All patients with definite or suspected acute MI should receive aspirin at a dose of 162 mg or 325 mg at once regardless of whether fibrinolytic therapy is being considered or the patient has been taking aspirin. Chewable aspirin provides more rapid blood levels. Patients with a definite aspirin allergy should be treated with a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor).
P2Y12 inhibitors, in combination with aspirin, have been shown to provide important benefits in patients with acute STEMI. Thus, guidelines call for a P2Y12 inhibitor to be added to aspirin for all patients with STEMI, regardless of whether reperfusion is given, and continued for at least 14 days, and generally for 1 year. The preferred P2Y12 inhibitors are prasugrel (60 mg orally on day 1, then 10 mg daily) or ticagrelor (180 mg orally on day 1, then 90 mg twice daily). Both of these medications demonstrated superior outcomes to clopidogrel in clinical studies of primary PCI. Clopidogrel should be administered as a loading dose of 300–600 mg orally for faster onset of action than the 75 mg maintenance dose. With fibrinolytic therapy, ticagrelor appears to be a reasonable alternative to clopidogrel, at least after an initial clopidogrel dose. Prasugrel is contraindicated in patients with history of stroke or who are older than 75 years. In the TRITON study, prasugrel was shown to be of greater benefit than clopidogrel in reducing thrombotic cevents in the subgroup of patients with STEMI, including a 50% reduction in stent thrombosis. In the PLATO trial, ticagrelor was shown to be of greater benefit than clopidogrel in reducing cardiovascular death, MI, and stroke as well as in reducing stent thrombosis.
Compared with standard dose clopidogrel, “double dose” clopidogrel (600 mg oral loading dose followed by 150 mg orally daily) for 1 week reduces stent thrombosis at the cost of a modest increase in bleeding. In the CLARITY trial, a loading dose of 300 mg ofclopidogrel given with fibrinolytic therapy, followed by 75 mg a day, led to substantial improvement in coronary patency on catheterization 3.5 days following thrombolysis. Moreover, there was no increase in serious bleeding in this population of patients up to 75 years of age. The COMMIT/CCS-2 trial randomized over 45,000 patients in China with acute MI to clopidogrel 75 mg a day or placebo and found a small but statistically significant reduction in early death, myocardial reinfarction, and stroke, with no excess in major bleeding.
Patients with STEMI who seek medical attention within 12 hours of the onset of symptoms should be treated with reperfusion therapy, either primary PCI or fibrinolytic therapy. Patients without ST-segment elevation (previously labeled “non-Q wave” infarctions) do not benefit, and may derive harm, from thrombolysis.
1. Primary percutaneous coronary intervention
Immediate coronary angiography and primary PCI (including stenting) of the infarct-related artery have been shown to be superior to thrombolysis when done by experienced operators in high-volume centers with rapid time from first medical contact to intervention (“door-to-balloon”). US and European guidelines call for first medical contact or door-to-balloon times of 90 minutes or less. Several trials have shown that if efficient transfer systems are in place, transfer of patients with acute MI from hospitals without primary PCI capability to hospitals with primary PCI capability with first door-to-device times of 120 minutes or less can improve outcome compared with fibrinolytic therapy at the presenting hospital, although this requires sophisticated systems to ensure rapid identification, transfer, and expertise in PCI. Because PCI also carries a lower risk of hemorrhagic complications, including intracranial hemorrhage, it may be the preferred strategy in many older patients and others with contraindications to fibrinolytic therapy (see Table 10–10 for factors to consider in choosing fibrinolytic therapy or primary PCI).
Table 10–10.Fibrinolytic therapy for acute myocardial infarction. ||Download (.pdf) Table 10–10. Fibrinolytic therapy for acute myocardial infarction.
| ||Alteplase; Tissue Plasminogen Activator (t-PA) ||Reteplase ||Tenecteplase (TNK-t-PA) ||Streptokinase |
|Source ||Recombinant DNA ||Recombinant DNA ||Recombinant DNA ||Group C Streptococcus |
|Half-life ||5 minutes ||15 minutes ||20 minutes ||20 minutes |
|Usual dose ||100 mg ||20 units ||40 mg ||1.5 million units |
|Administration ||Initial bolus of 15 mg, followed by 50 mg infused over the next 30 minutes and 35 mg over the following 60 minutes ||10 units as a bolus over 2 minutes, repeated after 30 minutes ||Single weight-adjusted bolus, 0.5 mg/kg ||750,000 units over 20 minutes followed by 750,000 units over 40 minutes |
|Anticoagulation after infusion ||Aspirin, 325 mg daily; heparin, 5000 units as bolus, followed by 1000 units per hour infusion, subsequently adjusted to maintain PTT 1.5–2 times control ||Aspirin, 325 mg; heparin as with t-PA ||Aspirin, 325 mg daily ||Aspirin, 325 mg daily; there is no evidence that adjunctive heparin improves outcome following streptokinase |
|Clot selectivity ||High ||High ||High ||Low |
|Fibrinogenolysis ||+ ||+ ||+ ||+++ |
|Bleeding ||+ ||+ ||+ ||+ |
|Hypotension ||+ ||+ ||+ ||+++ |
|Allergic reactions ||+ ||+ ||+ ||++ |
|Reocclusion ||10–30% ||— ||5–20% ||5–20% |
|Approximate cost1 ||$10,560.43 ||$5964.98 ||$7462.63 ||Not available in the United States |
PCI with stenting is standard for patients with acute MI. Although randomized trials have shown a benefit with regard to fewer repeat interventions for restenosis with the use of drug-eluting stents in STEMI patients, and current generation drug-eluting stents have similar or lower rates of stent thrombosis than bare metal stents, bare metal stents may still be used for selected patients without the ability to obtain and comply with P2Y12 inhibitor therapy. In the subgroup of patients with cardiogenic shock, early catheterization and percutaneous or surgical revascularization are the preferred management and have been shown to reduce mortality.
Glycoprotein IIb/IIIa inhibitors, and specifically abciximab, have been shown to reduce major thrombotic events, and possibly mortality, when added to heparin for patients undergoing primary PCI. The HORIZONS trial showed that compared with unfractionated heparin plus abciximab, bivalirudin (with provisional use of “bail-out” IIb/IIIa inhibitors) results in similar rates of thrombotic events and 40% less bleeding. This appeared to be accompanied by lower mortality at 30 days and 1 year, providing support for the efficacy of bivalirudin in this setting. There was a signal of early (less than 24 hours) increased stent thrombosis with bivalirudin in HORIZONS that was also seen in the EUROMAX trial despite prolongation of the bivalirudin infusion. The Heat PPCI trial showed increased stent thrombosis and more adverse cardiovascular events with bivalirudin compared to unfractionated heparin.
“Facilitated” PCI, whereby a combination of medications (full- or reduced-dose fibrinolytic agents, with or without glycoprotein IIb/IIIa inhibitors) is given followed by immediate PCI, is not recommended. Patients should be treated either with primary PCI or with fibrinolytic agents (and immediate rescue PCI for reperfusion failure), if it can be done promptly as outlined in the ACC/AHA and European guidelines. Timely access to most appropriate reperfusion, including primary PCI, can be expanded with development of regional systems of care, including emergency medical systems and networks of hospitals. Patients treated with fibrinolytic therapy appear to have improved outcomes if transferred for routine coronary angiography and PCI within 24 hours. The AHA has a program called “Mission: Lifeline” to support the development of regional systems of care (http://www.heart.org/missionlifeline).
B. ANTIPLATELET THERAPY AFTER DRUG-ELUTING OR BARE METAL STENTS
In patients with an acute coronary syndrome, dual antiplatelet therapy is indicated for 1 year in all patients (including those with medical therapy and those patients undergoing revascularization irrespective of stent type). For patients undergoing elective or stable PCI, the duration of dual antiplatelet therapy is recommended for at least 1 month for patients receiving bare metal stents. For patients receiving drug-eluting stents for acute coronary syndromes, dual antiplatelet therapy is recommended for at least 1 year by the ACC/AHA and European guidelines. These recommendations are based both on the durations of therapies during the studies evaluating the stents, and the pathophysiologic understanding of the timing of endothelialization following bare metal versus drug-eluting stent implantation. The DAPT (dual antiplatelet therapy) study showed fewer death, MI, and stroke events with longer (up to 30 months) dual antiplatelet therapy for patients who had received drug-eluting stents, but it also showed more bleeding and a tendency for higher mortality. Treatment with clopidogrel for longer than 1 year after drug-eluting stents, therefore, should be individualized based on thrombotic and bleeding risks.
Fibrinolytic therapy reduces mortality and limits infarct size in patients with STEMI (defined as 0.1 mV or more in two inferior or lateral leads or two contiguous precordial leads), or with left bundle branch block (not known to be old). The greatest benefit occurs if treatment is initiated within the first 3 hours after the onset of presentation, when up to a 50% reduction in mortality rate can be achieved. The magnitude of benefit declines rapidly thereafter, but a 10% relative mortality reduction can be achieved up to 12 hours after the onset of chest pain. The survival benefit is greatest in patients with large—usually anterior—infarctions. Primary PCI (including stenting) of the infarct-related artery, however, is superior to thrombolysis when done by experienced operators with rapid time from first medical contact to intervention (“door-to-balloon”).
Major bleeding complications occur in 0.5–5% of patients, the most serious of which is intracranial hemorrhage. The major risk factors for intracranial bleeding are age 75 years or older, hypertension at presentation (especially over 180/110 mm Hg), low body weight (less than 70 kg), and the use of fibrin-specific fibrinolytic agents (alteplase, reteplase, tenecteplase). Although patients over age 75 years have a much higher mortality rate with acute MI and therefore may derive greater benefit, the risk of severe bleeding is also higher, particularly among patients with risk factors for intracranial hemorrhage, such as severe hypertension or recent stroke. Patients presenting more than 12 hours after the onset of chest pain may also derive a small benefit, particularly if pain and ST-segment elevation persist, but rarely does this benefit outweigh the attendant risk.
Absolute contraindications to fibrinolytic therapy include previous hemorrhagic stroke, other strokes or cerebrovascular events within 1 year, known intracranial neoplasm, recent head trauma (including minor trauma), active internal bleeding (excluding menstruation), or suspected aortic dissection. Relative contraindications are BP greater than 180/110 mm Hg at presentation, other intracerebral pathology not listed above as a contraindication, known bleeding diathesis, trauma within 2–4 weeks, major surgery within 3 weeks, prolonged (more than 10 minutes) or traumatic cardiopulmonary resuscitation, recent (within 2–4 weeks) internal bleeding, noncompressible vascular punctures, active diabetic retinopathy, pregnancy, active peptic ulcer disease, a history of severe hypertension, current use of anticoagulants (INR greater than 2.0–3.0), and (for streptokinase) prior allergic reaction or exposure to streptokinase or anistreplase within 2 years.
The following fibrinolytic agents are available for acute MI and are characterized in Table 10–10.
Alteplase (recombinant tissue plasminogen activator; t-PA) results in about a 50% reduction in circulating fibrinogen. In the first GUSTO trial, which compared a 90-minute dosing of t-PA (with unfractionated heparin) with streptokinase, the 30-day mortality rate with t-PA was one absolute percentage point lower (one additional life saved per 100 patients treated), though there was also a small increase in the rate of intracranial hemorrhage. An angiographic substudy confirmed a higher 90-minute patency rate and a higher rate of normal (TIMI grade 3) flow in patients.
Reteplase is a recombinant deletion mutant of t-PA that is slightly less fibrin specific. In comparative trials, it appeared to have efficacy similar to that of alteplase, but it has a longer duration of action and can be administered as two boluses 30 minutes apart.
Tenecteplase (TNK-t-PA) is a genetically engineered substitution mutant of native t-PA that has reduced plasma clearance, increased fibrin sensitivity, and increased resistance to plasminogen activator inhibitor-1. It can be given as a single weight-adjusted bolus. In the ASSENT 2 trial, this agent was equivalent to t-PA with regard to efficacy and resulted in significantly less noncerebral bleeding. In the STREAM trial, as part of pharmacoinvasive therapy with use of clopidogrel, aspirin, and enoxaparin and routine catheterization within 24 hours, the tenecteplase dose was reduced in half for patients age 75 years or older with an apparent reduction in intracranial hemorrhage.
Streptokinase, commonly used outside of the United States, is somewhat less effective at opening occluded arteries and less effective at reducing mortality. It is non–fibrin-specific, causes depletion of circulating fibrinogen, and has a tendency to induce hypotension, particularly if infused rapidly. This can be managed by slowing or interrupting the infusion and administering fluids. There is controversy as to whether adjunctive heparin is beneficial in patients given streptokinase, unlike its administration with the more clot-specific agents. Allergic reactions, including anaphylaxis, occur in 1–2% of patients, and this agent should generally not be administered to patients with prior exposure.
(1) Selection of a fibrinolytic agent
In the United States, most patients are treated with alteplase, reteplase, or tenecteplase. The differences in efficacy between them are small compared with the potential benefit of treating a greater proportion of appropriate candidates in a more prompt manner. The principal objective should be to administer a thrombolytic agent within 30 minutes of presentation—or even during transport. The ability to administer tenecteplase as a single bolus is an attractive feature that may facilitate earlier treatment. The combination of a reduced-dose thrombolytic given with a platelet glycoprotein IIb/IIIa inhibitor does not reduce mortality but does cause a modest increase in bleeding complications.
(2) Postfibrinolytic management
After completion of the fibrinolytic infusion, aspirin (81–325 mg/day) and anticoagulation should be continued until revascularization or for the duration of the hospital stay (or up to 8 days). Anticoagulation with LMWH (enoxaparin or fondaparinux) is preferable to unfractionated heparin.
(A) LOW-MOLECULAR-WEIGHT HEPARIN
In the EXTRACT trial, enoxaparin significantly reduced death and MI at day 30 (compared with unfractionated heparin), at the expense of a modest increase in bleeding. In patients younger than age 75, enoxaparin was given as a 30-mg intravenous bolus and 1 mg/kg subcutaneously every 12 hours; in patients aged 75 years and older, it was given with no bolus and 0.75 mg/kg subcutaneously every 12 hours. This appeared to attenuate the risk of intracranial hemorrhage in older adults that had been seen with full-dose enoxaparin. Another antithrombotic option is fondaparinux, given at a dose of 2.5 mg subcutaneously once a day. In the OASIS-6 trial, fondaparinux resulted in significant reductions in death and reinfarction when compared with control (unfractionated heparin when indicated, otherwise placebo). Similar to the findings of the OASIS-5 trial, fondaparinux tended to result in less bleeding, despite its longer duration compared with heparin and despite its comparison to placebo in about half of the enrolled patients. There is no benefit of fondaparinux among patients undergoing primary PCI, and fondaparinux is not recommended as a sole anticoagulant during PCI due to risk of catheter thrombosis.
(B) UNFRACTIONATED HEPARIN
Anticoagulation with intravenous heparin (initial dose of 60 units/kg bolus to a maximum of 4000 units, followed by an infusion of 12 units/kg/h to a maximum of 1000 units/hour, then adjusted to maintain an aPTT of 50–75 seconds beginning with an aPTT drawn 3 hours after thrombolytic) is continued for at least 48 hours after alteplase, reteplase, or tenecteplase, and with continuation of an anticoagulant until revascularization (if performed) or until hospital discharge (or day 8).
The VALIDATE trial found no benefit to bivalirudin compared to unfractionated heparin regarding the outcome of death, MI, or major bleeding.
(C) PROPHYLACTIC THERAPY AGAINST GASTROINTESTINAL BLEEDING
For all patients with STEMI treated with intensive antithrombotic therapy, prophylactic treatment with proton pump inhibitors, or antacids and an H2-blocker, is advisable, although certain proton pump inhibitors, such as omeprazole and esomeprazole, decrease the effect of clopidogrel.
3. Assessment of myocardial reperfusion, recurrent ischemic pain, reinfarction
Myocardial reperfusion can be recognized clinically by the early cessation of pain and the resolution of ST-segment elevation. Although at least 50% resolution of ST-segment elevation by 90 minutes may occur without coronary reperfusion, ST resolution is a strong predictor of better outcome. Even with anticoagulation, 10–20% of reperfused vessels will reocclude during hospitalization, although reocclusion and reinfarction appear to be reduced following intervention. Reinfarction, indicated by recurrence of pain and ST-segment elevation, can be treated by readministration of a thrombolytic agent or immediate angiography and PCI.
Cardiac care unit monitoring should be instituted as soon as possible. Patients without complications can be transferred to a telemetry unit after 24 hours. Activity should initially be limited to bed rest but can be advanced within 24 hours. Progressive ambulation should be started after 24–72 hours if tolerated. For patients without complications, discharge by day 4 appears to be appropriate. Low-flow oxygen therapy (2–4 L/min) should be given if oxygen saturation is reduced, but there is no value to routine use of oxygen.
An initial attempt should be made to relieve pain with sublingual nitroglycerin. However, if no response occurs after two or three tablets, intravenous opioids provide the most rapid and effective analgesia and may also reduce pulmonary congestion. Morphine sulfate, 4–8 mg, or meperidine, 50–75 mg, should be given. Subsequent small doses can be given every 15 minutes until pain abates.
Nonsteroidal anti-inflammatory agents, other than aspirin, should be avoided during hospitalization for STEMI due to increased risk of mortality, myocardial rupture, hypertension, heart failure, and kidney injury with their use.
E. Beta-Adrenergic Blocking Agents
Trials have shown modest short-term benefit from beta-blockers started during the first 24 hours after acute MI if there are no contraindications (metoprolol 25–50 mg orally twice daily). Aggressive beta-blockade can increase shock, with overall harm in patients with heart failure. Thus, early beta-blockade should be avoided in patients with any degree of heart failure, evidence of low output state, increased risk of cardiogenic shock, or other relative contraindications to beta-blockade. Carvedilol (beginning at 6.25 mg twice a day, titrated to 25 mg twice a day) was shown to be beneficial in the CAPRICORN trial following the acute phase of large MI.
Nitroglycerin is the agent of choice for continued or recurrent ischemic pain and is useful in lowering BP or relieving pulmonary congestion. However, routine nitrate administration is not recommended, since no improvement in outcome has been observed in the ISIS-4 or GISSI-3 trials. Nitrates should be avoided in patients who received phosphodiesterase inhibitors (sildenafil, vardenafil, and tadalafil) in the prior 24 hours.
G. Angiotensin-Converting Enzyme (ACE) Inhibitors
A series of trials (SAVE, AIRE, SMILE, TRACE, GISSI-III, and ISIS-4) have shown both short- and long-term improvement in survival with ACE inhibitor therapy. The benefits are greatest in patients with an EF of 40% or less, large infarctions, or clinical evidence of heart failure. Because substantial amounts of the survival benefit occur on the first day, ACE inhibitor treatment should be commenced early in patients without hypotension, especially patients with large or anterior MI. Given the benefits of ACE inhibitors for patients with vascular disease, it is reasonable to use ACE inhibitors for all patients following STEMI who do not have contraindications.
H. Angiotensin Receptor Blockers
Although there has been inconsistency in the effects of different ARBs on mortality for patients post-MI with heart failure and/or LV dysfunction, the VALIANT trial showed that valsartan 160 mg orally twice a day is equivalent to captopril in reducing mortality. Thus, valsartan should be used for all patients with ACE inhibitor intolerance, and is a reasonable, albeit more expensive, alternative to captopril. The combination of captopril and valsartan (at a reduced dose) was no better than either agent alone and resulted in more side effects.
I. Aldosterone Antagonists
The RALES trial showed that 25-mg spironolactone can reduce the mortality rate of patients with advanced heart failure, and the EPHESUS trial showed a 15% relative risk reduction in mortality with eplerenone 25 mg daily for patients post-MI with LV dysfunction (LVEF of 40% or less) and either clinical heart failure or diabetes. Kidney dysfunction or hyperkalemia are contraindications, and patients must be monitored carefully for development of hyperkalemia.
J. Calcium Channel Blockers
There are no studies to support the routine use of calcium channel blockers in most patients with acute MI—and indeed, they have the potential to exacerbate ischemia and cause death from reflex tachycardia or myocardial depression. Long-acting calcium channel blockers should generally be reserved for management of hypertension or ischemia as second- or third-line medications after beta-blockers and nitrates.
K. Long-Term Antithrombotic Therapy
Discharge on aspirin, 81–325 mg/day, since it is highly effective, inexpensive, and well tolerated, is a key quality indicator of MI care. Patients who received a coronary stent should also receive a P2Y12 inhibitor (see Antiplatelet therapy after drug-eluting or bare metal stents, above).
Patients who have received a coronary stent and who require warfarin anticoagulation present a particular challenge, since “triple therapy” with aspirin, clopidogrel, and warfarin has a high risk of bleeding. Triple therapy should be (1) limited to patients with a clear indication for warfarin (such as CHADS2 score of 2 or more or a mechanical prosthetic valve), (2) used for the shortest period of time (such as 1 month after placement of bare metal stent; drug-eluting stents that would require longer clopidogrel duration should be avoided if possible), (3) used with low-dose aspirin and with strategies to reduce risk of bleeding (eg, proton pump inhibitors for patients with a history of gastrointestinal bleeding), and (4) used with consideration of a lower target anticoagulation intensity (INR 2.0–2.5, at least for the indication of atrial fibrillation) during the period of concomitant treatment with aspirin and P2Y12 therapy. The PIONEER trial studied three treatment regimens for patients with atrial fibrillation who had coronary stent placement with a primary outcome of bleeding: (1) rivaroxaban 2.5 mg twice daily plus clopidogrel, (2) rivaroxaban 15 mg once daily plus clopidogrel, and (3) warfarin plus aspirin plus clopidogrel. There was less bleeding in the patients who received rivaroxaban plus clopidogrel than in those who received “triple therapy,” although the trial was not powered to assess efficacy, and thus the low dose of rivaroxaban may be inadequate. Consensus statements recommend oral anticoagulation (with either warfarin or a DOAC) be combined with clopidogrel and with a relatively short duration of aspirin until hospital discharge up to 3 months for the typical patient with atrial fibrillation and coronary stents. Dabigatran, 110 mg and 150 mg, was also studied in patients with atrial fibrillation who underwent PCI. Dual therapy with dabigatran and clopidogrel was shown to be beneficial for bleeding compared to triple therapy, with similar rates of thrombotic cardiovascular events. However, there were too few thrombotic events to be certain about efficacy of discontinuing the aspirin, and there was a suggestion that MI and stent thrombosis occurred more often with the 110-mg dose of dabigatran than with clopidogrel alone. Given the trial evidence to date, for a typical patient, it is reasonable to use a DOAC and clopidogrel and to discontinue aspirin at the time of hospital discharge. The AUGUSTUS trial, which tested apixaban versus warfarin and aspirin versus placebo in a factorial trial, found that apixaban resulted in 31% less major and clinically relevant non-major bleeding than warfarin for patients with atrial fibrillation and coronary stents or acute coronary syndromes or both. Avoiding aspirin, after an average of 6 days after the PCI, resulted in less bleeding and a nonsignificant increase in stent thrombosis. It is reasonable to stop aspirin at hospital discharge for patients with atrial fibrillation who are taking apixaban or warfarin at the time of discharge, although continuing aspirin for 1 month may reduce stent thrombosis.
For patients who do not reperfuse based on lack of at least 50% resolution of ST elevation, rescue angioplasty should be performed and has been shown to reduce the composite risk of death, reinfarction, stroke, or severe heart failure. Patients treated with coronary angiography and PCI 3–24 hours after fibrinolytic therapy showed improved outcomes. Patients with recurrent ischemic pain prior to discharge should undergo catheterization and, if indicated, revascularization. PCI of a totally occluded infarct-related artery more than 24 hours after STEMI should generally not be performed in asymptomatic patients with one or two vessel disease without evidence of severe ischemia.