Pharmacological Management of Coronary Disease

 

By: M. Mohsen Ibrahim, MD

Prof. of Cardiology - Cairo University

President of the Egyptian Hypertension Society

The role of pharmacologic therapy in management of coronary artery disease is possibly underestimated in the current era of coronary interventions where the main focus of attention is directed to PCI, stents and developing new types of stents. Interventional therapy targets only focal manifestations of a systemic disorder. In addition to culpurit lesion seen in coronary angiogram, there are other active unstable plaques that are not encroaching on coronary artery lumen, but are waiting as timed bombs to rupture and produce acute coronary events. The ideal approach should address the diffuse and systemic nature of coronary atherosclerosis. Modern pharmacologic therapy proved effective in ameliorating ischemia, preventing infarction and reinfarction and prolonging survival. Following acute myocardial infarction, aggressive medical anti ischemic therapy e.g., beta adrenergic blockers, calcium antagonists and nitrates in the maximal tolerable doses have the same favorable effect as PCI on myocardial perfusions defects detected by nuclear imaging. The addition of statins and angiotensin converting enzyme inhibitors (ACE-I) delays the development of atherosclerotic complications i.e. MI, stroke and death in high risk patients and prolongs survival. Furthermore, while coronary interventions are limited to the focal coronary stenotic lesion, drug therapy can also address atherosclerotic disease in other territories e.g. carotid, cerebral and peripheral arteries which is commonly present with coronary atherosclerosis. In patients with stable non acute coronary disease, the results of drug therapy regarding development of MI and survival were similar, sometimes better than PCI.

 Therapeutic Targets of Pharmacologic Therapy

Coronary Atherosclerotic Plaque

This is the mother of all evil. It develops early in life and produces symptoms by encroaching on coronary artery lumen or by rupture with thrombus formation occluding the coronary artery and resulting in acute coronary syndromes (ACS) .

Strategies addressing atherosclerotic plaques aim at its regression and/or stabilization i.e. makes it less prone to rupture. Plaques liable to rupture are known as vulnerable plaques. Vulnerable or unstable plaques are characterized by having a large lipid core rich in cholesterol esters, thin fibrous cap separating the lipid core from the coronary artery lumen. The thin cap contains few collagen fibres and is poor in smooth muscle cells- which are the main source for collagen formation. Collagen gives the tensile strength to the fibrous cap  and  resists rupture. Also vulnerable plaques contain many inflammatory cells namely, macrophages and T-lymphocytes. Macrophages produce proteolytic enzymes known as matrix metalloproteinases (MMPs) which degrade the collagen and weaken the fibrous cap. Vulnerable plaques remain clinically silent until they rupture or their covering endothelium is eroded, exposing the contents of their strongly thrombogenic core to blood stream. Tissue factor in the lipid core activates blood clotting resulting in thrombin generation. Also exposed are adhesion molecules e.g., collagen and von Willebrand factor which activate blood platelets particularly the fibrinogen receptors (GP II b / III a receptors) resulting in the formation of platelet thrombi. The process of plaque unstabiity, rupture, platelet and fibrin thrombi formation is favoured and potentiated by a local and systemic inflammatory state and a general tendency to blood coagulation- a procoagulant state.

Plaque passivation or stabilization can be achieved by aggressive lipid lowering, improving endothelial function, suppressing the systemic and local proinfalmmatory and procoagulant states and decreasing stress on the palque.

Pharmacologic agents that help in stabilizing the vulnerable plaque include statins, ACE-I, beta adrenergic blockers, aspirin, antibiotics and anticoagulants. Statins in addition to reduction in the lipid core, they change the plaque composition favoring cholesterol crystals formation which are more solid than cholesterol esters. Also statins have anti inflammatory effects and improve endothelial function. ACE-I stabilize plaques by inhibiting enzymes degrading the fibrous cap (MMPs), and decreasing wall stress. ACE-I have also antiinfalmmatory effects and antithrombotic potential.

 Coronary Thrombus

The second target of pharmacologic therapy is the thrombus formed within and on the ruptured plaque occluding partially or totally the coronary artery lumen. Coronary thrombi are dynamic structures, they develop and dissolve depending upon the activity of the endogenous lytic system. Once occluding coronary thrombi develop, the immediate aim of drug therapy is to dissolve them and prevent their extension. In persistent total occlusion with fibrin rich thrombi i.e. MI, thrombolytic therapy should be initiated immediately to restore flow. In partial or intermittent occlusion by platelet rich thrombi in non ST elevation acute coronary syndromes the aim is to prevent thrombus extension and to relieve ischemia by antiplatelet, anticoagulant and antiischemic therapy.

Thrombolytic therapy is the principal pharmacologic intervention in MI. However, it has its limitations. Primary failure occurs in more than 15% possibly due to platelet rich thrombi that can not be dissolved by fibrinolytic therapy. Reocculsion occurs in 10% at hospital discharge following lytic therapy and in 30% within one year. Complete coronary patency i.e., achieving TIMI 3 flow is possible only in 40%. Even in spite of good epicardial coronary flow there is myocyte perfusion failure in about 20%.  The effects of lytic therapy are time dependent, delay in initiation will attenuate its beneficial effects, furthermore there is a delay in canalization of 45 minutes after start of therapy. A long list of contraindications is present and some complications may develop after lytic therapy.

To overcome some of the previous limitations, newer thrombolytics were developed e.g. tenecteplase, which are more fibrin specific and of long duration of action allowing bolus administration. Another approach is to add to lytic therapy antiplatelets, antithrombin and anticoagulants (adjunctive therapy).

The adjunctive use of antiplatelets GP II b/ III a blockers will target the platelet components of the occluding thrombus which are resistant to thrombolytics and will allow a smaller dose of the latter, increasing the safety profile. GP II b/ III a blockers benefit more troponin positive patients and patients referred to PCI. However, this adjunctive therapy carries the risk of increased bleeding.

Administration of bolus lytic therapy at home or in the ambulance- prehospital throbolytic will overcome the delay limitation and proved effective in improving the outcome with results similar to primary PCI.

 Systemic Milieu

A generalized systemic proinfalmmatory and procoagulant state is present in patients with ACS that persists for months after MI. It is possibly responsible for the high event rate during the early weeks following MI. Aspirin has both antiinfammatory and antiplatelet effects. Antibiotics, namely amoxicillin, azithromycin (one week each) and clarithromycin (for 3 months) were tried in patients with ACS with favorable results. Systemic anticoagulation with Warfarin achieving on INR 2.0-3.0 units proved better than ASA alone in patients afetr MI.

 Myocardial Protection

The final therapeutic target is the myocardium. The aims are its protection against myocyte necrosis, no reflow phenomenon and reperfusion injury. Pharmacologic agents used for myocardial protection are undergoing clinical trials and the results of completed studies are mixed. Drugs used for myocardial protection include inhibitors of Na/H exchanger in cell membrane (which decreases C++ inflex) such as cariporide and eniporide, inhibitors of complement by pexelizumab and adhesion molecules blockers. Other approaches include supersaturated oxygen and systemic hypothermia.