Warfarin‐Associated Adverse Events

Warfarin is 1 of the most common causes of adverse drug events, with hospitalized patients being particularly at risk compared to outpatients.[1] Despite the availability of new oral anticoagulants (NOACs), physicians commonly prescribe warfarin to hospitalized patients,[2] likely in part due to the greater difficulty in reversing NOACs compared to warfarin. Furthermore, uptake of the NOACs is likely to be slow in resource‐poor countries due to the lower cost of warfarin.[3] However, the narrow therapeutic index, frequent drug‐drug interactions, and patient variability in metabolism of warfarin makes management challenging.[4] Thus, warfarin remains a significant cause of adverse events in hospitalized patients, occurring in approximately 3% to 8% of exposed patients, depending on underlying condition.[2, 5]

An elevated international normalized ratio (INR) is a strong predictor of drug‐associated adverse events (patient harm). In a study employing 21 different electronic triggers to identify potential adverse events, an elevated INR had the highest yield for events associated with harm (96% of INRs >5.0 associated with harm).[6] Although pharmacist‐managed inpatient anticoagulation services have been shown to improve warfarin management,[7, 8] there are evidence gaps regarding the causes of warfarin‐related adverse events and practice changes that could decrease their frequency. Although overanticoagulation is a well‐known risk factor for warfarin‐related adverse events,[9, 10] there are few evidence‐based warfarin monitoring and dosing recommendations for hospitalized patients.[10] For example, the 2012 American College of Chest Physicians Antithrombotic Guidelines[11] provide a weak recommendation on initial dosing of warfarin, but no recommendations on how frequently to monitor the INR, or appropriate dosing responses to INR levels. Although many hospitals employ protocols that suggest daily INR monitoring until stable, there are no evidence‐based guidelines to support this practice.[12] Conversely, there are reports of flags to order an INR level that are not activated unless greater than 2[13] or 3 days[14] pass since the prior INR. Protocols from some major academic medical centers suggest that after a therapeutic INR is reached, INR levels can be measured intermittently, as infrequently as twice a week.[15, 16]

The 2015 Joint Commission anticoagulant‐focused National Patient Safety Goal[17] (initially issued in 2008) mandates the assessment of baseline coagulation status before starting warfarin, and warfarin dosing based on a current INR; however, current is not defined. Neither the extent to which the mandate for assessing baseline coagulation status is adhered to nor the relationship between this process of care and patient outcomes is known. The importance of adverse drug events associated with anticoagulants, included warfarin, was also recently highlighted in the 2014 federal National Action Plan for Adverse Drug Event Prevention. In this document, the prevention of adverse drug events associated with anticoagulants was 1 of the 3 areas selected for special national attention and action.[18]

The Medicare Patient Safety Monitoring System (MPSMS) is a national chart abstraction‐based system that includes 21 in‐hospital adverse event measures, including warfarin‐associated adverse drug events.[2] Because of the importance of warfarin‐associated bleeding in hospitalized patients, we analyzed MPSMS data to determine what factors related to INR monitoring practices place patients at risk for these events. We were particularly interested in determining if we could detect potentially modifiable predictors of overanticoagulation and warfarin‐associated adverse events.

METHODS

RESULTS

There were 130,828 patients included in the 2009 to 2013 MPSMS sample, of whom 19,445 (14.9%) received warfarin during their hospital stay and had at least 1 INR measurement. Among these patients, 5228 (26.9%) had no INR level above 1.5 and were excluded from further analysis, leaving 14,217 included patients. Of these patients, 1055 (7.4%) developed a warfarin‐associated adverse event. Table 1 demonstrates the baseline demographics and comorbidities of the included patients.

Warfarin was started on hospital day 1 for 6825 (48.0%) of 14,217 patients. Among these patients, 6539 (95.8%) had an INR measured within 1 calendar day. We were unable to determine how many patients who started warfarin later in their hospital stay had a baseline INR, as we did not capture INRs performed prior to the day that warfarin was initiated.

Supporting Table 1 in the online version of this article demonstrates the association between an INR 6.0 and the occurrence of warfarin‐associated adverse events. A maximum INR 6.0 occurred in 469 (3.3%) of the patients included in the study, and among those patients, 133 (28.4%) experienced a warfarin‐associated adverse event compared to 922 (6.7%) adverse events in the 13,748 patients who did not develop an INR 6.0 (P < 0.001).

Among 8529 patients who received warfarin for at least 3 days, beginning on the third day of warfarin, 1549 patients (18.2%) did not have INR measured at least once each day that they received warfarin. Table 2 demonstrates that patients who had 2 or more days on which the INR was not measured had higher rates of INR 6.0 than patients for whom the INR was measured daily. A similar association was seen for warfarin‐associated adverse events (Table 2).

Figure 1A demonstrates the association between the number of days without an INR measurement and the subsequent development of an INR 6.0 or a warfarin‐associated adverse event, adjusted for baseline patient characteristics, receipt of heparin and LMWH, and number of days on warfarin. Patients with 1 or more days without an INR measurement had higher risk‐adjusted ORs of a subsequent INR 6.0, although the difference was not statistically significant for surgical patients. The analysis results based on inverse propensity scoring are seen in Figure 1B. Cardiac and surgical patients with 2 or more days without an INR measurement were at higher risk of having a warfarin‐associated adverse event, whereas cardiac and pneumonia patients with 1 or more days without an INR measurement were at higher risk of developing an INR 6.0.

Figure 1

Supporting Table 2 in the online version of this article demonstrates the relationship between patient characteristics and the occurrence of an INR 6.0 or a warfarin‐related adverse event. The only characteristic that was associated with either of these outcomes for all 3 patient conditions was renal disease, which was positively associated with a warfarin‐associated adverse event. Warfarin use prior to arrival was associated with lower risks of both an INR 6.0 and a warfarin‐associated adverse event, except for among surgical patients. Supporting Table 3 in the online version of this article demonstrates the differences in patient characteristics between patients who had daily INR measurement and those who had at least 1 day without an INR measurement.

Figure 2 illustrates the relationship of the maximum INR to the prior 1‐day change in INR in 4963 patients whose INR on the day prior to the maximum INR was 2.0 to 3.5. When the increase in INR was <0.9, the risk of the next day's INR being 6.0 was 0.7%, and if the increase was 0.9, the risk was 5.2%. The risk of developing an INR 5.0 was 1.9% if the preceding day's INR increase was <0.9 and 15.3% if the prior day's INR rise was 0.9. Overall, 51% of INRs 6.0 and 55% of INRs 5.0 were immediately preceded by an INR increase of 0.9. The positive likelihood ratio (LR) for a 0.9 rise in INR predicting an INR of 6.0 was 4.2, and the positive LR was 4.9 for predicting an INR 5.0.

Figure 2

There was no decline in the frequency of warfarin use among the patients in the MPSMS sample during the study period (16.7% in 2009 and 17.3% in 2013).

DISCUSSION

We studied warfarin‐associated adverse events in a nationally representative study of patients who received warfarin while in an acute care hospital for a primary diagnosis of cardiac disease, pneumonia, or major surgery. Several findings resulted from our analysis. First, warfarin is still commonly prescribed to hospitalized patients and remains a frequent cause of adverse events; 7.4% of the 2009 to 2013 MPSMS population who received warfarin and had at least 1 INR >1.5 developed a warfarin‐associated adverse event.

Over 95% of patients who received warfarin on the day of hospital admission had an INR performed within 1 day. This is similar to the results from a 2006 single center study in which 95% of patients had an INR measured prior to their first dose of warfarin.[10] Since 2008, The Joint Commission's National Patient Safety Goal has required the assessment of coagulation status before starting warfarin.[17] The high level of adherence to this standard suggests that further attention to this process of care is unlikely to significantly improve patient safety.

We also found that the lack of daily INR measurements was associated with an increased risk of an INR 6.0 and warfarin‐associated adverse events in some patient populations. There is limited evidence addressing the appropriate frequency of INR measurement in hospitalized patients receiving warfarin. The Joint Commission National Patient Safety Goal requires use of a current INR to adjust this therapy, but provides no specifics.[17] Although some experts believe that INRs should be monitored daily in hospitalized patients, this does not appear to be uniformly accepted. In some reports, 2[13] or 3[14] consecutive days without the performance of an INR was required to activate a reminder. Protocols from some major teaching hospitals specify intermittent monitoring once the INR is therapeutic.[15, 16] Because our results suggest that lapses in INR measurement lead to overanticoagulation and warfarin‐related adverse events, it may be appropriate to measure INRs daily in most hospitalized patients receiving warfarin. This would be consistent with the many known causes of INR instability in patients admitted to the hospital, including drug‐drug interactions, hepatic dysfunction, and changes in volume of distribution, such that truly stable hospitalized patients are likely rare. Indeed, hospital admission is a well‐known predictor of instability of warfarin effect. [9] Although our results suggest that daily INR measurement is associated with a lower rate of overanticoagulation, future studies might better define lower risk patients for whom daily INR measurement would not be necessary.

A prior INR increase 0.9 in 1 day was associated with an increased risk of subsequent overanticoagulation. Although a rapidly rising INR is known to predict overanticoagulation[10, 14] we could find no evidence as to what specific rate of rise confers this risk. Our results suggest that use of a warfarin dosing protocol that considers both the absolute value of the INR and the rate of rise could reduce warfarin‐related adverse events.

There are important limitations of our study. We did not abstract warfarin dosages, which precluded study of the appropriateness of both initial warfarin dosing and adjustment of the warfarin dose based on INR results. MPSMS does not reliably capture antiplatelet agents or other agents that result in drug‐drug interactions with warfarin, such as antibiotics, so this factor could theoretically have confounded our results. Antibiotic use seems unlikely to be a major confounder, because patients with acute cardiovascular disease demonstrated a similar relationship between INR measurement and an INR 6.0 to that seen with pneumonia and surgical patients, despite the latter patients likely having greater antibiotics exposure. Furthermore, MPSMS does not capture indices of severity of illness, so other unmeasured confounders could have influenced our results. Although we have data for patients admitted to the hospital for only 4 conditions, these are conditions that represent approximately 22% of hospital admissions in the United States.[2] Strengths of our study include the nationally representative and randomly selected cases and use of data that were obtained from chart abstraction as opposed to administrative data. Through the use of centralized data abstraction, we avoided the potential bias introduced when hospitals self‐report adverse events.

In summary, in a national sample of patients admitted to the hospital for 4 common conditions, warfarin‐associated adverse events were detected in 7.4% of patients who received warfarin. Lack of daily INR measurement was associated with an increased risk of overanticoagulation and warfarin‐associated adverse events in certain patient populations. A 1‐day increase in the INR of 0.9 predicted subsequent overanticoagulation. These results provide actionable opportunities to improve safety in some hospitalized patients receiving warfarin.

Warfarin is 1 of the most common causes of adverse drug events, with hospitalized patients being particularly at risk compared to outpatients.[1] Despite the availability of new oral anticoagulants (NOACs), physicians commonly prescribe warfarin to hospitalized patients,[2] likely in part due to the greater difficulty in reversing NOACs compared to warfarin. Furthermore, uptake of the NOACs is likely to be slow in resource‐poor countries due to the lower cost of warfarin.[3] However, the narrow therapeutic index, frequent drug‐drug interactions, and patient variability in metabolism of warfarin makes management challenging.[4] Thus, warfarin remains a significant cause of adverse events in hospitalized patients, occurring in approximately 3% to 8% of exposed patients, depending on underlying condition.[2, 5]

An elevated international normalized ratio (INR) is a strong predictor of drug‐associated adverse events (patient harm). In a study employing 21 different electronic triggers to identify potential adverse events, an elevated INR had the highest yield for events associated with harm (96% of INRs >5.0 associated with harm).[6] Although pharmacist‐managed inpatient anticoagulation services have been shown to improve warfarin management,[7, 8] there are evidence gaps regarding the causes of warfarin‐related adverse events and practice changes that could decrease their frequency. Although overanticoagulation is a well‐known risk factor for warfarin‐related adverse events,[9, 10] there are few evidence‐based warfarin monitoring and dosing recommendations for hospitalized patients.[10] For example, the 2012 American College of Chest Physicians Antithrombotic Guidelines[11] provide a weak recommendation on initial dosing of warfarin, but no recommendations on how frequently to monitor the INR, or appropriate dosing responses to INR levels. Although many hospitals employ protocols that suggest daily INR monitoring until stable, there are no evidence‐based guidelines to support this practice.[12] Conversely, there are reports of flags to order an INR level that are not activated unless greater than 2[13] or 3 days[14] pass since the prior INR. Protocols from some major academic medical centers suggest that after a therapeutic INR is reached, INR levels can be measured intermittently, as infrequently as twice a week.[15, 16]

The 2015 Joint Commission anticoagulant‐focused National Patient Safety Goal[17] (initially issued in 2008) mandates the assessment of baseline coagulation status before starting warfarin, and warfarin dosing based on a current INR; however, current is not defined. Neither the extent to which the mandate for assessing baseline coagulation status is adhered to nor the relationship between this process of care and patient outcomes is known. The importance of adverse drug events associated with anticoagulants, included warfarin, was also recently highlighted in the 2014 federal National Action Plan for Adverse Drug Event Prevention. In this document, the prevention of adverse drug events associated with anticoagulants was 1 of the 3 areas selected for special national attention and action.[18]

The Medicare Patient Safety Monitoring System (MPSMS) is a national chart abstraction‐based system that includes 21 in‐hospital adverse event measures, including warfarin‐associated adverse drug events.[2] Because of the importance of warfarin‐associated bleeding in hospitalized patients, we analyzed MPSMS data to determine what factors related to INR monitoring practices place patients at risk for these events. We were particularly interested in determining if we could detect potentially modifiable predictors of overanticoagulation and warfarin‐associated adverse events.

METHODS

RESULTS

There were 130,828 patients included in the 2009 to 2013 MPSMS sample, of whom 19,445 (14.9%) received warfarin during their hospital stay and had at least 1 INR measurement. Among these patients, 5228 (26.9%) had no INR level above 1.5 and were excluded from further analysis, leaving 14,217 included patients. Of these patients, 1055 (7.4%) developed a warfarin‐associated adverse event. Table 1 demonstrates the baseline demographics and comorbidities of the included patients.

Warfarin was started on hospital day 1 for 6825 (48.0%) of 14,217 patients. Among these patients, 6539 (95.8%) had an INR measured within 1 calendar day. We were unable to determine how many patients who started warfarin later in their hospital stay had a baseline INR, as we did not capture INRs performed prior to the day that warfarin was initiated.

Supporting Table 1 in the online version of this article demonstrates the association between an INR 6.0 and the occurrence of warfarin‐associated adverse events. A maximum INR 6.0 occurred in 469 (3.3%) of the patients included in the study, and among those patients, 133 (28.4%) experienced a warfarin‐associated adverse event compared to 922 (6.7%) adverse events in the 13,748 patients who did not develop an INR 6.0 (P < 0.001).

Among 8529 patients who received warfarin for at least 3 days, beginning on the third day of warfarin, 1549 patients (18.2%) did not have INR measured at least once each day that they received warfarin. Table 2 demonstrates that patients who had 2 or more days on which the INR was not measured had higher rates of INR 6.0 than patients for whom the INR was measured daily. A similar association was seen for warfarin‐associated adverse events (Table 2).

Figure 1A demonstrates the association between the number of days without an INR measurement and the subsequent development of an INR 6.0 or a warfarin‐associated adverse event, adjusted for baseline patient characteristics, receipt of heparin and LMWH, and number of days on warfarin. Patients with 1 or more days without an INR measurement had higher risk‐adjusted ORs of a subsequent INR 6.0, although the difference was not statistically significant for surgical patients. The analysis results based on inverse propensity scoring are seen in Figure 1B. Cardiac and surgical patients with 2 or more days without an INR measurement were at higher risk of having a warfarin‐associated adverse event, whereas cardiac and pneumonia patients with 1 or more days without an INR measurement were at higher risk of developing an INR 6.0.

Figure 1

Supporting Table 2 in the online version of this article demonstrates the relationship between patient characteristics and the occurrence of an INR 6.0 or a warfarin‐related adverse event. The only characteristic that was associated with either of these outcomes for all 3 patient conditions was renal disease, which was positively associated with a warfarin‐associated adverse event. Warfarin use prior to arrival was associated with lower risks of both an INR 6.0 and a warfarin‐associated adverse event, except for among surgical patients. Supporting Table 3 in the online version of this article demonstrates the differences in patient characteristics between patients who had daily INR measurement and those who had at least 1 day without an INR measurement.

Figure 2 illustrates the relationship of the maximum INR to the prior 1‐day change in INR in 4963 patients whose INR on the day prior to the maximum INR was 2.0 to 3.5. When the increase in INR was <0.9, the risk of the next day's INR being 6.0 was 0.7%, and if the increase was 0.9, the risk was 5.2%. The risk of developing an INR 5.0 was 1.9% if the preceding day's INR increase was <0.9 and 15.3% if the prior day's INR rise was 0.9. Overall, 51% of INRs 6.0 and 55% of INRs 5.0 were immediately preceded by an INR increase of 0.9. The positive likelihood ratio (LR) for a 0.9 rise in INR predicting an INR of 6.0 was 4.2, and the positive LR was 4.9 for predicting an INR 5.0.

Figure 2

There was no decline in the frequency of warfarin use among the patients in the MPSMS sample during the study period (16.7% in 2009 and 17.3% in 2013).

DISCUSSION

We studied warfarin‐associated adverse events in a nationally representative study of patients who received warfarin while in an acute care hospital for a primary diagnosis of cardiac disease, pneumonia, or major surgery. Several findings resulted from our analysis. First, warfarin is still commonly prescribed to hospitalized patients and remains a frequent cause of adverse events; 7.4% of the 2009 to 2013 MPSMS population who received warfarin and had at least 1 INR >1.5 developed a warfarin‐associated adverse event.

Over 95% of patients who received warfarin on the day of hospital admission had an INR performed within 1 day. This is similar to the results from a 2006 single center study in which 95% of patients had an INR measured prior to their first dose of warfarin.[10] Since 2008, The Joint Commission's National Patient Safety Goal has required the assessment of coagulation status before starting warfarin.[17] The high level of adherence to this standard suggests that further attention to this process of care is unlikely to significantly improve patient safety.

We also found that the lack of daily INR measurements was associated with an increased risk of an INR 6.0 and warfarin‐associated adverse events in some patient populations. There is limited evidence addressing the appropriate frequency of INR measurement in hospitalized patients receiving warfarin. The Joint Commission National Patient Safety Goal requires use of a current INR to adjust this therapy, but provides no specifics.[17] Although some experts believe that INRs should be monitored daily in hospitalized patients, this does not appear to be uniformly accepted. In some reports, 2[13] or 3[14] consecutive days without the performance of an INR was required to activate a reminder. Protocols from some major teaching hospitals specify intermittent monitoring once the INR is therapeutic.[15, 16] Because our results suggest that lapses in INR measurement lead to overanticoagulation and warfarin‐related adverse events, it may be appropriate to measure INRs daily in most hospitalized patients receiving warfarin. This would be consistent with the many known causes of INR instability in patients admitted to the hospital, including drug‐drug interactions, hepatic dysfunction, and changes in volume of distribution, such that truly stable hospitalized patients are likely rare. Indeed, hospital admission is a well‐known predictor of instability of warfarin effect. [9] Although our results suggest that daily INR measurement is associated with a lower rate of overanticoagulation, future studies might better define lower risk patients for whom daily INR measurement would not be necessary.

A prior INR increase 0.9 in 1 day was associated with an increased risk of subsequent overanticoagulation. Although a rapidly rising INR is known to predict overanticoagulation[10, 14] we could find no evidence as to what specific rate of rise confers this risk. Our results suggest that use of a warfarin dosing protocol that considers both the absolute value of the INR and the rate of rise could reduce warfarin‐related adverse events.

There are important limitations of our study. We did not abstract warfarin dosages, which precluded study of the appropriateness of both initial warfarin dosing and adjustment of the warfarin dose based on INR results. MPSMS does not reliably capture antiplatelet agents or other agents that result in drug‐drug interactions with warfarin, such as antibiotics, so this factor could theoretically have confounded our results. Antibiotic use seems unlikely to be a major confounder, because patients with acute cardiovascular disease demonstrated a similar relationship between INR measurement and an INR 6.0 to that seen with pneumonia and surgical patients, despite the latter patients likely having greater antibiotics exposure. Furthermore, MPSMS does not capture indices of severity of illness, so other unmeasured confounders could have influenced our results. Although we have data for patients admitted to the hospital for only 4 conditions, these are conditions that represent approximately 22% of hospital admissions in the United States.[2] Strengths of our study include the nationally representative and randomly selected cases and use of data that were obtained from chart abstraction as opposed to administrative data. Through the use of centralized data abstraction, we avoided the potential bias introduced when hospitals self‐report adverse events.

In summary, in a national sample of patients admitted to the hospital for 4 common conditions, warfarin‐associated adverse events were detected in 7.4% of patients who received warfarin. Lack of daily INR measurement was associated with an increased risk of overanticoagulation and warfarin‐associated adverse events in certain patient populations. A 1‐day increase in the INR of 0.9 predicted subsequent overanticoagulation. These results provide actionable opportunities to improve safety in some hospitalized patients receiving warfarin.

Warfarin is 1 of the most common causes of adverse drug events, with hospitalized patients being particularly at risk compared to outpatients.[1] Despite the availability of new oral anticoagulants (NOACs), physicians commonly prescribe warfarin to hospitalized patients,[2] likely in part due to the greater difficulty in reversing NOACs compared to warfarin. Furthermore, uptake of the NOACs is likely to be slow in resource‐poor countries due to the lower cost of warfarin.[3] However, the narrow therapeutic index, frequent drug‐drug interactions, and patient variability in metabolism of warfarin makes management challenging.[4] Thus, warfarin remains a significant cause of adverse events in hospitalized patients, occurring in approximately 3% to 8% of exposed patients, depending on underlying condition.[2, 5]

An elevated international normalized ratio (INR) is a strong predictor of drug‐associated adverse events (patient harm). In a study employing 21 different electronic triggers to identify potential adverse events, an elevated INR had the highest yield for events associated with harm (96% of INRs >5.0 associated with harm).[6] Although pharmacist‐managed inpatient anticoagulation services have been shown to improve warfarin management,[7, 8] there are evidence gaps regarding the causes of warfarin‐related adverse events and practice changes that could decrease their frequency. Although overanticoagulation is a well‐known risk factor for warfarin‐related adverse events,[9, 10] there are few evidence‐based warfarin monitoring and dosing recommendations for hospitalized patients.[10] For example, the 2012 American College of Chest Physicians Antithrombotic Guidelines[11] provide a weak recommendation on initial dosing of warfarin, but no recommendations on how frequently to monitor the INR, or appropriate dosing responses to INR levels. Although many hospitals employ protocols that suggest daily INR monitoring until stable, there are no evidence‐based guidelines to support this practice.[12] Conversely, there are reports of flags to order an INR level that are not activated unless greater than 2[13] or 3 days[14] pass since the prior INR. Protocols from some major academic medical centers suggest that after a therapeutic INR is reached, INR levels can be measured intermittently, as infrequently as twice a week.[15, 16]

The 2015 Joint Commission anticoagulant‐focused National Patient Safety Goal[17] (initially issued in 2008) mandates the assessment of baseline coagulation status before starting warfarin, and warfarin dosing based on a current INR; however, current is not defined. Neither the extent to which the mandate for assessing baseline coagulation status is adhered to nor the relationship between this process of care and patient outcomes is known. The importance of adverse drug events associated with anticoagulants, included warfarin, was also recently highlighted in the 2014 federal National Action Plan for Adverse Drug Event Prevention. In this document, the prevention of adverse drug events associated with anticoagulants was 1 of the 3 areas selected for special national attention and action.[18]

The Medicare Patient Safety Monitoring System (MPSMS) is a national chart abstraction‐based system that includes 21 in‐hospital adverse event measures, including warfarin‐associated adverse drug events.[2] Because of the importance of warfarin‐associated bleeding in hospitalized patients, we analyzed MPSMS data to determine what factors related to INR monitoring practices place patients at risk for these events. We were particularly interested in determining if we could detect potentially modifiable predictors of overanticoagulation and warfarin‐associated adverse events.

METHODS

RESULTS

There were 130,828 patients included in the 2009 to 2013 MPSMS sample, of whom 19,445 (14.9%) received warfarin during their hospital stay and had at least 1 INR measurement. Among these patients, 5228 (26.9%) had no INR level above 1.5 and were excluded from further analysis, leaving 14,217 included patients. Of these patients, 1055 (7.4%) developed a warfarin‐associated adverse event. Table 1 demonstrates the baseline demographics and comorbidities of the included patients.

Warfarin was started on hospital day 1 for 6825 (48.0%) of 14,217 patients. Among these patients, 6539 (95.8%) had an INR measured within 1 calendar day. We were unable to determine how many patients who started warfarin later in their hospital stay had a baseline INR, as we did not capture INRs performed prior to the day that warfarin was initiated.

Supporting Table 1 in the online version of this article demonstrates the association between an INR 6.0 and the occurrence of warfarin‐associated adverse events. A maximum INR 6.0 occurred in 469 (3.3%) of the patients included in the study, and among those patients, 133 (28.4%) experienced a warfarin‐associated adverse event compared to 922 (6.7%) adverse events in the 13,748 patients who did not develop an INR 6.0 (P < 0.001).

Among 8529 patients who received warfarin for at least 3 days, beginning on the third day of warfarin, 1549 patients (18.2%) did not have INR measured at least once each day that they received warfarin. Table 2 demonstrates that patients who had 2 or more days on which the INR was not measured had higher rates of INR 6.0 than patients for whom the INR was measured daily. A similar association was seen for warfarin‐associated adverse events (Table 2).

Figure 1A demonstrates the association between the number of days without an INR measurement and the subsequent development of an INR 6.0 or a warfarin‐associated adverse event, adjusted for baseline patient characteristics, receipt of heparin and LMWH, and number of days on warfarin. Patients with 1 or more days without an INR measurement had higher risk‐adjusted ORs of a subsequent INR 6.0, although the difference was not statistically significant for surgical patients. The analysis results based on inverse propensity scoring are seen in Figure 1B. Cardiac and surgical patients with 2 or more days without an INR measurement were at higher risk of having a warfarin‐associated adverse event, whereas cardiac and pneumonia patients with 1 or more days without an INR measurement were at higher risk of developing an INR 6.0.

Figure 1

Supporting Table 2 in the online version of this article demonstrates the relationship between patient characteristics and the occurrence of an INR 6.0 or a warfarin‐related adverse event. The only characteristic that was associated with either of these outcomes for all 3 patient conditions was renal disease, which was positively associated with a warfarin‐associated adverse event. Warfarin use prior to arrival was associated with lower risks of both an INR 6.0 and a warfarin‐associated adverse event, except for among surgical patients. Supporting Table 3 in the online version of this article demonstrates the differences in patient characteristics between patients who had daily INR measurement and those who had at least 1 day without an INR measurement.

Figure 2 illustrates the relationship of the maximum INR to the prior 1‐day change in INR in 4963 patients whose INR on the day prior to the maximum INR was 2.0 to 3.5. When the increase in INR was <0.9, the risk of the next day's INR being 6.0 was 0.7%, and if the increase was 0.9, the risk was 5.2%. The risk of developing an INR 5.0 was 1.9% if the preceding day's INR increase was <0.9 and 15.3% if the prior day's INR rise was 0.9. Overall, 51% of INRs 6.0 and 55% of INRs 5.0 were immediately preceded by an INR increase of 0.9. The positive likelihood ratio (LR) for a 0.9 rise in INR predicting an INR of 6.0 was 4.2, and the positive LR was 4.9 for predicting an INR 5.0.

Figure 2

There was no decline in the frequency of warfarin use among the patients in the MPSMS sample during the study period (16.7% in 2009 and 17.3% in 2013).

DISCUSSION

We studied warfarin‐associated adverse events in a nationally representative study of patients who received warfarin while in an acute care hospital for a primary diagnosis of cardiac disease, pneumonia, or major surgery. Several findings resulted from our analysis. First, warfarin is still commonly prescribed to hospitalized patients and remains a frequent cause of adverse events; 7.4% of the 2009 to 2013 MPSMS population who received warfarin and had at least 1 INR >1.5 developed a warfarin‐associated adverse event.

Over 95% of patients who received warfarin on the day of hospital admission had an INR performed within 1 day. This is similar to the results from a 2006 single center study in which 95% of patients had an INR measured prior to their first dose of warfarin.[10] Since 2008, The Joint Commission's National Patient Safety Goal has required the assessment of coagulation status before starting warfarin.[17] The high level of adherence to this standard suggests that further attention to this process of care is unlikely to significantly improve patient safety.

We also found that the lack of daily INR measurements was associated with an increased risk of an INR 6.0 and warfarin‐associated adverse events in some patient populations. There is limited evidence addressing the appropriate frequency of INR measurement in hospitalized patients receiving warfarin. The Joint Commission National Patient Safety Goal requires use of a current INR to adjust this therapy, but provides no specifics.[17] Although some experts believe that INRs should be monitored daily in hospitalized patients, this does not appear to be uniformly accepted. In some reports, 2[13] or 3[14] consecutive days without the performance of an INR was required to activate a reminder. Protocols from some major teaching hospitals specify intermittent monitoring once the INR is therapeutic.[15, 16] Because our results suggest that lapses in INR measurement lead to overanticoagulation and warfarin‐related adverse events, it may be appropriate to measure INRs daily in most hospitalized patients receiving warfarin. This would be consistent with the many known causes of INR instability in patients admitted to the hospital, including drug‐drug interactions, hepatic dysfunction, and changes in volume of distribution, such that truly stable hospitalized patients are likely rare. Indeed, hospital admission is a well‐known predictor of instability of warfarin effect. [9] Although our results suggest that daily INR measurement is associated with a lower rate of overanticoagulation, future studies might better define lower risk patients for whom daily INR measurement would not be necessary.

A prior INR increase 0.9 in 1 day was associated with an increased risk of subsequent overanticoagulation. Although a rapidly rising INR is known to predict overanticoagulation[10, 14] we could find no evidence as to what specific rate of rise confers this risk. Our results suggest that use of a warfarin dosing protocol that considers both the absolute value of the INR and the rate of rise could reduce warfarin‐related adverse events.

There are important limitations of our study. We did not abstract warfarin dosages, which precluded study of the appropriateness of both initial warfarin dosing and adjustment of the warfarin dose based on INR results. MPSMS does not reliably capture antiplatelet agents or other agents that result in drug‐drug interactions with warfarin, such as antibiotics, so this factor could theoretically have confounded our results. Antibiotic use seems unlikely to be a major confounder, because patients with acute cardiovascular disease demonstrated a similar relationship between INR measurement and an INR 6.0 to that seen with pneumonia and surgical patients, despite the latter patients likely having greater antibiotics exposure. Furthermore, MPSMS does not capture indices of severity of illness, so other unmeasured confounders could have influenced our results. Although we have data for patients admitted to the hospital for only 4 conditions, these are conditions that represent approximately 22% of hospital admissions in the United States.[2] Strengths of our study include the nationally representative and randomly selected cases and use of data that were obtained from chart abstraction as opposed to administrative data. Through the use of centralized data abstraction, we avoided the potential bias introduced when hospitals self‐report adverse events.

In summary, in a national sample of patients admitted to the hospital for 4 common conditions, warfarin‐associated adverse events were detected in 7.4% of patients who received warfarin. Lack of daily INR measurement was associated with an increased risk of overanticoagulation and warfarin‐associated adverse events in certain patient populations. A 1‐day increase in the INR of 0.9 predicted subsequent overanticoagulation. These results provide actionable opportunities to improve safety in some hospitalized patients receiving warfarin.