One of the most common causes of hospitalization in the elderly is aspiration pneumonia related to dysphagia due to numerous underlying diseases.1 Thus, it is clinically important to identify prognostic factors associated with increased mortality in elderly patients with aspiration pneumonia. Hyponatremia is the most common electrolyte abnormality in hospitalized patients occurring in up to 11% of elderly patients in hospital.2 Previous studies have suggested that the presence and degree of hyponatremia is associated with the severity of pneumonia in adults and children, although the results have differed among studies.37

Hyponatremia is caused by various factors, including volume depletion, use of diuretics, hypothyroidism, adrenal insufficiency, heart failure, renal failure, and cirrhosis. Additionally, the syndrome of inappropriate antidiuresis (SIAD) is a frequent and heterogeneous disorder characterized by hyponatremia and impaired urinary dilution in the absence of any recognized stimulation of antidiuretic hormone secretion.8 Because not all patients with SIAD have elevated circulating levels of arginine vasopressin (AVP), the term SIAD is preferred to the term syndrome of inappropriate secretion of antidiuretic hormone (SIADH).9 One study has shown an association between the severity of pneumonia in children and the development of hyponatremia due to SIAD.10 To our knowledge, there have been no studies evaluating the impact of different causes of hyponatremia on mortality in elderly patients with aspiration pneumonia.

We therefore sought to investigate whether hyponatremia of all etiologies (all‐cause hyponatremia) was associated with mortality in elderly patients with aspiration pneumonia. Additionally, we compared the impact of hyponatremia due to SIAD, with hyponatremia of other etiologies, on mortality in this population

METHODS

RESULTS

The baseline characteristics of the study population are listed in Table 2. There were 221 elderly patients identified as having aspiration pneumonia. Of those, 65 (29%) had hyponatremia; 3 (5%) with non‐hypotonic and 62 (95%) with hypotonic hyponatremia. In the latter group, patients were characterized has having hypovolemic (39 [63%]), hypervolemic (3 [5%]), and euvolemic (20 [32%]) hyponatremia. Among the euvolemic patients, SIAD occurred in 14 (70%) of patients. Non‐SIAD euvolemic hyponatremia occurred in 6 (30%) patients and was associated with hypothyroidism (1 patient), adrenal insufficiency (1 patient), and was unclassifiable due to lack of available clinical data in 4 patients. The kappa value was 0.87 for inter‐rater agreement of the classification of hypotonic hyponatremia.

The following variables were included in multivariate logistic analyses: congestive heart failure, cirrhosis, chronic renal failure, disorientation, body temperature <35C or >40C, anemia, and serum albumin <3 g/dL (see Supporting Information, Appendix, in the online version of this article).

In the multivariate logistic analyses, all‐cause hyponatremia was not associated with increased 30‐day mortality (odds ratio [OR] 1.85, 95% confidence interval [CI] 0.635.48; P = 0.262), but was associated with a trend toward increased risk of in‐hospital mortality (OR 2.10, 95% CI 1.004.42; P = 0.050) (Table 3). Moderate and severe hyponatremia were both significantly associated with increased in‐hospital mortality (OR 6.05, 95% CI 1.4625.0; P = 0.013 and OR 5.65, 95% CI 1.1428.1; P = 0.034, respectively). The same trends were observed for 30‐day mortality, although the results were not statistically significant. No such trend was observed for mild hyponatremia.

In the multivariate logistic regression analyses, hypotonic hyponatremia due to SIAD was significantly associated with both increased risk of 30‐day mortality (OR 7.40, 95% CI 1.7331.7; P = 0.007) and increased risk of in‐hospital mortality (OR 22.3, 95% CI 4.26117; P < 0.001) (Table 4). In contrast, hypovolemic or non‐SIAD euvolemic hyponatremia was associated with neither increased risk of 30‐day mortality nor increased risk of in‐hospital mortality. There were too few hypervolemic hyponatremia patients for us to perform effective logistic analyses. The P values of the HosmerLemeshow tests were 0.45 for the multivariate logistic regression model (hypovolemic, SIAD, and non‐SIAD euvolemic vs normonatremia) with 30‐day mortality, and 0.30 for the model with in‐hospital mortality.

Six patients with SIAD were classified as having an A‐DROP severity class of mild, 4 as moderate, and 4 as severe (P = 0.908, Wilcoxon‐type test for trend). There was no association between the occurrence of SIAD and the severity of pneumonia.

DISCUSSION

We demonstrated that mortality in elderly patients with aspiration pneumonia was significantly associated with SIAD, but not with all‐cause hyponatremia. Unlike SIAD, other etiologies of hyponatremia were not associated with mortality in elderly patients with aspiration pneumonia. A recent study by Waikar and colleagues concluded that hyponatremia subgrouped by severity was not significantly associated with in‐hospital mortality in pneumonia patients, although a trend between severe hyponatremia and mortality was observed.16 Likewise, a study by Zilberberg and colleagues reported no significant increased risk of death with hyponatremia compared with normonatremia.4 These results are similar to our results for all‐cause hyponatremia and for hyponatremia subgrouped by severity. In contrast, a study by Nair and colleagues reported some increased risk of death with hyponatremia.5 Our results suggest that the heterogeneity of these previous results was probably due to the fact that SIAD was not identified in these other studies.

While the rationale for increased mortality in patients with pneumonia associated with SIAD is not known, it may be that there is a direct deleterious effect of elevated AVP. AVP has 3 distinct receptor subtypes, V1A, V1B, and V2. Stimulation of the V1A receptor in vascular smooth muscle promotes an increase in systemic vascular resistance, and stimulation of the same receptor in cardiac myocytes promotes myocyte hypertrophy. Stimulation of the V1B receptor in the anterior pituitary promotes adrenocorticotropic hormone release, and stimulation of the V2 receptor in the renal collecting ducts promotes an increase in water retention, which plays the main role in SIAD.1719 Our hypothesis in elderly SIAD patients with aspiration pneumonia is that increased AVP levels may lead not only to water retention and hyponatremia, but also to other effects such as vasoconstriction and myocyte hypertrophy, which may adversely influence the cardiovascular systems of elderly patients (Figure 1).

Figure 1

In our study, SIAD in elderly patients with aspiration pneumonia was more strongly associated with in‐hospital mortality than with 30‐day mortality. The average length of stay (LOS) of all patients dying in hospital (42 days) was significantly longer than the average LOS of those dying within 30 days of admission (15 days; P < 0.001, MannWhitney Test; Table 2). These findings suggest that SIAD was associated more strongly with longer‐term mortality than with acute‐stage mortality. The reason for the association between SIAD and longer‐term mortality remains unclear, although there may be some association between longer‐term mortality and the pathophysiologic mechanisms of AVP.

Our study has some limitations. First, because of the retrospective observational design, there is a potential for bias. We used multivariate analyses adjusted for confounding factors, however, other residual confounding factors may have remained. In addition, since the diagnosis of pneumonia was based on chart review, there may have been imprecision in the accuracy of diagnosing aspiration pneumonia. Aspiration pneumonia sometimes occurs without apparent episodes of aspiration, and this would have led to underdiagnosis. In contrast, aspiration pneumonitis can be mistaken for aspiration pneumonia; this would have led to overdiagnosis.

Second, volume status is difficult to evaluate prospectively, and thus by nature of our design, appropriate assignment of volume status was difficult. Several studies have used test infusions of isotonic saline to discriminate between these alternatives, but because our study was retrospective, we were unable to use this test.11, 20 Some studies have reported that, in patients in a state of volume depletion, volume repletion removes the stimulus for antidiuretic hormone release, allowing excess water to be excreted in a dilute urine and the serum sodium concentration to return toward normal.21, 22 According to this theory, instead of using an isotonic test infusion, we added in our study a criterion of volume depletion in which patients with a sustained increase in serum sodium concentration of 5 mEq/L and a sustained decrease in blood urea nitrogen, even with administration of hypotonic solution, were classified as volume depleted.

Third, all patients were analyzed according to status on admission, although some patients with hypovolemic hyponatremia at admission were found to have hyponatremia due to SIAD after admission.

Fourth, because the sample size of this study was small with our results revealing wide confidence intervals, an effect between other causes of hyponatremia and mortality might not have been identified. However, for 80% power, the calculated sample size was 100 non‐SIAD patients with aspiration pneumonia versus 10 SIAD patients, given that the mortality rate of elderly patients with aspiration pneumonia was, at a moderate estimate, 15% according to the studies of both Stukenborg and colleagues and Oliver and colleagues, and the mortality rate of SIAD patients was increased by 400% compared with that of non‐SIAD patients according to the study of Song and colleagues, with an alpha error of 0.05.7, 23, 24 Our sample size was therefore greater than the required size.

Fifth, because the APD dataset was compiled in 2007 for another study, it was not concurrent, and this may have led to other limitations in interpreting the data.

Finally, in Japan, the average length of hospital stay was 36.3 days in 2004 and 34.1 days in 2007much longer than other developed countries.25 Because of this situation, in‐hospital mortality, and not 30‐day mortality, represented long‐term mortality. Therefore, our results may not be easily applicable to the situation in other developed countries.

In conclusion, our results suggest that the presence of SIAD on admission in elderly patients with aspiration pneumonia is associated with increased mortality. This novel finding should be re‐evaluated, but it does raise the question of a direct, negative impact of AVP on patients' clinical outcomes. In the future, a larger prospective cohort study should be conducted to confirm the findings of this study, given the small sample size and the retrospective nature of the study. Additionally, a different population of pneumonia patients, such as those with community‐acquired pneumonia, should be examined to further evaluate the etiologies of hyponatremia in pneumonia and the association between hyponatremia of these different etiologies and mortality.

One of the most common causes of hospitalization in the elderly is aspiration pneumonia related to dysphagia due to numerous underlying diseases.1 Thus, it is clinically important to identify prognostic factors associated with increased mortality in elderly patients with aspiration pneumonia. Hyponatremia is the most common electrolyte abnormality in hospitalized patients occurring in up to 11% of elderly patients in hospital.2 Previous studies have suggested that the presence and degree of hyponatremia is associated with the severity of pneumonia in adults and children, although the results have differed among studies.37

Hyponatremia is caused by various factors, including volume depletion, use of diuretics, hypothyroidism, adrenal insufficiency, heart failure, renal failure, and cirrhosis. Additionally, the syndrome of inappropriate antidiuresis (SIAD) is a frequent and heterogeneous disorder characterized by hyponatremia and impaired urinary dilution in the absence of any recognized stimulation of antidiuretic hormone secretion.8 Because not all patients with SIAD have elevated circulating levels of arginine vasopressin (AVP), the term SIAD is preferred to the term syndrome of inappropriate secretion of antidiuretic hormone (SIADH).9 One study has shown an association between the severity of pneumonia in children and the development of hyponatremia due to SIAD.10 To our knowledge, there have been no studies evaluating the impact of different causes of hyponatremia on mortality in elderly patients with aspiration pneumonia.

We therefore sought to investigate whether hyponatremia of all etiologies (all‐cause hyponatremia) was associated with mortality in elderly patients with aspiration pneumonia. Additionally, we compared the impact of hyponatremia due to SIAD, with hyponatremia of other etiologies, on mortality in this population

METHODS

RESULTS

The baseline characteristics of the study population are listed in Table 2. There were 221 elderly patients identified as having aspiration pneumonia. Of those, 65 (29%) had hyponatremia; 3 (5%) with non‐hypotonic and 62 (95%) with hypotonic hyponatremia. In the latter group, patients were characterized has having hypovolemic (39 [63%]), hypervolemic (3 [5%]), and euvolemic (20 [32%]) hyponatremia. Among the euvolemic patients, SIAD occurred in 14 (70%) of patients. Non‐SIAD euvolemic hyponatremia occurred in 6 (30%) patients and was associated with hypothyroidism (1 patient), adrenal insufficiency (1 patient), and was unclassifiable due to lack of available clinical data in 4 patients. The kappa value was 0.87 for inter‐rater agreement of the classification of hypotonic hyponatremia.

The following variables were included in multivariate logistic analyses: congestive heart failure, cirrhosis, chronic renal failure, disorientation, body temperature <35C or >40C, anemia, and serum albumin <3 g/dL (see Supporting Information, Appendix, in the online version of this article).

In the multivariate logistic analyses, all‐cause hyponatremia was not associated with increased 30‐day mortality (odds ratio [OR] 1.85, 95% confidence interval [CI] 0.635.48; P = 0.262), but was associated with a trend toward increased risk of in‐hospital mortality (OR 2.10, 95% CI 1.004.42; P = 0.050) (Table 3). Moderate and severe hyponatremia were both significantly associated with increased in‐hospital mortality (OR 6.05, 95% CI 1.4625.0; P = 0.013 and OR 5.65, 95% CI 1.1428.1; P = 0.034, respectively). The same trends were observed for 30‐day mortality, although the results were not statistically significant. No such trend was observed for mild hyponatremia.

In the multivariate logistic regression analyses, hypotonic hyponatremia due to SIAD was significantly associated with both increased risk of 30‐day mortality (OR 7.40, 95% CI 1.7331.7; P = 0.007) and increased risk of in‐hospital mortality (OR 22.3, 95% CI 4.26117; P < 0.001) (Table 4). In contrast, hypovolemic or non‐SIAD euvolemic hyponatremia was associated with neither increased risk of 30‐day mortality nor increased risk of in‐hospital mortality. There were too few hypervolemic hyponatremia patients for us to perform effective logistic analyses. The P values of the HosmerLemeshow tests were 0.45 for the multivariate logistic regression model (hypovolemic, SIAD, and non‐SIAD euvolemic vs normonatremia) with 30‐day mortality, and 0.30 for the model with in‐hospital mortality.

Six patients with SIAD were classified as having an A‐DROP severity class of mild, 4 as moderate, and 4 as severe (P = 0.908, Wilcoxon‐type test for trend). There was no association between the occurrence of SIAD and the severity of pneumonia.

DISCUSSION

We demonstrated that mortality in elderly patients with aspiration pneumonia was significantly associated with SIAD, but not with all‐cause hyponatremia. Unlike SIAD, other etiologies of hyponatremia were not associated with mortality in elderly patients with aspiration pneumonia. A recent study by Waikar and colleagues concluded that hyponatremia subgrouped by severity was not significantly associated with in‐hospital mortality in pneumonia patients, although a trend between severe hyponatremia and mortality was observed.16 Likewise, a study by Zilberberg and colleagues reported no significant increased risk of death with hyponatremia compared with normonatremia.4 These results are similar to our results for all‐cause hyponatremia and for hyponatremia subgrouped by severity. In contrast, a study by Nair and colleagues reported some increased risk of death with hyponatremia.5 Our results suggest that the heterogeneity of these previous results was probably due to the fact that SIAD was not identified in these other studies.

While the rationale for increased mortality in patients with pneumonia associated with SIAD is not known, it may be that there is a direct deleterious effect of elevated AVP. AVP has 3 distinct receptor subtypes, V1A, V1B, and V2. Stimulation of the V1A receptor in vascular smooth muscle promotes an increase in systemic vascular resistance, and stimulation of the same receptor in cardiac myocytes promotes myocyte hypertrophy. Stimulation of the V1B receptor in the anterior pituitary promotes adrenocorticotropic hormone release, and stimulation of the V2 receptor in the renal collecting ducts promotes an increase in water retention, which plays the main role in SIAD.1719 Our hypothesis in elderly SIAD patients with aspiration pneumonia is that increased AVP levels may lead not only to water retention and hyponatremia, but also to other effects such as vasoconstriction and myocyte hypertrophy, which may adversely influence the cardiovascular systems of elderly patients (Figure 1).

Figure 1

In our study, SIAD in elderly patients with aspiration pneumonia was more strongly associated with in‐hospital mortality than with 30‐day mortality. The average length of stay (LOS) of all patients dying in hospital (42 days) was significantly longer than the average LOS of those dying within 30 days of admission (15 days; P < 0.001, MannWhitney Test; Table 2). These findings suggest that SIAD was associated more strongly with longer‐term mortality than with acute‐stage mortality. The reason for the association between SIAD and longer‐term mortality remains unclear, although there may be some association between longer‐term mortality and the pathophysiologic mechanisms of AVP.

Our study has some limitations. First, because of the retrospective observational design, there is a potential for bias. We used multivariate analyses adjusted for confounding factors, however, other residual confounding factors may have remained. In addition, since the diagnosis of pneumonia was based on chart review, there may have been imprecision in the accuracy of diagnosing aspiration pneumonia. Aspiration pneumonia sometimes occurs without apparent episodes of aspiration, and this would have led to underdiagnosis. In contrast, aspiration pneumonitis can be mistaken for aspiration pneumonia; this would have led to overdiagnosis.

Second, volume status is difficult to evaluate prospectively, and thus by nature of our design, appropriate assignment of volume status was difficult. Several studies have used test infusions of isotonic saline to discriminate between these alternatives, but because our study was retrospective, we were unable to use this test.11, 20 Some studies have reported that, in patients in a state of volume depletion, volume repletion removes the stimulus for antidiuretic hormone release, allowing excess water to be excreted in a dilute urine and the serum sodium concentration to return toward normal.21, 22 According to this theory, instead of using an isotonic test infusion, we added in our study a criterion of volume depletion in which patients with a sustained increase in serum sodium concentration of 5 mEq/L and a sustained decrease in blood urea nitrogen, even with administration of hypotonic solution, were classified as volume depleted.

Third, all patients were analyzed according to status on admission, although some patients with hypovolemic hyponatremia at admission were found to have hyponatremia due to SIAD after admission.

Fourth, because the sample size of this study was small with our results revealing wide confidence intervals, an effect between other causes of hyponatremia and mortality might not have been identified. However, for 80% power, the calculated sample size was 100 non‐SIAD patients with aspiration pneumonia versus 10 SIAD patients, given that the mortality rate of elderly patients with aspiration pneumonia was, at a moderate estimate, 15% according to the studies of both Stukenborg and colleagues and Oliver and colleagues, and the mortality rate of SIAD patients was increased by 400% compared with that of non‐SIAD patients according to the study of Song and colleagues, with an alpha error of 0.05.7, 23, 24 Our sample size was therefore greater than the required size.

Fifth, because the APD dataset was compiled in 2007 for another study, it was not concurrent, and this may have led to other limitations in interpreting the data.

Finally, in Japan, the average length of hospital stay was 36.3 days in 2004 and 34.1 days in 2007much longer than other developed countries.25 Because of this situation, in‐hospital mortality, and not 30‐day mortality, represented long‐term mortality. Therefore, our results may not be easily applicable to the situation in other developed countries.

In conclusion, our results suggest that the presence of SIAD on admission in elderly patients with aspiration pneumonia is associated with increased mortality. This novel finding should be re‐evaluated, but it does raise the question of a direct, negative impact of AVP on patients' clinical outcomes. In the future, a larger prospective cohort study should be conducted to confirm the findings of this study, given the small sample size and the retrospective nature of the study. Additionally, a different population of pneumonia patients, such as those with community‐acquired pneumonia, should be examined to further evaluate the etiologies of hyponatremia in pneumonia and the association between hyponatremia of these different etiologies and mortality.

One of the most common causes of hospitalization in the elderly is aspiration pneumonia related to dysphagia due to numerous underlying diseases.1 Thus, it is clinically important to identify prognostic factors associated with increased mortality in elderly patients with aspiration pneumonia. Hyponatremia is the most common electrolyte abnormality in hospitalized patients occurring in up to 11% of elderly patients in hospital.2 Previous studies have suggested that the presence and degree of hyponatremia is associated with the severity of pneumonia in adults and children, although the results have differed among studies.37

Hyponatremia is caused by various factors, including volume depletion, use of diuretics, hypothyroidism, adrenal insufficiency, heart failure, renal failure, and cirrhosis. Additionally, the syndrome of inappropriate antidiuresis (SIAD) is a frequent and heterogeneous disorder characterized by hyponatremia and impaired urinary dilution in the absence of any recognized stimulation of antidiuretic hormone secretion.8 Because not all patients with SIAD have elevated circulating levels of arginine vasopressin (AVP), the term SIAD is preferred to the term syndrome of inappropriate secretion of antidiuretic hormone (SIADH).9 One study has shown an association between the severity of pneumonia in children and the development of hyponatremia due to SIAD.10 To our knowledge, there have been no studies evaluating the impact of different causes of hyponatremia on mortality in elderly patients with aspiration pneumonia.

We therefore sought to investigate whether hyponatremia of all etiologies (all‐cause hyponatremia) was associated with mortality in elderly patients with aspiration pneumonia. Additionally, we compared the impact of hyponatremia due to SIAD, with hyponatremia of other etiologies, on mortality in this population

METHODS

RESULTS

The baseline characteristics of the study population are listed in Table 2. There were 221 elderly patients identified as having aspiration pneumonia. Of those, 65 (29%) had hyponatremia; 3 (5%) with non‐hypotonic and 62 (95%) with hypotonic hyponatremia. In the latter group, patients were characterized has having hypovolemic (39 [63%]), hypervolemic (3 [5%]), and euvolemic (20 [32%]) hyponatremia. Among the euvolemic patients, SIAD occurred in 14 (70%) of patients. Non‐SIAD euvolemic hyponatremia occurred in 6 (30%) patients and was associated with hypothyroidism (1 patient), adrenal insufficiency (1 patient), and was unclassifiable due to lack of available clinical data in 4 patients. The kappa value was 0.87 for inter‐rater agreement of the classification of hypotonic hyponatremia.

The following variables were included in multivariate logistic analyses: congestive heart failure, cirrhosis, chronic renal failure, disorientation, body temperature <35C or >40C, anemia, and serum albumin <3 g/dL (see Supporting Information, Appendix, in the online version of this article).

In the multivariate logistic analyses, all‐cause hyponatremia was not associated with increased 30‐day mortality (odds ratio [OR] 1.85, 95% confidence interval [CI] 0.635.48; P = 0.262), but was associated with a trend toward increased risk of in‐hospital mortality (OR 2.10, 95% CI 1.004.42; P = 0.050) (Table 3). Moderate and severe hyponatremia were both significantly associated with increased in‐hospital mortality (OR 6.05, 95% CI 1.4625.0; P = 0.013 and OR 5.65, 95% CI 1.1428.1; P = 0.034, respectively). The same trends were observed for 30‐day mortality, although the results were not statistically significant. No such trend was observed for mild hyponatremia.

In the multivariate logistic regression analyses, hypotonic hyponatremia due to SIAD was significantly associated with both increased risk of 30‐day mortality (OR 7.40, 95% CI 1.7331.7; P = 0.007) and increased risk of in‐hospital mortality (OR 22.3, 95% CI 4.26117; P < 0.001) (Table 4). In contrast, hypovolemic or non‐SIAD euvolemic hyponatremia was associated with neither increased risk of 30‐day mortality nor increased risk of in‐hospital mortality. There were too few hypervolemic hyponatremia patients for us to perform effective logistic analyses. The P values of the HosmerLemeshow tests were 0.45 for the multivariate logistic regression model (hypovolemic, SIAD, and non‐SIAD euvolemic vs normonatremia) with 30‐day mortality, and 0.30 for the model with in‐hospital mortality.

Six patients with SIAD were classified as having an A‐DROP severity class of mild, 4 as moderate, and 4 as severe (P = 0.908, Wilcoxon‐type test for trend). There was no association between the occurrence of SIAD and the severity of pneumonia.

DISCUSSION

We demonstrated that mortality in elderly patients with aspiration pneumonia was significantly associated with SIAD, but not with all‐cause hyponatremia. Unlike SIAD, other etiologies of hyponatremia were not associated with mortality in elderly patients with aspiration pneumonia. A recent study by Waikar and colleagues concluded that hyponatremia subgrouped by severity was not significantly associated with in‐hospital mortality in pneumonia patients, although a trend between severe hyponatremia and mortality was observed.16 Likewise, a study by Zilberberg and colleagues reported no significant increased risk of death with hyponatremia compared with normonatremia.4 These results are similar to our results for all‐cause hyponatremia and for hyponatremia subgrouped by severity. In contrast, a study by Nair and colleagues reported some increased risk of death with hyponatremia.5 Our results suggest that the heterogeneity of these previous results was probably due to the fact that SIAD was not identified in these other studies.

While the rationale for increased mortality in patients with pneumonia associated with SIAD is not known, it may be that there is a direct deleterious effect of elevated AVP. AVP has 3 distinct receptor subtypes, V1A, V1B, and V2. Stimulation of the V1A receptor in vascular smooth muscle promotes an increase in systemic vascular resistance, and stimulation of the same receptor in cardiac myocytes promotes myocyte hypertrophy. Stimulation of the V1B receptor in the anterior pituitary promotes adrenocorticotropic hormone release, and stimulation of the V2 receptor in the renal collecting ducts promotes an increase in water retention, which plays the main role in SIAD.1719 Our hypothesis in elderly SIAD patients with aspiration pneumonia is that increased AVP levels may lead not only to water retention and hyponatremia, but also to other effects such as vasoconstriction and myocyte hypertrophy, which may adversely influence the cardiovascular systems of elderly patients (Figure 1).

Figure 1

In our study, SIAD in elderly patients with aspiration pneumonia was more strongly associated with in‐hospital mortality than with 30‐day mortality. The average length of stay (LOS) of all patients dying in hospital (42 days) was significantly longer than the average LOS of those dying within 30 days of admission (15 days; P < 0.001, MannWhitney Test; Table 2). These findings suggest that SIAD was associated more strongly with longer‐term mortality than with acute‐stage mortality. The reason for the association between SIAD and longer‐term mortality remains unclear, although there may be some association between longer‐term mortality and the pathophysiologic mechanisms of AVP.

Our study has some limitations. First, because of the retrospective observational design, there is a potential for bias. We used multivariate analyses adjusted for confounding factors, however, other residual confounding factors may have remained. In addition, since the diagnosis of pneumonia was based on chart review, there may have been imprecision in the accuracy of diagnosing aspiration pneumonia. Aspiration pneumonia sometimes occurs without apparent episodes of aspiration, and this would have led to underdiagnosis. In contrast, aspiration pneumonitis can be mistaken for aspiration pneumonia; this would have led to overdiagnosis.

Second, volume status is difficult to evaluate prospectively, and thus by nature of our design, appropriate assignment of volume status was difficult. Several studies have used test infusions of isotonic saline to discriminate between these alternatives, but because our study was retrospective, we were unable to use this test.11, 20 Some studies have reported that, in patients in a state of volume depletion, volume repletion removes the stimulus for antidiuretic hormone release, allowing excess water to be excreted in a dilute urine and the serum sodium concentration to return toward normal.21, 22 According to this theory, instead of using an isotonic test infusion, we added in our study a criterion of volume depletion in which patients with a sustained increase in serum sodium concentration of 5 mEq/L and a sustained decrease in blood urea nitrogen, even with administration of hypotonic solution, were classified as volume depleted.

Third, all patients were analyzed according to status on admission, although some patients with hypovolemic hyponatremia at admission were found to have hyponatremia due to SIAD after admission.

Fourth, because the sample size of this study was small with our results revealing wide confidence intervals, an effect between other causes of hyponatremia and mortality might not have been identified. However, for 80% power, the calculated sample size was 100 non‐SIAD patients with aspiration pneumonia versus 10 SIAD patients, given that the mortality rate of elderly patients with aspiration pneumonia was, at a moderate estimate, 15% according to the studies of both Stukenborg and colleagues and Oliver and colleagues, and the mortality rate of SIAD patients was increased by 400% compared with that of non‐SIAD patients according to the study of Song and colleagues, with an alpha error of 0.05.7, 23, 24 Our sample size was therefore greater than the required size.

Fifth, because the APD dataset was compiled in 2007 for another study, it was not concurrent, and this may have led to other limitations in interpreting the data.

Finally, in Japan, the average length of hospital stay was 36.3 days in 2004 and 34.1 days in 2007much longer than other developed countries.25 Because of this situation, in‐hospital mortality, and not 30‐day mortality, represented long‐term mortality. Therefore, our results may not be easily applicable to the situation in other developed countries.

In conclusion, our results suggest that the presence of SIAD on admission in elderly patients with aspiration pneumonia is associated with increased mortality. This novel finding should be re‐evaluated, but it does raise the question of a direct, negative impact of AVP on patients' clinical outcomes. In the future, a larger prospective cohort study should be conducted to confirm the findings of this study, given the small sample size and the retrospective nature of the study. Additionally, a different population of pneumonia patients, such as those with community‐acquired pneumonia, should be examined to further evaluate the etiologies of hyponatremia in pneumonia and the association between hyponatremia of these different etiologies and mortality.

Venous thromboembolism (VTE) is a major source of morbidity and mortality for hospitalized patients, with as many as 16% of high‐risk medical patients developing VTE during their hospital stay.1, 2 Pharmacologic prophylaxis with subcutaneous heparin reduces the risk of VTE by approximately 50%,3, 4 and guidelines produced by the American College of Chest Physicians (ACCP) recommend thromboprophylaxis for patients at moderate‐to‐high risk of VTE with either low‐molecular‐weight heparin (LMWH) or unfractionated heparin (UFH).2 UFH is less expensive per dose, but meta‐analyses have suggested that UFH may be either less effective than LMWH3 or more likely to cause complications, such as bleeding5 or heparin‐induced thrombocytopenia (HIT).6 Others have argued that the efficacy and risk of bleeding with UFH and LMWH are similar.7, 8 In either case, there are few head‐to‐head studies of LMWH and UFH in medical patients and they tend to be small. In the most recent meta‐analysis, which included fewer than 4500 patients, several different low‐molecular‐weight heparins were assessed together, and the observed rate of deep vein thrombosis (DVT) with UFH was high (5.4%), with evidence suggesting publication bias.3

Given the current Joint Commission requirement9 that all medical patients either receive VTE prophylaxis or have documented a reason not to, the implications related to choosing one form of VTE prophylaxis over another are substantial on a national scale. In order to compare the effectiveness of UFH and LMWH in routine practice among hospitalized medical patients, we conducted a retrospective cohort study in a national sample of hospitals and compared the risk of VTE, bleeding, HIT, and death associated with each treatment.

METHODS

RESULTS

Our final sample included 32,104 patients who received prophylaxis at 333 hospitals (see Supporting Information, e‐Figure, in the online version of this article). Patient characteristics appear in Table 1. Most patients (66%) were over age 65; 59% were female and 61% were white. The most common primary diagnoses were pneumonia (40%) and congestive heart failure (25%). Additional risk factors for thromboembolism included cancer (13%), paralysis (8%), or diabetes (35%). Most patients' attending physicians were either internists (61%) or family practitioners (14%). Almost half of the patients were cared for at hospitals in the South (46%).

Fifty‐five percent of patients received LMWH and the remainder received UFH; 1274 (4%) patients switched type of heparin during their stay. The proportion of patients receiving LMWH at an individual hospital varied from 0% to 100% with a u‐shaped distribution, with almost one‐third of hospitals prescribing one treatment or the other exclusively (Figure 1). Similarly, the proportion of an individual physician's patients who received prophylaxis with UFH (vs LMWH) varied from 0% to 100% (Figure 1), with 51% prescribing LMWH exclusively and 31% prescribing UFH exclusively. Compared to patients who received UFH, patients receiving LMWH were older and were more likely to be white, female, and to have pneumonia. By far the biggest difference between the groups was the hospitals at which they received their care (see Supporting Information, e‐Table, in the online version of this article). Patients receiving LMWH were much more likely to be from smaller, rural, non‐teaching hospitals in the South or the West. There were also numerous small differences in comorbidities and individual VTE risk factors between the 2 groups. The only large difference was that patients with a secondary diagnosis of renal failure (for which LMWH is not US Food and Drug Administration [FDA] approved) were almost twice as likely to receive UFH.

Figure 1

We identified 163 (0.51%) episodes of VTE (Table 2). Compared to patients receiving UFH, those receiving standard LMWH had similar unadjusted rates of VTE (0.53% vs 0.48%; P = 0.54), major bleeding (0.77% vs 0.76%; P = 0.88), thrombocytopenia (1.9% vs 2.0%; P = 0.48), definite HIT (n = 1 vs n = 3; P = 0.34), and mortality (2.8% vs 3.1%; P = 0.07). Definite complications of prophylaxis (HIT or major bleed combined with the discontinuation of heparin) were more common among patients receiving UFH (0.2% vs 0.1%; P = 0.022). Patients treated with UFH had longer unadjusted lengths of stay (P < 0.0001) and higher unadjusted costs (P < 0.0001).

A propensity model for UFH treatment based upon patient characteristics and treatments was not strongly predictive of treatment (c = 0.58) and propensity matching failed to balance many of the patient characteristics. However, hospital alone, ignoring patient characteristics was strongly predictive (c = 0.91) of treatment.

In a model adjusting only for clustering within hospitals, patients treated with UFH had an odds ratio (OR) for VTE of 1.08 (95% confidence interval [CI] 0.79 to 1.49) compared to patients receiving LMWH (Figure 2). Adjustment for propensity for UFH and other covariates attenuated the effect of LMWH (OR 1.04, 95% CI 0.76 to 1.43). When individual patients were assigned a probability of treatment with UFH equal to the hospital rate where they received care, UFH use was associated with a nonsignificant change in the odds of VTE (OR 1.14, 95% CI 0.72 to 1.81).

Figure 2

Adjusted for clustering within hospital only, patients treated with UFH had an odds ratio for major bleed of 1.38 (95% CI 1.00 to 1.91) compared to patients receiving LMWH (Figure 3). Adjustment for propensity for UFH and other covariates gave similar results (OR 1.34, 95% CI 0.97 to 1.84). When individual patients were assigned a probability of treatment with UFH equal to the hospital rate where they received care, UFH treatment was associated with a nonsignificant increase in the odds of major bleed (OR 1.64, 95% CI 0.50 to 5.33). When we compared the rate of transfusion across hospitals, including 576,231 additional patients who were excluded from the original analyses because they did not receive daily prophylaxis or had a diagnosis of myocardial infarction or COPD, there was a slight negative correlation between transfusion rates and use of UFH (Spearman Correlation Coefficient 0.03; P = 0.61). Hospitals that used primarily UFH had a transfusion rate of 0.60% versus 0.76% at hospitals using primarily LMWH (P = 0.54), indicating that the increased risk of major bleeding associated with UFH was not confounded by local transfusion practices.

Figure 3

Adjusted for clustering only, patients treated with UFH had an odds ratio for definite complication of 2.35 (95% CI 1.17 to 4.72) compared to those treated with LMWH. Adjustment for propensity and covariates accentuated the association (OR 2.84, 95% CI 1.43 to 5.66). When assigned a probability of treatment with UFH equal to the hospital rate where they received care, UFH treatment was associated with an increase in the risk of definite complication (OR 2.79, 95% CI 1.00 to 7.74).

Adjusted for clustering only, patients treated with UFH had higher costs than those treated with LMWH (cost ratio 1.07, 95% CI 1.05 to 1.09). Adjustment for propensity for UFH and other covariates attenuated the association (cost ratio 1.02, 95% CI 1.00 to 1.03). Finally, when individual patients were assigned a probability of initial treatment with UFH equal to the hospital rate where they received care, treatment with UFH was associated with a nonsignificant change in the relative cost (cost ratio 0.97, 95% CI 0.90 to 1.05).

DISCUSSION

In this retrospective cohort study, we found that low‐molecular‐weight heparin and unfractionated heparin were associated with similar rates of VTE in moderate‐to‐high risk medical patients. However, unfractionated heparin was associated with a small, but higher risk of complications, even after adjustment. There were no statistical differences in rates of heparin‐induced thrombocytopenia, but this complication was exceedingly rare. Finally, overall costs associated with both treatments were similar.

A number of industry‐funded studies have compared LMWH to UFH in randomized clinical trials. These trials have generally been small and used endpoints of uncertain significance, such as asymptomatic deep vein thrombosis assessed by ultrasound. At least 3 meta‐analyses of these trials have been published. Each used different inclusion criteria. The only one to find an efficacy benefit to LMWH over UFH was heavily influenced by the inclusion of a number of studies of stroke patients.3 In that study, LMWH reduced VTE by approximately one‐third relative to UFH. The other 2 analyses found smaller reductions in DVT and pulmonary embolism (PE), and these results were not statistically significant.5, 8 Similarly, 1 analysis5 found a reduction in major bleeding events with LMWH versus UFH, whereas the other 2 studies found smaller reductions which were not statistically significant. The assessment of major bleeding is further complicated by differences in the definition of major bleeding across studies. Using a standard definition of 2 units of packed red blood cells transfused in 1 day to denote major bleeding, we found an associated reduction in bleeding with LMWH that was similar to that observed in the meta‐analyses. Moreover, patients receiving UFH were twice as likely to have a complication that resulted in stopping the prophylaxis, although these complications were overall quite rare. Lastly, there are no cost comparisons based on randomized trials. Several comparisons based on modeling have favored LMWH. One assumed that 3% of patients receiving UFH would develop HIT;13 something we did not observe. At least 3 additional analyses,1416 all funded by the manufacturer of enoxaparin, assumed that LMWH was both more effective and safer than UFH. We found that adjusted costs were similar or slightly lower with UFH than LMWH.

Our study has a number of limitations. First, its observational design makes it vulnerable to selection bias. We attempted to overcome this with rigorous multivariable adjustment, including the propensity for treatment and by using an adaptation of the instrumental variable approach. This method is of particular interest because individual hospitals were strongly predictive of choice of heparin. Still, we cannot exclude the possibility of residual confounding, especially if other outcomes, such as transfusion decisions, were also tied to specific hospital practices. Second, our study used administrative data, and therefore we could not directly adjust for certain differences which may exist between patients who received LMWH and those who received UFH. However, we did adjust for many classic risk factors for VTE. More importantly, it seems that the chance of being treated with a particular form of heparin depends more on the hospital where one receives care than on any combination of patient characteristics. Thus, apart from renal failure, for which we adjusted, it seems unlikely that there were major differences in unmeasured physiological confounders. Third, we limited our analysis to patients who received standard dosing of either type of heparin. We did this to bolster the validity of our findings, but they may not apply to unconventional dosing often observed in clinical practice. Fourth, we measured only outcomes that occurred in the hospital or that prompted a return to the hospital. VTEs which were diagnosed and treated in ambulatory care were not included. While this may have led us to underestimate the true risk of VTE, we have little reason to believe that the choice of whether to admit a patient with VTE is influenced by the original choice of VTE prophylaxis. Finally, our study was conducted before the introduction of generic LMWH, which would be expected to reduce costs associated with LMWH prophylaxis.

VTE prophylaxis for medical patients has emerged as a major focus for quality improvement initiatives. As a result, a significant proportion of general medical patients receive some form of chemoprophylaxis during their hospital stay. Small differences in efficacy or safety of different forms of prophylaxis multiplied by millions of admissions each year can have profound effects on the health of hospitalized patients. Similarly, differences in cost could also have a substantial impact on the healthcare system. We found no difference in efficacy or cost, but treatment with LMWH was less likely to be associated with subsequent transfusion of 2 or more units of packed red blood cells, a surrogate marker for bleeding. In addition, LMWH is more convenient since it can be dosed once daily, and for that reason may be more acceptable to patients. For these reasons, LMWH may be the drug of choice for inpatient prophylaxis of general medical patients. In situations where the cost of the medication itself is important, UFH represents an equally effective alternative.

Venous thromboembolism (VTE) is a major source of morbidity and mortality for hospitalized patients, with as many as 16% of high‐risk medical patients developing VTE during their hospital stay.1, 2 Pharmacologic prophylaxis with subcutaneous heparin reduces the risk of VTE by approximately 50%,3, 4 and guidelines produced by the American College of Chest Physicians (ACCP) recommend thromboprophylaxis for patients at moderate‐to‐high risk of VTE with either low‐molecular‐weight heparin (LMWH) or unfractionated heparin (UFH).2 UFH is less expensive per dose, but meta‐analyses have suggested that UFH may be either less effective than LMWH3 or more likely to cause complications, such as bleeding5 or heparin‐induced thrombocytopenia (HIT).6 Others have argued that the efficacy and risk of bleeding with UFH and LMWH are similar.7, 8 In either case, there are few head‐to‐head studies of LMWH and UFH in medical patients and they tend to be small. In the most recent meta‐analysis, which included fewer than 4500 patients, several different low‐molecular‐weight heparins were assessed together, and the observed rate of deep vein thrombosis (DVT) with UFH was high (5.4%), with evidence suggesting publication bias.3

Given the current Joint Commission requirement9 that all medical patients either receive VTE prophylaxis or have documented a reason not to, the implications related to choosing one form of VTE prophylaxis over another are substantial on a national scale. In order to compare the effectiveness of UFH and LMWH in routine practice among hospitalized medical patients, we conducted a retrospective cohort study in a national sample of hospitals and compared the risk of VTE, bleeding, HIT, and death associated with each treatment.

METHODS

RESULTS

Our final sample included 32,104 patients who received prophylaxis at 333 hospitals (see Supporting Information, e‐Figure, in the online version of this article). Patient characteristics appear in Table 1. Most patients (66%) were over age 65; 59% were female and 61% were white. The most common primary diagnoses were pneumonia (40%) and congestive heart failure (25%). Additional risk factors for thromboembolism included cancer (13%), paralysis (8%), or diabetes (35%). Most patients' attending physicians were either internists (61%) or family practitioners (14%). Almost half of the patients were cared for at hospitals in the South (46%).

Fifty‐five percent of patients received LMWH and the remainder received UFH; 1274 (4%) patients switched type of heparin during their stay. The proportion of patients receiving LMWH at an individual hospital varied from 0% to 100% with a u‐shaped distribution, with almost one‐third of hospitals prescribing one treatment or the other exclusively (Figure 1). Similarly, the proportion of an individual physician's patients who received prophylaxis with UFH (vs LMWH) varied from 0% to 100% (Figure 1), with 51% prescribing LMWH exclusively and 31% prescribing UFH exclusively. Compared to patients who received UFH, patients receiving LMWH were older and were more likely to be white, female, and to have pneumonia. By far the biggest difference between the groups was the hospitals at which they received their care (see Supporting Information, e‐Table, in the online version of this article). Patients receiving LMWH were much more likely to be from smaller, rural, non‐teaching hospitals in the South or the West. There were also numerous small differences in comorbidities and individual VTE risk factors between the 2 groups. The only large difference was that patients with a secondary diagnosis of renal failure (for which LMWH is not US Food and Drug Administration [FDA] approved) were almost twice as likely to receive UFH.

Figure 1

We identified 163 (0.51%) episodes of VTE (Table 2). Compared to patients receiving UFH, those receiving standard LMWH had similar unadjusted rates of VTE (0.53% vs 0.48%; P = 0.54), major bleeding (0.77% vs 0.76%; P = 0.88), thrombocytopenia (1.9% vs 2.0%; P = 0.48), definite HIT (n = 1 vs n = 3; P = 0.34), and mortality (2.8% vs 3.1%; P = 0.07). Definite complications of prophylaxis (HIT or major bleed combined with the discontinuation of heparin) were more common among patients receiving UFH (0.2% vs 0.1%; P = 0.022). Patients treated with UFH had longer unadjusted lengths of stay (P < 0.0001) and higher unadjusted costs (P < 0.0001).

A propensity model for UFH treatment based upon patient characteristics and treatments was not strongly predictive of treatment (c = 0.58) and propensity matching failed to balance many of the patient characteristics. However, hospital alone, ignoring patient characteristics was strongly predictive (c = 0.91) of treatment.

In a model adjusting only for clustering within hospitals, patients treated with UFH had an odds ratio (OR) for VTE of 1.08 (95% confidence interval [CI] 0.79 to 1.49) compared to patients receiving LMWH (Figure 2). Adjustment for propensity for UFH and other covariates attenuated the effect of LMWH (OR 1.04, 95% CI 0.76 to 1.43). When individual patients were assigned a probability of treatment with UFH equal to the hospital rate where they received care, UFH use was associated with a nonsignificant change in the odds of VTE (OR 1.14, 95% CI 0.72 to 1.81).

Figure 2

Adjusted for clustering within hospital only, patients treated with UFH had an odds ratio for major bleed of 1.38 (95% CI 1.00 to 1.91) compared to patients receiving LMWH (Figure 3). Adjustment for propensity for UFH and other covariates gave similar results (OR 1.34, 95% CI 0.97 to 1.84). When individual patients were assigned a probability of treatment with UFH equal to the hospital rate where they received care, UFH treatment was associated with a nonsignificant increase in the odds of major bleed (OR 1.64, 95% CI 0.50 to 5.33). When we compared the rate of transfusion across hospitals, including 576,231 additional patients who were excluded from the original analyses because they did not receive daily prophylaxis or had a diagnosis of myocardial infarction or COPD, there was a slight negative correlation between transfusion rates and use of UFH (Spearman Correlation Coefficient 0.03; P = 0.61). Hospitals that used primarily UFH had a transfusion rate of 0.60% versus 0.76% at hospitals using primarily LMWH (P = 0.54), indicating that the increased risk of major bleeding associated with UFH was not confounded by local transfusion practices.

Figure 3

Adjusted for clustering only, patients treated with UFH had an odds ratio for definite complication of 2.35 (95% CI 1.17 to 4.72) compared to those treated with LMWH. Adjustment for propensity and covariates accentuated the association (OR 2.84, 95% CI 1.43 to 5.66). When assigned a probability of treatment with UFH equal to the hospital rate where they received care, UFH treatment was associated with an increase in the risk of definite complication (OR 2.79, 95% CI 1.00 to 7.74).

Adjusted for clustering only, patients treated with UFH had higher costs than those treated with LMWH (cost ratio 1.07, 95% CI 1.05 to 1.09). Adjustment for propensity for UFH and other covariates attenuated the association (cost ratio 1.02, 95% CI 1.00 to 1.03). Finally, when individual patients were assigned a probability of initial treatment with UFH equal to the hospital rate where they received care, treatment with UFH was associated with a nonsignificant change in the relative cost (cost ratio 0.97, 95% CI 0.90 to 1.05).

DISCUSSION

In this retrospective cohort study, we found that low‐molecular‐weight heparin and unfractionated heparin were associated with similar rates of VTE in moderate‐to‐high risk medical patients. However, unfractionated heparin was associated with a small, but higher risk of complications, even after adjustment. There were no statistical differences in rates of heparin‐induced thrombocytopenia, but this complication was exceedingly rare. Finally, overall costs associated with both treatments were similar.

A number of industry‐funded studies have compared LMWH to UFH in randomized clinical trials. These trials have generally been small and used endpoints of uncertain significance, such as asymptomatic deep vein thrombosis assessed by ultrasound. At least 3 meta‐analyses of these trials have been published. Each used different inclusion criteria. The only one to find an efficacy benefit to LMWH over UFH was heavily influenced by the inclusion of a number of studies of stroke patients.3 In that study, LMWH reduced VTE by approximately one‐third relative to UFH. The other 2 analyses found smaller reductions in DVT and pulmonary embolism (PE), and these results were not statistically significant.5, 8 Similarly, 1 analysis5 found a reduction in major bleeding events with LMWH versus UFH, whereas the other 2 studies found smaller reductions which were not statistically significant. The assessment of major bleeding is further complicated by differences in the definition of major bleeding across studies. Using a standard definition of 2 units of packed red blood cells transfused in 1 day to denote major bleeding, we found an associated reduction in bleeding with LMWH that was similar to that observed in the meta‐analyses. Moreover, patients receiving UFH were twice as likely to have a complication that resulted in stopping the prophylaxis, although these complications were overall quite rare. Lastly, there are no cost comparisons based on randomized trials. Several comparisons based on modeling have favored LMWH. One assumed that 3% of patients receiving UFH would develop HIT;13 something we did not observe. At least 3 additional analyses,1416 all funded by the manufacturer of enoxaparin, assumed that LMWH was both more effective and safer than UFH. We found that adjusted costs were similar or slightly lower with UFH than LMWH.

Our study has a number of limitations. First, its observational design makes it vulnerable to selection bias. We attempted to overcome this with rigorous multivariable adjustment, including the propensity for treatment and by using an adaptation of the instrumental variable approach. This method is of particular interest because individual hospitals were strongly predictive of choice of heparin. Still, we cannot exclude the possibility of residual confounding, especially if other outcomes, such as transfusion decisions, were also tied to specific hospital practices. Second, our study used administrative data, and therefore we could not directly adjust for certain differences which may exist between patients who received LMWH and those who received UFH. However, we did adjust for many classic risk factors for VTE. More importantly, it seems that the chance of being treated with a particular form of heparin depends more on the hospital where one receives care than on any combination of patient characteristics. Thus, apart from renal failure, for which we adjusted, it seems unlikely that there were major differences in unmeasured physiological confounders. Third, we limited our analysis to patients who received standard dosing of either type of heparin. We did this to bolster the validity of our findings, but they may not apply to unconventional dosing often observed in clinical practice. Fourth, we measured only outcomes that occurred in the hospital or that prompted a return to the hospital. VTEs which were diagnosed and treated in ambulatory care were not included. While this may have led us to underestimate the true risk of VTE, we have little reason to believe that the choice of whether to admit a patient with VTE is influenced by the original choice of VTE prophylaxis. Finally, our study was conducted before the introduction of generic LMWH, which would be expected to reduce costs associated with LMWH prophylaxis.

VTE prophylaxis for medical patients has emerged as a major focus for quality improvement initiatives. As a result, a significant proportion of general medical patients receive some form of chemoprophylaxis during their hospital stay. Small differences in efficacy or safety of different forms of prophylaxis multiplied by millions of admissions each year can have profound effects on the health of hospitalized patients. Similarly, differences in cost could also have a substantial impact on the healthcare system. We found no difference in efficacy or cost, but treatment with LMWH was less likely to be associated with subsequent transfusion of 2 or more units of packed red blood cells, a surrogate marker for bleeding. In addition, LMWH is more convenient since it can be dosed once daily, and for that reason may be more acceptable to patients. For these reasons, LMWH may be the drug of choice for inpatient prophylaxis of general medical patients. In situations where the cost of the medication itself is important, UFH represents an equally effective alternative.

Venous thromboembolism (VTE) is a major source of morbidity and mortality for hospitalized patients, with as many as 16% of high‐risk medical patients developing VTE during their hospital stay.1, 2 Pharmacologic prophylaxis with subcutaneous heparin reduces the risk of VTE by approximately 50%,3, 4 and guidelines produced by the American College of Chest Physicians (ACCP) recommend thromboprophylaxis for patients at moderate‐to‐high risk of VTE with either low‐molecular‐weight heparin (LMWH) or unfractionated heparin (UFH).2 UFH is less expensive per dose, but meta‐analyses have suggested that UFH may be either less effective than LMWH3 or more likely to cause complications, such as bleeding5 or heparin‐induced thrombocytopenia (HIT).6 Others have argued that the efficacy and risk of bleeding with UFH and LMWH are similar.7, 8 In either case, there are few head‐to‐head studies of LMWH and UFH in medical patients and they tend to be small. In the most recent meta‐analysis, which included fewer than 4500 patients, several different low‐molecular‐weight heparins were assessed together, and the observed rate of deep vein thrombosis (DVT) with UFH was high (5.4%), with evidence suggesting publication bias.3

Given the current Joint Commission requirement9 that all medical patients either receive VTE prophylaxis or have documented a reason not to, the implications related to choosing one form of VTE prophylaxis over another are substantial on a national scale. In order to compare the effectiveness of UFH and LMWH in routine practice among hospitalized medical patients, we conducted a retrospective cohort study in a national sample of hospitals and compared the risk of VTE, bleeding, HIT, and death associated with each treatment.

METHODS

RESULTS

Our final sample included 32,104 patients who received prophylaxis at 333 hospitals (see Supporting Information, e‐Figure, in the online version of this article). Patient characteristics appear in Table 1. Most patients (66%) were over age 65; 59% were female and 61% were white. The most common primary diagnoses were pneumonia (40%) and congestive heart failure (25%). Additional risk factors for thromboembolism included cancer (13%), paralysis (8%), or diabetes (35%). Most patients' attending physicians were either internists (61%) or family practitioners (14%). Almost half of the patients were cared for at hospitals in the South (46%).

Fifty‐five percent of patients received LMWH and the remainder received UFH; 1274 (4%) patients switched type of heparin during their stay. The proportion of patients receiving LMWH at an individual hospital varied from 0% to 100% with a u‐shaped distribution, with almost one‐third of hospitals prescribing one treatment or the other exclusively (Figure 1). Similarly, the proportion of an individual physician's patients who received prophylaxis with UFH (vs LMWH) varied from 0% to 100% (Figure 1), with 51% prescribing LMWH exclusively and 31% prescribing UFH exclusively. Compared to patients who received UFH, patients receiving LMWH were older and were more likely to be white, female, and to have pneumonia. By far the biggest difference between the groups was the hospitals at which they received their care (see Supporting Information, e‐Table, in the online version of this article). Patients receiving LMWH were much more likely to be from smaller, rural, non‐teaching hospitals in the South or the West. There were also numerous small differences in comorbidities and individual VTE risk factors between the 2 groups. The only large difference was that patients with a secondary diagnosis of renal failure (for which LMWH is not US Food and Drug Administration [FDA] approved) were almost twice as likely to receive UFH.

Figure 1

We identified 163 (0.51%) episodes of VTE (Table 2). Compared to patients receiving UFH, those receiving standard LMWH had similar unadjusted rates of VTE (0.53% vs 0.48%; P = 0.54), major bleeding (0.77% vs 0.76%; P = 0.88), thrombocytopenia (1.9% vs 2.0%; P = 0.48), definite HIT (n = 1 vs n = 3; P = 0.34), and mortality (2.8% vs 3.1%; P = 0.07). Definite complications of prophylaxis (HIT or major bleed combined with the discontinuation of heparin) were more common among patients receiving UFH (0.2% vs 0.1%; P = 0.022). Patients treated with UFH had longer unadjusted lengths of stay (P < 0.0001) and higher unadjusted costs (P < 0.0001).

A propensity model for UFH treatment based upon patient characteristics and treatments was not strongly predictive of treatment (c = 0.58) and propensity matching failed to balance many of the patient characteristics. However, hospital alone, ignoring patient characteristics was strongly predictive (c = 0.91) of treatment.

In a model adjusting only for clustering within hospitals, patients treated with UFH had an odds ratio (OR) for VTE of 1.08 (95% confidence interval [CI] 0.79 to 1.49) compared to patients receiving LMWH (Figure 2). Adjustment for propensity for UFH and other covariates attenuated the effect of LMWH (OR 1.04, 95% CI 0.76 to 1.43). When individual patients were assigned a probability of treatment with UFH equal to the hospital rate where they received care, UFH use was associated with a nonsignificant change in the odds of VTE (OR 1.14, 95% CI 0.72 to 1.81).

Figure 2

Adjusted for clustering within hospital only, patients treated with UFH had an odds ratio for major bleed of 1.38 (95% CI 1.00 to 1.91) compared to patients receiving LMWH (Figure 3). Adjustment for propensity for UFH and other covariates gave similar results (OR 1.34, 95% CI 0.97 to 1.84). When individual patients were assigned a probability of treatment with UFH equal to the hospital rate where they received care, UFH treatment was associated with a nonsignificant increase in the odds of major bleed (OR 1.64, 95% CI 0.50 to 5.33). When we compared the rate of transfusion across hospitals, including 576,231 additional patients who were excluded from the original analyses because they did not receive daily prophylaxis or had a diagnosis of myocardial infarction or COPD, there was a slight negative correlation between transfusion rates and use of UFH (Spearman Correlation Coefficient 0.03; P = 0.61). Hospitals that used primarily UFH had a transfusion rate of 0.60% versus 0.76% at hospitals using primarily LMWH (P = 0.54), indicating that the increased risk of major bleeding associated with UFH was not confounded by local transfusion practices.

Figure 3

Adjusted for clustering only, patients treated with UFH had an odds ratio for definite complication of 2.35 (95% CI 1.17 to 4.72) compared to those treated with LMWH. Adjustment for propensity and covariates accentuated the association (OR 2.84, 95% CI 1.43 to 5.66). When assigned a probability of treatment with UFH equal to the hospital rate where they received care, UFH treatment was associated with an increase in the risk of definite complication (OR 2.79, 95% CI 1.00 to 7.74).

Adjusted for clustering only, patients treated with UFH had higher costs than those treated with LMWH (cost ratio 1.07, 95% CI 1.05 to 1.09). Adjustment for propensity for UFH and other covariates attenuated the association (cost ratio 1.02, 95% CI 1.00 to 1.03). Finally, when individual patients were assigned a probability of initial treatment with UFH equal to the hospital rate where they received care, treatment with UFH was associated with a nonsignificant change in the relative cost (cost ratio 0.97, 95% CI 0.90 to 1.05).

DISCUSSION

In this retrospective cohort study, we found that low‐molecular‐weight heparin and unfractionated heparin were associated with similar rates of VTE in moderate‐to‐high risk medical patients. However, unfractionated heparin was associated with a small, but higher risk of complications, even after adjustment. There were no statistical differences in rates of heparin‐induced thrombocytopenia, but this complication was exceedingly rare. Finally, overall costs associated with both treatments were similar.

A number of industry‐funded studies have compared LMWH to UFH in randomized clinical trials. These trials have generally been small and used endpoints of uncertain significance, such as asymptomatic deep vein thrombosis assessed by ultrasound. At least 3 meta‐analyses of these trials have been published. Each used different inclusion criteria. The only one to find an efficacy benefit to LMWH over UFH was heavily influenced by the inclusion of a number of studies of stroke patients.3 In that study, LMWH reduced VTE by approximately one‐third relative to UFH. The other 2 analyses found smaller reductions in DVT and pulmonary embolism (PE), and these results were not statistically significant.5, 8 Similarly, 1 analysis5 found a reduction in major bleeding events with LMWH versus UFH, whereas the other 2 studies found smaller reductions which were not statistically significant. The assessment of major bleeding is further complicated by differences in the definition of major bleeding across studies. Using a standard definition of 2 units of packed red blood cells transfused in 1 day to denote major bleeding, we found an associated reduction in bleeding with LMWH that was similar to that observed in the meta‐analyses. Moreover, patients receiving UFH were twice as likely to have a complication that resulted in stopping the prophylaxis, although these complications were overall quite rare. Lastly, there are no cost comparisons based on randomized trials. Several comparisons based on modeling have favored LMWH. One assumed that 3% of patients receiving UFH would develop HIT;13 something we did not observe. At least 3 additional analyses,1416 all funded by the manufacturer of enoxaparin, assumed that LMWH was both more effective and safer than UFH. We found that adjusted costs were similar or slightly lower with UFH than LMWH.

Our study has a number of limitations. First, its observational design makes it vulnerable to selection bias. We attempted to overcome this with rigorous multivariable adjustment, including the propensity for treatment and by using an adaptation of the instrumental variable approach. This method is of particular interest because individual hospitals were strongly predictive of choice of heparin. Still, we cannot exclude the possibility of residual confounding, especially if other outcomes, such as transfusion decisions, were also tied to specific hospital practices. Second, our study used administrative data, and therefore we could not directly adjust for certain differences which may exist between patients who received LMWH and those who received UFH. However, we did adjust for many classic risk factors for VTE. More importantly, it seems that the chance of being treated with a particular form of heparin depends more on the hospital where one receives care than on any combination of patient characteristics. Thus, apart from renal failure, for which we adjusted, it seems unlikely that there were major differences in unmeasured physiological confounders. Third, we limited our analysis to patients who received standard dosing of either type of heparin. We did this to bolster the validity of our findings, but they may not apply to unconventional dosing often observed in clinical practice. Fourth, we measured only outcomes that occurred in the hospital or that prompted a return to the hospital. VTEs which were diagnosed and treated in ambulatory care were not included. While this may have led us to underestimate the true risk of VTE, we have little reason to believe that the choice of whether to admit a patient with VTE is influenced by the original choice of VTE prophylaxis. Finally, our study was conducted before the introduction of generic LMWH, which would be expected to reduce costs associated with LMWH prophylaxis.

VTE prophylaxis for medical patients has emerged as a major focus for quality improvement initiatives. As a result, a significant proportion of general medical patients receive some form of chemoprophylaxis during their hospital stay. Small differences in efficacy or safety of different forms of prophylaxis multiplied by millions of admissions each year can have profound effects on the health of hospitalized patients. Similarly, differences in cost could also have a substantial impact on the healthcare system. We found no difference in efficacy or cost, but treatment with LMWH was less likely to be associated with subsequent transfusion of 2 or more units of packed red blood cells, a surrogate marker for bleeding. In addition, LMWH is more convenient since it can be dosed once daily, and for that reason may be more acceptable to patients. For these reasons, LMWH may be the drug of choice for inpatient prophylaxis of general medical patients. In situations where the cost of the medication itself is important, UFH represents an equally effective alternative.