Use of statins in the management of Unstable Angina Statin Therapy in the 21st Century Use of statins in the management of Unstable Angina As the 21st century approaches, heart disease and stroke continue to be two of the world’s major health-care challenges in spite of the treatment options commonly used to manage these patients. One of the most recent advances in the treatment of heart disease and stroke is the use of statin therapy. Unequivocal evidence from five major trials has confirmed that statins are an effective therapy for the prevention and treatment of heart disease and stroke. With the completion of these trials and further research, there is a growing body of evidence that the effects of some statins go beyond cholesterol lowering. Differences among the statins reinforce the need to rely on long-term morbidity and mortality trials to confirm clinical benefit and long-term safety. To help put the prevalence of heart disease and stroke into perspective….

Vascular Disease: A Worldwide Challenge 40 32% 30% 30 Percent of at-risk patients on lipid-lowering medication 20 10 Despite the best efforts of health-care professionals, many patients with and at risk of vascular disease are currently not identified or treated. This graph illustrates the proportion of patients treated with lipid-lowering treatments. United States Europe American Heart Association: 1998 Heart and Stroke Statistical Update EUROASPIRE Study Group: Eur Heart J 1997;18:1569–1582

Therapeutic Advances in the Treatment of Cardiovascular Disease Therapy class Thrombolysis1–4 Antiplatelets2,5 b-blockers6 ACE inhibitors7-11 7–11 Statins12,13 -10 45 -20 35 -20% Percentage reduction in risk of total mortality post-MI -30 25 -23% -7%–27% -22%–30% -40 15 -50 5 -10%–50% GISSI Lancet 1986, 1987; 2. ISIS 2 Lancet 1988; 3. AIMS Lancet 1988, 1990; 4. ASSET Lancet 1988, 1990; 5. Antiplatelet Trialists Collaboration BMJ 1994; 6. Yusuf et al: Cardiovasc Dis 1985;27:335–1571; 7. SAVE N Engl J Med 1992; 8. AIRE Lancet 1993; 9. GISSI 3 J Am Coll Cardiol 1996; 10. ISIS 4 Lancet 1995; 11. TRACE N Engl J Med 1995; 12. 4S Lancet 1994; 13. LIPID N Engl J Med 1998

Unstable Angina: A Worldwide Challenge 1,000,000 UA is as serious a problem as MI 2%–10% treated UA patients will experience an MI prior to discharge As many as 5% die despite hospital treatment for UA 30-day event rate (death or MI) is 20% despite conventional therapy 10%–14% of patients with UA experience an MI, death, or both within 3–6 months of onset 900,000 747,000 800,000 700,000 651,000 Number of patients 600,000 500,000 400,000 300,000 Slide 2. Unstable angina (UA) is as serious a problem as myocardial infarction (MI). In the United States, approximately 747,000 patients will be hospitalised for MI and 651,000 will be hospitalised for UA.1 Of those hospitalised for UA, 2% to 10% will suffer an MI prior to discharge and as many as 5% will die despite treatment for UA.2 Another 20% will experience an MI or will die within 30 days.3 Within 3 to 6 months of onset of UA, another 10% to 14% will subsequently have an MI or will die.4 Despite aggressive, state-of-the-art treatment for UA, the risk for infarction or death within a year is high. 1. White. Am J Cardiol. 1997;80:2B–10B 2. Landau et al. N Engl J Med. 1994;330:981–993 3. Klootwijk et al. Lancet. 1999;353 (suppl 2):10–15 4. Balsano et al. Circulation. 1990;82:17–26 200,000 100,000 MI UA Discharge diagnosis White. Am J Cardiol. 1997;80:2B–10B, Landau et al. N Engl J Med.1994;330:981–993, Klootwijk et al. Lancet. 1999;353(suppl):10–15, Balsano et al. Circulation. 1990;82:17–26

Angiography of Unstable Angina Slide 6. This is an angiographic example of arterial stenosis in a patient with crescendo resting (Braunwald IIIB) UA.1 The intraluminal filling defects suggest thrombus formation. 1. Davies. Atlas of Coronary Artery Disease. Lippincott-Raven, Philadelphia, Pennsylvania: 1998:79 Davies. Atlas of Coronary Artery Disease. Lippincott-Raven, Philadelphia, Pennsylvania: 1998:79

Unstable Angina With Plaque Disruption Slide 7. This photograph depicts a typical plaque disruption with a thrombus. The fibrous cap is torn with a thrombus that projects into, but does not occlude, the lumen.1 The angiographic example, as shown in slide 6, may have been caused by a plaque disruption like this. 1. Davies. Atlas of Coronary Artery Disease. Lippincott-Raven, Philadelphia, Pennsylvania: 1998:81 Davies. Atlas of Coronary Artery Disease. Lippincott-Raven, Philadelphia, Pennsylvania: 1998:81

Primary Mechanism of Unstable Angina: Pathogenesis of Atherosclerosis Exposure to modified lipids Endothelial activation Inflammatory cell migration Inflammatory cell activation VSMC recruitment Matrix synthesis VSMC death Slide 8. Development of UA is based on underlying atherosclerosis. Endothelial cells on the surface of the arterial lumen become activated in response to exposure to modified circulating lipids.1 As a result, inflammatory cells migrate to the site and become activated, which leads to vascular smooth muscle cell (VSMC) recruitment to assist with repair. If the VSMCs initiate matrix collagen synthesis, which strengthens the fibrous cap formation, a stable cap will result. However, over time, VSMCs can die, the matrix can be degraded, and an unstable plaque results. 1. Weissberg. Atherosclerosis. 1999;147:S3–S10 Fibrous cap formation Matrix degradation Stable plaque Unstable plaque Adapted from Weissberg. Atherosclerosis. 1999;147:S3–S10

Unstable Angina: Treatment Goals Acute – Relieve angina – Prevent MI – Preserve viable myocardium if there is an infarction – Prevent death Chronic – Cardiac rehabilitation – Identify and treat coronary risk factors/underlying disease – Prevent recurrent admissions Slide 9. The immediate goal of acute treatment of UA is to relieve pain and to prevent MI and potential death by stabilising the thrombotic process.1 Cardiac rehabilitation should be a part of chronic treatment of UA. Other long-term goals include cardiac rehabilitation and identification and treatment of cardiovascular risk factors such as dyslipidaemia, hypertension, smoking, and the underlying disease, atherosclerosis. This strategy may prevent recurrent admissions for UA or an infarction. 1. White. Unstable angina: Ischemic syndromes. In: Topol EJ (ed). Textbook of Cardiovascular Medicine. Lippincott-Raven, Philadelphia, Pennsylvania: 1998:365–393 White. Unstable angina: Ischemic syndromes. In: Topol EJ (ed). Textbook of Cardiovascular Medicine. Lippincott-Raven, Philadelphia, Pennsylvania: 1998:365–393

The Evidence in Unstable Angina Only one statin trial has demonstrated benefit in patients with a history of Unstable Angina Long Term Intervention With Pravastatin in Ischaemic Disease (The LIPID study) Slide 12. Pravastatin therapy for UA is based on treatment of the underlying atherosclerotic disease process. Long-term clinical data support the safety benefits of pravastatin in reducing the risk of clinical outcomes. Recent studies on the early initiation of pravastatin demonstrate the safety and potential early benefits of pravastatin. The impact on clinical outcomes goes beyond lipid lowering and involves additional mechanisms such as endothelial function, coagulation, inflammation, smooth muscle cell proliferation, and synthesis of collagen. This section reviews the available data to date for statin initiation in patients with UA. Pravastatin is currently the only statin indicated in patients with a history of UA based on the results of the landmark trial LIPID—the largest statin trial to date. Four studies will be discussed: • PAIS (Pravastatin in Acute Ischaemic Syndromes) • RECIFE (Reduction of Cholesterol in Ischaemia and Function of the Endothelium) • Lipid-CAD (Lipid–Coronary Artery Disease) • LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease) In addition to patients with UA, these trials included patients with acute MI. The LIPID Study Group: N Engl J Med 1998;339:1349–1357

Pravastatin therapy in patients Post-MI or with a history of Unstable Angina: LIPID study design 9014 men and women with post-MI or hospitalisation for unstable angina Cholesterol 4–7 mmol/L (155–271 mg/dL) Pravastatin 40 mg v. placebo, mean follow-up 6.1 years 83% aspirin, 47% b-blockers, 41% PTCA/CABG at baseline Prespecified end points CHD mortality Total mortality Revascularizations Stroke The LIPID Study Group: N Engl J Med 1998;339:1349–1357

Pravastatin Reduces Events in Patients With Unstable Angina as Qualifier* 20 29%† Placebo Pravastatin 10 Percent with event Slide 14. In the prespecified subgroup of patients with UA randomised to pravastatin therapy, there was a significant reduction in coronary heart disease (CHD) death or nonfatal MI.1 The reduction in risk with pravastatin in patients with UA was consistent with the overall 24% risk reduction for the entire cohort.1 Since UA is now a more frequent cause of hospital admission than MI, this represents an important new finding in the treatment of cardiovascular disease. 1. The LIPID Study Group. N Engl J Med. 1998;339:1349–1357 CHD death or nonfatal MI * Prespecified subgroup analysis † 95% confidence interval (12–42) The LIPID Study Group. N Engl J Med. 1998;339:1349–1357

Pravastatin Benefits in MI and Unstable Angina patients Events Prevented Per 1000 Patients Treated Over 6 Years Event Deaths 30 Nonfatal MI 28 CABG 23 PTCA 20 Hospital admissions for UA 82 Nonfatal stroke 9 Slide 15. Results of the LIPID study demonstrate the clinical benefit of pravastatin therapy. For every 1000 patients treated with pravastatin over 6 years, this agent prevented 30 deaths, 28 nonfatal MIs, 23 coronary artery bypass graft (CABG) procedures, 20 angioplasty procedures, 82 episodes of UA, and nine nonfatal strokes. Put another way, if 20 patients received pravastatin therapy for 6 years, one fatal or one serious nonfatal cardiovascular event could be prevented. These benefits were not offset by any adverse effects.1 1. The LIPID Study Group. N Engl J Med. 1998;339:1349–1357 The LIPID Study Group. N Engl J Med. 1998;339:1349–1357

Rationale for pravastatin use in patients with a history of Unstable Angina Proven efficacy in secondary prevention Low potential for drug interactions Excellent long-term safety and tolerability Slide 40. Despite the extensive clinical data demonstrating the tolerability and efficacy of pravastatin for secondary prevention,1,2 the vast majority of post-MI or UA patients continue to go untreated.3 Data to date have shown that pravastatin initiation in the post-MI or UA setting is well tolerated. Moreover, early initiation of pravastatin may provide clinical benefits.4-7 Since post-MI and UA patients are unlikely to be started on statin therapy if it is not initiated prior to discharge, initiation should be considered in all post-MI patients prior to discharge. 1. Sacks et al. N Engl J Med. 1996;335:1001–1009 2. The LIPID Study Group. N Engl J Med. 1998;339:1349–1357 3. Eur Heart J. 1997;18:1569–1582 4. den Hartog et al. Eur Heart J. 1998;19:492 5. Kesteloot et al. Acta Cardiol. 1997;2:107–116 6. Arntz et al. Eur Heart J. 1997;18:35 7. Dupuis et al. J Am Coll Cardiol. 1998;31 (suppl A) :380A Sacks et al. N Engl J Med. 1996;335:1001–1009, The LIPID Study Group. N Engl J Med. 1998;339:1349–1357, Quion JAV et al. Clin Pharmacokinet 1994; 27(2): 94-103