Gonzalez Carmona Victor - Statins and its Role in Coronary Primary Prevention

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1 QCVC Committees Scientific Activities Central Hall General Information FAC Thematic Units Arrhythmias and Electrophysiology Basic Research Bioengineering and Medical Informatics Cardiac Surgical Intensive Care Cardiomyopathies Cardiovascular Nursing Cardiovascular Pharmacology Cardiovascular Surgery Chagas Disease Echocardiography Epidemiology and Cardiovascular Prevention Heart Failure Hemodynamics - Cardiovascular Interventions High Blood Pressure Ischemic Heart Disease Nuclear Cardiology Pediatric Cardiology Peripheral and Cerebral Vascular Diseases Sports Cardiology Transdisciplinary Cardiology and Mental Health in Cardiology Statins and its Role in Coronary Primary Prevention Víctor Manuel González Carmona * Cardiologia Integral, La Florida, Naucalpan, Estado de México, México Summary At the dawn of XXIst. Century, primary prevention of any condition goes and will go through the human genoma, and DNA will be the card of identity, and the onset of long term preventive measures. As this environement is still not viable, basis for primary prevention are currently made on comprehensive clinical study, family history, and risk factors present at the moment of first clinical approach. Currently, coronary risk stratification is the global strategy to stablish primary preventive measures. Several engines of global use are used, although none has a achieved an unanimous acceptance. The Framingham method or Framingham score [1] was generally used in coronary heart disease (CHD) primary prevention, according to clinical parameters, classical risk factors detected, in order to prevent CHD, complications of the disease or even cardiovascular mortality (CVM). The development of large populations trials with strong statistic values, in different countries, ethnical differences, income status, and wide range of age, gave rise to recognition that the Framingham score was hardly of global use, and other methods of risk stratification, with a closer application to local populations as the SCORE method [2] had a wider application to central Europe populations. Unfortunately in Latin America there is not a risk stratification method applicable to our ethnic characteristics, and primary prevention of CHD has been made on the Framingham score, and treatment guidelines used in USA, as the NCEP (National chlesterol Education Panel), and their updated ATP [3] (Adult Treatment Panels) are the procedures currently used along with AHA and ACC guidelines for CHD: Looking for lifestyle modifications, the guidelines in use in USA, are not necessarily valid in our populations. Methods and Results The current paper was planned through the evaluation of large trials related to the use of statins, with statistical validity and evidence based medicine (EBM) structure, trials in which the statistical results showed positive effects in the prevention of CHD, and the discrimination of other engines than the Framingham score in the coronary risk stratification measures to prevent CHD in a determined period. The MEGA trial [4] carried out in Japan, included 7832 subjects on primary prevention of CHD, in groups of diet, and diet plus 10 mg. of pravastatin, obtaining significant reductions of LDL C fractions. Only 25 % of subjects received 20 mg. of pravastatin. This doses, relatively low in USA groups, achieved clear reductions of basal figures (M 156 mg/dl of LDL). On their primary and secondary goals, a 36 % reduction of coronary events was achieved in a 6 years follow-up. (p< 0.01) and 28 % reduction on global mortality (Confidence interval of 95 % from 0.5 to 1.1) In American population, the OMNIHEART study [5], diet only, improved blood pressure and basal figures of LDL and triglycerides, (TG) with a 5 % reduction in risk using the Framingham Score. The degree of mathematical deformation of Framingham and SCORE engines in extreme ranges of age and income can induce an error of 30 % and therefore other methods are needed to reduce those variations.

2 An interesting study performed in Germany [6], evaluated prognostic studies on the following common bases: 1. Discrimination between risk groups. 2. Predictive values. 3. Prognostic acceptance, and 4. Reproducibility among different populations They evaluated 12 stratification methods significantly: Framingham score, PROCAM; UKPDS and SCORE charts among others. The Framingham score overestimated the cardiovascular risk up to 30 % in Central Europe populations, and needs a recalibration of the method using regional data on cardiovascular mortality and significantly the socio-economic status. Sensitivity, Specificity, and C statistics. External validation with AUC (area under the curve) of 0.6were clearly inferior to internal validation with values under the curve (AUC) of 0.8, and therefore intervention measures and/or treatment, are clearly under or overestimated. Compliance to preventive measures means a high degree of acceptance, mainly on education and knowledge of usefulness, mainly in asymptomatic subjects in face of a costly treatment to be followed for long periods. It is desirable, and a goal for our societies and cardiological foundations, the promotion of public campaigns, to improve compliance, mostly on lifestyle modifications and perhaps drug treatment as preventive measures for long periods. In secondary prevention measures, the coronary event is so impressive that lifestyle modifications and drugs usually expensive, are more easily accepted. Public Health campaigns in our countries have been diffused largely on hypertension, Diabetes, obesity and smoking, have helped the acceptance of our patients in modifying lifestyle and drug compliance. In young subjects, primary prevention measures can be applied from the first consultation in face of family or personal hypertension, diabetes and obesity. Stop smoking must be stressed on both cardiovascular and pulmonary disease prevention. In primary prevention the multiplicating effect of several risk factors must be stressed. In dislipidemias family history and basal figures of total cholesterol, LDL, HDL triglycerides, and significantly Atherogenic score and ApoB/ApoA1 [7] are the basis for diet and/or use of statins. The favourable immunomodulating effect of these drugs must be presented to our patients. In the absence of coronary syndromes or laboratory evidence of CHD, usually diet and exercise are capable to reduce up to % the basal figures of TC LDL HDL and TG. Failure in obtaining normal levels of any fraction or TC, are indications for drug treatment with statins. Hypercholesterolemia and diabetes are indication to early use of statins. Additive action of other risk factors and age may include these patients in high and very high risk patients according to the NCEP- ATP III. Summarized and accepted by the AHA, ACC and ESC [8], currently in use and with no changes in AHA has recommended coronary risk stratification in subjects older than 40 years and no evidence of CHD, al least every 5 years. However, afro-american population with hypertension and diabetic patients, have been underevaluated with the Framingham score in large population trials. These studies on coronary primary prevention, are taken in consideration by the NCEP and the ATP III, since the last decade, and are ALLHAT LLT [9], WOSCOPS [10], HPS [11], PROSPER [12], and ASCOT LLA [13]. In all of them, basal TC, LDL, HDL and TG are measured. In quite a few, Apo B/ApoA1 are considered. Recommendations to start treatment with statins are made when risk stratification has considered the subject as high or very high risk to develop CHD in five years. In this group are considered diabetic patients (type II), who are generally older, and with more risk factors associated., and are compared with the risk of non diabetic patients with previous CHD, in which, use of statins in basal values over 130 mg./dl, have reduced LDL values %, and in parallel fashion the risk of a cardiovascular event in 5 years.

3 However, in patients in the high and very high risk with LDL values way over 160 mg./dl, intensive treatment doses are recommended to get levels of LDL around 100 mg/dl., or a LDL reduction of % of the basal levels, with important statistical data from secondary prevention trials as IDEAL [14], PROVE IT TIMMI 22 [15], TNT [16] and HPS. In a younger diabetic with few or none risk factors, no reduction with statins is recommended unless the basal figures are above 160 mg./dl. High and very high risk patients with goals under 70 mg/dl LDL, are family dislipidemias or with previous coronary events and out of the scope of this paper. In all trials, the decision of using statins is taken with the institution of diets as the DASH, Atkins or Mediterranean diet, suggested by the AHA. Patients with advanced age only, are not considered for the use of statins in absence of CHD unless they have diabetes. In those patients, HPS, ASCOT-LLA and PROSPER, have proven the benefits of using statins with the goal of reducing basal levels of LDL % In subjects without CHD and moderate risk, with 1 or 2 risk factors and risk of CHD of % in 10 years, the use of statins at low doses will achieve levels around 130 mg./dl as demonstrated in the ASCOT- LLA. There are some trials evaluating the effect of increasing HDL with statins in order to stop or even regress the atherosclerotic plaque. All the trials have been on secondary prevention and invasive studies as REVERSAL [17]. Any increment of HDL over basal levels over 7.5 % had a positive action in plaque regression (p< 0.001). According with the main 5 trials (HPS, ASCOT-LLA, PROSPER, and ALLHAT- LLT, the recommended doses of statins to lower the basal LDL figures % are: atorvastatin 10 mg., lovastatin 4 mg., pravastatin 40 mg., simvastatin mg., fluvastatin mg., and rosuvastatin 5-10 mg. An evaluation of collateral effects of statins, is presented in the CTT (cholesterol treatment trialists) [18]. The results of the use of standard and high doses of statins were presented in a global population of 90,000 patients. Considering all trials, alterations on muscular enzymes and hepatic function tests were seen in 1.3 % of the standard or high doses of statins, against 1.2 % in the placebo groups. In patients considered for reduction goals of <70 mg. /dl there were clinical manifestations of myopathy and CK elevations in 3 %. In the CTT was considered rabdomyolisis an extremely rare condition (9 cases ; %) in patients in standard or high doses, vs. 6 cases (0.015 %) in those in the placebo groups. Summary The procedures to stratify the risk to have a clinically apparent coronary sindrome In different periods, are revised. The probabilistic nature of different methods, specially the Framingham score, are commented. Differences as high as %. When they are applied in populations out of the USA are noted. Other procedures as SCORE, PROCAM, and UKPDS are evaluated in their sensitivity, specificity and predictive values...infra and overestimation in extreme ranges of age, ethnic characteristics, income status and other are commented. The guidelines from the NCEP and ATP III on the treatment with statins are evaluated, and currently applied in different countries, our country included. A brief analysis of the CTT related to collateral effects of statins is noted, with the very low incidence of rabdomyolisis in the statins and the placebo groups. Bibliography 1. Sheridan S, Pignone M, y Mulrow C. Framingham based tools to calculate the global risk of coronary heart disease. J GEN. INTERN MED. 2003;18(12): Mostaza JM, Vicente I, Taboada M et al. The aplication of SCORE charts to advanced age males, triple the number of high risk subjects, compared to the Framingham Function. MED: CLIN: (BARC) 2005;124(13): 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 2001;285:

4 4. Nakamura H. et al. Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese. (MEGA) CIRC. J. 2004;68: Appel LJ, Sacks FM, Carey VJ et al. Effects of protein, monounsaturated fat and carbohydrate intake on blood pressure and serum lipids. Results of the Omniheart randomized trial. JAMA 2005;294: Lenz M y Mathauser J. Cardiovascular risk assesment for informed decision-making. Validity of prediction tools. MED. KLIN. (MUNCH) 2004;99(11): Ray KK, Cannon CP,,Morrow DA et al. CRP is additive and independent of ApoB/A1 ratio in explaining the clinical benefits of atorvastatin 80 mg. In ACS patients in PROVEIT-TIMI22. CIRCULATION 2005;112 (Suppl II): National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. CIRCULATION 2002;106: ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Anti-hypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. Major Outcomes in moderately hipercholesterolemic, hypertensive patients randomized to pravastatin vs. usual care: The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT LLT) JAMA 2002;228: Shepherd J, Cobbe SM, Ford I, el al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West Of Scotland Coronary Prevention Study Group. N. ENG.J.MED. 1995;333: Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of Cholesterol Lowering with simvastatin. A randomized placebo-control Trial. LANCET 2003; 361: Shepherd J, Blauw GJ, Murphy MB et al. The PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER) randomized control trial: Prospective Pravastatin in elderly individuals at risk of vascular disease (PROSPER). LANCET 2002;360: Sever PS, Dahlöf B, Poulter NR et al. 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 randomized controled trial. LANCET 2003; 361: Pedersen TR, Faegeman O, Kastelein JJP et al. The Incremental Decrease in Eventsthroug Aggressive Lipid Lowering (IDEAL) Study Group. High dose atorvastatin vs. usual dose simvastatin for secondary prevention after myocardial infarction. The IDEAL Study: A randomized control trial. JAMA 2005;294: Cannon CP, Braunwald E, McCabe CH, et al. The Pravastatin or Atorvastatin Evaluation and Infetion Therapy. Thrombolysis in myocardial in farction. Prove It Timi 22 Study Group. N. ENG. J. MED 2004;350: Waters DD, Guyton JR, Herrington DM et al. TNT Steering Comitte Members and Investigators. Treating To New Targets (TNT) Study. Does lowering low-density-lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit?.. AM. J. CARDIOL ; 93: Nissen SE, Tuzcu EM, Schoenhagen P et al. REVERSAL Investigators. Effect of intensive compared with moderate lipid lowering therapy on progression of coronary atherosclerosis. A randomized control trial. JAMA 2004;291: Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol lowering treatment: Prospective meta-analisis of data from 90,056 participants in 14 randomized trials of statins (CTT Cholesterol treatment trialists). LANCET 2005; 366: CV of the author - Miembro titular de la Sociedad Mexicana de Cardiología de 1977 a la fecha. - Miembro del Consejo Mexicano de Cardiología desde Miembro de la Asociación Nacional de Cardiólogos de México desde 1986 a la fecha. - Jefe de Consulta Externa y Urgencias del Hospital de Cardiología del Centro Médico Nacional Siglo XXI de 1978 a Profesor titular de Cardiología de pregrado en la UNAM de 1973 a Profesor titular de Postgrado de Cardiología de 1992 a Investigador asociado C del IMSS de 1988 a Fellow del International College of Chest Physicians, y del American College of Chest Physicians de 1972 a Miembro honorario de la Sociedad Venezolana de Cardiología desde Maestro Distinguido de la Asociación Nacional de Cardiólogos de México. Nov Miembro de la Mesa Directiva (Tesorero) de La Sociedad Mexicana de Cardiología Publication: September 2007 Your questions, contributions and commentaries will be answered by the lecturer or experts on the subject in the Cardiovascular Pharmacology list. Please fill in de form and Press the "Send" button.

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