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CLINICAL EFFECTS OF LONG-TERM STATINS (ATORVASTATIN, SIMVASTATIN) TREATMENT IN PATIENTS WITH STABLE ANGINA

Sh. Chumburidze, N. Kipshidze
National Center of Therapy, Tbilisi, Georgia

Key word: stable angina, treatment, statins (atorvastatin, simvastatin).

The link between increased risk for coronary heart disease and elevated plasma cholesterol is firmly established.

Dietary intervention is recommended as the first-line therapy to reduce circulating cholesterol in patients with multiple risk factors for coronary heart disease. However, not all patients achieve the necessary reduction in cholesterol levels with diet alone and the additional use of a pharmacological agent is often necessary.

One of the major advances in clinical medicine in the last few years has been the introduction of sta­tins for the treatment of patients with coronary heart disease and hypercholesterolemia. Clinical tri­als investigating statin therapy in primary prevention (WOSCOPS, AFCAPS/TexCAPS) and in secon­da­ry prevention (4S, CARE, LIPID) [1] supported the hypothesis that drugs that lower plasma chole­sterol concentration are of benefit to patients with and at risk of developing coronary artery disease.

The goal of the present study was to evaluate the lipid lowering effect of statins (atorvastatin, simvastatin) on clinical status of patients with established coronary heart disease and hypercholesterolemia, measured by the changes in exercise tolerance, number of angina attacks and nitroglycerine consumption and on fibrinogen levels.

Methods. We studied 76 patients with stable coronary artery disease, a relatively normal left ventricular function, symptomatic or mild to moderate angina, and low density lipoprotein cholesterol (LDL-C) of at least 160 mg/dl and serum level of triglycerides of less than 300 mg/dl, despite adherence to a fat-restricted diet (American Heart Association phase I) for a minimum of 4 weeks.

Patients mean age was 51 years (range 30 to 75). All patients were able to complete at least four minutes of a treadmill test conducted according to the Bruce protocol without marked electro­car­diographic changes indicative if ischemia.

Major criteria for exclusion from the study were unstable angina or myocardial infarction within the previous two weeks. All lipid lowering drugs were stopped six weeks before start of active treatment period.

Plasma concentrations of total cholesterol, high density lipoprotein (HDL)-cholesterol and TG were determined using automated methods (Boehringer Mannheim for cholesterol and triglycerides). LDL-cholesterol was calculated using the Fridwalde formula.

All patients were screened to determine complete blood counts, urinalyses, creatinine, creatine kinase, bilirubin, transaminases (ASAT, ALAT and GGT), glucose, uric acid.

The patient’s quality of life were evaluated with the questionnaire, that was composed with us according to special questionnaires: The Nottingham Heart Profile; The General Health Questionnaire; The SF 36 general health status survey to document health-related quality of life in patients with coronary artery disease.

Patients were randomly divided in three groups. First group (25 pts) received simvastatin 20 mg daily, second group (27 pts) received atorvastatin 10 mg daily, third group (24 pts) received only background therapy (the control group). Background therapy was similar for each group and consisted of Nitrates, Beta-blockers, Ca-antagonists, ACE inhibitors and Aspirin. Duration of the study was 6 months.

Statistical significance was evaluated by the “Two Sample T-Test and confidence interval” (“Mini-tab”).

Results.

Patient disposition. Baseline demographic features are shown in Table 1.

Lipid levels. There were significant and sustained decreases in plasma levels of total and LDL cholesterol and triglycerides and increase in HDL cholesterol during atorvastatin and simvastatin treatment compared with the control group.

In the simvastatin group the average percent changes from baseline were as follows: total cholesterol –23,97%, LDL-cholesterol –31,1%, HDL-cholesterol +8% and TG –12%.

Table 1. Baseline cardiovascular Risk Factors and Demographic Variables

In the atorvastatin group the corresponding changes were –31,2%;  –41,6%; +14,39%; –25,09% respectively.

In the control group the corresponding changes were –4,94%;  –3,37%; +1,8%; –3,4% respectively.

Angina. There were significant decreases in the number of effort of angina attacks per week and in the consumption of nitroglycerine tablets per week during atorvastatin and simvastatin treatment compared with the control group.

In the simvastatin group the number of effort of angina attacks per week decreased by 65,31% (p<0,0001); The consumption of nitroglycerine tablets by 62,3% (p<0,0001).

In the atorvastatin group the corresponding changes were: –75,8% (p<0,0001); and

–73,37% (p<0,0001) respectively.

In the control group the corresponding changes were: –52,3% (p<0,0001) and 49,12% (p<0,0001) respectively (Fig. 1, Fig. 2).

^a = The simvastatin group vs The control group; ^b = The atorvastatin group vs The control group;

^c = The simvastatin group vs The atorvastatin group; ¹ = <0.05; ² = <0.01.

 Exercise tolerance. Our data show statistically significant improvements in total exercise tolerance during statins treatment compared with the control group. Improved exercise capacity was seen as increased exercise duration, exercise capacity (N), the total oxygen consumption (VO₂ max), the metabolic equivalent (MET) (Table 2).

Table 2. Percent changes on exercise tolerance in the statins(I, II) and the control(III) group

Values are means ± SD.

 Patient’s quality of life. At the end of the study there were statistically significant improvement in patient’s quality of life during atorvastatin treatment compared with the simvastatin and the control groups (Fig.3).

Safety. Therapy with statins (atorvastatin, simvastatin) were well tolerated. Adverse events occurred with similar frequency in groups.

No patients in either treatment group had clinically important elevations in the level of aspartate or alanine aminotransperase (defined as a level that was more than three times the upper limit of normal).

The syndrome of drug-induced myopathy (myalgia and increase in CK levels to > 10 times the upper limit of normal) was not observed in any patients.

Discussion. Our study suggest that decrease in LDL cholesterol and increase in HDL cholesterol with statins (especially with atorvastatin) is associated with a significant reduction in angina symptoms and the greatest improvement in total exercise tolerance and quality of life of patients with stable coronary heart disease.

It is increasingly likely that we can not attribute the above mentioned changes solely to LDL dependent reduction in plaque volume, plaque lipid and regression on coronary atherosclerosis.

There is evidence that statins have effects on immune function, macrophage metabolism, cell proliferation, endothelial function, vasomotion, platelet reactivity and hymoral thrombogenetic factors independent of changes in plasma LDL concentrations [2, 3].

We observed a marked anti-inflammatory activity of atorvastatin. There were significant and sustained decrease in fibrinogen level in the statins (especially in the atorvastatin group) groups compared with the placebo group.

In conclusion, the ensemble of data summarized above, suggest that patients with known coronary heart disease (patients with stable coronary heart disease, patients after angioplasty or after coronary artery bypass grafting) and elevated serum LDL cholesterol levels > 130 mg/dl should be placed on an effective diet and drug therapy, preferably a reductase inhibitor.

 
 Moreover, it appears that in patients with relatively normal left ventricular function lipid lowering with statins (with simvastatin, especially with atorvastatin) may reduce the likelihood of ischemic events and thereby delay or prevent the need for revascularisation [4, 5, 6,7,8,9,10,11,12,13,14,15].

Referenses

1.       Sprecher DL. – Where to draw the line using statins: lessons from 4S to AFCAPS/Tex CAPS// Cleve Clin. J. Med., 2000, 76, p. 169-171.

2.       Vaughan C.J., Murphy M.B., Buckley B.M. – Statins do more just lower cholesterol// Lancet, 1996, 348, p. 1079-1082.

3.       Vita A.J., Jeung A.C. et al. – Effect of cholesterol lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease// Circulation, 2000, 102, p. 846-851.

4.       Vaughan CJ., Gotto AM., Basson CT. – The evolving role of statins in the management of atherosclerosis// J. am. Coll. Cardiol., 2000, 35, p. 1-10.

5.       La Rossa JC., He J., Vupputuri S. – Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials// JAMA, 1999, 282, p. 2340-2346.

6.       Feely J., McGettigan P., Kelly A. – Increase in statin prescription Rates Following Landmark trials. Growth in use of statins after trials is not targeted to most appropriate patients// Clin. Pharmacol. Ther., 2000, 67, p. 438-441.

7.       yifSiZe n., WumburiZe S. – atorvastatinis klinikuri efeqturoba pacientebSi gulis iSemiuri daavadebiT //“saqarTvelos samedicino moambe”, 2000, 3-4, gv. 18-24.

8.       yifSiZe n., WumburiZe S. – statinebi- hipolipidemiuri saSualebebis mZlavri jgufi aTerosklerozis winaaRmdeg //Sinagani medicinis miRwevebi da problemebi, SromaTa krebuli, 2001, II tomi, gv. 13-23.

9.      CafiZe g., kapanaZe s., doliZe n. da Tanaavt. hiperlipidemiis koreqciis pirveli Sedegebi liprimaris gamoyenebiT meorad koronarul prevenciaSi //kardiologia da Sinagani medicina, 2002, gv.43-47.

10.   Чумбуридзе Ш.Д., Кипшидзе Н.Н. Переносимость и сравнительная экономическая эффективность статинов при лечении больных со стабильной стенокардией напряжения //Медицинские Новости Грузии. 2002, 4 (85), с. 74-77

11.   Chumburidze SH.D., Kipshidze N.N. Early HMG-CoA reductase inhibition with Liprimar in patients with unstable angina (abstract. N2PO-128) //26 th International Congress of Internal medicine. May-26-30. 2002, Kyoto, Japan.

12.   Chumburidze SH.D. Anti-inflammatory activity of liprimar in patients with coronary heart disease (abstract. N21O) //11 th International Congress on Cardiovascular Pharmacotherapy. May-18-21. 2002, Monreal, Canada.

13.   Chumburidze SH.D. Influence of Long-term statins therapy on serum lipids, exercise performance and quality of life in patients with stable coronary heart disease// Georgian Medical News. 2002, 4 (85), p.72-74.

14.   Kipshidze N.N., Chumburidze Sh.D., Nadaraia K.A. On the beneficial effects of cholesterol-lowering therapy with atorvastatin in patients with coronary heart disease //J. Georgian Engeenering news, 2000, 3, p.131-134.

15.   Kipshidze N.N., Chumburidze Sh.D., Nadaraia K.A. Effects of lipid-lowering drug therapy with Atorvastatin in patients with high hypercholesterolemia and coronary artery disease//3 rd International Congress on Coronaty Artery Disease from prevention and intervention. Lyon, France, October 2-5-2000. Abstract book.

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