Acute Treatment and Prevention of ACS

Pharmacologic or interventional treatments, or both, may be used

Acute coronary syndrome (ACS) is triggered by the rupture or ulceration of an intracoronary atherosclerotic plaque. When the endothelium is breached, blood comes in contact with plaque that is rich in tissue-factor, leading to thrombus formation.⁵

Thrombi formed in this manner cause variable degrees of obstruction in the coronary artery and subsequent myocardial ischaemia. Complete coronary artery obstruction generally leads to an ST-elevation myocardial infarction (STEMI).⁸³ The standard of care for this medical emergency is treatment with the goal of achieving reperfusion. This can be attempted pharmacologically, with thrombolytic therapy (ie, fibrinolytic medications, such as tissue plasminogen activator), or mechanically, using percutaneous coronary intervention (PCI) or coronary artery bypass surgery. The decision to attempt immediate reperfusion in patients with non-ST-elevation ACS is based on risk stratification.⁸³

The goal of treatment: stabilisation and prevention of recurrence

For all ACS patients, including patients with unstable angina as well as those suffering a myocardial infarction (MI), principles of care include stabilisation of the acute coronary artery lesion, relief of cardiac ischaemia, and long-term measures to prevent recurrent arterial thrombotic events, such a recurrent ACS or stroke.¹²⁹

Platelet-rich thrombi tend to form under conditions of high-shear stress, as occurs in arterial circulation. For this reason, antiplatelet agents are an essential component in the treatment of ACS to suppress platelet activation as the coronary lesion evolves. The course of recovery in ACS involves spontaneous, mechanical, or pharmacologic thrombolysis. Clot lysis is associated with hypercoagulability, as thrombin molecules are exposed during the process. This sets the stage for recurrent thrombosis and possible vessel reocclusion. For this reason, anticoagulant therapy is critical during the acute phase of treatment. The combination of antiplatelet and anticoagulant therapy is more effective than either strategy alone.^{23, 129}

In patients without contraindications, acute care often includes dual antiplatelet therapy with Aspirin and clopidogrel. Parenteral glycoprotein IIb/IIIa inhibitors provide additional protection against platelet aggregation, particularly in those undergoing PCI. Unfractionated heparin or low-molecular-weight heparin is generally used for anticoagulation. Fondaparinux has also been successfully studied for use in ACS. Other anticoagulant options for use during PCI include the direct thrombin inhibitors bivalirudin and argatroban.^{23, 106}

Secondary prevention is essential

Patients who experience an episode of ACS often have atherosclerosis affecting other coronary arteries or peripheral or cerebral arteries. For this reason, secondary prevention is an important facet of long-term care.¹²⁹ Drugs from several classes have been shown to reduce risk, including antiplatelet agents, ACE inhibitors, statins, and beta-blockers.²³ These medications work by decreasing shear stress in the arteries, affecting the properties of the arterial wall, or slowing the progression of atherosclerosis.

Lifelong therapy with low-dose Aspirin is generally recommended for patients without contraindications (such as GI bleeding). Dual antiplatelet therapy with Aspirin and clopidogrel is recommended for at least one month, and preferably for a year, following the acute event, particularly in those treated with drug-eluting stents.^{83, 95} Long-term oral anticoagulation with a vitamin K antagonist is more effective than Aspirin alone, but it has a greater risk of bleeding, so this treatment is generally limited to patients with atrial fibrillation or to those who develop a left-ventricular thrombus after an MI.^{129, 130}

The 2009 NICE guidelines for ACS recommend use of prasugrel in combination with Aspirin as an alternative to clopidogrel when primary percutaneous coronary intervention (PCI) is necessary to treat STEMI or when stent occlusion occurs during clopidogrel treatment, or in patients with diabetes mellitus. However, prasugrel poses a greater risk of bleeding than clopidogrel.²⁴⁵

In 2007, the EMEA (now known as the EMA) approved the use of the Factor Xa inhibitor fondaparinux for the treatment of patients with ACS. Approval was based on the results of 2 Phase III trials (OASIS 5 and 6) that showed reduced mortality and reinfarction without increasing bleeding risk compared with enoxaparin or unfractionated heparin.²⁶⁴

Triple therapy

Current guidelines recommend dual antiplatelet therapy (Aspirin plus a thienopyridine, usually clopidogrel) after ACS, regardless of whether patients undergo PCI, and after intracoronary stent placement. This need for dual antiplatelet therapy presents special challenges in patients with atrial fibrillation (AF) at moderate to high risk of stroke, as these individuals also require long-term oral anticoagulant therapy. In this situation, clinicians need to weigh the risk of triple oral antithrombotic therapy against the risk of bleeding. To address this need, the Working Group on Thrombosis of the European Society of Cardiology recently convened a task force to generate evidence-based guidelines for antithrombotic management in patients with AF who present with ACS or who undergo intracoronary stent insertion.²²⁷

The task force acknowledges that many of their recommendations are level of evidence “C”, because of the dearth of prospective randomised studies and/or registries related to this clinical scenario. The group based its recommendations for treatment of patients with AF undergoing stent placement in whom oral anticoagulants are required (because of a moderate to high risk of stroke) on bleeding risk, the clinical setting and the type of stent used.²²⁷ The table below summarises the conclusions of the task force.

Recommendations for Antithrombotic Therapy Following Coronary Artery Stenting in Patients with AF at Moderate to High Risk for Thromboembolic Stroke (Requiring Oral Anticoagulation)

^a Drug-eluting stents should be avoided.
^b Recommended continuation of therapy indefinitely or until cancer resolves

Bleeding Risk	Clinical Setting	Stent Implanted	Recommendations
Low or intermediate	Elective	Bare metal	1 month: triple therapy of warfarin (INR 2.0-2.5) + Aspirin < 100 mg/day + clopidogrel 75 mg/day Lifelong: warfarin (INR 2.0-3.0) alone
	Elective	Drug-eluting	3 (-olimus group) to 6 (paclitaxel) months; triple therapy of warfarin (INR 2.0-2.5) + Aspirin < 100 mg/day + clopidogrel 75 mg/day Up to 12 months: combination of warfarin (INR 2.0-2.5) + clopidogrel 75 mg/day (or Aspirin 100 mg/day)^b Lifelong: warfarin (INR 2.0-3.0) alone
	ACS	Bare metal/ drug-eluting	6 months: triple therapy of warfarin (INR 2.0-2.5) + Aspirin < 100 mg/day + clopidogrel 75 mg/day Up to 12 months: combination of warfarin (INR 2.0-2.5) + clopidogrel 75 mg/day (or Aspirin 100 mg/day)^b Lifelong: warfarin (INR 2.0-3.0) alone
High	Elective	Bare metal	2-4 weeks: triple therapy of warfarin (INR 2.0-2.5) + Aspirin < 100 mg/day + clopidogrel 75 mg/day Lifelong: warfarin (INR 2.0-3.0) alone
	ACS	Bare metal^a	4 weeks: triple therapy of warfarin (INR 2.0-2.5) + Aspirin < 100 mg/day + clopidogrel 75 mg/day Up to 12 months: combination of warfarin (INR 2.9-2.5) + clopidogrel 75 mg/day (or Aspirin 100 mg/day)^b Lifelong: warfarin (INR 2.0-3.0) alone

Adapted from Lip, Huber, Anderotti, et al, Eur Heart J, 2010.²²⁷

When patients present with ACS in the acute setting, they are often managed with Aspirin, a thienopyridine, heparin or bivalirudin, and/or glycoprotein IIb/IIIa inhibitors (GPIs). In patients with AF on oral anticoagulants who present with ACS, it may be prudent to interrupt the oral anticoagulant therapy and to administer antithrombin agents or GPIs only if the INR is 2 or less. In anticoagulated patients at very high risk of thromboembolism, however, continuing the oral anticoagulant can be the preferred approach, with radial PCI access used as the first choice to decrease the risk or periprocedural bleeding.²²⁷

Percutaneous coronary intervention

PCI is commonly employed to restore normal coronary blood flow in patients with coronary artery disease. Early invasive PCI therapy improves long-term survival and reduces late MI in patients with non-ST-segment elevation MI (NSTEMI).¹⁶³ The use of PCI also improves overall survival and prolongs the time to recurrent MI in STEMI patients.²¹³

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Article references

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Acute coronary syndrome: This is an umbrella term used to cover any group of clinical symptoms compatible with acute myocardial ischaemia (chest pain due to insufficient blood supply to the heart muscle that results from coronary artery disease). Acute coronary syndrome covers the spectrum of clinical conditions ranging from unstable angina to STEMI and NSTEMI.
Myocardial infarction: Destruction of heart tissue due to reduced blood flow to the heart. Also known as a heart attack. It usually results from coronary artery disease and is more severe than angina.
Angina: Heart condition characterised by intermittent chest pain. Angina usually results from coronary artery disease and may further be classified as stable or unstable angina. Stable angina refers to the more common understanding of angina related to myocardial ischemia. Unstable angina may occur unpredictably at rest which may be a serious indicator of an impending heart attack.
Hypercoagulability: A potentially dangerous state of an increased tendency for blood to coagulate, even within blood vessels. Hypercoagulability can be an inherited condition (e.g., Factor V Leiden mutation) or acquired through circumstance (e.g., cancer).
Platelet: (Thrombocyte) Cell circulating in the blood that is involved in the cellular mechanisms of primary haemostasis leading to the formation of blood clots. When a blood vessel is injured, platelets gather at the site of injury and stick together to form a plug, thereby preventing blood loss.
Thrombin: Also called Factor IIa, thrombin performs two functions in the coagulation cascade: activating platelets, and catalysing the conversion of soluble fibrinogen into insoluble fibrin. It is formed from prothrombin by a reaction that is catalysed by Factor Xa.
Aspirin: The brand name of acetylsalicylic acid (ASA), an antithrombotic medication that prevents thrombosis by inhibiting the activity of platelets – a component of blood that helps to prevent blood loss.
Clopidogrel: Oral antiplatelet agent used in the treatment of coronary artery disease, peripheral vascular disease and cerebrovascular disease.
Fondaparinux: An indirect Factor Xa inhibitor comprising a synthetic pentasaccharide sequence matching the part of the heparin molecule that binds to antithrombin. It is administered by subcutaneous injection.
Heparin: An anticoagulant that exerts its activity by binding to antithrombin and greatly increasing its activity. The principal coagulation factors inhibited by heparin are Factors IIa and Xa. It is administered by intravenous or subcutaneous injection.
Parenteral: Not through the alimentary canal but rather by injection through another route.
Angiotensin-converting enzyme: Hydrolase enzyme that cleaves angiotensin I (biologically inactive) to form active angiotensin II. The inhibition of ACE is used for the treatment of high blood pressure, heart failure, diabetic nephropathy, and to delay type 2 diabetes mellitus.
Vitamin K: An essential cofactor in the carboxylation of glutamic residues on the procoagulant forms of Factors II, VII, IX, and X. This ultimately leads to increased formation of thrombin and fibrin.
ST-segment elevation myocardial infarction: Acute ischaemia of heart tissue sufficient to cause tissue damage where there is ST-segment elevation on electrocardiographic (ECG) recordings.
Enoxaparin: A low-molecular-weight heparin currently regarded as the standard of care for VTE prevention in orthopaedic surgery. Enoxaparin is administered by subcutaneous injection and is associated with a low risk of heparin-induced thrombocytopaenia.
Factor Xa: The activated form of Factor X. It catalyses the conversion of prothrombin to thrombin in conjunction with other cofactors.
Antithrombin: Antithrombin, also known as antithrombin III, is the most important member of a larger family of antithrombins. It is a small protein molecule (a glycoprotein) produced in the liver that binds to a specific pentasaccharide sequence on heparin. This binding to heparin leads to an anticoagulant effect through two different mechanisms: It causes a conformational change in antithrombin that allows antithrombin to bind to and thereby inhibit Factor Xa, which leads to a subsequent decrease in thrombin levels It causes a direct increase of thrombin inhibition as a result of antithrombin binding to the heparin pentasaccharide sequence and thrombin binding to an adjacent segment of heparin at the same time.
International Normalised Ratio: A system for standardising the reports of blood clotting tests and used to monitor the effects of warfarin. INR values should remain within 2.0–3.0 to ensure optimal safety and efficacy in patients with atrial fibrillation.
Coronary artery disease: Coronary artery disease (CAD) is the end result of the accumulation of plaques within the walls of the arteries that supply the muscle of the heart with oxygen and nutrients. The process by which the coronary arteries become narrowed or completely occluded is known as atherosclerosis.