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NHS Surrey Lipid Guidelines

NHS Surrey Lipid Guidelines. Dr Adam Jacques adamjacques@doctors.org.uk Ashford & St Peter’s Hospital NHS Foundation Trust. The Evidence for Intensive Statin Therapy. M yocardial I schaemia R eduction with A ggressive C holesterol L owering ( MIRACL).

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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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