Trial Results
Three initial multicenter, randomized trials found that there was no difference in outcome between an early invasive strategy and an early conservative strategy, whereas three subsequent trials showed benefit in favor of the invasive strategy. TIMI IIIB showed no difference in death or MI at 42 days with either strategy in patients with unstable angina/NSTEMI36; the Veterans Affairs Non-Q-Wave Myocardial Infarction Strategies In-Hospi-tal (VANQWISH) trial showed no difference in death or recurrent MI in the early invasive versus the conservative group at 2 years’ average follow-up (32.9% versus 30.3%; P = 0.35), although there were more deaths in the early invasive group at 1 year37; and the Medicine versus Angiography in Thrombolytic Exclusion (MATE) trial, conducted in patients with acute coronary syndrome who were ineligible for thrombolysis, showed no difference in clinical outcome between either strategy.38
The three subsequent studies have begun to move opinion toward the invasive strategy. The Fragmin in Unstable Coronary Artery Disease II (FRISC II) study was conducted in patients with unstable angina/NSTEMI who were receiving dalteparin; death or MI occurred in 9.4% of patients who received invasive treatment, as compared with 12.1% of those treated conservatively (P < 0.031; risk ratio, 0.78; confidence interval, 0.62 to 0.98).39 However, a substudy of FRISC II showed that the most benefit of the early invasive strategy accrued to those patients with an ST segment shift of more than 2.5 mm or in five or more leads.40 The Therapy with an Invasive or Conservative Strate-gy-Thrombolysis—TIMI 18 (TACTICS-TIMI 18) trial involved patients with unstable angina/NSTEMI who had ST or T wave changes, increased cardiac markers, and a history of coronary artery disease and who were taking aspirin, heparin, and tirofiban. This trial showed a combined end point (death, MI, or rehospitalization at 6 months) of 15.9% in the early invasive group, as compared with 19.4% in the early conservative group (P = 0.025; relative risk, 0.78; confidence interval, 0.62 to 0.97). Major bleeding was similar in both groups (1.9% versus 1.3%; P = 0.24). Subgroup analysis of the trial suggested that early invasive treatment benefited only patients whose TnI or TnT level was initially elevated.41 Of note, median length of stay was somewhat shorter with the invasive strategy (3.9 days versus 4.3 days; P < 0.001). The cost of care in the invasive group was somewhat higher for the initial hospitalization ($15,714 versus $14,047 in year 2000 dollars), though the 6-month average total costs did not differ between the two groups ($21,813 for the invasive group versus $21,227 for the conservative group; P = nonsignificant).42 In the Randomized Intervention Trial of unstable Angi-na-3 (RITA-3) in unstable angina/NSTEMI patients treated with enoxaparin, rates of death or MI at 4 months were lower in the early invasive group (9.6% versus 14.5%; P = 0.001; relative risk, 0.66; confidence interval, 0.51 to 0.85).43
Although the results of these three trials differed, patients who were considered to be at high risk for death or MI consistently seemed to benefit the most from a strategy of early angiog-raphy and revascularization. Because of the low event rate in patients considered to be at low risk, it is not clear that the early invasive approach offers a clear advantage over an early conservative strategy for this population. Therefore, until further evidence becomes available, an early conservative strategy may be a reasonable initial approach for the management of low-risk patients with unstable angina/NSTEMI.
Treatment Recommendations
High-risk patients A class I recommendation and level A evidence support the use of an early invasive strategy in patients with unstable angina/NSTEMI who have no serious comorbidity and have any of the following high-risk indicators:
• Recurrent angina at rest or with low-level activity despite intensive medical therapy.
• Elevated TnI or TnT levels.
• New, or presumably new, ST segment depression.
• Recurrent angina or ischemia with symptoms or signs of heart failure.
• High-risk findings on noninvasive stress testing.
• Depressed left ventricular function (ejection fraction < 40%) on noninvasive study.
• Hemodynamic instability.
• Sustained ventricular tachycardia.
• Percutaneous coronary intervention within the past 6 months.
• Previous coronary artery bypass grafting (CABG).
In the absence of any of these findings, either a conservative or an invasive strategy may be offered to hospitalized patients without contraindications for revascularization. This option is supported by a class 1 recommendation and level B evidence.
Women and the elderly There should be no difference in the management of men and women. The elderly should be treated no differently than younger patients, although management should take into consideration general health, comorbid conditions, cognitive status, life expectancy, and altered pharma-cokinetics of and sensitivity to hypotensive drugs.
Table 4 Antiplatelet Therapy in Unstable Angina or Non-ST Segment Elevation Myocardial Infarction
|
Drug (Trade Name) |
Initial Dose |
Route |
Duration |
Adverse Effects |
Adverse Drug Reactions |
Contraindications |
|
Aspirin |
81-325 mg q.d. |
Oral (first dose chewed) |
Indefinite |
Bleeding, tinnitus, rash, GI intolerance |
None |
Active, severe bleeding |
|
Clopidogrel (Plavix) |
300 mg loading dose, then 75 mg q.d. |
Oral |
1 yr |
Bleeding, rare TTP |
Partial inhibition of effect with statin drugs |
Active, severe bleeding; major surgery within < 5 days |
|
Ticlopidine (Ticlid) |
250 mg b.i.d. |
Oral |
1 yr |
Bleeding, TTP, rash, neutropenia, diarrhea |
None |
Active, severe bleeding; major surgery planned |
|
Abciximab (ReoPro) |
0.25 mg/kg bolus, then 0.125 |ig/kg/min; max 10 |g/min |
I.V. |
12 hr |
Bleeding, thrombocytopenia |
None |
Active, severe bleeding; major surgery planned |
|
Eptifibatide (Integrilin) |
180 |g/kg bolus, then 2 |g/kg/min |
I.V. |
72-96 hr or 18 hr if PCI performed |
Bleeding |
None |
Active, severe bleeding; major surgery planned |
|
Tirofiban (Aggrastat) |
0.4 |g/kg/min bolus (x 30 min), then 0.1 | g/kg/min |
I.V. |
48 hr |
Bleeding |
None |
Active, severe bleeding; major surgery planned |
PCI—percutaneous coronary intervention
TTP—thrombotic thrombocytopenic purpura
Pharmacologic therapy
Antiplatelet Drugs
Antiplatelet medications used in unstable angina/NSTEMI include aspirin, thienopyridines (clopidogrel and ticlopidine), abciximab, eptifibatide, and tirofiban [see Table 4].
Aspirin Aspirin is considered the benchmark antiplatelet agent for the treatment of unstable angina/NSTEMI. A class I recommendation and level A evidence suggest that aspirin be started immediately in these patients and continued indefinitely.1,2
Aspirin’s mechanism of action is to decrease the formation of the potent platelet aggregator thromboxane A2 by irreversibly binding cyclooxygenase-1 in platelets. The effect on platelets is rapid (occurring within 15 to 30 minutes), and it is achieved with an oral dose as low as 81 mg.
Four pivotal randomized trials that evaluated the effectiveness of aspirin in the treatment of acute coronary syndrome showed consistent and durable long-term benefit at doses ranging from 75 to 325 mg daily.4"7 The Antiplatelet Trialists’ Collaboration meta-analysis of more than 100,000 patients in 145 trials showed such benefits in several cardiovascular disorders. For example, in 4,000 patients with unstable angina, rates of so-called vascular events (nonfatal MI, nonfatal stroke, or vascular death) were reduced from 14% to 9% (P < 0.00001) after 6 months.48 Furthermore, the benefit of aspirin in these high-risk patients was sustained for at least 2 years.
Aspirin dosages have varied among several trials; no dosage has been definitively shown to be preferable. For patients with suspected MI in the International Studies of Infarct Survival-2 (ISIS-2) trial, the effective dosage was 160 mg daily.49 A dose of aspirin between 160 and 325 mg should be administered immediately; the first dose should be chewed, for rapid absorption, and subsequent doses swallowed.
Adverse effects of aspirin include allergy, which may manifest as rash, angioedema, or asthma; a tendency to bleed; gastrointestinal effects, including gastric ulcer; and, rarely, precipitation of acute gout. Contraindications include allergy (especially if the allergic reaction is in the form of asthma), active bleeding, a serious bleeding disorder, severe untreated hypertension, and an active peptic ulcer.
Thienopyridines Thienopyridines irreversibly bind the adenosine diphosphate receptor on platelets, preventing fibrino-gen binding and platelet aggregation. The two thienopyridines that have been used clinically are ticlopidine (Ticlid) and clopi-dogrel (Plavix).
In a single open-label trial in patients with unstable angina, ticlopidine (250 mg twice daily) significantly reduced vascular death and nonfatal MI at 6 months (13.6% versus 7.3%; P = 0.009), compared with standard aspirin therapy.50 Several trials have shown the value of clopidogrel. In 12,562 patients with unstable angina, all of whom were also treated with aspirin, clopi-dogrel (300 mg followed by 75 mg daily), administered for 3 to 12 months, reduced a combined end point of cardiovascular death, nonfatal MI, and stroke from 11.4% to 9.3% (P < 0.001) and also decreased the incidence of ischemia, heart failure, and revascularization procedures. Benefit occurred as early as 24 hours after initiating treatment and persisted for up to 1 year. Clopidogrel increased major bleeding from 2.7% to 3.7% (P = 0.003), but there was no difference in life-threatening bleeding or hemorrhagic shock. Importantly, bleeding was increased in patients who underwent CABG within 5 days after stopping clopi-dogrel.51 Two other studies found that clopidogrel benefited patients treated with percutaneous coronary intervention. 52,53 The Clopidogrel for the Reduction of Events During Observation (CREDO) study examined the timing of therapy with a combination of clopidogrel and aspirin. In one arm of the study, patients received a bolus load of aspirin and clopidogrel 6 to 24 hours before undergoing percutaneous coronary intervention. In the other arm of the study, patients received a bolus load less than 6 hours before the procedure. Benefit was observed in those patients who received the bolus 6 to 24 hours before the procedure.
The dosage of ticlopidine is 250 mg orally, twice daily; the dosage of clopidogrel is 300 mg orally. Both agents should be started immediately on presentation. The duration of therapy, which has been better defined for clopidogrel, is up to 1 year at a dose of 75 mg daily.
The principal adverse reaction that has limited the clinical use of ticlopidine is severe neutropenia; rarely, thrombotic thrombo-cytopenic purpura develops within the first 3 months of therapy. Both conditions are life threatening unless the drug is discontinued promptly. Clopidogrel has been associated with increased bleeding complications when administered with other an-tithrombotic agents, particularly when arterial puncture is performed for intervention. Bleeding during surgery is an important complication of clopidogrel use; for this reason, surgery should be avoided for 5 and preferably 7 days after the last dose, because of the prolonged duration of action. Recommendations for the use of clopidogrel are as follows:
1. Patients with unstable angina/NSTEMI in whom a nonin-terventional approach is planned should receive clopidogrel for at least 1 month (this class I recommendation is supported by level A evidence) and for up to 9 months (class I recommendation, level B evidence).
2. Patients with unstable angina/NSTEMI for whom a percutaneous coronary intervention is planned and who are not at high risk for bleeding should receive clopidogrel for at least 1 month (class I recommendation, level A evidence) and for up to 9 months (class I recommendation, level B evidence).
3. Clopidogrel should be stopped for 5 to 7 days before elective surgical revascularization (class I recommendation, level B evidence).
4. When used to pretreat patients undergoing percutaneous coronary intervention, clopidogrel should be given more than 6 hours before the procedure (level B evidence).53
Glycoprotein Ilb-IIIa receptor antagonists Abciximab, ep-tifibatide, and tirofiban act by specifically binding the glycopro-tein (GP) IIb-IIIa receptor on platelet surfaces, thereby preventing fibrinogen binding and ultimately preventing platelet aggregation. Abciximab is the Fab fragment of a monoclonal antibody that has a short plasma half-life but irreversibly binds the GPIIb-IIIa receptor for 24 to 48 hours. The half-lives of eptifibatide and tirofiban are 2 to 3 hours, with platelet aggregation returning to normal 4 to 8 hours after drug discontinuance.
In three large clinical trials of patients with unstable angi-na/NSTEMI who underwent percutaneous coronary intervention, all of these GPIIb-IIIa inhibitors provided significant benefit in the composite outcome of death, MI, or urgent repeat revascu-larization, with the major benefit seen in recurrent MI and urgent repeat revascularization.2’654’55 The Do Tirofiban and Reopro Give Similar Efficacy Trial (TARGET), which was conducted in patients with unstable angina/NSTEMI who underwent percutaneous coronary intervention with stenting, found that abcix-imab conferred greater benefit than tirofiban (although tirofiban was administered at a suboptimal dosage).56
For patients not undergoing planned percutaneous intervention, the results with GPIIb-IIIa inhibitors have been less impressive. Abciximab, given for 24 or 48 hours, was found to be no better than placebo in the Global Use of Strategies to Open Occluded Coronary Arteries IV (GUSTO IV) trial in patients with acute coronary syndrome.57 On the other hand, two trials with tirofiban and eptifibatide demonstrated modest benefit in patients who did not undergo an interventional procedure26,54; the benefit was greatest in high-risk patients.
Abciximab, which is recommended for use during percutaneous coronary intervention, is administered as a 0.25 mg/kg in travenous bolus, followed by an infusion at 0.125 ^g/kg/min for 12 hours. Eptifibatide is administered as a 180 Hg/kg intravenous bolus, followed by a second bolus after 10 minutes. Thereafter, it is infused at a rate of 2 ^g/kg/min for 72 to 96 hours if no percutaneous intervention is performed or for 18 hours if such a procedure is performed. Tirofiban is given in an intravenous 0.4 ^g/kg/min bolus over 30 minutes, then infused at a rate of 0.1 ^g/kg/min for 48 hours.
Bleeding is the most common complication of GPIIb-IIIa inhibitors. Special care should be taken to prevent bleeding in high-risk patients such as the elderly, women, those with low body weight, and those who require arterial puncture for an intervention. Because of their short half-lives, eptifibatide or tirofiban may be better suited for patients who may require surgical revascularization. Abciximab results in serious thrombocy-topenia in about 0.3% of patients,56 so serial platelet measurements are recommended in patients receiving this agent. In a meta-analysis, GPIIb-IIIa inhibitors were found to increase major bleeding from 1.4% to 2.4 % (P < 0.0001). There was no increase in the rate of intracranial hemorrhage.58
Three evidence-based recommendations can be made for the use of GPIIb-IIIa inhibitors:
1. In patients with unstable angina/NSTEMI who are to undergo a planned percutaneous coronary intervention, a GPIIb-IIIa inhibitor should be given either before or during the procedure. This class I recommendation is supported by level A evidence.
2. Patients with unstable angina/NSTEMI who have high-risk features and who are not to undergo a planned percutaneous intervention should receive eptifibatide or tirofiban (class IIa recommendation, level A evidence).
3. Patients with unstable angina/NSTEMI in whom percutaneous intervention is not planned should not receive abcix-imab (class III recommendation, level A evidence).
Fibrinolytic Drugs
Fibrinolytic therapy is not indicated for patients with unstable angina/NSTEMI. Level A evidence indicates that intravenous fi-brinolytic therapy should not be administered to patients who do not have acute ST segment elevation, unless they have a true posterior MI or a presumed new left bundle branch block (class III recommendation).59
Anticoagulants
Heparin, low-molecular-weight heparin (LMWH), bivalirudin, or warfarin can be used for anticoagulant therapy in patients with unstable angina/NSTEMI [see Table 5].
Heparin Unfractionated heparin is composed of a number of chains of varying molecular weights that differ with regard to anticoagulant activity. Heparin generally increases the action of circulating antithrombin, which inactivates factor IIa, factor IXa, and factor Xa and prevents thrombus formation.60
Three randomized, placebo-controlled trials suggested that early intravenous administration of heparin leads to a modest reduction in the incidence of MI or recurrent ischemia.61-63 A metaanalysis of six trials showed a relative risk of 0.67 (95% confidence interval, 0.44 to 1.02) in favor of the combination of heparin and aspirin.64
Heparin should be given in an initial intravenous bolus of 60 to 70 U/kg (maximum, 5,000 U), followed by an infusion of 12 to 15 U/kg/hr (maximum, 1,000 U/hr). Doses should be adjusted to maintain an activated partial thromboplastin time (aPTT) of 1.5 to 2.5 times control values.1
Table 5 Anticoagulant Therapy in Unstable Angina/ Non-ST Segment Elevation Myocardial Infarction
|
Drug |
Dose |
Route |
Duration |
Adverse Effects |
Adverse Drug Reactions |
Contraindications |
|
Unfractionated heparin |
60-70 U/kg bolus (max 5,000 U); 12-15 U/kg/hr (max 1,000 U/hr) |
I.V. |
48-72 hr |
Bleeding, HIT, mild thrombocytopenia |
None |
Active, severe bleeding; HIT |
|
Enoxaparin |
1 mg/kg b.i.d. |
S.C. |
48-72 hr |
Bleeding, HIT |
None |
Active bleeding; major surgery planned |
|
Bivalirudin |
0.75 mg/kg bolus; 1.75 mg/kg/hr |
I.V. |
Duration of PCI |
Bleeding |
None |
Active, severe bleeding |
|
Warfarin |
5-10 mg; dose adjusted to maintain desired INR, typically 2-3 |
Oral |
Varies with indication |
Bleeding, warfarin skin necrosis |
Dose adjustment with macrolides, cimetidine, digoxin, amiodarone, other drugs |
Active, severe bleeding; major surgery planned |
HIT—heparin-induced thrombocytopenia
INR—international normalized ratio PCI—percutaneous coronary intervention
As with any anticoagulant, heparin is contraindicated in patients with active severe bleeding or who are to undergo imminent surgery. Heparin-induced thrombocytopenia (HIT) is a serious but rare (< 0.2% incidence) antibody-mediated reaction leading to reduced platelet counts and thrombosis [see 5:XIV Thrombotic Disorders]. HIT mandates immediate cessation of hep-arin, including heparinized solutions used for the flushing of intravenous ports. From 10% to 20% of patients receiving heparin may experience mild thrombocytopenia that is not associated with severe thrombosis or excessive bleeding.1 For serious bleeding, heparin anticoagulation can be immediately reversed with intravenous protamine sulfate.
Low-molecular-weight heparin LMWHs are produced by enzymatic depolymerization of unfractionated heparin, resulting in smaller chain units. Advantages include less protein binding; longer half-life; more stable, dose-dependent clearance; and a greater anti-factor Xa effect that is associated with more thrombin inhibition. The standard aPTT assay cannot be used for LMWH, because this assay is not sensitive to the anti-Xa effects of LMWHs. Rapid factor Xa assays are not widely available, but the stable kinetics of LMWH tends to reduce the need for monitoring.
A number of trials have compared individual LMWHs with unfractionated heparin. Meta-analysis of two trials revealed a modest benefit of enoxaparin over heparin in terms of death and MI at 45 days (7.1% versus 8.6%; P = 0.02).65 In trials with dalteparin and nadroparin, neither showed benefit.66,67 FRISC showed a significant improvement in death, MI, or urgent revascularization with dalteparin (1.8% versus 4.8%; P = 0.001) for up to 43 days.68 In the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial, enoxaparin was found to be associated with less ischemia, as evidenced on ECG (14.3% versus 25.4%; P = 0.002), and to lead to an improvement in the composite end point of death or MI at 30 days (5% versus 9%; P = 0.031).69 Several trials showed evidence of a small increase in minor bleeding with LMWH, as compared with heparin, but no difference in major bleeding was seen.66-69 One small trial demonstrated that enoxaparin was safe with regard to serious bleeding in unstable angina/NSTEMI patients undergoing percutaneous coronary intervention.70 Another trial showed significantly lower rates of major CABG-related bleeding with LMWH, as compared with enoxaparin, by 96 hours after percutaneous coronary intervention (1.8% versus 4.6%; P = 0.03).23 When enoxaparin was added to abciximab, no difference in the rate of bleeding events and adverse ischemic outcomes was seen, as compared with historical controls.71
In summary, evidence to date suggests that LMWH is at least as effective as unfractionated heparin and is generally safe in patients with unstable angina/NSTEMI in whom surgery or percutaneous coronary intervention is not planned. The dosing of LMWH is simpler than that of unfractionated heparin, and LMWH therapy does not require monitoring with coagulation studies. Abundant data (e.g., from the TIMI 11B, ESSENCE, and INTERACT studies) suggest that enoxaparin is the preferred agent.23,24,69 In patients for whom percutaneous coronary intervention is planned, LMWH may be started or continued, provided that meticulous attention is given to dosing and the timing of its administration. Enoxaparin has not found wide use in contemporary interventional practice, however, because of practitioners’ uneasiness over the inability to monitor the level of anti-coagulation. In patients in whom surgery is planned, LMWH should be avoided; if an LMWH has already been started, the patient should be switched to unfractionated heparin, whose effects can be monitored closely.
Enoxaparin is given subcutaneously at a dosage of 1 mg/kg every 12 hours for at least 48 hours. Percutaneous coronary intervention may be performed within 8 hours of starting the drug, without additional anticoagulation therapy. If the percutaneous procedure is performed 8 to 12 hours after starting the drug, an additional intravenous bolus of 0.3 mg/kg may be given. Dose adjustment must be made in patients with moderate to severe renal impairment.
Compared with unfractionated heparin, LMWH has a slightly higher rate of minor bleeding complications and the same rate of major bleeding complications. Although the risk of HIT seems to be lower with LMWH than with unfractionated heparin, LMWH is absolutely contraindicated in patients with a history of HIT because of the danger posed by this reaction.
A class I recommendation and level A evidence support the use of anticoagulation with intravenous heparin or subcutaneous LMWH in patients with unstable angina/NSTEMI; the anticoagulant is given in addition to aspirin, clopidogrel, or both.
Level A evidence indicates that enoxaparin is preferable to un-fractionated heparin in patients without renal failure, unless CABG is planned within 24 hours (class IIa recommendation).
Direct thrombin inhibitors These agents directly bind to the fibrinogen-recognition and catalytic sites of thrombin, neutralize clot-bound thrombin, and inhibit thrombin-mediated platelet aggregation; the result is sustained anticoagulation. Hirudin and bivalirudin are the two principal agents that have undergone clinical testing, but hirudin is not used.
In the Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events-2 (REPLACE-2) trial, which involved patients undergoing percutaneous coronary intervention, bivalirudin in combination with provisional GPIIb-IIIa inhibition was found to be equivalent to unfractionated heparin plus GPIIb-IIIa inhibition in terms of death, MI, urgent repeat revascularization, and in-hospital major bleeding after 30 days of therapy.72 Rates of in-hospital major bleeding were significantly lower with bivalirudin (2.4% versus 4.1%; P < 0.001), although it has been noted that activated clotting time (ACT) values in the patients who received unfraction-ated heparin and a GpIIb-IIIa inhibitor were higher than was seen in other trials.
Bivalirudin is given as an intravenous bolus of 0.75 mg/kg at the start of percutaneous coronary intervention; for the duration of the procedure, an infusion of 1.75 mg/kg/hr is given. Because of the predictable profile of bivalirudin, measurement of ACT levels is usually not necessary. If the ACT is measured, typical values are 300 to 400 seconds.
Although bleeding seems to occur less commonly with bi-valirudin than with unfractionated heparin or GPIIb-IIIa inhibitors, any serious bleeding that does occur could be disastrous because there is no effective way to immediately reverse the anticoagulation (as can be done with protamine sulfate for heparin). However, thrombocytopenia is not a problem, and the offset of bivalirudin’s effect is relatively more rapid than that of heparin (1 hour), permitting sheaths to be pulled sooner after the procedure. Mainly because of its better safety profile, some interventional cardiologists have embraced the use of bi-valirudin in the catheterization laboratory, but its general use awaits further trials.
If percutaneous coronary intervention is planned, level B evidence indicates that bivalirudin may be used as an alternative to unfractionated heparin and a GPIIb-IIIa inhibitor.
Warfarin Warfarin works by inhibiting the vitamin K-de-pendent clotting factors II, VII, IX, and X. Achievement of the desired antithrombotic effect takes 4 to 7 days.
In a few small pilot studies, starting warfarin therapy shortly after presentation in patients with unstable angina/NSTEMI showed benefit.1 In a large trial of patients with unstable angi-na/NSTEMI who had previously undergone CABG, warfarin provided no advantage over aspirin alone and was associated with excess minor and major bleeding complications.73
Warfarin is taken orally once daily. The dose is titrated to maintain the desired international normalized ratio (INR), which is from 2 to 3 for most indications.
Bleeding is the main complication associated with warfarin therapy. Several drugs (e.g., cimetidine, amiodarone) can markedly increase warfarin’s effect. Warfarin anticoagulation is reversed by stopping the drug; reversal by administration of vitamin K or of fresh frozen plasma is usually reserved for emergent and life-threatening bleeding.
The available evidence does not support the routine use of warfarin in patients with unstable angina/NSTEMI unless there are other indications for warfarin (e.g., atrial fibrillation, mechanical prosthetic heart valve).
