Guidelines recommend early anticoagulation for patients with acute PE.[3,17] These guidelines come from data showing that anticoagulation reduces overall mortality and VTE recurrence.[6,9,11–13,21–27] However, prior studies have not evaluated how the timing of anticoagulation relates to mortality. This study is the first to consider how the timing of anticoagulation is associated with mortality for acute PE. Our data demonstrate reduced in-hospital and 30-day mortality in patients who received heparin in the ED. The findings associated with therapeutic aPTT within 24 h were similar but less significant.
Quality improvement is directed toward expediting management in critical care.[28–30] Despite guidelines, some studies contest the need for expedited anticoagulation for acute PE. It has been proposed that PE is overdiagnosed and overtreated, citing the lack of correlation between increased diagnosis and decreased mortality.[1,6,26,31–33] Kline et al reported that delayed diagnosis increases the risks of in-hospital adverse events, including shock, intubation, and death. Their study was similar to this investigation in that both evaluated the correlation of early care and clinical outcomes, but this study was not limited to ICU care and focused on the timing of anticoagulation rather than diagnosis.
Our data imply benefit to early anticoagulation, raising the mechanistic question of why receiving heparin in the ED or achieving a therapeutic aPTT within 24 h would improve mortality. Heparin is not thrombolytic, but rather it prevents clot propagation and recurrent VTE.[34,35] Our data did not find a difference in the rates of recurrent VTE, but data regarding recurrent VTE and timing of anticoagulation are mixed. Anand et al found that patients who were subtherapeutic at 48 h did not have increased recurrent VTE. In contrast, Hull et al[15,37,38] report in multiple publications that patients who were not therapeutic within 24 h had an increased rate of recurrent VTE. Given our demonstration of an association between early anticoagulation and survival, we hypothesize that by reducing the rate of clot propagation and its associated deleterious hemodynamic effects, heparin provides survival benefit. An alternate mechanism would be that heparin reduces the rate of acute secondary thromboembolic phenomena, although this is not directly supported by our results. Regardless, it is important to note that our retrospective results do not prove direct causation between early anticoagulation and survival, and so these discussions regarding mechanism must remain in the realm of speculation.
We identified several important demographic and comorbidity differences between patients who had early vs delayed anticoagulation (Tables 3,4). Our findings suggest that older patients with more comorbid conditions may have presented a diagnostic challenge, because the cardiopulmonary symptoms of acute PE may be mistaken for symptoms of CAD, CHF, or COPD. To account further for baseline differences, we used propensity score modeling to account for variables that may have increased the likelihood that patients received heparin in the ED or achieved a therapeutic aPTT within 24 h. Although there were several differences in the populations, the regression modeling of the propensity scores suggested that the survivor and nonsurvivor populations were not inherently different with regard to conditions that might have predisposed to early anticoagulation. Nevertheless, this was a retrospective study that did not have the advantage of randomization of patients to early vs late anticoagulation. Therefore, even with propensity score modeling, we can only demonstrate associations rather than prove cause and effect.
Mortality has been associated in previous studies with malignancy, COPD, older age, male sex, cardiovascular disease, and hemodynamic instability.[5,39–42] In our cohort, malignancy and COPD were indeed univariate predictors of mortality, and there was a trend toward older age in nonsurvivors. Sex and rate of cardiovascular disease were not significantly different between survivors and nonsurvivors. COPD and a positive troponin were potential confounding comorbidities that were associated with both delayed anticoagulation and increased mortality. Subgroup analyses found that receiving heparin in the ED remained predictive of reduced mortality in patients with and without either COPD or a positive troponin. Furthermore, COPD was accounted for by the propensity scores, but the population with a positive troponin remains an area of limitation and further investigation.
We found an association between decreased SBP and in-hospital mortality (Table 1). However, SBPs and the rates of hypotension did not differ between the patients who received heparin in the ED or after admission. Further investigation regarding the timing of anticoagulation could be directed toward the subgroup of patients with hemodynamic instability, especially because guidelines recommend anticoagulation before diagnosis in these patients. In our study, only a minority of patients (5.0%) were started on IV heparin prior to diagnosis. Although this study does not have the power to address this issue, this number is strikingly low and represents an area of potential quality improvement.
We initially hypothesized that more rapid anticoagulation would be associated with hemorrhagic events, but this was not the case. The heparin nomogram has been shown to be effective without increasing the risk of hemorrhagic events. Patients who had hemorrhagic complications were taken off IV heparin, so their mortality data are difficult to compare with those who remained on anticoagulation. Furthermore, our data did not include aPTT values after the initial therapeutic value, so perhaps patients who required longer times to achieve a therapeutic level were also more difficult to maintain in a therapeutic range. Despite use of a standard nomogram, it is theoretically possible that patients with higher bleeding risks were anticoagulated more cautiously and therefore required longer to achieve a therapeutic aPTT. These issues require further investigation.
We considered only IV unfractionated heparin rather than LMWH, given our institution's practice for treating acute PE. Guidelines now support LMWH for acute PE, and LMWH has been shown to achieve therapeutic anticoagulation more rapidly than IV unfractionated heparin.[3,18] We are initiating protocols and further study to determine how the timing of LMWH administration affects outcomes.
Precise times of initial IV infusion were not available for all patients, and thus we chose to characterize patients as having received heparin in the ED or after admission. This is an artificial discriminatory timeframe, and different institutions have varying practices of ED management. For example, some institutions manage patients in their ED for significant lengths of time prior to admission because of bed availability. Therefore, although we feel that our data present important temporal findings, we recognize that initiating heparin in the ED is an artificial timeframe that may not readily translate for all institutions.
This was a retrospective study rather than a randomized trial that manipulated when patients were given heparin. However, a randomized study manipulating the timing of heparinization would be unethical given current guidelines. Our data are therefore correlative, and we describe a relationship between early anticoagulation and mortality rather than proving cause and effect. Given some of the inconsistencies observed with respect to aPTT after adjustment, further research is warranted with respect to the timing variable. The attenuation of the results may suggest confounding, or it may mean that the target time of 24 h may not be universally appropriate. There could be patient-specific profiles that could be developed to increase the reliability of the prediction of mortality. Future research is warranted on these matters.
CHEST. 2010;137(6):1382-1390. © 2010 American College of Chest Physicians
Cite this: Early Anticoagulation is Associated with Reduced Mortality for Acute Pulmonary Embolism - Medscape - Jun 01, 2010.