1Department of Vascular Surgery, Uppsala University Hospital, SE-751 85 Uppsala, Sweden
2Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden
3Department of Vascular Surgery, Lund University, Malmö University Hospital, Sweden
4Department of Pathology, Lund University, Malmö University Hospital, Sweden
Received 12 October 2004; revised 24 December 2004; accepted 5 January 2005; online publish-ahead-of-print 4 February 2005.
* Corresponding author. Tel: +46 70 972 7030; fax: +46 31 776 3745. E-mail address: mats.ogren{at}astrazeneca.com
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Abstract |
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Methods and Results Between 1970 and 1982, 23 796 autopsies, representing 84% of all in-hospital deaths in the Malmö city population, were performed, using a standardized procedure. The relationship between IT and PE was evaluated by cohort analyses and nested casecontrol studies. IT was present in 1706 (7.2%) patients, 727 and 747 of whom had right and left atrial IT, respectively. PE prevalence in patients with isolated left IT, isolated right IT, and combined IT was 28.5, 35.6, and 48.9%, with RR (95% CI) of 1.5 (1.31.8), 2.0 (1.62.5), and 3.5 (2.74.7), respectively, compared with age- and gender-matched controls. Patients dying from ischaemic heart disease had a 3.2 (2.73.6) times higher risk of right IT, which was associated with 43% PE prevalence. Of all patients with PE at autopsy, right IT was found in 354 (6.5%), and the only detected source of PE in 220 (4.0%).
Conclusion Right cardiac thrombosis, though difficult to assess clinically, is as common as left cardiac thrombosis and is associated with an increased risk of PE. The diagnosis should be considered in all cases of PE, especially in patients with atrial fibrillation or myocardial infarction and in the absence of confirmed deep vein thrombosis.
Key Words: Venous thromboembolism Atrial thrombosis Ventricular thrombosis Necropsy Atrial fibrillation complication Epidemiology
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Introduction |
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The occurrence of right intracardiac thrombosis (IT) in patients with PE has indeed been described in several small case series,710 and the prognostic significance of thrombosis associated with right ventricular (RV) dysfunction has been subject to evaluation.11 The comparative inaccessibility of the right heart to non-invasive diagnostic procedures is the most likely explanation for why no large population studies have yet been conducted to elucidate the prevalence of right atrial (RA) thrombosis and associated absolute PE risks.
For several decades, the city of Malmö in southern Sweden has been a centre for epidemiological research, including clinical and autopsy-based studies of atherosclerotic and other cardiovascular diseases.1214 Between 1970 and 1982, close to 24 000 autopsies were performed, prospectively using a standardized protocol and comprising 84% of all in-hospital deaths in the city. The aims of the present study have been to establish the age- and gender-specific prevalence of IT in a population-based autopsy cohort, and to elucidate the relationship between IT and PE.
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Methods |
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Classification of IT and other pathologies
All autopsies were performed using a standardized protocol and carried out or supervised by senior pathologists. All findings were classified and coded according to the Standardized Nomenclature of Pathology (SNOP), as defined by the College of American Pathologists in 1965. The procedure included examination of the heart cavities and walls. All protocols with one or more of the SNOP codes 32-20-3703, 32-50-3703, 32-30-3703, and 32-60-3703 denoting, respectively, RA thrombosis, RV thrombosis, LA thrombosis, and LV thrombosis, were identified, with or without the presence of SNOP code 32-10-3703, being descriptive of a broad mural adherence of the thrombus. The SNOP codes 32-00-2432 and 32-00-1551 denote, respectively, persistent foramen ovale (PFO) and the presence of intracardiac pacemaker catheter.
In the further analysis of IT, the following patient clusters were identified:
Classification of PE
During autopsy, the pulmonary arteries and the lungs were routinely examined for signs of PE, including microscopic examination of lung specimens. All protocols with one or more of the SNOP codes 44-00-3702, 44-00-3710, and 28-00-3710, indicating PE, were identified. PE cases coded with 44-00-3702 and/or 44-00-3710 were further classified as macroscopic PE, whereas cases coded with 28-00-3710 only were classified as microscopic PE.
Classification of causes of death
Death certificates were issued by the pathologist. On the basis of the clinical picture and autopsy findings, an underlying cause of death and up to six contributing causes were determined and classified using the ICD-8 code. In this study, cases coded ICD 410.0410.9 or 412.0412.9 were classified as ischaemic heart disease (IHD)-related deaths. Correspondingly, cases coded ICD 140.0239.9 were classified as cancer-related deaths and cases coded ICD 1.0139.9 as infection related.
Identification of cases and controls
In a nested casecontrol study of risk for IT in PE, one PE-free control, matched for gender, age at death, and year of death, but otherwise randomly chosen, was assigned to each PE case. Similarly, in another nested casecontrol study of PE risk in IT, four IT-free controls were assigned to each case of IT.
Statistical methods
Distributions were expressed in terms of means and variance. One-way analysis of variance (ANOVA) was used to evaluate differences in mean and 2 test to evaluate differences in proportions, adopting two-sided significance tests.
The robustness of the association between IT and PE was explored by sensitivity analysis of subgroups according to causes of death. These analyses were performed without adjustments for multiplicity of significance level. In addition, logistic regression analyses were performed to investigate the partial effects on PE risk of right and left IT, when entering gender, age, and death cause from the univariate analyses.
The analysis of the nested casecontrol study of PE, one-to-one matched, was performed using a stratified analysis in which the strata consisted of the collection of matched pairs. The MantelHaenszel 2 test for association based on 5448 strata was performed and the MantelHaenszel odds ratio was calculated as a summary odds ratio that adjusts for the matched variables.
Similarly, the nested casecontrol study of IT, four-to-one matched, was also analysed using the MantelHaenszel stratification method. In this case, the strata consisted of the collection of matched sets including five subjects each, and the calculations were thus based on 1706 strata.
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Results |
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PE risk in patients with IT
Thirty-eight per cent (647/1706) of the patients where an IT was found at autopsy also had a manifest PE (Table 1). Figure 1 illustrates the relationship between the anatomical localization of IT and PE prevalence. Fifty-five per cent of patients with RV thrombosis and 53% of patients with both right and left IT also had PE (Table 1).
No association between PFO and PE was found in patients with IT: the prevalence of PE was 35.8% (49/137) in those with PFO and 38.1% (598/1569) in those without PFO (P=0.646). Similarly, no significant differences in PE rate were found between thrombosis patients with (27.0%; 17/63) or without (38.3%; 630/1643) a pacemaker catheter (P=0.085).
The association between PE and right vs. left IT remained when stratifying for death from IHD and for death from cancer disease, respectively (Table 2). Of patients dying from infectious disease, right-sided thrombosis occurred only in 11 (2%), but seven of those (64%) had developed PE, in contrast to 21% in the control group (OR 6.5; 95% CI 2.323). When controlling for these death causes and for gender and age at death in a logistic regression analysis, right and left IT were still, independently of each other, associated with an OR (95% CI) of 2.3 (2.02.7) and 2.0 (1.82.2), respectively (Table 2).
Age- and gender-adjusted risk for PE in IT
In a nested casecontrol study, cases with IT had twice as high odds for PE as controls, matched for gender, age, and year of death (95% CI 1.82.2) (P<0.001) (Table 3). Correspondingly, the association with isolated left IT was less pronounced (OR 1.6; 95% CI 1.41.9) (P<0.001), whereas the odds for PE was 3.4 times higher in cases with combined right and left IT than in controls (95% CI 2.64.4) (P<0.001).
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Discussion |
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What then does IT represent? Among conditions associated with LA thrombosis, atrial fibrillation predominates.15,18 Although the present study does not allow an assessment of this or other functional diagnoses, the high concordance between right- and left-sided thrombosis and the advanced age of these patients are indirect indicators. Among other causes, IT may be formed at the scar after a myocardial infarction, and an association was also found in the present study. Tumour emboli caught in transit and thrombosis secondary to infectious lesions are infrequent explanations but should be considered in an autopsy cohort of this magnitude. Right cardiac thrombosis was present in only 2% of patients dying from infectious disease, but was associated with a 6.5-fold increased prevalence of PE. As with any sensitivity analysis of subgroups, some caution is warranted when interpreting multiple analyses.
Some aspects should be addressed when attempting to generalize from these results. Being an autopsy study, it represents a selection of the sickest patients. Fresh clots resulting from terminally hypodynamic circulation were not counted, but it cannot be ruled out that in some patients, IT might reflect a pre-terminal state. This would result in an overestimation of prevalence, but probably not cause bias or affect the PE risk in those patients who had a right IT. Population data with which to compare our results are scarce, but in a unique transoesophageal echocardiogram (TOE) study of a representative sample of the general population of healthy elderly, Roijer et al.19 found a potential cardio-embolic source in the left atrium in as many as 38% of all subjects.
Would the study, if performed today, have yielded similar results? Here one must consider the implementation of antithrombotic treatment in atrial fibrillation16,17 and the increased use of low-dose aspirin. Given the high age and the comorbidity pattern in most patients of the present study, the imputed effect of aspirin in this context can be questioned.16,17 Diligent use of anticoagulants will probably lower the prevalence of IT, but not eradicate itin the large TOE study performed by Agmon et al.,15 half of the patients with a finding of atrial thrombosis were on anticoagulant treatment. Moreover, even in recent studies, far from all eligible atrial fibrillation patients as yet receive effective anticoagulation.20,21
More relevant than the magnitude of prevalence of right cardiac thrombosis is the question of associated PE risk, and especially, to what extent this represents causality. A cross-sectional study has limitations over a longitudinal one for inference on causality, and here, prospective clinical studies are needed. Assessment of strength of association is another tool for inference on causality in epidemiological studies.22 An increased PE risk in patients with solitary left thrombosis can only be explained, in the absence of PFO, by a state of hypercoagulability, and in these patients a moderate 50% increased risk was found. In comparison, in patients with isolated right thrombus, which then might be causative for PE, the overrisk was 100%, and in patients with bilateral thrombosis, an excess PE risk of 250% was found.
We conclude from this population-based autopsy study that right IT, though difficult to assess in clinical practice, is as common as left IT. Of patients dying from or with PE, 7% had right IT as a potential cause, which constituted the only evident source for embolism in 4% of all cases. The diagnosis should be considered in all cases of PE, especially in patients with atrial fibrillation or myocardial infarction and in the absence of confirmed DVT.
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References |
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