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New Insights into the Benefits of Early Statin Initiation in Acute Coronary Syndromes

New Insights into the Benefits of Early Statin Initiation in Acute Coronary Syndromes. Pathophysiology of ACS and potential pharmacological interventions. 1. Downstream from thrombus myocardial ischaemia/necrosis (  -blockers, nitrates etc). Fibrin clot. 2. Activation of clotting

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New Insights into the Benefits of Early Statin Initiation in Acute Coronary Syndromes

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  1. New Insights into the Benefits of Early Statin Initiation in Acute Coronary Syndromes

  2. Pathophysiology of ACS and potential pharmacological interventions 1. Downstream from thrombus myocardial ischaemia/necrosis (-blockers, nitrates etc) Fibrin clot 2. Activation of clotting cascade – thrombin (heparin/LMWH) Fibrinogen Thrombin GP IIb/IIIa receptor 3. Platelet adhesion/ activation/aggregation (aspirin, clopidogrel, GP IIb/IIIa inhibitors) Platelet 4. Plaque rupture, cholesterol content, inflammation (hs-CRP) (statins)

  3. 25 20 15 10 5 0 0 1 2 3 4 5 6 Risk of death in patients with coronary heart disease is greatest early after an ACS Deaths/100 patients/month Acute MI Unstable angina Stable angina Time (months after hospital admission) Braunwald (1996)

  4. PURSUIT: Retrospective analysis shows early mortality reduction with lipid-lowering therapy Survival (%) 100 99 98 97 96 95 94 93 92 Lipid-lowering agents (n=2141) No lipid-lowering agents (n=6374) Log rank 2=87, p<0.001 0 30 60 90 120 150 180 Days Aronow et al (2000)

  5. GUSTO IIb/PRISM: Early reduction in death/MI in patients on lipid-lowering therapy • GUSTO IIb – Retrospective analysis of 12,630 ACS patients (±ST elevation) • Mortality at 30 days and 6 months was significantly reduced in patients receiving lipid-lowering agent • 52% reduction in 6-month mortality (RR 0.48, 95% CI 0.28-0.83) after adjusting for other variables • PRISM – Retrospective analysis of 1616 patients • 302 patients were continued on background statin therapy • Death/MI rate at 30 days was significantly lower in these patients (p<0.01) Aronow et al, Hamm et al (AHA 2000)

  6. Swedish registry: Early statin and revascularisation significantly reduces mortality Relative risk reduction in mortality after 1 year 70 64% 60 50 36% 34% 40 30 20 10 0 Combined therapy Statins Revascularisation XXII ESC Congress (2000)

  7. Statin therapy after stent placement in ACS patients • Prospective study of statin therapy initiation immediately after coronary stent implantation in 224 ACS patients • Incidence of major cardiovascular events, including death and MI, at 6 months were: • 1.0% in statin patients • 7.9% in control group (p<0.03) • Statin therapy associated with profound clinical benefit • Suggests pivotal role of statins for plaque passivation to reduce death and MI Walter et al (AHA 2000)

  8. Rationale for early statin therapy Gives constant reduction in risk most effective when absolute risk is highest May stabilise plaque maximum benefit when given early Other non-lipid-lowering effects eg anti-inflammatory, effects on endothelial dysfunction Patient already in hospital patient more likely to adhere to therapy Discharged on statin therapy underscores need for continued statins

  9. Timing of statin therapy initiation after ACS in recent clinical studies Atorvastatin Pravastatin PACT MIRACL Simvastatin PTT PAIS Fluvastatin PROVE IT 4S LAMIL WOSCOPS FLORIDA CARE L-CAD ACS RECIFE LIPID Primary prevention Secondary prevention 3 6 0 6 12 18 24 2 4 6 8 10 12 Hours Days Months

  10. Clinical evidence for the benefits of early statin initiation StudyTime to Statin Results initiation PTT1 6 h pravastatin coronary events restenosis rates L-CAD2 6 d pravastatin Improved outcomes mean progression  coronary lesion regression RECIFE3 10 d pravastatin Rapid improvement of (mean) endothelial function FLORIDA4 8 d fluvastatin No significant benefit MIRACL5 24–96 hatorvastatin time to first event • 1 Pravastatin and Thrombolytic Therapy • 2 Lipids in Coronary Artery Disease • 3 Reduction of Cholesterol in Ischaemia and Function of the Endothelium • 4 FLuvastatin On RIsk Diminishing after Acute myocardial infarction • 5 Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering

  11. Timing of statin therapy initiation after ACS in recent clinical studies Atorvastatin Pravastatin MIRACL Simvastatin PTT PAIS Fluvastatin 4S LAMIL WOSCOPS FLORIDA CARE L-CAD ACS RECIFE LIPID Primary prevention Secondary prevention 3 6 0 6 12 18 24 2 4 6 8 10 12 Hours Days Months Kayikcioglu et al (1999)

  12. Pravastatin and Thrombolytic Therapy trial: Early* therapy improves event-free survival Patients with event (%) 30 Pravastatin (n=72) Control (n=78) 20 ‡ † 10 0 Non-fatal MI ** Recurrentangina ** In-hospitaldeath *Within 6 hours of MI; **6 months follow-up †p=0.01, ‡p=0.03 Kayikcioglu et al (1999)

  13. Timing of statin therapy initiation after ACS in recent clinical studies Atorvastatin Pravastatin MIRACL Simvastatin PTT PAIS Fluvastatin 4S LAMIL WOSCOPS FLORIDA CARE L-CAD ACS RECIFE LIPID Primary prevention Secondary prevention 3 6 0 6 12 18 24 2 4 6 8 10 12 Hours Days Months Arntz (1999)

  14. L-CAD study design Baseline cholesterol 3.4–6.5 mmol/L (130–250 mg/dL) 126 men and women post acute MI and/or PTCA for UA Pravastatin 20–40 mg (+cholestyramine and nicotinic acid) to achieve an LDL <3.4 mmol/L (130 mg/dL) Usual care Clinical – 2 years, Angiography – 6 months and 2 years QCA and major CV clinical events • L-CAD = Lipids in Coronary Artery Disease

  15. L-CAD: Survival without major cardiovascular events 1.0 0.8 Pravastatin-basedintensified (n=70) 0.6 Conventional (n=56) 0.4 0.2 Log rank = 0.0024 Breslow = 0.0042 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (months) Arntz et al (1998)

  16. Timing of statin therapy initiation after ACS in recent clinical studies Atorvastatin Pravastatin MIRACL Simvastatin PTT PAIS Fluvastatin 4S LAMIL WOSCOPS FLORIDA CARE L-CAD ACS RECIFE LIPID Primary prevention Secondary prevention 3 6 0 6 12 18 24 2 4 6 8 10 12 Hours Days Months Dupuis et al (1999)

  17. p<0.05 The RECIFE study: Pravastatin rapidly improves endothelial function after ACS Flow-mediated dilatation (%)* 8 7 Pravastatin 40 mg/day 6 Placebo 5 4 6 0 Time (weeks) *60 patients admitted for acute MI or unstable angina, enrolled before hospital discharge Dupuis et al (1999)

  18. Timing of statin therapy initiation after ACS in recent clinical studies Atorvastatin Pravastatin MIRACL Simvastatin PTT PAIS Fluvastatin 4S LAMIL WOSCOPS FLORIDA CARE L-CAD ACS RECIFE LIPID Primary prevention Secondary prevention 3 6 0 6 12 18 24 2 4 6 8 10 12 Hours Days Months Schwartz et al (1998)

  19. What MIRACL was designed to show The Hypothesis Diminished incidence of recurrent ischaemic events Rapid and early cholesterol reduction Early plaque stabilisation Objective “To prove that early, rapid, and intensive cholesterol lowering therapy will reduce early recurrent ischaemic events in patients with unstable angina or non-Q-wave MI” MIRACL = The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering study Schwartz et al (1998)

  20. MIRACL study design Prospective, randomised, multicentre, double-blind • Exclusion criteria • Serum cholesterol >7 mmol/L (270 mg/dL) • Concurrent or previous interventional therapy (6 months) or surgery (3 months) • Concurrent lipid-lowering therapy • Any agent likely to induce rhabdomyolysis when taken with statins 3,086 patients Inclusion criteriaUA or non-Q-wave MI in previous 1–4 days 80 mg atorvastatin, commenced within 24–96 h of event Placebo, commenced within 24–96 h of event Follow up at 2, 6 and 16 weeks for endpoints, ECG, labs and AEs

  21. MIRACL study outcome measures • Primary • Time from randomisation to first occurrence of any of the • following: • Death (any cause) • Non-fatal MI • Resuscitated cardiac arrest • Worsening angina pectoris with new objective evidence of myocardial ischaemia, requiring urgent rehospitalisation • Secondary • Time to occurrence and incidence of each of the primary • outcome components, plus: • Stroke • Myocardial revascularisation (CABG or PTCA) • Worsening congestive heart failure • Worsening angina without new objective evidence of ischaemia

  22. MIRACL patient disposition Number of patientsAtorvastatin Placebo Randomised 1538 1548 Lost to follow-up 8 4

  23. Baseline characteristics of patients Atorvastatin Placebon=1538n=1548 Mean age (years) 65 65 Male 64% 66% Caucasian 86% 85% Prior MI 25% 25% Prior CABG or PTCA 10% 11% Current smoking 28% 28% Hypertension 55% 55% Diabetes 22% 24%

  24. Baseline characteristics of patients Atorvastatin Placebon=1538n=1548 Inclusion event: Unstable angina 47% 46% Non-Q-wave MI 53% 55% Median time from hospital admissionto randomisation 63 h 63 h

  25. Primary efficacy measure Cumulative incidence (%) 17.4% Placebo 15 14.8% Atorvastatin 10 Time to first occurrence of composite endpoint of: • Death (any cause) • Non-fatal MI • Resuscitated cardiac arrest • Worsening angina with new objective evidence and urgent rehospitalisation Risk reduction = 16% p=0.048 5 95% CI = 0.701–0.999 0 0 4 8 12 16 Time since randomisation (weeks)

  26. Individual endpoint results – incidence Event AtorvastatinPlacebo% reductionp Worsening angina* 6.2% 8.4% 26% 0.02 Total stroke 0.75% 1.5% 50% 0.045 Death ns Non-fatal acute MI ns Resuscitated cardiac arrest ns *with new objective evidence of ischaemia requiring urgent rehospitalisation

  27. Blood lipids BaselineMean of both groupsmg/dl End of studyPlaceboAtorvastatinmg/dl (% change) Total cholesterolLDL cholesterolHDL cholesterolTriglycerides 20612446182 217(+7%)135(+12%)46(+4%)187(+9%) 147(-27%)72(-40%)48(+5%)139(-16%)

  28. Safety Atorvastatin Placebon=1538n=1548 Elevated liver transaminases(>3 times ULN on 2 occasions) 2.5% 0.6% Myositis(with CK >10 times ULNon 2 occasions) 0% 0%

  29. Potential mechanisms of benefit of statins in ACS Statins* LDL-C reduction Reduction in chylomicron and VLDL remnants, IDL, LDL-C • Restore endothelial function • Maintain SMC function • Anti-inflammatory effects • Decreased thrombosis Macrophages Lumen *Statins differ significantly in terms of these effects/mechanisms Lipid core Smooth muscle cells

  30. Balancing the stability equation Increased lipidsLipid oxidationInfection?Genetic susceptibility Lipid-lowering drugs Antioxidants? Antibiotics? Mechanical injury Inflammation Repair Unstable plaque Stable plaque Modified from Weissberg (1999)

  31. Timing of statin therapy initiation after ACS in recent clinical studies Atorvastatin Pravastatin PACT MIRACL Simvastatin PTT PAIS Fluvastatin PROVE IT 4S LAMIL WOSCOPS FLORIDA CARE L-CAD ACS RECIFE LIPID Primary prevention Secondary prevention 3 6 0 6 12 18 24 2 4 6 8 10 12 Days Months Hours BMS Data on file

  32. Pravastatin Acute Coronary Treatment (PACT) • Design • safety and short-, medium- and long-term efficacy • 4 weeks double-blind treatment with pravastatin • initiation within 24 hours of the onset of symptoms in patients with AMI or UA • 12 months open-label follow-up • Objective • to demonstrate conclusively that early treatment with a statin is both safe and effective in the acute phase after MI or UA

  33. PACT design features • Randomised, double-blind • Acute MI or unstable angina, n=10,000 • Pravastatin 20 or 40 mg daily or placebo for 4 weeks • Initiation within 24 hours of the onset of symptoms • Primary endpoint recurrent coronary events • Ongoing lipid management after 4 weeks open-label determined by the patient’s local physician • Follow up for clinical and adverse events at 4, 26, and 52 weeks • Includes PIMS (Pravastatin Inflammatory Markers Study)

  34. Timing of statin therapy initiation after ACS in recent clinical studies Atorvastatin Pravastatin PACT MIRACL Simvastatin PTT PAIS Fluvastatin PROVE IT 4S LAMIL WOSCOPS FLORIDA CARE L-CAD ACS RECIFE LIPID Primary prevention Secondary prevention 3 6 0 6 12 18 24 2 4 6 8 10 12 Days Months Hours BMS Data on file

  35. PROVE IT: PRavastatin Or AtorVastatin Evaluation and Infection TherapyThe definitive head-to-head comparison of pravastatin and atorvastatin • The first major trial to compare the effects of pravastatin versus atorvastatin in reducing the risk of heart attacks and other cardiac events • Designed to evaluate further the role of infection in cardiovascular disease

  36. PROVE IT study design Double-blind, randomised, 4,000 patients with ACS <10 days and total cholesterol <240 mg/dL (6.2 mmol/L) Standard medical therapy Pravastatin 40 mg qhs Atorvastatin 80 mg qhs Gatifloxacin Placebo Gatifloxacin Placebo Follow-up visit 30 days Minimum duration 18 months

  37. Conclusions • Several clinical trials with pravastatin have indicated the benefits of early treatment in ACS • MIRACL with atorvastatin supports this in a large trial • Effects beyond lipid lowering may contribute to the early benefit • PACT with pravastatin will answer whether even earlier initiation (within 24 h) is beneficial • PROVE IT, a head-to-head trial of pravastatin vs atorvastatin, will determine any difference between these two agents

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