FACTA UNIVERSITATIS Series: Medicine and Biology Vol.8, No 1, 2001, pp. 11 - 18 UC 612.17; 611.12

THE ADVANTAGES OF CARVEDILOL IN CORONARY ARTERY DISEASE

Svetlana Apostolović¹, Milan Pavlović¹, Miloje Tomašević¹, Aleksandar Stojković¹, Ružica Janković¹, Slobodan Ilić²

¹Clinic for Cardiology, Clinical Center, Niš, Yugoslavia, ²Society for Liason Psychiatry, Niš, Yugoslavia E-mail: [email protected]

Summary. Dilatrend (carvedilol) is a nonselective beta and alpha blocker with antioxidation and antiprolipherative effects. These effects prevent mechanical damage of the endothelium of coronary arteries and have no negative influ- ence on metabolic risk factors: lipid prophyl and insulin resistence. With beta-blockade, dilatrend (carvedilol) reduces the heart rate and blood pressure, with alpha-blockade it reduces the peripheral vascular resistence and in that way decreases the myocardial oxygen consumption and myocardial wall stress. Dilatrend (carvedilol) prolonges exercise limits (duration of exercise). Applied in the acute phase of myocardial infarction, dilatrend (carvedilol) increases the patients' survival rate, reduces new coronary events, and with antioxydation action it prevents reperfusion arrhyth- mias. With positive hymodinamic effects it improves the left ventricle function in patients with ischemic cardiomyopa- thy, and gives a chance for survival to the coronary patients who run high surgery risk. Key words: Carvedilol, coronary disease, myocardial infarction

The effect of carvedilol we strive to maintain the function and the integrity of upon the coronary arteries endothelium the endothelium of coronary arteries, primarily by controling the variable risk factors. Today, by using a The central position in the onset and the determina- particular drug it is possible to influence most of the tion of the course of the coronary disease is occupied by mentioned processes that lead to the damage of the the atherosclerotic plaque of the coronary artery. endothelium and the onset of the atherosclerotic plaque. The initial event in the appearance of the atheroscle- Carvedilol is a non-selective β blocker and α blocker rotic plaque is a chronic and gradual mechanical dam- that by controlling the (size and oscillation) of the blood age of the endothelium (hypertension, oscillations of pressure, heart rate, prevents the mechanical damage of heart rate, turbulent blood flow at certain points of the the endothelium. blood vessel or intervention manipulations). Hypercho- Circulating catecholamines through numerous β re- lesterolemia, glucolized end products in diabetes ceptors demonstrate a toxic effect on the endothelium of (mostly insulin-dependent), chemical irritants (tobacco human coronary arteries which results in the apoptosis smoke), circulating catecholamines, inflammatory pro- of the endothelial cells. (By the mechanisms of calcium cesses (immuno complexes, infectants, free oxygen overload of the endothelial cells, by releasing free oxy- radicals) emphasize the already present damage of the gen radicals, by increasing the permeability of the sar- endothelium. colemes and by the increased concentration of cAMP). The damage of the endothelium results in the in- Carvedilol and atenolol reduce the epinefrin-induced creased vascular permeability for lipids and monocytes. lipid peroxidation of the endothelial sarcolemes, where The receptory control of the accumulation of cholesterol carvedilol is significantly more powerful in comparison is lost (mostly of LDL-a) which passively goes through with atenolol in the equimolar concentration of the me- the endothelial barrier, gets oxygenated by the free oxy- dicament (p<0.05). The powerful antioxydation effect of gen radicals. The expression of glucoproteins at the sur- cardidilol is considered responsible for this superior face of the endothelial cells starts the activation of the antiapopptotic effect compared to other selective β1- macrophages that phagocyte the oxygenated LDL, there blockers (2). Compared to propranolol, carvedilol is a appears a bubbling "foam cell" - the part of the nucleus ten times more powerful antioxidant (3). of the atherosclerotic plaque. After the saturation with Oxygenated LDL damages the endothelium by cy- the lipids the macrophages can release a large number totoxic products of lipid peroxidation, emphasizes the of chemotactic factors that further activate the mono- release of vasoconstrictor substances from the endothe- cytes, enzymes and free oxygen radicals and thus em- lial cells and at the same time it activates the macro- phasize the damage of the endothelium and the destabi- phages. With its antioxidation characteristics carvedilol lization of the plaque. (1). prevents the harmful influence of free oxygen radicals In the prevention of the onset of the coronary disease on the endothelium itself and also prevents the oxidation 12 S. Apostolović, M. Pavlović, M. Tomašević, A. Stojković, R. Janković, S. Ilić of LDL cholesterol particles. Yue and Feuerstein ex- With its chemoreologic effect it improves the myo- perimentally demonstrated the protective effect of cardial perfusion and prevents the appearance of the carvedilol on the cultivated endothelial cells of the um- thrombus. Applied at the dose of 10-20 mg per day, bilical vein exposed to the effect of free oxygen radi- carvedilol reduced in vitro blood viscosity, aggregation cals. Carvedilol inhibits the activation and adhesion of of thrombocytes (8). The decrease of blood viscosity neutrofiles at the damaged endothelium of coronary improves the flow degree, reduces the risk of the desta- arteries (3). bilization of the plaque by blood currents. At the place where the endothelium is damaged the Carvedilol doesn't show a significant influence on production of the endothelial factors of relaxation is the metabolism of carbo-hydrates, and is a suitable me- reduced, while the synthesis of factors of vasoconstric- dicament for treating the coronary disease in diabetic tion is increased. Apart from the protective effect in patients. (9). relation to the function and morphology of the endothe- Unlike other beta-blockers carvedilol doesn't show lium by blocking the α receptors carvedilol prevents undesirable effects on the lipid profile and thus doesn't the repetition of the vasospastic reaction of coronary have a negative influence on the progression of the ath- arteries which would contribute to the damage of the erosclerotic process. endothelium. The liposolubility of carvedilol correlates In the group of 15 patients with the chronic, stabile with its antioxidation potential as well as with its an- angina pectoris it was shown that, compared to placebo, tiatherogenic effect (4). a 25 mg dose of carvedilol od 25 mg significantly pro- Vascular smooth muscle cells, which migrate into longs the total duration of exercise as well as the time intima during the atherosclerotic processes can produce until the appearance of the ST segment depression of 1 endothelial factors of vasoconstriction (ET-1, ET-2, ET-3), mm (10). which synergistically with angiotensin II increase the Further placebo-controlled studies have shown that vascular tonus, proliferation and the growth of the cell (5). carvedilol reduced the incidence of symptomatic and At the same time proliferation and migration of smooth asymptomatic myocardial ischemia (11,12). The studies muscle cells of intima contribute to the increase of the by Das Gupt (12), Jamal (13), show that carvedilol plaque and to remodelling of the blood vessel, so the shows the antiischemic effect and considerably significance of the antiprolipheration effect of carvedilol increases the threshold for the onset of the effort- in preventing the onset and progress of coronary disease induced ischemia. comes to the foreground. Experimentally proved, the All the three doses of carvedilol (12.5; 25; 50 mg antiprolipherative effect of carvedilol is manifested via its twice per day) prolong the time until the appearance of metabolithes M14 and M21. Carvedilol inhibits the the depression of the ST segment of 1 mm at the ECG, proliferation of the cells of the vascular smooth muscle of but the significance of the difference, compared to the rat stimulated in vitro by various mitogenes, unlike placebo, increases with the dosage (14). celiprolol, sotalol and labetalol. Apart from the antiischemic effect, carvedilol has been shown to affect the parameters of the function of Carvedilol in the stable angina pectoris the left ventricle in patients with stable angina pectoris. Carvedilol in the dose of 25 mg ×2 and 50 mg ×2, When the atherosclerotic plaque of the coronary ar- during the two-week treatment significantly reduces the tery appears, the aim of the therapy is to prevent the end-systolic and end-diastolic volume of the left growth and maintain the stability of the plaque. ventricle compared to placebo (p<0.001 and p<0.0001), Carvedilol prevents oscillations of heart frequency where the significance increases with the increased dose and blood pressure and thus prevents the mechanical of the medicament. Carvedilol significantly increases destabilization of the plaque. the peak of the degree of the left ventricle filling With its antioxidation effects it inhibits the gathering (EDV/sec) and the first third of the filling fraction, by of macrophages and the effect of their proteolitic en- which it improves the diastolic performances of the left zymes, which decompose the fibrous cap of the plaque. ventricle (15). Lahiri was among the first to show, in a By inhibiting the oxidation of LDL cholesterol particles group of patients with the stable angina pectoris and the it prevents the growth of the lipid nucleus of the plaque damaged function of the left ventricle at the rest, that and of its destabilization as well (6). By beta and alpha carvedilol (25 mg once per day, and then 50 mg twice blockade, carvedilol reduced the myocardial oxygen per day during two weeks) improves the ejection consumption, thereby reducing the ischemia risk. Non- fraction (EF) from 40±4% to 48±8% (p<0.05) (15). selective beta-blockers can increase the peripheral vas- It was shown that the combination of propranolol cular resistance by inhibiting vasodilatation through + isosorbid-dinitrata (ISDN + P) had a greater acute blocking beta-2 receptors. With the additional alpha antiischemic effect at exercise, compared to carvedilol. blockade carvedilol contributes to the peripheral vaso- Afer 6 months of therapy, the time until the dilatation, with which its reduces the myocardial wall appearence of the ST segment depression of 1 mm and stress and the energy demand. It doesn't have the intrin- the total duration of exercise, did not considerably sic sympathetic activity (ISA) nor does it increase the differ in the group treated with the placebo and the oxygen demand during the night (7). ISDN + P combination, while the antiischemic effect THE ADVANTAGES OF CARVEDILOL IN CORONARY ARTERY DISEASE 13 of carvedilol has been retained during the study period. atherectomy restenosis) study aims at showing the effect It is considerd that the development of tolerance to of the carvedilol therapy (25 mg twice per day) during 6 ISDN is responsible for the decrease of the efficiency months compared to the placebo in the prevention of of the mentioned combination of medicaments (16). restenosis, after a successful directional coronary ather- The studies by Watanaba show that antioxidant ectomies, with or without complementary angioplastic characteristics of carvedilol prevent the onset of (serruys PW. Personal communication in Maqueda). nitrate tolerance during a continuous nitroglycerine The results of the study have not been published. therapy unlike arotinolol that doesn't have antioxidant characteristics (17). The metabolite of carvedilol BM920228, inhibits the development of nitrate The advantages of carvedilol in the tolerance, contributes to the nitrate-induced acute phase of the myocardial infarction vasodilatation and by reducing the oxidation stress it With the occlusion of the coronary artery, which reduces the activity of thrombocytes (18). lasts long enough, there appears the acute myocardial Comparing the effect of metoprolol and carvedilol it infarction (AIM). The aim of the therapy in AIM is to was shown that both medicaments considerably prolong achieve, as early as possible, the reperfusion of infarct- the time until the appearance of the symptoms or of the related artery (by thrombolysis), retain its passability depression of the ST segment of 1 mm in the test using (by anticoagulant and antiaggregation therapy) as well the physical exercise of the patients with stable angina as to maximally limit the size of the infarction. pectoris, where the effect of carvedilol was greater (19). Beta blockers applied in early hours of AIM aim at This advantage of carvedilol sombody explained by its reducing the size of the myocardial infarction and the antioxidation effect on the improvement of the function frequency of the disturbance of the heart rhythm (27). of the coronary endothelium artery an a more adequate This effect of β blockers is achieved by reducing the response during effort (20) myocardial oxigen consumption (through the reduction Carvedilol is a more efficient antiischemic medicament of heart rate and blood pressure) and reducing the compared to verapamil (21) and the slow-releasing ischemia, that is, by the rapid alleviation of pain. nifedipin (22). The total number of undesired effects was The effect of β blockers in AIM can be divided into greater in the group of patients treated by verapamil the acute ones (when the medicament is given early in (58.2%) compared to carvedilol (48%). the development of the infarction) and long-term ones (the secondary prevention), when the medicament is Carvedilol in unstable angina pectoris applied after the acute phase of the infarction. During the first 24 hours from the appearance of the Destabilization of the coronary plaque creates con- chest pain in AIM there is a considerably increased ditions for thrombus forming and a considerable reduc- secretion of catecholamines. The intravenous application tion of the coronary flow. The aim of the therapy in the of β blockers reduces the effect of catecholamines (CTH) acute coronary syndrome, of the unstable angina pectoris on heart rate and blood pressure (which thus reduces the type is to prevent the growth of the thrombus and to myocardial oxygen consumption), reduces the circulating stabilize the plaque. Carvedilol normalizes the concen- level of free fatty acids by antagonizing the lyposoluble tration of beta-thromboglobullin, thrombocytes factor-4, effect of catecholamines and at the same time reduces the thromboxan B2, inhibits the aggregation of thrombocytes, incidence of arrhytmias. Comparing the effects of beta- thus reducing the possibility of forming of the thrombus blockers, it has been experimentally shown that at the dynamic destabilized plaque (23). Carvedilol carvedilol is significantly more efficient in reducing the improves the fibrinolitic response of the endothelium to size of the infarction compared to propranolol, celiprolol anoxia, reduces the blood viscosity and reduces the and diltiazem (28). possibility of the aggregation of thrombocytes (24). The advantage of carvedilol over other beta blockers Carvedilol in the dose of 50 mg per day, added to can also be found in the fact that the acute beta blockade aspirin, intravenously applied nitrates and heparin, con- in AIM can cause a deeper ischemia caused by siderably reduce the frequency and the seriousness of neurohormonal activation and vascular constriction ischemic events compared to placebo in the double through the non-blocked alpha-receptors (29). With the blind study in the group of 116 patients with unstable simultaneous beta and alpha blockade carvedilol angina pectoris. The frequency of repeated ischemia improves the subendocardial flow and reduces the was 15% in the carvedilol group compared to 25% in myocardial ischemia. the placebo group (p<0.05) (25). In AIM the density of beta receptors increases for The efficiency of carvedilol in the prevention of re- about 25-30%. Unlike metoprolol, carvedilol due to its stenosis after the coronary angioplastic was shown in characteristic of specific binding to beta receptors (gua- the study that included 276 patients subjected to PTCA, nine nucleotide modulatable binding) does not lead to the where the restenosis appeared in 4.2% if the patients increase of the density of beta receptors in the myo- received carvedilol (25mg 2 × per day) 6 months after cardium and enables the complete sympathetic antago- the intervention, i.e. in 18.5% patients receiving the nism without the unfavourable effect of the CTH on the placebo (26). The EUROCARE (European Carvedilol CNS (30). Circulating catecholamines increase the 14 S. Apostolović, M. Pavlović, M. Tomašević, A. Stojković, R. Janković, S. Ilić aggreagation of thrombocytes, the release of the powerful threedays. It was up to the admitance doctor to decide vasoconstrictor thromboxan A2 that increases the on the thrombolysis. WIthin 24 hours from the start of resistance in the coronary microcirculation. The increased the pain, the patients were IV treated with 2.5 mg of tonus of SNS and the concentration of CTH lead to the carvedilol or the placebo during 15 minutes. It was increase of the coronary tonus, the inability of followed by the oral dose of 6.25 mg of carvedilol or vasodilatation of microcirculation and the deterioration of placebo 4 hours after the injection, and then 6.25 mg 2× myocardial perfusion. With the blockade of α receptors, per day during 2 days. The dose was increased to carvedilol achieves the prevention of the appearance of 12.5 mg 2× per day on the third day of the therapy and vasoconstricting of microcirculation and enables the was retained at 12.5 mg - 25 mg 2× per day during the adequate perfusion of the myocardium after the whole study (6 months) or the onset of a CVS event that recanalization of the infarct-related artery, it also achieves marked the end of the study when the medicament was the reduction of the peripheral vascular resistance and terminated. The adjustment of the dose was done on the reduces the afterload of the left ventricle, which reduces l4th day, when carvedilol was increased from 25 mg 2× the myocardium wall stress and the expansion of the per day if TA was >120/95 mm Hg and HR at least 55 infarction. beats in a minute. The end of the study was defined by: With its strong antioxydation effect carvedilol heart death, reinfarction, USAP, heart insufficiency, neutralizes the activity of free oxygen radicals and urgent revascularization, ventricular arrhytmia, CVI, or prevents reperfusion damages of the myocardium, limits the need for the additional CVS therapy (ACE inhibitors the size of the infarction by inhibiting the migration of have not been routinely applied for the asympthomatic polymorphonuclear leucocytes towards the necrosis dysfunction of the left ventricle.) area. In the group of AIM patients, treated with carvedilol Until now in the thrombolytic era, there have been a the frequency of serious cardiac events (reinfarctions, few large studies of the application of beta-blockers in unstable angina, urgent revascularization) was reduced AIM. ISIS-1 and GUSTO studies show that atenolol for 42%, which was a significantly larger percentage applied in the acute phase of myocardial infarction re- compared to the placebo-treated group (p<0.03). duces mortality, but also increases the frequency of Despite a large number of patients with heart failure the shocks, congestive heart failure and the need for pacing applied carvedilol was well-tolerated. The patients as the result of the antagonism of sympathomimetic treated with carvedilol showed a significant stimulation (31). TIMI II study has shown that meto- improvement of EF compared to the placebo group prolol applied in the acute phase of the myocardial in- (p<0.05), the lowering of the systolic volume of the left farction together with the thrombolytic therapy reduced ventricle (p<0.03), the increase of the stroke volume the frequency of new coronary events and reinfarction (p<0.01), a considerable improvement of the E/A ratio but without affecting the improvement of the patients' as the parameter of the diastolic function (p<0.001) and survival (32). of the improvement of the left ventricle filling, which The negative inotropic effect limits a wide use of proved a favourable effect of carvedilol on the beta-blockers in AIM, especially in the group of risky improvement of the function of the left ventricle in AIM patients, with the damaged function of the left ventricle. patients. The group treated with carvedilol showed the The favourable effect of metoprolol (33) and bisoprolol improvement of the regional wall motion abnormalities (34) has been manifested mostly in the dilatation (p<0.001), both in and outside the infarction zone. This cardiomyopaties. Therefore Basu supposed that difference turned out to be significant already on the carvedilol with its characteristics would be a safe seventh day of the carvedilol therapy and in the medicament to apply intravenously in most AIM following 6 months of treatment. With the break of the patients, including the group of patients with a mildly carvedilol therapy, despite the application of other serious heart insufficiency (35). The primary aim of antiischemic medicaments (atenolol, diltiazem or CHAPS (Carvedilol Heart Attack Pilot Study) study nicardipine) there appear new cardiovascular events, so (36) was to compare a group of AIM patients treated the survival curves start to converge and the significant with carvedilol to a group of patients treated with difference between the carvedilol-treated group and the placebo until the moment of the appearance of one of placebo-treated group of patients is lost. This showed the serious cardiovascular events. The other aim was to that the antiiscemic effect is important in the acute show the safety of the medicament in comparison to the phase of the infarction but also in the retaining and undesirable effects, as well as its influence on the improving of the function of the saved myocardium (by functional capacity, hemodynamics, systolic and thrombolysis) which is viable but still at high risk from diastolic function of the left ventricle in the group of new coronary events. patients admited at the coronary ward with typical signs In the subgroup of patients with EF <45% that and symptoms for AIM. The patients with NYHA class experienced AIM, after 3 months of carvedilol therapy IV or the cardiogenic shock, heart rate <45/min., there appears a significant reduction of end-systolic hypotension, AV block II-III, creatinine >159 µmol/L (p<0.01) and end-diastolic volume (p<0.01) of the left were excluded. ventricle compared to the placebo group. The sum of the All the patients received Aspirin and SC heparin for segmental motions and the ejection fraction have been THE ADVANTAGES OF CARVEDILOL IN CORONARY ARTERY DISEASE 15 significantly improved in the group of patients with way it was shown that carvedilol has an essential, AIM and the dysfunction of the left ventricle after three protective effect on the progressive remodelling of the months of carvedilol therapy. The results of this study left ventricle after the acute myocardial infarction, pointed at the favourable effect of carvedilol on the which is related to the significant reduction of the process of remodelling of the left ventricle after AIM frequency of new coronary events in the group of in the group of patients with the left ventricle carvedilol-treated patients. The mechanism at the basis dysfunction and gave the guidelines for further research. of the slowing down/prevention of remodelling by The importance of carvedilol in the remodelling pre- carvedilol is multifactorial. Unlike the conventional β vention in patients with the left ventricle dysfunction blockers, carvedilol by alpha blockade causes the after the acute myocardial infarction reduction of the left ventricle filling pressure, reduces The chief determinant of the prognosis for patients the myocardial wall stress, oxygen consumption. Apart after AIM is the function of the left ventricle (37), which from the hemodynamic effects, with the neurohumoral is determined by the loss of functional myocardium effects it reduces the myocardium mass, the volumes of (affected by necrosis), residual ischemia, the worsening the left ventricle, and improves the left ventricle effect of the pathological remodelling. function. Remodelling after AIM is a progression of the It is considered that the effect of carvedilol is even changes in the size of the left ventricle, the shape, underestimated, because it is applied on the first day of thickness of the myocardium, including the infarction AIM, and the echocardiogram was not performed earlier and non-infarction segments. The process of ventricular than 5-7 days. Dought et al. (39) in the independent study remodelling is influenced by the size of the infarction, showed that carvedilol reduces the size of the left the healing of the infarction area, residual ischemia, the ventricle after 6 months of treatment in patients with overload of the left ventricle (the pressure of expanding congestive heart failure caused by the myocardium of the left ventricle, the inotropic condition of the left disease and thus improves the prognosis of such patients. ventricle, the heart rate and the neuroendochrine It is the safety of its application even in patients with activity,) the increase of the total ventricular mass and Killip class II and III, with the evident heart failure after the change of the geometry of the left ventricle. The AIM that accounts for the advantages of carvedilol. prevention or the slowing down of the remodeling of the Carvedilol has been shown to be uniquely suitable for LV after AIM, are an important therapeutic goal. the therapy of high-risk patients after AIM. The result of the acute reperfusion (thrombolysis) is This resulted in the first, prospective, randomized, saving of the myocardium and the limitation of the double-blind placebo controlled CAPRICORN study infarction size, which at the same time means the (with 1900 patients) whose aim was to examine the prevention or slowing down of the remodelling precess. influence of beta-blockers (carvedilol) on the morbidity It is known that ACE inhibitors improve the prognosis and mortality in the high-risk group of patients, with the after AIM mostly because of their favourable effect on left ventricle dysfunction after AIM (40). The criteria the process of remodelling of the left ventricle. for the including into the study are the AIM diagnosis Favourable results of carvedilol application in AIM within the last 21 days, ejection fraction (EF) of the left patients with the damaged left ventricle function pointed ventricle ≤40% measured by 2D echocardiography, at the possible role of carvedilol on the remodelling radionuclide or contrast ventriculography, the score of index. The goal of Senior et al. (38) was to show a segment motility (WMSI) < 1.3. All the patients are also favourable effect of carvedilol on some additional treated with the ACE inhibitors. The results of the study markers that are at the basis of the changes of the left have not been published yet. ventricle volume – the reduction of the area of The effect of carvedilol on the improvement of the abnormality of the wall thickening at the infarction hybernated myocardium function in patients with the point, the reduction of the wall thickness of the left left ventricle dysfunction of ischemic origin ventricle in non-infarction segments and the total mass In the group of coronary patients with heart failure the of the left ventricle and the favourable change of the improvement of the ejection fraction under the influence geometry of the left ventricle. The patients selected for of beta-blockers and ACE inhibitors is of heterogenuous this study are part of the mentioned CHAP study, with origin unlike the response obtained in patients with the same protocol of patients' treatment. Two-dimen- dilatation cardiomyopathy. The ratio between the dose of sional echocardiography was performed before the pa- the medicament and the EF increase is less prominent in tient was released and three months after AIM. coronary patients. The results of the study showed that in the group of One of the mechanisms with which beta-blockers patients who were treated with carvedilol for three improve the left ventricle function are the prevention of months there was a significant reduction of the myocardium ischemia, that is the postischemic thickness of the myocardium in non-infarction areas, the myocardial dizziness. Hibernation means a functional reduction of the total mass of left ventricle, the decrease and metabolic 'down', a regulated protective mechanism of abnormality of regional kynethics in the infarction in order to retain the myocyte viability. It is thought that area, and the improvement of the sphericity index, in the appearance of the myocardium hibernation the which differed from the placebo-treated group. In this repeated dizziness are important in the circumstances of 16 S. Apostolović, M. Pavlović, M. Tomašević, A. Stojković, R. Janković, S. Ilić the reduction of blood flow below the threshold of the hibernated myocardium as the specific goal for the necessary for retaining the normal myocyte function. medicament treatment among the patiens with heart failure. By reducing the coronary style in the zones Also, it will provide the answer as to whether surrounding the ischemia or the subendocardium, by revascularization is really necessary for the patients with prolonging the diastolic coronary flow and reducing the the hibernated myocardium. metabolic demand of the surrounding myocardium, β The detection of ischemia, hibernation, dizziness blockers increase the flow into the zones of the among the patients with heart failure can identify the hibernated myocardium. The blockade of α1 and β1 and group of patients that benefit from the beta blockers 2 receptors with carvedilol has its advantages because it treatment. The patients in whom the left ventricle protects a wider area of adrenoreceptors from the function was not improved by the carvedilol therapy can catecholamine excess. The blocking of α receptors be protected from lethal arrhytmias and recurrent acheives the coronary vasodilatation that can further infarctions by their β blocking effects and this still improve the myocardial blood flow, the peripheral achieve clinical benefits. venous and arterial dilatation reduce the pre- and after- The seriousness of the left ventricle dysfuncion is load. The protection of the ischemic myocardium from the determinant of the operational mortality, and free oxygen radicals provides additional mechanisms, improved by beta-blockers before the cardiosurgical with which carvedilol can regain the function of the intervention it can reduce the surgical risk. dizzy and hibernated myocardium and prevent heart The results of CHRISTMAS study should suggest failure. whether the medicament treatment for the dizzy and/or After successful thrombolysis, the patients run the hibernated myocardium (potentially reversible further risk of possible new cardial events and heart contractile dysfunction) is the addition or the alternative failure. The residual ischemia is the risk for repeated to revascularization, especially in cases when acute coronary syndromes, but also the area of the still revascularization is not the acceptible solution. vital myocardium. Basu et al. in 1996 showed that the carvedilol treatement significantly reduced the onset of Carvedilol and the quality of life new coronary events (compared to the placebo p<0.04), of coronary patients in the group of patients with Tl-201 proved reversible Health-Related Quality of Life means the physical ischemia, 6 weeks after the application of thrombolysis felling of well-being that affects psychological and in AIM (41). This study clearly demonstrated the economic aspects of life, social and family interaction antiischemic and protective effect of carvedilol in the (44). With its antiischemic effect carvedilol reduces the group of patients treated by thrombolysis in AIM. seriousness and the number of anginal attacks, increases Experimental studies showed that carvedilol in the the threshold for the effort-induced ischemia and instances of ischemia and reperfusion reduces the improves the functional capacity of the coronary patient, number of apopptotic myocyites in the ischemic area for thereby providing the active professional life, realistic 77%, with the effect independent of beta-blockade (42). insight into the restrictions caused by the disease (with The patients with a large area of the ischemic or the termination of the medicament the symptoms and hibernated myocardium can respond to the β blockers the signs of the disease get worse). Carvedilol therapy therapy in a similar way as the patients with dilatation improves the ejection fraction of the left ventricle, the cardiomyopathy, unlike the left ventricle function that is symptoms and signs of heart failure, which affects the mostly determined by the postinfarction scar. adequate psychosocial adaptation and the quality of life Having in mind the importance of the retention of in restriction circumstances caused by the coronary the vital myocardium after the acute infarction, disease (45). CHRISTMAS-(43) study was started with the aim of determining whether the presence of hibernation of the myocardium in coronary patients with the left ventricle Conclusion dysfunction (EF<40%), predicts the degree of Dilatrend (carvedilol) is an efficient antiischemic improvement of the left ventricle, by application of medicament that inreases the threshold for the effort- carvedilol compared to placebo. induced ischemia, and reduces the number of The patients were divided into groups with or asympthomatic ischemic episodes. Dilatrend (carvedilol), without hibernated myocardium. The diagnosis of applied in the early stage of the myocardial infarction hibernation was based on the mismatch between the reduces new coronary events and the patients' mortality, echocardiographically detected abnormality of wall prevents the left ventricle remodelling. It improves the motility and the radioisotopic myocardial perfusion left ventricle function in patients with ischemic scan, at rest by using Tc 99m sestamibi. cardiomyopathy and the quality of life of such patients. Orally applied carvedilol was adjusted until the goal The results of new studies will show whether by dose of 25 mg., twice per day for the patients weighing improving the function of the hibernated myocardium, up to 85 kg, or 50 mg 2× per day if the patient weighed dilatrend (carvedilol) can bridge the period until more than 85 kg. revascularizarion or it can be the alternative in patients It is believed that this study will help the identification with high surgery risks. THE ADVANTAGES OF CARVEDILOL IN CORONARY ARTERY DISEASE 17

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PREDNOSTI KARVEDILOLA U KORONARNOJ BOLESTI

Svetlana Apostolović¹, Milan Pavlović¹, Miloje Tomašević¹, Aleksandar Stojković¹, Ružica Janković¹, Slobodan Ilić²

¹Klinika za kardiovaskularne bolesti, Klinički centar Niš, ²Udruženje za liason terapiju, Klinički centar, Niš E-mail:[email protected]

Kratak sadržaj: Dilatrend (karvedilol) je neselektivni beta i alfa blokator sa antioksidativnim i antiproliferativnim dejstvom. Pomenutim efektima prevenira mehaničko oštećenje endotela koronarnog krvnog suda, i ujedno ne utiče nepovoljno na metaboličke faktore rizika: lipidni profil i insulinsku rezistenciju. Beta blokadom redukuje srčanu frekvencu i krvni pritisak, alfa-blokadom redukuje perifernu vaskularnu rezistenciju što ima za rezultat smanjenje miokardne potrošnje kiseonika i miokardnog zidnog stresa. Dilatrend (karvedilol) podiže prag za naporom indukovanu ishemiju. Primenjen u akutnoj fazi infarkta miokarda, dilatrend (karvedilol) popravlja preživljavanje bolesnika, redukuje nove koronarne događaje, dok antioksidativnim svojstvima sprečava reperfuzione poremećaje ritma. Povoljnim hemodinamskim efektima popravlja funkciju leve komore bolesnika sa ishemičnom kardiomiopatijom, i daje šansu za preživljavanje bolesnicima sa visokim operativnim rizikom. Ključne reči: Karvedilol, koronarna bolest, infarkt miokarda