Life Sciences, Vol. 49, pp. 689-705 Printed in the U.S.A.
Pergamon Press
MINIREVIEW CORONARY ATHEROSCLEROSIS: CURRENT THERAPEUTIC APPROACHES AND FUTURE TRENDS
F. V. DeFeudis Institute for BioScience, 3 Spanish River Road, Grafton, MA 01519, U. S. A. (Received in final form June 28, 1991)
Summary Invasive cardiovascular procedures, such as percutaneous translumenal coronary angioplasty (PTCA) and aorto-coronary bypass surgery (ACBS), that are currently employed in treating the coronary stenosis or occlusion caused by atherosclerosis represent a major therapeutic advance for managing coronary heart disease (CHD). However, the cellular proliferative response and associated intimal hyperplasia that can follow the damage to blood vessels that occurs with these procedures leads to late complications which cannot be effectively controlled by presently available drugs. Hence, a new approach is required for managing these complications, termed "restenosis" (in the case of PTCA) or "stenosis" (in the case of ACBS). Existing drug therapy is reviewed and some new approaches to this problem are provided herein. Further studies of growth factors and other substances that influence the cellular proliferative response that follows injury to the blood vessel wall could lead to the development of effective therapy. Inhibition of intimal hyperplasia and/or acceleration of endothelial cell re-growth provide a basis for such new approaches. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), as well as endothelium-derived relaxing factor(s) (EDRF) and calcitonin gene-related peptide (CGRP) are among the substances discussed. Modification of certain currently available drugs (e.g. Ca2+-antagonists) could also be of value in meeting this therapeutic demand. At present, coronary heart disease (CHD) accounts for about half of all deaths in the United States. Coronary atherosclerosis is probably the major pathological component involved in most cases of CHD, and it is usually pronounced in individuals suffering from angina pectoris. Two general types of angina pectoris may be defined: stable angina in which a stable atheroma causes symptoms when oxygen demand exceeds oxygen supply, and unstable angina, or "evolving myocardial infarction", which denotes a most heterogeneous group of syndromes with much lower predictability with respect to the onset of symptoms (1). Individuals who experience anginal pain for longer than 15 minutes or suffer frequent anginal attacks can develop acute coronary occlusion which can be followed by myocardial infarction or death, and in such cases invasive approaches such as percutaneous translumenal coronary angioplasty (PTCA) or aorto-coronary bypass surgery (ACBS) may be required for therapeutic 0 0 2 4 - 3 2 0 5 / 9 1 $ 3 . 0 0 + .00 Copyright (c) 1991 Pergamon Press plc
690
Therapy for Coronary Atherosclerosis
Vol. 49, No. i0, 1991
management. However, major problems are inherent to the use of these procedures. "Late" complications (usually occurring during the first year after invasive therapy) related to intimal hyperplasia (due to enhanced cellular proliferative responses) can lead to narrowing of the blood vessel, i.e. restenosis of the recanalized artery (in the case of PTCA) or stenosis of grafted blood vessels (in the case of ACBS), and these conditions are generally not effectively remedied by existing drug therapy. Intimal hyperplasia plays a role in localizing the pathologic process, but while restricting the lesion this reaction leads to a progressive occlusion of the vessel lumen, which, if further increased by a thrombus, can critically impede blood supply, causing myocardial ischaemia, myocardial infarction and death. How can this problem be approached? It is known that atherosclerotic damage, consisting mainly of proliferating smooth muscle cells, connective tissue, lipid-laden macrophages and lymphocytes, occurs at the arterial intima, and that growth factors are likely involved in stimulating the cellular proliferative response that causes intimal hyperplasia (see e.g. 2-5). The subtle, but chronic, endothelial injury that can occur at certain intimal sites would favor the adhesion and aggregation of platelets and their release of growth factors. Platelets adhering to de-endothelialized areas of blood vessels release several growth/chemotactic factors from their a-granules, including platelet-derived ~owth factor (PDQF), eoidermal growth factor (EGF), B-thrombo~lobin and nlatelet factor 4 (PF4). PDGF and PF4 stimulate the proliferation of smooth muscle cells and fibroblasts (6,7) and the chemotactic migration of these cells toward the intima (6-8), and proliferating intimal smooth muscle cells can then synthesize fibrous elements of the atherosclerotic plaque. Monocytes that migrate into the developing plaque become transformed into macrophages, which, together with the disturbed endothelium itself, also release growth factors that can enhance the proliferation of both smooth muscle and fibrous tissue (e.g. 3,4,6,7). PDGF may also possess chemotactic activity for monocytes that produce monocvte-derived growth factor (MDGF), which is also mitogenic and chemotactic for smooth muscle cells and fibroblasts (6,7). Macrophage-derived growth factors that might play roles in atherogenesis are basic fibroblast ~rowth factor (bFGF). PDGF. transformin~ ~rowth factor~ (TGF~). transformine growth factor-B (TGF-fl). tumor necrosis factor-a (TNF-a) (e.g. 9-12), and a heparin-binding EGF-like growth factor (HB-EGF) (13; see below). Eventually, fibromuscular nlaques and the more necrotic complicated plaques form. This sequence of events involving growth factors, in somewhat modified form, probably underlies the development of the restenosis or stenosis that can follow invasive therapy. Thus, approaches aimed at inhibiting (or, in some cases, stimulating) the release or action of various growth factors could provide the required therapy for these complications. Both atherogenesis and thrombogenesis can contribute to restenosis/stenosis. The significant involvement of growth factors in both atherogenesis and in the blood vessel stenosis that can follow invasive therapies for CHD provides clues for designing new therapeutic approaches. This article will not be focussed directly on therapy for CHD, but rather on drug therapy for the comnlications that follow the use of PTCA and ACBS. Current drug therapy will be briefly analyzed, and novel approaches based on growth factors or certain other active substances and aimed at slowing or preventing cellular proliferative responses (to injury) that favor blood vessel stenosis and occlusion will be particularly emphasized. The urgency for such a new type of therapy is obvious. Although the efficacy of invasive cardiovascular procedures in relieving symptoms is well established, it is not yet known if they will prolong life, and the late complications (e.g. the restenosis that occurs within the first 3-8 months in about one-third of the patients who undergo initially successful PTCA; see 14) could be more detrimental than the original condition.
Vol. 49, No. I0, 1991
Therapy for Coronary Atherosclerosis
691
CURRENT DRUG THERAPY FOR RESTENOSIS OR STENOSIS
Currently available drugs offer very limited benefit as therapy for restenosis or stenosis. It is essentially because there are no drugs with proven efficacy for treating coronary arterial stenosis that PTCA is so extensively employed today. PTCA is the only available therapeutic orocedur¢ that can notentiallv nrevent nlatelet adhesion or thrombosis in serious coronary lesions. In contrast,-ACBS etlhances the tendency for local thrombosis since the decrease in blood flow through the residual lumen resulting from this procedure generally induces total occlusion in proximal obstructions. What drugs exist and what do they do? Three major types of drug therapy - "platelet-inhil?itors" (e.g. aspirin, sulfinpyrazone, dipyridamole), ¢onventional anticoa~lants which prevent the formation of thrombi (e.g. heparin), and thr0mbolytic agents which dissolve blood clots [e.g. streptokinase, uroldnase and tissue plasminogen-activator (t-PA)] - have been developed in efforts to prevent enlargement of existing thrombi or to achieve thrombolysis. Other drugs which may act mainly by reducing spasm include the nitrates and Ca 2+ -antagonists (vasodilators), and/I-blockin~ a~ents are used mainly to reduce cardiac work. Lipid/cholesterol-lowerin~ a~ents are used to decrease the concentrations of lipidic species that contribute to the development of atherosclerotic plaques. However, there is no firm evidence that any of these drugs can decrease the incidence of restenosis (stenosis) and reocclusion that can occur after PTCA or ACBS. Plat¢let-lnhibit0rs
Platelet-inhibitors can limit platelet aggregation, but aspirin, a cyclooxygenase-inhibitor and prototype of this drug class, does not inhibit platelet adhesion, an imoortant initial steo in rcstenosis, or the release of growth/¢hcmotactic substances from platelets, and therefore it is expected that it will not influence atherosclerotic lesions characterized by intimal hyperplasia and fibrous transformation (15-17). Nevertheless, regarding therapy for coronary restenosis, results of a randomized trial have indicated that aspirin (325 mg/day) produced a statistically significant difference, with respect to coumadin, in patients who had symptoms for more than six months before PTCA; restenosis rate was 21% with aspirin and 44% with coumadin (see 14). A significant action of aspirin in unstable angina has been shown in two randomized, double-blind, placebo-controlled trials (18, 19). On this basis, aspirin is recommended as a "secondary prevention" after recovery from an initial attack of unstable angina (see 1), and could be beneficial in treating advanced stages of restenosis that might involve thrombosis. Inhibitors of thromboxane-A2 (TXA2) that act directly at the TXA 2 receptor represent another pharmacological means of conceivable significance in managing coronary arterial stenosis. Certain TXA 2 receptor-blockers, like aspirin, may be found useful in controlling unstable angina, and although they would not be expected to interfere directly with platelet adhesion they could inhibit arterial smooth muscle proliferation (intimal hyperplasia). In this regard, it has been shown that TXA 2 is mitogenlc for smooth muscle ceils Ja vitro. Stable TXA 2 analogues stimulated [3H]thymidine incorporation into cultured smooth muscle cells of human and rat aorta (19a,19b). It might be envisioned that TXA 2 synthesis-inhibitors (e.g. imidazole), which selectively block the conversion of the cyclic endoperoxides prostaglandinG 2 and prostaglandin-H2 into TXA 2 (20), would be superior to aspirin since prostacyclin (PGI2) synthesis would not be inhibited. However, these agents exhibit anti-thrombotic potencies that are less than half that of aspirin, perhaps because the cyclic endoperoxides that accumulate in their presence may themselves possess pro-aggregant activity (21,22). Dipyridamole inhibits platelet adherence to collagen (23) and sub-endothelium (24), but only at doses that are substantially higher than those used in the clinical setting (see 25). No firm
692
Therapy for Coronary Atherosclerosis
Vol. 49, No. i0, 1991
evidence indicates that other platelet-inhibitors (e.g. ticlopidine, sufinpyrazone) can inhibit the cellular oroliferative resoonse of the arterial wall. AnticoaL~ulants/Thrombolvtic Agents
Anticoagulant drugs which prevent thrombogenesis, such as heoarin and warfarin-like _ag.c._n~, and thrombolytic agents which dissolve blood clots, such as streptokinase, urokinase and t-PA, have been used in treating restenosis or stenosis. One might conceive that such therapy would be beneficial, at least in limiting the thrombotic component of arterial reocclusion. Presently, heparin or warfarin-like agents are indicated for the stasis or "primary" coronary thrombosis that might occur in coronary arteries or vein grafts. Intravenous heparin significantly reduces progression to transmural infarction in patients with unstable angina, as compared with atenolol (26). Heparin could possibly have some inhibitory action on the intimal hyperplasia that characterizes restenosis or stenosis, a contention that is supported by the findings that heparin infusion suppressed smooth muscle cell proliferation and intimal thickening in balloon catheter-injured carotid arteries of rats (26a). In this regard, it might also be noted that thrombin is a potent mitogen for bovine aortic smooth muscle ceils maintained in culture (26b). Thrombolyti¢ agen~, such as streptokinase and recombinant tPA (rt-PA) appear to be useful in treating patients with unstable angina (see e.g. 27). Recent studies have indicated that early reperfusion with intracoronary streptokinase decreases the death rate in such patients by about 50% (see 1,28,29). According to Yusuf (30), about 75% of the coronary thrombotic occlusions that occur in patients showing early signs of myocardial infarction can be dissolved by intracoronary infusion of thrombolytic agents such as streptokinase. An assessment of more than 20 trials that were conducted with intravenous streptokinase revealed a highly significant 21% decrease in the probability of death (30). These results are encouraging, but acute coronary artery reocclusion and reinfarction and a risk of serious hemorrhagic complications are associated with these approaches (30-33). About 25% of the vessels initially recanalized with thrombolytic therapy reocclude within a few days (28,34). Such problems have stimulated efforts to improve this type of therapy. Early intravenous heparin has been compared with oral aspirin as adjunctive therapy when rt-PA was used for coronary thrombolysis in patients experiencing acute myocardial infarction ("chest pains") (35). At the time of the first angiograrn, 82% of the infarct-related arteries in the patients assigned to heparin were patent as compared with only 52% in the aspirin group. Of the initially patent vessels, 88% remained patent after 7 days in the heparin group as compared with 95% in the aspirin group. The numbers of hemorrhagic events and recurrent ischaemic events were similar in the two groups. It was concluded that coronary patency rates associated with rt-PA are higher with early concomitant heparin treatment than with concomitant low-dose aspirin. However, the efficacies of both aspirin and heparin in accelerating coronary thrombolysis, in overcoming resistance to lysis, and in preventing reocclusion are limited, and even with concomitant administration of heparin and aspirin, thrombolytic therapy does not produce maximal coronary artery recanalization in patients with evolving myocardial infarction (see 36). At best, such combined therapies would be expected to interfere with the thrombotic manifestations, but not directly with the restenosis or stenosis that can follow PTCA or other invasive therapeutic procedures. Nitrates
Nitrates (e.g. nitroglycerin) act mainly by diminishing "preload" by causing marked venous dilatation throughout the body, which leads to decreases in venous return to the heart, cardiac output and arterial pressure. To a lesser extent, they reduce "afterload" (i.e. the resistance against which the heart contracts) via arterial dilatation. These agents might also
Vol. 49, No. i0, 1991
Therapy for Coronary Atheroselerosis
693
cause platelet disaggregation and dilatation of large epicardial coronary arteries, effects which could contribute to their beneficial action on coronary blood flow (e.g. 1). As the syntheses of those products of ischaemic metabolism that might cause pain are reduced by these agents, they provide excellent relief during anginal attacks in most individuals and are also useful for prophylaxis. Assessment of results obtained with intravenous nitroprusside (3 trials) and intravenous nitroglycerin (6 trials) have revealed a significant reduction in mortality rate (30). This result was observed mainly during the first two to three weeks after initiating therapy, indicating that nitrates (because of their vasodilatatory action) could be useful in managing certain early complications (e.g. possible "recoil" vasoconstriction) that can follow PTCA, but not the intimal hyperolasia that characterizes the late complication, restenosis. However, tolerance develops to the anti-ischaemic effect of nitrates, and in some cases they may actually favor ischaemia by diverting coronary blood flow away from ischaemic regions ("steal effect") and/or by inducing reflex increases in heart rate (see 30). 2÷
°
Conventional Ca2+-antagonists, such as nifedipine, verapamil and diltiazern, act mainly by decreasing coronary and peripheral vascular resistance. In addition, verapamil and diltiazem have negative inotropic and chronotropic effects. These agents are about 3-10 times more potent in inhibiting coronary artery smooth muscle than myocardial contractile cells (37), thereby permitting dilatation of coronary arteries in doses that do not decrease myocardial contractility (38,39). They are useful in managing nearly all myocardial ischaemic syndromes, including stable and unstable angina pectoris (e.g. 40-43). However, no evidence exists, either from individual studies or from the pooled data of all trials conducted until 1987 1 n that Ca 2 + -antagomsts • to support the n ot'o reduce mortality in cases of unstable angina or acute myocardial infarction (e.g. 30). Ca2+-antagonists such as nifedipine are also inefficient when administered after myocardial infarction has occurred (44). Although Ca2+-antagonists might impede the progression of atherosclerosis (i.e. the development of arterial stenosis that does not occur in response tq invasive therapy) (45-47), the results of randomized clinical trials indicate that neither diltiazem nor nifedipine can prevent or diminish the extent of coronary artery restenosis that follows PTCA (see 14). In summary, CaZ÷-antagonists may possibly retard the progression of atherosclerosis (see below), but no firm statements can be made at this time regarding their use as therapy for the restenosis or stenosis that can occur in response to invasive cardiovascular interventions. Also, an adverse effect on ischaemia could occur via a "steal phenomenon" in certain patients.
B-Blocker~ B-Blockers, such as propranolol, metoprolol, atenolol and timolol, probably relieve anginal pain by blocking cardiac fll-adrenoceptors whose activation leads to increased cardiac performance. Blockade of these receptors causes decreases in heart muscle contractility, heart rate, cardiac work and blood pressure, which in turn leads to reduced cardiac oxygen consumption. A decrease in the ratio of oxygen need/oxygen supply is thereby produced which eliminates anginal pain. Some workers contend that t-blockers are the most effective prophylactic agents for both the short- and long-term management of patients who have experienced myocardial infarction (see 27). t-Blockers can raise the threshold for infarction and reduce complex ventricular arrhythmias in man (see 30), effects which would be expected to reduce early mortality, reinfarction and ventricular fibrillation after myocardial infarction. In a large study (16,027 cases of suspected acute myocardial infarction), vascular mortality was
694
Therapy for Coronary Atherosclerosis
Vol. 49, No. I0, 1991
significantly decreased by about 15% during seven days of intravenous atenolol therapy, this effect being observed mainly during the first two days of therapy (48). Results of another large study (2877 patients allocated to metoprolol, and 2901 to placebo) indicated that metoprolol had no significant effect on death rate from myocardial infarction (49; see also 1). Chamberlain (50) has concluded that no firm evidence of a therapeutic effect of B-blocker therapy can be claimed with respect to acute mortality in cases of acute myocardial infarction. However, Yusuf (30), upon examining the data from all 27 randomized trials that were available until 1987, concluded that t-blocker therapy probably does reduce total mortality at seven days by about 13% (p
Pergamon Press
MINIREVIEW CORONARY ATHEROSCLEROSIS: CURRENT THERAPEUTIC APPROACHES AND FUTURE TRENDS
F. V. DeFeudis Institute for BioScience, 3 Spanish River Road, Grafton, MA 01519, U. S. A. (Received in final form June 28, 1991)
Summary Invasive cardiovascular procedures, such as percutaneous translumenal coronary angioplasty (PTCA) and aorto-coronary bypass surgery (ACBS), that are currently employed in treating the coronary stenosis or occlusion caused by atherosclerosis represent a major therapeutic advance for managing coronary heart disease (CHD). However, the cellular proliferative response and associated intimal hyperplasia that can follow the damage to blood vessels that occurs with these procedures leads to late complications which cannot be effectively controlled by presently available drugs. Hence, a new approach is required for managing these complications, termed "restenosis" (in the case of PTCA) or "stenosis" (in the case of ACBS). Existing drug therapy is reviewed and some new approaches to this problem are provided herein. Further studies of growth factors and other substances that influence the cellular proliferative response that follows injury to the blood vessel wall could lead to the development of effective therapy. Inhibition of intimal hyperplasia and/or acceleration of endothelial cell re-growth provide a basis for such new approaches. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), as well as endothelium-derived relaxing factor(s) (EDRF) and calcitonin gene-related peptide (CGRP) are among the substances discussed. Modification of certain currently available drugs (e.g. Ca2+-antagonists) could also be of value in meeting this therapeutic demand. At present, coronary heart disease (CHD) accounts for about half of all deaths in the United States. Coronary atherosclerosis is probably the major pathological component involved in most cases of CHD, and it is usually pronounced in individuals suffering from angina pectoris. Two general types of angina pectoris may be defined: stable angina in which a stable atheroma causes symptoms when oxygen demand exceeds oxygen supply, and unstable angina, or "evolving myocardial infarction", which denotes a most heterogeneous group of syndromes with much lower predictability with respect to the onset of symptoms (1). Individuals who experience anginal pain for longer than 15 minutes or suffer frequent anginal attacks can develop acute coronary occlusion which can be followed by myocardial infarction or death, and in such cases invasive approaches such as percutaneous translumenal coronary angioplasty (PTCA) or aorto-coronary bypass surgery (ACBS) may be required for therapeutic 0 0 2 4 - 3 2 0 5 / 9 1 $ 3 . 0 0 + .00 Copyright (c) 1991 Pergamon Press plc
690
Therapy for Coronary Atherosclerosis
Vol. 49, No. i0, 1991
management. However, major problems are inherent to the use of these procedures. "Late" complications (usually occurring during the first year after invasive therapy) related to intimal hyperplasia (due to enhanced cellular proliferative responses) can lead to narrowing of the blood vessel, i.e. restenosis of the recanalized artery (in the case of PTCA) or stenosis of grafted blood vessels (in the case of ACBS), and these conditions are generally not effectively remedied by existing drug therapy. Intimal hyperplasia plays a role in localizing the pathologic process, but while restricting the lesion this reaction leads to a progressive occlusion of the vessel lumen, which, if further increased by a thrombus, can critically impede blood supply, causing myocardial ischaemia, myocardial infarction and death. How can this problem be approached? It is known that atherosclerotic damage, consisting mainly of proliferating smooth muscle cells, connective tissue, lipid-laden macrophages and lymphocytes, occurs at the arterial intima, and that growth factors are likely involved in stimulating the cellular proliferative response that causes intimal hyperplasia (see e.g. 2-5). The subtle, but chronic, endothelial injury that can occur at certain intimal sites would favor the adhesion and aggregation of platelets and their release of growth factors. Platelets adhering to de-endothelialized areas of blood vessels release several growth/chemotactic factors from their a-granules, including platelet-derived ~owth factor (PDQF), eoidermal growth factor (EGF), B-thrombo~lobin and nlatelet factor 4 (PF4). PDGF and PF4 stimulate the proliferation of smooth muscle cells and fibroblasts (6,7) and the chemotactic migration of these cells toward the intima (6-8), and proliferating intimal smooth muscle cells can then synthesize fibrous elements of the atherosclerotic plaque. Monocytes that migrate into the developing plaque become transformed into macrophages, which, together with the disturbed endothelium itself, also release growth factors that can enhance the proliferation of both smooth muscle and fibrous tissue (e.g. 3,4,6,7). PDGF may also possess chemotactic activity for monocytes that produce monocvte-derived growth factor (MDGF), which is also mitogenic and chemotactic for smooth muscle cells and fibroblasts (6,7). Macrophage-derived growth factors that might play roles in atherogenesis are basic fibroblast ~rowth factor (bFGF). PDGF. transformin~ ~rowth factor~ (TGF~). transformine growth factor-B (TGF-fl). tumor necrosis factor-a (TNF-a) (e.g. 9-12), and a heparin-binding EGF-like growth factor (HB-EGF) (13; see below). Eventually, fibromuscular nlaques and the more necrotic complicated plaques form. This sequence of events involving growth factors, in somewhat modified form, probably underlies the development of the restenosis or stenosis that can follow invasive therapy. Thus, approaches aimed at inhibiting (or, in some cases, stimulating) the release or action of various growth factors could provide the required therapy for these complications. Both atherogenesis and thrombogenesis can contribute to restenosis/stenosis. The significant involvement of growth factors in both atherogenesis and in the blood vessel stenosis that can follow invasive therapies for CHD provides clues for designing new therapeutic approaches. This article will not be focussed directly on therapy for CHD, but rather on drug therapy for the comnlications that follow the use of PTCA and ACBS. Current drug therapy will be briefly analyzed, and novel approaches based on growth factors or certain other active substances and aimed at slowing or preventing cellular proliferative responses (to injury) that favor blood vessel stenosis and occlusion will be particularly emphasized. The urgency for such a new type of therapy is obvious. Although the efficacy of invasive cardiovascular procedures in relieving symptoms is well established, it is not yet known if they will prolong life, and the late complications (e.g. the restenosis that occurs within the first 3-8 months in about one-third of the patients who undergo initially successful PTCA; see 14) could be more detrimental than the original condition.
Vol. 49, No. I0, 1991
Therapy for Coronary Atherosclerosis
691
CURRENT DRUG THERAPY FOR RESTENOSIS OR STENOSIS
Currently available drugs offer very limited benefit as therapy for restenosis or stenosis. It is essentially because there are no drugs with proven efficacy for treating coronary arterial stenosis that PTCA is so extensively employed today. PTCA is the only available therapeutic orocedur¢ that can notentiallv nrevent nlatelet adhesion or thrombosis in serious coronary lesions. In contrast,-ACBS etlhances the tendency for local thrombosis since the decrease in blood flow through the residual lumen resulting from this procedure generally induces total occlusion in proximal obstructions. What drugs exist and what do they do? Three major types of drug therapy - "platelet-inhil?itors" (e.g. aspirin, sulfinpyrazone, dipyridamole), ¢onventional anticoa~lants which prevent the formation of thrombi (e.g. heparin), and thr0mbolytic agents which dissolve blood clots [e.g. streptokinase, uroldnase and tissue plasminogen-activator (t-PA)] - have been developed in efforts to prevent enlargement of existing thrombi or to achieve thrombolysis. Other drugs which may act mainly by reducing spasm include the nitrates and Ca 2+ -antagonists (vasodilators), and/I-blockin~ a~ents are used mainly to reduce cardiac work. Lipid/cholesterol-lowerin~ a~ents are used to decrease the concentrations of lipidic species that contribute to the development of atherosclerotic plaques. However, there is no firm evidence that any of these drugs can decrease the incidence of restenosis (stenosis) and reocclusion that can occur after PTCA or ACBS. Plat¢let-lnhibit0rs
Platelet-inhibitors can limit platelet aggregation, but aspirin, a cyclooxygenase-inhibitor and prototype of this drug class, does not inhibit platelet adhesion, an imoortant initial steo in rcstenosis, or the release of growth/¢hcmotactic substances from platelets, and therefore it is expected that it will not influence atherosclerotic lesions characterized by intimal hyperplasia and fibrous transformation (15-17). Nevertheless, regarding therapy for coronary restenosis, results of a randomized trial have indicated that aspirin (325 mg/day) produced a statistically significant difference, with respect to coumadin, in patients who had symptoms for more than six months before PTCA; restenosis rate was 21% with aspirin and 44% with coumadin (see 14). A significant action of aspirin in unstable angina has been shown in two randomized, double-blind, placebo-controlled trials (18, 19). On this basis, aspirin is recommended as a "secondary prevention" after recovery from an initial attack of unstable angina (see 1), and could be beneficial in treating advanced stages of restenosis that might involve thrombosis. Inhibitors of thromboxane-A2 (TXA2) that act directly at the TXA 2 receptor represent another pharmacological means of conceivable significance in managing coronary arterial stenosis. Certain TXA 2 receptor-blockers, like aspirin, may be found useful in controlling unstable angina, and although they would not be expected to interfere directly with platelet adhesion they could inhibit arterial smooth muscle proliferation (intimal hyperplasia). In this regard, it has been shown that TXA 2 is mitogenlc for smooth muscle ceils Ja vitro. Stable TXA 2 analogues stimulated [3H]thymidine incorporation into cultured smooth muscle cells of human and rat aorta (19a,19b). It might be envisioned that TXA 2 synthesis-inhibitors (e.g. imidazole), which selectively block the conversion of the cyclic endoperoxides prostaglandinG 2 and prostaglandin-H2 into TXA 2 (20), would be superior to aspirin since prostacyclin (PGI2) synthesis would not be inhibited. However, these agents exhibit anti-thrombotic potencies that are less than half that of aspirin, perhaps because the cyclic endoperoxides that accumulate in their presence may themselves possess pro-aggregant activity (21,22). Dipyridamole inhibits platelet adherence to collagen (23) and sub-endothelium (24), but only at doses that are substantially higher than those used in the clinical setting (see 25). No firm
692
Therapy for Coronary Atherosclerosis
Vol. 49, No. i0, 1991
evidence indicates that other platelet-inhibitors (e.g. ticlopidine, sufinpyrazone) can inhibit the cellular oroliferative resoonse of the arterial wall. AnticoaL~ulants/Thrombolvtic Agents
Anticoagulant drugs which prevent thrombogenesis, such as heoarin and warfarin-like _ag.c._n~, and thrombolytic agents which dissolve blood clots, such as streptokinase, urokinase and t-PA, have been used in treating restenosis or stenosis. One might conceive that such therapy would be beneficial, at least in limiting the thrombotic component of arterial reocclusion. Presently, heparin or warfarin-like agents are indicated for the stasis or "primary" coronary thrombosis that might occur in coronary arteries or vein grafts. Intravenous heparin significantly reduces progression to transmural infarction in patients with unstable angina, as compared with atenolol (26). Heparin could possibly have some inhibitory action on the intimal hyperplasia that characterizes restenosis or stenosis, a contention that is supported by the findings that heparin infusion suppressed smooth muscle cell proliferation and intimal thickening in balloon catheter-injured carotid arteries of rats (26a). In this regard, it might also be noted that thrombin is a potent mitogen for bovine aortic smooth muscle ceils maintained in culture (26b). Thrombolyti¢ agen~, such as streptokinase and recombinant tPA (rt-PA) appear to be useful in treating patients with unstable angina (see e.g. 27). Recent studies have indicated that early reperfusion with intracoronary streptokinase decreases the death rate in such patients by about 50% (see 1,28,29). According to Yusuf (30), about 75% of the coronary thrombotic occlusions that occur in patients showing early signs of myocardial infarction can be dissolved by intracoronary infusion of thrombolytic agents such as streptokinase. An assessment of more than 20 trials that were conducted with intravenous streptokinase revealed a highly significant 21% decrease in the probability of death (30). These results are encouraging, but acute coronary artery reocclusion and reinfarction and a risk of serious hemorrhagic complications are associated with these approaches (30-33). About 25% of the vessels initially recanalized with thrombolytic therapy reocclude within a few days (28,34). Such problems have stimulated efforts to improve this type of therapy. Early intravenous heparin has been compared with oral aspirin as adjunctive therapy when rt-PA was used for coronary thrombolysis in patients experiencing acute myocardial infarction ("chest pains") (35). At the time of the first angiograrn, 82% of the infarct-related arteries in the patients assigned to heparin were patent as compared with only 52% in the aspirin group. Of the initially patent vessels, 88% remained patent after 7 days in the heparin group as compared with 95% in the aspirin group. The numbers of hemorrhagic events and recurrent ischaemic events were similar in the two groups. It was concluded that coronary patency rates associated with rt-PA are higher with early concomitant heparin treatment than with concomitant low-dose aspirin. However, the efficacies of both aspirin and heparin in accelerating coronary thrombolysis, in overcoming resistance to lysis, and in preventing reocclusion are limited, and even with concomitant administration of heparin and aspirin, thrombolytic therapy does not produce maximal coronary artery recanalization in patients with evolving myocardial infarction (see 36). At best, such combined therapies would be expected to interfere with the thrombotic manifestations, but not directly with the restenosis or stenosis that can follow PTCA or other invasive therapeutic procedures. Nitrates
Nitrates (e.g. nitroglycerin) act mainly by diminishing "preload" by causing marked venous dilatation throughout the body, which leads to decreases in venous return to the heart, cardiac output and arterial pressure. To a lesser extent, they reduce "afterload" (i.e. the resistance against which the heart contracts) via arterial dilatation. These agents might also
Vol. 49, No. i0, 1991
Therapy for Coronary Atheroselerosis
693
cause platelet disaggregation and dilatation of large epicardial coronary arteries, effects which could contribute to their beneficial action on coronary blood flow (e.g. 1). As the syntheses of those products of ischaemic metabolism that might cause pain are reduced by these agents, they provide excellent relief during anginal attacks in most individuals and are also useful for prophylaxis. Assessment of results obtained with intravenous nitroprusside (3 trials) and intravenous nitroglycerin (6 trials) have revealed a significant reduction in mortality rate (30). This result was observed mainly during the first two to three weeks after initiating therapy, indicating that nitrates (because of their vasodilatatory action) could be useful in managing certain early complications (e.g. possible "recoil" vasoconstriction) that can follow PTCA, but not the intimal hyperolasia that characterizes the late complication, restenosis. However, tolerance develops to the anti-ischaemic effect of nitrates, and in some cases they may actually favor ischaemia by diverting coronary blood flow away from ischaemic regions ("steal effect") and/or by inducing reflex increases in heart rate (see 30). 2÷
°
Conventional Ca2+-antagonists, such as nifedipine, verapamil and diltiazern, act mainly by decreasing coronary and peripheral vascular resistance. In addition, verapamil and diltiazem have negative inotropic and chronotropic effects. These agents are about 3-10 times more potent in inhibiting coronary artery smooth muscle than myocardial contractile cells (37), thereby permitting dilatation of coronary arteries in doses that do not decrease myocardial contractility (38,39). They are useful in managing nearly all myocardial ischaemic syndromes, including stable and unstable angina pectoris (e.g. 40-43). However, no evidence exists, either from individual studies or from the pooled data of all trials conducted until 1987 1 n that Ca 2 + -antagomsts • to support the n ot'o reduce mortality in cases of unstable angina or acute myocardial infarction (e.g. 30). Ca2+-antagonists such as nifedipine are also inefficient when administered after myocardial infarction has occurred (44). Although Ca2+-antagonists might impede the progression of atherosclerosis (i.e. the development of arterial stenosis that does not occur in response tq invasive therapy) (45-47), the results of randomized clinical trials indicate that neither diltiazem nor nifedipine can prevent or diminish the extent of coronary artery restenosis that follows PTCA (see 14). In summary, CaZ÷-antagonists may possibly retard the progression of atherosclerosis (see below), but no firm statements can be made at this time regarding their use as therapy for the restenosis or stenosis that can occur in response to invasive cardiovascular interventions. Also, an adverse effect on ischaemia could occur via a "steal phenomenon" in certain patients.
B-Blocker~ B-Blockers, such as propranolol, metoprolol, atenolol and timolol, probably relieve anginal pain by blocking cardiac fll-adrenoceptors whose activation leads to increased cardiac performance. Blockade of these receptors causes decreases in heart muscle contractility, heart rate, cardiac work and blood pressure, which in turn leads to reduced cardiac oxygen consumption. A decrease in the ratio of oxygen need/oxygen supply is thereby produced which eliminates anginal pain. Some workers contend that t-blockers are the most effective prophylactic agents for both the short- and long-term management of patients who have experienced myocardial infarction (see 27). t-Blockers can raise the threshold for infarction and reduce complex ventricular arrhythmias in man (see 30), effects which would be expected to reduce early mortality, reinfarction and ventricular fibrillation after myocardial infarction. In a large study (16,027 cases of suspected acute myocardial infarction), vascular mortality was
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significantly decreased by about 15% during seven days of intravenous atenolol therapy, this effect being observed mainly during the first two days of therapy (48). Results of another large study (2877 patients allocated to metoprolol, and 2901 to placebo) indicated that metoprolol had no significant effect on death rate from myocardial infarction (49; see also 1). Chamberlain (50) has concluded that no firm evidence of a therapeutic effect of B-blocker therapy can be claimed with respect to acute mortality in cases of acute myocardial infarction. However, Yusuf (30), upon examining the data from all 27 randomized trials that were available until 1987, concluded that t-blocker therapy probably does reduce total mortality at seven days by about 13% (p
