al. N Engl J Med. 1999;341:70-76.
    17. 17. HPS 20536 WITH CAD OR DM/ RANDOMIZED TO SIMVASTATIN 40 MG VS PLACEBO/ FU 5 YRS PRIMARY OUTCOME:- MORTALITY OR FATAL OR NON FATAL CV EVENTS Among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70–100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). Lancet 2002; 360: 7–22
    18. 18. TNT TRIAL 10000 PTS,STABLE CAD,COMPARING HIGH AND LOW DOSE ATORVASTATIN Primary Composite of CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke 12% 10.9% 8.7% mean follow-up of 4.9 years 8% 4% 0% MEDIAN LDL 77 mg/dl High-dose N = 4995 MEDIAN LDL 101 MG/DL RRR= 22% HR=0.78 (0.69–0.89) P<0.001 Low-dose N = 5006 N Engl J Med. 2005;352:1425-1435
    19. 19. TNT TRIAL The individual components of the primary endpoint were also lower or tended to be lower in the high-dose group compared to the low-dose group with the exception of resuscitation after cardiac arrest, which was the equal in both groups. 8% P=0.004 6.2% 6% P=0.09 4.9% P=0.02 4% 3.1% 2.0% 2.5% 2.3% P=0.89 2% 0.5% 0.5% 0% CHD death Nonfatal MI High-dose Resuscitation after cardiac arrest Stroke Low-Dose N Engl J Med. 2005;352:1425-1435
    20. 20. IDEAL INCREMENTAL DECREASE IN ENDPOINTS THROUGH AGGRESSIVE LIPID LOWERING 8888 PTS WITH PRIOR MI.F U 4.8 YRS,ATV 80 MG V/S SIMVA 20 MG Reduction in primary endpoint Major coronary event* 16 Cumulative hazard (%) Simvastatin(20 -40mg) 11% RRR HR = 0.89 (95% CI, 0.78–1.01) P = 0.07 12 8 Atorvastatin(80 mg) 4 0 0 2 3 4 5 Time from randomization (years) No. at risk Simvastatin Atorvastatin 1 4449 4439 *Death from CAD, nonfatal MI, cardiac arrest with resuscitation 4293 4285 4165 4170 4037 4053 3917 3940 1200 1182 Pedersen TR et al. JAMA. 2005;294:2437-45.
    21. 21. IDEAL INCREMENTAL DECREASE IN ENDPOINTS THROUGH AGGRESSIVE LIPID LOWERING Reduction in SECONDARY endpoint Incremental Decrease in End Points Through Aggressive Lipid Lowering Any cardiovascular disease† Any coronary heart disease* 40 40 16% RRR HR = 0.84 (95% CI, 0.76–0.91) P < 0.001 30 16% RRR HR = 0.84 (95% CI, 0.78–0.91) P < 0.001 30 Simvastatin Cumulative hazard (%) Simvastatin 20 20 Atorvastatin 10 Atorvastatin 10 0 0 0 1 2 3 4 5 0 Time from randomization (years) No. at risk Simvastatin Atorvastatin 4449 4439 3937 3984 3920 3799 3527 3632 3370 3496 1 2 3 4 5 Time from randomization (years) 1002 1032 4449 4439 3841 3902 3580 3671 3338 3469 3127 3299 908 963 *Major coronary event, hospitalization for UA, coronary revascularizations †CHD endpoints, peripheral vascular disease, hospitalization for nonfatal CHF Pedersen TR et al. JAMA. 2005;294:2437-45.
    22. 22. POST CABG TRIAL 1351 PTS 1 TO 11 YRS POST CABG,ANGIOGRAPHIC F/ U FOR 4 YRS ANOTHER ARM OF STUDY COMPARED WARFARIN VS PLACEBO Mean ldl level in aggressive group was 85mg v/s 135 mg in placebo group AGGRESSIVE MODERATE GROUP TREATMENT N = 675 N = 675 LDL LEVEL (mg/dL) P VALUE 93-97 132-136 0.001 GRAFT Ath PROGRESSION 27 39 0.001 REVASCULARISATION AT 4 YRS 6.5 9.2 0.03 LOVASTATIN (mg/day) 40,80 2.5, 5mg - 8 8 - CHOLESTYRAMINE (gm) Primary end point: Mean per-patient percentage of grafts with significant progression in SVG ( 0.6 mm change) Secondary end point: New occlusions, new lesions, lumen narrowing Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.
    23. 23. POST-CABG ANGIOGRAPHIC OUTCOMES MRE Difference Moderate Aggressive % P value Progression 39 28 28 <0.001 New occlusions 16 10 40 <0.001 New lesions 21 10 52 <0.001 Mean lumen change in mm Minimum diameter -0.38 -0.20 48 <0.001 Mean diameter -0.34 -0.16 52 <0.001 MRE=Mean per-patient percentage of grafts. Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.
    24. 24. POST-CABG Event=PTCA or bypass surgery 15 P=0.03. 10 Moderate % Aggressive 5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Yr after enrollment Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.
    25. 25. STATINS USE IMPROVES SURVIVAL EVEN IN PATIENTS WITH EXTREMELY LOW LDL LEVELS 4295 PATIENTS (70%) MEAN AGE WAS 65 YEARS, 43% HAD PRIOR ISCHEMIC HEART DISEASE, AND 47% HAD DIABETES MELLITUS. FOLLOW-UP OF 2.0+-1.4 YEARS Mortality reduction by 35% CAVEATS NON RANDOMIZED STUDY NON BLINDED PRIMARY PHYSICIAN DEPENDENT DOSING AND DRUG PROTOCOL HIGH INCIDENCE OF CROSSOVER REDUCTION IN LDL FROM PLACEBO GROUP WAS LESS THAN EXPECTED MORBID PATIENTS WERE PROBABLY TAKEN OFF STATINS LEADING TO INFLATION OF MORTALITY IN NON STATIN GROUP No cases of rhabdomyolysis ↑ hepatic transaminase elevations, de novo malignancy or renal insufficiency Nicholas J. Leeper et al Circulation 2007;116:613-8
    26. 26. ACS
    27. 27. MIRACL 3086 PTS WITH UA:-24-96 HRS AFTER ADMISSION FOR 16 WEEKS Placebo + DIET Cumulative Incidence (%) 15 17.4% 14.8% Atorvastatin 80 mg + Diet 10 Relative risk = 0.84 p=0.048 Time to first occurrence of: • Death (any cause) • Nonfatal MI • Resuscitated cardiac arrest • Worsening angina with new objective evidence requiring urgent rehospitalization 5 0 0 4 8 12 16 Time since randomization (weeks) Schwartz GG et al. Jama 2001; 285: 1711-1718
    28. 28. Figure 4 Achieved CRP and LDL vs. Outcomes 4500PTS,40 MG OF SIMVASTATIN FOR 1 MONTH OF ACS F/B 80 MG THEREAFTER V/S PLACEBO FOR 4 MONTHS F/B 20 MG SIMVA FAILED TO ACHIEVE PRIMARY END POINT(P=0.14)BUT FAVOURED EARLY AND AGGRESSIVE STATIN REGIMENS JAMA. 2004;292:1307-1316
    29. 29. PROVE IT –TIMI 22 PRAVASTATIN OR ATORVASTATIN EVALUATION AND INFECTION THERAPY 4162 ACS (WITHIN 10 DAYS)PTS/STABLE AFTER WITH NO PCI PLANNING/F/U 18-36 MNTHS THERAPY 16 % Cannon CP, Eugene Braunwald, et al. N Engl J Med. 2004;350:1495-1504
    30. 30. PROVE IT–TIMI 22 Recurrent MI or Coronary Death (%) Clinical Relevance of Achieved LDL-C and Achieved CRP Combined after Statin Therapy 0.10 LDL 70 mg/dl, CRP 2 mg/L 0.08 LDL 70 mg/dl, CRP <2 mg/L LDL <70 mg/dl, CRP 2 mg/L 0.06 LDL <70 mg/dl, CRP <2 mg/L 0.04 LDL <70 mg/dl, CRP <1 mg/L 0.02 0.00 0.0 0.5 1.0 1.5 2.0 2.5 Follow-up (Years) Ridker PM et al. N Engl J Med 2005;352:20-28
    31. 31. LUNAR STUDY 825 PTS WITH ACS WITHIN 48 HOURS OF FIRST SYMPTOMS WERE RANDOMIZEDTO, ONCE-DAILY TREATMENT WITH RSV20,RSV40 OR ATV80 FOR 12 WEEKS.PRIMARY END POINT:-LDL LEVELS RSV40 more effectively decreased LDL cholesterol, increased HDL cholesterol, and improved other blood lipid parameters than ATV80 in patients with acute coronary syndrome. Bertram Pitt et al Am J Cardiol 2012;109:1239 –1246
    32. 32. PCI
    33. 33. ARMYDA ATORVASTATIN FOR REDUCTION OF MYOCARDIAL DAMAGE DURING ANGIOPLASTY 153 STATIN NAÏVE PTS WITH CHRONIC STABLE ANGINA RANDOMIZED TO 40 MG /DAY ATORVASTATIN V/S PLACEBO,CARDIAC ENZ MEASURED AT 0,8 AND 24 HRS PRIMARY END POINT;- PERIPROCEDURAL MI AND 30 DAY MACE Vincenzo Pasceri et al Circulation. 2004;110:674-678
    34. 34. ARMYDA-ACS 191 PTSWITH NSTEMI<48 HRS, ATORVASTATIN 80 MG 12 HRS AND 40 MG 2 HRS BEFORE PROCEDURE PRIMARY END POINT :-30 DAY MACE,SECONDARY :-PERIPROCEDURAL MI % 21 18 14/85 (17%) 13/85 (15%) 15 P=0.01 P=0.04 12 88% 9 4/86 (5%) 4/86 (5%) 6 1/85 (2%) 3 Individual and Combined Outcome Measures of the Primary End Point at 30 days 0 Death MI Atorvastatin TVR Placebo MACE Composite Primary End Point (30-day death, MI, TVR) J Am Coll Cardiol 2007;49:1272-8
    35. 35. ARMYDA-RECAPTURE 80 MG+40 MG BOLUS 12 HRS PRE PCI, EXCLUDED PATIENTS WITH STEMI,HIGH RISK ACS, DERANGED LFT AND RFT CR>3,EF<30% PRIMARY ENDPOINT:- OUTCOME MEASURES OF THE AT 30 DAYS 12 % 9.1 8.6 9 P=0.045 Atorvastatin 6 Placebo 3.4 3.4 3 0.5 0 Cardiac death 0.5 MI TVR MACE Composite Primary End Point REDUCTION OF 30 COMPOSITE MACE,NNT 17 Di Sciascio G et al J Am Coll Cardiol 2009
    36. 36. NAPLES II NOVEL APPROACHES FOR PREVENTING OR LIMITING EVENTS 80 MG LOADING 24 HRS BEFORE PCI/PTS WITH CHR STABLE ANGINA/30 DAY MACE Atorvastatin Group (N=338) Control Group (N=330) P value Death 1 (0.3%) 0 NS MI 33 (9.8%) 52 (15.8%) 0.014 Q-wave MI 1 (0.3%) 0 NS Non Q-wave MI 32 (9.5%) 52 (15.8%) 0.014 Unplanned revasc 0 0 - Stent thrombosis 2 (0.58%) 1 (0.30%) 0.57 Composite 34 (10%) 52 (15.7%) 0.029 EFFECT MORE PRONOUNCED IN PTS WITH HIGH BASELINE CRP Carlo Briguori et al J Am Coll Cardiol 2009;54:00–00
    37. 37. STATINS IN PERIPROCEDURAL ANALYSIS PCI META MI 30 DAY MACE Giuseppe Patti, et al Circulation. 2011;123:1622-1632
    38. 38. REGRESSION OF ATHEROSCLEROSIS
    39. 39. REVERSAL REVERSAL OF ATHEROSCLEROSIS WITH AGGRESSIVE LIPID LOWERING 502 SYMPTOMATIC CORONARY ARTERY DISEASE PATIENTS WITH ELEVATED LDL/FU 18 MNTHS/PRAVA 40 MG VS ATV 80 MG NISSEN SE ET AL, JAMA : 291 : 1071-1080 ; 2004
    40. 40. REVERSAL CONTINUOUS RELATIONSHIP BETWEEN LDL, CRP, AND PERCENT ATHEROMA VOLUME 3.5 3 2.5 2 1.5 Change In Percent Atheroma Volume (%) 1 0.5 0 -100 -75 -50 -25 0 Change In LDL-C (mg/dL) 25 3.5 2.5 1.5 0.5 Change In Percent Atheroma Volume (%) -0.5 -1.5 -2.5 -14 -12 -10 -8 -6 -4 -2 0 Change In CRP (mg/L) 2 4 6 Nissen et al. N Engl J Med. 2005;352:29. Nissen. Am J Cardiol. 2005;96(suppl):61F.
    41. 41. INTRAVASCULAR ULTRASOUND IMAGES AT BASELINE AND FU NISSEN SE ET AL, JAMA : 291 : 1071-1080 ; 2004
    42. 42. ARBITER ARTERIAL BIOLOGY FOR THE INVESTIGATION OF THE TREATMENT EFFECTS OF REDUCING CHOLESTEROL* COMPARISON OF ATV 80 mg, N = 79 VS PRAVASTATIN 40 mg, N = 82 ON CIMT 1 YEAR ATORVASTATIN  LDL ( mg/L) AT 1 YR  CIMT REGRESSION PRAVASTATIN P VALUE 76 23 ( - 48.5%) 110 30 ( - 27.2%) P = 0.001 - 0.034 0.02 0.025 + 0.017 p = 0.03 MARKED LDL REDUCTION WITH ATORVASTATIN PROVIDES SUPERIOR EFFICACY OR ATHEROSCLEROSIS REGRESSION AT 1 YR TAYLOR AJ ET AL : CIRCULATION 2002 ; 106 : 2055 – 2060
    43. 43. METEOR MEASURING EFFECTS ON INTIMA-MEDIA THICKNESS: AN EVALUATION OF ROSUVASTATIN 984 INDIVIDUALS,LOW RISK FACTORS MODEST CIMT THICKENING (1.2-3.5 MM), AND LDL MEAN, 154 mg/dl/F/U 2 YEARS/40 MG RSV VS PLACEBO Rosuvastatin resulted in statistically significant reductions in the rate of progression of maximum CIMT over 2 years vs placebo in pts of low cardiovascular risk(Framingham risk score<10%). Rosuvastatin did not induce disease regression. John R. Crouse IIIet al JAMA. 2007;297:1344-1353
    44. 44. ASTEROID • 507 patients randomized to Rosuvastatin 40mg/d vs placebo and atheroma volume measured by IVUS (349 pts followed up at 2y) • LDL-C decreased from 130mg/dL to 61mg/dL and HDL increased by 14.7% • Median change in atheroma volume – 0.79% with 5.6% decrease in the most diseased subsegments (p<0.001) • Well tolerated (1.8% patients had transaminase rise, none had CK >10 times) • Atheroma regression occurred in most patients and was not linked to the LDL cholesterol achieved Stephen D. Wiviott et al Am J Cardiol 2009;104:29–35
    45. 45. SATURN 1039 SUBJECTS ESTABLISHED CORONARY ARTERY DISEASE (CAD) ON ANGIOGRAPHY RSV40 MG OR ATV80 MG 24 MONTHS OTHER ATHEROSCLEROSIS REGRESSION STUDIES Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of PLACEBO FOR 6 MONTHS IN ACS ESTABLISH-ATORVASTATIN 20 MG V/Scoronary atherosclerosis. COSMOS-LOW DOSE RSV IN JAPANESE PTS FOR 76 WKS Despite the lower level of 20 MG-EQUIVALENT JAPAN ACS-PITAVASTAIN 4 MG VS ATV LDL cholesterol and the TOGETHAR-52higher level of HDL cholesterol achieved END POINTS ACHIEVED WKS OF 2MG PITAVASTATIN-SOME with rosuvastatin, a similar degree of regression of PAV was HATS:-COMBINATION OF STATIN AND NIACIN observed in the two treatment groups. ASAP:-SIMVASTATIN IN HYPERCHOLESTEROLEMIC PTS DECREASED CIMT STUDY IN DANISH MEN:-40 MG SIMVASTATIN Stephen J. Nicholls et al N Engl J Med 2011;365:2078-87.
    46. 46. HIGH DOSE STATINS META ANALYSIS 10 RCTs enrolling a total of 41778 participants. Trials followed patients for a mean of 2.5 years. Did not find statistically significant effects on all-cause mortality [relative risk (RR) 0.92]or cardiovascular disease (CVD) deaths (RR 0.89) Significant effect on non-fatal MIs (RR 0.82, P ≤ 0.0001) and a significant reduction in the composite of fatal and non-fatal strokes reported in 10 RCTs (RR 0.86,P=0.006).  A subgroup analysis of three trials examining ACS patients found significant effects on all-cause (RR 0.75 P ¼ 0.005) and CVD mortality (RR 0.74,P= 0.013) with intensive dosing. Edward J. Mills et al European Heart Journal (2011) 32, 1409–1415
    47. 47. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (p<0·0001) and other cardiac causes (p=0·002), with no significant effect on deaths due to stroke (p=0·5) or other vascular causes (p=0·8). MACE Cholesterol Treatment Trialists’ (CTT) Collaboration Lancet 2010; 376: 1670–81
    48. 48. ESC/EAS GUIDELINES European Heart Journal (2011) 32, 1769–1818
    49. 49. SPECIFIC SUBSETS DIABETES HYPERTENSION STROKE CONGESTIVE CARDIAC FAILURE PERIPHERAL AETERIAL DISEASE CHRONIC KIDNEY DISEASE AORTIC STENOSIS PERIOPERTIVE MORBIDITY ATRIAL FIBRILLATION WOMEN V/S MEN ELDERLY
    50. 50. EFFICACY OF CHOLESTEROL-LOWERING IN DIABETES META-ANALYSIS DIABETES Cholesterol Treatment Trialists’ (CTT) Collaborators,Lancet 2008; 371: 117–25
    51. 51. STATINS AND RISK OF INCIDENT DIABETES META-ANALYSIS 13 statin trials with 91140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy is associated with a slightly increased risk of development of Statin therapy was associated in absolute terms and when incident diabetes, but the risk is low both with a 9% increased risk for compared with diabetes (odds coronary events. the reduction in ratio [OR] 1·09; 95% CI 1·02–1·17), with little heterogeneity (I²=11%) between trials. Clinical practice in patients with moderate or high cardiovascular risk or Meta-regression showed that risk of development existing cardiovascular disease should not change. of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in difference between various statins Analyses also showed no clear LDL-cholesterol concentrations in terms accounted for of diabetes risk.residual variation in risk. Treatment of 255 (95% CI 150–852) patients with statins for 4 years resulted in one extra case of diabetes. Naveed Sattar et al Lancet 2010; 375: 735–42
    52. 52. EFFECT OF DIFFERENT STATINS ON INSULIN SENSITIVITY META ANALYSIS 16 studies (n = 1146) were included, with patients receiving Euglycemic three pravastatin inclamp trials (n =164), atorvastatin in five trials (n Minimum model (MIDMOD) = 315), rosuvastatin in five trials (n = 419),and simvastatin in Fasting (n = 369). five trialssampled intravenous glucose tolerance test (FSIVGTT) Insulin suppressiontest Quantitative When pooled insulin sensitivity check no significant impact on IS as a class, statins had index (QUICKI) Homeostasis model assessment (HOMA) as compared with placebo/control[ p = 0.19]. Matsuda index Stumvoll index Pravastatin was found to significantly improved IS [p Avignon index =.03], whereas simvastatin significantly worsened [p = 0.03]. William L. Baker Et Al Diabetes Research And Clinical Practice 87 (2010 ) 98 – 107
    53. 53. ALLHAT LLT HYPERTENSION 10355 HT PTS ,AGE >55 ,MEAN LDL 146,PRAVASTATIN40 MG V/S USUAL CARE/FU 8 YRS CAVEATS NON BLINDED DESIGN SMALLER THAN EXPECTED DECREASE IN CHOLESTROL IN THE 2 GROUPS 30% CROSS OVER RATE SUBSTANTIAL CHOLESTROL REDUCTION IN THE PLACEBO GROUP ASSESSMENT ONLY IN HYPERTENSIVE POPULATION PRAVASTATIN WAS USED
    54. 54. ASCOT 10305 PTS WITH HTN AND 3 OTHER RISK FACTORS, FU FOR 5.5 YRS PRIMARY ENDPOINT—NONFATAL MI AND FATAL CHD Cumulative Incidence (%) Atorvastatin 10 mg 100 Placebo 4 Number of events Number of events 154 36% reduction 3 2 1 0 0.0 HR = 0.64 (0.50–0.83); p = 0.0005 0.5 1.0 1.5 2.0 Years Excluded patients with MI, current angina or Cerebrovascular events within 3 months 2.5 3.0 3.5 Sever PS et al. Lancet 2003;361:1149–1158.
    55. 55. ASCOT SECONDARY ENDPOINT—FATAL MI AND NONFATAL STROKE Cumulative Incidence (%) 3 Atorvastatin 10 mg Number of events 89 Placebo Number of events 121 27% reduction 2 1 HR = 0.73 (0.56–0.96); p = 0.0236 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Sever PS et al. Lancet 2003;361:1149–1158.
    56. 56. ASCOT SECONDARY ENDPOINT—ALL CV EVENTS AND PROCEDURES Cumulative Incidence (%) 12 Atorvastatin 10 mg 389 Placebo 10 Number of events Number of events 486 21% reduction 8 6 Stopped prematurely after 3.3 y of f/u due to early benefits noted 4 2 HR = 0.79 (0.69–0.90); p = 0.0005 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Sever PS et al. Lancet 2003;361:1149–1158.
    57. 57. STROKE META ANALYSIS OF STATINS IN STROKE Statins is not associated with an increase in haemorrhagic stroke Statins reduce the incidence of stroke in high-risk populations (mainly patients with coronary heart disease, diabetes, or hypertension) even with a normal baseline cholesterol concentration. Whether they actually reduce the incidence of recurrent strokes in secondary prevention is unproved. Pierre Amarenco et al Lancet Neurol 2004; 3: 271–78
    58. 58. SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) HR=0.58 (95% CI, 0.46-0.73) P<.001; NNT/yr=144 HR=0.84 (95% CI, 0.71-0.99) P=.03; NNT/yr=257 Any Coronary Event (%) Fatal or Nonfatal Stroke (%) Placebo 13.1% Stroke (14.5%) Placebo 8.6% Coronary Event Cause-specific adjusted hazard ratios in the atorvastatin (33%) group, as compared with the placebo group, were 0.78 for ischemic stroke, 1.66 for hemorrhagic stroke, and 0.55 for unclassified stroke. Atorvastatin, 80 mg 11.2% 0 Atorvastatin, 80 mg 5.2% 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years since Randomization N=4731 patients with stroke or TIA within 1 to 6 months; Median follow-up: 4.9 years; Exclusion: patients with atrial fibrillation, and other cardiac sources of embolism, subarachnoid hemorrhage SPARCL Investigators. N Engl J Med. 2006;355:549-559.
    59. 59. Included published and unpublished data from 23 randomized trials and 19 observational studies. No evidence that statins were associated with intracerebral Hemorrhage; if The complete data set comprised 248 391 patients is likely to intracerebral hemorrhages. such a risk is present, its absolute magnitude and 14 784 be small and outweighed by the other cardiovascular benefits of these drugs Statins were not associated with an increased risk of intracerebral hemorrhage in randomized trials (risk ratio, 1.10)cohort studies (risk ratio, 0.94), or case-control studies (risk ratio, 0.60). Daniel G. Hackam et al Circulation2011;124:2233-2242
    60. 60. ESC/EAS GUIDELINES European Heart Journal (2011) 32, 1769–1818
    61. 61. HEART FAILURE Ten studies (10,192 patients) with follow-up from 3 to 47 months were included. Three trials randomized patients to rosuvastatin, 1 tosimvastatin, and 6 to atorvastatin. Overall, statins did not affect all-cause or cardiovascular mortality but did CAVEATS significantly decrease hospitalization for worsening HF during follow-up In conclusion, 0.008). (odds ratio [OR] 0.67, p meta-analysis of randomized controlled GISSI and CORONA study showed no benefit trials demonstrated trials are less The number of subjects in otherthat statins are safe and improve Patients randomized decrease had a significant 4.2% increase inHF. at LVEF and to statins hospitalization for worsening LVEF LVEF was not available for GISSI and CORONA studies and end of protocol. follow-up (95% confidence interval 1.3 to 7.1, p 0.004). No pathophysiological reason available to discriminate against rosuvastatin Heterogenous group of pts including iscaemic and non ischaemic HF patients Furthermore, post hoc analyses showed heterogeneity among different statins and demonstrated that randomization to atorvastatin significantly decreased all-cause mortality (OR 0.39, p 0.004), decreased hospitalization for worsening HF (OR 0.30, p <0.000 01), and randomization to atorvastatin and simvastatin led to a significant improvement in LVEF, whereas these benefits were not observed in patients randomized to rosuvastatin. Michael J. Lipinski et al Am J Cardiol 2009;104:1708–1716
    62. 62. EFFICACY OF STATIN THERAPY IN CHRONIC SYSTOLIC CARDIAC INSUFFICIENCY: META-ANALYSIS The pooling analysis showed that statin treatment did not significantly reduce the risk of all-cause death (RR=0.93, p=0.31), death for cardiovascular cause or pump failure (p=0.10), and rehospitalization for heart failure (RR=0.90, p=0.15). Although statin has little impact on clinical outcomes in overall CHF patients, non-significant trend towards is In addition, statin therapy had astatin administration if neededreduced risk of feasible to CHF patients, and the treatment might be nonfatal myocardial infarction (RR=0.84, p=0.08). effective when restricted to specific statins or populations. When restricted to various statins and patients' age, the analysis demonstrated that atorvastatin was associated with reduced all cause mortality (p=0.009) and readmission rate for heart failure (p=0.005), and the superiority of statin therapy was significant in CHF patients less than 65 years (both p=0.01). Shuning Zhang et al European Journal of Internal Medicine 22 (2011) 478–484
    63. 63. PERIPHERAL ARTERIAL DISEASE • Eighteen randomised controlled trials were included in the review, involving a total of 10,049 participants (78% were men). • Lipid-lowering therapies improved walking distance. • No mortality benefit. • CardiovascularLEADER MACE significantly decreased PQRST • Benefit only present with statins. HPS • The greatest evidence was with simvastatin in people with a blood cholesterol level of at least 3.5 mmol/litre ST THOMAS TRIAL • An improvement in total walking distance (Mean Difference152 m) and pain-free walking distance (MD 89.76 m) but no significant impact on ankle brachial index.(MD 0.04) • Results on Disease progression are inconclusive Aung PP et al. Cochrane Database of Systematic Reviews 2007
    64. 64. AURORA CHRONIC KIDNEY DISEASE ROSUVASTATIN IN SUBJECTS ON REGULAR HEMODIALYSIS: AND ASSESSMENT OF SURVIVAL AND CARDIOVASCULAR EVENTS MULTICENTER RCT,2776 PTS B/N 50-80 YRS ON MAINTAINENCE HD,BASELINE LDL 100 MG,RSV 10 MG V/S PLACEBO,F/U 3.8 YRS END POINT DEATH,NONFATAL MI AND STROKE MAJOR CARDIOVASCULAR EVENT CAVEATS BASELINE LDL 100 MG 10 MG ROSUVASTATIN EXCLUDED PATIENTS ALREADY ON STATIN LOWER PRIMARY END POINT SUGGESTS THAT SELECTION BIAS IN EXCLUDING PTS WHO WERE BELIEVED BY INVESTIGATORS TO REQUIRE STATINS INCLUDED ONLY PTS IN AGE GROUP OF 50-80 YRS HIGH PROPORTION OF DISCONTINUATION 4D ON DIALYSIS DEPENDENT DIABETIC PATIENTS AND ALERT ON RENAL TRANSPLANT PATIENTS CORROBORATED THE FINDINGS Bengt C. Fellstrom et al N Engl J Med 2009;360:1395-407
    65. 65. SHARP TRIAL STUDY OF HEART AND RENAL PROTECTION 9270CKD PTS,3023ON DIALYSIS,6427 NOT ON ,SIMVA 20 MG +EZETIMIBE 10 MG V/S PLACEBO /F/U 4.9 YRS CAVEATS NOT ENOUGH POWER TO COMPARE DIALYSIS AND NON DIALYSIS PATIENTS ONE THIRD OF PATIENTS CROSSED OVER TO THE DIALYSIS GROUP THE TRENDS OF DIFFERENCE IN MACE IN VARIOUS STAGES OF CKD WITH T/T WAS NOT DIFFERENT Colin Baigent et al Lancet 2011; 377: 2181–92
    66. 66. Bengt C. Fellstrom et al N Engl J Med 2009;360:1395-407
    67. 67. ESC/EAS GUIDELINES European Heart Journal (2011) 32, 1769–1818
    68. 68. NON RHEUMATIC AORTIC STENOSIS Meta-analysis identified 10 studies with a total of 3822 participants (2214 non-statin-treated and 1608statin-treated); five studies were classified as prospective and five as retrospective; three trials were randomised whereas seven were not. Currently available data do not support the use of statins to improve outcomes and toNo significantprogression in non-rheumatic calcific aortic valve stenosis. reduce disease differences were found in all-cause mortality, cardiovascular mortality or in the need for aortic valve surgery. Statins did not significantly affect the progression over time of peak and mean aortic gradient. Alessandro Parolaret al Heart 2011;97:523e529.
    69. 69. SEAS SIMVASTATIN AND EZETIMIBE IN AORTIC STENOSIS 1873 PATIENTS WITH MILD-TOMODERATE,ASYMPTOMATIC AORTIC STENOSIS. 40 MG OF SIMVASTATINPLUS 10 MG OF EZETIMIBE OR PLACEBO DAILY/FU 53.3 MONTHS N Engl J Med 2008;359:1343-56.
    70. 70. META ANALYSIS OR >30000 PATIENTS PERI OPERATIVE MORBIDITY 19 studies were identified [three RCT , 16 observational] that reported outcomes of 31725 cardiac surgery patients with (n ¼ 17 201; 54%) or without (n ¼ 14 524; 46%) preoperative statin therapy. Preoperative statin therapy resulted in a 1.5% absolute risk reduction (2.2 vs. 3.7%; P , 0.0001) and 43% odds reduction for early allcause mortality (OR 0.57; 95%CI: 0.49–0.67). A significant reduction (P , 0.01) in statin pretreated patients was also observed for AF (OR 0.67,), stroke (OR-0.74,), but not for MI (OR 1.11) or renal failure (OR 0.78, 95%CI: 0.46–1.31). Oliver J. Liakopoulos et al European Heart Journal (2008) 29, 1548–1559
    71. 71. ATRIAL FIBRILLATION In published data from 13 short term trials (4414 randomised patients, 659 events), statin treatment seemed to reduce the odds of an episode of atrial fibrillation by 39% (odds ratio 0.61, P<0.001), but there was significant heterogeneity (P<0.001) between the trials. The suggested beneficial effect of statins on atrial fibrillation from publishedterm and mostly studies is not In contrast,among 22 longer shorter term larger trials of statin versus a comprehensive review of published supported bycontrol (105 791 randomised patients, 2535 events), statin treatment was not associated with a significant and unpublished evidence from larger to 1.03; P=0.24) reduction in atrial fibrillation (0.95, 0.88 scale trials. (P<0.001 for test of difference between the two sets of trials). Seven longer term trials of more intensive versus standard statin regimens (28 964 randomised patients and 1419 events) also showed no evidence of a reduction in the risk of atrial fibrillation(1.00, 0.90 to 1.12; P=0.99). Kazem Rahimi et al BMJ 2011;342:d1250
    72. 72. WOMEN V/S MEN META ANALYSIS The cardiovascular event rate similar in women and men (OR: 0.81 and 0.77 respectively). Statin therapy is associated with significant decreases in The benefit of statins in all-cause mortality in women cardiovascular events and was statistically significant in both and men. sexes, regardless of the type of control, baseline risk, or type should be and in appropriate patients without Statin therapyof endpoint usedin both primary and secondary prevention. regard to sex.  All-cause mortality was also lower with statin therapy both in women and men without significant interaction by sex (p for interaction 0.4457). William J. Kostis et al J Am Coll Cardiol 2012;59:572–82
    73. 73. SECONDARY PREVENTION META -ANALYSIS ELDERLY (AGE>65) Jonathan Afilalo et al J Am Coll Cardiol 2008;51:37–45
    74. 74. NIACIN
    75. 75. Meta-analysis: Predictive Value of HDL Cholesterol CPPT: Coronary Primary Prevention Trial LRCF: Lipid Research Clinics Prevalence Mortality Follow-up Study MRFIT: Multiple Risk Factor Intervention Trial FHS: Framingham Heart Study 1% increase in HDL-C reduces CHD risk by 2-3%
    76. 76. Efficacy of Extended-Release Niacin HDL-C Change from Baseline 30 20 10 0 -10 -20 10% –3% –5% -30 15% 22% –9% –14% –17% –12% –22% –17% –11% –24% –28% -40 -50 500 mg 26% 30% 29.5% –21% LDL-C Lp(a) –30% –26% –35% –44% TG –39% 1000 1500 2000 2500 3000 mg mg mg mg mg Goldberg A et al. Am J Cardiol 2000;85:1100-1105.
    77. 77. RANDOMIZED CONTROLLED CLINICAL TRIALS OF NICOTINIC ACID Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol Source Imaging Studies Special Agent(s) Patients Receiving Treatment n/Total (%) Follow-up Duration, years Outcomesa ARBITER 2 Niacin + statin 87/167 (52.1) 1 Decreased carotid IMT (P>0.05) ARBITER 3 Niacin + statin 87/167 (52.1) 2 Decreased carotid IMT ARBITER 6 Niacin + statin 97/208 (46.6) 1.2 Decreased carotid IMT increase HDL-C by 21–24% Singh IM et al. JAMA. 2007;298:786–798.
    78. 78. AIM HIGH ADDITIONAL INVESTIGATORS IN THE ATHEROTHROMBOSISINTERVENTION IN METABOLIC SYNDROME WITH LOW HDL/HIGH TRIGLYCERIDES: IMPACT ON GLOBAL HEALTH OUTCOMES • 3414 participants with a history of CVD, LOW FALLACIES LDL<80 mg /dl low HDL-C(35 mg/dl), and high TG(164 mg), all of them on simvastatin and STOPPED PREMATURELY ezetimibe were randomized to either niacin in PLACEBO GROUP ALSO RECEIVED 50 MG IMMEDIATE RELEASE gradually increasing doses DISCLOSURE DUE TO day NIACIN TO MASK THE IDENTITY up to 2000 mg per FLUSHING (n=1718) or placebo (n=1696). STROKE INCIDENCE INCREASE WAS NOT SIGNIFICANT • NO CAUSAL RELATION OF NIACIN IN STROKE WAS ESTABLISHED OTHER STUDIES AND META ANALYSIS DO NOT CORROBORATE THE FINDINGS  LDL LEVELS WERE VERY LOW AT ENTRY AS 94% PTS WERE ON Of the participants, 515 were given a second STATINS LDL-cholesterol-lowering drug, ezetimibe , in order LESS GENERALIZABLE RESULTS DUE TO LOW WOMEN PERCENTAGE to maintain LDL-cholesterol levels at the target range -15% between 40 and 80 mg/dL. The AIM-HIGH Investigators N Engl J Med 2011;365:2255-67
    79. 79. MACE STROKE ANY CARDIOVASCULAR EVENT Eric Bruckerta et al Atherosclerosis 210 (2010) 353–361
    80. 80. HPS 2- THRIVE EXTENDED RELEASE NIACIN/LAROPIPRANT VERSUS MATCHING PLACEBO Primary endpoints:-heart attack or coronary death, stroke, or the need for revascularisation. Secondary endpoints:- is to assess the effects on heart attack, coronary death, stroke, and revascularisation separately and to assess the effects on mortality both overall and in various categories of causes of death, and of the effects on major cardiovascular events in people with a history of different diseases at the beginning of the study. Enrollment: 25673 Start Date: January 2007 Estimated Study Completion Date: January 2013
    81. 81. CETP INHIBITORS
    82. 82. RADIANCE 850 PTS WEITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA/ATORVA+-TORCETRAPIB,F/U 2 YRS N Engl J Med 2007;356:1620-30.
    83. 83. ILLUSTRATE 1188 CAD PTS ON ATV WITH LDL<100,RANDOMIZED,24 MONTH ,IVUS GUIDED FOLLOW UP PRIMARY ENDPOINT Change in Atheroma Volume from Baseline (%) 0.3 p=0.72  0.19% 0.2 0.12% 0.1 The percent change in atheroma volume did not differ between treatment groups 0 Torcetrapib Placebo N = 591 N = 597 Nissen SE et al. N Engl J Med 2007;356:13041316.
    84. 84. ILLUSTRATE Potential mechanism of adverse outcomes associated with Torcetrapib • Interaction with e-NOS lead to BP rise (RAAS) • Enlarged HDL with impaired interaction with SR-B1 of the liver • Induction of Endothelin1 secretion • Interfere with the reverse cholesterol transport • Aldosterone Like Effect
    85. 85. ILLUMINATE TRIAL RCT OF TORCETRAPIB+ATORVASTATIN (N = 7,533) VS. ATORVASTATIN ALONE (N = 7,534) IN PATIENTS AT HIGH RISK FOR CV EVENTS. PRIMARY ENDPOINT WAS MAJOR CV EVENT. Major CV Event Death 8 (HR 1.25, p = 0.001) 2 (HR 1.58, p = 0.006) 6.2 6 5.0 % 1.2 1 4 0.8 2 Results • Trial stopped early due to ↑ events in torcetrapib group • Increase in HDL at 12 months ↑ in torcetrapib group (+34.2 mg/dl vs. +0.5 mg/dl, p < 0.001) • SBP increase at 12 months ↑ in torcetrapib group (5.4 mm Hg vs. 0.9 mm Hg, p < 0.001) Conclusions • Torcetrapib in addition to atorvastatin was associated with increased major CV events and increased mortality compared with atorvastatin alone, despite being highly effective in raising HDL • Increase in blood pressure with torcetrapib did not fully explain the increased mortality • 0 0 Torcetrapib + Atorvastatin Atorvastatin N Engl J Med 2007;357:2109-22
    86. 86. DAL VESSEL/OUTCOMES TRIAL The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD. Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function, blood pressure, or markers of inflammation and oxidative stress. Thomas F. Lu scher1et al European Heart Journal (2012) 33, 857–865
    87. 87. • 30,000 patients with occlusive arterial disease in North America, Europe and Asia • Background LDL-lowering with atorvastatin • Randomized to anacetrapib 100 mg vs. placebo • Scheduled follow-up: 4 years • Primary outcome: Coronary death, myocardial infarction or coronary revascularization
    88. 88. FIBRATES
    89. 89. VA-HIT VETERANS AFFAIRS HIGH-DENSITY LIPOPROTEIN CHOLESTEROL INTERVENTION TRIAL (HIT) 2351 MALE PTS WITH CAD LOW HDL(MEAN 32 MG) AND MODERATE LDL(MEAN 111 MG)/GEMFIBROZIL1200 MG/ F U 5.1 YRS % Change 10 6% 5 0 0% -5 Gemfibrozil therapy resulted in a significant -10 reduction in the risk of major cardiovascular -15 events in patients with coronary disease whose primary -20 lipid abnormality was a low HDL cholesterol level. -25 -22% -22% -30 -29% -35 -31% LDL HDL TG NonfatalCHD Stroke MI or Death CHD Death Rubins HB et al. N Engl J Med. 1999
    90. 90. DAIS DIABETES ATHEROSCLEROSIS INTERVENTION STUDY 418 DIABETIC WITH GOOD GLYCEMIC CONTROL ,MILD LIPID ABNORMALITY AND DOCUMENTED CAD/50% PTS ASYMPTOMATIC,FENOFIBRATE V/S PLACEBO,FU 3YRS The trial was not powered to examine clinical endpoints, but there were fewer in the fenofibrate group than the placebo group (38 vs 50) DAIS suggests that treatment with fenofibrate reduces the angiographic progression of coronary-artery disease in type 2 diabetes.
    91. 91. FIELD 9795PTS WITH DM TYPE 2 /78% PTS WITH NO CAD/PRIMARY CHD DEATH OR NON FATAL MI,ALSO ASSESSED PROGRSSION OF COMPLCATIONS/F/U 5 YRS 11% Reduction P=.035 14 Event Rate, % 12 10 8 6 4 2 0 13.9 Placebo Fenofibrate was associated with less albuminuria progression 12.5 Fenofibrate (p=0·002), and less retinopathy needing laser treatment (5·2% vs 3·6%, p=0·0003). 21% Reduction P=.003 11% Reduction There was a slight increase in pancreatitis (0·5% vs 0·8%, p=0·031) P=.16 7.4 and pulmonary embolism (0·7% vs 1·1%, p=0·022), but no other 24% Reduction P=.01 5.9 5.9 significant adverse effects. 19% Increase 5.2 P=.22 4.2 Fenofibrate did not 3.2 significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular 2.2 1.9 events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. CHD events Nonfatal MI CHD Death Total CVD Coronary revascularization *Nonfatal MI and CHD death †CHD events, stroke, CVD death, revascularizations Keech A, et al. Lancet. 2005;366:1849-1861.
    92. 92. ACCORD 5518 DIABETIC PTS,SIMVASTATIN +/- FENOFIBRATE FU FOR 4.6 YRS PRIMARY OUTCOME OCCURNCE OF FIRST MACE The ACCORD Study Group N Engl J Med 2010;362:1563-74.
    93. 93. FIBRATES IN RISK REDUCTION META ANALYSIS Fibrate therapy reduced risk of vascular events (RR 0.75, P < 0.001); and in 5068 subjects with both high triglycerides and low HDL-C (RR0.71, P < 0.001). Fibrate treatment directed at markers of atherogenic dyslipidemia substantiallyneither high triglycerides Among 9872 subjects with reduce subsequent nor low event risk. vascularHDL-C,fibrate therapy did not reduce subsequent vascular events (RR 0.96, 95% CI 0.85 to 1.09, P = 0.53). Meng Lee et al Atherosclerosis 217 (2011) 492– 498
    94. 94. NUMBER OF CASES OF RHABDOMYOLYSIS IN COMBINATION THERAPY WITH STATINS* No. Cases Reported Per Million Prescriptions 10 8.6 9 8 7 6 5 15-Fold Increase 4 3 2 1 0.58 0 Fenofibrate Gemfibrozil *Excludes cases involving cerivastatin Jones PH, et al. Am J Cardiol. 2005;95:120-122.
    95. 95. EZETIMIBE
    96. 96. EXTENDED-RELEASE NIACIN OR EZETIMIBE AND CAROTID INTIMA–MEDIA THICKNESS Allen J. Taylor, M.D et al N Engl J Med 2009;361:2113-22
    97. 97. ARBITER 6-HALTS 315CAD PTS WITH LDL<100 AND HDL<50,F /U 14 MONTHSNIACIN/EZETIMIBE AS ADD ON THERAPY TO BASELINE STATINS/END POINT CHANGE IN CIMT Todd C. Villines, MD et al Am Coll Cardiol2010;55:2721–6
    98. 98. ENHANCE 720 PTS OF FAMILIAL HYPERCHOLESTEROLEMIA ON SIMVASTATIN+- EZETEMIBE/F/U 24 MONTHS END POINT –B MODE USG GUIDED MEASUREMENT OF CIMT John J.P. Kastelein Et Al N Engl J Med 358;14
    99. 99. IMPROVE IT IMPROVED REDUCTION OF OUTCOMES: VYTORIN EFFICACY INTERNATIONAL TRIAL • A multicenter, double-blind, randomized study to establish the clinical benefit and safety of vytorin (ezetimibe/simvastatin tablet) vs simvastatin monotherapy in high-risk subjects presenting with acute coronary syndrome • Primary Outcome Measures: death due to any cardiovascular events, non-fatal coronary events, and non-fatal strokes • Time Frame: Trial will continue until a minimum of 5,250 subjects have a primary endpoint event and each subject is followed for a minimum of 2.5 years • Enrollment: 18141 Study • Start Date: October 2005 • Estimated Study Completion Date: June 2013
    100. 100. BILE ACID SEQUESTRANTS • WHO CO-OPERATIVE TRIAL:-Pts randomized to clofibtrate had significantly higher mortality during 9.3 yr follow up . Cause unknown. Lancet. 1980 Aug 23;2(8191):379-85 • CORONARY DRUG PROJECT:-8341 post MI Men. Patients randomized to 5 groups.2 arms of estrogen,1 of thyroxine,1 arm of niacin and clofibrate1ST 3 arms discontinued,clofibrate had no benefit .only niacin showed 11% lower mortality compared to placebo.JAm Coll CardioI1986;8:1245-55 • LIPID RESEARCH CLINICS PRIMARY PREVENTION STUDY:-3806 Asymptomatic Pts With Familial Hypercholestrolemia randomized to cholestyramine v/s placebo.24% risk in CHD death.19% reduction in non fatal MI. This trial provided correlation of LDL and mortality. JAMA. 1984 Jan 20;251(3):351-64
    101. 101. META ANALYSIS ON COLSEVALAM (N = 1018). THIS INCLUDED 301( COL + METFORMIN TRIAL,)280 (COL + INSULIN TRIAL), AND 437 (COL + SULFONYLUREA TRIAL.  Three double-blind, placebo-controlled trials in T2DM have now independently confi rmed the HbA1c and LDL-C reductions with COL.  In each of the primary studies, a significant mean treatment difference in HbA1c (−0.54%, −0.50%, and −0.54%) and LDL-C (−15.9%, −12.8%, and −16.7%) resulted from the addition of 3.75 grams/day of COL to existing metformin, insulin, or sulfonylureabased therapy, respectively,  TG (15%)and APOA I increased and HDL was constant. Ishwarlal Jialal METABOLIC SYNDROME AND RELATED DISORDERS Volume 7, Number 3, 2009
    102. 102. OMEGA 3 FATTY ACIDS IN HIGH-RISK CV PATIENTS META-ANALYSIS A total of 29 RCTs (n = 35,144) with 25 reporting mortality and Possible 14 reporting restenosis. mechanisms of benefit Although not reaching conventional Reduction of arrhythmias statisticalrate Heart significance, the evidence to a statistically Omega-3 fatty acids were not associated with date suggests that omega-3(relative riskinjury 0.88) or with significant  Ischemia/reperfusion-inducedmay result decreased mortality fatty acids [RR]= in a Serum triglyceride levels  modest (RR = 0.89,), though and restenosis prevention reduction in mortalitythe probability of restenosis Inflammation some benefit remains high (0.93 and 0.90, respectively).  Improved endothelial function No serious safety issues were identified.
    103. 103. LIPID AND SIDE EFFECTS MONITORING
    104. 104. Adult Treatment Panel III guidelines 2003
    105. 105. ESC/EAS GUIDELINES European Heart Journal (2011) 32, 1769–1818
    106. 106. SUMMARY OF GUIDELINES OF PHARMACOTHERPY ESC/EAS GUIDELINES European Heart Journal (2011) 32, 1769–1818
    107. 107. TAKE HOME MESSAGE  In coronary artery disease ,stroke,perioperative morbidity the role of statins is unquestionable  Role of statins in heart failure, aortic stenosis, and atrial fibrillation needs further evaluation.  Ezetimibe lowers cholesterol but not the primary end points  Niacin are rather underused.  CETP inhibitors are not recommended(as of now)

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