Activated Partial Thromboplastin Time and Outcome After Thrombolytic Therapy for Acute Myocardial Infarction
Results From the GUSTO-I Trial
Background Although intravenous heparin is commonly used after thrombolytic therapy, few reports have addressed the relationship between the degree of anticoagulation and clinical outcomes. We examined the activated partial thromboplastin time (aPTT) in 29 656 patients in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial and analyzed the relationship between the aPTT and both baseline patient characteristics and clinical outcomes.
Methods and Results Intravenous heparin was administered as a 5000-U bolus followed by an initial infusion of 1000 U/h, with dose adjustment to achieve a target aPTT of 60 to 85 seconds. aPTTs were collected 6, 12, and 24 hours after thrombolytic administration. Higher aPTT at 24 hours was strongly related to lower patient weight (P<.00001) as well as older age, female sex, and lack of cigarette smoking (all P<.0001). At 12 hours, the aPTT associated with the lowest 30-day mortality, stroke, and bleeding rates was 50 to 70 seconds. There was an unexpected direct relationship between the aPTT and the risk of subsequent reinfarction. There was a clustering of reinfarction in the first 10 hours after discontinuation of intravenous heparin.
Conclusions Although the relationship between aPTT and clinical outcome was confounded to some degree by the influence of baseline prognostic characteristics, aPTTs higher than 70 seconds were found to be associated with higher likelihood of mortality, stroke, bleeding, and reinfarction. These findings suggest that until proven otherwise, we should consider the aPTT range of 50 to 70 seconds as optimal with intravenous heparin after thrombolytic therapy.
The role of intravenous heparin after thrombolytic therapy for acute myocardial infarction is ill defined. Despite the lack of definitive evidence of its effectiveness, intravenous heparin is recommended after thrombolytic therapy in the American College of Cardiology/American Heart Association guidelines.1 The anticoagulant effect of intravenous heparin usually is monitored with the activated partial thromboplastin time (aPTT).2 Data from two trials have demonstrated that aPTT values in the range of at least 45 seconds3 or at least two times control4 are associated with higher degrees of infarct-related coronary artery perfusion after administration of tissue-type plasminogen activator (TPA). However, there have been no large studies relating the degree of aPTT prolongation to clinical outcome after thrombolysis. Of note, the largest trials evaluating thrombolytic therapy−ISIS-2,5 ISIS-3,6 GISSI-1,7 and GISSI-28 −did not have the opportunity to address this issue because intravenous heparin was not used.
From 1990 to 1993, the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial enrolled 41 021 patients with acute myocardial infarction in 15 countries in a randomized comparison of four thrombolytic treatment strategies,9 three of which included intravenous heparin. The GUSTO-I protocol called for aPTT determinations at 6, 12, and 24 hours after enrollment in patients assigned to intravenous heparin and used a standard nomogram to adjust the heparin dose. This study was intended to investigate the relationship of clinical outcomes to the aPTT response and specifically does not address whether intravenous heparin is necessary with thrombolytic therapy. We hypothesized a direct relationship of aPTT with bleeding and an inverse correlation with the end points of death and reinfarction. In addition, we investigated in this large population the relationship between key demographic factors such as weight and age and the anticoagulant effect of heparin.
Eligibility criteria for the GUSTO-I trial have been described elsewhere.9 Briefly, patients who were within 6 hours of symptom onset of acute myocardial infarction with ECG ST-segment elevation were eligible as long as they did not have a history of stroke, active bleeding, recent major surgery, recent noncompressible vascular puncture, prior enrollment in the trial, or prior treatment with streptokinase or anistreplase.
Qualifying patients were randomly assigned to one of four treatment strategies: streptokinase 1.5 million U over 60 minutes, with subcutaneous heparin 12 500 U twice daily beginning 4 hours after the start of thrombolytic therapy; streptokinase 1.5 million U over 60 minutes with intravenous heparin; accelerated TPA with a bolus dose of 15 mg followed by an infusion of 0.75 mg/kg (up to 50 mg) over 30 minutes and 0.5 mg/kg (up to 35 mg) over the next 60 minutes, with intravenous heparin; or the combination of intravenous TPA (1.0 mg/kg over 60 minutes, not to exceed 90 mg, with 10% given as a bolus) and streptokinase (1.0 million U over 60 minutes) with intravenous heparin. The intravenous heparin regimen was a bolus dose of 5000 U and then 1000 U/h for at least 48 hours, and investigators had the option of delaying the heparin infusion (not the bolus) until the completion of the thrombolytic therapy if there was a problem with lack of intravenous access. In May 1992, after it was determined that the aPTTs were below the target range in approximately half of GUSTO-I patients at 24 hours and that the aPTTs were much more commonly below the target range in heavier patients,10 an informal recommendation via the project’s newsletter (not a protocol amendment) was made to increase the initial dose of heparin to 1200 U/h for patients who weighed more than 80 kg.11
The main analyses in this study include only patients assigned to one of the three strategies with intravenous heparin who had at least one aPTT obtained.
aPTT Monitoring and Heparin Adjustment
The protocol called for aPTT measurements at 6, 12, and 24 hours after initiation of thrombolytic therapy in all patients assigned to intravenous heparin. The heparin dose was adjusted according to a nomogram (Table 1⇓) adapted from Cruikshank et al,12 to achieve a target aPTT range of 60 to 85 seconds for standard aPTT reagents and median control aPTTs in the 26- to 36-second range. If the median control aPTT fell outside that range, a customized nomogram was developed that had a target range of 2.0 to 2.7 times that hospital’s control aPTT. This aPTT range was intended to correspond to heparin levels in the 0.2 to 0.4 U/mL range measured by protamine titration.2 These levels were found to be effective in a rabbit model of jugular venous thrombosis.13 On the basis of the 6- and 12-hour aPTTs, the heparin dose was to be titrated upward for aPTTs less than 60 seconds. However, because the systemic fibrinogenolytic state commonly induced by plasminogen activators is known to cause aPTT prolongation in the early hours after thrombolytic therapy,14 the heparin dose was not to be titrated downward based on 6- or 12-hour aPTTs greater than 85 seconds.
As an alternative to routine laboratory assessment, investigators were permitted to use the CoaguChek Plus (Boehringer Mannheim) bedside anticoagulation monitor. A nomogram was customized for that device with a target aPTT of 55 to 70 seconds, which correlates with a heparin level of 0.2 to 0.4 U/mL by protamine titration (J. Hirsh, personal communication).
The primary means of expressing aPTT in this report is in seconds rather than multiples of control. In the GUSTO-I trial, seconds were chosen as the unit of measure for aPTT because that was thought to best represent clinical practice. The control aPTT values were available from 92% of participating hospitals, so that the aPTT could be displayed either as seconds or as a multiple of control for analyses. The distribution of the controls reveals a clustering around the median of 30 seconds (25th to 75th percentile, 27 to 32 seconds), with 90% of the sites having a control aPTT in the 26- to 36-second range.
Clinical End Point Definitions
Reinfarction was defined as “assessment by the physician that a second myocardial infarction had occurred . . . based on the presence of at least two of the following four criteria: recurrent ischemic symptoms lasting >15 minutes, after resolution of symptoms of the index infarction; occurrence of new ST-T wave changes or new Q waves; a second elevation in cardiac enzymes to over the normal upper limit (or by a further 20% if already over the normal upper limit); or angiographic reocclusion of a documented previously patent infarct-related artery.”9
Moderate bleeding was defined as bleeding that required transfusion but did not lead to hemodynamic compromise requiring intervention. Severe bleeding was defined as bleeding that caused hemodynamic compromise requiring intervention. Other clinical definitions are included in the original GUSTO-I report.9
Baseline characteristics of study patients were summarized in terms of frequencies and percentages for categorical variables and by the median and 25th and 75th percentiles for continuous variables. Baseline factors associated with variability in aPTTs were identified by univariable and multivariable general linear regression.
The relationship of aPTT to 30-day mortality was evaluated with the use of a logistic regression model, both unadjusted and adjusted for baseline features known to be important predictors of 30-day mortality. These baseline features were identified and included in a multivariable logistic regression model previously developed and validated using the overall GUSTO-I trial population. This model has been described in detail elsewhere.15 The adjustment variables included demographics, history and risk factors, presenting characteristics, and treatment assignment.
The relationships of aPTT at 12 and 24 hours to reinfarction, cerebral infarction, intracranial hemorrhage, and moderate or severe bleeding also were evaluated with the use of logistic regression models. All of the risk modeling incorporated the use of a flexible model-fitting approach involving cubic spline functions.15 16 For reinfarction and stroke analyses, patients were excluded when the aPTTs at 12 and 24 hours were drawn after the time of onset of symptoms of reinfarction or stroke. Because the timing of bleeding was not recorded on the case report form, all aPTTs were included in the relationships with bleeding.
The comparison of primary interest in this analysis was the relationship of aPTT at 12 hours and 30-day mortality. Because of the retrospective nature of the analysis and the multiple comparisons performed, the statistical testing of other relationships should be considered to be exploratory and the significance should be interpreted with caution.
The median aPTTs according to thrombolytic group assignment are summarized in Fig 1⇓, showing that aPTTs were higher at 6 and 12 hours than at 24 hours (P<.0001) and were higher in the streptokinase-treated and intravenous heparin–treated patients in the first 12 hours after thrombolytic administration (P<.0001). At 24 hours, nearly 50% of patients in all treatment groups had an aPTT below the target range of 60 to 85 seconds.
Demographic Variables as Predictors of aPTT
The median 24-hour aPTTs according to categorical baseline features are shown in Table 2⇓. Women, nonsmokers, patients without diabetes, and patients presenting in cardiogenic shock had higher aPTTs. Fig 2⇓ shows that patients who were lighter-weight, older, and shorter had higher 24-hour aPTTs. The univariable and multivariable significance of these relationships is shown in Table 3⇓. The major determinant of the aPTT response to fixed doses of heparin was patient weight. Every 10-kg increase in weight was associated on the average with a 6-second decrease in aPTT. Age and sex also were highly statistically significant predictors of aPTT, with each 10 years of additional age corresponding to an average increase in aPTT of 5 seconds and women having a median aPTT 11 seconds higher than men. Cigarette smokers had lower aPTTs than nonsmokers, even after adjustment for weight, age, and sex. Height, systolic blood pressure, and pulse were no longer significant predictors after adjustment for other variables.
Outcomes and aPTT
As expected, the higher the aPTT, the higher the incidence of moderate or severe bleeding (Fig 3A⇓). The risk appeared to increase dramatically beyond an aPTT of 60 to 70 seconds. For aPTTs between 60 and 100 seconds, there was approximately a 1% increase in the risk of bleeding for every 10-second increase in the 12-hour aPTT.
The relationships of 12- and 24-hour aPTTs with subsequent stroke (primary intracranial hemorrhage and cerebral infarction) are shown in Figs 3B⇑ and 3C⇑. Thirty-six and 38 of the intracranial hemorrhages and 11 and 17 of the cerebral infarcts were removed from analyses of 12- and 24-hour aPTTs, respectively, because the stroke onset was before the aPTT determination. Stroke rates, both primary hemorrhagic and nonhemorrhagic, were either similar or higher with higher aPTTs compared with lower aPTTs at 12 hours.
The relationships of 12- and 24-hour aPTTs with subsequent reinfarction for patients assigned to intravenous heparin are illustrated in Fig 3D⇑. The median time to reinfarction onset among the 1285 patients with reinfarction was 3.8 days. For the 12- and 24-hour aPTT data, one and five of the reinfarctions, respectively, were removed because the onset was before the aPTT determination. The likelihood of subsequent reinfarction was higher for higher aPTT values. Of the 543 patients who were assigned to intravenous heparin and suffered reinfarction while on intravenous heparin, the median aPTT values at 6, 12, and 24 hours were 100, 86, and 66 seconds. Of the 613 patients who were assigned to intravenous heparin, suffered reinfarction after intravenous heparin was discontinued, and had the time of heparin discontinuation noted, 44% occurred within 20 hours of stopping heparin and 33% occurred within 10 hours of stopping heparin (Fig 4⇓). The likelihood of reinfarction after intravenous heparin discontinuation was highest at 2 to 4 hours after discontinuation. Of patients who had reinfarction in the first day after heparin discontinuation, median aPTTs at 12 and 24 hours were 85 and 68 seconds, respectively.
Fig 5⇓ displays the relationship of 12-hour aPTT with 30-day mortality for the 26 759 patients assigned to intravenous heparin who had 12-hour aPTT determinations. The lowest 30-day mortality was seen when the aPTT was in the range of 50 to 70 seconds 12 hours after thrombolytic therapy; patients with aPTTs of 150 seconds had more than a 50% higher mortality than those with aPTTs of 60 seconds. Because higher aPTTs are related to both higher mortality and older age, adjustment for mortality differences for various aPTT levels explained by differences in baseline characteristics is important to determine the independent relationship of aPTT with mortality. After adjustment for baseline characteristics (Fig 5⇓), the relationship between increasing mortality with aPTT greater than 70 seconds persisted (P=.01). A similar relationship was seen when aPTT was examined as a multiple of the control value, as expected because of the tight clustering of control aPTTs around the 30-second range.
Because the relative lack of fibrinogenolysis with TPA might make higher levels of heparin anticoagulation more important for patient outcome compared with streptokinase, we also examined the relationship between aPTT and 30-day mortality in TPA-assigned patients alone. We found the same relationship with the lowest mortality in the mid-level aPTT range of 50 to 70 seconds. There was no statistical interaction (P=.17) between thrombolytic assignment and relationship of 12-hour aPTT with 30-day mortality.
Of the patients in this analysis, 515 and 626 had coronary angioplasty prior to the 12- and 24-hour aPTTs, respectively. The median aPTTs were 100 seconds and 61 seconds at 12 hours and 24 hours, respectively, among patients with preceding angioplasty versus 79 seconds and 62 seconds for patients without preceding angioplasty. The relationships of 12-hour aPTT with mortality and with reinfarction were reanalyzed after removing the patients undergoing angioplasty prior to 12 hours, and the findings were unchanged, with the lowest mortality at 50 to 70 seconds (P<.001) and the lowest reinfarction rate at the lowest aPTT level (P<.001).
To determine the relationship between change in aPTT over time and outcome, we determined the change in aPTT between the 12- and 24-hour time points and compared it with outcomes. The lowest mortality was seen in patients who had no substantial change in aPTT over time, and mortality was higher among patients with a significant increase or decrease in aPTT. The risk of bleeding was higher with increasing aPTT and lower with decreasing aPTT, and the risk of reinfarction was higher with increasing aPTT and not different with decreasing aPTT.
There are three novel findings of this study, two of which are biologically plausible and therefore not unexpected, while the third is difficult to explain and unexpected. The expected findings are that the aPTT is inversely correlated with patient weight and is strongly associated with an increase in bleeding. The unexpected finding is that the rates of mortality and reinfarction are strongly and significantly associated with higher aPTT values.
Determinants of aPTT
Previous studies of pharmacokinetics of heparin in patients with venous thromboembolic disease have demonstrated that heparin is eliminated more rapidly among smokers and in men and that higher doses of heparin are required for heavier patients.17 Our study is much larger than previous studies and therefore provides robust estimates of the influence of factors that affect the aPTT response to heparin in the setting of modern coronary care.
The information obtained on the 24-hour aPTT allowed us to explore patient factors that influence the anticoagulant response to intravenous heparin. The majority of these patients did not have their heparin dose adjusted in the first 24 hours because the aPTT was below 60 seconds in less than 30% of patients and because the protocol did not call for dosage adjustment when the aPTT was above 85 seconds in the first 24 hours.
The inverse relationship between patient weight and heparin effect in this study is consistent with previous experimental studies that have reported a relationship between patient weight and either aPTT18 or heparin requirements.19 This may be related to the finding that heparin distributes into plasma volume,20 which is proportional to body weight. Our patients received thrombolytic therapy, but the results are likely to be generalizable to all patients treated with heparin because most effects of thrombolytic therapy on coagulation disappear by 24 hours.14
The reason that patient characteristics of age, sex, and smoking status are important predictors of aPTT is not readily apparent; the mediators of the effect and half-life of heparin are complex.2 Clearance is thought to be largely due to metabolism by endothelial cells and macrophages21 22 as well as by the renal route.23
Association of aPTT and Bleeding
As expected, the incidence of moderate or severe bleeding was higher among patients with higher aPTTs. Although the incidence of bleeding has been shown to be higher with the use of intravenous heparin after thrombolytic therapy24 and with higher doses of heparin,25 the relationship of degree of aPTT prolongation and bleeding risk has been less clear. Although some studies have found a significant relationship between higher aPTTs and higher risk of hemorrhage among heparin-treated patients after thrombolysis,4 26 others have not.3 27 This may relate to the fact that patients who suffer bleeding complications have their heparin discontinued; therefore, the true relationship of aPTT and bleeding risk is obscured by a subset of patients in whom lower aPTTs are a consequence of the bleeding complications. This is the most likely explanation for the higher incidence of bleeding observed in this study with low aPTTs at 24 hours and the finding in the TIMI 9A trial26 of a statistically lower incidence of bleeding with higher aPTT values at 24 hours (P=.04). The current study demonstrates that increasing aPTT values, especially greater than 70 seconds, both in the early hours and in the later hours after thrombolysis, are associated with increasing risk of bleeding.
Association of aPTT and Stroke
The higher incidence of hemorrhagic stroke with higher aPTTs is consistent with an expected increased bleeding risk with greater anticoagulation and with the findings of higher aPTTs among patients who suffered intracranial hemorrhage in GUSTO IIa.28 Moreover, certain patient characteristics—lower weight, older age, and female sex—are associated with both a higher rate of intracranial hemorrhage after thrombolytic therapy29 and higher aPTTs. There was no evidence of a lower subsequent incidence of cerebral infarction with increasing aPTT values above 60 to 70 seconds. Although lower levels of heparin anticoagulation, for example 12 500 U subcutaneous twice daily,30 are known to protect against left ventricular thrombus formation after acute myocardial infarction, this study suggests that higher degrees of anticoagulation may not protect against ischemic or embolic stroke after thrombolysis.
Association of aPTT and Reinfarction
An unexpected finding was the higher incidence of reinfarction among patients with higher aPTT. This relationship suggests that higher degrees of anticoagulation with heparin do not protect against reinfarction. Similar to the finding of Theroux et al31 in patients with unstable angina, we identified a clustering of reinfarction events among patients who suffered reinfarction after discontinuation of heparin, with one third occurring within 10 hours of heparin discontinuation and nearly one half within 20 hours. The finding that the most likely time for reinfarction is 2 to 4 hours after stopping intravenous heparin suggests that patients should be observed carefully in the early hours after stopping intravenous heparin and that methods are needed to protect patients from reinfarction during this high-risk period. Unlike the findings of Theroux et al, in this study the clustering of events occurred despite the universal use of aspirin. aPTTs were higher among patients who suffered reinfarctions whether the reinfarctions occurred during or after heparin discontinuation.
The reason that higher aPTTs were associated with a higher rate of reinfarction is unknown. Higher aPTTs may be associated with other factors that result in a higher risk of reinfarction, or reinfarction could be delayed among patients with higher aPTTs on the first day until it is more likely to be clinically recognized. Another possible explanation is that higher early aPTTs due to fibrin degradation products, fibrinogenolysis, and plasmin degradation of factors V and VIII would prompt a reduction in the heparin dose, which would expose patients to a higher subsequent risk of reinfarction. The persistence of the relationship between higher 24-hour aPTTs and the higher risk of reinfarction does not support this possibility. Finally, higher aPTTs may be associated with higher rates of earlier infarct-related artery opening, resulting in an increased opportunity for reocclusion and reinfarction.
Association of aPTT and Mortality
Because the angiographic evidence shows that infarct-related coronary artery patency is better with aPTTs greater than two times control,3 4 the observed relationship between the aPTT and mortality in GUSTO I is unexpected. A number of patient characteristics including lighter weight, female sex, older age, and nonsmoking are predictors of both higher risk of death and longer aPTT times. After adjustments are made for these and other differences in baseline characteristics, aPTT values higher than approximately 60 to 70 seconds remain associated (P=.01) with an increase in the risk of death.
The reasons for the higher mortality among patients with aPTT values greater than 70 seconds, even after adjustment for baseline differences, are unclear. The increased risk of serious hemorrhage, including intracranial hemorrhage, only partially explains the increased mortality with higher aPTTs. The finding that there was no apparent protection against reinfarction or recurrent ischemia with higher early aPTTs is counterintuitive. This could be explained by the greater heparin effect either not preventing thrombosis or preventing the thrombotic events during administration, with an increase in risk upon stopping the heparin. Possible prothrombotic effects of higher doses of heparin by directly promoting platelet aggregation32 or via “rebound” hypercoagulability after heparin cessation,33 possibly in part by decreasing anti–thrombin III levels,34 are called into question.
Relationship of Change in aPTT Over Time and Outcome
As expected, a decrease in aPTT between the 12- and 24-hour time points was associated with a lower risk of bleeding. A decrease in aPTT over time was not associated with an increased risk of reinfarction. This suggests that the reason for the increased risk of reinfarction with higher aPTTs at 12 hours was not due to the high aPTTs prompting a decrease in heparin dose with a resultant fall in the aPTT. The lowest mortality was associated with a stable aPTT at 12 and 24 hours in the 50- to 70-second range.
Because analyses of the 12- and 24-hour aPTTs could include only patients who survived long enough to have the samples drawn and 40% of the 30-day mortality occurred within 24 hours, the results are based on data less representative of patients at high risk for early death. The 12- and 24-hour aPTTs were chosen to compare with clinical outcomes because they relate more to heparin effect than the 6-hour aPTT, which is more strongly influenced by which thrombolytic agent was used. The relationships between 12-hour aPTT and outcomes may be the most informative because fewer patients are excluded because of early death, and more subsequent events (death, reinfarction, and stroke) are available to which correlations can be made. Whether these data relating aPTT to outcome, obtained from only two samples per patient during the first 24 hours after thrombolytic therapy, apply to subsequent aPTTs is unknown.
Although mortality appears to be higher with aPTTs less than 50 seconds, the confidence intervals are wide because there are relatively few data points, and more data are needed to clearly define the relationship of aPTT to outcome in the low aPTT range. Although this analysis does show that higher aPTTs are associated with worse outcomes, the data do not specifically address how an individual practitioner should respond to a patient with a high aPTT.
The lack of standardized or normalized methods for aPTT determination is a limitation of any large multicenter study examining aPTT values because of the variation in responsiveness of the aPTT to heparin among different reagents.35 36 However, unless a standardized approach is established, any large-scale multicenter study representing a broad experience of clinical practice will be limited by the heterogeneity of aPTT determination methods.
At present, there has been no definitive large randomized trial that has shown that adjuvant therapy with intravenous heparin is beneficial in improving major clinical outcomes in patients with acute myocardial infarction treated with thrombolytic therapy. However, if there is a role for intravenous heparin, then any beneficial anticoagulant effect of heparin when given to prolong the aPTT beyond approximately 70 seconds is overridden by a combination of patient-related determinants that influence both the aPTT and the mortality rate in the same direction and a possible detrimental effect of high levels of heparin anticoagulation.
This analysis does not provide definitive conclusions as to the optimal aPTT target range. The lower mortality observed among patients with middle-level aPTTs is confounded by differences in baseline characteristics. Even after adjustment for baseline differences among patients with different aPTT levels, it is unclear whether higher aPTTs are a cause or a result of worse clinical outcome. Even so, the association is noteworthy and has not been documented previously. To definitively address the issue of optimal aPTT range, patients would need to be randomized to various aPTT target ranges using a standardized aPTT determination method. Nevertheless, these data caution against routine use of heparin to achieve aPTT levels greater than 70 seconds and suggest that until more data are available, an optimal range may be 50 to 70 seconds, or approximately two times control. Although heparin anticoagulation has been used in routine clinical practice for many years, there is need for continued investigation to both understand and optimize its effects.
This study was supported by Bayer (New York, NY), CIBA-Corning (Medfield, Mass), Genentech (South San Francisco, Calif), ICI Pharmaceuticals (Wilmington, Del), and Sanofi Pharmaceuticals (Paris, France).
Reprint requests to Christopher B. Granger, MD, Box 3409, Duke University Medical Center, Durham, NC 27710.
- Received May 22, 1995.
- Revision received October 9, 1995.
- Accepted October 10, 1995.
- Copyright © 1996 by American Heart Association
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