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Atorvastatin:  Statins in CVD management. Is just lipid lowering enough

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Atorvastatin:  Statins in CVD management. Is just lipid lowering enough

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When it comes to management of cardiovascular diseases, are achieving lipid lowering targets sufficient. Here Dr Vivek Baliga, Consultant Internal medicine discusses the additional benefits of statins in CVD in India.

When it comes to management of cardiovascular diseases, are achieving lipid lowering targets sufficient. Here Dr Vivek Baliga, Consultant Internal medicine discusses the additional benefits of statins in CVD in India.

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Atorvastatin:  Statins in CVD management. Is just lipid lowering enough

  1. 1. Statins in CVD management : Is just lipid lowering enough? Dr Vivek Baliga Consultant Internal Medicine Director, HeartSenseTM www.heartsense.in
  2. 2. Preamble • Statins were originally introduced as lipid lowering drugs, but today they are recommended in many high risk patient groups irrespective of baseline lipid levels. • This suggests that benefits of statins are beyond and independent of lipid lowering effects. • So Choice of statin should be based on evidence of CV benefits rather than lipid lowering
  3. 3. Primary Prevention of CVD • As per AHA 2013, guidelines all T2DM patients of age 40-75 require either moderate or high dose statin therapy
  4. 4. 2016 ADA guidelines for statins in DM Diabetes Care 2016;39(supple 1): S1-S112
  5. 5. All DM patients with> 1 CV risk factor require moderate to high dose statin But what is the evidence that statins reduce CV events in T2DM patients without high LDL-C?
  6. 6. MI Risk in Diabetics Without Prior MI Equivalent to Nondiabetic With MI Haffner SM et al. N Engl J Med. 1998;339:229-234. Numbers in bars represent number of persons in category at baseline. Finnish population study (7-year follow-up) 3.5 20.218.8 45 0 10 20 30 40 50 60 Patients without diabetes Patients with diabetes Incidenceoffatal/nonfatalMI during7-yearfollow-up(%) No prior MI Prior MI P<0.001 P<0.001 P<0.001 for diabetes vs no diabetes 8901304 69 169
  7. 7. Diabetes is CHD equivalent
  8. 8. RM Parikh et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 4 (2010) 10–12 85.5% Dyslipidemia 97.8 % Dyslipidemia 85.5 % Prevalence of Dyslipidemia (%) in Male T2 DM Prevalence of Dyslipidemia (%) in Female T2DM In India, 90% diabetics have dyslipidemia
  9. 9. Study Patients Follow up Results ASCOT LLA * 2532 Atorvastatin 10 mg 3.3 yrs 23% risk reduction CARDS 2838 Atorvastatin 10 mg 3.9 yrs 37% risk reduction HPS * 2912 Simvastatin 40 mg 5 yrs 33% risk reduction Major Statin Primary Prevention Trials In DM * sub-analysis Only Atorvastatin and Simvastatin have evidence that statin reduce CV events in Primary prevention. OTHERS DO NOT HAVE SUCH EVIDENCE!
  10. 10. 4-year follow-up CARDS: primary prevention in T2DM Atorvastatin 10 mg/day (n=1428) Placebo (n=1410) 2838 patients Primary end point:  Incidence of major cardiovascular events: – Cardiovascular-related death – Nonfatal MI – Stroke – Resuscitated cardiac arrest – Unstable angina – Coronary revascularization procedures Patient population:  Age: 40-75 years  LDL-C 160 mg/dL  Triglycerides 600 mg/dL  Type 2 diabetes  No prior MI or CHD  1+ CHD risk factor C o l h o u n H M e t a l . L a n c e t . 2 0 0 4 ; 3 6 4 : 6 8 5 - 6 9 6 . CARDS: Collaborative Atorvastatin Diabetes Study At Baseline, LDL-C: 120 mg/dl HDL-C: 54.5 mg/dl Non-HDL-C: 153 mg/dl
  11. 11. CARDS: Atorvastatin reduces CV events by 37% *Acute CHD event, coronary revascularization, stroke. RRR: Relative risk reduction Colhoun HM et al. Lancet. 2004;364:685-696. 0 5 10 15 0 1 2 3 4 5 6 RRR=37% p=0.001 Cumulativeincidence ofevents(%ofpatients) 127 events 83 events Time (years) Atorvastatin 10 mg (n=1428) Placebo (n=1410) median follow-up 3.9 years
  12. 12. 0 1 2 3 4 5 6 0 1 2 3 4 5 6 CARDS: Atorvastatin Reduces Stroke by 48% in T2DM Newman C et al. American Heart Association 78th Scientific Sessions, 2005. RRR= 48% (95% CI: 31%-89%) P=0.016 Cumulativeincidence ofevents(%ofpatients) 39 events 21 events Time (years) Atorvastatin 10 mg (n=1428) Placebo (n=1410) Median follow-up 3.9 years Stroke was a component of the primary endpoint, evaluated individually as a secondary survival analysis.
  13. 13. AHA and ADA guidelines for statin therapy in T2DM for primary prevention are based on Atorvastatin’s CARDS trial
  14. 14. Atorvastatin for Primary Prevention in High risk patients: ASCOT-LLA A double-blind, placebo-controlled trial of atorvastatin 10 mg Vs Placebo in 10305 hypertensive patients studied Median follow up: 3.3 years Study end points Primary: Combined nonfatal MI (including silent MI) and fatal CHD Secondary: Fatal and nonfatal stroke Total cardiovascular events and procedures Total coronary events
  15. 15. Atorvastatin 10 mg Number of events 89 Placebo Number of events 121 0 1 2 3 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years CumulativeIncidence(%) HR = 0.73 (0.56-0.96) P = .0236 27% reduction ASCOT-LLA Primary Endpoint: Nonfatal MI and Fatal CHD Secondary Endpoint: Fatal and Nonfatal Stroke 0 1 2 3 4 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years CumulativeIncidence(%) Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 36% reduction HR = 0.64 (0.50-0.83) P = .0005 Sever PS, et al. Lancet. 2003;361:1149-1158.
  16. 16. ASCOT-LLA: Primary prevention– DM Sub- analysis (yellow cells) Highlighted boxes indicate diabetes patients enrolled in lipid-lowering arm. -blocker ± diuretic CCB ± ACE inhibitor TC >250 mg/dL (>6.5 mmol/L) 2532 TC 250 mg/dL (6.5 mmol/L) TC >250 mg/dL (>6.5 mmol/L) Open lipid lowering 1258 Atorvastatin 10 mg 1274 Placebo Open lipid lowering 19,342 patients Randomized Randomized Primary end point: Composite of fatal CHD and nonfatal MI ASCOT: LLA: Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm Sever PS et al. J Hypertens. 2001;19:1139-1147. CCB: Calcium Channel Blocker ACE: Angiotension Convertase Inhibitor TC: Total Cholesterol
  17. 17. ASCOT-LLA :23% RRR for total CV events in DM patients with atorvastatin Sever PS et al. Diabetes Care. 2005;28:1151-1157. 0 5 10 15 0 1 2 3 4 5 6 RRR=23% P=0.036 151 events 116 events median follow-up 3.3 years Cumulativeincidence ofevents(%ofpatients) Time (years) Atorvastatin 10 mg Placebo
  18. 18. Statin in CKD patients Alterations in Lipid Profiles in CKD Clin J Am Soc Nephrol 2007; 2(4):766-85. Triglycerides HDL Lipoprotein (a) Normal or low LDL Normal or low TC VLDL remnants
  19. 19. Dose of statins in patients with CKD • Atorvastatin: No dose adjustment required • Rosuvastatin: In patients severe CKD with creatinine clearance < 30 ml/min (not on hemodialysis), Maximum dose: 10 mg/day • Pitavastatin: in patients with moderate/severe CKD (GFR: 15-59 ml/min) Maximum dose: 2 mg/day, GFR: Glomerular Filtration Rate
  20. 20. • Patients: 325 DM nephropathy patients urinary protein/creatinine ratios (UPCR): 500-5000 mg/g, LDL >90 mg/dL, and on ACEIs/ARBs for > 3 months. • Patients divided in 3 groups: Rosuvastatin 10 mg, Rosuvastatin 40 mg and Atorvastatin 80 mg for duration of 52 weeks • Baseline eGFR: 69-72 ml/min Baseline UPCR: 1160-1260 mg/g • The primary end point: Change in urinary protein/ creatinine ratio from baseline to week 52 Atorvastatin vs Rosuvastatin in DM+ CKD PLANET I study The Lancet Diabetes & Endocrinology 2015;3(3):181-90
  21. 21. PLANET I: % Change in UPCR and eGFR -13 2 -4 -14 -12 -10 -8 -6 -4 -2 0 2 4 UPCR Change (%) Atorvastatin 80 mg Rosuvastatin 10 mg Rosuvastatin 40 mg p=0.033 p=0.83 p=0.53 The Lancet Diabetes & Endocrinology 2015;3(3):181-90 -1.61 -3.7 -7.29 -8 -7 -6 -5 -4 -3 -2 -1 0 Change in eGFR Atorvastatin 80 mg Rosuvastatin 10 mg Rosuvastatin 40 mg Conclusion: Atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population.
  22. 22. de Zeeuw D. 2010European Renal Association-European Dialysis and Transplant Association Congress; June 27, 2010; Munich, Germany. Atorvastatin vs Rosuvastatin for renal function PLANET I: Adverse event Rosuvastatin 10 mg/day (n = 116) Rosuvastatin 40 mg/day (n = 123) Atorvastatin 80 mg/day (n = 110) p Any renal adverse event 7.8 9.8 4.5 NS Acute renal failure 0.0 4.1 0.9 <0.05 Serum creatinine doubling 0.0 4.9 0.0 <0.01 Serum creatinine doubling or acute renal failure 0.0 7.3 0.9 <0.01
  23. 23. • A meta-analysis of 5 clinical trials head to head comparing atorvastatin vs rosuvastatin Atorvastatin Vs Rosuvastatin For Proteinuria: A Meta-analysis Circ J 2012;76:1259-66
  24. 24. Atorvastatin is safer than Rosuvastatin in DM patients with proteinuria Atorvastatin is better than Rosuvastatin for reduction in proteinuria
  25. 25. 2013 KDIGO Guidelines for dyslipidemia management in CKD • In adults aged > 50 years with eGFR< 60 ml/min/1.73 m2 but not treated with chronic dialysis or kidney transplantation (GFR categories G3a-G5), we recommend treatment with a statin or statin/ezetimibe combination. (1A) • In adults aged > 50 years with CKD and eGFR> 60 ml/min/1.73m2 (GFR categories G1-G2) we recommend treatment with a statin. (1B)
  26. 26. Rosuvastatin 20 mg (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA 4-week run-in Ridker PM et al, Circulation 2003;108:2292-2297 No Prior CVD/CKD/DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L Placebo (N=8901) Follow up: 1.9 yrs Can we consider rosuvastatin for primary prevention in DM/CKD based on JUPITER? Patients with DM and CKD were excluded from JUPITER, So there is no evidence for primary CV prevention with rosuvastatin in DM/CKD!!!
  27. 27. Statin for secondary prevention • Current guidelines recommend moderate to high dose of statins for secondary prevention. • Atorvastatin has multiple landmark trials for secondary prevention
  28. 28. 771 pts with NSTE-ACS sent to early coronary angiography (<48 hours) Randomization(N=191) Atorvastatin 80 mg 12 hrs pre-angio; further 40 mg 2 hrs before N=96 Coronary angiography Placebo 12 hrs pre-angio; further dose 2 hrs before N=95 Primary end point: 30-day death, MI, TVR 1st blood sample (pre-PCI) CK-MB, troponin-I, myoglobin, CRP High dose Atorvastatin in ACS ARMYDA-ACS trial 2nd and 3rd blood samples (8 and 24 hrs post-PCI) 30 days 580 pts excluded for: - 451 statin therapy - 41 emergency angiography - 43 LVEF <30% - 30 contraindications to statins - 15 severe renal failure PCI atorvastatin N=86 PCI placebo N=85 20 pts excluded for indication to: - medical therapy (N=8) - bypass surgery (N=12) atorvast
  29. 29. ARMYDA-ACS: Secondary end point Post-PCI percent increase of CRP levels from baseline % 63 147 P=0.01 JACC 2007:49:1272-78
  30. 30. ARMYDA-ACS trial Composite primary end-point (30-day death, MI, TVR) % 5 17 P=0.01 JACC 2007:49:1272-78
  31. 31. • 383 patients with stable angina (53%) or NST-ACS (47%) and on chronic statin therapy (55% atorvastatin) undergoing PCI were randomized to atorvastatin reload (80 mg 12 h before intervention, 40-mg pre-procedural dose or placebo (n=191). • All patients received long-term atorvastatin treatment thereafter (40 mg/day). • The primary end point was 30-day incidence of major adverse cardiac events (cardiac death, myocardial infarction, or unplanned revascularization). Loading atorvastatin in patients already on statin ARMYDA-RECAPTURE J. Am. Coll. Cardiol. 2009;54;558-565
  32. 32. ARMYDA-RECAPTURE: PRIMARY ENDPOINT 0 3 6 9 12 3.4 9.1 P=0.045 PlaceboAtorvastatin Loading of Atorvastatin high dose before PCI can reduce the CV events J. Am. Coll. Cardiol. 2009;54;558-565
  33. 33. Atorvastatin 80 mg n=4,995 Primary Endpoint: Major cardiovascular event defined as coronary heart death (CHD), nonfatal M, resuscitated cardiac arrest, and fatal or nonfatal stroke at a mean follow-up of 4.9 years. Atorvastatin for stable CAD TNT Trial Presented at ACC 2005 Atorvastatin 10 mg n=5,006 10,003 patients with stable coronary heart disease Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL 19% female, mean age 60.3 years All received atorvastatin 10 mg during 8 week open-label run-in period
  34. 34. TNT Trial: Primary endpoint Hazard Ratio [HR]=0.78 p<0.001 Presented at ACC 2005
  35. 35. 4,162 patients with an Acute Coronary Syndrome < 10 days ASA + Standard Medical Therapy “Standard Therapy” Pravastatin 40 mg “Intensive Therapy” Atorvastatin 80 mg Duration: Mean 2 year follow-up (>925 events) Atorvastatin in ACS: PROVE IT - TIMI 22 2x2 Factorial: Gatifloxacin vs. placebo Double-blind Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
  36. 36. CV events in PROVE IT study Cannon et al. NEJM 2004 Ray et al. Am J Cardiol 2006 Death/MACEDeath/MI/Urg. Revascu. ↓33% ↓16% Intensive statin therapy provides more benefits than low/moderate Intensity statin
  37. 37. Take Home Message • CV protection with statin is not completely dependent on lipid lowering. • Though rosuvastatin is slightly more effective than atorvastatin for lipid lowering, Atorvastatin has stronger evidence for CV protection • Atorvastatin is approved in both primary and secondary prevention, while rosuvastatin is approved only in primary prevention in patients with hsCRP > 2 mg/L WITHOUT DM/CKD

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