Early Anticoagulation is Associated with Reduced Mortality for Acute Pulmonary Embolism

Sean B. Smith, MD; Jeffrey B. Geske, MD; Jennifer M. Maguire, MD; Nicholas A. Zane, BA; Rickey E. Carter, PhD; Timothy I. Morgenthaler, MD, FCCP

Disclosures

CHEST. 2010;137(6):1382-1390. 

In This Article

Results

Search of the Mayo Clinic electronic medical record yielded 400 patients seen in the ED between 2002 and 2005 who met the aforementioned criteria for acute PE ( Table 1 and Table 2 ). Median age was 68.0 years (IQR, 54.0–76.0), with 48.8% men. Patients were hospitalized for a median 4.6 days (IQR, 2.1–6.9). Seventy-seven patients (19.3%) required ICU admission, and the median ICU length-of-stay was 2.0 days (IQR, 1.0–3.0). The median follow-up time was 1,411.9 days (IQR 294.9–1,777.8), and 392 patients (98.0%) were accounted for by 30 days. Acute PE was the primary cause of death listed on the medical records or, if available, the autopsy reports for all patients who died in the hospital.

The median time from ED arrival to CT diagnosis was 2.4 h (IQR, 1.4–7.6). Two hundred sixty patients (65.0%) were diagnosed in the ED, and 280 patients (70.0%) received heparin in the ED; thus at least 20 patients (5.0%) were given heparin prior to diagnosis. The median time from ED arrival to therapeutic aPTT was 10.8 h (IQR, 7.7–17.3), and 325 patients (85.8%) had a therapeutic aPTT within 24 h of ED arrival. Twenty-one patients (5.3%) were excluded because they did not achieve a therapeutic aPTT: Four died before they achieved a therapeutic aPTT, and 17 were changed from unfractionated to low-molecular-weight heparin (LMWH) before a therapeutic aPTT was achieved.

Primary Outcomes

In-hospital and 30-day mortality rates were 3.0% and 7.7%, respectively. Patients who received heparin in the ED had lower in-hospital mortality (1.4% vs 6.7%; OR, 0.20; 95% CI, 0.06–0.69; P = .009) and 30-day mortality (4.4% vs 15.3%; OR, 0.25; 95% CI, 0.12–0.55; P < .001) (Fig 1). Patients who achieved a therapeutic aPTT within 24 h had lower 30-day mortality (5.6% vs 14.8%; OR, 0.34; 95% CI, 0.14–0.84; P = .037) and tended to have lower in-hospital mortality (1.5% vs 5.6%; OR, 0.27; 95% CI, 0.06–1.15; P = .091) (Fig 2).

Figure 1.

Hospital and 30-day mortality rates for patients who received heparin in the ED compared with those who received heparin after admission.

Figure 2.

Hospital and 30-day mortality rates for patients who achieved a therapeutic aPTT prior to 24 h from ED arrival compared with those who achieved a therapeutic aPTT after 24 hours. aPTT = activated partial thromboplastin time.

Patients who died in the hospital required longer times to achieve a therapeutic aPTT (median 10.7 h [IQR, 7.7–16.6] vs 20.9 h [IQR, 8.4–28.8]; P < .001). Similarly, patients who died by 30 days also required longer times to achieve a therapeutic aPTT (median 10.8 h [IQR, 7.8–16.5] vs 16.3 h [IQR, 5.3–28.6]; P = .002). Kaplan-Meier curves supported these differences between survivor and nonsurvivor populations (Fig 3).

Figure 3.

Kaplan-Meier plots of when survivors and nonsurvivors achieved a therapeutic aPTT. See Figure 2 legend for expansion of abbreviation.

Patients who required ICU admission had higher in-hospital and 30-day mortality ( Table 1 and Table 2 ). Patients with COPD had higher in-hospital mortality, whereas patients with malignancies had higher 30-day mortality ( Table 1 and Table 2 ). Patients with tachycardia had higher in-hospital and 30-day mortality. Patients who died in the hospital presented with lower SBP, although hypotension was not associated with in-hospital or 30-day mortality. Patients with a positive troponin, higher Wells score, or who had recent immobilization or surgery had higher 30-day mortality. Eleven patients (2.8%) were intubated, which was associated with higher in-hospital mortality.

Patients who received heparin in the ED were younger with a higher Wells score and less likely to have CAD, CHF, COPD, positive D-dimer, or positive troponin ( Table 3 ). Patients who achieved a therapeutic aPTT within 24 h were also younger and less likely to have CAD ( Table 4 ). Patients for whom it was believed that an alternative diagnosis was less likely were more likely to receive heparin in the ED and to achieve a therapeutic aPTT within 24 h. The baseline demographics, presenting vital signs, laboratory data, and comorbidities were otherwise not significantly different between patients who received heparin in the ED or after admission; the same is true for patients who achieved a therapeutic aPTT within 24 h or later.

To account for comorbidities that would confound the relationship between the timing of anticoagulation and mortality, we calculated propensity scores and did subgroup analyses. The propensity scores for hospital and 30-day survivors and nonsurvivors were compared in standard box plot fashion and found to be similar (data not shown). This suggests that adjusting for propensity scores would allow for appropriate comparisons of survivor and nonsurvivor populations with regard to early vs delayed anticoagulation. We then cross-referenced comorbidities associated with mortality ( Table 2 ) with those associated with delayed anticoagulation ( Table 3 ) and identified COPD and a positive troponin as comorbidities that were associated with both delayed anticoagulation and increased mortality. The Breslow Day test of the common OR (pooled estimate across strata) for COPD found that the subgroup results did not contradict the propensity score, so propensity scores remained valid for multiple variate analyses to account for COPD. Troponin data were not incorporated into the propensity score model because data were available for only 312 patients (78%). Furthermore, for patients with and without COPD, receiving heparin in the ED remained predictive of reduced 30-day mortality. For patients with and without a positive troponin, receiving heparin in the ED remained predictive of reduced in-hospital mortality. Early anticoagulation did not remain predictive of reduced mortality in the other COPD and troponin subgroup analyses.

Because of the limited number of in-hospital deaths (n = 12), a multiple logistic regression model for in-hospital mortality was not constructed, because it would be over-fit. Because there were 30 deaths by 30 days, multiple logistic regression models with three variables were considered to be most appropriate to avoid over-fitting. The first variable in these models was the timing of anticoagulation. We created two separate models: one for whether patients received heparin in the ED and another for whether they achieved a therapeutic aPTT within 24 h. Indeed, these two timing variables had inherent covariance (χ2 = 60.1; P < .001), so including them in one model would have confounded results. Admission to the ICU was used as the second variable in both models because it was a significant clinical factor associated with mortality but not included in the propensity score. The propensity score was used as the third variable in both models because it accounted for many demographic, laboratory, and comorbidity baseline characteristics. Each model used a propensity score that had been calculated for the respective timing variable (ie, either the score for receiving heparin in the ED or for achieving a therapeutic aPTT within 24 h).

In the first model, receiving heparin in the ED remained an independent predictor of reduced 30-day mortality (OR, 0.22; 95% CI, 0.08–0.60; P = .003), and the point estimate of the association remained comparable to the unadjusted value ( Table 5 ). In the second model, no variables remained independent predictors of 30-day mortality. There was more attenuation in the association (unadjusted OR, 0.34; adjusted OR, 0.49), which suggests that some of the baseline differences observed above may have introduced some confounding into the unadjusted results.

Secondary Outcomes

Patients who received heparin in the ED had reduced hospital lengths-of-stay (3.9 days [IQR, 1.8–6.0] vs 6.6 days [IQR, 4.0–8.9]; P < .001) and ICU lengths-of-stay (2.0 days [IQR, 1.0–3.0] vs 2.0 days [IQR, 1.0–5.0]; P = .032). Twenty-one patients (5.3%) had a hemorrhagic event that required heparin cessation. These patients had higher in-hospital but not 30-day mortality ( Table 1 and Table 2 ). Patients who received heparin in the ED had similar rates of hemorrhagic events compared with patients who received heparin after admission. Patients who had hemorrhagic events had similar initial aPTT values as compared with those who did not have events. However, achieving a therapeutic aPTT within 24 h was associated with a reduced risk of hemorrhagic events (OR, 0.28; 95% CI, 0.11–0.74; P = .014). Six patients (1.5%) had a recurrent VTE within 90 days, although none of these VTEs were fatal.

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