Antithrombotic agents

Prevention of stroke, heart attack, and numerous other thromboembolic diseases requires selective inhibition of the hemostasis process. Numerous products have been developed to inhibit platelet aggregation or block specific steps in the coagulation cascade (Fig 5-3), including several oral agents, which are frequently used in the outpatient setting (Table 5-1). Those drugs requiring intravenous or subcutaneous injection are predominantly used in an inpatient setting (Table 5-2).

Figure 5-3 Coagulation cascade. The various anticoagulant drugs interrupt the cascade at different points in the process.

(Reproduced with permission from Leung LLK. Direct oral anticoagulants and parenteral direct thrombin inhibitors: dosing and adverse effects. In: UpToDate, Mannucci PM, Tirnauer JS [eds]. Available at www.uptodate.com. Accessed August 15, 2018.)

Table 5-1 Direct Oral Antithrombotic Agents

Table 5-1 Intravenous and Subcutaneous Antithrombotic Agents

Treatment of stable angina pectoris

Medical management of angina pectoris is designed to deliver as much oxygen as possible to the potentially ischemic myocardium, to decrease the oxygen demand to a level at which symptoms are eliminated or reduced to a comfortable level, or both.

Therapeutic agents include the following:

• β-Adrenergic blockers. Also called β-blockers, these drugs represent the first line of treatment. They reduce heart rate and contractility (decreasing oxygen demand) and are demonstrated to prolong life in CHD patients. They should be avoided in patients with Prinzmetal angina.

• Slow calcium channel blockers. These agents, including diltiazem, verapamil, and amlodipine, are useful for long-term angina treatment. They should be used with caution in patients with left ventricular dysfunction.

• Nitrates and nitroglycerin. These agents increase oxygen delivery through coronary vasodilation. Systemic effects (eg, venous dilation, reduction in blood pressure) decrease oxygen demand. They should be used with caution in patients taking erectile dysfunction drugs.

• Aspirin with or without clopidogrel, prasugrel, or ticagrelor. These drugs can be used for anticoagulation. The regimen of aspirin plus 1 of these other drugs is called dual antiplatelet therapy (DAT).

• Statins. Statins are recommended for use in virtually all ACS patients, regardless of serum lipid levels, if not contraindicated.

Improving the oxygen-carrying capacity of the blood by treating anemia or coexisting pulmonary disease provides some additional benefit. Patients in whom medical therapy is unsuccessful may be candidates for revascularization procedures.

Revascularization Procedures for revascularization include percutaneous coronary intervention (PCI) with or without stenting or coronary artery bypass grafting (CABG). These approaches may improve coronary blood flow, control angina, and increase exercise tolerance. In high-risk patients, the risk of infarction is reduced, and long-term survival is enhanced. Revascularization is indicated in otherwise healthy patients with advanced left main coronary artery disease, left ventricular dysfunction with 3-vessel disease, or angina that is not adequately controlled with medical treatment. Either PCI or CABG is effective for relieving angina; however, CABG is superior to PCI in terms of survival for some patients who have significant areas of at-risk myocardium or substantial left ventricular dysfunction. Recently, some authors have questioned whether PCI is superior to maximal medical therapy in the treatment of stable angina.

PCI was developed as an alternative to surgical revascularization. One PCI technique, angioplasty, involves passing a balloon catheter into a stenosed vessel and inflating the balloon at the site of the narrowing to widen the lumen. Although 85%–90% of vessels can be opened with PCI, the rate of restenosis is approximately 25%–40% at 6 months. The insertion of a wire-mesh stent at the time of PCI improves patency and reduces the risk of restenosis by nearly 50%. Drug-eluting stents are superior to bare-metal stents in preventing restenosis but are also more likely to lead to late stent thrombosis. Stent thrombosis may result in MI or death, so patients receiving stents should be given aggressive anticoagulation at the time of placement. European and US guidelines for anticoagulant use during stent placement are similar. DAT (aspirin plus clopidogrel, prasugrel, or ticagrelor) should continue for at least 1 month after stenting for a bare-metal stent and 6–12 months for a drug-eluting stent. DAT should not be stopped during this period, and elective surgery should be postponed unless the patient is able to continue on DAT. Patients intolerant of aspirin may use clopidogrel alone.

When angioplasty is inappropriate or ineffective and medical therapy has failed to control symptoms in patients with severe multivessel disease, CABG may be considered. CABG may be indicated in patients with high-risk disease, including those with significant left main, proximal left anterior descending, or 3-vessel disease, especially if accompanied by left ventricular dysfunction. During CABG, a shunt is installed from the aorta to the diseased coronary artery to bypass the area of obstruction and increase blood flow. CABG has been shown to increase left ventricular function, improve quality of life, relieve angina, and, often, reduce the risk of infarction and cardiac death. Some patients now receive “off-pump bypass surgery,” in which the grafts are sewn onto the beating heart. This technique decreases the risk of adverse effects of cardiopulmonary bypass, which include memory, cognitive, and other neurologic deficits.

PCI and CABG have similar mortality rates; but patients undergoing PCI are more likely to require a second procedure, and CABG has better long-term survival outcomes than PCI in most studies.

Although revascularization may produce good outcomes, the underlying disease process requires ongoing management. The Bypass Angioplasty Revascularization Investigation demonstrated that even after PCI or CABG, arterial disease will continue to progress unless cardiac risk factors are reduced. Optimal medical management is also required.

• Al-Lamee R, Thompson D, Dehbi H-M, et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet. 2018;391(10115):31–40.

  Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease. J Am Coll Cardiol. 2014;64(18):1929–1949.

  Task Force members; Montalescot G, Sechtem U, Achenback S, et al. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J. 2013;34(38):2949–3003.

  Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Circulation. 2007;116(22):2634–2653.

Treatment of acute coronary syndromes

Patients with an ACS are admitted to a hospital or a chest pain observation unit for monitoring and treatment. They are initially treated aggressively with anti-ischemic pharmacotherapy. Once these initial measures are instituted, further management and triage of patients with an ACS are based on the presence or absence of ST-segment elevation. Patients with ST-segment elevation undergo reperfusion therapy with thrombolysis, CABG, or catheter-based interventions; patients with non–ST-segment elevation may be managed with medical treatment alone or a more aggressive interventional approach. The use of a risk calculator (eg, TIMI, GRACE, PURSUIT) may help identify high-risk patients and determine subsequent management; the TIMI and GRACE risk calculators are available at www.timi.org/index.php?page=calculators and www.mdcalc.com/grace-acs-risk-mortality-calculator, respectively.

Management of non–ST-segment elevation ACS During the initial evaluation, before biomarker results are available, unstable angina and NSTEMI may be indistinguishable and, if so, are treated the same way. In general, myocardial oxygen demands are managed with medications and supplemental oxygen. β-Blocker therapy, which reduces myocardial oxygen demands and improves survival, should be considered for all patients with evolving MI in the absence of contraindications. Medical therapy for NSTEMI includes

• β-blockers in nearly all patients (avoid in cases of cocaine-associated MI or if patient is already hemodynamically compromised)

• nitrates and/or nitroglycerin

• DAT

• anticoagulant therapy (heparins, factor Xa, and direct thrombin inhibitors)

• statins, regardless of serum lipid levels, if not contraindicated

• possible use of angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril, lisinopril, ramipril)

CHF and pulmonary edema should be treated if present. If β-blockers cannot be used, the clinician may consider verapamil or diltiazem. ACE inhibitors decrease the risk of death if given within 24 hours of MI, but they should be avoided in patients with hypotension or renal insufficiency.

Anticoagulant therapy is beneficial in ACS. It involves a variety of agents, including unfractionated heparin; low-molecular-weight heparins; direct thrombin inhibitors; and factor Xa inhibitors (see Table 5-1). Choice of the optimal regimen depends on what other medications are being used and whether the treatment strategy is conservative or interventional. Glycoprotein IIb/IIIa inhibitors are of limited use in patients with NSTEMI, although they may be tried if other agents have failed to provide sufficient anticoagulation.

Once unstable angina and NSTEMI have been managed as described, patients may be treated with either a conservative noninvasive approach or an early invasive (angiographic) strategy, depending on their level of risk for adverse outcomes. Controlled trials have shown the superiority of an invasive approach in managing ACS patients, particularly those who have refractory angina, hemodynamic instability, or elevated risk as measured by bedside risk stratification tools (eg, TIMI, GRACE). The decision to proceed from diagnostic angiography to revascularization (PCI or CABG) is influenced not only by the coronary anatomy but also by several other factors, including anticipated life expectancy, ventricular function, comorbidity, functional capacity, severity of symptoms, and quantity of viable myocardium at risk. Fibrinolysis should not be performed on patients with unstable angina or NSTEMI.

Management of ST-segment elevation ACS Current therapy for evolving Q-wave MI involves rapid and effective reperfusion because necrosis is a time-dependent process. Optimal myocardial salvage requires nearly complete reperfusion as soon as possible: reperfusion within 1 hour of symptom onset yields maximal benefit. The benefit of reperfusion therapy 12 hours after symptom onset has not been established.

Methods of reperfusion include thrombolysis and catheter-based PCIs (balloon angioplasty with or without stent placement). Numerous clinical trials have shown the superiority of early PCI over thrombolysis, particularly if performed in the first 90 minutes following medical contact. Hospitals without PCI capability should transfer the patient to a facility that can perform PCI if the procedure can be done within 120 minutes after first medical contact. Otherwise, thrombolytic therapy should be started within 30 minutes of first medical contact. PCI following full-dose thrombolytics carries significant risks but may be done in high-risk patients or if thrombolytic therapy has failed (“rescue PCI”). Totally occluded arteries generally do not benefit from PCI.

CABG may be considered if PCI or fibrinolysis fails, but the potential benefits must be weighed against an increased mortality risk in the first 3–7 days after STEMI.

Initial medical management before and after reperfusion therapy should include aspirin, clopidogrel, morphine (for pain), nitrates, statins, and β-blockers if there are no contraindications. Except for aspirin, nonsteroidal agents should not be used acutely or during hospitalization, because they increase the risk of CHF and death. Other adjuncts to therapy may include low-molecular-weight heparins and glycoprotein IIb/IIIa inhibitors, particularly if PCI is anticipated.

Thrombolysis Patients with a STEMI who are treated with thrombolytics in the first 3 hours show a 50% reduction in mortality; those treated at 12 hours show a 10% reduction. Thrombolytic agents lyse coronary thrombi and restore coronary blood flow in most patients. Tissue plasminogen activators (tPAs) are the most commonly used thrombolytics; they are more effective than streptokinase in opening arteries and reducing mortality. When any tPA is used, aspirin and intravenous unfractionated heparin should be administered concurrently.

Major bleeding complications occur in up to 5% of patients undergoing thrombolytic therapy. Contraindications to thrombolysis include known sites of potential bleeding, a history of cerebrovascular accident, recent surgery, and prolonged cardiopulmonary resuscitation efforts. Thrombolysis should not be used in the treatment of NSTEMI due to decreased benefits and, possibly, increased hemorrhagic risks.

• Ibanez B, James S, Agewall S, et al; ESC Scientific Document Group. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–177.

  O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. Circulation. 2013;127(4):e362–e425.

Excerpted from BCSC 2020-2021 series: Section 1 - Update on General Medicine. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.