Background and Methods for the Lovastatin Restenosis Trial After Percutaneous Transluminal Coronary Angioplasty William S. Weintraub, MD, Stephen J. Boccuzzi, PhD, Charles L. Brown Ill, MD, Caryn L. Cohen, RN, MN, Laurence J. Hirsch, MD, Spencer B. King Ill, MD, R. Wayne Alexander, MD, and the Lovastatin Restenosis Trial Study Group Restenosis remains a critical limitation of percutaneous transluminal coronary angioplasty (PTCA). Recent experimental and clinical data have suggested that lovastatin, an hydroxymethylglutaryl coenzyme A reductase inhibitor, may reduce the rate of restenosls through reduction of low density-lipoprotein (LDL) cholesterol or possibly by direct effects. Lovastatin may therefore produce favorable alterations in endothelial healing, resulting in a decreased smooth muscle cell prollferative response to injury after angioplasty. Emory University, in conjunction with Merck Research Laboratories, has initiated a lo-center double-blinded, placebo-controlled, randomized trial to assess the effect of both pretreatment and aggressive lipid lowering with lovastatin in reducing the rate of rostenosis. Lovastatin achieves approximately 75% of its effect on LDL cholesterol by 1 week. Thus, patients scheduled for PTCA are randomly assigned pretreatment with lovastatln, 40 mg twice daily, or placebo 7 to 10 days before PTCA. Therapy is continued for 6 months, at which time repeat coronary arteriography is performed. A detailed safety algorithm was designed, with patients receiving lovastatin and matching placebo back-titrated on a 1:l basis for LDL cholesterol 350 mg/dl Unreliable/communication barrier Inaccessible for follow-up Creatinine > 1.8 mg/dl; 1.5 if age >75 years, blood glucose >200 mg/dl or on oral hypoglycemic SGPT SGOT or pyruvic transaminase > 20% above upper limit of normal Diabetic on insulin or blood glucose 2240 mg/dl Hypercholesterolemia due to secondary causes Liver disease within 6 months Hypersensitivity to HMG-CoA reductase inhibitors Creatine phosphokinase levels > 50% above upper limit of normal Active drug or alcohol abuse lmmunosuppressants therapy Other investigational drug(s) Serious coexisting illness Marked change in ischemiccardiac pain within 2 weeks Luminal thrombus requiring heparin Woman of child-bearing potential HMG-COA = hydroxymethylglutaryl coenzyme A; SGOT = serum glutamic tic transaminase; SGPT = serum glutamic pyruvic transaminase.

METHODS

oxaloace-

urn, and restenosis is largely related to abnormal healing of the endothelium, then it is possible that amelioration of the abnormal lipid milieu may result in less myointimal proliferation. Restoration of normal endothelial function has been demonstrated in experimental animals with correction of serum lipids, but to date not in humans.18 In addition, correction of serum lipid abnormalities in non-human primates has been shown to promote microscopic healing of atherosclerotic lesions.‘sJ9 Lowering of LDL cholesterol may therefore stabilize and promote healing of atherosclerotic lesions not visible on the coronary arteriogram. A partially healed lesion may have less mechanical injury, and experience a less severe myointimal proliferative response. The hypothesis that lipid lowering may play a role in endothelial healing, and restoration of normal endotheliurn-derived relaxation may be beneficial in preventing restenosis and argues in favor of an aggressive pretreatment phase before PTCA. Experimental and dinical backgnnnnl: Two experimental studies support the use of lovastatin to prevent restenosis. Gelhnan et al9 randomized 38 atherosclerotic rabbits to lovastatin (6 mg/kg/day) or placebo after balloon PTCA of the femoral artery. There was better preservation of huninal diameter and less intimal thickening in the lovastatin group. In a rat carotid model,

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The lovastatin restenosis trial is a double-blind, placebo-controlled trial to determine whether administration of lovastatin, 40 mg orally twice daily starting 7 to 10 days before and continuing for 6 months after PTCA, will reduce the rate of restenosis after successful PTCA. A successful PTCA is defined as reduction in percent luminal diameter of the first native vessel dilated (index lesion) to 1.5 mm in diameter supplying viable myocardium, offering at least a 90% procedural chance of a successful result by standard balloon PTCA as assessedby the PTCA operator.

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This lesion is then the “nominated index lesion.” The “index lesion” for the trial is the first successfully dilated native vessel lesion. The patient follow-up throughout the trial from visit 1 (randomization) through visit 6 (restudy angiography) is detailed in Table II. Once determined to be eligible and informed consent obtained, the patient is randomized to lovastatin 40 mg twice a day, or to matching placebo. Baseline fasting serum lipids, serum glutamic oxalacetic and pyruvic transaminases, creatine phosphokinase (safety chemistries) and other chemistries and hematology tests will be determined, and therapy with study medication begun. Patient education for compliance with the step 1 American Heart Association diet will also be provided. The patient will return at 1 week for PTCA, as well as serum lipids and a pill compliancy check. If PTCA is angiographically successful, and not complicated by acute myocardial infarction, death or the need for coronary surgery, the patient will continue in the trial. Repeat safety chemistries and lipid levels and compliance checks will be performed at 4, 12, 18 and 26 weeks. An exercise electrocardiogram with thallium scintigraphy and restudy coronary arteriogram will be obtained at 26 weeks. If the patient cannot exercise, dipyridamole will be administered. All lipid measurements and safety chemistries are analyzed throughout the trial at a central core laboratory (Table II). Total serum cholesterol between 160 and 300 mg/dl to determine eligibility is the only locally measured lipid parameter. All local laboratories were standardized for measurement of cholesterol. A detailed safety algorithm was developed to back-titrate or discontinue treatment as follows: discontinue for creatine phosphokinase elevation to >lO times the upper limit of normal on repeat analysis, creatinine phosphokinase >lO times the upper limit of normal without repeat if there are unexplained myalgias, or serum glutamic oxalacetic transaminase or pyruvic transaminase to >3 times the upper limit on repeat analysis. If LDL cholesterol is lO%, giogram is the primary end point. The primary end the recruitment period will be extended to ensure that point will be analyzed on a per patient basis. Patients 360 patients with full angiographic follow-up are ranare scheduled for repeat angiograms at 6 months. How- domized. With an anticipated restenosis rate of 30% in ever, arteriograms recorded after 4 months, or earlier if the control group, a sample size of 180 in each group restenosis occurs, may be used for end point analysis. will have 190% probability of detecting a reduction of Arteriograms recorded before 4 months and not show- 50% in the incidence of restenosis in the index lesion at the (Y= 0.05 level (2-tailed).27 This sample size will also ing restenosis will be repeated at 6 months. SECONDARY: The secondary end points include the be sufficient to detect a difference of 0.36 mm in minirecurrence of 250% diameter narrowing for all success- mal lumen diameter between the 2 groups with >90% fully dilated lesions, continuous measures of minimal power. All baseline and end point variables in the 2 treatvessel diameter (in mm) at restudy angiogram, the change in absolute vessel diameter (in mm) from the ment arms compared by the Mantel-Haenszel procepostPICA to restudy, the percent diameter narrowing dure for categorical variables and 1 or 2-way analysis of at restudy and fractional loss of the gain from post- variance (depending on the end point) for continuous PTCA to restudy. Each of these end points are mea- variables. Data will be analyzed using an intention-tosured both per patient for the index lesion and per lesion treat approach, but limited to patients with successful for all successfully dilated lesions. A categorical analysis PTCA. Data will also be analyzed on a per patient basis is also performed to evaluate restenosis in no sites, some using both the index lesion and by all dilated vessels. Predictors of restenosis will be identified by stepwise losites and all sites per patient. gistic regression. Angiographic failure defined by failure In addition, the need for repeat revascularization including coronary artery bypass surgery and repeat to dilate to 50% diameter constriction occurs. After the acetylcholine infusions, nitroglycerin is given as a 40 pg infusion and a coronary arteriogram performed. The protocol is terminated if the patient becomes uncomfortable or develops chest pain, electrocardiographic signs of ischemia, adverse hemodynamic changes or any adverse symptom. Dose response curves of changes in quantitatively measured coronary artery dimensions will be constructed for each patient. Comparison of acetylcholine dose response curves from initial and follow-up studies and between patient groups will be made using an analysis of variance for repeated measures. For (Y= 0.05 2tailed, 90% power to detect l/2 standard deviation of difference, a sample size of 20 is required in each group. Cost-effectiv~ss

of lovastatin

in the prevention

of

re&enosis: A cost-effectiveness analysis will be performed to determine the potential costs or savings by preventing an episode of restenosis. The measure of effectiveness will be the rate of reduction in restenosis. There is the associated cost of 6 months therapy with lovastatin, including the drug, office visits and associated blood tests. The potential savings are the direct and indirect costs avoided by preventing restenosis. Most patients with restenosis will require further therapy, and differences in resource utilization (direct and indirect) for patients who have restenosis and those who do not will be measured. The simplest measures are repeat PTCA and coronary surgery at the time of reste

nosis. The use of other medical services including other hospitalizations, physician office visits and antianginal therapy will be collected. Hospital charges are collected from the standard UB-82 billing form and from physician charges from office bills. With use of medicare guidelines, cost estimates from these charges will be constructed. Indirect costs such as loss of income will also be estimated. This will be further studied with sensitivity analysis. By including initial costs associated with restenosis, and indirect costs into the model, a picture of the full economic impact of restenosis, and potential cost saving by preventing it, will be created. Using published data, a simulation to estimate cost savings up to 5 years will be performed.28~29 Procedures and documentation: All major policy decisions in the trial are the responsibility of the steering committee, chaired by the principal investigator for the trial. The members of the steering committee include the co-principal investigators, the site principal investigators, the directors of the core laboratories, the biostatistician in charge, the clinical coordinator in charge, and the clinical monitors from Merck Research Laboratories. The original protocol was developed jointly by the Emory University investigators and Merck Research Laboratories. The principal investigator and each core laboratory report on progress through the trial to the steering committee. The steering committee also acts as a publication committee for the trial. Meetings of the steering committee are held at Emory University Hospital when needed to discuss policy issues and on a biannual basis at national meetings. The data handling aspects of the trial are coordiiated by a registry advisory subcommittee (in consultation with Merck Research Laboratories) that reports to the steering committee. The principal investigator is chairman of the registry committee; other members include the biostatistician in charge, the clinical coordinator, and the administrative director of the biostatistical coordinating center. This committee coordinates the flow of forms in detail including medical review and audit, data entry, and system checks and audits. The registry committee is responsible for structuring of reports for the biostatistician to prepare for the data and safety monitoring board. Merck Research Laboratories reviews and audits all clinical data at the clinical sites, core laboratories and at the biostatistical coordinating center while remaining unaware of treatment allocation. The data and safety monitoring board is responsible for the safe and ethical conduct of the trial. This is the only committee that is unblinded. Monthly reports are prepared by the study biostatistician. The principal investigator is responsible to the data and safety monitoring board for discussing problems in recruitment, protocol violations, safety concerns and concerns over the ethical conduct of the trial. The data and safety monitoring board may stop the trial if any of issues become sufficiently critical as to interfere with its safe or effective completion. No interim analysis is planned. The protocol was approved by the institutional review board at each site. A consent form was initially developed by Emory and Merck Research Laboratories and provided to each institution to adapt to the specific LOVASTATIN

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requirements for that institution. The steering committee and the sponsor have the right to approve changes to the protocol or informed consent of each site. APPENDIX hlVestigatonr: CLINICALCOORDINATING CENTER: William S. Weintraub, MD (Principal Investigator), Charles L. Brown III, MD (Co-Principal Investigator), Spencer B. King III, MD (Co-Principal Investigator), R. Wayne Alexander, MD, PhD (Co-Principal Investigator), Caryn L. Cohen, RN, MN (Clinical Coordinator), Berverly Cormican, MBA (Administrator), Diane Owen (Research Coordinator), Patricia Schumacher (Administrative Assistant). MERCK RESEARCH LABORATORIES: Stephen J. Boccuzzi, PhD, Yale B. Mitchel, MD, Laurence J. Hirsch, MD (Clinical Monitors), Michael R. Melino, PhD, Olga P. Beattie, MS, Donna Gudel, Diane Plotkin PhD, Anne Tate (Medical Program Coordinators), Robert Zupkis, PhD (Biostatistics). DATA AND SAFETY MONITORING BOARD: W. Dallas Hall, MD (Chairman), Michael Kutner, PhD, Nelson Watts, MD, Robert Schlant, MD. BIOSTATISTICAL COORDINATING CENTER: Andrzej Kosinki, PhD (Director), Xudong Tao, MS (Data Analyst), Fara Hicks (Administrative Director), Debbie Canup (Systems Manager), Philip Per-Lee (Computer Programmer). LIPID CORE LABORATORY: Ngoc-Anh Le, PhD (Principal Investigator), James Howard, MD (CoPrincipal Investigator), David Robbins, MD, Barbara Howard, MD, Virgil Brown, MD, Xianzhou Li, PhD, George Webb. ANGIOGRAPHIC CORE LABORATORY: J. Larry Klein, MD (Director), Charles Treasure, MD, Steven Manoukian, MD, Sara Gatlin, MD. ELECTROCARDIOGRAPHICCORELABORATORY: J. Willis Hurst, MD (Director). THALLIUMCORELABORATORY: Naomi Alazraki, MD (Director), Andrew Taylor, MD.

EMORY UNIVERSITY

HOSPITALS, ATLANTA,

GEORGIA:

Charles L. Brown, MD (Principal Investigator), William S. Weintraub, MD, Spencer B. King III, MD, R. Wayne Alexander, MD, PhD, John S. Douglas, Jr, MD, Susan Kim, RN (Clinical Coordinator), Caryn L. Cohen, RN, MN, John Merlino, MD (Co-Principal Investigator for Crawford Long Hospital), Donna Watson, RN (Clinical Coordinator), Douglas C. Morris, MD, Henry A. Liberman, MD, Charles Treasure, MD (Co-Principal Investigator for Grady Hospital), J. Larry Klein, MD, Naomi Alazraki, MD (Thallium). FLORIDA HOSPITAL, ORLANDO, FLORIDA: Russell Ivanhoe, MD (Principal Investigator and Thallium), Curtis Weaver, MD, Charles Curry, MD, William Willis, MD, Dianne Ross, RN (Clinical Coordinator), CHARLOTTE MEMORIAL HOSPITAL, CHARLOTTE, NORTH CAROLINA: John Cedarholm, MD (Principal Investigator

and Thallium), Terry Tucker, RN (Clinical Coordinator), Elizabeth Porter, RN (Clinical Coordinator), Charles Simonton, MD. SAINTTHOMASHOSPITAL,NASHVILLE,TENNESSEE: Marshall Crenshaw, MD (Principal Investigator), David 298

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Hall, MD, Howard Walpole, MD, Mark Glazer, MD, Andre Churchwell, MD (Thallium), Jeannette Thompson, RN (Clinical Coordinator). BAYLOR HOSPITAL, DALLAS, TEXAS: Samuel J. DeMaio, MD (Principal Investigator), Robert L. Rosenthal, MD, John R. Schumacher, MD, Jerrold M. Grodin, MD, Stephen B. Johnston, MD, Jay Olen Franklin, MD, Bradley M. Leonard, MD, Allison Raich, RN (Clinical Coordinator). MEDICAL CENTER OF DELAWARE, WILMINGTON, DELAWARE: Michael E. Stillabower, MD (Principal Investi-

gator), Edward M. Goldenberg, MD, Andrew J. Doorey, MD, James West, MD, James T. Hopkins, MD, James W. Blasetto, MD, James M. Ritter, MD, Mark R. Zolnick, MD, Angela DiSabatino, RN (Clinical Coordinator), Sheri Feens, RN, (Clinical Coordinator). ALLEGHENYMEDICALCENTER,PITTSBURGH,PENNSYLVANIA: John E. Frazier, MD (Principal Investigator), Mi-

chael J. Pecora, MD, Neil Hart, MD, Rodney Randall, MD, Mark Greathouse, MD, Thomas C. Gay, MD, Don L. Fisher, MD, Jerome Granato, MD, Howard Grill, MD, Frank R. Begg, MD, Manuel Salvoza, MD, Angel Flares, MD, Douglas Schulman, MD, Judith E. Orie, MD (Thallium), Loretta Zahren, RN (Clinical Coordinator). WILLIAM BEAUMONT HOSPITAL,ROYAL

OAK,MICHIGAN:

William O’Neal, MD (Principal Investigator), Carol O’Neal, RN (Clinical Coordinator), Karen Beatty-Kennedy, RN (Clinical Coordinator). UNIVERSITY OF LOUISVILLE, LOUISVILLE, KENTUCKY: J. David Talley, MD (Principal Investigator), ZoeAnn Yussman, RN (Clinical Coordinator), Jean Corwin, RN (Clinical Coordinator). MINNEAPOLIS HEART, MINNEAPOLIS, MINNESOTA: Michael Mooney, MD (Principal Investigator), Jodi Fishman-Mooney, RN (Clinical Coordinator), Barbara Kummer (Clinical Coordinator).

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