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Interval Increase in Right-Left Ventricular Diameter Ratios at CT as a Predictor of 30-day Mortality after Acute Pulmonary Embolism: Initial Experience¹

¹ From the Department of Radiology (M.T.L., H.E., A.G.W., F.J.R.) and Cardiovascular Division (S.Z.G.), Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115; Department of Biostatistics, Harvard University, Boston, Mass (T.C.); and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Mass (R.Q.). From the 2006 RSNA Annual Meeting. Received April 23, 2006; revision requested January 24, 2007; revision received March 9; accepted April 13; final version accepted June 1. Address correspondence to F.J.R. (e-mail: frybicki{at}partners.org).

	ABSTRACT

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Purpose: To retrospectively determine if the interval increase of right ventricular–left ventricular (RV/LV) diameter ratio from negative prior to positive current computed tomographic (CT) examination findings for pulmonary embolism (PE) is more accurate for predicting 30-day mortality than positive CT ratio alone, by using patient 30-day mortality as reference standard.

Materials and Methods: This IRB-approved, HIPAA-compliant study had waiver of informed consent and retrospectively reviewed 50 patients (19 men, 31 women; mean age, 60 years) with negative prior and positive current CT findings for acute PE (median interval, 63 days). Interval increase was defined as percentage change in RV/LV diameter ratio by using reformatted four-chamber views. Receiver operating characteristic (ROC) analysis compared the interval increase with the RV/LV diameter ratio from the positive findings alone for PE-related and all-cause mortality.

Results: Twelve (24%) patients died in 30 days; nine were PE-related. The interval increase was significantly more accurate overall than the ratio from the positive study alone for PE-related (area under the ROC curve [AUC] = 0.95 vs 0.73, P = .003) and all-cause (AUC = 0.81 vs 0.66, P = .05) mortality. The respective sensitivity, specificity, positive predictive value, and negative predictive value were 0.78 (seven of nine; 95% confidence interval [CI]: 0.43, 1.00), 0.93 (38 of 41; 95% CI: 0.83, 1.00), 0.70 (seven of 10; 95% CI: 0.38, 1.00), and 0.95 (38 of 40; 95% CI: 0.87, 1.00) for PE-related mortality (interval increase, >18%) and 0.75 (nine of 12; 95% CI: 0.49, 1.00), 0.89 (34 of 38; 95% CI: 0.80, 0.99), 0.69 (nine of 13; 95% CI: 0.44, 0.95), and 0.92 (34 of 37; 95% CI: 0.83, 1.00) for all-cause mortality (interval increase, >15%). At target sensitivity (0.75), specificity of interval increase was significantly higher than from positive scans alone for both PE-related (0.93 vs 0.59, P = .001) and all-cause (0.89 vs 0.58, P = .05) mortality.

Conclusion: The interval increase in four-chamber RV/LV diameter ratio is more accurate than the diameter ratio of the CT examination with with positive findings for PE alone for mortality prediction after acute PE.

© RSNA, 2008

	INTRODUCTION

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Risk stratification after acute pulmonary embolism (PE) is important because it allows for appropriate clinical treatment (1). Echocardiography is the established imaging modality used for risk stratification after PE; patients with ultrasonographic (US) right ventricular (RV) dilatation are more likely to progress to RV failure and death (2–5).

Computed tomography (CT) is the first-line diagnostic study for identifying PE (6,7). Because the entire heart is imaged on nearly every PE protocol CT scan, there has been substantial interest in identifying CT signs of RV dilatation. The four-chamber right ventricular–left ventricular (RV/LV) diameter ratio, an established sign of US RV dilatation, is among the most studied parameters at CT (8–16) and has been the subject of recent review (17). Several retrospective studies reported that an enlarged RV/LV diameter ratio seen at CT is a sensitive though fairly nonspecific marker for mortality after PE (18–20).

The specificity of the RV/LV diameter ratio may be limited because it is measured at only a single examination. An increased RV/LV diameter ratio may result from acutely elevated RV pressures secondary to PE; alternatively, it may result from a preexisting process that is independent of acute PE. The RV/LV diameter ratio from a single examination cannot be used to distinguish between these two possibilities.

As CT use increases, a growing number of patients have a prior examination that is negative for PE findings available at their current CT-aided positive diagnosis of PE. This presents an opportunity to determine whether an interval change in RV size is more accurate than RV size alone. In our study we define a new parameter, "interval increase," as the percentage change in the reformatted four-chamber RV/LV diameter ratio from the prior CT examination with negative findings to the current diagnostic CT examination with positive findings for PE.

Thus, the purpose of our study was to retrospectively determine if the interval increase in the ratio of RV/LV diameter from a prior CT scan with negative findings for PE to a current CT scan with positive findings for PE is more accurate for the prediction of 30-day mortality than is the ratio from the CT scan with positive findings alone by using patient 30-day mortality as the reference standard.

	MATERIALS AND METHODS

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Study Population
Our Institutional Review Board approved this Health Insurance Portability and Accountability Act–compliant study and informed consent was waived. The reports of all PE protocol CT examinations performed from August 2003 to February 2006 were divided among three authors (M.T.L., A.G.W., F.J.R.) and retrospectively reviewed, yielding 656 patients with a CT-aided diagnosis of acute PE. Of these patients, 52 had prior negative findings for PE during the study period. Prior contrast material–enhanced CT scans of the chest performed for other clinical indications (eg, metastatic work-up) were not considered. Two of the patients were excluded: one owing to dextrotransposition of the great arteries, and one because the heart was not fully imaged on the prior CT scan. Thus 50 patients (19 men, 31 women; mean age ± standard deviation, 60 years ± 13; range, 29–82 years) were included. The median interval between the examinations with prior negative and current positive findings was 63 days (range, 3–840 days).

For patients with more then one examination with a CT-aided diagnosis of PE in the study period, only the earliest positive examination was considered. For patients with more than one examination negative for PE findings, only the examination immediately preceding the one positive for PE findings was considered.

Imaging Studies
CT examinations for PE were performed by using four- to 64-section scanners (Siemens Medical Solutions; Erlangen, Germany) with these parameters: section thickness, 1.0–1.25 x 0.75–1.0 mm; pitch, 1.0–1.5; 120 kV; and effective milliampere-second level of approximately 200. A 125-mL bolus of iodinated contrast material (370 mg iodine per milliliter; Isovue 370, Bracco Diagnostics, Princeton, NJ) was timed with bolus tracking on the main pulmonary artery. The contrast injection rate was 3 mL/sec with a power injector (Empower; E-Z-Em, Lake Success, NY). Electrocardiographic gating was not employed (21).

Image Postprocessing and Measurements
For each study, the reformatted four-chamber view was generated on a dedicated three-dimensional workstation (Vitrea 2; Vital Images, Minnetonka, Minn) by identifying a line that bisects the center of the mitral valve and the cardiac apex on true sagittal reformations. The four-chamber view is a plane along this line and its location was confirmed on orthogonal views. On the four-chamber view, ventricular diameters were identified as the maximum distance from the interventricular septum to the endocardial border perpendicular to the long axis of the heart (Fig 1). Two observers (M.T.L., F.J.R., with 1 and 10 years cardiothoracic CT experience, respectively) performed all measurements by consensus. Both observers were blinded to clinical presentation and outcome; neither observer was responsible for the official interpretation of the images or the clinical care of the study patients. Both observers were aware that they were viewing CT examinations with negative prior and positive current findings for PE.

View larger version (127K): [in this window] [in a new window] [Download PPT slide]   Figure 1a: CT scans show four-chamber views from examinations (a) negative and (b) positive for PE indications. RV/LV diameter ratios were (a) 0.90 and (b) 1.18. Interval increase was 31%.

View larger version (149K): [in this window] [in a new window] [Download PPT slide]   Figure 1b: CT scans show four-chamber views from examinations (a) negative and (b) positive for PE indications. RV/LV diameter ratios were (a) 0.90 and (b) 1.18. Interval increase was 31%.

Statistical Analysis
As already noted, the interval increase was defined as the percentage change in RV/LV diameter ratio from prior negative to positive current findings seen at CT:

Receiver operating characteristic (ROC) analysis was performed to compare the accuracy of the interval increase with that of the RV/LV diameter ratio from the positive study alone for both clinical 30-day end points: PE-related mortality and all-cause mortality.

The remainder of the analysis focused on comparing the interval increase with the RV/LV diameter ratio at a fixed sensitivity (as opposed to comparison at a fixed threshold level) for two reasons. First, to our knowledge, the ideal threshold level for the four-chamber RV/LV diameter ratio has not been accurately defined. Second, since the interval increase has not been previously described, a consensus on this level should be the subject of future studies. For all-cause mortality, a sensitivity of 0.75 was chosen because it is comparable to the published sensitivity of a single four-chamber RV/LV diameter ratio for the same end point (19). For PE-related mortality, a sensitivity of 0.75 could not be achieved, given the patient population; thus, the comparison was performed at the closest achievable sensitivity of 0.78.

In the first stage of this analysis, the threshold levels for the interval increase were identified at a sensitivity of 0.78 for PE-related mortality and 0.75 for all-cause mortality. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the interval increase at these threshold levels were computed. In the second stage of the analysis, the specificity, NPV, PPV, and hazard ratios of the interval increase and the RV/LV diameter ratio were compared at a fixed sensitivity of 0.78 (PE-related mortality) and 0.75 (all-cause mortality).

Point estimates of sensitivity, specificity, PPV, and NPV were obtained by using nonparametric methods (22). Calculations of confidence intervals (CIs) were performed on the basis of the bootstrap method (23). P values for hypothesis testing were calculated by using the Wald test; hazard ratios were calculated on the basis of the Cox proportional hazards model. The distribution of age, sex, comorbidities, and recent events between those patients who suffered PE-related death and those who did not was compared by using the Fisher exact test for binary variables and the Student t test for continuous variables. The statistical analysis was performed by using software (R, version 2.0.0, 2004; R Foundation, Vienna, Austria). A P value of .05 or less was considered to indicate a significant difference.

	RESULTS

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Mortality and ROC Analysis
Twelve (24%) patients died within 30 days of their CT-aided diagnosis of PE (Table 1). Death was PE-related in nine (18%) of these. The remaining three died from complications of sepsis (n = 1) and malignancy (n = 2).

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 2: ROC curves show interval increase and RV/LV diameter ratio of CT examinations with findings positive for PE. The outcome was PE-related mortality. Interval increase was significantly more accurate overall than RV/LV diameter ratio (P = .003).

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 3: ROC curves show interval increase and RV/LV diameter ratio of CT examinations with findings positive for PE. The outcome was all-cause mortality. Interval increase was significantly more accurate overall than RV/LV diameter ratio (P = .05).

In the second stage, the interval increase and the RV/LV diameter ratio were compared at a fixed sensitivity of 0.78 for PE-related mortality (Table 2) and a fixed sensitivity of 0.75 for all-cause mortality (Table 3). At these sensitivities, the threshold level for the RV/LV diameter ratio was 1.0 for PE-related and all-cause mortality. For PE-related mortality and all-cause mortality, the specificity of the interval increase was statistically better than the RV/LV diameter ratio from the positive scan alone. The PPV and hazard ratio proved statistically better for PE-related mortality with a strong trend without significance for all-cause mortality.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 4: Standards for Reporting Diagnostic Accuracy Studies flow diagram for interval increase as PE-related mortality predictor.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 5: Standards for Reporting Diagnostic Accuracy Studies flow diagram for the interval increase as all-cause mortality predictor.

	DISCUSSION

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Existing algorithms for risk stratification after PE incorporate hypotension, echocardiography (2,3), and biomarkers, including cardiac troponins and brain natriuretic peptide (1,24–29), to identify those patients who are at high risk. Several reports suggest that the RV/LV diameter ratio seen at CT may also be helpful for predicting death after PE (17). Schoepf et al (19) demonstrated that a reformatted four-chamber RV/LV diameter ratio of more than 0.9 provided a highly sensitive but fairly nonspecific test for all-cause mortality after PE. Van der Meer et al (18) found that a transverse RV/LV diameter ratio higher than 1.0 had a sensitivity of 100% for 90-day PE-related death.

More recently, Ghaye et al (20) confirmed that the transverse RV/LV diameter ratio was significantly higher in patients who died in the hospital than patients who survived. As these studies only examined the single CT scan with positive findings for PE, the implicit assumption has been that RV dilatation, if present, was caused by the acute PE.

A single CT scan does not reliably help to distinguish between an enlarged RV/LV diameter ratio owing to acute PE and an enlarged ratio owing to a preexisting condition. As described in the results, 13 (26%) patients had an RV/LV diameter ratio of more than 1.0 on their prior CT scans that were negative for PE findings. These patients met the criterion for RV dilatation as defined in our study, even though no PE was present. On the CT scan with positive findings used to diagnose PE, 24 (48%) patients had an RV/LV diameter ratio of more than 1.0. The high prevalence of an enlarged RV/LV diameter ratio before acute PE limited the specificity of a single diameter ratio.

Our study demonstrated that comparison with a prior CT examination enabled a better assessment of whether acute dilatation of the RV was present and provided a more accurate prediction of short-term mortality. The results were not significantly influenced by patient demographics, comorbidities, or recent clinical events. For PE-related mortality, an interval increase of more than 18% was significantly more specific and had a significantly higher PPV and hazard ratio than did a diameter ratio of more than 1.0 from the positive scan alone. For all-cause mortality, an interval increase of more than 15% was significantly more specific than a diameter ratio of more than 1.0 from the positive scan alone.

To our knowledge, our study is the first of any modality to employ prior CT examinations negative for PE findings for risk stratification in acute PE. However, there is precedent for assessing the RV over time. To date, these studies have focused on the resolution of RV dilatation after treatment (ie, examining the RV at the time of diagnosis, and then again at a later date). Serial echocardiography has demonstrated recovery of RV function after thrombolysis (30). Grifoni et al (31) found that persistent US RV dysfunction at discharge was associated with future recurrent venous thromboembolism. At CT examination, Kipfmueller et al (32) found that 23 patients with PE experienced a significant decrease in their RV/LV diameter ratios after receiving thrombolysis or thrombectomy, although no association with mortality was reported.

Several limitations of our study should be considered. First, since this study was retrospective, the time interval between CT examinations was not consistent. When a significant interval increase was present, it was assumed to have been caused by the PE. However, interval enlargement of the RV owing to a process independent of acute PE could not be excluded. Nevertheless, the interval increase proved to be an accurate predictor of 30-day mortality. Second, we assumed that the prior examinations negative for PE findings were negative, meaning that when no evidence of PE was found on a PE protocol CT that no PE was present.

Third, measurements were based on the four-chamber view. While we recognize variability in RV assessment by using the four-chamber view, it has become standard in cardiovascular CT. Fourth, as measurements were made by consensus, no assessment of the reproducibility of the diameter ratio measurements was made. Fifth, the mortality rate of the study patients, each of whom had at least one negative examination prior to the CT-aided diagnosis of PE, was higher than that reported for all patients who received a CT-aided diagnosis of PE (24% vs 14%) (19). Furthermore, the proportion of 30-day deaths related to PE was slightly higher than has been previously reported (nine of 12 vs seven of 13) (18). The discrepancy in post-PE mortality rates may be explained in that patients who require multiple CT examinations are more likely to succumb to PE than patients who only underwent a single examination.

Finally, only PE protocol CT examinations were used as examinations negative for PE findings in this study. Contrast-enhanced CT examinations of the chest obtained for other indications (eg, work-up for metastases) were not included because, during the study period at our institution, these studies were reconstructed at 5-mm intervals, precluding accurate reformatting of four-chamber views. In the future, as use of CT scanning continues to increase, more patients will have CT examinations negative for PE findings. In addition, the trend in multidetector CT is to acquire and archive thinner sections for all thoracic clinical indications, and it is possible that these can be used as prior studies. The impact of the interval increase would be greater if this larger pool of studies could be drawn on as prior examinations. Ongoing work is investigating whether these studies have comparable utility as prior CT examinations negative for PE.

In conclusion, the interval increase in four-chamber RV/LV diameter ratio from a prior CT examination negative for PE indications to an current examination positive for PE indications is more accurate than the diameter ratio from the current positive examination alone for predicting 30-day mortality after acute PE. We believe the interval increase is important to report when a previous examination negative for PE is available.

	ADVANCE IN KNOWLEDGE

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• The interval increase in four-chamber right ventricular–left ventricular (RV/LV) diameter ratio from a prior CT examination negative for pulmonary embolism (PE) findings to a current one positive for PE findings is overall significantly more accurate than the diameter ratio from the examination with positive findings alone for predicting 30-day (area under the receiver operating characteristic curve [AUC] = 0.95 vs 0.73, P = .003) and all-cause (AUC = 0.81 vs 0.66, P = .05) mortality after acute PE.
  

	IMPLICATION FOR PATIENT CARE

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• The interval increase in four-chamber RV/LV diameter ratio is a predictor of mortality after PE; we believe this parameter is important to report when a prior CT examination negative for PE indications is available.
  

	FOOTNOTES

 

Abbreviations: AUC = area under the ROC curve • LV = left ventricular • NPV = negative predictive value • PE = pulmonary embolism • PPV = positive predictive value • ROC = receiver operating characteristic • RV = right ventricular

Author contributions: Guarantor of integrity of entire study, F.J.R.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; final manuscript version approved, all authors; literature research, M.T.L., T.C., A.G.W.; clinical studies, M.T.L., H.E., A.G.W., F.J.R.; statistical analysis, T.C.; and manuscript editing, all authors

Authors stated no financial relationship to disclose.

	References

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This Article Abstract Figures Only Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lu, M. T. Articles by Rybicki, F. J. Search for Related Content PubMed PubMed Citation Articles by Lu, M. T. Articles by Rybicki, F. J.