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Pharmacological treatment of acute coronary syndromes

Karen Hughes, BSc (Hons), RN.

Clinical Nurse Leader, Cardiology, Coronary Care Unit, Fairfield General Hospital, Bury, Lancashire

Changes in the delivery of health care and the increasing awareness of the need to urgently treat patients with acute coronary syndromes has led to the inauguration of a range of pharmaceutical therapies. Clinical trials have reviewed the effectiveness and safety of drugs that have been proposed as the standard treatment for acute coronary syndromes, and guidelines instigated, including those published by the National Institute for Clinical Excellence (2002), the European Society of Cardiology (Bertrand et al, 2000) and the British Cardiac Society and Royal College of Physicians (BCS/RCP, 2001).

Changes in the delivery of health care and the increasing awareness of the need to urgently treat patients with acute coronary syndromes has led to the inauguration of a range of pharmaceutical therapies. Clinical trials have reviewed the effectiveness and safety of drugs that have been proposed as the standard treatment for acute coronary syndromes, and guidelines instigated, including those published by the National Institute for Clinical Excellence (2002), the European Society of Cardiology (Bertrand et al, 2000) and the British Cardiac Society and Royal College of Physicians (BCS/RCP, 2001).

Acute coronary syndromes represent a pathophysiological spectrum that covers unstable angina, non-Q-wave or non-ST-segment elevation myocardial infarction (NSTEMI) and acute ST-elevation myocardial infarction (STEMI). As the management of STEMI is well documented, this paper will discuss the pharmacological management of patients with acute coronary syndromes in respect of unstable angina and NSTEMI only.

Patients who present with NSTEMI or unstable angina are considered to be at high risk of developing an acute transmural myocardial infarction and possible sudden death. It is now universally accepted that they require prompt, intensive treatment to relieve their symptoms and to reduce the risk of further events.

A number of drugs may be used in the acute phase of this condition (Box 1).

Antiplatelet and anti-thrombotic agents
Antithrombotic therapy consists potentially of:

- Thrombolytics

- Antiplatelet therapy

- Anticoagulants.

There is no evidence to support the use of intravenous thrombolytics in NSTEMI and unstable angina (BCS/RCP, 2001) therefore this paper will concentrate on the latter two.

Aspirin - One of the most important, yet inexpensive, treatments of acute coronary syndromes is the anti-thrombotic drug aspirin. It is the reference standard antiplatelet agent and several independent studies have shown a significant risk reduction of acute myocardial infarction or death for patients who received aspirin at the time of the acute event (Theroux et al, 1988; RISK group, 1990; Theroux et al, 1993). A meta-analysis by the Antiplatelets Trialists' Collaboration in 1994, updated in 2000, reviewed both the long- and short-term usage of aspirin and found that aspirin reduced the incidence of acute myocardial infarction, stroke and vascular death of patients at risk by up to 50%.

Aspirin works as a platelet inhibitor by affecting the aggregative properties (adhesion) of blood platelets, thereby reducing the risk of thrombus formation. The effect of aspirin on platelets is irreversible and lasts for the lifespan of the platelets affected (Hepinstall, 2000).

Suggested dosages of aspirin are an initial dose of 300mg followed by a maintenance daily dose of 75-150mg for patients who have no clear contraindications, such as risk of bleeding or hypersensitivity (Antithrombotic Trialists' Collaboration, 2002).

Heparin - Heparin is the most frequently used anticoagulant in acute coronary syndromes (Verheught, 1999). Guidelines from the BCS/RCP (2001) recommend that all patients diagnosed as having acute coronary syndromes should be prescribed either intravenous unfractioned heparin (UFH) or low molecular weight heparin (LMWH).

Unfractioned heparin - Clinical trials have found that intravenous UFH was effective in reducing risk complications of patients with acute coronary syndromes, especially if combined with aspirin therapy (Oler et al, 1996). The activated partial thromboplastin time (aPTT) needs to be closely monitored during therapy, and the heparin dosage titrated accordingly in order to achieve therapeutic levels and to reduce the risk of major bleeding (Eikelboom et al, 2000).

Low molecular weight heparin - The practical advantages of giving LMWH are its ease of subcutaneous administration, a longer half-life, thereby giving a more reliable and sustained dose than UFH, and a predictable pharmacological response, thereby halting the need for laboratory monitoring. Patients receiving LMWH should have their dosage weight adjusted (BCS/RCP, 2001).

It is suggested that heparin be given for a minimum of two and up to eight days. However, patients with recurrent ischaemia or where myocardial revascularisation is contraindicated or delayed may be prescribed heparin for longer periods. Due to their ease of administration and pharmaceutical properties, the LMWHs enoxaparin and dalteparin have become the preferred anticoagulant treatment in acute coronary syndromes (Verheught, 1999; Holdright, 2001).

Thienopyridines
The thienopyridine derivatives clopidogrel and ticlopidine are second-generation platelet inhibitors. These antiplatelet agents are adenosine diphosphate (ADP) antagonists, which act by preventing ADP interacting with ADP receptors on the platelet surface. Therefore ADP that is released from a ruptured atherosclerotic plaque or from damaged red blood cells is not able to activate platelet aggregation. Additionally, stored ADP released from activated platelets cannot amplify the whole of the process (Hepinstall, 2000), reducing the risk of ischaemic events.

Studies evaluating the use of ticlopidine found that it carried the risk of severe adverse haematological side-effects. These were excess cases of neutropenia and thrombotic thrombocytopenic purpura (Love et al, 1998). This has resulted in the safer drug option of clopidogrel being used.

The use of clopidogrel stems mainly from the CAPRIE trial (1996) in which the benefits of clopidogrel and aspirin were compared. It was found to be slightly more effective than aspirin and well tolerated. Until lately the use of clopidogrel has been primarily for patients intolerant of aspirin; however, a recent trial has compared the efficiency and safety of clopidogrel plus aspirin with aspirin alone for patients with acute coronary syndromes (CURE, 2001). The trial concluded that clopidogrel and aspirin were well tolerated with early benefit and had a significant effect on the reduction in combined outcome of death from cardiovascular events, non-fatal myocardial infarction and stroke, as well as a range of ischaemic events. There was, however, an increased risk of bleeding using this combined therapy.

The suggested dose for clopidogrel is a loading dose of 300mg orally followed by a maintenance dose of 75mg daily.

Platelet glycoprotein IIb/IIIa inhibitors
Glycoprotein inhibitors belong to a new class of drugs that are third-generation platelet inhibitors and are starting to play an important role in the management of patients with acute coronary syndromes. Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists work by inhibiting platelet activity at the injured coronary plaque by blocking the GPIIb/ IIIa receptors at the platelet surface membrane. By attaching to these receptors they help to prevent fibrinogen, von Willebrand factor and other adhesive ligands from attaching to activated platelets, thereby blocking the final common pathway of platelet aggregation (Levy, 2001).

Guidelines issued suggest that intravenous small molecule platelet GPIIb/IIIa inhibitors should be administered for up to 96 hours in patients with acute coronary syndromes who are at high risk of developing a transmural infarction (STEMI) and/or death (BCS/RCP, 2001; NICE, 2002). Early data supports the role of LMWH in conjunction with GPIIb/IIIa inhibitors (GUSTO IV-ACS) (Simoons, 2001; Cohen et al, 2002).

Patients with recurrent and refractory acute coronary syndromes, despite treatment, should also be prescribed GPIIb/IIIa inhibitors (CAPTURE, 1997) and heparin continued until they undergo coronary angiography and possible myocardial revascularisation (BCS/RCP, 2001; NICE, 2002).

There are currently three GPIIb/IIIa inhibitors that are available for use: tirofiban and eptifibatide, which are small molecule inhibitors, and abciximab, a monoclonal antibody inhibitor. Current findings suggest that abciximab should be utilised only for patients who are to undergo early cardiac catheterisation (Hamm et al, 2001; NICE, 2002). GP IIb/IIIa inhibitors should be weight adjusted and administered according to the approved literature. Close monitoring and control of the infusions will reduce the risk of potential bleeding.

Anti-ischaemic agents
The purpose of anti-ischaemic treatment is to reduce or arrest myocardial ischaemia in acute coronary syndromes. There are several types of anti-ischaemic agents that are available with the ability to be given through a variety of routes.

Nitrates - One of the most common anti-ischaemic agents used in acute coronary syndromes to relieve ischaemic pain are nitrates. Nitrates are potent vasodilators that work by dilating peripheral vessels, thereby reducing preload and left ventricular end-diastolic volume. In higher doses they dilate arterioles, thereby reducing afterload of the heart. This leads to a reduction in the myocardial oxygen consumption, which in turn leads to a decrease or cessation of myocardial ischaemia and subsequent pain relief. Coronary artery dilatation is also achieved; however, researchers propose it is unclear whether this is effective in relieving ischaemia and preventing infarction in patients with acute coronary syndromes (Verheught, 1999).

Nitrates are given in accordance with the symptoms of the patient and may be administered as a prophylactic or acute treatment of angina (BCS/RCP, 2001). They may be given sublingually or via the buccal area for acute or prophylactic treatment or orally for long-term management. In acute coronary syndromes nitrates are often given intravenously, either as an acute treatment or maintenance dose, as infusions are quicker and easier to manage. Infusions are titrated according to the symptoms of the patient but may be limited due to side-effects such as headaches, flushing, hypotension and the rapid development of tolerance (Verheught, 1999).

Beta-adrenoceptor blockers - Beta-blockers block the beta-adrenoceptors in the heart, peripheral vasculature, bronchi, liver and pancreas. The inhibition of these receptors reduces the effects of circulating catecholamines such as adrenaline. They also reduce the level of catecholamines in the circulation and decrease myocardial oxygen demand, resulting in a reduction in myocardial contractility, heart rate and blood pressure, thereby reducing cardiac workload (Verheught, 1999). Beta-blockers may reduce the size of a myocardial infarction and/or control angina in patients with acute coronary syndromes (Yusef et al, 1988).

In general beta-blockers are all equally effective; however, the choice of drug is often dependent on the particular disease and the individual patient (BMA/RPSGB, 2002). Beta-blockers may be both short- and long-term acting and should be prescribed accordingly. Beta-blockers should be prescribed for all patients with acute coronary syndromes unless contraindicated (BCS/RCP, 2001; McLeod and Fox, 2001), the most common choice being atenolol or metoprolol.

Contraindications to beta-blockers are asthma or a history of severe obstructive airways disease, acute left ventricular dysfunction, significantly impaired atrioventricular conduction, severe peripheral artery disease, cardiogenic shock, marked bradycardia, hypotension and Prinzmetal's angina (Bertrand et al, 2000; BMA/RPSGB, 2002).

Calcium channel blockers - Certain calcium channel blockers/antagonists may be prescribed to control heart rate when beta-blockers are contraindicated, or as an additional therapy where symptoms persist despite treatment with nitrates and beta-blockers (BCS/RCP, 2001).

Calcium channel blockers inhibit the flow of calcium ions through the membranes of the cardiac cells - thereby producing varying degrees of vasodilatation - lower blood pressure, reduce contractility and delay atrioventricular conduction (dependent on the class of agent used) (McLeod and Fox, 2001).

There are important differences in the type of calcium channel blockers used and these must be considered before prescribing; the drugs of choice in acute coronary syndromes are diltiazem and verapamil. Calcium channel blockers are contraindicated in patients with left ventricular dysfunction, severe bradycardia, sick sinus syndrome, second- or third-degree AV block and, in view of current literature that suggests they may be counterproductive, should not be used as monotherapy (McLeod and Fox, 2001; Verheught, 1999).

Potassium channel activators - The potassium channel activator nicorandil has similar vasodilator properties to those of nitrates and may be indicated (unlicensed indication) in the treatment of refractory unstable angina in addition to nitrates, beta-blockers or calcium channel blockers where symptoms persist (BCS/RCP, 2001).

A study by Patel et al (1999) suggests that, by opening the potassium channel, this mediates ischaemic preconditioning, which protects the myocardium. This may then afford protection against further ischaemic attacks. The study proposes that, in addition to other anti-anginal treatments, it may reduce the frequency of ischaemia and cardiac disrhythmias.

Angiotensin-converting enzyme (ACE) inhibitors
It is suggested that there is a role for ACE inhibitors in the secondary prevention of acute coronary syndromes for patients who have evidence of left ventricular impairment (BCS/RCP, 2001). Angiotensin II is a powerful vasoconstrictor produced in the body by the conversion of inactive angiotensin I to angiotensin II by the angiotensin-converting enzyme. Angiotensin II is responsible for narrowing blood vessels and consequently raising blood pressure. ACE inhibitors reduce the effect of this conversion, thereby directly reducing blood pressure and indirectly reducing left ventricular workload. Evidence demonstrated by the HOPE study (2000) found that the ACE inhibitor ramipril significantly reduced the rates of cardiovascular events in high-risk patients, even in the presence of normal left ventricular dysfunction.

ACE inhibitors are generally tolerated well but are contraindicated in severe renal failure, aortic stenosis or outflow tract obstruction and hypersensitivity to ACE inhibitors. Patients may complain of a cough when therapy is introduced. Treatments include ramipril, perindopril, enalapril, captopril and lisinopril (BMA/RPSGB, 2002).

Statins
Statin therapy was first introduced in an attempt to reduce patients' cholesterol levels and, although effective for this purpose, it is now thought to have the additional benefits of improving coronary plaque stability by improving endothelial function, decreasing vascular inflammation and reducing platelet aggregation and instability (Liao, 2002). Several large studies have demonstrated the benefit of lipid lowering by decreasing the number of cardiac adverse events in patients with coronary heart disease (Scandinavian Simvastatin Survival Study Group, 1994; Sacks et al, 1996; LIPID Study Group, 1998). The MIRACL study (Schwartz et al, 2001) was the first trial to assess whether statins might be of clinical benefit for patients with acute coronary syndromes and showed the benefit of early aggressive lipid lowering following an acute event.

Lipid-lowering therapies currently in use include atorvastatin, pravastatin and simvastatin.

Additional medications
Diamorphine, a powerful opioid analgesic, may be given intravenously in the acute phase of acute coronary syndromes to relieve chest pain and discomfort. Although diamorphine causes less nausea and hypotension than morphine, an intravenous anti-emetic such as metoclopramide or, if the left ventricular function is not compromised, cyclizine should also be given.

Oxygen therapy should be considered for patients at risk of developing hypoxia, the concentration of which should be administered in accordance with the patient's condition.

Conclusion
There are many large ongoing trials investigating all aspects of the pharmaceutical management of patients with acute coronary syndromes. The current treatment options are considerable and should be instigated on the basis of risk stratification during the in-hospital period and continued into the community to provide effective secondary prevention.

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