Data Alert. Vascular Biology Working Group. Blunting the atherosclerotic process in patients with coronary artery disease.

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1 Vascular Biology Working Group c/o Medical Education Consultants, LLC 25 Sylvan Road South, Westport, CT 688 Chairman: Carl J. Pepine, MD Eminent Scholar American Heart Association Suncoast Chapter Chair Professor and Director Division of Cardiovascular Medicine University of Florida College of Medicine Gainesville, Florida Data Alert Blunting the atherosclerotic process in patients with coronary artery disease Dear Colleague: Statin therapy lowers serum levels of atherogenic lipoproteins and reduces cardiovascular (CV) morbidity and mortality in a wide range of patients in clinical trials. 1-7 These major trials were placebo-controlled, and provide limited evidence about differences between individual statins, or about target levels for lipid lowering. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial 8 has now compared the effects of two different statin treatments in patients with established coronary artery disease (CAD). This is the first major study to measure the progression of coronary atherosclerosis using intravascular ultrasound (IVUS), a technique that can quantify plaque by visualization of the coronary arterial wall. The results from the REVERSAL trial demonstrate that intensive lipid-lowering treatment with atorvastatin 8 mg halts the progression of atherosclerosis in CAD patients. In contrast, patients treated with moderate lipid lowering using pravastatin 4 mg experience continued atherosclerotic disease progression. REVERSAL: Study design Prospective, randomized, double-blind, multicenter trial comparing the effects of atorvastatin 8 mg vs pravastatin 4 mg 654 patients with symptomatic CAD, % stenosis on angiography, LDL-C mg/dl Primary endpoint = atheroma in coronary artery with % stenosis Atheroma measured by IVUS at baseline and at 18-month follow-up IVUS = intravascular ultrasound 1

2 REVERSAL was a prospective, randomized, double-blind, multicenter trial enrolling 654 patients with symptomatic CAD, as shown by % stenosis with angiography, and low-density lipoprotein cholesterol (LDL-C) levels of 125 to 21 mg/dl. Patients were randomized to atorvastatin 8 mg or pravastatin 4 mg, and IVUS measurements were taken at baseline and at the 18-month follow-up. The primary outcome was the rate of atherosclerotic progression measured by the percent change in atheroma. REVERSAL: Change in LDL-C and CRP Change at 18 months Pravastatin 4 mg Atorvastatin 8 mg Mean LDL-C 6 (mg/dl) 4 25% 11 46% * LDL-C 6 <1mg/dL (%) Reduction (%) LDL-C on treatment % Patients reaching goal * CRP changes on treatment *P <.1, atorvastatin vs pravastatin LDL-C and the inflammatory marker C-reactive protein (CRP) were reduced significantly more by treatment with atorvastatin compared with pravastatin. CRP reductions were 36.4% versus 5.2%, respectively (P <.1). LDL-C was reduced 46.3% with atorvastatin compared with 25.2% with pravastatin (P <.1) and mean LDL-C was reduced to 79 mg/dl versus 11 mg/dl, respectively (P <.1). Of the patients treated with atorvastatin, 97% achieved LDL-C <1 mg/dl compared with 65% in the pravastatin group. IVUS provides detailed images of the blood vessel wall by using a miniature ultrasound transducer placed within the coronary artery to make cross-sectional images. Images can be generated along the vessel s length and in this study were analyzed at 1.-mm intervals. Atherosclerotic disease progression was quantified by computing atheroma and percent atheroma along the index artery, as shown in the following figure (see Definitions). The figure also shows the calculations used for the primary outcome (percent change in atheroma ) as well as the change in percent atheroma, one of several pre-specified secondary outcomes. Patients receiving intensive lipid lowering showed no apparent progression of atheroma measured by the primary outcome (percent change in atheroma ). In fact, these patients achieved a small regression (.4% vs baseline; 95% CI, 2.4% to 1.5%). Significant atheroma progression did occur in patients treated with modest lipid lowering (+2.7% vs baseline; 95% CI,.2% to 4.7%) (P =.2, atorvastatin vs pravastatin). 2

3 REVERSAL: Measures of coronary atherosclerotic progression Primary outcome Secondary outcome Response variables measured by IVUS Percent change in atheroma Change in percent atheroma Atheroma month 18 Atheroma baseline = 1 Atheroma baseline = Percent atheroma month 18 Percent atheroma baseline Definitions Atheroma = Σ (EEM CSA LUMEN CSA ) Percent atheroma = Σ (EEM CSA LUMEN CSA ) 1 Σ (EEM CSA ) CSA = cross-sectional area; EEM = elastic external membrane; IVUS = intravascular ultrasound A significant difference in the rate of progression of atheroma was also demonstrated by changes in the percent atheroma, a secondary outcome (.2% change with atorvastatin vs 1.6% change with pravastatin; P <.1, atorvastatin vs pravastatin). Another secondary outcome, atheroma in the most severely diseased 1-mm vessel subsegment, was also significantly lower with atorvastatin (P =.1, atorvastatin vs pravastatin; data not shown). The absence of atheroma progression versus baseline was consistent across 22 pre-specified subgroups in the atorvastatin-treated patients, while progression occurred in the pravastatin-treated cohort of 15 subgroups. When subgroups that attained the National Cholesterol Education Program (NCEP) guideline level for LDL-C (<1 mg/dl) 9 were compared, there was progression in the pravastatin group (P <.1) and no progression in the atorvastatin-treated patients (P =.93), compared with baseline. Safety data showed that both lipid-lowering regimens were well tolerated and safe. REVERSAL: Primary and secondary outcomes Median change (%) P = P <.1.3 Pravastatin 4 mg Atorvastatin 8 mg Atheroma Percent atheroma

4 REVERSAL: Clinical Implications Findings warrant consideration of more intensive treatment with atorvastatin 8 mg for secondary prevention Maximally intensive lipid lowering can essentially halt atherosclerotic disease progression Differences between atorvastatin and pravastatin in reducing atherosclerotic progression evident, even in pravastatin patients reaching NCEP goal No increase in adverse events with intensive treatment REVERSAL demonstrates that maximally intensive lipid lowering can halt progression of atherosclerosis, a result not achieved with modest lipid lowering. The differential effects of intensive therapy with atorvastatin were evident even in patients with LDL-C levels below the achieved means (atorvastatin 79 mg/dl, pravastatin 11 mg/dl) and may be, at least partly, related to the greater reduction in CRP levels. Importantly, the results in the more intensive treatment group were achieved with a safety and tolerability profile similar to the more moderate lipidlowering regimen. REVERSAL suggests that intensive treatment with atorvastatin (to lower LDL-C below the currently recommended NCEP guideline level of LDL-C <1 mg/dl) should be considered in secondary prevention. REVERSAL did not assess clinical outcomes, due to the small number of patients. However, recent results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22 Investigators (PROVE IT TIMI 22) trial 1 now confirm the clinical significance of the findings in REVERSAL. PROVE IT TIMI 22: LDL-C levels during study LDL cholesterol (mg/dl) Pravastatin 4 mg Atorvastatin 8 mg Baseline 3 d 4 mo 8 mo 16 mo Final Time of visit Cannon CP et al. 1 4

5 PROVE IT TIMI 22 randomized 4162 patients who had been recently hospitalized for acute coronary syndromes (ACS) to atorvastatin 8 mg or pravastatin 4 mg, which had been considered the reference standard dose since it had been shown to prevent death and other adverse outcomes in several large clinical trials. Patients achieved median LDL-C 62 mg/dl with atorvastatin and 95 mg/dl with pravastatin (P <.1). The primary outcome (combined all-cause death, myocardial infarction, hospitalization for unstable angina, coronary revascularization, and stroke) occurred in 22.4% of atorvastatin-treated patients and 26.3% of pravastatin-treated patients (16% relative risk reduction in favor of atorvastatin, P =.5 at the mean 24-month follow-up). 1 PROVE IT TIMI 22: Primary outcome 3 25 Death or major 15 cardiovascular event (%) % risk reduction P =.5 Pravastatin 4 mg Atorvastatin 8 mg Follow-up (mo) Cannon CP et al. 1 Thus, in patients with a recent ACS, intensive versus moderate statin treatment provides greater protection against death or major CV events. Results from PROVE IT TIMI 22 also support the idea that the IVUS measurements of atherosclerotic progression used in the REVERSAL study may offer a clinically useful tool for assessing disease burden. Two other studies that have used an ultrasound method for vessel wall imaging (measurement of carotid intima-media thickness) showed that progression of atherosclerosis was reduced with intensive lipid lowering (atorvastatin 8 mg) versus modest lowering (simvastatin or pravastatin 4 mg). 11,12 Earlier studies have indicated that progression of coronary artery disease predicts future clinical coronary events. 13,14 These studies demonstrated that small differences in the rate of atherosclerotic progression were associated with significant differences in clinical outcomes. Potential mechanisms The REVERSAL investigators point out that the greater benefit seen with intensive lipid lowering may be due to several potential mechanisms. 8 Levels of LDL-C, total cholesterol, and triglycerides were all reduced to a greater extent with intensive treatment. Other factors may also contribute, including the differential effects of the two treatments on the inflammatory marker CRP. Furthermore, while linear regression analysis indicated an inverse relationship between percent 5

6 reduction in LDL-C level and atherosclerosis progression for both statins, LDL-C reduction alone did not explain all of the differences in efficacy. At any level of LDL-C reduction, the rate of atherosclerotic progression was lower with atorvastatin than with pravastatin (equivalent to an additional % or 3 mg/dl reduction in LDL-C). SUMMARY Intensive lipid-lowering treatment with atorvastatin 8 mg halted the progression of coronary atherosclerosis in patients with established CAD, whereas modest lipid lowering with pravastatin 4 mg was associated with significant disease progression. Intensive treatment produced greater reductions in atherogenic lipoproteins and CRP; both lipid lowering and anti-inflammatory effects may explain the improved outcomes. REVERSAL suggests, and PROVE IT confirms, that more intensive lipid lowering than currently recommended by national and international guidelines may be required for maximal secondary prevention of coronary disease. Sincerely, Carl J. Pepine, MD REFERENCES 1. 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: Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, 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: Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, 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: Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, 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:

7 5. 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: Heart Protection Study Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 536 high-risk individuals: A randomised placebo-controlled trial. Lancet. 2;36: Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al, for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo- Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): A multicentre randomised controlled trial. Lancet. 3;361: Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, et al, for the REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: A randomized controlled trial. JAMA. 4;291: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 1;285: Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22 Investigators. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 4;35. Early E-release March 8, 4. Available at: Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJP, Stalenhoef AFH. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): A prospective, randomised, double-blind trial. Lancet. 1;357: Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: A randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation. 2;16: Waters D, Craven TE, Lesperance J. Prognostic significance of progression of coronary atherosclerosis. Circulation. 1993;87: Azen SP, Mack WJ, Cashsin-Hemphill L, LaBree L, Shircore AM, Selzer RH, et al. Progression of coronary artery disease predicts clinical coronary events: Long-term follow-up from the Cholesterol Lowering Atherosclerosis Study. Circulation. 1996;93: UF-P-US Printed in USA 3/4 7