MXPA01003290A - Method for preventing or delaying catheter-based revascularization - Google Patents

Abstract

Aggressively lowering cholesterol in patients suffering from coronary artery disease prevents or delays the need for catheter-based revascularization.

Description

METHOD TO PREVENT OR DELAY CATALYSTS-BASED REVASCULARIZATION FIELD OF THE INVENTION This invention is related to the use of statins and other cholesterol lowering agents to avoid or delay the need for catheter-based revascularization in patients suffering from coronary artery disease and need such treatment BACKGROUND OF THE INVENTION Catheter-based revascularization procedures (such as percutaneous transluminal coronary angioplasty) [PTCA], atherectomy, stens and laser beam excision) aim to provide rapid and sustained pain relief to patients with symptomatic coronary artery disease (CAD) (angina pectoris). The effectiveness of PTCA, the most common of these procedures, in alleviating angina and improving the Exercise tolerance is well established. However, this method is limited by the risk of acute complications arising from the procedure, such as death, non-fatal myocardial infarction (MI), or need for emergency coronary artery bypass graft (CABG). In addition, the PTCA has technical limitations that depend on the site of the stenosis, as well as a restinosis index, of up to 40%. PTCA and similar techniques are more successful when dilating sections, limited cuts of the coronary artery system. Stenoses greater than 2cm in length are associated with decreased success rates. Other recanalization methods are being evaluated to try to circumvent some of the problems associated with PTCA, but these methods are limited by similar rates of restenosis, and their own inherent disadvantages. Currently there is no known effective treatment for restenosis. Importantly, recanalization procedures have no influence on the underlying disease that leads to coronary artery stenosis, mainly due to the formation of atherosclerotic plaques. There are several potential mechanisms by which lipid lowering therapy can affect the disease process. The first of these is to observe from many studies that by lowering low density lipoprotein cholesterol (LDL-C), one can slow the progression of atherosclerosis, or even induce regression of existing plaques. However, the slight increase in the area of the lumen that results from the regression of plaques may not be sufficient to explain the substantial reduction in coronary ischemic cases. A second hypothesis is that therapy to lower lipids may induce soft fatty plaques to be more fibrous, thereby reducing the risk of sudden rupture. It has been observed that the majority of clinical cases are caused by moderate light injuries (<70% stenosis) that abruptly progress to a severe obstruction. Histological findings suggest that a large load of lipids, and foam cells laden with profuse lipids in the fibrous cap of the atheroma, predispose cracking and interruption of subsequent plaques. Mechanical and experimental studies have shown that a lipid lowering therapy decreases the number of lipid-laden intimate macrophages and, the early regression process, is hydrolysed in the liquid ester cholesteryl to crystalline cholesterol monohydrate. This can increase the "rigidity" of the lipid load. Therapy to lower lipids eventually depletes both the cholesteryl ester from the center and the cholesterol monohydrate deposits. In this way, therapy to lower lipids can act to stabilize lesions, in addition to reducing their size. However, the correlation between lipid stiffness and reduction in cardiac cases is still speculative. A third theory is that by lowering plasma cholesterol leads to an improvement in endothelial dysfunction. Both human and animal studies have shown that CAD and / or hypercholesterolemia prevents coronary arterial vasodilation mediated by the endothelium. Studies in animals have shown that endothelium-dependent vasodilation improves after lowering cholesterol. A study by Gould, et al, in 15 patients suggests that the decrease in intense cholesterol over a period of 90 days improves the capacity of myocardial perfusion in patients with CAD, as evidenced by positron emission tomography (PET) after a dipyridamole, intravenous, more likely through an improvement in endothelial function. Finally, a number of hemorrhagic factors (eg, fibrinogen, factor VII plasma viscosity, hematocrit, aggregation of red blood cells, and total white blood cell count) if something can contribute to both acute thrombotic events, such as the development of atherosclerosis. Lipid lowering therapy has been shown to improve the viscosity of whole blood, plasma viscosity, and the aggregation of red blood cells. Regardless of the current mechanism, many clinical trials have shown the correlation between lowering lipids and improving cardiac outcomes. A recently published study, Scandinavian Simvastatin Survival Study, also showed that lipid depletion, in a hyperlipidermal population, led to a 42% reduction in cardiac mortality, and more than 30% in the reduction in total mortality. Although hypercholesterolemia is one of the most important risk factors for CAD, studies have not been compared with the long-term result of decreasing lipids aggressively for recanalization of coronary arteries.

One study that compared another mechanism of medical treatment to surgery was the angioplasty compared with medicine (ACME). The ACMÉ study compared the effects of PTCA with medical therapy (antianginal drugs) on angina and exercise tolerance in patients with single-vessel CAD. Although the PTCA offered rapid and more complete relief with medical therapy, and is associated with better exercise test performance, the PTCA treatment group had a higher incidence of cardiac cases and repeated revascularizations. Although PTCA is sometimes used in asymptomatic patients, or those with only mild symptoms of angina despite the presence of a positive exercise tolerance test, it is debatable whether PTCA or similar interventions can be indicated in this population. of patients. It has now been established, in an open-label randomized multi-center study in asymptomatic or mildly to moderately symptomatic patients with LDL-C > 130mg / dL, which is a dramatic improvement in clinical outcomes between lipid-lowering aggressively with atorvastatin compared to a recanalization procedure. The aggressive lipid decrease with atorvastatin significantly retards or even avoids the need for recanalization in these patients.

Atorvastatin is a HMG-CoA reductase inhibitor currently marketed as Lipitor is a member of the "statin" class of organic compounds. Preclinical and clinical studies have shown that atorvastatin reduces total plasma cholesterol, LDL-C, with very low density lipoprotein cholesterol (VLDL-C), and triglycerides (TG). Additionally, clinical studies that atorvastatin seems to have several potential advantages over inhibitors of reductase statin currently marketed as, for example, improved LDL-C and decreased TG. These factors can increase its potential effect on cardiac outcomes. In a study of six-week placebo-controlled dose variation in 79 hypercholesterolemic patients, atorvastatin doses of 2.5 to 80 mg per day produced LDL-C from 25% to 61%, significantly reducing total cholesterol and apolipoprotein B ( apo B), and reduced TG levels up to 32%. No significant changes were reported in high density lipoprotein cholesterol (HDL-C), apolipoprotein Al (apo Al) or Lp (a), a thousand serious adverse cases related to the drug. Other phase two and three clinical studies on 400 individuals and patients have supported these results. The most frequent adverse events that occurred for the patients were headache, infection (mainly flu), constipation and back pain.

Although not yet studied in humans, a study in rabbits shows that atorvastatin has at least as strong an effect on atherosclerotic lesions as other reductase inhibitors. Treatment of white rabbits from New Zealand males fed cholesterol with effective doses of different HMG-CoA reductase inhibitors for eight weeks as a result was also specified in the size of the lesion area of monocyte macrophages, and the relative cellular composition of atherosclerotic lesions. Atorvastatin did not deduce the size of the ligand-femoral lesions by approximately 68%, significantly reduced the extracellular matrix and the smooth muscle cell area by 63%, and reduced the percentage of discernible thoracic aortic lesions compared with the controls of progression. Atorvastatin caused these effects to a greater degree than the other statin reductase inhibitors evaluated.

PRIOR ART This invention provides a method for preventing or delaying catheter-based revascularization in patients suffering from coronary artery disease and in need of such treatment comprising administering an agent that lowers cholesterol in an amount to cause an aggressive lipid decrease . The method of preference is carried out by administering an agent that lowers the cholesterol selected from the statin class of HMG-CoA reductase inhibitors., for example atorvastatin, pravastatin, simvastatin, fluvastatin and mevastatin. Other agents that lower cholesterol when administered include those selected from the fibrate class, for example gemfibrozil, ciprofibrate and bezafibrate. In another embodiment, an agent that decreases carboxylic ether cholesterol is used to aggressively lower LDL cholesterol according to this invention, and thereby prevent or delay the need for catheter-based revascularization in patients suffering from coronary artery disease. .

DETAILED DESCRIPTION OF THE INVENTION The compounds that are used in the method of this invention are those that are effective in lowering cholesterol (LDL) in animals. Typical of the commonly used cholesterol-lowering agents are fibrates, HMG-CoA reductase inhibitors, that is, statins, and a new group of compounds known as carboxyalkyl ethers. Agents that lower cholesterol are given in a dose and frequency to aggressively lower cholesterol levels LDL. The term "aggressively decrease cholesterol levels LDL "means reducing serum LDL cholesterol by at least 40% of the baseline, and preferably by about 50% more.This level of LDL cholesterol generally corresponds to a serum LDL concentration of approximately 100 mg / dL or lower , preferably about 80 mg / dL, and even lower up to about 70 mg / dL or less.To achieve an aggressive decrease in cholesterol, the cholesterol lowering agent will generally be administered in a sufficient dose to effect said decrease in LDL- C per low of about 100 mg / dL For example, a typical dose of atorvastatin used to achieve aggressive cholesterol lowering is about 50 about 150 mg daily, preferably about 80 mg daily, for an adult of normal weight of approximately 70 kg Other agents that lower cholesterol can likewise be administered in doses to effect the decrease of cholesterol to gressive, and in some cases the agents can be used in combination with other agents to achieve said aggressive cholesterol decrease according to this invention. Various agents that lower cholesterol are known and can be used to cause the decrease of aggressive cholesterol according to the method of this invention. Typical agents that are used in the method of this invention include, but are not limited to, fibrates (e.g., clofibrate, gemfibrozil, fenofibrate, ciprofibrate and bezafibrate), niacin, carboxyalkyl ethers, thiazolinodiones, eicosapentaenoic acid (EPA) and compositions that contain EPA (for example, Max EPA, SuperEPA).

Thiazolinodiones useful in the present invention include, for example, darglitazone, Pioglitazone, BRL49653 (rosiglitazone), and troglitazone. Carboxyalkyl ethers useful in the invention are described in Patent No. 5, 648, 387. Specifically, said compounds have the structure of formula I where n and m independently are integers of 2 to 9; Ri, R2 > R3 and R4 independently are Ci-Ce alkyl, C? -C6 alkenyl, C? -C6 alkynyl, and R1 and R2 together with the carbon to which they are attached and R3 and R4 together with the carbon to which they are attached, they can complete a carboxylic ring having from 3 to 6 carbons; Y 1 and Y 2 independently are COOH, CHO, tetrazole, and COOR 5 wherein R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; And where the alkyl, alkenyl and alkynyl groups can be substituted with one or two groups selected from halo, hydroxy, C-i-Cß alkoxy, and phenyl. The preferred carboxyalkyl ethers used in the invention have the above formula wherein n and m are the same integer, and wherein R 1, R 2, R 3 and R are each alkyl.

Further preferred carboxyalkyl ethers are those in which Yi and Y2 independently are COOH or COOR5 where R5 is alkyl. The most preferred carboxyalkyl ethers used in the invention have the formula wherein n and m are each an integer selected from 2, 3, 4 or 5, ideally 4 or 5. An especially preferred carboxyalkylether used in the invention has the formula The ability of agents that lower cholesterol to cause an aggressive decrease in LDL cholesterol and thereby prevent or delay the need for catheter-based revascularization in patients diagnosed with coronary artery disease has been established in clinical trial studies. The following detailed examples are provided to illustrate the significant ability of the aggressive cholesterol decrease according to this invention to prevent or retard the need for a catheter-based revascularization.

EXAMPLE 1 Atorvastatin was evaluated in an open-label, multi-center clinical trial involving 341 patients. This test aims to determine whether aggressive lipid depletion with an agent that lowers cholesterol can significantly delay or even prevent the need for catheter-based revascularization in patients diagnosed with coronary artery disease.

STUDY OBJECTIVE (S) The objective of this study is to compare the clinical effects of aggressive lipid depletion with atorvastatin against revascularization treatments (AVERT) followed by usual care in asymptomatic or mildly to moderately symptomatic patients with CAD and LDL- C > 130mg / dL that have been referred by a recanalization procedure. This will be determined by assessing cardiovascular outcomes, all causes of mortality, quality of life, economic evaluation of results and safety measures.

STUDY SUMMARY This is a randomized 18-month open-label randomized study with 341 patients with LDL-C (> 130mg / dL elevated whether or not they are receiving a drug to lower lipids) who have had angiography . Patients who can qualify for the study are those whose angiogram indicates that they can be elected for a recanalization procedure and who have an asymptomatic or mild to moderately symptomatic CAD (with respect to angina symptoms with or without antianginal therapy). Patients should be of class 1 or 2 based on the classification of angina severity according to the Canadian Cardiovascular Society, and they should be able to complete 4 minutes of the Bruce protocol band test, or a test of supine bicycle exercise of 20-W / min. Qualified patients will be randomized into one of the treatment groups: Group 1 will receive atorvastatin at 80 mg QD, and group 2 will undergo a recanalization procedure followed by usual care.

STUDY POPULATION Source and Number of Patients Source: Patients will be recruited from the population of patients who have passed or are about to undergo an angiography and who are recommended a recanalization procedure. Number of patients: 341 (163 patients received atorvastatin, 178 received revascularization).

Patient Selection Criteria Inclusion Criteria • Men or women. They can enroll women with potential for delivery but should plan not to get pregnant during the course of the study and should practice a method of birth control that is considered appropriate by the researcher. If it is established in hormonal contraceptives for more than three months, patients can participate, taking into account that this therapy will remain constant throughout the study. If a patient becomes pregnant or starts breast-feeding during the study and is receiving atorvastatin, it should be withdrawn immediately; • Patients to whom a recanalization procedure approved by the regulatory agency is recommended; • Patients with > _1 major coronary vessel never subjected to an intervention with > 50% stenosis; • Patients with LDL-C 30 mg / dL (^ 3.4 mmol / L) as calculated by the Friedewald formula; • Patients who are allowed to take medications to lower lipids at the time that LDL-C was determined; • Patients with TG serum < 400mg / dL (£ .4.5 mmoles / L) • Patients who can complete 4 minutes of a Bruce protocol band test or a 20W / min supine bicycle test while still finding objective evidence of ischemia (ST depression segment of >2mm); and • Patients with asymptomatic or mild to moderately light CAD (Class 1 or Class 2 of the severe angina classification of the Canadian Cardiovascular Society (CCS).

Exclusion Criterion • Patients under 18 or over 80 years of age; • Women who are nursing or pregnant; • Patients with major left coronary disease or three coronary disease (defined by the presence of> 50% stenosis in the three main coronary arteries); • Patients with unstable angina or patients who experience angina after light exercise. • Patients who have been recommended to undergo immediate direct angioplasty to evolve acute Ml; • Patients who have experienced an ML within the previous 28 days; • Patients with a fraction of expulsion < 40% • Patients with CHF who are NYHA class III or IV • Patients who have undergone a CABG, unless a current recanalization is recommended for a native vessel and a current angiogram indicates that passing grafts are present. • Patients in whom a CABG is recommended based on the current angiogram. • Patients who underwent a recanalization procedure during the previous 6 months; • Patients who consume an average of more than 21 weekly alcoholic beverages (approximately 277 g of pure alcohol); • Patients with significant renal dysfunction, active liver disease or hepatic dysfunction, SGOT (AST) or SGPT (ALT) > 2x the upper limit of the normal range (ULN); • Patients with CPK levels > 3xULN or unexplained CPK elevations; • Patients who have uncontrolled hypertension, defined by a diastolic blood pressure > 100 mm Hg identified by the disappearance of all sounds (Korotkoff Phase V) after sitting silently for at least 3 minutes, whether or not taking a current antihypertensive medication; • Patients who may be unreliable as study participants based on prior knowledge of the patient's investigator, such as an individual who abuses alcohol; • Patients participating in other chemical studies currently or within the 30-day phase prior to selection of entry to the current study; • Patients with known hypersensitivity to HMG-CoA reductase inhibitors; Patients with other significant abnormalities that the investigator considers may compromise patient safety or successful participation in the study.

Prohibited Medications or Precautions • The following medications are not allowed in group 1 (therapy with atorvastatin) during this study; «Drugs that regulate lipids: niacin, probucol, Metamucil® (> 2 teaspoons daily), fibrates and derivatives, other reductase inhibitors, HMG-CoA, or fish oils; • Immunosuppressive agents; and • Known drugs that are associated with rhabdomyolysis in combination with reductase inhibitors HMG-CoA (eg cyclosporine, erythromycin, gemfibrozil, or niacin) There are no restrictions of the study on medication for patients in group 2 (recanalization procedure followed by usual care).

The dosage and regimen of any currently permitted chronic medication should be handled appropriately throughout the study. Patients in group 1 who received medication to lower lipids during the selection period should continue that medication at the time of aleoteorization and start atorvastatin instead. Patients in group 2 who received medications to lower lipids during screening can continue with this medication, if desired. Occasional use of antacids is allowed. Intensive antianginal therapy is strongly recommended for patients in both treatment groups.

STUDY DESIGN AND METHODOLOGY Study Design This is a randomized 18-month open-label randomized study comparing aggressive lipid depletion with atorvastatin (80 mg QD) with a recanalization procedure. For the usual care. The study is conducted in patients with LDL-C > _130 mg / dL and TG < _400 mg / dL that have asymptomatic or mild to moderately symptomatic CAD (with or without antianginal therapy) and in which a recanalization procedure is recommended. The "usual care" represents a heterogeneous mix of therapies that may include the use of calcium channel blocker or a therapy to lower lipids (including diet, behavior modification or antihyperlipidermal medication). Patients who have undergone angiography, or are about to undergo angiography, will be considered for this study based on the results of the angiogram and other inclusion criteria. The study will be conducted using a common protocol in all study sites. Researchers and patients will not be segmented to the treatment group, but will be segmented to lipid measurements throughout the study.

Study Schedule The visiting hours for this study and the procedures to be performed at each visit will be checked carefully. However, a patient can be checked at any time for safety reasons. No more than 6 weeks should pass between the screening visits (visit S1) and the first visit of the treatment phase (visit T1), and no more than 8 weeks should pass between the angiogram and the original recanalization procedure for patients in group 2. All laboratory procedures, such as clinical laboratory measurements and determinations of lipoproteins and apolipoproteins used for effective measurement, would be performed by a central laboratory. Part of the samples obtained at the screening visit can be sent to a local laboratory for a quick response to determine the patient's selection. The rest of the sample should be sent to the central laboratory (divided sample). The time of the clinical visits should be consistent throughout the study and as for patients in group 1, they should take atorvastatin at approximately the same time of day, that is, before going to bed. Clinical visits during all phases of the study in which lipid profiles will be determined should occur after a minimum of 12 hours of fasting (allowing water). The only exception to this is in the screening visit in which it is preferred, but not required, that patients be in a fasting state. For patients in group 1, the blood sample should be taken 6 to 18 hours after the previous dose of the study medication. The previous study design is illustrated below in Table 1.

Table 1 Study design What have you? < referred for an angiography Preliminary selection for the study - Measure lipids and clinical laboratory parameters. - Patient history / examination Physical angiography. - Exercise test.

Selection for the Study - Measurement of lipids and clinical laboratory T parameters. Angiography - Patient's history / physical examination. - Exercise test.

Randomization Group 1: Ator channels 80mgQDx18 months recanalization procedure followed by usual care for 18 months.

Selection Phase The purpose of the selection phase is to evaluate a patient's score for randomization of the study. If the institution commonly performs the angiography and then performs the recanalization procedure at a later date, the following sequence of steps should be followed (per Table 1): Patients who have undergone angiography and who have met the inclusion criteria coronary and that do not have any of the coronary exclusion criteria will be evaluated by this study. The investigator should inform the patient about the study, obtain the patient's medical history and informed consent, take blood samples for lipid measurements and clinical laboratory parameters, and perform an exercise and physical examination test. If the person qualifies for the study based on their lipid measurements and approves the results of the exercise test, and does not have any of the exclusion criteria, it will be randomized to receive atorvastatin, or to undergo or undergo a recanalization process. For the usual care, depending on the scrambling code. All selection procedures should be completed and patients randomized during the 6 weeks after the angiogram. The original recanalization procedure in group 2 should be completed during the 8 weeks after the angiogram.

If the institution commonly performs the recanalization procedure during catheterization for the angiogram, the following sequence of cases should be followed: The investigator should inform the patient about the possibility of qualifying for this study and should obtain informed consent before angiography . In addition, a medical history, exercise test and physical examination should be completed, and blood samples taken for lipid measurements and clinical laboratory parameters. If the patient qualifies for the study based on their lipid measurements and exercise test results, and they do not have any of the exclusion criteria, they must go through an angiography and then, if they meet the criteria for coronary artery inclusion. and does not have any of the criteria for coronary exclusion, it will be randomized either to receive atorvastatin or to undergo a recanalization procedure. For the usual care, depending on the scrambling code. Patients in North American sites should follow a Bruce protocol for a band exercise test, while patients in European sites can follow either a Bruce protocol or a 20-W / min supine bicycle test. The protocols for any of the tests are well known. In order to qualify for the study, patients should be able to complete 4 minutes of Bruce protocol or a 20-w / min supine bicycle test without developing objective evidence of ischemia (SP segment depression of> 2nnm). If a patient is able to complete 4 minutes, he must complete the rest of the test as he is able. When blood samples are taken for clinical laboratory selection measurements, the sample should be divided. Half of the sample should be sent to the local laboratory for a quick response to determine the illegibility of the patient, and the other half should be sent to the laboratory central. All subsequent samples should be sent in full to the central laboratory. The results of angiography will be recorded (in some cases retrospectively) in the CRFs study. Angiography films should be stored on site as source documents. Randomization should occur no more than 6 weeks after angiography and the intervention for patients in group 2 should occur within 8 weeks after angiography.

Phase of the Open Label Treatment All patients will be randomized to either group 1 or group 2 according to a randomization code. Patients in group 1 should discontinue any medication that decreases the lipids they may have received and initiate open label therapy with atorvastatin 80 mg (two 40 mg tablets) taken once a day before bedtime. Patients in group 2 will undergo the recanalization procedure recommended by the usual care. "Usual care" represents a heterogeneous mix of therapies that may or may not include lipid-lowering therapy (eg, diet, behavior modification, or antihyperlipidermal medications). The usual care will be determined by the investigator or the patient's main doctor (or who typically decides the patient's follow-up care) as it sees fit. These patients will return to the investigator as scheduled and report the therapies they are receiving. Since any number of people can dictate the follow-up care of a patient, and any number of people can review the patient for study visits (for example, the investigator, a nurse, a companion), a standard list of questions will be provided. that will be done to the patient to try to reduce deviations. Patients in both treatment groups should take an aspirin daily. Optimal antianginal therapy is strongly recommended for all patients. The visit T1 (week 0) is the visit in which the patients who have qualified have been randomized. This will be the same day of the angiography and the recanalization procedure (for patients in group 2) in institutions that combine angiography with the recanalization procedure. In the institutions that separate the angiography from the recanalization procedure, this is the day in which the researcher knows that the patient meets all the inclusion criteria and none of the exclusion criteria, assigns the patient with a number, and opens the code of randomization to determine to which treatment group the patient should be included. It will not necessarily be the day that the recanalization procedure will be performed for patients in group 2. For the purposes of this study, certain information about the original recanalization procedure in group 2, and any other recanalization procedure in any of the groups, will be registered in the CRFs in the study. This includes the type of intervention, intervention vessel, percent stenosis before and after the intervention and the success of the procedure (defined as a> 20% change in narrowing luminal diameter and a residual diameter of < 50% stenosis without the occurrence of death, acute Ml or the need for an acute CABG during hospitalization). In order to undergo a revascularization procedure after randomization (and after the original recanalization procedure in group 2), a patient must show objective evidence of deterioration in their condition defined as one of the following: • Angina during rest with ECG changes; or • A 3 minute deterioration in a Bruce protocol band test or supine bicycle test (ST segment depression of time a> 2 mm while in a maximum antianginal therapy) or • An acute myocardial infarction verified by evidence objective Patients who experience a non-fatal izchemic effect or who undergo a revascularization procedure (other than the initial recanalization in group 2) at any time after randomization should not be excluded from the study. Clinical visits will occur after 6 to 12 weeks, 6 months, and then every 6 months after this. At all visits blood samples will be taken and sent to the central laboratory for the determination of safety parameters, lipoproteins and additional parameters. The central laboratory will notify the site and the sponsor if the patient's LDL-C decreases to <50 mg / dL. The investigator may choose to reduce the dose of atorvastatin at his discretion. A patient can be checked at any time for safety reasons. The quality of life questionnaire, the SF-36 health survey (SF-36), will be administered at the baseline (visit T1), at month 6 and at end of the study. This is a short questionnaire of 36 articles that was designed to measure the general health status from the patient's point of view. The SF-36 is available in a number of languages and can usually be completed by patients taking 5 to 10 minutes. During the course of the study, the patient should be encouraged to maintain a healthy lifestyle, which may include modifications to eating habits, exercise or smoking.

Efficacy Evaluation Primary efficacy parameters The primary efficacy parameter will be the incidence rates associated with the izchemic case in each treatment group. In addition to obtaining the associated proportion in an izchemic case, there is also the interest to evaluate (by treatment group) the total number of these izchemic cases and the distribution of each of the cases that define an izchemic case. An izchemic case is defined as the occurrence of at least one of the following cases: cardiac death, heart attack, non-fatal MLA, izchemic CVA, CABG, recanalization (different from the original recanalization procedure in group 2), or unstable angina with objective evidence.

Secondary efficacy parameters • The evaluation of secondary efficacy will include the following: • Time of randomization to the occurrence of an izchemic case; • Change of baseline in the angina class (CCS); • Percentage of baseline change of LDL-C, HDL-C, total cholesterol, total TG, apo Al, apo B and Lp (a); • Quality of life (QOL) determined by the SF-36 questionnaire; and • Mortality list for all causes.

• Other parameters of interest include: • Patients in the atorvastatin group (grupol) who suffer a PTCA or other recanalization procedure will have their subsequent ischemic incidence rates compared with patients in group 2 (all patients in this group have a PTCA or a similar procedure); • An assessment of the number of PTCAs or other recanalization procedures required in the atorvastatin group compared to the usual care group; Y, • A correlation analysis between the incidence rates of izchemic cases and LDL-C and triglyceride measurements.

Economic Evaluation This study will evaluate the cost of asymptomatic or mild to moderately symptomatic treatment, either with atorvastatin or a recanalization procedure followed by usual care. Costs to be considered will include the cost of clinical endpoints, the cost of treatment regimens (recanalization procedure or atorvastatin medication), and costs associated with serious attributable adverse effects. Serious attributable adverse effects are distinguished by group 2 as pseudoaunerism, groin hematoma, bleeding at the access site, abrupt vessel closure, dissection or reaction to the point of contrast; and for group 1 hepatitis or rhabdomyolysis. The generalized costs for the services of the provider for the aforementioned cases and the interventions will be obtained from national databases. In addition, these costs can also be collected from some or all of the participating study sites.

Safety evaluation HMG-CoA reductase inhibitors have been associated with significant side effects: elevated liver transaminases and the occurrence of myopathy. Therefore, at each predetermined visit, all patients should have measurements of AST, ALT, and CPK as commonly recommended. Additionally, patients in group 2 should be monitored as appropriate regarding the agents used.

Physical Examination A physical examination and medical history will be performed at the screening visit (S1), and a repeated physical examination will be performed every six months after this. Significant deleterious changes will be recorded as adverse effects.

Adverse Effects Adverse effects will be recorded at each clinic visit and up to 15 days after cessation of treatment.

Laboratory evaluation Complete clinical laboratory determinations should be performed including urinalysis by Ames Multistix® in the Selection, Week 0 (Visit T1), month 6, and at the end of the study. An abbreviated clinical laboratory determination of key safety parameters (liver enzymes and CPK) will be made on all other visits for the patients in both treatment groups. A verified clinically significant laboratory abnormality that occurs during the study will be reported as an adverse effect and will be followed up until the abnormality has been resolved or has had a satisfactory explanation. Elevations in laboratory parameters that may be associated with the medical therapy that constitutes "usual care" (Group 2) should be handled as deemed appropriate by the principal care investigator / doctor.

Elevations in CPK and liver transaminase levels that occur during therapy with atorvastatin (Group 1) should be handled as follows. If at any time during the study, the patient's ALT or AST levels 5 increase to a range of > 3 x ULN. The patient should be scheduled for a repeated laboratory measurement in a week (± days). If the repeated value is still in the range of > 3 x ULN, the dose should be reduced by 50% (to 40 mg QD). Patients who continue in the study and in the dose reduced should have their ALT / AST levels re-evaluated within one more week (± 3 days). If the repeated value is still in the range of > 3 x ULN, the dose should be halved once more at 20 mg QD. The dose can once again be divided up to 10 mg QD, if necessary, or the patient can discontinue Atorvastatin but remain in the study. If at any time during the study, the CPK level of the patient increases to the range of > 10 x ULN, the patient must be scheduled for a repeated laboratory measurement within a week (+ 3 days). If the repeated value is still in the range of > 10 x ULN WITH muscle weakness or sensitivity, the patient should have atorvastatin removed but should remain in the study. If the repeated value is still in the range of > 10 x ULN WITHOUT muscle weakness or sensitivity, the dose should be reduced to 50% (to 40 mg QD). Patients who continue in the study at a reduced dose should see their CPK level reassessed within one week (± 3 days). If the repeated value is still in the range of > 10 x ULN without symptoms, the dose should be divided in half once more at 20 mg QD. The dose can once again be divided up to 10 mg QD, if necessary, the patient can discontinue atorvastatin but remain in the study. Patients should be advised to report weakness, sensitivity or inexplicable muscle pain immediately, particularly if accompanied by fever or discomfort NOTE: Once a patient has decreased the dose of atorvastatin due to elevated liver enzyme level or elevated CPK levels, that patient can not be titrated. return to the highest dose. Consideration should be given to temporarily maintain or discontinue atorvastatin in any patient with a risk factor predisposed to the development of secondary renal failure or rhabdomyolysis, including severe acute infection; hypotension; major surgery; trauma; electrolyte disorders such as endocrine or severe metabolic disorders; and uncontrolled attacks.

Safety Profile At each visit, the following minimum safety data will be collected: pulse, blood pressure and weight.

Electrocardiogram A 12-lead electrocardiogram will be performed at standard rest during the beginning of the treatment phase (visit T1) and every 6 months after this.

DATA ANALYSIS AND STATISTICAL CONSIDERATIONS Sample Size Considerations The statistical analysis associated with this study considers a parameter number. The main efficacy parameter is the incidence rate of an izchemic case (defined as the occurrence of at least one of the following cases: cardiac death, heart attack, non-fatal Ml, izchemic CVA, CAVG, recanalization [other than that of the original procedure in group 2] or unstable angina with objective evidence The secondary parameter analysis considers: the time of randomization to the occurrence of the izchemic case, the change of the baseline in the class of angina, the percent of change of baseline at the end of the treatment in number of lipid parameters, a QOL measurement (based on the results of the SF-36 health survey), the mortality rates of all the causes. based on the number of patients required to obtain a reliable statistical test to test the difference between the two groups in terms of incidence rates of izquémic cases. The recommended sample will provide an adequate sample size for a powerful statistical test to compare the two groups at the time of the zchemical event and the change of the baseline in the lipid parameters. Suppose an incidence rate of 35% for the group with usual care and a 20% incidence rate for atorvastatin; The recommended sample size is 340 patients (170 / group). The sample size derived provides a 0.05 level of significance with 85% ability to detect a significant difference between the two groups of these incidence rates. When deriving the sample size, an expected rate of patient withdrawal of 5% is taken into consideration. These statistical analyzes will be performed on all randomized patients.

Analysis of the Primary Efficacy Parameter The primary efficacy parameter is defined as the incidence rates of an izchemic case. The Cochran-Mantel-Haenszel test will be used to compare ischemic incidence rates within the two treatment groups. This test will provide a method to compare the proportions between the two groups while adjusting other variables in the model. The odd ratios with 95% confidence intervals will also occur.

As a follow-up, the distribution of the first izchemic case (defined below) will be investigated between the two treatment groups: • Cardiac death • Cardiac attack • Ml, nonfatal, izotemic CVA More serious - Less Serious Descriptive statistics will be provided by treatment group in the total number of izchemic cases.

Analysis of Secondary Efficacy Parameters • The following secondary parameters will be analyzed: • Time of randomization to the occurrence of the izchemic case; • Change in the baseline in the angina class; • Percent change of baseline at the end of treatment for the following lipid parameters: - LDL-C, - HDL-C, - Total cholesterol, - Total TG, - Apo B, - Apo Al, and - Lp ( a) • Measurement of QOL; • Mortality rates of all causes In order to compare the two treatment groups at the time of the occurrence of the izchemic case, survival analyzes were conducted using a Cox regression analysis in a model having the following structures: Time to the izquémico case = l2 trial treatment; where: \ < identifies the patient as having a single-vessel or two-vessel disease; l2 identifies the patient as asymptomatic or symptomatic; Test is an indicator variable that identifies the particular center associated with a patient; and Treatment identifies the group in which the patient was randomized. When using the Cox regression analysis, the two treatment groups will be compared in the survival times, while the concomitant variables included in the model are adjusted and taking into account any censored observations. Survival times for censored observations will be defined as: • If a patient withdraws before the 18 month follow-up period, any attempt will be made to make contact with the patient in order to obtain the current time in which the izchemic case occurred (if it happened); and if the contact for the patient was not successful, the survival time will be the period of time from randomization to the last contact period; • If an izchemic case does not occur during the study period, then the survival time will be the period of time of randomization at the end of the study. In addition, the interaction of treatment by test will be investigated. When using the PL (limit product) calculations provided by Kaplan and Meir, survival curve calculations will be provided with total confidence intervals of 95% and within each center. In addition, graphs of the estimated survival curves for the two treatments will be provided. The change of the baseline in the class of angina, the change of percent of the baseline at the end of the treatment associated with the lipid parameters described above, and the QOL measurements will be analyzed using the following model: Y = YB II 12 Test Treatment where \ < \ e l2 have been defined as mentioned above; and 5 YB corresponds to the baseline value of Y. Confidence intervals of ninety-five percent will be generated for the difference in the percent change for each of the parameters, general and within each test. Once again the test is investigated by treatment interaction. 10 To compare the mortality rates of all cases between the two treatment groups, the Cochran-Mantel-Haenszel test mentioned above will be used in the discussion of the primary efficacy parameter. Again, they will reduce odd proportions with confidence intervals of 15 95%. Other parameters of interest include: • Patients in the atorvastatin group who have a PTCA or other recanalization procedure will be compared with the incidence rates of izchemic cases. subsequent with patients in the usual recanalization / care procedure group (all patients in this group have a recanalization procedure); • An evaluation of the number of PTCAs or other recanalization procedures required in the group of atorvastatin in comparison with group 2; • A correlation analysis between the incidence rates of the izchemic cases and the triglyceride and LDL-C measurements. Also, an additional analysis of the primary efficacy parameter will be performed to exclude those CABG recanalization procedures that occurred in the treatment group and that were indicated based on the criteria for the intervention delineated in the Open Label Treatment section. The result of the previous study establishes that aggressive reduction of LDL with an agent that lowers cholesterol is effective in preventing or delaying the need for catheter-based revascularization. In the trial of 341 patients, only 13% of those who were treated with high doses (80 mg) of atorvastatin suffered an adverse cardiac event in the following 18 months, while 21% of the patients who were released from the blockages with An angioplasty procedure suffered such adverse cases in the same period of time. The two patients treated with atorvastatin had their LDL cholesterol reduced by an average of 77 mg / dL of 140 mg / dL before treatment. This is well below the level of 130 mg / dL considered as the target for people without heart disease, and the 100 mg / dL threshold for patients with symptoms of heart disease. LDL cholesterol in patients treated with angioplasty fell to approximately 119 mg / dL during the study. This study clearly states that LDL levels well below the target of 100 mg / dL is unexpectedly better and preferred. The results establish that lowering LDL aggressively by administering an effective amount of an agent that lowers cholesterol will allow patients to undergo expensive angioplasty without fear of increasing the risk of a heart attack. The data establish that 87% of patients randomized to treatment with atorvastatin, who were originally candidates for angioplasty, were instead able to remain in a drug therapy alone in the duration of the 18-month trial, without experiencing any adverse cardiovascular event.

Claims (10)

1. CLAIMS 1. A method for preventing or delaying catheter-based revascularization in patients suffering from coronary artery disease and in need of such treatment comprising administering an agent that lowers cholesterol in an effective amount to cause an aggressive lowering of LDL cholesterol .
2. 2. The method according to claim 1, characterized in that the cholesterol lowering agent is a HMG-CoA reductase inhibitor.
3. The method according to claim 2, characterized in that the reductase inhibitor HMG-CoA is selected from atorvastatin, mevastatin, cerivastatin, simvastatin, fluvastatin, dalvastatin, pravastatin and lovastatin, or a pharmaceutically acceptable salt thereof.
4. 4. The method according to claim 3, characterized in that the HMG-CoA reductase inhibitor administered is atorvastatin, or a pharmaceutically acceptable salt thereof.
5. 5. The method according to claim 4, characterized in that the amount of atorvastatin administered is from about 50 mg / day to about 150 mg / day.
6. 6. The method according to claim 5, characterized in that atorvastatin is administered in a dose of approximately 80 mg / day.
7. 7. The method according to claim 1, characterized in that the cholesterol lowering agent is a carboxyalkyl ether of the formula or a pharmaceutically acceptable salt thereof.
8. 8. The method according to claim 7, characterized in that the agent that lowers cholesterol 10 administered is 6,6'-oxybis- (2,2-dimethylhexanoic acid), or a pharmaceutically acceptable salt thereof.
9. 9. The method according to claim 1, characterized in that the cholesterol lowering agent is selected from a fibrate.
10. 10. The method according to claim 9, characterized in that the cholesterol lowering agent is selected from clofibrate, gemfibrozil, fenofibrate, ciprofibrate and benafibrate.