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- Antiplatelet Drugs
- Anticoagulant Drugs
- Other Drugs
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Drugs for Acute Coronary Syndromes
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 drug therapy to treat ACS and underlying coronary artery disease.
Drugs used depend on the type of ACS and include
Aspirin, clopidogrel, or both (prasugrel or ticagrelor is an alternative to clopidogrel if fibrinolytic therapy has not been given)
Glycoprotein IIb/IIIa inhibitor considered for certain patients undergoing PCI and for some others at high risk (eg, with markedly elevated cardiac markers, thrombolysis in myocardial infarction (TIMI) risk score ≥ 4, persistent symptoms)
A heparin (unfractionated or low molecular weight heparin) or bivalirudin (particularly in ST-segment elevation myocardial infarction [STEMI] patients at high risk of bleeding)
IV nitroglycerin (unless low-risk, uncomplicated myocardial infarction)
Fibrinolytics for select patients with STEMI when timely PCI unavailable
ACE inhibitor (as early as possible)
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: Drugs for Coronary Artery Disease*).
Fibrinolytics should 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 morphine or nitroglycerin. Morphine 2 to 4 mg IV, repeated q 15 min as needed, is highly effective but can depress respiration, can reduce myocardial contractility, and is a potent venous vasodilator. Hypotension and bradycardia secondary to morphine can usually be overcome by prompt elevation of the lower extremities. Nitroglycerin is initially given sublingually, followed by continuous IV drip if needed.
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.
Drugs for Coronary Artery Disease*
Aspirin, clopidogrel, ticagrelor, ticlopidine, and glycoprotein (GP) IIb/IIIa inhibitors are examples. All patients are given aspirin 160 to 325 mg (not enteric-coated), if not contraindicated, at presentation and 81 mg once/day indefinitely thereafter. Chewing the first dose before swallowing quickens absorption. Aspirin reduces short- and long-term mortality risk.
If aspirin cannot be taken, clopidogrel 75 mg po once/day or ticlopidine 250 mg po bid may be used. Clopidogrel has largely replaced ticlopidine for routine use because neutropenia is a risk with ticlopidine and the WBC count must be monitored regularly.
Patients with unstable angina or NSTEMI in whom intervention is not possible or recommended are given both aspirin and clopidogrel for at least 1 mo. The optimal duration of double antiplatelet therapy for these patients is the subject of ongoing investigation, but evidence is accumulating that a longer duration (eg, 9 to 12 mo) may be beneficial. In general, the concern with dosage and duration of antiplatelet drugs is to balance the decreased risk of coronary thrombosis with the increased risk of bleeding.
If PCI is not being done, some clinicians give a GP IIb/IIIa inhibitor to all high-risk patients (eg, those with markedly elevated cardiac markers, a TIMI risk score ≥ 4, or persistent symptoms despite adequate drug therapy). The GP IIb/IIIa inhibitor is continued for 24 to 36 h, 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 drug should depend on other factors (eg, cost, availability, familiarity).
In patients undergoing PCI, a loading dose of clopidogrel (300 to 600 mg po once), prasugrel (60 mg po once), or ticagrelor (180 mg po once) improves outcomes, particularly when administered 24 h in advance. For urgent PCI, prasugrel and ticagrelor are more rapid in onset and may be preferred. However, delaying PCI for 24 h is not appropriate for many patients. Further, such a loading dose increases risk of perioperative bleeding in patients who require coronary artery bypass grafting (CABG) because their coronary anatomy proves unfavorable for PCI. Thus, many clinicians administer a loading dose of one of these drugs only in the catheterization laboratory once coronary anatomy and lesions are determined to be amenable to PCI.
For patients receiving a stent for revascularization, aspirin is continued indefinitely. Clopidogrel 75 mg po once/day, prasugrel 10 mg po once/day, or ticagrelor 90 mg po bid should be used for at least 1 mo in patients with a bare-metal stent. Patients with a drug-eluting stent have a prolonged risk of thrombosis and may benefit from 12 mo of clopidogrel (or prasugrel or ticagrelor) treatment, although the recommended duration is still unclear.
Either a low molecular weight heparin (LMWH), unfractionated heparin, or bivalirudin is given routinely to patients with ACS unless contraindicated (eg, by active bleeding or planned use of streptokinase or anistreplase). Choice of agent is somewhat involved.
Patients at high risk of systemic emboli also require long-term therapy with oral warfarin. Conversion to warfarin should begin 48 h after symptom resolution or PCI.
Unfractionated heparin is more complicated to use because it requires frequent (q 6 h) dosing adjustments to achieve an activated PTT (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 sec if the patient is treated with a GP IIb/IIIa inhibitor and 250 to 300 sec 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).
The LMWHs have better bioavailability, are given by simple weight-based dose 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, and its effects are not completely reversible with protamine.
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 < 75 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 h, and when patients are at high risk of bleeding complications (eg, history of GI bleeding within the last 6 mo) or have creatinine clearance < 30 mL/min. Ongoing studies should help clarify the choice between LMWH and unfractionated heparin.
For patients undergoing PCI, postprocedure 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 drugs. For patients not undergoing PCI, heparin is continued for 48 h (or longer if symptoms persist).
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 better 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 drugs). The factor Xa inhibitor, fondaparinux, reduces mortality and reinfarction in patients with NSTEMI who undergo PCI without increasing bleeding but may result in worse outcomes than unfractionated heparin in patients with STEMI. 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.
Bivalirudin is an acceptable anticoagulant for patients undergoing primary PCI who are at high risk of bleeding and is recommended for those with a known or suspected history of heparin-induced thrombocytopenia. For patients with unstable angina or NSTEMI, dose is an initial bolus of 0.1 mg/kg IV followed by a drip of 0.25 mg/kg/h. For patients with STEMI, initial dose is 0.75 mg/kg IV followed by 1.75 mg/kg/h.
These drugs 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/min.
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 h for patients with heart failure, large anterior myocardial infarction, persistent chest discomfort, or hypertension. BP can be reduced by 10 to 20 mm Hg but not to < 80 to 90 mm Hg systolic.
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.
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 Drugs Available in the US) 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 sec and reteplase as a double bolus 30 min apart. Administration time and drug errors are reduced compared with other fibrinolytics. Tenecteplase, like alteplase, has an intermediate risk of intracranial hemorrhage, has a higher rate of recanalization than other fibrinolytics, and is expensive. Reteplase has the highest risk of intracranial hemorrhage and a recanalization rate similar to that of tenecteplase, and it is expensive.
Streptokinase may induce allergic reactions, especially if it has been used previously, and must be given by infusion over 30 to 60 min; 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.
Alteplase is given in an accelerated or front-loaded dosage over 90 min. Alteplase with concomitant IV heparin improves patency, is nonallergenic, has a higher recanalization rate than other fibrinolytics, and is expensive.
IV Fibrinolytic Drugs Available in the US
ACE inhibitors reduce mortality risk in MI patients, 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 h after thrombolysis stabilization and, because of continued beneficial effect, may be prescribed long-term.
Angiotensin II receptor blockers may be an effective alternative for patients who cannot tolerate ACE inhibitors (eg, because of cough). Currently, they are not first-line treatment after MI. 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 ACS, 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 to therapy should receive a statin as early as possible following ACS. Low-density lipoprotein levels of 70 to 80 mg/dL (1.81 to 2.07 mmol/L) are the recommended ultimate target.
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