Лікарські препарати для лікування гострих коронарних синдромів

ЗаRanya N. Sweis, MD, MS, Northwestern University Feinberg School of Medicine;
Arif Jivan, MD, PhD, Northwestern University Feinberg School of Medicine
Переглянуто/перевірено лют. 2024

Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications. An ACS is a medical emergency; outcome is greatly influenced by rapid diagnosis and treatment. Treatment occurs simultaneously with diagnosis. Treatment includes revascularization (with percutaneous coronary intervention, coronary artery bypass grafting, or fibrinolytic therapy) and pharmacologic therapy to treat ACS and underlying coronary artery disease.

Medications used depend on the type of ACS and include

  • Aspirin, clopidogrel, or both (prasugrel or ticagrelor are alternatives to clopidogrel if fibrinolytic therapy has not been given)

  • Beta-blocker

  • Glycoprotein IIb/IIIa inhibitor for certain patients undergoing percutaneous coronary intervention (PCI) and high-risk lesions (eg, high thrombus burden, no reflow)

  • A heparin (unfractionated or low molecular weight heparin) or bivalirudin (particularly in patients with ST-segment elevation myocardial infarction [STEMI] who are at high risk of bleeding)

  • IV nitroglycerin (unless low-risk, uncomplicated myocardial infarction)

  • Fibrinolytics for select patients with STEMI when timely PCI unavailable

  • Angiotensin-converting enzyme (ACE) inhibitor (as early as possible)

  • Statins

Antiplatelet and antithrombotic drugs, which stop clots from forming, are used routinely. Anti-ischemic drugs (eg, beta-blockers, IV nitroglycerin) are frequently added, particularly when chest pain or hypertension is present (see table Medications for Coronary Artery Disease).

Fibrinolyticsshould be used if not contraindicated for STEMI if primary PCI is not immediately available but worsen outcome for unstable angina and non-ST elevation myocardial infarction (NSTEMI).

Chest pain can be treated with nitroglycerin or sometimes morphine. Nitroglycerin is preferable to morphine, which should be used judiciously (eg, if a patient has a contraindication to nitroglycerin or is in pain despite nitroglycerin therapy). Nitroglycerin is initially given sublingually, followed by continuous IV drip if needed. Morphine 2 to 4 mg IV, repeated every 15 minutes as needed, is highly effective but can depress respiration, can reduce myocardial contractility, and is a potent venous vasodilator. Evidence also suggests that morphine interferes with some P2Y12 receptor inhibitors. A large retrospective trial showed that morphine may increase mortality in patients with acute myocardial infarction (1, 2). Hypotension and bradycardia secondary to morphine can usually be overcome by prompt elevation of the lower extremities.

Blood pressure (BP) is normal or slightly elevated in most patients on arrival at the emergency department; BP gradually falls over the next several hours. Continued hypertension requires treatment with antihypertensives, preferably IV nitroglycerin, to lower BP and reduce cardiac workload. Severe hypotension or other signs of shock are ominous and must be treated aggressively with IV fluids and sometimes vasopressors.

Таблиця
Таблиця

Довідкові матеріали

  1. 1. Meine TJ, Roe MT, Chen AY, et al: Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. Am Heart J 149(6):1043-1049, 2005. doi 10.1016/j.ahj.2005.02.010

  2. 2. Kubica J, Adamski P, Ostrowska M, et al: Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J 37(3):245–252, 2016. doi: 10.1093/eurheartj/ehv547

Антиагреганти

Aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, and glycoprotein (GP) IIb/IIIa inhibitors are examples of antiplatelet agents. All patients are given aspirin 160 to 325 mg (not enteric-coated), if not contraindicated (eg, life-threatening active bleeding), at presentation and 81 mg once a day indefinitely thereafter. Chewing the first dose before swallowing quickens absorption. Aspirin reduces short- and long-term mortality risk (1).

If aspirin cannot be taken, clopidogrel 75 mg orally once a day or ticlopidine 250 mg orally twice a day may be used. Clopidogrel has largely replaced ticlopidine for routine use because neutropenia is a risk with ticlopidine, and the white blood cell count must be monitored regularly if patients are taking ticlopidine.

Пацієнти, яким не проводили реваскуляризацію

Patients with acute coronary syndrome (ACS) in whom intervention is not possible or recommended are given both aspirin and clopidogrel (or ticagrelor) for at least 12 months. In general, the concern with dosage and duration of antiplatelet agents is to balance the decreased risk of coronary thrombosis with the increased risk of bleeding.

Пацієнти, яким проводили реваскуляризацію

In patients undergoing PCI, a loading dose of clopidogrel (300 to 600 mg orally once), prasugrel (60 mg orally once), or ticagrelor (180 mg orally once) improves outcomes (1).

Some clinicians give a GP IIb/IIIa inhibitor during PCI to all high-risk patients (eg, those with markedly elevated cardiac biomarkers, a TIMI risk score 4, or persistent symptoms despite adequate pharmacologic therapy) with large thrombus burden. The GP IIb/IIIa inhibitor is continued for 6 to 24 hours, and angiography is done before the infusion period is over. GP IIb/IIIa inhibitors are not recommended for patients receiving fibrinolytics. Abciximab, tirofiban, and eptifibatide appear to have equivalent efficacy, and the choice of agent should depend on other factors (eg, cost, availability, familiarity).

For patients receiving a stent for revascularization, aspirin is continued indefinitely. Clopidogrel 75 mg orally once a day, prasugrel 10 mg orally once a day, or ticagrelor 90 mg orally twice a day should be used for at least 1 month in patients with a bare-metal stent. Patients with a drug-eluting stent after ACS have a prolonged risk of thrombosis and benefit from up to 12 months of clopidogrel (or prasugrel or ticagrelor) treatment.

Довідковий матеріал щодо антиагрегантів

  1. 1. Lawton JS, Tamis-Holland JE, Bangalore S, et al: 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the ACC/AHA Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 79(2):e21–e129, 2022. doi: 10.1016/j.jacc.2021.09.006

Антикоагулянти

Either a low molecular weight heparin (LMWH), unfractionated heparin, or bivalirudin is given routinely to patients with acute coronary syndrome unless contraindicated (eg, by active bleeding or planned use of streptokinase or anistreplase). Choice of agent depends on whether revascularization is anticipated, as well as other factors such as patient characteristics, cost, and local practice.

Patients at high risk of systemic emboli (eg, atrial fibrillation with CHA2DS2VASc score ≥ 2) also require long-term therapy with an oral anticoagulant (eg, warfarin, dabigatran, apixaban, rivaroxaban). Conversion to oral anticoagulants should begin 48 hours after symptom resolution or PCI.

Нефракціонований гепарин

Unfractionated heparin is more complicated to use because it requires frequent (every 6 hours) dosing adjustments to achieve an activated partial thromboplastin time (aPTT) 1.5 to 2 times the control value. In patients undergoing angiography, further dosing adjustment is done to achieve an activated clotting time (ACT) of 200 to 250 seconds if the patient is treated with a GP IIb/IIIa inhibitor and 250 to 300 seconds if a GP IIb/IIIa inhibitor is not being given. However, if bleeding develops after catheterization, the effects of unfractionated heparin are shorter and can be reversed (by promptly stopping the heparin infusion and giving protamine sulfate).

Низькомолекулярний гепарин

The LMWHs have better bioavailability, are given by simple weight-based dosing without monitoring aPTT and dose titration, and have lower risk of heparin-induced thrombocytopenia. They also may produce an incremental benefit in outcomes relative to unfractionated heparin in patients with ACS. Of the LMWHs, enoxaparin appears to be superior to dalteparin or nadroparin. However, enoxaparin may pose a higher bleeding risk in patients with STEMI who are > 75 years, and its effects are not completely reversible with protamine.

Вибір гепарин

Thus, taking all into account, many published guidelines recommend LMWH (eg, enoxaparin) over unfractionated heparin in patients with unstable angina or NSTEMI and in patients < age 75 years with STEMI who are not undergoing PCI.

By contrast, unfractionated heparin is recommended when emergency PCI is done (eg, patients with acute STEMI who proceed to the catheterization laboratory), when CABG is indicated within the next 24 hours, and when patients are at high risk of bleeding complications (eg, history of gastrointestinal bleeding within the last 6 months) or have creatinine clearance < 30 mL/minute (0.5 mL/second).

For patients undergoing PCI, post-procedure heparin is no longer recommended unless patients are at high risk of thromboembolic events (eg, patients with large anterior MI, known LV thrombus, atrial fibrillation), because postprocedure ischemic events have decreased with the use of stents and antiplatelet agents. For patients not undergoing PCI, heparin is continued for 48 hours (or longer if symptoms persist).

гепарини альтернативних варіантів

The difficulties with the heparins (including bleeding complications, the possibility of heparin-induced thrombocytopenia, and, with unfractionated heparin, the need for dosing adjustments) have led to the search for alternative anticoagulants.

The direct thrombin inhibitors, bivalirudin and argatroban, may have a lower incidence of serious bleeding and improved outcomes, particularly in patients with renal insufficiency (hirudin, another direct thrombin inhibitor, appears to cause more bleeding than the other agents). Bivalirudin is an acceptable alternative to unfractionated heparin for patients undergoing PCI who are at high risk of bleeding. The factor Xa inhibitor fondaparinux reduces mortality and reinfarction in patients with NSTEMI who undergo PCI without increasing bleeding but has no clear benefit compared with unfractionated heparin in patients with STEMI (1). Although routine use of these alternative anticoagulants is thus not currently recommended, they should be used in place of unfractionated heparin or LMWH in patients with a known or suspected history of heparin-induced thrombocytopenia.

For patients who require anticoagulation for another reason (eg, atrial fibrillation), direct-acting oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) are preferred long term over warfarin, unless there is a contraindication to them. For most patients requiring anticoagulation, triple therapy with oral anticoagulation, a P2Y12 inhibitor, and aspirin is continued up to 1 week to 1 month after intervention, and then patients are continued on oral anticoagulation and a P2Y12 inhibitor for 6 months to 1 year. Calcium channel blockers and nitrates may also be given to reduce risk of coronary spasm.

Довідковий матеріал щодо антикоагулянтів

  1. 1. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006;295(13):1519-1530. doi:10.1001/jama.295.13.joc60038

Бета-блокатори

Beta-blockers are recommended unless contraindicated (eg, by bradycardia, heart block, hypotension, or asthma), especially for high-risk patients. Beta-blockers reduce heart rate, arterial pressure, and contractility, thereby reducing cardiac workload and oxygen demand. Infarct size largely determines cardiac performance after recovery. Oral beta-blockers given within the first few hours improve prognosis by reducing infarct size, recurrence rate, incidence of ventricular fibrillation, and mortality risk (1).

Heart rate and BP must be carefully monitored during treatment with beta-blockers. Dosage is reduced if bradycardia or hypotension develops. Excessive adverse effects may be reversed by infusion of the beta-adrenergic agonist isoproterenol 1 to 5 mcg/minute.

Довідкові матеріали щодо бета-блокаторів

  1. 1. Chen ZM, Pan HC, Chen YP, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo controlled trial. Lancet 366:1622–1632, 2005.

Нітрати

 A short-acting nitrate, nitroglycerin, is used to reduce cardiac workload in selected patients. Nitroglycerin dilates veins, arteries, and arterioles, reducing left ventricular preload and afterload. As a result, myocardial oxygen demand is reduced, lessening ischemia.

IV nitroglycerin is recommended during the first 24 to 48 hours for patients with heart failure, large anterior myocardial infarction, persistent chest discomfort, or hypertension. BP should not be reduced to < 110 to 120 mm Hg systolic; patients who remain symptomatic at that BP should have emergency PCI rather than further BP reduction.

Longer use may benefit patients with recurrent chest pain or persistent pulmonary congestion. In high-risk patients, nitroglycerin given in the first few hours reduces infarct size and short-term and possibly long-term mortality risk. Nitroglycerin is not routinely given to low-risk patients with uncomplicated myocardial infarction.

Фібринолітики

Tenecteplase (TNK), alteplase (rTPA), reteplase (rPA), streptokinase, and anistreplase (anisoylated plasminogen activator complex—APSAC), all given IV, are plasminogen activators. They convert single-chain plasminogen to double-chain plasminogen, which has fibrinolytic activity. They have different characteristics and dosing regimens (see table IV Fibrinolytic Therapies) and are appropriate only for selected patients with STEMI).

Tenecteplase and reteplase are recommended most often because of their simplicity of administration; tenecteplase is given as a single bolus over 5 seconds and reteplase as a double bolus 30 minutes apart. Administration time and medication errors are reduced compared with other fibrinolytics. Tenecteplase, like alteplase, has an intermediate risk of intracranial hemorrhage and has a higher rate of recanalization than other fibrinolytics. Reteplase has the highest risk of intracranial hemorrhage and a recanalization rate similar to that of tenecteplase, and it is expensive.

Streptokinase (not available in the United States) may induce allergic reactions, especially if it has been used previously, and must be given by infusion over 30 to 60 minutes; however, it has a low incidence of intracerebral hemorrhage and is relatively inexpensive. Anistreplase, related to streptokinase, is similarly allergenic and slightly more expensive but can be given as a single bolus. Neither drug requires concomitant heparin use. For both, recanalization rate is lower than that with other plasminogen activators. Because of the possibility of allergic reactions, patients who previously received streptokinase or anistreplase are not given that drug again.

Alteplase is given in an accelerated or front-loaded dosage over 90 minutes. Alteplase with concomitant IV heparin improves patency, is nonallergenic, and has a higher recanalization rate than other fibrinolytics.

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Таблиця

Протипоказання до фібринолітичної терапії

There are many absolute and relative contraindications to fibrinolytic therapy. In general, the presence of active bleeding or a condition where bleeding would be life-threatening is an absolute contraindication. The contraindications to fibrinolytic therapy are listed in the table Contraindications to Fibrinolytic Therapy.

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Таблиця

Other Medications for Acute Coronary Syndromes

Angiotensin-converting enzyme (ACE) inhibitors reduce mortality risk in patients with myocardial infarction, especially in those with anterior infarction, heart failure, or tachycardia. The greatest benefit occurs in the highest-risk patients early during convalescence. ACE inhibitors are given > 24 hours after thrombolysis stabilization and, because of continued beneficial effect, may be prescribed long-term.

Angiotensin II receptor blockers (ARBs) may be an effective alternative for patients who cannot tolerate ACE inhibitors (eg, because of cough). They are not first-line treatment after myocardial infarction. Contraindications include hypotension, kidney failure, bilateral renal artery stenosis, and known allergy.

Statins (HMG-CoA reductase inhibitors) have long been used for prevention of coronary artery disease and acute coronary syndromes, but there is now increasing evidence that they also have short-term benefits, such as stabilizing plaque, reversing endothelial dysfunction, decreasing thrombogenicity, and reducing inflammation. Thus, all patients without contraindications (eg, statin-induced myopathy, liver dysfunction) to therapy should receive a statin at the maximally tolerated dose as early as possible following ACS regardless of their serum lipid levels (1).

PCSK-9 inhibitors (evolocumab, alirocumab) are used for patients not at target low-density lipoprotein cholesterol levels. They are used alone or in combination with other lipid-lowering therapies (eg, statins, ezetimibe) for the treatment of adults with primary hyperlipidemia (including familial hypercholesterolemia).

In patients who have had an MI, icosapent ethyl is also used to reduce lipid levels (2).

Довідкові матеріали щодо інших лікарських препаратів

  1. 1. Wang WT, Hellkamp A, Doll JA, et al. Lipid Testing and Statin Dosing After Acute Myocardial Infarction. J Am Heart Assoc 2018;7(3):e006460. Published 2018 Jan 25. doi:10.1161/JAHA.117.006460

  2. 2. Gaba P, Bhatt DL, Steg PG, et al. Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction. J Am Coll Cardiol 2022;79(17):1660-1671. doi:10.1016/j.jacc.2022.02.035