Treatment Strategies for Acute Coronary Syndromes: Optimizing Antiplatelet and Antithrombin Therapy in Special Populations CME


Complete author affiliations and disclosures are at the end of this activity.


Release Date: September 28, 2007

Patient History and Introduction

 

Patient Image

The patient is a 75-year-old woman with a history of type 2 diabetes mellitus and hypertension who presents with a complaint of mid epigastric burning discomfort and diaphoresis for 6 hours. On examination, she weighs 58 kg, her blood pressure is 165/92 mm Hg, and her heart rate is 106 beats/min. Cardiac examination reveals a regular rhythm, with an S4 gallop. Examination of her lungs reveals fine basilar crackles.

An electrocardiogram (ECG) performed 25 minutes after arrival to the emergency department reveals sinus tachycardia with 1 mm of ST-segment depression in leads II, III, F, I, and L. Laboratory evaluation reveals a hematocrit of 38%, white blood cell count of 6, and serum creatinine of 1.5 mg/dL. Cardiac troponin is 0.11 ng/mL (99th percentile for this assay is 0.08 ng/mL). The patient's suitability for an early invasive strategy is considered.


Coronary heart disease is the leading cause of death in the United States, accounting for approximately 20% of all deaths (Rosamond, 2007). There are an estimated 565,000 cases of new myocardial infarction (MI) each year, and another 300,000 cases of recurrent MI, with estimated total direct and indirect treatment costs exceeding $150 billion per year. The acute coronary syndromes (ACS) of unstable angina (UA), non-ST-segment elevation MI (NSTEMI), and ST-segment elevation MI (STEMI) account for more than 1.5 million hospitalizations annually. Several factors are expected to contribute to an increase in the burden of cardiovascular disease during the next several decades in the United States and around the world (Turpie, 2006). The average age of the US population is increasing, resulting in a growing number of people with coronary artery disease (CAD) and other chronic health problems. In addition, the rising prevalence of risk factors such as diabetes and obesity is an important factor in the growing burden of ACS (Fox, 2007a; Diercks, 2006).


Rapid recognition and treatment are essential to reduce the consequences of ACS. Data from the Intracoronary Stenting With Antithrombotic Regimen Cooling Off (ISAR-COOL) study showed that delayed intervention in patients experiencing symptoms of unstable angina is associated with an increased risk of death and MI. Patients in this study were split into an early intervention group and a delayed intervention group. Patients in the early intervention group underwent coronary angiography within 6 hours of arriving at the hospital; they also received concomitant antithrombotic therapy. Patients in the delayed intervention group received antithrombotic therapy for 3 to 5 days followed by coronary intervention. This study demonstrated that early intervention is superior to delayed intervention in patients presenting with acute unstable coronary syndromes (Figure 1) (Neumann, 2003).

Figure 1: Cumulative incidence of death and myocardial infarction at 30 days.
Figure 1. Cumulative incidence of death and myocardial infarction at 30 days. P value is from unadjusted χ2 test. From Neumann, JAMA., 2003.

Despite the benefits of early treatment, there are obstacles to the rapid recognition and treatment of ACS. Only about 20% of cases of ACS are preceded by longstanding angina, and approximately 15% of patients with STEMI or NSTEMI die before they ever reach a hospital (Turpie, 2006). Recognition of ACS may be especially challenging in older patients, who often lack chest pain at the time of presentation, and are more likely to present with atypical symptoms that include dyspnea, diaphoresis, nausea and vomiting, or syncope (Alexander, 2007). Patients with diabetes are also more likely to present with mild or atypical symptoms of ACS (Trichon, 2004).

The ACC/AHA guidelines recommend that patients with symptoms of ACS should undergo immediate (within 10 minutes) 12-lead ECG upon arrival in the emergency department (Anderson, 2007). However, only about one third of patients in US hospitals undergo ECG within this time period. The delay between presentation and ECG is longer for elderly patients: a mean of 47 minutes for patients over the age of 85 vs a mean of 40 minutes for younger patients (Alexander, 2007). Older patients are also more likely to have nondiagnostic ECGs.

Individuals with diabetes are at increased risk for CAD, are more likely to experience poor treatment outcomes, and are less likely to receive effective therapies (Bakhai, 2005; Trichon, 2004; Klein, 2004). Compared with patients without diabetes, a history of diabetes increases the risk of CAD by approximately 2- to 4-fold and the mortality rate following MI by approximately 1.5- to 2-fold (Trichon, 2004; Klein, 2004). Patients with diabetes exhibit numerous biological abnormalities that increase their risk of additional ischemic events following MI, including endothelial dysfunction, increased platelet activity, high levels of fibrinogen, and low levels of antithrombin III (Klein, 2004). Prospective registry studies have found that patients with diabetes have a low rate of invasive management and use of preventive medications (eg, beta blockers, antiplatelet agents) despite their high risk for mortality and future cardiovascular events (Bakhai, 2005; Hackam, 2004).

Other clinical characteristics also suggest a high risk of adverse outcomes for patients with ACS. One simple-to-use system to estimate the risk of mortality or new ischemic events is the Thrombolysis In Myocardial Infarction (TIMI) risk score, which was derived using data from several large clinical trials of patients with UA/NSTEMI (Antman, 2000). A total of 7 risk factors were identified that predicted increasing cardiovascular risk:

The likelihood of new ischemic events within 14 days of presentation increased significantly with TIMI risk score, from 4.7% for patients with a score of 0 to approximately 40% for patients with a score of 6 (Figure 2) (Antman, 2000). This easy-to-calculate score provides a rapid method to use data that are commonly ascertained for patients hospitalized with UA/NSTEMI to estimate the patient's degree of risk of mortality and other clinical outcomes.

Figure 2: Results of all-cause mortality, myocardial infarction, and severe recurrent ischemic prompting urgent revascularization through 14 days after randomization were calculated for various patient subgroups based on the number of risk factors present in the test cohort
Figure 2. Results of all-cause mortality, myocardial infarction, and severe recurrent ischemic prompting urgent revascularization through 14 days after randomization were calculated for various patient subgroups based on the number of risk factors present in the test cohort (the unfractionated heparin group in the Thrombolysis in Myocardial Infarction [TIMI] 11B trial; n = 1957). Event rates increased significantly as the TIMI score increased (P < .001 by χ2 for trend). From Antman, JAMA., 2000.

The ACC/AHA guidelines for UA/NSTEMI recommend an early invasive strategy of angiography and revascularization for patients with high-risk characteristics, which include the following:

Patients with none of these characteristics may be managed using either an invasive or conservative strategy. These recommendations were based on the results of several randomized controlled trials demonstrating that an early invasive strategy for patients with UA/NSTEMI is associated with a lower risk of mortality or new ischemic events (Anderson, 2007). Despite the benefits of an early invasive strategy for patients with high-risk features, only about 60% of patients with high-risk NSTEMI undergo early (within 48 hours) intervention, and patients who are at highest risk -- who are most likely to benefit -- are least likely to undergo invasive treatment. Although the number of high-risk patients who are treated invasively increased from approximately 50% before the introduction of the guidelines, this increase largely occurred in lower-risk patients (Tricoci, 2006).

The contemporary management of ACS, which relies on invasive procedures and many medications, presents special challenges in the treatment of elderly patients. These patients are often excluded from clinical trials, and their response to therapy is therefore less well understood than younger patients. They are also more likely than younger patients to exhibit changes in cardiac function, such as decreased arterial compliance, increased cardiac afterload, and left ventricular dysfunction, and they are more likely to have impaired physical or cognitive function, comorbid illnesses, and changes in drug metabolism (Alexander, 2007). Despite these obstacles, a recent review of acute coronary care by the AHA concluded that the potential benefits of an early invasive strategy also extend to elderly patients (Alexander, 2007). As in younger patients, adherence to ACC/AHA treatment guidelines is associated with improved outcomes even in patients aged 90 and older (Skolnick, 2007). In the Trial of Invasive Versus Medical Therapy in Elderly Patients (TIME), patients over the age of 75 with chronic symptomatic CAD were randomized to optimized medical management or invasive treatment (Pfisterer, 2003). The incidence of death or MI was similar for the 2 strategies over a 1-year follow-up period, but patients who were assigned to invasive treatment were less likely to require subsequent invasive procedures, and their total number of major adverse clinical events (a composite of death, new MI, and rehospitalization) was significantly lower than with medical management, largely as a result of a lower rate of late revascularization procedures for patients in the invasive group (Figure 3) (Pfisterer, 2003).

Figure 3: Rates of major adverse clinical events over time.
Figure 3. Rates of major adverse clinical events over time. The curves continue to diverge throughout 12 months due to an increasing number of late revascularizations in optimized medical therapy patients. From Pfisterer, JAMA., 2003.

The ACC/AHA evidence-based guidelines divide recommendations for treatment into 3 classes (Anderson, 2007). Class I recommendations are those for which there is evidence and/or general agreement that a procedure is useful and effective. Class II recommendations are those for which the evidence is conflicting. This class is further subdivided into class IIa (weight of opinion or evidence favors efficacy) or IIb (usefulness is less well established by evidence). Class III indicates that there is evidence or expert opinion that the procedure is not useful and may be harmful.

The ACC/AHA guidelines for the treatment of UA/NSTEMI recommend the use of aspirin for all patients except those with aspirin allergy or high bleeding risk, beginning as soon as possible after the onset of symptoms and continuing indefinitely. Clopidogrel is recommended for at least 1 month and ideally up to 12 months whether patients are expected to be managed noninvasively or by PCI, except for those at high risk for bleeding. Both of these are class I recommendations. The efficacy of clopidogrel for the treatment of UA/NSTEMI was demonstrated in the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) clinical trial, in which 15,562 patients with UA/NSTEMI who presented for treatment within 24 hours of the onset of symptoms were treated with aspirin and were randomized to also receive clopidogrel or placebo (Fox, 2004). Patients at high risk for bleeding, including patients who required oral anticoagulants or nonstudy antiplatelet agents, were excluded from the study. Clopidogrel was administered as a loading dose of 300 mg followed by 75 mg daily for up to 12 months (with an average duration of 9 months). The effects of clopidogrel treatment on new cardiac event are illustrated in Figure 4. An analysis of treatment response for different patient subgroups found that clopidogrel was effective for patients who were managed medically or who underwent PCI. Patients who underwent CABG tended to have a lower incidence of new events with clopidogrel, but the difference between groups was not statistically significant (Fox, 2004).

Figure 4: Cardiovascular death, myocardial infarction, or stroke in patients managed by medical therapy (A)
Figure 4. Cardiovascular death, myocardial infarction, or stroke in patients managed by medical therapy (A), in patients undergoing revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) at any time (B), in patients undergoing PCI at any time (C), and in patients undergoing CABG at any time (D). From Fox, Circulation., 2004.

In the 2007 ACC/AHA guidelines for the management of UA/NSTEMI, anticoagulation with either subcutaneous enoxaparin, fondaparinux, or intravenous unfractionated heparin (UFH) was recommended for all patients, in addition to aspirin and/or clopidogrel (class I). Bivalirudin is an additional option for patients in whom an invasive strategy is selected. As a class IIa recommendation, the guidelines recommended the use of enoxaparin or fondaparinux rather than UFH in patients in whom an initial conservative strategy is selected unless CABG surgery was planned within the next 24 hours. A number of clinical trials conducted over the last decade have demonstrated that enoxaparin was either noninferior or superior to UFH for the reduction of ischemic events for patients with UA/NSTEMI. These studies include TIMI 11B and the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) trial, which showed enoxaparin to be superior to UFH primarily in patients who were managed conservatively; and the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) and the Aggrastat to Zocor (A to Z) trials, in which enoxaparin was noninferior to UFH in patients who were managed more aggressively and were more often treated with glycoprotein (GP) IIb/IIIa inhibitors (Petersen, 2004). A subsequent meta-analysis that combined data from these and other randomized controlled trials, with a total population of nearly 22,000 patients, found that the combined incidence of death or MI during 30 days after treatment was lower for patients treated with enoxaparin (10.1%) than for those treated with UFH (11.0%; P <.05). No significant differences were observed between UFH and enoxaparin for mortality (3.0% for both groups) or for bleeding complications (major bleeding or blood transfusion) (Petersen, 2004). However, more frequent minor bleeding, such as ecchymoses at the injection site, was evident with enoxaparin in most studies. As noted previously, the TIMI risk score provides a method to estimate the risk of new ischemic events on the basis of the patient's clinical characteristics (Antman, 2000). An analysis of data from trials that compared the efficacy of enoxaparin and UFH for NSTEMI (primarily in patients who were managed conservatively) found that the increase in the risk of new events with higher TIMI risk scores was attenuated by enoxaparin treatment (Figure 5) (Antman, 2000).

Figure 5: The rate of a composite endpoint of death, myocardial infarction, or urgent revascularization increased with TIMI risk score in 2 large, randomized controlled trials
Figure 5. The rate of a composite endpoint of death, myocardial infarction, or urgent revascularization increased with TIMI risk score in 2 large, randomized controlled trials that compared enoxaparin with unfractionated heparin in patients with UA/NSTEMI. The increase in the rate of ischemic events with TIMI risk score was significantly reduced by enoxaparin in both TIMI 11B (P = .01) and ESSENCE (P = .03). From Antman, JAMA., 2000.

More recently, the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial compared enoxaparin vs UFH in 746 high-risk patients who were treated with aspirin and the GP IIb/IIIa inhibitor eptifibatide (Goodman, 2003; Fitchett, 2006). Approximately 30% of patients underwent PCI and 12% underwent CABG. Compared with UFH, enoxaparin produced significantly lower rates of major bleeding (4.6% vs 1.8% for the eptifibatide plus UFH and the eptifibatide plus enoxaparin groups, respectively; P = .03). Minor bleeding events were more common with enoxaparin. After 30 days, the incidence of death, MI, or recurrent angina with ECG changes was significantly lower with enoxaparin than with UFH (5% vs 9%; P = .03) (Goodman, 2003). Recently published long-term outcome data from this trial demonstrated that over a mean follow-up period of 2.5 years, the combined incidence of death or MI was 14.7% with UFH and 8.9% with enoxaparin, reflecting a 39% relative risk reduction (P = .024) (Fitchett, 2006).

Fondaparinux, a synthetic pentasaccharide, selectively binds antithrombin and causes rapid and predictable inhibition of factor Xa (Yusuf, 2006). The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators (OASIS-5) study compared the efficacy and safety of fondaparinux 2.5 mg daily vs enoxaparin 1 mg/kg twice daily in 20,078 patients with high-risk UA/NSTEMI; 34% were treated using PCI and 10% underwent CABG (Yusuf, 2006). The incidence of the primary endpoint of new ischemic events (death, MI, or refractory ischemia within 9 days) was nearly identical for the 2 groups (5.8% with fondaparinux, 5.7% with enoxaparin; not statistically significant), but the incidence of major bleeding and other bleeding complications was lower with fondaparinux (Figure 6). Overall mortality was significantly lower with fondaparinux after 30 days (3.5% vs 2.9%; P = .02) and 180 days (6.5% vs 5.8%; P = .05). An increased risk of catheter-related thrombosis was observed with fondaparinux.

Figure 6: Cumulative risks of death, myocardial infarction, or refractory ischemia (panel A) and of major bleeding (panel B) through day 9.
Figure 6. Cumulative risks of death, myocardial infarction, or refractory ischemia (panel A) and of major bleeding (panel B) through day 9. The hazard ratios are for the fondaparinux group as compared with the enoxaparin group. CI: confidence interval. From Yusuf, N Engl J Med., 2006.

Bivalirudin is a direct-acting synthetic antithrombotic agent (Stone, 2006). The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) study evaluated the efficacy and safety of bivalirudin vs heparin (either UFH or LMWH) in moderate- or high-risk patients with UA/NSTEMI treated using an early invasive strategy (Stone, 2006). The investigators compared 3 treatments: heparin plus a GP IIb/IIIa inhibitor; bivalirudin plus a GP IIb/IIIa inhibitor; or bivalirudin alone with a GP IIb/IIIa inhibitor only when needed for procedural complications (administered in 9.1% of patients). The rates of ischemic outcomes (a composite endpoint of death, MI, or unplanned revascularization) and major bleeding complications were similar for the bivalirudin plus GP IIb/IIIa inhibitor or the heparin plus GP IIa/IIIa inhibitor groups. Patients who received bivalirudin alone exhibited an incidence of ischemic events similar to the other 2 groups, but with a lower rate of major bleeding. Figure 7 shows a net clinical outcome measure that combines the incidence of ischemic and major bleeding outcomes for the 3 study groups. The clinical implications of this study must be interpreted with consideration of the overall very short duration of time from initiation of study drug to coronary angiography in the study.

Figure 7: Kaplan-Meier time-to-event curves for net clinical outcome, measured at 30 plus/minus 5 days; thus, follow-up is reported to 35 days.
Figure 7. Kaplan-Meier time-to-event curves for net clinical outcome, measured at 30 ? 5 days; thus, follow-up is reported to 35 days. P values are for comparison with the control group (unfractionated heparin or enoxaparin plus glycoprotein (GP) IIb/IIIa inhibitors). From Stone, N Engl J Med., 2006.

Based on clinical trials that were conducted primarily during the 1990s, the 2007 ACC/AHA guidelines for the management of UA/NSTEMI recommended the use of either clopidogrel or a platelet GP IIb/IIIa inhibitor (abciximab, tirofiban, or eptifibatide) for patients with UA/NSTEMI when an invasive intervention is planned (class I) (Anderson, 2007). For patients in whom an initial invasive strategy is selected, treatment with both clopidogrel and a GP IIb/IIIa inhibitor is reasonable if any of the following are present: delay to angiography, refractory ischemia or high risk features.

If patients are managed conservatively and PCI is not planned, the GP IIb/IIIa inhibitor abciximab should not be administered (class III). If patients who were initially managed conservatively begin to experience recurrent symptoms/ischemia, heart failure, or serious arrhythmias, the GP IIb/IIIa inhibitors eptifibatide or tirofiban, or clopidogrel should be added to aspirin and anticoagulant therapy before diagnostic angiography (class I) (Anderson, 2007).

A meta-analysis performed by Boersma and colleagues examined the results of several large, randomized clinical trials with a combined population of more than 31,000 patients with UA/NSTEMI who were not routinely scheduled for early coronary revascularization (Boersma, 2002). As shown in Figure 8, the likelihood of death or MI during 30 days after hospitalization was significantly lower for patients randomized to receive a GP IIb/IIIa inhibitor than placebo, with a reduction in ischemic events apparent as early as 5 days after treatment. It should be noted that these effects were observed only in patients with positive troponins. In general, the beneficial effects of GP IIb/IIIa inhibitors were greater in men than in women, although this difference may have been related to a greater baseline severity of heart disease in men. The difference between men and women was no longer evident when the results were adjusted for differences in baseline troponin concentrations.

The recent Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR/REACT-2) study evaluated the efficacy and safety of abciximab before PCI for high-risk patients with UA/NSTEMI who were also treated with a high loading dose of 600 mg of clopidogrel before the procedure (Kastrati, 2006). The combined incidence of death, MI, or urgent target vessel revascularization within 30 days was significantly lower with abciximab (8.9%) than with placebo (11.9%; P = .03), although the benefit of additional abciximab was observed only in patients with elevated troponins at baseline. The rates of major or minor bleeding complications did not vary between the 2 groups.

The use of enoxaparin requires consideration of dose adjustment for patients with severe renal dysfunction. Enoxaparin is primarily eliminated by the renal route, and renal impairment can increase the elimination half-life and anti-Xa activity of enoxaparin (Hulot, 2004; Lim, 2006). A recent meta-analysis of studies that examined the efficacy and safety of LMWHs (primarily enoxaparin) in patients with renal impairment found that the use of enoxaparin in these patients -- and especially in patients with CrCl < 30 mL/min -- was associated with increased risk of major bleeding complications (Lim, 2006). These results suggest that the use of tools to estimate CrCl may be more effective than relying on creatinine concentration alone. According to the prescribing information provided by the manufacturer, enoxaparin should be administered at a dosage of 1 mg/kg once daily in patients with CrCl values < 30 mL/min. However, practitioners should be aware that there exists a potential for accumulation of anticoagulant effect and an associated increase in bleeding risk in patients with reduced a CrCl that is not below 30 mL/min.

No dose adjustment is recommended for patients with renal disease who are treated with fondaparinux (Arixtra PI). In the OASIS-5 clinical trial described previously, the incidence of major bleeding complications with fondaparinux was not significantly higher for patients with CrCl < 30 mL/min (2.4% of patients) than for the study population as a whole (2.2%) (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators; 2006). In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) clinical trial of bivalirudin for patients undergoing PCI, the incidence of bleeding was lower with bivalirudin than with heparin for patients at all levels of renal function, and no increased risk of bleeding was noted for patients with renal impairment (Chew, 2005). According to the prescribing instructions provided by the manufacturer, anticoagulation status should be monitored in patients with impaired renal function who are being treated with bivalirudin. For patients with CrCl values < 30 mL/min, a reduction in the infusion rate (from 1.75 mg/kg/h to 1.0 mg/kg/h) may be considered. No adjustment of the initial bolus dose is recommended (Angiomax PI). Unfractionated heparin remains an option for patients with severe renal dysfunction.

Patients with NSTEMI who have impaired renal function (eg, CrCl < 50 mL/min) and who receive GP IIb/IIIa inhibitors are at increased risk for bleeding complications (Kirtane, 2006). Reducing the dose of GP IIb/IIIa inhibitor may reduce the risk of bleeding complications in patients with kidney disease. For example, a reduced-dose eptifibatide infusion for patients with CrCl < 50 mL/min who were undergoing PCI has been shown to reduce the risk of major bleeding complications (Kirtane, 2006). These authors also found that CrCl was more closely associated with bleeding risk than serum creatinine level.

Clinical trials of GP IIb/IIIa inhibitors have reported significantly elevated risk of bleeding complications among women (Alexander, 2006). An analysis of data from more than 500 US hospitals found that women with NSTEMI are at increased risk for bleeding complications with or without GP IIb/IIIa inhibitors, but that the increased bleeding risk associated with GP IIb/IIIa inhibitor treatment was greater for women than for men. These investigators also found that women who received GP IIb/IIIa inhibitors tended to be older than men, weighed less, had higher rates of diabetes and hypertension, were more likely to have a history of prior MI or stroke, and were more likely to have impaired renal function (Alexander, 2006). Excess dosing was significantly more common among women than men (46.4% vs 17.2%), even after adjusting for baseline clinical differences between men and women (P < .05). The authors concluded that much of the excess bleeding risk associated with GP IIb/IIIa inhibitor use in women is related to excessive dosing, and that assessment of CrCl and dose adjustment for renal impairment is especially important to avoid excess bleeding in women who are treated with these agents.

Patients with CrCl values < 50 mL/min should receive the conventional intravenous (IV) bolus dose of eptifibatide (180 mcg/kg), followed by a reduced-dose continuous IV infusion (1 mcg/kg/min, rather than the 2 mcg/kg/min conventional infusion dose) (Integrilin PI). Tirofiban should be administered as an initial IV infusion of 0.4 mcg/kg/min for 30 minutes, followed by infusion of 0.05 mcg/kg/min for patients with CrCl values < 30 mL/min, or 0.1 mcg/kg/min for patients with higher CrCl values (Aggrastat PI).

Older patients should also be considered candidates for GP IIb/IIIa inhibitors. A recent meta-analysis of randomized clinical trials of patients with UA/NSTEMI found that the benefits of GP IIb/IIIa inhibition were similar for patients across several age subgroups (< 60, 60-69, 70-79, and ≥ 80 years) (Hernandez, 2007). Older patients had larger absolute increases in the risk of major bleeding complications, but also had larger absolute reductions in the risk of death or MI (Figure 9). No specific age-related dose adjustments have been described for GP IIb/IIIa inhibitors. However, impaired renal function should always be considered as a potential reason for dose adjustment in the elderly.

Patients with diabetes often exhibit enhanced platelet reactivity and diminished responsiveness to antiplatelet medications (Angiolillo, 2007). They are also more likely to develop re-stenoses -- including completely occlusive re-stenoses -- after PCI (Flaherty, 2005). These patients may therefore benefit from more intensive antiplatelet therapy. The Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) pilot study recently evaluated a high-dose maintenance clopidogrel regimen (150 mg/d) in patients with type 2 diabetes with suboptimal platelet inhibition following conventional clopidogrel dosing (Angiolillo, 2007). The high maintenance dose produced significantly more platelet inhibition than the conventional dose of 75 mg/d, as measured on platelet aggregation laboratory tests. However, many of the patients continued to exhibit high levels of platelet reactivity even with the more intensive dosing. Clinical outcomes were not assessed in this study.

Some clinical studies have suggested that patients with diabetes may be especially likely to benefit from antiplatelet therapy. In a meta-analysis of 6 large, randomized, double-blind clinical trials that examined the efficacy of intravenous GP IIb/IIIa inhibitors for the treatment of UA/NSTEMI, the magnitude of the reduction in ischemic events was larger for patients with diabetes than for nondiabetic patients (Roffi, 2001). Patients with diabetes exhibited a significant reduction in 30-day mortality, from 6.2% in placebo-treated patients to 4.6% with GP IIb/IIIa inhibitors (P = .007). For patients without diabetes, the mortality rate was similar for untreated patients or for those who received GP IIb/IIIa inhibitors (3.0% for both groups), although the investigators noted that GP IIb/IIIa inhibitors might be effective in some subgroups of nondiabetic patients (eg, those with elevated troponins). The magnitude of benefit among patients with diabetes was greatest for those who underwent PCI (Figures 10, 11).

A second similar meta-analysis of more than 31,000 mostly conservatively treated patients with NSTEMI in large clinical trials of GP IIb/IIIa inhibitors found that these agents were effective in patients with and without diabetes (Boersma, 2002). Although patients with diabetes had a somewhat larger response to treatment than patients without diabetes, this difference was not statistically significant.

Recent reports from a large nationwide quality improvement program have shown that increased adherence to NSTEMI treatment guidelines produces better quality of care and fewer subsequent ischemic events. The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Pectoris Suppress Adverse Outcomes With Early Implementation?) quality improvement initiative is a nationwide program in more than 500 US hospitals to improve adherence to ACC/AHA guidelines for the management of NSTEMI (Mehta, 2006). Treatment patterns were assessed between January 2002 and September 2004, and guideline adherence was evaluated by comparing treatment utilization between the first and last 3-month periods of this study. Utilization of guideline-recommended acute-care medications and discharge medications improved during the course of the study, and the authors noted a corresponding decrease in overall mortality and in several cardiovascular outcomes (eg, reduced postadmission MI, congestive heart failure, and need for red blood cell transfusions; all P < .001). This study demonstrates that it is possible to improve adherence to NSTEMI treatment guidelines, and that improved adherence helps to reduce mortality and ischemic complications. Similar findings were observed in the GRACE international patient registry of more than 44,000 patients with ACS who were hospitalized between 1999 and 2006 (Fox, 2007b). In patients with STEMI and NSTEMI, the investigators reported significant reductions in a number of outcomes as a result of recent advances in the management of ACS, including hospital mortality, congestive heart failure, pulmonary edema, and stroke.

Although these studies show that adherence to treatment guidelines improves outcomes for patients with ACS, large patient registries have also found surprisingly low rates of adherence to some highly effective recommended therapies, including aspirin, beta blockers, and cardiac catheterization, especially in patients with NSTEMI (Cannon, 2003). One approach that may help to improve the quality of care is the development of "critical pathways" within the hospital. Critical pathways are standardized, detailed algorithms or other procedures (eg, the use of standard order sets or pocket reference cards) to speed diagnosis or treatment selection and increase the use of evidence-based treatments. Development of critical pathways by a hospital typically involves a 5-step process (Cannon, 2003):

The AHA has also developed a hospital-based quality improvement program -- "Get With the Guidelines" -- that is intended to help close the gap between ideal clinical practices recommended in AHA/ACC guidelines and the actual practice delivered in clinical settings (Flynn, 2007). The program includes 3 modules (for CAD, heart failure, and stroke). The AHA provides tools and support resources to help participating institutions improve adherence to evidence-based guidelines. More information about the program, as well as registration materials, is available via the internet at http://www.americanheart.org/presenter.jhtml?identifier=1165.

Supported by an independent educational grant from sanofi-aventis.


References

  1. Aggrastat (tirofiban) [prescribing information]. Baltimore, Md: Guilford Pharmaceuticals; 2004.
  2. Alexander KP, Newby LK, Cannon CP, et al. Acute coronary care in the elderly, part I: Non-ST-segment-elevation acute coronary syndromes: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation. 2007;115:2549-2569.
  3. Alexander KP, Chen AY, Newby LK, et al. Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: results from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) initiative. Circulation. 2006;114:1380-1387.
  4. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: Executive summary. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (writing committee to revise the 2002 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction). Circulation. 2007;116:803-877.
  5. Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation. 2007;115:708-716.
  6. Angiomax (bivalirudin) [prescribing information]. Parsippany, NJ: The Medicines Company; 2005.
  7. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000;284:835-842.
  8. Arixtra (fondaparinux sodium) (prescribing information). Research Triangle Park: GlaxoSmithKline; 2005.
  9. Bakhai A, Collinson J, Flather MD, et al. Diabetic patients with acute coronary syndromes in the UK: high risk and under treated. Results from the prospective registry of acute ischaemic syndromes in the UK (PRAIS-UK). Int J Cardiol. 2005;100:79-84.
  10. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet. 2002;359:189-198.
  11. Cannon CP. Treatment algorithms and critical pathways for acute coronary syndromes. Semin Vasc Med. 2003;3:425-432.
  12. Chew DP, Lincoff AM, Gurm H, et al. Bivalirudin versus heparin and glycoprotein IIb/IIIa inhibition among patients with renal impairment undergoing percutaneous coronary intervention (a subanalysis of the REPLACE-2 trial). Am J Cardiol. 2005;95:581-585.
  13. Diercks DB, Roe MT, Mulgund J, et al. The obesity paradox in non-ST-segment elevation acute coronary syndromes: results from the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association Guidelines Quality Improvement Initiative. Am Heart J. 2006;152:140-148.
  14. Fitchett DH, Langer A, Armstrong PW, et al. Randomized evaluation of the efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Long-term results of the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial. Am Heart J. 2006;151:373-379.
  15. Flaherty JD, Davidson CJ. Diabetes and coronary revascularization. JAMA. 2005;293:1501-1508.
  16. Flynn FM, Cafarelli M, Petrakos K, Christophersen P. Improving outcomes for acute coronary syndrome patients in the hospital setting: successful implementation of the American Heart Association "Get With The Guidelines" program by Phase I cardiac rehabilitation nurses. J Cardiovasc Nurs. 2007;22:166-176.
  17. Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation. 2004;110:1202-1208.
  18. Fox CS, Coady S, Sorlie PD, et al. Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation. 2007a;115:1544-1550.
  19. Fox KA, Steg PG, Eagle KA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006. JAMA. 2007b;297:1892-1900.
  20. Goodman SG, Fitchett D, Armstrong PW, et al. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation. 2003;107:238-244.
  21. Hackam DG, Tan MK, Honos GN, et al. How does the prognosis of diabetes compare with that of established vascular disease ? Insights from the Canadian Vascular Protection (VP) Registry. Am J Heart. 2004;148:1028-1033.
  22. Hernandez AV, Westerhout CM, Steyerberg EW, et al. Effects of platelet glycoprotein IIb/IIIa receptor blockers in non-ST segment elevation acute coronary syndromes: benefit and harm in different age subgroups. Heart. 2007;93:450-455.
  23. Hulot JS, Vantelon C, Urien S, et al. Effect of renal function on the pharmacokinetics of enoxaparin and consequences on dose adjustment. Ther Drug Monit. 2004;26:305-310.
  24. Integrilin (eptifibatide) [prescribing information]. Kenilworth, NJ: Schering Corporation; 2006.
  25. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA. 2006;295:1531-1538.
  26. Kirtane AJ, Piazza G, Murphy SA, et al. Correlates of bleeding events among moderate- to high-risk patients undergoing percutaneous coronary intervention and treated with eptifibatide: observations from the PROTECT-TIMI-30 trial. J Am Coll Cardiol. 2006;47:2374-2349.
  27. Klein L, Gheorghiade M. Management of the patient with diabetes mellitus and myocardial infarction: clinical trials update. Am J Med. 2004;116(Suppl 5A):47S-63S.
  28. Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med. 2006;144:673-684.
  29. Magid DJ, Wang Y, Herrin J, etal. Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction. JAMA. 2005;294:803-812.
  30. McNamara RL, Wang Y, Herrin J, et al. Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2006;47:2180-2186.
  31. Mehta RH, Roe MT, Chen AY, et al. Recent trends in the care of patients with non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE initiative. Arch Intern Med. 2006;166:2027-2034.
  32. Neumann FJ, Kastrati A, Pogatsa-Murray G, et al. Evaluation of prolonged antithrombotic pretreatment ("cooling-off" strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial. JAMA 2003;290(12):1593-1599.
  33. Petersen JL, Mahaffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview. JAMA. 2004;292:89-96.
  34. Pfisterer M, Buser P, Osswald S, et al. Outcome of elderly patients with chronic symptomatic coronary artery disease with an invasive vs optimized medical treatment strategy: one-year results of the randomized TIME trial. JAMA. 2003;289:1117-1123.
  35. Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Circulation. 2001;104:2767-2771.
  36. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69-e171.
  37. Skolnick AH, Alexander KP, Chen AY, et al. Characteristics, management, and outcomes of 5,557 patients age ≥ 90 years with acute coronary syndromes: results from the CRUSADE Initiative. J Am Coll Cardiol. 2007;49:1790-1797.
  38. Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363-2372.
  39. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:2203-2216.
  40. Trichon BH, Roe MT. Acute coronary syndromes and diabetes mellitus. Diab Vasc Dis Res. 2004;1:23-32.
  41. Tricoci P, Peterson ED, Roe MT; et al. Patterns of guideline adherence and care delivery for patients with unstable angina and non-ST-segment elevation myocardial infarction (from the CRUSADE Quality Improvement Initiative). Am J Cardiol. 2006;98:30Q-35Q.
  42. Turpie AG. Burden of disease: medical and economic impact of acute coronary syndromes. Am J Manag Care. 2006;12(16 Suppl):S430-S434.
  43. Yusuf S, Mehta SR, Chrolavicius S, et al; for the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:1464-1476.



Authors and Disclosures

Editor

David A. Morrow, MD, MPH

Assistant Professor of Medicine, Harvard Medical School; Investigator, TIMI Study Group; Cardiovascular Division, Brigham & Women's Hospital, Boston, Massachusetts

Disclosure: Dr. Morrow has received research grant support administered via Brigham & Women?s Hospital from Bayer Diagnostics; Biosite, Inc.; Beckman-Coulter; Dade-Behring; and Roche Diagnostics.