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NHS Surrey Lipid Guidelines

This study explores the effects of intensive statin therapy in reducing the risk of myocardial ischemia in patients with acute coronary syndrome. The study compares the outcomes of patients treated with high-dose atorvastatin (80 mg) versus placebo or lower-dose statin therapy.

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NHS Surrey Lipid Guidelines

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  1. NHS Surrey Lipid Guidelines Dr Adam Jacques adamjacques@doctors.org.uk Ashford & St Peter’s Hospital NHS Foundation Trust

  2. The Evidence for Intensive Statin Therapy

  3. Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering(MIRACL) Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718

  4. MIRACL • Effects of early-initiated atorvastatin 80 mg after an acute coronary syndrome on death and recurrent ischaemic events • Multicentre, randomised, double-blind, placebo-controlled trial • Patients were assigned to atorvastatin 80 mg or placebo 24–96 hours after hospital admission for ACS Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718

  5. Primary endpoint* 16% Relative Risk Reduction Placebo 17.4% 15 Atorvastatin 14.8% 10 Cumulative incidence (%) 16% RRR HR 0.84 (0.70-0.99) P=0.048 5 0 0 4 8 12 16 Time since randomisation (weeks) * Primary endpoint=death, non-fatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischaemia with objective evidence and requiring emergency rehospitalisation Adapted from Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718

  6. Safety Adapted from Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718

  7. Conclusions In stable CHD patients with ACS, early lipid-lowering therapy with atorvastatin (80 mg/day) reduces the risk of: • Early recurrent ischaemic events, primarily recurrent symptomatic ischaemia requiring rehospitalisation • Non-fatal or fatal stroke Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718

  8. The PRavastatin Or AtorVastatin Evaluation and Infection Therapy–Thrombolysis In MyocardialInfarction 22(PROVE IT: TIMI 22) Cannon CP et al. NEJM 2004; 350 (15): 1495-1504

  9. PROVE IT: TIMI 22 • Intensive versus moderate lipid-lowering with statins after ACS • Atorvastatin 80 mg vs pravastatin 40 mg (lowering LDL-C to <1.60 mmol/L vs <2.46 mmol/L, respectively) • Randomised, double-blind, double-dummy non-inferiority trial • Follow-up: mean 24 months Cannon CP et al. NEJM 2004; 350:1495-1504

  10. Endpoints • Primary Endpoint: Composite of death from any cause, MI, documented unstable angina requiring hospitalisation, revascularisation* and stroke • Secondary Endpoints: Risk of death from CHD, non-fatal MI, or revascularisation*, risk of death from CHD or non-fatal MI, and the risk of the individual components of the primary endpoint * If performed at least 30 days after randomisation Cannon CP et al. NEJM 2004; 350:1495-1504

  11. Median LDL-C levels during the study 21%  49%  • Median LDL-C achieved • Pravastatin: 2.5 mmol/L • Atorvastatin: 1.6 mmol/L • (P<0.001) Pravastatin 40 mg LDL-C (mmol/L) Atorvastatin 80 mg Time of visit Adapted from Cannon CP et al. NEJM 2004; 350:1495-1504

  12. Primary endpoint: Incidence of all- cause mortality or major CV event* 16% Relative Risk Reduction 30 25 20 15 10 5 0 0 30 3 6 9 12 15 18 21 24 27 Pravastatin 40 mg (event rate 26.3%) Atorvastatin 80mg (event rate 22.4%) % with event 16% RRR HR 0.84 (0.74-0.95) P=0.005 Months of follow-up * Major CV events included: MI, documented unstable angina requiring hospitalisation, revascularisation with either PCI or CABG (if performed at least 30 days after randomisation), and stroke Adapted from Cannon CP et al. NEJM 2004; 350:1495-1504

  13. Early benefits* 28% Relative Risk Reduction Different endpoint used - Triple composite of: Death, MI, or rehospitalisation for recurrent ACS 5 Pravastatin 40 mg 4.2 % 4 28% RRR HR 0.72 (0.52-0.99)P=0.046 3 % of patients with death, MI or rehospitalisation for ACS Atorvastatin 80 mg 3.0 % 2 1 0 0 5 10 15 20 25 30 Days following randomisation *Early phase = first 30 days Adapted from Ray KK et al. J Am Coll Cardiol 2005; 46:1405-1410

  14. Late benefits* Different endpoint used - Triple composite of: Death, MI, or rehospitalisation for recurrent ACS 12 Pravastatin 40 mg 13.1% 28% Relative Risk Reduction 10 28% RRR HR 0.72 (0.58-0.89) P=0.003 8 % of patients with death, MI or rehospitalisation for ACS 6 Atorvastatin 80 mg 9.6% 4 2 *Late Phase = 6 months–2 years** 0 6 12 18 24 Months following randomisation **Analysis excluding patients with events in the first 6 months Adapted from Ray KK et al. J Am Coll Cardiol 2005; 46:1405-1410

  15. Safety Adapted from Cannon CP et al. NEJM 2004; 350:1495-1504

  16. Summary • In patients hospitalised within 10 days of an acute coronary event: • ‘Intensive’ lipid-lowering with 80 mg atorvastatin to a median LDL-C of 1.6 mmol/L was associated with a significant reduction in the risk of combined all-cause mortality and major CV events by 16% compared to ‘moderate’ lipid-lowering therapy with 40 mg pravastatin which achieved a median LDL-C of 2.5 mmol/L (P=0.005) • Benefits emerged within 30 days of randomisation with continued divergence of the event curves over time Cannon CP et al. NEJM 2004; 350:1495-1504

  17. The Treating to New Targets Study(TNT) LaRosa JC et al. N Engl J Med 2005; 352 (14): 1425-1435

  18. TNT • Intensive lipid-lowering with atorvastatin in patients with stable coronary disease • Mean LDL-C of 2 mmol/L with atorvastatin 80 mg vs mean LDL-C of 2.6 mmol/L with atorvastatin 10 mg • Multicentre, randomised, double-blind trial • Follow-up: median 4.9 years LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435

  19. Endpoints Primary endpoints • Major CV event • CHD death • Non-fatal, non-procedure-related MI • Resuscitated cardiac arrest • Fatal or non-fatal stroke LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435

  20. Lipid results Screen 0 3 12 24 36 48 60 Final Baseline 160 4.0 Atorvastatin 80 mg (n=4995) 140 3.5 Atorvastatin 10 mg (n=5006) 120 3.0 Mean LDL-C level = 101 mg/dL (2.6 mmol/L) 100 2.5 Mean LDL-C (mmol/L) Mean LDL-C (mg/dL) 80 2.0 Mean LDL-C level = 77 mg/dL (2.0 mmol/L) P<0.001 1.5 60 1.0 40 0.5 20 0 0 Study visit (months) Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435

  21. Primary endpoint: Major cardiovascular events* 22% Relative Risk Reduction Atorvastatin 10 mg Atorvastatin 80 mg 0.15 0.10 Proportion of patients experiencing major cardiovascular event (%) 0.05 22% RRR HR = 0.78 (95% CI 0.69, 0.89) P< 0.001 0 0 1 2 3 4 5 6 Time (years) *CHD death, non-fatal non–procedure-related MI, resuscitated cardiac arrest, fatal or non-fatal stroke Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435

  22. CHD death or non-fatal, non-procedure-related MI 22% Relative Risk Reduction Atorvastatin 10 mg Atorvastatin 80 mg 0.10 Proportion of patients experiencing CHD death or non-fatal non-PR MI (%) 0.05 22% RRR HR = 0.78 (95% CI 0.68, 0.91) P<0.001 0 0 1 2 3 4 5 6 Time (years) Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435

  23. Fatal or non-fatal stroke Atorvastatin 10 mg Atorvastatin 80 mg 25% Relative Risk Reduction 0.04 0.03 25% RRR HR = 0.75 (95%CI 0.59, 0.96) P=0.02 Proportion of patients experiencing fatal or non-fatal stroke (%) 0.02 0.01 0 0 1 2 3 4 5 6 Time (years) Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435

  24. Safety Note: n=197 patients were excluded at baseline due to AEs after 8 weeks open-label 10 mg treatment and n=96 were also excluded at baseline due to ALT/AST > 1.5 x ULN * No cases were considered by the investigator with direct responsibility for the patient to be causally related to atorvastatin, and none met ACC/AHA/NHLBI criteria4 for rhabdomyolysis 1P<0.001, 2P=0.72, 3P<0.001, 4 Pasternak RC et al. Circulation 2002; 106: 1024-1028 Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435

  25. Summary • The TNT study is the first randomised trial designed to demonstrate the benefits of lowering LDL-C below 2.6 mmol/L in stable CHD patients • Significant (>20%) reductions in CV events including stroke were achieved with atorvastatin 80 mg vs atorvastatin 10 mg • Even at high atorvastatin dose, there was a very low incidence of adverse events and no treatment-related rhabdomyolysis • The findings add to other data showing the efficacy and safety of high-dose (80 mg) atorvastatin LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435

  26. Effect of Statin Therapy on Lipid Lowering, Ischaemic Heart Disease & Stroke: Meta-Analyses Law MR et al. BMJ 2003; 326: 1423-1429

  27. Meta-analysis 1: Percentage reduction in serum LDL-C concentration by statin & daily dose atorvastatin pravastatin simvastatin rosuvastatin 10mg 20mg 10mg 40mg 20mg 40mg 10mg 80mg 10mg 20mg 20mg 40mg 40mg 80mg 0 -10 -20 -20 -24 -27 Mean percentage change LDL-C from baseline -30 -29 -32 -37 -37 -40 -42 -43 -43 -48 -49 -50 -53 -55 -60 Adapted from a meta-analysis of 164 randomised, placebo controlled trials involving over 24,000 patients treated with statins and 14,000 treated with placebo. Percentage reductions are independent of pre-treatment LDL-C concentration. Data not shown for fluvastatin and lovastatin. P-values not available. Adapted from Law MR et al. BMJ 2003; 326: 1423-1429

  28. Safety Muscle-related adverse effects • In the meta-analysis of 35,000 people treated with statins and placebo rhabdomyolosis was diagnosed (variable criteria) in eight treated and five placebo patients, none with serious illness or death • Raised serum creatine kinase activity ( ≥ 10 times the ‘upper limit of normal’) was reported in 55 treated patients (0.17%) and 43 placebo patients (0.13%); muscle symptoms were present in 13 and 4 respectively Liver-related adverse effects • There were no cases of liver failure in the trials • Raised ALT ( ≥ 3 x ULN) was reported in 449 treated (1.3%) and 383 placebo patients (1.1%) Law MR et al. BMJ 2003; 326: 1423-1429

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