Use of Heparins in Non-ST-Elevation Acute Coronary Syndromes

Article Outline

• Abstract
• Methods
  • Data Analysis
• Results
  • Study Population
  • Trends in Medication Use
  • Patient Demographics
  • Concomitant Treatment
  • Outcomes
• Discussion
  • Study Strengths and Limitations
• Conclusions
• Acknowledgments
• References
• Copyright

Abstract 

Purpose

We describe the use of antithrombotic therapy in the management of patients with acute coronary syndromes.

Methods

Patients from the Global Registry of Acute Coronary Events, a multinational coronary disease registry, were characterized according to the early and continued use of low-molecular-weight heparin, unfractionated heparin, any crossover of heparin therapy (change in early vs late heparin treatment), and no heparin treatment. Hospital outcomes were analyzed according to the heparin treatment and the timing of percutaneous coronary interventions.

Results

Data from 23,172 patients with non-ST-segment elevation myocardial infarction or unstable angina were analyzed. A total of 8791 patients were treated with low-molecular-weight heparin within the first 24 hours and continued thereafter; 4076 patients received unfractionated heparin; 2953 patients received neither heparin therapy; and 7352 patients received crossover heparin treatment. Concomitant treatment, including early or late percutaneous coronary intervention, varied according to the type of heparin therapy. Patients treated with a crossover therapy were more likely to undergo percutaneous coronary intervention. The rates of major bleeding and death were lower with low-molecular-weight heparin (1.4% and 1.8%, respectively) compared with unfractionated heparin (1.9% and 2.5%, respectively), crossover heparin (2.0% and 2.3%, respectively), or neither heparin (1.5% and 2.4%, respectively).

Conclusions

There is significant variability in heparin use in patients with acute coronary syndromes. Heparin type and use seem to be related to the timing and use of percutaneous coronary interventions. The early use of low-molecular-weight heparin in the setting of an acute coronary syndrome is associated with better short-term outcomes.

Keywords: Heparin, Acute coronary syndrome, Antithrombotic outcomes

Historically, unfractionated heparin has been the mainstay of antithrombotic therapy in patients with an acute coronary syndrome. However, no single randomized trial has demonstrated a significant improvement in the outcomes of patients with an acute coronary syndrome treated with unfractionated heparin and aspirin versus aspirin alone.¹ In contrast, the use of low-molecular-weight heparin and aspirin has been associated with improved outcomes in trials of patients with non-ST-elevation acute coronary syndrome compared with the use of aspirin plus unfractionated heparin.², ³ Low-molecular-weight heparins are easier to administer, do not require close monitoring, and are less likely to activate platelets or to be associated with heparin-induced thrombocytopenia.⁴, ⁵ Low-molecular-weight heparins are recommended for the management of patients with acute coronary syndrome in the United States and European guidelines.⁶, ⁷

Important advances in the management of patients with an acute coronary syndrome include the increased use of an early invasive strategy, improved stent technology, and more aggressive use of multiple antiplatelet therapies. Questions remain, however, about the appropriate use of low-molecular-weight heparins in the current era, particularly in the early stages of acute coronary syndrome. Furthermore, data evaluating current use patterns of low-molecular-weight heparins versus unfractionated heparin, and their efficacy and safety from the more generalizable community setting, are limited. With data from the multinational Global Registry of Acute Coronary Events (GRACE), we characterized contemporary patterns in the use of low-molecular-weight heparin, and unfractionated heparin and associated clinical outcomes in patients with non-ST-elevation acute coronary syndromes.

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Methods 

The design and data-collection methods of the GRACE study have been published.⁸, ⁹ A total of 111 hospitals in 14 countries contributed data to this study. Patients had to have at least 1 of the following: electrocardiographic changes consistent with acute coronary syndrome, serial increases in serum biochemical markers, and/or documentation of coronary artery disease. The qualifying acute coronary syndrome must not have been precipitated by significant noncardiovascular comorbidity.

Data were collected by trained study coordinators using a standardized case report form. Standardized definitions were used for all patient-related variables.⁹ For the purposes of this study, we used data from patients hospitalized with non-ST-elevation/unstable angina acute coronary syndrome who were enrolled between April 1999 and December 2005.

Data Analysis 

Differences in the distribution of baseline characteristics and treatment strategies among various comparison groups were compared using the chi-square and Kruskal-Wallis tests for categoric and continuous variables, respectively.

We used multivariable logistic regression to examine the relation between early and continued use of low-molecular-weight heparin, early and continued use of unfractionated heparin, or any crossover of treatment type, compared with our reference group (no heparin use), and the hospital outcomes of death, major bleeding, and the composite end point of death, recurrent myocardial infarction, or recurrent myocardial ischemia. The crossover group was defined by any change in early versus late heparin-treatment strategy, including change in treatment type, discontinuation of therapy (after 24 hours), or late initiation of therapy (after 24 hours). Heparin used only as part of the cardiac catheterization was not considered to be a treatment for acute coronary syndrome but rather part of the standard cardiac catheterization procedure; thus, this was classified as “no heparin treatment.” Candidate variables in the stepwise logistic regression model included percutaneous coronary intervention use/timing (percutaneous coronary intervention≤24 hours vs no percutaneous coronary intervention, percutaneous coronary intervention>24 hours vs no percutaneous coronary intervention) plus variables from the GRACE risk models for death¹⁰ and major bleeding.¹¹ The following additional variables were included in the stepwise regression models in which we examined the association between the type of treatment and the composite hospital end point: sex, prior angina, stroke, and positive stress test. The final adjustment included only variables differing at a P value less than .05 after backward elimination.

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Results 

Study Population 

A total of 32,347 patients with a final diagnosis of non-ST-elevation acute coronary syndrome were enrolled in the GRACE study during the period under study. Of these, 28.4% were excluded for one or more of the following reasons: initial creatinine greater than 2 mg/dL (5.4%); history of major bleeding (including hemorrhagic stroke; 2.0%); systolic blood pressure greater than 220 mm Hg (0.9%) and/or diastolic blood pressure greater than 120 mm Hg (1.3%); death within 24 hours of presentation (0.8%); chronic coumadin treatment (5.4%); transfer from another hospital to a GRACE hospital (11.1%); prior malignancy (3.0%); missing data on the use of low-molecular-weight heparin/unfractionated heparin (2.9%); and documented contraindication to low-molecular-weight heparin/unfractionated heparin (0.6%). The final study population comprised 23,172 patients. In this sample, 37.9% of patients received low-molecular-weight heparin in the first 24 hours of hospitalization with continued use thereafter; 17.0% received unfractionated heparin in the first 24 hours, with continued use of unfractionated heparin after 24 hours; 12.7% received neither therapy at any time during hospitalization; and 31.7% were classified as receiving crossover treatment during the index hospitalization.

Trends in Medication Use 

There was a steady increase in the use of low-molecular-weight heparin and crossover treatment relative to unfractionated heparin and no treatment over the course of the study (Figure 1). We also looked at time trends by geographic regions. In patients enrolled in the United States, crossover therapy and low-molecular-weight heparin treatment increased over time, use of neither therapy remained relatively constant, and unfractionated heparin treatment decreased dramatically (Figure 2).

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• Figure 1. 

  Changing trends in the use of heparins during hospitalization in patients with non-ST-elevation acute coronary syndrome (all regions). LMWH=low-molecular-weight heparin; UFH=unfractionated heparin.

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• Figure 2. 

  Temporal use of heparins in the United States during hospitalization in patients with non-ST-elevation acute coronary syndrome. LMWH=low-molecular-weight heparin; UFH=unfractionated heparin.

Patient Demographics 

Patients who received low-molecular-weight heparin or neither therapy were older and less likely to be obese compared with patients treated with unfractionated heparin or crossover therapy (Table 1). Patients treated with low-molecular-weight heparin or crossover treatment were less likely to have a history of cardiac disease than patients treated with unfractionated heparin or neither. The use of low-molecular-weight heparin or crossover treatment was more common in men, whereas neither treatment was most common in women.

Table 1. Characteristics of Patients with Non-ST-Elevation Acute Coronary Syndrome According to Heparin Treatment During Hospitalization

Characteristics	Low-Molecular-Weight Heparin (n=8791)	Unfractionated Heparin (n=4076)	Crossover (n=7352)	No Heparin (n=2953)	P Value
Age (median, y)	67.3(56.7-76.1)	66.0(55.5-75.1)	65.5(55.7-74.4)	67.3(56.4-76.4)	<.001
Age≥75 y (%)	28.1	25.5	23.5	28.6	<.001
Male (%)	64.6	63.2	68.2	61.6	<.001
Body mass index (%)
<18.5 kg/m2	1.2	1.5	1.1	1.4	<.001
18.5-24.9 kg/m2	31.2	28.2	29.1	28.6
25.0-29.9 kg/m2	43.0	40.3	42.0	43.9
≥30 kg/m2	24.6	30.1	27.8	26.1
Medical history (%)
Myocardial infarction	33.8	40.0	33.3	36.7	<.001
CABG	13.8	19.1	14.8	16.6	<.001
PCI	18.9	23.5	22.8	23.2	<.001
Diabetes	24.4	28.3	24.9	24.4	<.001
Hypertension	62.2	70.3	62.5	65.3	<.001
Stroke	6.8	7.7	6.8	7.9	.05
Congestive heart failure	8.4	12.8	9.0	12.3	<.001
Renal disease⁎	4.3	5.4	5.5	5.3	.002
Peripheral arterial disease	9.1	9.7	9.8	9.3	.44
Median diastolic blood pressure, mm Hg (IQR)	80(70, 90)	80(70, 90)	80(70, 90)	80(68, 90)	<.001
Killip class (%)
I	86.3	85.8	86.3	85.7	.02
II	10.2	11.0	11.1	11.0
III	3.2	2.8	2.3	2.7
IV	0.3	0.4	0.3	0.5
Cardiac arrest (%)	0.6	0.9	0.7	1.1	.01
Positive cardiac enzymes (%)	35.1	32.0	34.8	21.9	<.001
Index electrocardiogram (%)
ST-segment depression	32.0	24.8	30.2	22.2	<.001
T-wave inversion	33.6	32.9	32.8	27.7	<.001
In-hospital therapies (%)
Angiotensin-converting enzyme inhibitor	58.7	63.3	59.1	53.2	<.001
Aspirin	95.1	95.9	93.3	88.6	<.001
Beta-blocker	82.3	87.2	82.7	74.6	<.001
Calcium-channel blocker	30.0	24.7	28.5	29.7	<.001
Diuretic	27.8	36.1	32.1	29.4	<.001
Glycoprotein IIb/IIIa inhibitor	11.4	24.6	27.3	9.6	<.001
Statin	67.8	53.3	65.4	50.1	<.001
Fibrinolytic therapy	1.7	3.6	3.9	3.1	<.001
Ticlopidine/clopidogrel	47.6	36.5	54.3	33.5	<.001

CABG=coronary artery bypass graft; IQR=interquartile range; PCI=percutaneous coronary intervention.

The majority of patients in Europe, Australia/New Zealand/Canada, and Argentina/Brazil were treated with low-molecular-weight heparin, whereas most patients in the United States were treated with unfractionated heparin or crossover therapy (Table 2). A minority of patients in each region, with the exception of the United States, received no heparin treatment.

Table 2. Type of Heparin Received by Patients with Non-ST-Elevation Acute Coronary Syndrome by Region

Regions	Low-Molecular-Weight Heparin n (%)	Unfractionated Heparin n (%)	Crossover Therapy n (%)	No Heparin n (%)
Argentina/Brazil (n=4973)	1747(35.1)	1360(27.3)	1179(23.7)	687(13.8)
Australia/New Zealand/Canada (n=3417)	1777(52.0)	432(12.6)	968(28.3)	240(7.0)
Europe (n=9337)	4536(48.6)	439(4.7)	3382(36.2)	980(10.5)
United States (n=5445)	731(13.4)	1845(33.9)	1823(33.5)	1046(19.2)

Concomitant Treatment 

Aspirin use was similar among all heparin groups, although it was used less often in patients who failed to receive heparin treatment (Table 1). Patients who received unfractionated heparin were more likely to receive an angiotensin-converting enzyme inhibitor or beta-blocker but were less likely to receive a statin. Patients receiving a glycoprotein IIb/IIIa receptor antagonist were more likely to be treated with unfractionated heparin (23%), low-molecular-weight heparin (23%), or crossover treatment (47%), compared with neither heparin (7%). Patients treated with low-molecular-weight heparin and any crossover treatment more often received ticlopidine or clopidogrel. Fibrinolytic therapy was least often used in conjunction with low-molecular-weight heparin.

Patients treated with low-molecular-weight heparin or unfractionated heparin were less likely to undergo percutaneous coronary intervention within 24 hours of hospitalization (Table 3). Percutaneous coronary intervention performed after 24 hours was more frequently associated with unfractionated heparin or any crossover treatment; patients treated with neither heparin were unlikely to receive percutaneous coronary intervention after 24 hours. Patients treated with neither or low-molecular-weight heparin were less likely to undergo percutaneous coronary intervention, cardiac catheterization, or coronary artery bypass graft at any time during their hospital stay, compared with patients treated with unfractionated heparin or crossover heparin treatment (Figure 3).

Table 3. Heparin Type at Any Time During Hospitalization in Relation to Use of Percutaneous Coronary Intervention

Procedure	N	Low-Molecular-Weight Heparin (%)	N	Unfractionated Heparin (%)	N	Any Crossover Therapy (%)	N	Neither Therapy (%)
PCI≤24 h	315	3.7	236	6.1	1021	14.8	281	10.0
PCI>24 h	1296	15.4	664	17.1	1371	19.9	282	10.0
No PCI	6806	80.9	2983	76.8	4491	65.2	2253	80.0

PCI=percutaneous coronary intervention.

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• Figure 3. 

  Rates of cardiac catheterization, percutaneous coronary intervention, and coronary artery bypass graft surgery by type of heparin during hospitalization in patients with non-ST-elevation acute coronary syndrome. CABG=coronary artery bypass graft; LMWH=low-molecular-weight heparin; PCI=percutaneous coronary intervention; UFH=unfractionated heparin.

Outcomes 

Rates of stroke were similar for patients treated with low-molecular-weight heparin, unfractionated heparin, crossover heparin, or neither treatment (Figure 4). The rates of major bleeding were lower in low-molecular-weight heparin and non–heparin-treated patients compared with those receiving unfractionated heparin or crossover treatment. The occurrence of myocardial (re)infarction after 24 hours was lower in the low-molecular-weight heparin and no heparin groups (4.0% and 3.0%, respectively) compared with the unfractionated heparin and crossover groups (5.3% and 5.3%, respectively). Patients receiving low-molecular-weight heparin only also had lower rates of death compared with the other 3 groups. The composite hospital end point was lowest in the no heparin group and highest in the crossover group.

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• Figure 4. 

  Risk of selected hospital outcomes by type of heparin treatment in patients with non-ST-elevation acute coronary syndrome. LMWH=low-molecular-weight heparin; MI=myocardial infarction; UFH=unfractionated heparin.

Some differences among treatment groups were noted for outcomes analyzed according to the receipt of early percutaneous coronary intervention (≤24 hours) versus late percutaneous coronary intervention (>24 hours) or no percutaneous coronary intervention (Table 4). With percutaneous coronary intervention in 24 hours or less, patients who were not treated with heparin therapy had the lowest frequency of the composite end point. With percutaneous coronary intervention in more than 24 hours, patients treated with no heparin or low-molecular-weight heparin only were less likely to experience the composite end point compared with unfractionated heparin only and crossover groups. However, patients receiving low-molecular-weight heparin only or unfractionated heparin only had a lower frequency of death with percutaneous coronary intervention in more than 24 hours compared with other treatment groups. Among patients who did not undergo percutaneous coronary intervention during hospitalization, patients receiving no heparin or low-molecular-weight heparin were less likely than those receiving unfractionated heparin or crossover heparin to have a major bleed. Patients receiving no heparin were less likely to experience the composite end point compared with other patients receiving heparin (Table 4). Hospital death rates for patients not undergoing percutaneous coronary intervention were higher for those who underwent percutaneous coronary intervention at any time and were lowest in the low-molecular-weight heparin group.

Table 4. Outcome by Timing and Use of Percutaneous Coronary Intervention Treatment by Heparin Treatment Groups

Outcome and Timing/Use of PCI	LMWH	UFH	Crossover Therapy	Neither Therapy	P Value
Mortality n (%)
PCI≤24 h	6(1.9)	2(0.9)	10(1.0)	4(1.4)	⁎NS
PCI>24 h	6(0.5)	5(0.8)	17(1.2)	6(2.1)	.03
No PCI	140(2.1%)	92(3.1%)	138(3.1)	61(2.7)	.002
Major bleeding n (%)
PCI≤24 h	10(3.2)	5(2.1)	18(1.8)	9(3.3)	.31
PCI>24 h	21(1.7)	12(1.8)	35(2.6)	4(1.5)	.31
No PCI	83(1.2)	55(1.9)	81(1.8)	28(1.3)	.02
Death/recurrent myocardial infarction/recurrent ischemia n (%)
PCI≤24 h	71(22.5)	55(23.5)	199(19.6)	38(13.7)	.02
PCI>24 h	332(26.0)	227(34.6)	513(37.8)	74(26.7)	<.001
No PCI	1861(27.6)	849(28.8)	1472(33.1)	463(20.7)	<.001

LMWH=low-molecular-weight heparin; UF=unfractionated heparin; NS=not significant; PCI=percutaneous coronary intervention.

The multivariable adjusted odds of dying during hospitalization was 0.79 (95% confidence interval [CI], 0.56-1.11) for patients treated with low-molecular-weight heparin, 1.18 (95% CI, 0.81-1.70) for patients treated with unfractionated heparin, and 1.15 (95% CI, 0.81-1.62) for patients treated with crossover therapy (vs the no heparin reference group). After a variety of potential confounding variables were controlled, patients treated with any heparin treatment strategy were significantly more likely to experience the composite end point than those not treated with heparin. There was no significant difference in the rate of major bleeding in patients treated with low-molecular-weight heparin (odds ratio [OR] 0.97, 95% CI, 0.66-1.43), patients treated with crossover treatment (OR 1.00, 95% CI 0.68-1.47), or patients treated with unfractionated heparin (OR 0.91, 95% 0.60-1.39), compared with those receiving no heparin treatment (Table 5).

Table 5. Adjusted Odds Ratios for Selected Outcomes for Various Heparin Treatment Groups

Outcome	Low-Molecular-Weight Heparin	Unfractionated Heparin	Crossover
	OR (95% CI)
Death	0.79(0.56-1.11)	1.18(0.81-1.70)	1.15(0.81-1.62)
Major bleeding	0.97(0.66-1.43)	0.91(0.60-1.39)	1.00(0.68-1.47)
Composite (death/myocardial infarction/recurrent ischemia)	1.44(1.29-1.62)	1.63(1.43-1.85)	1.93(1.71-2.17)

OR=odds ratio; CI=confidence interval.

Candidate variables in adjustment models: PCI≤24 hours, PCI>24 hours (both vs no PCI) for all models. Death: age, Killip Class, systolic blood pressure, pulse, initial creatinine, cardiac arrest, positive initial cardiac markers, ST deviation on admission electrocardiogram. Major bleeding: age, gender, history of renal disease, mean arterial pressure, thrombolytics in hospital, glycoprotein IIb/IIIa inhibitors in hospital, both thrombolytics and glycoprotein IIb/IIIa inhibitors (last three variables with reference neither medication), diuretic in hospital, intravenous inotropic drug in hospital, pulmonary artery catheter. Death/myocardial infarction/recurrent ischemia: all variables from death model above, prior angina, gender, prior positive stress test. Final models included only significant variables (P < .05).

*Reference=no heparin at any time during hospitalization.

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Discussion 

This study is the first multinational investigation that describes the contemporary use of heparins in patients with non-ST-elevation acute coronary syndromes. Despite widespread acceptance of the importance of antithrombotic therapy for acute coronary syndrome, a significant number of patients fail to receive any heparin product during their acute hospitalization. Although data supporting the addition of unfractionated heparin to aspirin in acute coronary syndromes have been limited, evidence from 2 large randomized trials (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events and Thrombolysis in Myocardial Infarction-11B) comparing the use of low-molecular-weight heparin with unfractionated heparin in patients with unstable angina and non-ST-elevation myocardial infarction suggests a 16% reduction in 14-day case fatality, recurrent myocardial infarction, and recurrent ischemia.², ³ Despite these findings, our data suggest that approximately one in five patients with non-ST-elevation acute coronary syndromes are still being treated with unfractionated heparin only. In this study, increasing age and the presence of certain comorbidities were inversely associated with the early use of low-molecular-weight heparin.

The variables that seemed to most significantly affect the use of early low-molecular-weight heparin were geographic area and whether early percutaneous coronary intervention was planned. Patients from other parts of the world were up to 4 times more likely to receive early low-molecular-weight heparin than patients from the United States. Much of this discrepancy may stem from the delayed approval of low-molecular-weight heparins for the treatment of acute coronary syndromes in the United States, continued hesitancy about the use of these drugs during percutaneous coronary intervention, and more aggressive use of other antiplatelet and antithrombin drugs. Indeed, patients undergoing early percutaneous coronary intervention in the GRACE study were significantly less likely to receive early low-molecular-weight heparin therapy.

Several studies evaluating the low-molecular-weight heparin enoxaparin as part of an aggressive treatment strategy for acute coronary syndromes have been recently reported. In the A-to-Z trial, 3987 patients with non-ST-elevation acute coronary syndrome who were receiving tirofiban and aspirin were randomized to the receipt of enoxaparin or unfractionated heparin.¹² Enoxaparin proved to be a suitable alternative to unfractionated heparin, meeting prespecified, non-inferiority criteria, with a 12% relative risk reduction (1% absolute reduction) in the primary composite end point.

In the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial, 10,027 high-risk patients with non-ST-elevation myocardial infarction acute coronary syndromes and an intended early invasive strategy were randomized to receive enoxaparin or unfractionated heparin.¹³ The primary composite 30-day end point of all-cause death or nonfatal myocardial infarction occurred in 14.0% of patients treated with enoxaparin and 14.5% of unfractionated heparin-treated patients. The SYNERGY trial was characterized by a high rate of crossover between treatment strategies in either direction. We observed a similar phenomenon in our study. Approximately 4% of patients received both drugs in the first 24 hours of hospitalization for an acute coronary syndrome, 10% of patients initially receiving early low-molecular-weight heparin received unfractionated heparin after 24 hours, and 17% of patients initially receiving early unfractionated heparin received low-molecular-weight heparin after 24 hours. This relatively frequent practice of changing drugs during the early treatment of acute coronary syndrome deserves closer attention because it may result in suboptimal outcomes, as demonstrated in SYNERGY.

In contrast with these data from randomized trials, our analysis attempts to assess the efficacy and safety of low-molecular-weight heparin, unfractionated heparin, neither heparin, or crossover treatment in the more generalizable community setting. Similar to the findings noted in several previously noted randomized controlled trials, the use of low-molecular-weight heparin, even early in the course of an acute coronary syndrome, seemed to be at least as safe and effective as unfractionated heparin or receipt of neither treatment. Hospital death rates were similarly low in all treatment groups, particularly if percutaneous coronary intervention was performed. The risk of the primary composite end point was lowest in patients treated with neither treatment or low-molecular-weight heparin after controlling for other prognostic variables. The incidence of major bleeding was acceptably low (≤2.0%) in all treatment groups.

In the present study, the use of low-molecular-weight heparin was associated with an even more striking reduction in death and our composite end point in patients who underwent percutaneous coronary intervention after 24 hours or not at all. A similar association was noted in the A-to-Z trial. In patients designated for a conservative treatment strategy, those treated with enoxaparin had a significantly lower incidence of death, myocardial infarction, or refractory ischemia, compared with those treated with unfractionated heparin.¹⁴ On the other hand, the benefits observed with enoxaparin relative to unfractionated heparin were much smaller in patients with an acute coronary syndrome undergoing early percutaneous coronary intervention.², ³, ¹², ¹³

The large percentage of patients treated with crossover therapy in our study is of concern and underscores the lack of consensus on which heparin product to use, when to start treatment, and for how long. Crossover treatment was associated with an increased risk of bleeding episodes and worse hospital outcome.

Study Strengths and Limitations 

The present analysis was based on data from an observational study and carried out in a post hoc manner. Therefore, we are limited in our ability to systematically identify possible differences in our primary study outcomes according to the treatment with a specific drug regimen. However, these data provide a picture of current use patterns, as well as the relative safety and efficacy of these drugs in the “real world.” Patients enrolled in chronic disease registries are usually older and have more comorbidities, are more likely to experience medication errors, and tend to have higher death and bleeding rates than patients enrolled in randomized trials. Our adjustment for potentially confounding variables may not have been complete, but the major predictors of risk were taken into account. The switching of antithrombin drugs is potentially confounding; however, it represents the real-world use of these drugs. Although registry data are useful for identifying patterns of therapy use and generating testable hypotheses, they do not replace data from randomized controlled trials.

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Conclusions 

Marked geographic variation exists in the use of low-molecular-weight heparin in the treatment of non-ST-elevation acute coronary syndromes. Much of this variation may be attributable to concomitant geographic differences in the use of an early, aggressive interventional approach for which the role of the low-molecular-weight heparins had not previously been clearly defined. As data documenting the safety and efficacy of low-molecular-weight heparins as part of such a strategy have been published over the past several years, the use of this therapy in GRACE has steadily increased. Our data confirm that, even in the community setting where concomitant therapies and use of percutaneous coronary intervention may differ greatly, low-molecular-weight heparins are safe and at least as, if not more, effective than unfractionated heparin. We documented a significant amount of crossover between the use of low-molecular-weight heparin and unfractionated heparin, both before and after 24 hours of hospitalization.

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Acknowledgments 

We thank the physicians and nurses participating in GRACE, and Sophie Rushton-Smith, PhD, for providing editorial assistance (www.outcomes.org/grace).

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