E-Journal of the Society of Chest Pain Centers

Spring 2002, Volume I, Number I

REVIEW

Evidence-Based Approach for Managing Patients with Moderate to High Risk Chest Pain: Focus on the Role of Low Molecular Weight Heparin

J. Lee Garvey, MD
Carolinas Medical Center
Charlotte, North Carolina

Raymond D. Bahr, MD, FACP, FACC
St. Agnes Hospital
Baltimore, Maryland

Abstract

The incidence of patients presenting to the emergency department with chest pain of cardiac origin requires the development of enhanced management strategies to handle this patient population. These management strategies should rely on clinical data with proven beneficial outcomes. The implementation of chest pain centers and improvements in diagnostic modalities have contributed greatly to the initial risk stratification and triage of chest pain patients. Pharmacologic advances have also had a substantial impact on the management of acute coronary syndrome (ACS) patients. The antithrombin effects exerted by heparin and low-molecular-weight heparin (LMWH) play an integral part in diminishing the ischemic complications of ACS. Antithrombotic therapy has conventionally used unfractionated heparin. However, there now exists a significant amount of clinical data documenting the effectiveness of LMWH in ACS. Improved triage of chest pain patients through implementation of chest pain center protocols, and enhanced antithrombotic activity with the use of LMWH, have reduced utilization of resources, resulting in cost-savings to the healthcare system. This manuscript will provide an evidence-based approach to managing chest pain patients with a focus on the evolving role of LMWH.

Introduction

Over 5 million patients present to the emergency department (ED) each year with complaints of chest pain. Of these 5 million patients, approximately 1.5 million will be hospitalized with acute coronary syndrome (ACS).1 ACS represents a continuum of medical conditions ranging from unstable angina (UA) to ST-segment elevation myocardial infarction (MI) (Figure 1). Proper diagnosis and treatment of chest pain patients upon presentation to the ED is quite often a challenging situation. Difficulty in diagnosing chest pain patients can lead to delays in the time to effective treatment, which can significantly alter patient outcomes. In addition, patients with chest discomfort due to noncardiac causes are frequently admitted to coronary care units and telemetry units. This results in the allocation of costly resources for monitoring of many patients with ambiguous presentations resulting from benign disorders. Because the incidence of myocardial ischemia is so prevalent, there is a need for the development of management strategies to improve the care of this patient population.

Figure 1 - Spectrum of Myocardial Ischemia.
Click figure to see enlarged view.

Initial Management of Chest Pain Patients

All patients complaining of chest pain should be directed to an area dedicated to evaluation and treatment of ACS. A management strategy for patients presenting to ED with chest pain is presented in Figure 2 Within the first 6 to 10 hours after the patient has arrived to the ED, the information gathered can be used to assign patients into one of three categories corresponding to points on the ACS continuum:

• 5 -10% of patients are confirmed as having an acute MI.
• 20-25% are admitted with suspected or confirmed UA/nonST elevation (NSTE) MI, the primary target group for LMWH treatment.
• 65 - 70% have non-cardiac chest pain.

Patients can be risk-stratified based on a number of diagnostic criteria (Table 1). The most critical factor when managing chest pain patients is to perform diagnosis and treatment as rapidly as possible. A continuous re-evaluation of any treatment protocol is required to ensure that sources of possible delay are identified and appropriately modified. Some of the most valuable diagnostic tools available to the ED physician include the electrocardiogram (ECG)and serum markers. The history and physical examination remain the basic diagnostic tools.

Table 1 - Chest Pain Diagnostic Criteria.
Click figure to see enlarged view.

Upon presentation to the ED (Figure 2), patients with chest pain are immediately interviewed for a directed medical history, followed by a 12-lead ECG and chest x-ray. Patients with presumed cardiac pain are given aspirin (for its antiplatelet effect) and sublingual nitroglycerin (to reduce myocardial oxygen demand and increase epicardial blood flow). In addition, patients with potential cardiac pain have serial blood tests to measure cardiac markers of necrosis (troponin I or T, CK-MB, myoglobin).

Figure 2 - Emergency Management of Chest Pain (first 6 hours of treatment)
Click figure to see enlarged view.

Pharmacologic Patient Management

After chest pain has been determined to be of cardiac origin, pharmacologic intervention is initiated according to the working diagnosis of UA/NSTEMI) or ST-segment elevation MI. The goal of therapy is to restore blood flow, reduce myocardial oxygen demand, and improve myocardial oxygen supply. Because of the similarities in the pathophysiology of UA and NSTEMI, treatment strategies for these conditions are comparable.

Patients with ACS with high or intermediate risk of adverse outcomes should receive immediate treatment in the ED. The 2000 update o the ACC/AHA guidelines for the management of patients with acute MI, make the following pharmacologic recommendations for patients with UA/NSTEMI:3

• Aspirin. Aspirin should be given on day 1 of acute MI and continued indefinitely on a daily basis. Aspirin is contraindicated in patients with hypersensitivity to aspirin, active bleeding, or those at risk for severe bleeding. Patients can take clopidogrel (or less preferably, dipyridamole or ticlopidine) if there is an aspirin allergy or if the patient is unresponsive to aspirin.
• Nitrates. Sublingual nitroglycerin is given to all patients with suspected ischemic chest pain. Intravenous nitroglycerin should be given within the first 24 to 48 hours and continued in patients with recurrent angina.
• Analgesia. Morphine sulfate can be administered intravenously to alleviate feelings of pain and anxiety. It can also increase cardiac oxygen delivery.
• Unfractionated heparin (UFH) or LMWH. UFH should be administered intravenously using weight adjusted dosing. In addition, aPTT tests are recommended to guide UFH dosing adjustments (target aPTT= 50-70s, with a control of 26-36s). Clinicians should check the aPTT 4 to 6 hours after initiating or changing the dose. Subcutaneous LMWH is an effective alternative to UFH and offers convenient subcutaneous dosing, predictable dose response, decreased need for therapeutic monitoring, and cost-effective outcomes.
• Beta-blockers. Beta-blockers should be administered in patients without a contraindication. Dosing varies depending upon the specific agent. Commonly used agents include metoprolol, propranolol, and atenolol.
• Glycoprotein IIb/IIIa Inhibitors. These agents should be used in patients having an MI without ST-segment elevation who have some high risk features and/or refractory ischemia provided they donÕt have a major contraindication due to a bleeding risk.

Patient response to the above therapy will determine the next steps in evaluation and treatment of patients with ACS. For high-risk patients, those with recurrent ischemia, depressed LV function, widespread ECG changes, or prior MI, catheterization may be necessary.3 If the patient's anatomy is suitable for revascularization, consider percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft surgery (CABG). For patients unfit for revascularization, medical therapy should be continued. Medication adjustments should be made according to the clinical status of the patient.

There are now sufficient clinical data supporting the use of glycoprotein (GP) IIb/IIIa inhibitors in ACS patients.4,5,6 GP IIb/IIIa inhibitors work specifically in the platelet aggregation phase of the coagulation cascade. Platelet activation and aggregation, with resultant arterial thrombus formation, are pivotal in the pathophysiology of ACS. These agents block the GP IIb/IIIa receptors on the activated platelets, which prevents the platelets from linking to fibrin. The platelet aggregation reaction is one of the key steps in the coagulation cascade, the "final common pathway" for thrombus formation. The development of inhibitors of fibrinogen binding to the platelet GP IIb/IIIa receptor has expanded the therapeutic options for treating thrombotic disorders. 5 Three GP IIb/IIIa inhibitors are currently approved for use in the United States: abciximab (ReoPro¨), eptifibatide (Integrilinª), and tirofiban (Aggrastat¨). Each of these agents is slightly different in its pharmacological design and indications. In the clinical studies supporting their use in ACS, the GP IIb/IIIa inhibitors were used as adjunctive therapy to heparin and aspirin. GP IIb/IIIa receptor blockade has led to major improvements in outcomes of ACS, particularly in patients requiring stent placement.

Heparin and LMWH in ACS

The antithrombin affects exerted by heparin and LMWH play an integral part in diminishing the ischemic complications of ACS. Several randomized trials 7,8 have documented the ability of aspirin and UFH to reduce the likelihood of death and MI following UA compared to aspirin alone. The combination of aspirin and UFH has become the conventional treatment for ACS. However, there now exists significant clinical evidence to show that LMWHs are equivalent 9 or superior 10,11 to UFH in the treatment of patients with ACS.

Clinical Trials of LMWH in ACS

The chemical and enzymatic processes used to develop LMWHs produce products of varying molecular weights with different biological activity compared to standard heparin. The method of preparation also results in significant variability in the pharmacology within the class of LMWHs. As a result of these differences, LMWHs cannot be used interchangeably (unit for unit) with heparin or other LMWHs. There are two LMWHs available in the United States indicated for treatment of patients with UA/NSTEMI: enoxaparin (Lovenox¨) and dalteparin (Fragmin¨). The following section summarizes significant clinical trials of dalteparin and enoxaparin in ACS.

Dalteparin

Dalteparin has been evaluated in three trials in patients with UA/NSTEMI. The FRISC (Fragmin during Instability in Coronary Artery Disease)12 study group compared subcutaneous dalteparin (120 U/kg twice daily for 6 days followed by 7,500 anti-Xa units of dalteparin once daily for 35 to 45 days) plus aspirin to aspirin alone in patients presenting with UA or NSTEMI. Fifteen hundred and six patients took part in this randomized double-blind trial with a primary endpoint being rate of death and new MI during the first six days. All patients had to have newly developed or increased angina pectoris or angina at rest during the previous 2 months or persisting chest pain with a suspicion of myocardial infarction. Secondary endpoints were the rates of death, MI, revascularization, need for heparin infusion, and a composite endpoint after 40 and 150 days. At 6 days, there was a statistically significant difference favoring dalteparin versus placebo in the primary endpoint of death and MI (1.8% vs. 4.8%, p=0.001). The secondary endpoint also favored dalteparin over placebo at 6 days (5.4% vs. 10.3%, p 0.001). By 40 days, there was no statistical difference in primary endpoint between the treatment groups (8.0% dalteparin vs. 10.7% placebo, p=0.07). The composite endpoint was significant for dalteparin at 40 days compared to placebo (20.5% vs. 25.7%, p=0.011). By 150 days, there was no statistical difference between the primary or secondary endpoints.

Fourteen hundred eighty-two patients with UA or NSTEMI were enrolled in the FRIC (Fragmin in Unstable Coronary Artery Disease) study.9 The study had two phases. In the acute phase (open), patients received subcutaneous dalteparin 120 U/kg twice daily plus aspirin or dose-adjusted intravenous UFH, a 5,000-U bolus followed by 1,000 U/h plus aspirin for six days. On days 6-45 (blinded phase), patients were randomly assigned to either once-daily dalteparin (7,500 IU) or placebo. The results showed that at day 6 there was no significant difference in the primary endpoint (death, MI, recurrent angina) between the dalteparin (9.3%) and UFH (7.6%) groups. In addition, dalteparin was no more effective than placebo in the primary endpoint during days 6-45 (12.3% placebo vs. 12.3% dalteparin, p=0.96). Adverse events were infrequent and similar during the acute phase. Of the documented adverse events in the second phase, the groups differed only in minor bleeding (placebo 2.8% vs. dalteparin 5.1%).

The primary objective of the Fragmin During Instability in Coronary Artery Disease II (FRISC II)13 study was to compare rates of death or MI at 90 days in patients receiving continuous 3-month treatment with dalteparin compared to patients receiving placebo. In the initial acute, open-label phase, all patients received 120 IU/kg of dalteparin for 5-7 days and were subsequently randomized to either dalteparin or placebo. For patients receiving dalteparin during the second phase, dosing for females less than 70 kg or males less than 80 kg was 5,000 IU twice daily. Female patients &Mac179; 70 70 kg or males &Mac179; 80 kg received 7,500 IU twice daily. There was a statistically significant difference favoring dalteparin over placebo at 30 days in the incidence of death or MI (3.1% vs. 5.9%, p=0.002). However, results showed that there was no significant difference in the primary endpoint of death or MI at 90 days between dalteparin and placebo (6.7% vs. 8.0%, p=0.2). The incidence of major bleeding was 3.3% for dalteparin and 1.5% for placebo during the double-blind phase. Hemorrhagic stroke occurred in 0.8% (n=8) of dalteparin patients and in none of the patients receiving placebo.

Enoxaparin

In the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events)11 trial, enoxaparin was compared to UFH in patients with angina at rest or NSTEMI. This double-blind study randomized 3171 patients to either twice-daily subcutaneous enoxaparin (1 mg/kg SC every 12 hours) or continuous intravenous infusion of UFH. Patients in both arms received aspirin. Drug therapy was administered for a minimum of 48 hours and a maximum of 8 days. Follow-up was done at 14 and 30 days at which time the frequency of death, MI, or recurrent angina was assessed. At 14 days, patients receiving enoxaparin had a significantly lower risk of the composite endpoint (death/MI/recurrent angina) when compared with UFH (16.6% vs. 19.8%, p=0.019). The improvement seen with enoxaparin remained significant at day 30 (19.8% vs. 23.3%, p=0.016). Additionally, at 30 days, there was a significant reduction in the need for revascularization (27.0% for enoxaparin vs. 32.2% for UFH, p=0.001) and diagnostic catheterization (enoxaparin 47.9% vs. UFH 51.9%, p=0.02). The incidence of major bleeding was slightly higher for UFH compared to enoxaparin (7.0% vs. 6.5%), however, the overall incidence of bleeding was significantly higher in the enoxaparin treatment arm (18.4% vs. 14.2% for UFH, p=0.001). A one year follow-up conducted on patients involved in the ESSENCE trial showed that enoxaparin was superior to UFH in the triple endpoint of death, MI, or recurrent angina (32.0% vs. 36.7, p=0.022)11 .

The Thrombolysis in Myocardial Infarction trial (TIMI 11B)10 was a double-blind, randomized, placebo controlled study designed to compare the efficacy and safety of enoxaparin versus UFH during the acute period after UA/NSTEMI. Additional assessment was done to evaluate the benefits of enoxaparin on a continuing outpatient basis for 43 days. The primary endpoint was the composite, through day 43, of death, new nonfatal MI, or severe recurrent ischemia requiring urgent revascularization. At day 14, the incidence of death, MI, or revascularization was 14.2% for patients receiving enoxaparin compared to 16.6% for UFH, a relative risk reduction of 15% (p=0.03). The initial benefit of enoxaparin continued through the chronic phase (day 43), although no further relative decrease in death, MI, or revascularization was seen (17.3% for enoxaparin vs. 19.7% for those receiving UFH in acute phase, p=0.048, RR = 12%). Bleeding incidences during hospitalization were similar for enoxaparin and UFH (1.5% vs. 1.0%). During outpatient treatment, bleeding incidence was significantly higher for enoxaparin when compared to those patients in the placebo arm not receiving anticoagulant therapy (2.9% vs. 1.5%, p=0.02).

A meta-analysis of the TIMI-11B and ESSENCE trials was recently conducted to explore the potential advantage of enoxaparin over UFH.14 Analysis of the combined patient population (n=7081) showed that at day 14, patients treated with enoxaparin had a reduced rate of the triple endpoint (death, MI, or urgent revascularization) compared to those treated with UFH (12.8% vs. 15.7%, p=0.005). At day 43, there was a similar reduction in the triple endpoint favoring enoxaparin (15.6% vs. 18.8%, p=0.0006).

Advantages of LMWH over UFH

Beyond the superior efficacy seen with enoxaparin over UFH in treatment of UA/NSTEMI,10,11,14 there are additional advantages associated with LMWH as a class of drugs. Treatment with UFH is often associated with supra- and sub-therapeutic levels of anticoagulation. The ability of clinicians to titrate UFH to reach and maintain a therapeutic activated partial thromboplastin time (aPTT) is unpredictable 24 to 48 hours after administration.15 Therefore, dosage adjustments and monitoring of aPTT for anticoagulant effect become troublesome components of UFH therapy. LMWHs have a more predictable dose response, possibly due to decreased protein binding.15 The predictability of LMWH pharmacodynamics eliminates the need for therapeutic monitoring of anticoagulant response (i.e., aPTT).15 LMWH offers the convenience of subcutaneous dosing compared to intravenous administration usually required by UFH. LMWHs are also associated with a significantly reduced incidence of heparin induced thrombocytopenia (HIT).15

There are several biochemical and biophysical limitations associated with UFH therapy, which make LMWH an attractive alternative. The first issue relates to the significant amount of variability in the anticoagulation response seen in patients receiving UFH therapy. This variability can be attributed to the biophysical and pharmacokinetic characteristics of heparin, including non-specific binding to protein and cells, saturable clearance, and inactivation by platelet factor 4.16 There is also an increased potential for a rebound of clinical events after discontinuation of intravenous UFH therapy.16

Economic Assessment

It is important to consider both economic and clinical characteristics of drug therapy when determining which agents to use. Determinations should be made based on both short and long term outcomes. The development of treatment guidelines based upon clinical and economic parameters is critical.

Economic advantages of enoxaparin therapy can be realized when treatment data from the ESSENCE trial are evaluated. Mark et al.17 performed the economic analysis in which drug treatment costs of $80 per patient for UFH and $155 per patient for enoxaparin were included. Total costs included hospital and physician fees for both the initial hospitalization and extended treatment of 30 days. Results of the analysis showed that after 30 days, treatment costs with enoxaparin were approximately $1200 less compared to the costs associated with UFH treatment. The cost reduction was most likely due to the decreased need for revascularizations in the enoxaparin group.

LMWH in Percutaneous Coronary Interventions (PCI)

Improvements in efficacy achieved with both LMWH and GP IIb/IIIa inhibitors have led to interest in combining these therapies to further enhance clinical outcomes in ACS patients. The first and only study evaluating the use of dalteparin in combination with a glycoprotein IIb/IIIa inhibitor in patients undergoing PCI was recently reported at the 2000 Transcatheter Cardiovascular Therapeutics 2000 meeting. This was a dose-finding trial evaluating standard dose abciximab in combination with either 40 or 60 IU/kg of dalteparin.18 The 40 IU/kg arm was discontinued due to an increased incidence of thrombus. Following dalteparin 60 IU/kg (n=76), anti-Xa levels peaked at 30 minutes and dissipated at 4 hours. The incidence of death, Q-wave MI, and urgent revascularization occurred in 1.3%, 3.9%, and 1.3% of patients respectively. The incidence of major bleeding was 2.6% in patients receiving 60 IU/kg of dalteparin and there were no cases of severe thrombocytopenia.18

Enoxaparin was first evaluated in combination with GP IIb/IIIa inhibitors in the ACUTE-1 (Analysis of Coronary Ultrasound Thrombolysis Endpoints) study.19 In ACUTE-1, enoxaparin and UFH were compared in combination with tirofiban in the medical management of ACS patients. Enoxaparin was dosed at 1.0 mg/kg SC every 12 hours while UFH was administered as a bolus and infusion to achieve aPTT of 1.5-2.5 times control. The results of this study (n=53) showed that enoxaparin did not affect tirofiban clearance and had no effect on major bleeding or thrombocytopenia. In addition, greater platelet inhibition was achieved with enoxaparin compared to UFH.

The National Investigators Collaborating on Enoxaparin (NICE 1)20 study evaluated enoxaparin 1 mg/kg administered intravenously in 828 patients undergoing PCI without planned use of a glycoprotein IIb/IIIa inhibitor. The incidence of major non-CABG related bleeding was 0.5% and the composite clinical endpoint (death, MI, urgent revascularization was) 7.9% to 30 days. 20 The NICE 1 study was able to establish enoxaparin as a safe and effective procedural anticoagulant during PCI.

When the results of NICE 1 are compared to the EPISTENT (Evaluation of Platelet Inhibition in STENTing) stent + placebo group, safety and efficacy outcomes were similar. The frequent use of stents in NICE 1 allows plausible comparison with the EPISTENT placebo subgroup in that both received stents with adjunctive oral thienopyridine therapy and no glycoprotein IIb/IIIa inhibitors. In addition, the definition of major and minor hemorrhage is the same in both trials. The incidence of major non-CABG bleeding events were infrequent and similar between the two trials (0.5% in NICE 1 vs. 1.0% in EPISTENT).

The NICE 421 study evaluated reduced dose intravenous enoxaparin (0.75 mg/kg) with standard dose abciximab (0.25 mg/kg bolus, followed by 0.125 mg/kg/minute to maximum 10 mg/kg) at the time of PCI. The reduced dose of enoxaparin was modeled to simulate the weight-adjusted reduction in heparin dose used in EPISTENT and EPILOG. Vascular sheaths were removed 4 hours following the enoxaparin bolus. Periprocedural monitoring of ACT was not performed. The primary endpoint of NICE 4 was the incidence of major or minor bleeding and the need for transfusion. The incidence of the death, MI, and urgent revascularization comprised the secondary endpoints. Preliminary results show a 0.2% incidence in major non-CABG bleeding in 818 patients.22 The results of the study showed rates of major bleeding similar to historical cohorts treated with UFH and abciximab from EPILOG and EPISTENT trials. There was a 2.8% incidence in the composite endpoint of death/MI/UR to 30 days post-PCI.

Summary

Proper management of chest pain patients requires optimization of currently available diagnostic and treatment modalities. An evidence-based approach provides the clinician with the highest chance of achieving successful outcomes with chest pain patients. The implementation of chest pain observation units in the ED has vastly improved the triage and treatment of patients presenting with chest pain. A focused patient history, physical examination, and the ECG have critical roles in the early stages of diagnosis. Technological advances, such as bedside testing of biochemical markers, serial ECGs, and serial serum markers have also contributed greatly to earlier diagnosis of ACS. Inhibiting thrombin generation and clot formation is a critical part of controlling the progression of ACS. Conventional treatment has used UFH for all patients at moderate to high-risk because it has been proven to reduce the occurrence and severity of ischemic events following ACS. However, there is mounting clinical evidence to show that LMWHs are effective and safe in UA/NSTEMI. There are several biochemical and biophysical limitations of UFH therapy. These limitations translate into undesirable clinical outcomes, including a variable anticoagulant response. Therefore, vigilant monitoring, often accompanied by dosage modification, is a necessity with UFH. Conversely, LMWHs have a predictable dose response, do not significantly bind to protein, can be administered subcutaneously, and do not require monitoring of aPTT. The LMWH enoxaparin was shown to be superior to UFH in UA/NSTEMI with a corresponding economic advantage 30 days after initiation of therapy. The role of LMWHs in ACS is expanding, with the accumulation of data regarding combination therapy with GP IIb/IIIa inhibitors and use of LMWH in the cardiac catheterization laboratory. The prevalence of ACS necessitates the use of management strategies with documented effectiveness in improving both clinical and economic outcomes.

References

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Figure Legend

Figure 1. Spectrum of Myocardial Ischemia
Figure 2. Emergency Management of Chest Pain (first 6 hours of treatment)
Table 1. Chest Pain Diagnostic Criteria