Non–ST-Segment Elevation Acute Coronary Syndromes




In this chapter, we have drawn from evidence-based guidelines, adopted the standard classification schemas used to grade the level of recommendation and strength of supportive evidence, and provided updated information from the literature on non–ST-elevation acute coronary syndrome (NSTE-ACS). A recurring theme is the need for integrative risk assessment to allow tailoring of therapy based on a patient’s probability of adverse outcomes. Efforts have been made to incorporate physiologic, laboratory, and demographic characteristics of patients into risk scores such as the Thrombolysis in Myocardial Infarction (TIMI) risk score for unstable angina/non–ST-segment elevation myocardial infarction (UA/NSTEMI). Other scores derived from clinical trials and registries were developed to assess the risk of patients with NSTE-ACS and to help identify patients most likely to benefit from aggressive therapy. An analysis comparing three risk scores—TIMI, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and Global Registry of Acute Coronary Events (GRACE) scores ( Table 9-1 )—concluded that all three demonstrated good predictive accuracy for death or MI. The TIMI UA/NSTEMI Risk Score has been found to be useful in the prediction of angiographic severity and extent of coronary artery disease (CAD), including the prediction of greater intracoronary thrombus burden and impaired flow. Patients with higher TIMI risk scores derive greater benefit from aggressive antithrombotic strategies and an early invasive strategy of angiography and coronary intervention.



TABLE 9-1

Integrative Clinical Risk Scores for Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction




















SCORE FEATURES COMMENTS
TIMI Age ≥65 years or older, ≥3 cardiac risk factors, aspirin use in last 7 days, known CAD (previous stenosis ≥50%), recurrent angina in last 24 hours, ST-segment deviation, elevated markers of necrosis Sum of number of features (1 point each)
PURSUIT Age by decade, sex, worst CCS class in previous 6 weeks, signs of heart failure, ST-segment depression Weighted score based on different point total (range, 0-14) for each feature
GRACE Age, heart rate, systolic BP, creatinine level, Killip class, cardiac arrest, elevated markers, ST-segment deviation Weighted score based on different point total (range, 0-91) for each feature

BP, blood pressure; CAD, coronary artery disease; CCS class, Canadian Cardiovascular Society anginal class; GRACE, Global Registry of Acute Coronary Events; PURSUIT, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; TIMI, Thrombolysis in Myocardial Infarction.


Antiischemic Medications


Management of UA/NSTEMI should be directed toward the dual goals of relief of the symptoms of myocardial ischemia and prevention of the severe short- and long-term sequelae, which include recurrent myocardial infarction (MI), congestive heart failure (CHF), and death. Therapeutic efforts should be focused intensely on therapies that achieve both of these goals, and a multifaceted and continuously updated approach to the management of patients with NSTE-ACS may be necessary. For instance, a medication such as nitroglycerin, which may be used on first encounter with a patient with ongoing ischemic chest pain to provide symptomatic relief, may be replaced with agents such as angiotensin-converting enzyme (ACE) inhibitors, which are expected to modify long-term risk. Patients for whom initial intensive pharmacologic therapy does not produce relief of ischemic symptoms should be considered as candidates for early cardiac catheterization and revascularization or for ischemic relief with mechanical therapies, such as intraaortic balloon counterpulsation. For the majority of patients with NSTE-ACS, relief of ischemic symptoms can be achieved by pharmacologic measures.


Myocardial ischemia is a consequence of an imbalance in myocardial oxygen supply and demand. In most cases of UA/NSTEMI, the principal cause of this imbalance is abrupt reduction of blood flow resulting from nonocclusive coronary thrombosis. For this reason, mainstays of therapy for UA/NSTEMI include antithrombotic and antiplatelet therapies and coronary revascularization. Revascularization may not always be immediately available, practical, safe or appropriate, and pharmacologic management of myocardial oxygen demand (MVO 2 )—and, to a lesser extent, supply—may result in relief of symptoms. The principal components of MVO 2 are heart rate, myocardial contractility, and wall stress. Controlling and reducing these factors helps improve the balance and relieve angina. Major classes of antianginal therapy include nitrates, β-adrenergic receptor antagonists (β-blockers), and calcium channel blockers (CCBs). Morphine sulfate has mixed effects that reduce oxygen demand and angina.


Nitrates


The use of nitrates in NSTE-ACS is based on physiologic principles and expert consensus. Nitroglycerin should be used in UA/NSTEMI for the rapid relief of ischemia and ischemia-related symptoms, including angina and CHF ( Figure 9-1 ). In suitable patients, nitrate administration should begin with sublingual administration of 0.4 mg (tablets or spray) given at 5-minute intervals, up to three doses. Intravenous (IV) nitroglycerin treatment may be initiated in patients with refractory symptoms and without hypotension despite adequate doses of β-blocker. IV nitroglycerin is initiated at 5 to 10 µg/min of continuous infusion and may be titrated upward at 3- to 5-minute intervals, until 20 µg/min is reached. If this dose is tolerated without hypotension and anginal symptoms persist, larger titration steps of 20 µg/min are usually well tolerated. Titration should cease when symptom relief is achieved, when hypotension ensues, or when a maximum dose of approximately 200 to 300 µg/min is reached. Tolerance to the antiischemic effects of nitrates may develop within 12 to 24 hours and can be ameliorated by nitrate-free intervals. If symptoms do not allow for nitrate-free intervals, increasing the dose may be effective. Despite tolerance, abrupt removal of nitrates may result in recurrent ischemia and discontinuation of high-dose IV nitrates should be performed by stepped-down titration.




FIGURE 9-1


Schematic for early use of nitrates in acute coronary syndrome. *Use of phosphodiesterase-5 inhibitor within 24 hours, severe aortic stenosis, hypotension, hypertrophic cardiomyopathy, right ventricular infarction with hypotension, hemodynamically significant pulmonary embolism. BB, β-blocker; BP, blood pressure; IV, intravenous; NTG, nitroglycerin; SL, sublingual.


The pharmacologic effects of nitrates, predominantly the venodilation and reduction of ventricular preload, may be detrimental to patients who are highly dependent on ventricular preload for the maintenance of cardiac output, and it can result in substantial hypotension. Nitrates should generally be avoided, or used with considerable caution, in patients with right ventricular infarction, severe aortic stenosis, hypertrophic cardiomyopathy, or pulmonary embolism. Nitrates are contraindicated for patients who have used phosphodiesterase-5 (PDE-5) inhibitors—sildenafil, tadilafil, or vardenafil—within the preceding 24 to 48 hours because of exaggeration and prolongation of nitrate effects from the inhibition of the breakdown of cyclic guanosine monophosphate (cGMP), which modulates the vasodilator effects of nitrates. The combination of PDE-5 inhibitors and nitrates has been associated with severe hypotension, myocardial ischemia, and death.


β-Adrenergic Receptor Blockers


Clinical trial data for the use of β-blockers are sparse, specifically in UA/NSTEMI. A systematic review of the accumulated trial data suggests that β-blockers reduce the risk of progression to MI in NSTE-ACS. In contrast, a large body of randomized, controlled trial data suggests benefits in reducing recurrent MI and death by early use of β-blocker therapy in STEMI. Therefore the evidence for the use of β-blockers in NSTE-ACS results largely from extrapolation from STEMI trials and physiologic principles.


Based on these data, β-blockers should be initiated in the treatment of UA/NSTEMI as early as possible for patients without contraindications. IV β-blockers should be used with particular caution in patients with CHF on arrival at the care center, based on results from the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT); use in patients with STEMI shows adverse outcomes in this population. However, oral β-blockers are strongly recommended for patients who have stabilized CHF or reduced left ventricular (LV) function before discharge. β-Blockers should be used cautiously or avoided in patients with significant first-degree atrioventricular (AV) block, and they should be withheld in patients with severe bradycardia or second- or third-degree AV block without a pacemaker. Selective β-blockade should be used in patients for whom NSTE-ACS is secondary to profound catecholamine excess, such as with pheochromocytoma or cocaine use. For patients with reactive airway disease, the use of a cardioselective (β1) agent is recommended. Initial therapy for patients with evidence of ongoing ischemia should be an IV β-blocker, such as metoprolol, 5 mg every 5 minutes up to three doses as tolerated by heart rate and blood pressure. After initial IV dosing, oral β-blocker therapy should be initiated early to avoid a rebound effect between the offset of the IV agent and the onset of the oral agent.


Calcium Channel Antagonists


Dihydropyridine CCBs have predominantly peripheral vasodilatory actions, whereas nondihydropyridine CCBs have significant sinoatrial (SA) and AV node depressant effects and possible myocardial depressant effects with lesser amounts of peripheral vasodilation. Coronary vasodilation appears to be similar among various agents. The predominant clinical role for CCBs has been in the control of hypertension; however, the physiologic properties of arterial vasodilation, heart rate slowing, and contractility reduction favorably alter myocardial oxygen balance. Because of these differences in properties, the two types of CCBs are discussed separately.


The dihydropyridine CCBs cause a reflex tachycardia in the absence of adequate β-blocker therapy, a mechanism that may underlie apparent adverse effects of these agents on patients with NSTE-ACS. In contrast to the dihydropyridines, diltiazem and verapamil are heart rate–slowing agents and appear to not increase rates of ischemic events in patients with UA/NSTEMI. However, concerns have been raised that myocardial depressant effects may increase the risk of heart failure. The relationship of the nondihydropyridine CCBs to CHF is somewhat controversial. In retrospective analyses of CCB trials, evidence was found for increased rates of CHF and an increase in the mortality rate in patients with diminished ejection fraction. These findings, however, are counterbalanced by studies that show beneficial effects of CCBs in patients with heart failure who are treated concurrently with ACE inhibitors.


In summary, CCBs reduce symptomatic ischemia. Short-acting dihydropyridine CCBs have not been shown to improve cardiac outcomes and may result in worse outcomes in the absence of β-blockers. Newer, longer acting dihydropyridine CCBs have not been studied in NSTE-ACS. Nondihydropyridine CCBs are antianginal, do not result in harm, and may improve outcomes in patients with NSTE-ACS, especially those patients without LV dysfunction; therefore nondihydropyridine CCBs can be considered for use in patients who cannot tolerate β-blockers.


Ranolazine


Ranolazine is an antianginal agent that exerts its effects uniquely, without alteration of heart rate or blood pressure. The mechanism of the antianginal effects is thought to arise from inhibition of the late phase of the sodium current, which is pathologically increased during ischemia. Ranolazine has been demonstrated to be effective in the reduction of chronic stable angina as monotherapy and in combination with a CCB or β-blocker. When evaluated in a broad population of patients with NSTE-ACS in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-Elevation Coronary Syndromes (MERLIN)-TIMI 36 trial, ranolazine did not affect the primary outcome of cardiovascular (CV) death, MI, or recurrent ischemia, but it did reduce recurrent ischemia alone. No increase was seen in CV death or arrhythmia; therefore ranolazine can be administered safely for angina relief but does not appear to alter the disease process.




Antiplatelet Agents


Antiplatelet agents represent the cornerstone of therapy for patients with NSTE-ACS. Pharmacologic inhibition of platelet function can be achieved by interfering with a number of processes: inhibition of cyclooxygenase (COX), phosphodiesterase, adenosine diphosphate (ADP), thromboxane, serotonin, platelet adhesion, and platelet aggregation. This has led to the development of numerous platelet inhibitors ( Box 9-1 ), of which aspirin, the P2Y 12 ADP receptor blockers, and the intravenous glycoprotein (GP) IIb/IIIa inhibitors have been studied most extensively.



Box 9-1

Classification Scheme of Selected Antiplatelet Agents


Arachidonic Acid Inhibitors





  • COX Inhibitors: aspirin, indobufen, triflusal, nonsteroidal antiinflammatory agents, sulfinpyrazone



Non-COX inhibition of arachidonic acid;




  • phosphodiesterase inhibitors: dipyridamole, pentoxifylline, cilostazol, trapidil



  • Other: omega-3 fatty acids, eicosanoids (prostacyclin, prostaglandin analogues)



P2Y 12 ADP Receptor Inhibitors





  • Thienopyridines (ADP antagonists): ticlopidine, clopidogrel, prasugrel



  • ATP derivatives: cangrelor



  • CPTPs: ticagrelor



  • Elinogril



Thrombin Protease-Activated Receptor-1 Inhibitors





  • vorapaxar, E-5555



Platelet Glycoprotein IIb/IIIa Receptor Blockers





  • Intravenous: abciximab, tirofiban, eptifibatide



Drugs with Secondary Antiplatelet Activity





  • Direct thrombin inhibitors, heparin, nitrates, fibrates, calcium channel antagonists, others



ADP, adenosine diphosphate; ATP, adenosine triphosphate; COX, cyclooxygenase; CPTPs, cyclopentyltriazolopyrimidines.



Aspirin


Several small- to medium-sized clinical trials to compare aspirin with placebo in NSTE-ACS demonstrated an approximate 50% reduction in death or MI ( Figure 9-2 ). These data support the class I indication in the 2007 American College of Cardiology (ACC) and American Heart Association (AHA) UA/NSTEMI guidelines to begin aspirin immediately and to treat indefinitely upon establishment of the diagnosis of NSTE-ACS. Because aspirin is one of the most inexpensive drugs available, and with a known safety profile, it is unlikely that future placebo-controlled studies will be undertaken. Thus aspirin is likely to remain the first-line antiplatelet agent in NSTE-ACS for the foreseeable future.




FIGURE 9-2


Placebo-controlled trials with aspirin (ASA) in patients with non–ST-segment elevation acute coronary syndrome. Aspirin was associated with a 50% reduction in death or myocardial infarction (MI) compared with placebo.

(From Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction—2002. Summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [Committee on the Management of Patients with Unstable Angina]. Circulation 2002;106[14]:1893-1900.)


Despite its long history, the optimal dose of aspirin remains to be definitively established. Increased doses have been associated with more bleeding, yet the relationship of the dose with efficacy is less clear. A dose of 40 mg was found to achieve maximal inhibition once steady state has been achieved, although doses greater than 160 mg are needed to produce a rapid clinical antithrombotic effect, and doses of less than 75 mg daily have not been well studied in clinical trials. A meta-analysis by the Antiplatelet Trialists’ Collaboration demonstrated no increase in benefit of aspirin across maintenance doses ranging from 75 mg to 1500 mg daily, whereas gastrointestinal (GI) bleeding was increased at doses above 300 mg daily. Two nonrandomized subgroup analyses compared different doses of aspirin and confirmed that higher doses were associated with an increased risk of bleeding and no apparent reduction in ischemic complications. A random effects multivariate regression model concluded that efficacy of aspirin did not increase at higher doses; in fact, the point estimates suggest less benefit at higher doses.


The largest clinical trial of aspirin dosing in ACS is the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial. This trial was a 2 × 2 factorial study of standard versus higher dose clopidogrel and also of low- versus high-dose aspirin—a dose of 75 to 100 mg/day (low dose) compared with 300 to 325 mg/day (high dose) for 30 days. The aspirin comparison in this trial demonstrated no difference in either the primary outcome of CV death, MI, or stroke (4.2% vs. 4.4%; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.86 to 1.09; P = .61) or in major bleeding (2.3% vs. 2.3%; HR, 0.99; 95% CI, 0.84 to 1.17; P = .90); however, the higher dose aspirin group had slightly higher rates of study-defined minor bleeding. These data allow only for assessment of the effects of early aspirin dosing, but they are consistent with meta-analyses and are supportive of the concept of low-dose aspirin therapy.


Guidelines for patients with NSTE-ACS or for those undergoing percutaneous coronary intervention (PCI) recommend an initial dose of 162 mg to 325 mg. After stenting, the recommended dose has been 325 mg for at least 1 month (bare-metal stent), 3 months (sirolimus-coated stent), or 6 months (paclitaxel-coated stent). To decrease the risk of bleeding, the aspirin dose may be reduced to 81 mg to 162 mg. However, recent PCI-based guidelines allow for the long-term use of 81 mg daily in place of a higher dose.


P2Y 12 Antagonists


Management of ACS involves dual antiplatelet therapy with aspirin and a P2Y 12 antagonist such as clopidogrel or prasugrel, which are thienopyridines, or ticagrelor, a member of a different chemical class. Three currently available thienopyridines include ticlopidine, clopidogrel, and prasugrel. Thienopyridines act by irreversibly blocking the P2Y 12 ADP receptor on the platelet surface, thereby interrupting platelet activation and aggregation. When administered at the currently approved doses, clopidogrel 75 mg daily and ticlopidine 250 mg twice daily achieve at steady state a moderate level of median platelet inhibition (20% to 35%) as assessed by using 20 µmol/L ADP as the agonist. Prasugrel at 10 mg achieves a level of inhibition of approximately 60% to the same agonist. An earlier effect on platelet function occurs with administration of a loading dose, although the absolute degree of platelet inhibition is marginally increased with higher doses once steady state is achieved. The thienopyridines also have a number of other effects that are not fully characterized on platelet function beyond inhibition of ADP-induced aggregation, such as inhibition of platelet activation, reduction in fibrinogen levels and blood viscosity, and less erythrocyte deformability and aggregability. If rapid onset of platelet inhibition is required (e.g., at the time of intracoronary stenting), a loading dose should be administered.


Clopidogrel


The combination of aspirin plus clopidogrel was compared with aspirin alone in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial of 12,562 patients with NSTE-ACS treated for 3 to 12 months. Clopidogrel reduced the composite of death, MI, and stroke by 20% compared with placebo, with benefit evident both in the first 30 days and over the ensuing average follow-up of up to 9 months. In addition, a 38% increase was seen in the rate of bleeding overall, with patients who underwent coronary artery bypass graft (CABG) within 5 days of the discontinuation of clopidogrel at particular risk (53% increased rate). In a secondary analysis (PCI-CURE) of patients in the CURE trial who underwent PCI, patients pretreated with clopidogrel for a median of 10 days had a reduction in both early (30 day) and long-term CV events. ACC/AHA UA/NSTEMI guidelines consider the use of clopidogrel in addition to aspirin to have a class I indication for patients with NSTE-ACS who are undergoing an early noninterventional or interventional approach and who are not at risk for major bleeding. For patients with planned elective CABG, the drug should be withheld for 5 to 7 days to reduce the risk of perioperative bleeding and transfusion.


Several important issues regarding treatment with clopidogrel remain controversial: the optimal loading dose, duration of therapy, and clinical relevance of genetic differences and clopidogrel resistance. Without a loading dose, clopidogrel achieves steady-state levels of platelet inhibition in 4 to 7 days. Administration of various loading doses has been studied, with reductions in the time to steady state of 12 to 48 hours (for 300 mg) to 2 to 6 hours (for 600 to 900 mg). Data from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial suggested that a minimum of 12 to 15 hours between the loading dose and PCI was required for a 300-mg load to demonstrate clinical benefit compared with no load, whereas the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (ARMYDA)-2 study showed better outcomes with 600 mg versus 300 mg when clopidogrel was initiated 4 to 8 hours before PCI ( Figure 9-3 ). The CURRENT-OASIS 7 trial compared a high-dose (600-mg load followed by 150 mg/day for 7 days) to a standard dose (300-mg load followed by 75 mg/day) clopidogrel strategy in patients with ACS and planned PCI. More than 25,000 subjects were randomized in the trial. Overall, no difference was found in the primary outcome of CV death, MI, or stroke (4.2% vs. 4.4%; HR, 0.94; 95% CI, 0.83 to 1.06; P = .30); however, study-defined major bleeding was higher (2.5% vs. 2.0%; HR, 1.24; 95% CI, 1.05 to 1.46; P = .01). These data do not formally support the use of higher dose clopidogrel following ACS. However, in the more than 17,000 patients who underwent PCI during the trial, a 15% relative reduction in the primary endpoint was observed. Current ACS and PCI guidelines allow for loading doses of 300 to 600 mg, followed by 75 mg daily in patients with ACS.




FIGURE 9-3


Main results of the ARMYDA-2 trial. ARMYDA-2 compared 600 mg clopidogrel with 300 mg administered 4 to 8 hours before percutaneous coronary intervention (PCI) in 255 patients with known coronary artery disease. The rate of the primary composite endpoint of death, myocardial infarction (MI), or target vessel revascularization up to 30 days after PCI, as well as the rates of elevated biomarkers of myonecrosis after PCI, were reduced with clopidogrel 600 mg. The rate of MI following PCI with 300 mg was unexpectedly higher than has been reported in similar studies. CK-MB elev., creatine kinase–myocardial band elevation; TnI elev., Troponin I elevation.

(From Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet Therapy for Reduction of Myocardial Damage during Angioplasty) study. Circulation 2005;111:2099-2106.)


Prasugrel


Prasugrel is a thienopyridine, which compared with clopidogrel has 1) faster onset of action for more efficient metabolism, 2) a higher degree of ex vivo platelet inhibition, and 3) less intrapatient variability. In pharmacodynamic studies, prasugrel had fewer poor responders compared with a standard or higher dose of clopidogrel. Prasugrel (60-mg loading dose followed by 10 mg/day) was compared with clopidogrel (300-mg loading dose followed by 75 mg/day) for up to 15 months in patients with ACS and planned PCI in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON)–Thrombolysis in Myocardial Infarction TIMI 38. More than 13,500 subjects were randomized to prasugrel or clopidogrel in combination with aspirin. Prasugrel treatment resulted in a reduction in the primary endpoint of CV death, MI, or stroke (9.9% vs. 12.1%; HR, 0.81; 95% CI, 0.73 to 0.90; P < .001). The difference in the outcomes was largely related to a 24% reduction in MI. Rates of stent thrombosis were also significantly reduced with prasugrel, and prasugrel treatment also resulted in an increase in the primary safety assessment of non–coronary bypass–associated TIMI major bleeding with 1.8% versus 2.4% of subjects (HR, 1.32; 95% CI, 1.03 to 1.68; P = .03). The most severe bleeding events, including fatal bleeding, were also increased. An analysis of the data from this study identified patients with prior stroke or transient ischemic attack (TIA) as a subgroup that did not benefit from more intensive antiplatelet therapy with prasugrel compared with clopidogrel. In addition, patients who were older than 75 years or who weighed less than 60 kg were subgroups for whom the benefit did not clearly exceed the risk. As a result of these data, prasugrel was approved for use in patients with ACS and planned PCI. Based on trial design, in patients with NSTE-ACS, prasugrel should be given once it is known that PCI is planned; it should not be given in a broad ACS population, such as that studied in the CURE trial. Higher rates of CABG-related bleeding were also observed.


In the 2011 UA/NSTEMI ACC/AHA guideline update, prasugrel is given a class I indication for patients with ACS in whom PCI is planned but a class III recommendation (not recommended) in patients with a prior stroke or TIA. In patients for whom CABG is planned, it is recommended that prasugrel be withheld for 7 days prior to the procedure whenever possible.


Ticagrelor


Ticagrelor is an oral antiplatelet agent that is the first member of a new class of P2Y 12 receptor antagonists known as the cyclopentyltriazolopyrimidines (CPTPs) . Ticagrelor is a direct-acting antiplatelet agent that does not require metabolism for its effect, distinct from the thienopyridines. In addition, it does not bind irreversibly to the P2Y 12 receptor. Ticagrelor results in more rapid onset of antiplatelet effect, more potent antiplatelet effect, and fewer poor responders than standard-dose clopidogrel. Although ticagrelor is pharmacologically reversible because of the higher level of platelet inhibition even after discontinuation, compared with clopidogrel, higher levels of platelet inhibition remain for approximately 4 days. Ticagrelor (180-mg loading dose followed by 90 mg twice daily) was compared with clopidogrel (300- to 600-mg loading dose followed by 75 mg/day) in the Platelet Inhibition and Patient Outcomes (PLATO) trial. More than 18,500 subjects with ACS were randomized to be treated medically, surgically, or with PCI. Overall, ticagrelor treatment resulted in a reduction in the primary endpoint of CV death, MI, or stroke of 9.8% versus 11.7% with clopidogrel (HR, 0.84; 95% CI, 0.77 to 0.92; P < .001). The difference in primary outcome was driven by significant reductions in CV death (21%) and MI (16%). Rates of stent thrombosis were also reduced with ticagrelor, and it was not associated with an increase in total study-defined major bleeding episodes. However, study-defined non–CABG-related major bleeding was increased by 19%, and CABG-related bleeding was similar between groups. Consistent reductions in major efficacy events were seen across broad subgroups of patients, and no specific subgroups at risk were identified. No benefit was observed in patients who were treated long term with high-dose aspirin (predominantly in the United States), although no plausible mechanism of action to explain these results in known. Patients were more likely to experience dyspnea, which tended to be self-limited and was not demonstrated to be associated with CV or pulmonary pathology. As a result of these data, ticagrelor was approved for use across the spectrum of ACS; however, the U.S. Food and Drug Administration (FDA) has issued a warning that ticagrelor should be used in combination with low-dose aspirin (<100 mg) and should be withheld from patients undergoing CABG for 5 days prior whenever possible.


Duration of Therapy


The duration of treatment with antiplatelet therapy is an important clinical issue because the drug is costly to administer and is associated with an increased risk of bleeding. The major antiplatelet therapy trials in ACS had treatment durations of 9 to 15 months. Some data suggest increased risk of stent thrombosis in patients with drug-eluting stents when antiplatelet therapy is discontinued even beyond 1 year. In ACS patients who are not at high risk for bleeding complications, dual antiplatelet therapy is recommended for at least 1 year. After PCI, the optimal duration of clopidogrel therapy depends on the risk of subsequent thrombosis, which itself is related to the type of intervention, use of an intracoronary stent, and the type of drug-eluting stent placed, if any. These recommendations are based largely on observational data and randomized trial protocols, as opposed to randomized comparisons; further studies are awaited, including the definitive Dual Antiplatelet Therapy (DAPT) study. Other observational data have identified a strong link between the interruption of antiplatelet therapy after ACS and an increased risk of adverse outcomes, including stent thrombosis. Thus, the threshold to hold or terminate antiplatelet therapy early should be high (e.g., life-threatening bleeding or need for high-risk emergency surgery).


The Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial evaluated the usefulness of clopidogrel in addition to aspirin for a median of 28 months in high-risk patients with stable CV disease across a wide range of patients. Although no difference was noted in the primary endpoint of CV death, MI, or stroke between the clopidogrel plus aspirin group (6.8%) and the placebo plus aspirin group (7.3%; P = .22), the secondary endpoint, which also included rehospitalization for ischemic events, was reduced by 8% ( P = .04) with dual antiplatelet therapy. The secondary prevention subgroup—approximately 80% of patients enrolled had documented preexisting CV disease—had a 12% ( P = .046) lower incidence of the primary composite, whereas the remainder of asymptomatic patients (primary prevention) had a 20% excess ( P = .20), including a higher rate of CV death (3.9% vs. 2.2%; P = .01). The greatest benefit appeared to be in patients with prior MI. In the overall study population, severe bleeding tended to be more frequent in the clopidogrel group (1.7% vs. 1.3%; P = .09). Thus, longer term clopidogrel, in addition to aspirin, appeared beneficial in secondary prevention of ischemic complications among patients with established CV disease, with a trend toward more severe bleeding, but it was not useful and was found to be potentially harmful in asymptomatic patients (primary prevention).




Platelet Function Testing and Genetics


Several studies of platelet function have documented the variable pharmacologic response to standard dose clopidogrel among groups of individuals. Depending on the method, timing, and definition of “resistance,” between 5% and 30% of patients do not achieve the expected pharmacologic response to clopidogrel. Failure of clopidogrel to achieve the desired pharmacologic effect is associated with increased rates of CV events, including stent thrombosis and death. Several studies have demonstrated that increasing doses of clopidogrel can partly overcome this variability in subjects who respond poorly to standard doses. The largest study to date to examine modification of clopidogrel based on platelet function testing—Gauging Responsiveness with a Verify Now Assay: Impact on Thrombosis and Safety (GRAVITAS)—confirmed that low response to clopidogrel was associated with worse outcomes, but it failed to demonstrate that increasing doses could improve clinical outcomes. Both prasugrel and ticagrelor are associated with higher levels of platelet inhibition and lower rates of poor response. So the major results of TRITON-TIMI 38 and PLATO, showing lower ischemic event rates, support the hypothesis that targeting higher levels of platelet inhibition reduces recurrent thrombosis.


It is believed that this variable response is due in large part to genetic polymorphisms in cytochrome (CY) P450 enzymes responsible for metabolism of clopidogrel to its active metabolite. Approximately 25% to 30% of Western patients are carriers of at least one reduced-function allele of CYP 2C19. Multiple studies in patients treated with clopidogrel have demonstrated that carriers of one or more reduced-function alleles for this enzyme are associated with increased rates of ischemic events, particularly stent thrombosis. Like platelet function testing, some uncertainty remains regarding the clinical role of genetic testing. Prasugrel and ticagrelor have not been demonstrated to have worse outcomes in CYP 2C19 reduced-function carriers. The utility of altering therapy for clinical outcomes is uncertain, however; one study demonstrated that increasing the clopidogrel maintenance dose could in part overcome low platelet response in carriers of one CYP 2C19 reduced-function allele.


Intravenous Platelet Inhibitors


Glycoprotein (GP) IIb/IIIa blockers inhibit the final common pathway of platelet aggregation, namely, the binding of fibrinogen or von Willebrand factor (vWF) to the membrane GP IIb/IIIa integrin receptor. Thus they remain the most potent platelet inhibitors developed to date. Of the three agents commercially available, one is an irreversible monoclonal antibody (abciximab); the other two, eptifibatide and tirofiban, are reversible small-molecule inhibitors. The development of oral GP IIb/IIIa blockers was halted after five consecutive phase III studies demonstrated an associated increase in the mortality rate.


Initially introduced as adjuncts to PCI, the intravenous GP IIb/IIIa blockers were also studied in other populations, including patients with ACS managed medically, those about to undergo PCI, and those undergoing primary PCI for STEMI, albeit with mixed results when administered outside the catheterization laboratory. In six large, placebo-controlled trials of patients with NSTE-ACS who were undergoing PCI, the relative risks of death or MI at 30 days were reduced by 31% to 83% with the addition of IV GP IIb/IIIa inhibitors ( Figure 9-4 ). Although a meta-analysis suggested that addition of IV GP IIb/IIIa antagonists to aspirin may reduce mortality rate by one third across a wide range of patients undergoing PCI compared with those receiving single antiplatelet therapy with aspirin, the role for GP IIb/IIIa inhibitors in the era of dual oral antiplatelet inhibition is less clear.




FIGURE 9-4


Intravenous glycoprotein (GP) IIb/IIIa inhibitors in patients with non–ST-segment acute coronary syndrome undergoing percutaneous coronary intervention. The outcome of death or myocardial infarction (MI) in six clinical trials of intravenous GP IIb/IIIa inhibitors that involve more than 10,000 patients is shown. Abs, absolute; PCI, percutaneous coronary intervention; RR, relative risk.

(From Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction—2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2002;106:1893-1900.)


On a background of aspirin (varying dose) and clopidogrel (600 mg), abciximab reduced the composite of death, MI, or urgent target vessel revascularization within 30 days compared with placebo by 25% ( P = .003) in 2022 patients with NSTE-ACS enrolled in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 2 trial. However, the benefit of abciximab was restricted to those patients with an elevated baseline troponin level (relative risk [RR], 0.71) because those with a normal baseline troponin level demonstrated no benefit (RR, 0.99; P interaction = .07). No similar randomized studies have been performed on a background of the more potent oral P2Y 12 inhibitors that have been recently approved for use.


Two randomized trials did not demonstrate a benefit with routine early administration of IV GP IIb/IIIa antagonists prior to PCI compared with delayed provisional use at PCI in patients with NSTE-ACS. In a meta-analysis of these two large trials plus three smaller studies, routine upstream administration before PCI was associated with a 9% reduction in the odds of death or MI at 30 days of borderline statistical significance and no difference in mortality rate (odds ratio [OR], 1.00), at a cost of increases in major bleeding (OR, 1.34) and transfusion (OR, 1.31).


Among patients with NSTE-ACS who are not routinely scheduled to undergo coronary revascularization, a meta-analysis involving 31,402 patients demonstrated a smaller reduction in the odds of death or MI (9%; 95% CI, 0.02 to 0.16; P = .015) with addition of IV GP IIb/IIIa inhibitor therapy. However, evidence was found for heterogeneity by drug because the largest trial with abciximab, which does not sustain a high degree of platelet inhibition beyond 12 hours, showed a directionally negative effect, whereas trials with the small-molecule intravenous GP IIb/IIIa blockers revealed modest benefits. Furthermore, post-hoc analyses demonstrated greater benefit among patients at higher risk at baseline, as identified by an elevated baseline troponin level or higher TIMI risk score.


More recently, among 2022 patients with NSTE-ACS undergoing PCI, all of whom were preloaded with 600 mg of clopidogrel at least 2 hours before, the GP IIb/IIIa inhibitor abciximab reduced ischemic complications by 25% in the ISAR-REACT 2 trial. However, the benefit was seen only in patients with an elevated troponin level at baseline. An excess of thrombocytopenia was observed, but no difference in clinically important bleeding was seen among patients treated with abciximab.


Two other potent IV platelet inhibitors, cangrelor and elinogrel, are in late stages of clinical testing. Cangrelor is an IV inhibitor of the P2Y 12 receptor with a rapid action and quick onset and offset. It is more potent than clopidogrel, achieving 90% inhibition of platelet aggregation within minutes of administration of an IV infusion between 1 and 4 µg/kg/min. In the Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PLATFORM and CHAMPION-PCI trials conducted in patients undergoing PCI, the majority of whom had ACS, no statistically significant reduction was noted in the primary composite endpoint of death, MI, or ischemia-driven revascularization (OR, 0.97; P = .68) in a pooled analysis. However, secondary composite endpoints that included new Q-wave MI and stent thrombosis showed large, statistically significant benefits of 39% to 45%. An ongoing study, a Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects who Require Percutaneous Coronary Intervention (CHAMPION-PHOENIX), is evaluating cangrelor in more than 10,000 patients with stable and unstable ACS undergoing PCI who are thienopyridine naïve; it is expected to complete in late 2012.


Elinogrel is a reversible competitive P2Y 12 receptor antagonist that is direct acting and available for both IV and oral administration. It achieves immediate and near-maximal platelet inhibition intravenously and has a half-life of 12 hours. It has been studied in a pilot trial in patients undergoing primary PCI for STEMI and in patients undergoing nonurgent PCI, but large studies in patients with ACS are pending.


Conclusions


The current role of IV GP IIb/IIIa blockers in patients with NSTE-ACS is more restricted in the 2011 guidelines ( Box 9-2 ), with the strongest support as an adjunct in high-risk patients undergoing PCI or to manage thrombotic complications during PCI. A policy of routine early “upstream” administration of GP IIb/IIIa blockers is of marginal benefit, if any, and is associated with more bleeding and transfusion. Newer, potent IV inhibitors of the P2Y 12 receptor are being developed.



Box 9-2

Guideline Recommendations Regarding Intravenous GP IIb/IIIa Blockers in Patients with Non–ST-Segment Acute Coronary Syndromes


Early Invasive Management





  • Class I (LOE A): Antiplatelet therapy in addition to aspirin should be initiated before diagnostic angiography (upstream) with either clopidogrel or an intravenous GP IIb/IIIa inhibitor.



  • Class I (LOE A): Abciximab as the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to angiography and PCI is likely to be performed; otherwise, intravenous eptifibatide or tirofiban is the preferred choice of GP IIb/IIIa inhibitor.



  • Class IIa (LOE B): It is reasonable to initiate antiplatelet therapy with both clopidogrel and an intravenous GP IIb/IIIa inhibitor.



Early Conservative Management





  • Class I (LOE C): If recurrent symptoms, ischemia, heart failure, or serious arrhythmias subsequently appear, eptifibatide or tirofiban (LOE A) or clopidogrel (LOE A) should be added to aspirin and an anticoagulant before diagnostic angiography (upstream).



  • Class IIa (LOE C): If symptoms or ischemia recur with clopidogrel, aspirin, and anticoagulant therapy, it is reasonable to add a GP IIb/IIIa antagonist before diagnostic angiography.



  • Class IIa (LOE B): Abciximab is the choice for upstream GP IIb/IIIa therapy, which is indicated only if there is no appreciable delay to angiography, and PCI is likely to be performed; otherwise, intravenous eptifibatide or tirofiban is the preferred choice of GP IIb/IIIa inhibitor.



  • Class IIb (LOE B): It may be reasonable to add eptifibatide or tirofiban to anticoagulant and oral antiplatelet therapy.



  • Class III (LOE A): Abciximab should not be administered to patients in whom PCI is not planned.



GP, glycoprotein; LOE, level of evidence; PCI, percutaneous coronary intervention.


From Anderson JL, Adams CD, Antman EM, et al. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:e426-e579.




Anticoagulants


Beginning with the expression of tissue factor and ending with the production of thrombin, the biologic complexity of the coagulation cascade has yielded a number of promising targets for anticoagulation therapy ( Figure 9-5 ). Agents that inhibit the earlier portion of the cascade—tissue factor (TF) antibodies, TF/factor VIIa complex inhibitors, factor Xa inhibitors—are potent inhibitors of thrombin generation, whereas those that target more distally, such as direct thrombin inhibitors (DTIs), derive most of their pharmacologic effect by inhibiting preexisting thrombin and are important inhibitors of the contact pathway ( Table 9-2 ). Because of biologic redundancies and multiple feedback loops in the coagulation system, inhibition at one level of the cascade can have complex effects that make it difficult to predict the clinical response to these drugs.




FIGURE 9-5


Activation of the coagulation cascade and platelet aggregation in patients with acute coronary syndromes. After disruption of a vulnerable plaque, tissue factor (TF) is exposed, complexes with factor VIIa, and initiates the coagulation cascade. Factor X is activated and leads to the production of thrombin through its interaction with the prothrombinase complex (factor Va, factor Xa, calcium ion [ Ca ++ ]) on the membrane of activated platelets. Platelets may be activated via a number of pathways: two of the more potent agonists are thrombin and adenosine 5′-diphosphate. The final common step to platelet activation is fibrinogen binding, which mediates platelet-platelet interaction. Unfractionated heparin (UFH) inhibits factor Xa and thrombin to a similar degree, and low-molecular-weight heparin (LMWH) exerts a proportionally greater effect on factor Xa; direct thrombin inhibitors (DTIs) act predominantly on thrombin. Boldface indicates a qualitatively greater effect.

(Modified from Antman EM. The search for replacements for unfractionated heparin. Circulation 2001;103:2310-2314.)


TABLE 9-2

Pharmacokinetic and Pharmacodynamics of Five Novel Oral Anticoagulants










































































DABIGATRAN (PRADAXA) RIVAROXABAN (XARELTO) APIXABAN (ELIQUIS) EDOXABAN (LIXIANA) BETRIXABAN (PRT054021)
Target IIa (thrombin) Xa Xa Xa Xa
Hours to C max 2 2-4 1-3 1-2 NR
CYP metabolism None 32% 15% <4% None
Bioavailability 7% 80% 66% >45% 34%-47%
Transporters P-gp P-gp/BCRP P-gp P-gp P-gp
Protein binding 35% >90% 87% 55% NR
Half-life 12-14 h 9-13 h 8-15 h 8-10 h 19-20 h
Renal elimination 80% 66% * 25% 35% <5%
Linear PK Yes No Yes Yes Yes

BCRP, breast cancer resistance protein; CYP, cytochrome P450; NR, not reported; P-gp, P-glycoprotein; PK, pharmacokinetics.

Modified from Ruff CR, Giugliano RP. New oral antithrombotic strategies. Hot Topics in Cardiology 2010;4:7-14; Ericksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009;48:1-22; and Ruff CR, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation–Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 2010;160:635-641.

* 33% unchanged, 33% inactive metabolite.



Unfractionated heparin (UFH) had been the standard anticoagulant for decades, although extensive study over the past 2 decades with low-molecular-weight heparins (LMWHs), DTIs, and inhibitors of factor Xa are leading to updates of practice guidelines (see Chapter 8 ).


Unfractionated Heparin and Low-Molecular-Weight Heparin


The optimal dose of unfractionated heparin (UFH) has not been rigorously established; however, several studies support a lower, weight-based dosing regimen to improve the safety profile without apparent loss of efficacy ( Table 9-3 ). In the ISAR-REACT 3A trial, patients with symptoms of unstable angina and negative initial biomarkers were randomized to a lower, single bolus of UFH (100 U/kg) and compared with the standard UFH bolus used in Germany (140 U/kg). All patients received aspirin and clopidogrel prior to PCI. In these low-risk patients, the lower dose UFH was found to be very similar to higher dose heparin in suppressing ischemia and reducing bleeding. Even lower doses of UFH (e.g., 30 to 60 U/kg), particularly in combination with GP IIb/IIIa inhibitors, have been proposed and tested in small studies. Nevertheless, the presence of a number of limitations of UFH ( Table 9-4 ) have led to the search for a replacement anticoagulant.



TABLE 9-3

Dosing of Antithrombotic Agents in Patients with Non–ST-Segment Elevation ACS




















































During PCI
INITIAL MEDICAL THERAPY IF RECEIVED PRIOR TO PCI NO PRE-PCI THERAPY POST PCI
Bivalirudin Bolus: 0.1 mg/kg IV
Inf: 0.25 mg/kg/h
Bolus: 0.5 mg/kg IV
Inf: 1.75 mg/kg/h
Bolus: 0.75 mg/kg IV
Inf: 1.75 mg/kg/h
None or continue for up to 4 h
Dalteparin 120 IU/kg SC q12h * Add UFH to target ACT; dose depends on use of GP IIb/IIIa and device || Add UFH; dose depends on use of GP IIb/IIIa ** None
Enoxaparin Bolus (optional): 30 U IV
1 mg/kg SC q12h†
Last SC dose <8 h: none
Last SC dose >8 h: 0.3 mg/kg IV
0.5-0.75 mg/kg IV None
Fondaparinux 2.5 mg SC q24h Add UFH: 50-60 U/kg Add UFH: 50-60 U/kg None
UFH Bolus: 60 U/kg
Inf: 12 U/kg/h
Target ACT depending on use of GP IIb/IIIa § Dose depends on use of GP IIb/IIIa ** None
Rivaroxaban 2.5 mg PO twice daily Not applicable Not applicable 2.5 mg PO q12h

†q24h dosing if creatinine clearance <30 mL/min.

|| If GP IIb/IIIa inhibitor: target ACT 200 sec using UFH. If no GP IIb/IIIa inhibitor, target ACT 250-300 sec for HemoTec, 300-350 sec for Hemochron.

ACS, acute coronary syndrome; ACT, activated clotting time; aPTT, activated partial thromboplastin time; GP, glycoprotein; Inf., infusion; IV, intravenous; PCI, percutaneous coronary intervention; PO, oral; UFH, unfractionated heparin; SC, subcutaneous.

Modified from Anderson JL, Adams CD, Antman EM, et al. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:e426-e579.

* 10,000 IU maximum.


4000 U maximum.


1000 U/h maximum initial infusion, thereafter titrated to aPTT 1.5 to 2.5 times control.


§ If GP IIb/IIIa inhibitor: target ACT 200 sec. If no GP IIb/IIIa inhibitor, target ACT 250-300 sec for HemoTec, 300-350 sec for Hemochron.


** If GP IIb/IIIa inhibitor: UFH 60-70 U/kg. If no GP IIb/IIIa inhibitor, UFH 100-140 U/kg.



TABLE 9-4

Limitations of UFH and Comparison with Other Anticoagulants



















































































Comparator Anticoagulants
PROPERTIES OF UFH PHARMACOLOGIC CONSEQUENCES CLINICAL CONSEQUENCES LMWH DTI FXa Inhibitor
Thrombin-Dependent Properties
Nonspecific protein binding Less drug binding to thrombin Variable anticoagulation levels; requires frequent monitoring + 0 0
Sensitivity to inactivation by PF4 and histidine-rich glycoprotein + 0 0
Depletion of TFPI ↓ Attenuation of TF/factor VIIa complex Rebound hypercoaguability 0 ++ 0
Relative inability to inhibit fibrin-bound thrombin Thrombin generation after clot lysis at therapeutic levels Rebound thrombosis during and after therapy ++ 0 ?
Requires co-factor (AT III) to optimally bind thrombin ↓ Thrombin-inhibition if AT III not available Cannot be used in patients with AT III deficiency 0 0 ++
Thrombin-Independent Properties
↑ Binding to platelets Immunogenicity ↑ Potential for bleeding, HITTS, or thrombosis + 0 0
↑ Platelet activation/adhesion + 0 0
Inability to blunt the increase in vWF levels ↑ vWF levels ↑ Potential for thrombosis 0 + ?
Primarily excreted renally ↓ Drug clearance, ↑ blood levels with renal insufficiency ↑ Potential for bleeding in renal insufficiency ++ * *

AT, antithrombin; DTI, direct thrombin inhibitor; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; HITTS, heparin-induced thrombosis-thrombocytopenia syndrome; PF4, platelet factor IV, TF, tissue factor; TFPI, tissue factor pathway inhibitor; vWF, von Willebrand factor; ↑, increased; ↓, decreased.

Modified from Antman EM. The search for replacements for unfractionated heparin. Circulation 2001;103:2310-2314.

* Dependent on the specific drug.



Unlike UFH, the LMWHs have a number of other advantages that include less nonspecific binding to proteins and platelets, less depletion of TF pathway inhibitor, and greater inhibition of vWF. Furthermore, the better bioavailability and longer half-life permits subcutaneous dosing, thereby improving the ease of administration both in and out of the hospital (see Table 9-4 ). Although more than a dozen different LMWH preparations have been developed, only two—enoxaparin and dalteparin—have been widely studied in patients with ACS. Enoxaparin has a lower molecular weight (4200 vs. 6000 Da), slightly higher anti-Xa/anti-IIa ratio (3.8 : 1 vs. 2.7 : 1), and greater inhibition of vWF compared with dalteparin. Both drugs are administered subcutaneously in a weight-based fashion in their maintenance dosing, whereas an IV bolus dose of 30 mg enoxaparin has also been studied in NSTE-ACS and as an adjunct to fibrinolysis in STEMI (see Table 9-3 ). In the only randomized clinical trial that compared two LMWHs head to head, enoxaparin was more efficacious than tinzaparin.


A meta-analysis of four trials composed of 999 patients demonstrated a large reduction (5.5% to 2.6%; P = .018) in death or MI with the addition of UFH to aspirin compared with aspirin monotherapy. Similarly, the Fragmin During Instability in Coronary Artery Disease (FRISC) trial demonstrated a 63% reduction in death or MI at 7 days with dalteparin plus aspirin compared with aspirin monotherapy (4.8% vs. 1.8%; P = .001).


Several randomized trials have compared LMWH with UFH on a background of aspirin. Dalteparin and fraxiparin did not improve outcomes compared with UFH in the Fragmin in Unstable Coronary Artery Disease (FRIC) and Fraxaparin in Ischaemic Syndrome (FRAX.I.S) trials, respectively. However, several trials comparing enoxaparin with UFH have demonstrated either superiority of enoxaparin or, at worst, noninferiority compared to UFH with regard to prevention of ischemic complications. In a meta-analysis of six trials in more than 22,000 patients conducted over the past 15 years, enoxaparin was associated with a 9% reduction in the rate of death or MI with no increase in the rates of major bleeding or transfusions ( Figure 9-6 ). This robust dataset with enoxaparin has led to both major guidelines endorsing enoxaparin as a class I recommendation in patients with NSTE-ACS, whether managed conservatively or with plans for early angiography.




FIGURE 9-6


Systematic overview of trials comparing enoxaparin (Enox) with unfractionated heparin (UFH) in non–ST-segment acute coronary sydrome (NSTE-ACS). Enoxaparin reduced the rate of death or new myocardial infarction (MI) at 30 days by 0.9% (9% relative risk reduction) in an analysis of six trials in 21,946 patients with NSTE-ACS. No statistical difference was found between the treatments in the rates of transfusion or major bleeding. CI, confidence interval; TIMI, Thrombolysis in Myocardial Infarction.


In the Superior Yield of the new Strategy of Enoxaparin, Revasculization and Glycoprotein IIb/IIIa Inibitors (SYNERGY) trial comparing UFH with enoxaparin, patients who received an antithrombin before randomization experienced higher absolute rates of bleeding after randomization. This finding was confirmed in the Stack-on to Enoxaparin (STACKENOX) trial in which a 70 U/kg bolus of UFH 4 to 10 hours after the last dose of enoxaparin (1 mg/kg) resulted in excess peri- and post-PCI bleeding in the setting of supratherapeutic anti-Xa and anti-IIa levels. Furthermore, inhibition of thrombin generation was complete despite an activated clotting time less than 270 seconds. Thus, the practice of switching between antithrombins in the same patient in the course of a single hospitalization should be avoided whenever possible.


Given similar or slightly better efficacy with enoxaparin compared with UFH in patients and other practical conveniences—twice-daily subcutaneous injections, absence of the need for routine monitoring, and simple weight-based dosing—the use of enoxaparin should generally be preferred over UFH in most patients with NSTE-ACS (class IIa recommendation).


Direct Thrombin Inhibitors


Three parenteral DTIs—hirudin, bivalirudin, and argatroban—are currently available for clinical use in the United States. They are termed direct because they do not require a cofactor, as do the heparins, and they directly inhibit existing thrombin but have minimal effects on the proximal portions of the coagulation cascade (see Figure 9-5 ).


A meta-analysis of five trials involving 20,570 patients with NSTE-ACS randomized to a DTI versus UFH concluded that DTI reduced death or MI by 20% (OR, 0.80; 95% CI, 0.70 to 0.92) from 4.6% to 3.7% with similar effects on death (OR, 0.82) and MI (OR, 0.78) individually. DTIs were associated with a near doubling in the rate of major bleeding (1.0% vs. 0.5%; OR, 1.79; 95% CI, 1.29 to 2.50); however, heterogeneity in the applied definitions and observed results, both among different agents and across studies with the same agent, limits the precision of this estimate. In addition, the reductions in ischemic events were inconsistent across different DTIs, with no evidence of benefit with monovalent agents (inogatran, effegatran). Thus, in patients with a history of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS), hirudin, argatroban, and bivalirudin are reasonable alternatives to LMWHs and UFH.


More contemporary data are now available on the use of DTIs in patients who are treated with more modern adjuncts that include the thienopyridines, IV GP IIb/IIIa inhibitors, and drug-eluting stents. In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial of 6010 patients who were undergoing urgent or elective PCI, bivalirudin (with provisional use of an IV GP IIb/IIIa blocker in 7% of patients) was not inferior to the combination of UFH and an IV GP IIb/IIIa blocker, as assessed by the quadruple composite endpoint of death, MI, urgent target vessel revascularization, and major bleeding. No differences emerged in long-term efficacy relative to death, MI, or repeat revascularization.


The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial was a three-arm trial that compared bivalirudin with or without GP IIb/IIIa inhibition with heparin plus GP IIb/IIa inhibition in 13,819 patients with ACS managed with an early invasive strategy. The principal finding was that treatment with bivalirudin alone reduced the net clinical composite endpoint—death, reinfarction, unplanned revascularization for ischemia, major bleeding—at 30 days compared with either arm that included a GP IIb/IIIa blocker, although the results were primarily driven by a reduction in bleeding ( Figure 9-7 ). In addition, bivalirudin alone was noninferior (25% boundary) to UFH/enoxaparin plus a GP IIb/IIIa inhibitor for the triple ischemic endpoint of death, reinfarction, and unplanned revascularization for ischemia. The combination of bivalirudin plus a GP IIb/IIIa inhibitor did not appear to offer any additional ischemic benefit and was associated with more bleeding compared with bivalirudin monotherapy. In other analyses from the ACUITY trial, switching to bivalirudin monotherapy, either before or at the time of PCI, was as safe and effective as UFH plus a GP IIb/IIIa blocker.




FIGURE 9-7


Major findings at 30 days in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. In this trial, 13,819 patients were randomized to either bivalirudin monotherapy, bivalirudin plus a glycoprotein (GP) IIb/IIIa inhibitor, or heparin (unfractionated heparin [ UFH ] or enoxaparin) plus a GP IIb/IIIa inhibitor. Bivalirudin reduced the net clinical outcome (composite ischemia or major bleeding) compared with either arm with a GP IIb/IIIa inhibitor, a difference primarily driven by the reduction in ACUITY major bleeding. No difference was found in the composite ischemic endpoint among the three groups.

(From Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-2216.)


Results at 1 year were consistent with the 30-day results, and no difference in mortality rate was found among the three groups through 1 year, despite the early reduction in bleeding observed with bivalirudin. An economic analysis concluded that despite higher drug costs associated with bivalirudin-based strategies, the aggregate costs through 30 days were lowest with bivalirudin monotherapy compared with several alternative strategies that included GP IIb/IIIa inhibitors, whether administered routinely early or selectively at the time of PCI, with heparin. If bivalirudin monotherapy is selected, to avoid early stent thrombosis it is important to initiate early and potent oral dual antiplatelet therapy, such as aspirin plus 600 mg clopidogrel or one of the newer, more potent P2Y 12 inhibitors.


In ISAR-REACT 3, 4570 patients with stable or unstable angina pretreated with clopidogrel 600 mg at least 2 hours prior to PCI were randomized to bivalirudin or UFH 140 U/kg (no GP IIb/IIIa inhibitors). Similar rates of the net clinical composite, ischemia plus bleeding, occurred (8.3% vs. 8.7%; P = .57). Although fewer major bleeds occurred with bivalirudin, this was offset by a numeric excess in ischemic complications (5.9% vs. 5.0%). Of note, the dose of UFH used is higher than what is typically used in North America and higher than the dose recommended in current guidelines.


In the ISAR-REACT 4 trial, 1721 patients with NSTEMI were randomized to abciximab plus UFH 70 U/kg or bivalirudin monotherapy. No differences were seen in either the primary (death, large MI, urgent target-vessel revascularization, or major bleeding) or secondary (above minus bleeding) composite endpoints at 30 days between the groups. Major bleeding occurred less frequently with bivalirudin monotherapy (2.6% vs. 4.6%; P = .02).


Oral DTIs have also been developed and could potentially have a role during or after NSTE-ACS. In a dose-ranging trial after MI, ximelagatran was more effective than placebo at reducing ischemic complications, although an excess in asymptomatic elevation of liver function tests was noted with ximelagatran. Furthermore, in larger studies to prevent venothromboembolism and to prevent embolic stroke in atrial fibrillation, rare but serious clinical hepatotoxicity was observed with ximelagatran, and an FDA advisory panel has recommended against its approval.


In summary, use of bivalirudin without a GP IIb/IIIa blocker compared with heparin, either UFH or enoxaparin, reduces bleeding and offers similar to slightly less effective protection against ischemic events. This makes bivalirudin an excellent choice as an anticoagulant in patients undergoing an early invasive approach who are at high risk for bleeding.


Factor Xa Inhibitors


Several parenteral pure inhibitors of factor Xa have been developed, and one synthetic parenteral pentasaccharide, fondaparinux, is approved for use in the prevention and treatment of venothromboembolism in the United States. Fondaparinux has also been approved for use in ACS on the basis of the OASIS-5 trial, but notably not in the United States. This study compared fondaparinux 2.5 mg administered once daily subcutaneously (SC) with enoxaparin (1 mg/kg SC q12h) in 20,078 patients with NSTE-ACS. Fondaparinux was not inferior to enoxaparin with respect to the primary efficacy triple composite of death, MI, or recurrent ischemia through 9 days (5.8% vs. 5.7%; HR, 1.01 [0.90 to 1.13]). Fondaparinux was associated with approximately half the number of major bleeding events (2.2% vs. 4.1%; HR, 0.52; P < .001) and 25% fewer transfusions. Fondaparinux achieved significantly lower intensity and less variability of anticoagulation than enoxaparin, although the dosing of enoxaparin—particularly around the time of coronary angiography and PCI, when UFH was added in addition to enoxaparin—may not have been optimal. The mortality rates at 30 days ( P = .02) and 6 months ( P = .05) were lower with fondaparinux, although the explanation for the mortality reduction is not clear. An economic analysis from OASIS-5 estimated that fondaparinux during hospitalization for NSTE-ACS would save an average of $547 per patient over a 6-month period, and it increased the number of quality-adjusted life years (QALYs) under most scenarios. The European Society of Cardiology (ESC) now endorses fondaparinux as the preferred anticoagulant in patients with NSTE-ACS.


It should be noted that a higher rate of catheter-related thrombosis was seen in OASIS-5 as well as in patients undergoing primary PCI for STEMI in OASIS-6, and has limited the acceptance of fondaparinux, particularly among interventionalists. Because fondaparinux does not directly inhibit factor IIa, and is consequently less effective at blocking the contact pathway, the addition of UFH during PCI was studied. A low-dose UFH regimen of 50 U/kg to support PCI in patients treated upstream with fondaparinux 2.5 mg daily was found to be as safe and effective as standard-dose UFH in the Fondaparinux Trial with Unfractionated Heparin During Revascularization in Acute Coronary Syndromes (FUTURA)-OASIS 8 trial. Therefore in patients with NSTE-ACS who are treated with fondaparinux and require PCI, the addition of low-dose UFH is recommended to reduce the risk of catheter-related thrombosis.


A second parenteral and direct factor Xa inhibitor, otamixaban, that does not appear to increase catheter-related thrombosis is in late stage development. In the Otamixaban for the Treatment of Patients with Non–ST-Elevation Acute Coronary Syndromes (SEPIA-ACS1-TIMI) 42 trial, IV infusions of otamixaban of 0.105 and 0.140 mg/kg/h reduced ischemic complications and had a similar bleeding profile to UFH plus eptifibatide. The Randomized, Double-Blind, Triple-Dummy Trial to Compare the Efficacy of Otamixaban with UFH Plus Eptifibatide in Patients with Unstable Angina/NSTEMI Scheduled to Undergo an Early Invasive Strategy (TAO), a large phase III trial with otamixaban in patients with NSTE-ACS, is well under way.


A number of oral factor Xa inhibitors have been developed (see Table 9-2 ), and two have been studied in large phase III trials. Apixiban (5 mg twice daily) was investigated in the Apixaban for Prevention of Acute Ischemic Events (APPRAISE)-2 trial in combination with aspirin plus clopidogrel. The trial was prematurely terminated by an independent data safety monitoring board because of an unacceptably high rate of bleeding without demonstration of efficacy. Meanwhile, in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in MI (ATLAS AC2-TIMI) 51 trial, low doses of rivaroxaban (2.5 mg bid and 5.0 mg bid, which are 25% and 50% of the approved dose, respectively, for patients with atrial fibrillation) reduced the primary composite of death, MI, or stroke by 16% (8.9% and 10.7%, respectively; P = .008) compared with standard antiplatelet therapy alone without an anticoagulant in 15,527 patients following ACS ( Figure 9-8 ). In addition, substantial reductions were also noted in the overall mortality and stent thrombosis rates with rivaroxaban, although an excess of bleeding, including intracranial bleeding, was observed.




FIGURE 9-8


Primary efficacy and safety outcomes in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndromes (ATLAS-ACS) Thrombolysis in Myocardial Infarction (TIMI) 51. Rivaroxaban (2.5 mg and 5.0 mg twice daily, dose groups pooled) reduced the primary efficacy composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke by 1.8% absolute compared with placebo in the intention-to-treat analysis in 15,526 patients after acute coronary syndrome. A 1.5% absolute increase was seen in non–coronary artery bypass graft (CABG) Thrombolysis in Myocardial Infarction major bleeding, but CV mortality rate was reduced by 0.8% with rivaroxaban.

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Mar 21, 2019 | Posted by in GENERAL | Comments Off on Non–ST-Segment Elevation Acute Coronary Syndromes
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