3. Risk of death in patients with coronary heart disease is greatest early after an ACS Braunwald (1996) Deaths/100 patients/month Time (months after hospital admission) Acute MI Unstable angina Stable angina 0 5 10 15 20 25 0 1 2 3 4 5 6
4. Swedish registry: Early statin and revascularization significantly reduces mortality XXII ESC Congress (2000) Statins Revascularization Combined therapy 0 10 20 30 40 34% 36% 64% 50 60 70 Relative risk reduction in mortality after 1 year
5.
6. Pathophysiology of ACS and potential pharmacological interventions 4. Plaque rupture, cholesterol content, inflammation (hs-CRP) (statins) 3. Platelet adhesion/ activation/aggregation (aspirin, clopidogrel, GP IIb/IIIa inhibitors) 2. Activation of clotting cascade – thrombin (heparin/LMWH) 1. Downstream from thrombus myocardial ischemia/necrosis ( -blockers, nitrates etc) Platelet GP IIb/IIIa receptor Fibrinogen Thrombin Fibrin clot
7. Pleiotropic effects of statins Liao JK. Am J Cardiol . 2005;96(suppl 1):24F-33F. MMPs = matrix metalloproteinases Platelet activation Coagulation Endothelial progenitor cells Effects on collagen MMPs AT 1 receptor VSMC proliferation Endothelin Macrophages Inflammation Immunomodulation Endothelial function Reactive oxygen species NO bioactivity Statins
8. Statin Endpoint Trials: Reduction in Major Coronary Events 4S 4444 -36% AF/TexCAPS 6605 -27% LIPID 9014 -25% CARE 4159 -28% WOS 6595 -26% Trial N LDL Secondary Primary -38* -25* -25 § -31* -38* -27 ‡ HPS 20,536 -29% High Risk Reduction (%) ASCOT 10305 -26% -36 † * P <0.001; † P =0.0005; ‡ P <0.0001; § P =0.002. HPS Collaborative Group. Lancet . 2002;360:7-22; LaRosa et al. JAMA . 1999;282:2340-2346; Sever et al. Lancet . 2003;361:1149-1158.
9. PURSUIT: Retrospective analysis shows early mortality reduction with lipid-lowering therapy Aronow et al (2000) Survival (%) Days 100 99 98 97 96 95 94 93 92 0 30 60 90 120 150 180 Log rank 2 =87, p <0.001 No lipid-lowering agents (n=6374) Lipid-lowering agents (n=2141)
10. PRISM: Event Rates After Statin Withdrawal in Acute Coronary Syndrome Heeschen C, et al. Circulation. 2002;105:1446 1452. Event Rates in % (mortality, MI) 0 5 10 15 20 25 30 0 2 4 6 8 10 12 14 16 18 30-Day Follow-Up Period Statin continued Statin discontinued (N = 1616)
11. 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 e.g. 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
12. Timing of statin therapy initiation after ACS in recent clinical studies Days Secondary prevention 0 6 Months 3 2 PTT LAMIL L-CAD RECIFE CARE LIPID PAIS 24 Hours 10 6 8 12 12 18 4 PACT MIRACL 4S 6 Atorvastatin Pravastatin Simvastatin PROVE IT WOSCOPS Primary prevention ACS Fluvastatin FLORIDA A to Z
13.
14. MIRACL: study design Hospitalization for unstable angina or non-Q MI n =3086 Randomized 24–96 hours after admission Placebo + diet 16 weeks Assessments conducted at weeks 0, 2, 6 and 16 Schwartz GG et al. Am J Cardiol 1998; 81 :578–581. Atorvastatin 80 mg + diet
15.
16. MIRACL: worsening angina with new objective evidence of ischemia requiring urgent rehospitalization 0 3 6 9 0 4 8 12 16 Time since randomization (weeks) Cumulative Incidence (%) Relative risk = 0.74 p =0.02 Atorvastatin Placebo 8.4% 6.2% Data on file, Pfizer Inc.
17.
18.
19. Cannon CP et al. N Engl J Med . 2004;350:1495-1504. ASA + Standard medical therapy Duration: mean 2-y follow-up (>925 events) 2x2 Factorial: gatifloxacin versus placebo Standard therapy (Pravastatin 40 mg) Intensive therapy (Atorvastatin 80 mg) Primary end point: death MI, documented UA requiring hospitalization, revascularization (>30 days after randomization), or stroke Study Design: N=4,162 with acute coronary syndrome <10 days PROVE-IT: Pravastatin or Atorvastatin Evaluation and Infection Therapy
20. All-Cause Death or Major CV Events in All Randomized Subjects % with Event Months of Follow-up Pravastatin 40mg (26.3%) Atorvastatin 80mg (22.4%) 16% RR (P = 0.005) 30 25 20 15 10 5 0 0 3 18 21 24 27 30 6 9 12 15
21. PROVE IT – TIMI 22 (2-Year Trial) Log CHD Risk 100 LDL-C Level 60 Pravastatin 40 mg 16% Reduction in CVD Atorvastatin 80 mg Cannon CP et al. N Engl J Med 2004;350:1495-1504.
27. GALAXY lipid studies 1. Lablanche J-M et al. Atherosclerosis Supplements 2006 7 (3): 578, Abs Th-P16:384 ACRONYM OVERVIEW A 12-week, randomized, open-label study comparing CRESTOR 20mg or 40mg with that of atorvastatin 80 mg on lipid parameters and pleiotropic effects in subjects with acute coronary syndromes A planned study to evaluate CRESTOR in paediatric subjects with heterozygous familial hypercholesterolemia A 3-month, randomised, multicentre, parallel-group study with 2 periods, to compare the efficacy and safety of CRESTOR 20 mg with atorvastatin 80 mg on the ApoB/ApoA-I ratio and other lipid and inflammatory markers in subjects with acute coronary syndrome 1 .
31. Effect of lipid-modifying therapies on lipids Therapy Bile acid sequestrants Nicotinic acid Fibrates Probucol Statins* Ezetimibe TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. *Daily dose of 40 mg of atorvastatin, simvastatin, pravastatin and fluvastatin. TC Down 20% Down 25% Down 15% Down 25% Down 19–37% - LDL Down 15–30% Down 25% Down 5–15% Down 10–15% Down 25–50% Down 18% HDL Up 3–5% Up 15–30% Up 20% Down 20–30% Up 4–12% Up 1% TG Neutral or up Down 20–50% Down 20–50% Neutral Down 14-29% Down 8% Patient tolerability Poor Poor to reasonable Good Reasonable Good Good Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391. Knopp RH. N Engl J Med 1999;341:498–511. Product Prescribing Information. Gupta EK, Ito MK. Heart Dis 2002;4:399-409. ,
The vast majority of deaths associated with an acute coronary syndrome (ACS) occurs in the very first few weeks after presentation. Therefore, therapies that are likely to be effective in this disease should be initiated in this early period. The large secondary prevention trials of statins have enrolled patients in a time window where event rates are relatively low. So, initiation of statin therapy early following an ACS should result in a greater benefit than that seen when therapy is initiated much later after the event. Furthermore, the absolute benefit is likely to be greatest when the risk is highest. Reference 1. Braunwald E, Mark DB. Medical management of unstable angina. In: Fuster V, Ross R, Topol EJ eds. Atherosclerosis and coronary artery disease . Philadelphia: Lippincott-Raven; 1996: Chapter 79.
The effect of early statin initiation and revascularization on the event rate following a myocardial infarction (MI) was examined in a retrospective analysis of data contained in the Swedish Registry of Cardiac Intensive Care. This included approximately 23,000 patients from 73 coronary care units in Sweden and was merged with the national registries to obtain 1 year follow-up data. The start of a statin before discharge was associated with a 34% reduction in death over the first year (OR 0.66, 95% CI 0.55–0.79). Among patients who underwent revascularization before 14 days, a 36% reduction in mortality risk was found at 1 year (OR 0.64, 95% CI 0.42–0.71). Results showed that the combination of statin therapy initiated in post-MI patients before hospital discharge and early revascularization was associated with a 64% reduction in mortality in these patients at 1 year. Reference 1. Hotline presentation at European Society of Cardiology XXII Annual Congress, Amsterdam, Holland, August 2000.
4 There are a number of therapeutic approaches to acute coronary syndrome (ACS) treatment based on the various pathophysiological steps in the process. 1. -Blockers and nitrates are symptomatic therapies and exert their action downstream from the thrombus by balancing myocardial oxygen supply and demand. 2. Heparin is used to prevent further clot formation by inhibiting fibrin formation. 3. Antiplatelet agents, such as aspirin, clopidogrel and GP IIb/IIIa inhibitors, reduce platelet adhesion and aggregation, which play a key role in thrombus formation. 4. There is growing interest in agents that may stabilise the plaque and discourage rupture. Statins are currently being studied in this context.
The relationship between CAD and atherogenic dyslipidemia is evident from studies examining the effect of lipid-lowering treatment with statin-class drugs. The evidence supporting the value of lipid lowering applies in both the primary and secondary prevention settings and extends across individuals with cholesterol levels ranging from mildly to moderately elevated through severe hypercholesterolemia. In the primary-prevention studies WOSCOPS and the AFCAPS/TexCAPS, statin therapy reduced LDL cholesterol 26% and 27%, respectively, and was correspondingly associated with reductions in coronary death and nonfatal MI ranging from 31% to 38%. In the 4S, CARE, and LIPID studies in patients with previous coronary disease, statin therapy reduced LDL cholesterol from 25% to 36%, resulting in event reductions ranging from 25% to 38%. Furthermore, a 29% LDL reduction was associated with a 27% reduction in events in the Heart Protection Study (HPS), which included high-risk patients who had previous CHD, occlusive noncoronary disease (stroke, transient ischemic attack [TIA], peripheral arterial disease [PAD]), diabetes, or treated hypertension. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomized placebo-controlled trial. Lancet . 2002;360:7-22. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA . 1999;282:2340-2346. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with Pravastatin in men with hypercholesterolemia. N Engl J Med . 1995;333:1301-1307. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet . 1994;344:1383-1389. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of Pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med . 1996;335:1001-1009. Downs JR, Clearfield M, Weis S, et al, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA . 1998;279:1615-1622. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with Pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med . 1998;339:1349-1357.
A 6-month study by Aronow and colleagues looked at mortality among patients from the PURSUIT trial. Patients with non-ST-elevation acute coronary syndromes (ACS) who were discharged on lipid-lowering agents (LLA) following the initial hospitalisation were compared with those who did not receive these agents. A propensity analysis was used to match patients on the probability of receiving a LLA, and the resulting score entered into a Cox model. Overall, there were 354 deaths during the 6 months. Treatment with LLAs was associated with a reduced incidence of death at 6 months. After adjusting for age, gender, hyperlipidemia, heart failure medications, baseline ECG and other possible confounding factors, treatment with a LLA was associated with a significantly reduced risk of 6-month mortality (ratio=0.47; p =0.0002). Thus, LLA therapy is associated with a significant reduction in early mortality following ACS. Reference 1. Aronow HD, Roe MT, Lauer MS, et al. Early and striking mortality reduction after acute coronary syndromes following lipid lowering therapy. J Am Coll Cardiol 2000; 35 (Suppl. A) : 411.
To assess the impact of discontinuing statin therapy in patients with acute coronary syndromes, a subgroup analysis was conducted on the data set from the P latelet R eceptor Inhibition in I schemic S yndrome M anagement (PRISM) trial. Death and nonfatal myocardial infarction were recorded during a 30-day follow-up of 1616 patients who had coronary artery disease and chest pain in the preceding 24 hours. Statin therapy was associated with a reduced event rate at 30-day follow-up compared with patients who did not receive statins ( P = 0.004). If statins were withdrawn after admission, cardiac risk increased markedly compared with patients who continued to receive statins ( P = 0.005) and tended to be even higher than that of patients who never received statins. Thus, statin pretreatment in patients with acute coronary syndromes was associated with improved clinical outcome, but discontinuation of statins after onset of symptoms completely abolishes this beneficial effect. Heeschen C, Hamm CW, Laufs U, Snapinn S, Bohm M, White HD, for the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002;105:1446 – 1452.
Since the absolute risk of experiencing death or a further acute coronary syndrome (ACS) is highest in the period immediately following the initial event, any reduction in risk will be most effective during this period of time. Any effects of statin treatment, such as plaque stabilisation, anti-inflammatory activity or improvements in endothelial dysfunction, which may play an important role in the pharmacological effects of statins, will be of maximum benefit in the early post-ACS period. Initiation of statin treatment early after an ACS is likely to ensure that the therapy is considered while the patient is still in hospital which, in turn, is likely to lead to continuation of therapy after discharge.
Slide 11 The central hypothesis of MIRACL is that early , rapid , and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute MI [14]. Reference 14. Schwartz GG et al. Am J Cardiol 1998; 81 :578–581.
Slide 16 Between 24 and 96 hours after hospital admission, eligible patients were randomly assigned with stratification by center to double-blind treatment with atorvastatin (80 mg daily) or matching placebo for 16 weeks. The protocol did not otherwise restrict or specify any diagnostic or therapeutic measures during the study period. All patients received instruction and counselling to promote compliance with a National Cholesterol Education Program step I diet. Patients were seen in follow up 2, 6, and 16 weeks after the initiation of therapy to reinforce dietary counselling and to monitor for compliance, study end points, and adverse events, and to monitor laboratory parameters at 6 and 16 weeks. Laboratory testing was performed centrally. Study medication was discontinued if serum alanine or aspartate aminotransferase exceeded 3 times the upper limit of normal on two determinations 1 week apart, or if a patient developed muscle pain, weakness, or tenderness consistent with myositis and serum creatine kinase level exceeded 10 times the upper limit of normal on two determinations 1 week apart [14]. Reference 14. Schwartz GG et al. Am J Cardiol 1998; 81 :578–581.
Slide 29 The reduction in the combined primary end point with atorvastatin therapy, compared with placebo, was due mainly to a favourable effect of atorvastatin on worsening angina with new objective evidence requiring urgent rehospitalization. Atorvastatin produced a significant ( p =0.018) 26% relative risk reduction in worsening angina with new objective evidence requiring urgent rehospitalization (95% confidence interval 0.572–0.949) [15]. Reference 15. Data on file, Pfizer Inc.
Slide 34 Treatment with atorvastatin 80 mg/day was generally well tolerated. There were no serious adverse events, occurring with a frequency >1%, in either treatment group. Abnormal liver function tests (defined as aspartate or alanine aminotransferase levels greater than three times the upper limit of normal) occurred in 38 patients in the atorvastatin group (2.5%) and in 9 patients treated with placebo (0.6%). Two patients receiving atorvastatin were hospitalized with elevated liver transaminases and jaundice and/or fever. However, these liver-related abnormalities were resolved upon discontinuation of the drug. There were no documented cases of myositis [15]. Reference 15. Data on file, Pfizer Inc.
Slide 35 The results of the MIRACL study demonstrate that early, rapid, and profound cholesterol lowering therapy with atorvastatin reduced early recurrent ischemic events in patients with unstable angina or non-Q-wave acute MI. Furthermore, atorvastatin reduced the incidence of recurrent ischemic events within 16 weeks. In addition, treatment with atorvastatin 80 mg/day was generally well tolerated in this patient population [15]. Reference 15. Data on file, Pfizer Inc.
PROVE IT – TIMI 22 In PROVE IT, there was also not a lower threshold for LDL-C observed, and a curvilinear (or possibly linear) relationship was observed between LDL-C level on treatment and CHD risk across the full range of LDL-C levels achieved with either Pravastatin or atorvastatin. Reference: Cannon CP, Braunwald E, McCabe CH, et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504.
This slide shows the comparative effects of the currently available statins on lipid parameters. All reduce LDL cholesterol and triglycerides, and increase HDL cholesterol. 1 Reference 1. US Product Data Sheets.
LUNAR = L imiting UN dertreatment of lipids in A CS with R osuvastatin PLUTO (a planned study, so study details not provided externally) CENTAURUS = C omparison of the E ffects N oted in T he A poB/ApoA-I ratio U sing R osuvastatin and atorvastatin in patients with ac U te coronary S yndrome
Lipid-modifying therapies include inhibitors of HMG CoA reductase (statins), fibrates, bile acid sequestrants (resins), nicotinic acid and its derivatives, and probucol. They have all shown varying degrees of efficacy in delaying the progression of atherosclerosis and some have also been shown to reduce MI and sudden death. A combination of two agents may be used to achieve greater efficacy in cases of severe hypercholesterolaemia. However, the most convincing evidence has been demonstrated with statins and, at present, they are first-line drugs in the treatment of dyslipidaemias. Bile acid sequestrants are potent cholesterol-modifying agents. However, compliance can be a problem as patients may object to the taste and texture, and common adverse events are gastrointestinal bloating, nausea and constipation. 1,2 Nicotinic acid , a B-complex vitamin whose lipid-modifying properties were first described in the 1950s, is very effective at reducing both LDL-C and triglyceride concentrations, and increasing HDL-C levels. Thus, it is indicated for all dyslipidaemias except congenital lipoprotein lipase deficiency. To be effective, it must be given in pharmacologic doses. The value of nicotinic acid has been limited by the incidence of adverse events, which include flushing, skin problems, gastrointestinal distress, liver toxicity, hyperglycaemia and hyperuricaemia. 1,2 Fibrates are effective triglyceride-lowering and HDL-raising drugs. However, in the majority of patients they are only moderately successful in reducing LDL-C. 1,2 Probucol is not available in most countries. It is prescribed for the treatment of high cholesterol levels. However, it has only a modest LDL-C-modifying effect, and there is no evidence that it reduces CHD risk and there are limited long-term tolerability data. 1,2 Statins are highly effective in lowering LDL-C and have a good tolerability profile. 1-4 Ezetimibe is the first of a novel class of selective cholesterol-absorption inhibitors. Ezetimibe may be useful as monotherapy in patients who need modest reductions in LDL-C or who are intolerant to other lipid-modifying therapies, and in combination with a statin in patients who are intolerant to large doses of statins or need further reductions in LDL-C despite maximum doses of a statin. 5 References 1. Yeshurun D, Gotto AM. Southern Med J 1995; 88 (4):379–391. 2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001: 285 ;2486–2497. 3. Knopp RH. N Engl J Med 1999; 341 :498–511. 4. Product Prescribing Information. 5. Gupta EK, Ito MK. Heart Dis 2002; 4 :399–409. Adapted from Southern Med J 1995; 88 :379–391, with permission from Lippincott Williams & Wilkins.
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