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DOACs for treatment of cancer-associated venous thromboembolism
Bleeding risk may determine best option
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Bleeding risk may determine best option
Bleeding risk may determine best option
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Inappropriate Prescribing of PPIs
Proton pump inhibitors (PPIs) are the third most commonly prescribed class of medication in the United States, with $13.6 billion in yearly sales.1 Despite their effectiveness in treating acid reflux2 and their mortality benefit in the treatment of patients with gastrointestinal bleeding,3 recent literature has identified a number of risks associated with PPIs, including an increased incidence of Clostridium difficile infection,4 decreased effectiveness of clopidogrel in patients with acute coronary syndrome,5 increased risk of community‐ and hospital‐acquired pneumonia, and an increased risk of hip fracture.69 Additionally, in March of 2011, the US Food and Drug Administration (FDA) issued a warning regarding the potential for PPIs to cause low magnesium levels which can, in turn, cause muscle spasms, an irregular heartbeat, and convulsions.10
Inappropriate PPI prescription practice has been demonstrated in the primary care setting,11 as well as in small studies conducted in the hospital setting.1216 We hypothesized that many hospitalized patients receive these medications without having an accepted indication, and examined 2 populations of hospitalized patients, including administrative data from 6.5 million discharges from US university hospitals, to look for appropriate diagnoses justifying their use.
METHODS
We performed a retrospective review of administrative data collected between January 1, 2008 and December 31, 2009 from 2 patient populations: (a) those discharged from Denver Health (DH), a university‐affiliated public safety net hospital in Denver, CO; and (b) patients discharged from 112 academic health centers and 256 of their affiliated hospitals that participate in the University HealthSystem Consortium (UHC). The Colorado Multiple Institution Review Board reviewed and approved the conduct of this study.
Inclusion criteria for both populations were age >18 or <90 years, and hospitalization on a Medicine service. Prisoners and women known to be pregnant were excluded. In both cohorts, if patients had more than 1 admission during the 2‐year study period, only data from the first admission were used.
We recorded demographics, admitting diagnosis, and discharge diagnoses together with information pertaining to the name, route, and duration of administration of all PPIs (ie, omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole). We created a broadly inclusive set of valid indications for PPIs by incorporating diagnoses that could be identified by International Classification of Diseases, Ninth Revision.
(ICD‐9) codes from a number of previously published sources including the National Institute of Clinical Excellence (NICE) guidelines issued by the National Health Service (NHS) of the United Kingdom in 200012, 1721 (Table 1).
Indication | ICD‐9 Code |
---|---|
| |
Helicobacter pylori | 041.86 |
Abnormality of secretion of gastrin | 251.5 |
Esophageal varices with bleeding | 456.0 |
Esophageal varices without mention of bleeding | 456.1 |
Esophageal varices in diseases classified elsewhere | 456.2 |
Esophagitis | 530.10530.19 |
Perforation of esophagus | 530.4 |
Gastroesophageal laceration‐hemorrhage syndrome | 530.7 |
Esophageal reflux | 530.81 |
Barrett's esophagus | 530.85 |
Gastric ulcer | 531.0031.91 |
Duodenal ulcer | 532.00532.91 |
Peptic ulcer, site unspecified | 533.00533.91 |
Gastritis and duodenitis | 535.00535.71 |
Gastroparesis | 536.3 |
Dyspepsia and other specified disorders of function of stomach | 536.8 |
Hemorrhage of gastrointestinal tract, unspecified | 578.9 |
To assess the accuracy of the administrative data from DH, we also reviewed the Emergency Department histories, admission histories, progress notes, electronic pharmacy records, endoscopy reports, and discharge summaries of 123 patients randomly selected (ie, a 5% sample) from the group of patients identified by administrative data to have received a PPI without a valid indication, looking for any accepted indication that might have been missed in the administrative data.
All analyses were performed using SAS Enterprise Guide 4.1 (SAS Institute, Cary, NC). A Student t test was used to compare continuous variables and a chi‐square test was used to compare categorical variables. Bonferroni corrections were used for multiple comparisons, such that P values less than 0.01 were considered to be significant for categorical variables.
RESULTS
Inclusion criteria were met by 9875 patients in the Denver Health database and 6,592,100 patients in the UHC database. The demographics and primary discharge diagnoses for these patients are summarized in Table 2.
DH (N = 9875) | UHC (N = 6,592,100) | ||||
---|---|---|---|---|---|
Received a PPI | No PPI | Received a PPI | No PPI | ||
| |||||
No. (%) | 3962 (40) | 5913 (60) | 918,474 (14) | 5,673,626 (86) | |
Age (mean SD) | 53 15 | 51 16 | 59 17 | 55 18 | |
Gender (% male) | 2197 (55) | 3438 (58) | 464,552 (51) | 2,882,577 (51) | |
Race (% white) | 1610 (41) | 2425 (41) | 619,571 (67) | 3,670,450 (65) | |
Top 5 primary discharge diagnoses | |||||
Chest pain | 229 (6) | 462 (8) | Coronary atherosclerosis | 35,470 (4) | 186,321 (3) |
Alcohol withdrawal | 147 (4) | 174 (3) | Acute myocardial infarction | 26,507 (3) | 132,159 (2) |
Pneumonia, organism unspecified | 142 (4) | 262 (4) | Heart failure | 21,143 (2) | 103,751 (2) |
Acute pancreatitis | 132 (3) | 106 (2) | Septicemia | 20,345 (2) | 64,915 (1) |
Obstructive chronic bronchitis with (acute) exacerbation | 89 (2) | 154 (3) | Chest pain | 16,936 (2) | 107,497 (2) |
Only 39% and 27% of the patients in the DH and UHC databases, respectively, had a valid indication for PPIs on the basis of discharge diagnoses (Table 3). In the DH data, if admission ICD‐9 codes were also inspected for valid PPI indications, 1579 (40%) of patients receiving PPIs had a valid indication (admission ICD‐9 codes were not available for patients in the UHC database). Thirty‐one percent of Denver Health patients spent time in the intensive care unit (ICU) during their hospital stay and 65% of those patients received a PPI without a valid indication, as compared to 59% of patients who remained on the General Medicine ward (Table 3).
DH (N = 9875) | UHC (N = 6,592,100) | |
---|---|---|
| ||
Patients receiving PPIs (% of total) | 3962 (40) | 918,474 (14) |
Any ICU stay, N (% of all patients) | 1238 (31) | |
General Medicine ward only, N (% of all patients) | 2724 (69) | |
Patients with indication for PPI (% of all patients receiving PPIs)* | 1540 (39) | 247,142 (27) |
Any ICU stay, N (% of all ICU patients) | 434 (35) | |
General Medicine ward only, N (% of all ward patients) | 1106 (41) | |
Patients without indication for PPI (% of those receiving PPIs)* | 2422 (61) | 671,332 (73) |
Any ICU stay, N (% of all ICU patients) | 804 (65) | |
General Medicine ward only, N (% of all ward patients) | 1618 (59) |
Higher rates of concurrent C. difficile infections were observed in patients receiving PPIs in both databases; a higher rate of concurrent diagnosis of pneumonia was seen in patients receiving PPIs in the UHC population, with a nonsignificant trend towards the same finding in DH patients (Table 4).
Denver Health | UHC | |||||
---|---|---|---|---|---|---|
Concurrent diagnosis | (+) PPI 3962 | () PPI 5913 | P | (+) PPI 918,474 | () PPI 5,673,626 | P |
| ||||||
C. difficile | 46 (1.16) | 26 (0.44) | <0.0001 | 12,113 (1.32) | 175 (0.0031) | <0.0001 |
Pneumonia | 400 (10.1) | 517 (8.7) | 0.0232 | 75,274 (8.2) | 300,557 (5.3) | <0.0001 |
Chart review in the DH population found valid indications for PPIs in 19% of patients who were thought not have a valid indication on the basis of the administrative data (Table 5). For 56% of those in whom no valid indication was confirmed, physicians identified prophylaxis as the justification.
Characteristic | N (%) |
---|---|
| |
Valid indication found on chart review only | 23 (19) |
No valid indication after chart review | 100 (81) |
Written indication: prophylaxis | 56 (56) |
No written documentation of indication present in the chart | 33 (33) |
Written indication: continue home medication | 9 (9) |
Intubated with or without written indication of prophylaxis | 16 (16) |
DISCUSSION
The important finding of this study was that the majority of patients in 2 large groups of Medicine patients hospitalized in university‐affiliated hospitals received PPIs without having a valid indication. To our knowledge, the more than 900,000 UHC patients who received a PPI during their hospitalization represent the largest inpatient population evaluated for appropriateness of PPI prescriptions.
Our finding that 41% of the patients admitted to the DH Medicine service received a PPI during their hospital stay is similar to what has been observed by others.9, 14, 22 The rate of PPI prescription was lower in the UHC population (14%) for unclear reasons. By our definition, 61% lacked an adequate diagnosis to justify the prescription of the PPI. After performing a chart review on a randomly selected 5% of these records, we found that the DH administrative database had failed to identify 19% of patients who had a valid indication for receiving a PPI. Adjusting the administrative data accordingly still resulted in 50% of DH patients not having a valid indication for receiving a PPI. This is consistent with the 54% recorded by Batuwitage and colleagues11 in the outpatient setting by direct chart review, as well as a range of 60%‐75% for hospitalized patients in other studies.12, 13, 15, 23, 24
Stomach acidity is believed to provide an important host defense against lower gastrointestinal tract infections including Salmonella, Campylobacter, and Clostridium difficile.25 A recent study by Howell et al26 showed a doseresponse effect between PPI use and C. difficile infection, supporting a causal connection between loss of stomach acidity and development of Clostridium difficile‐associated diarrhea (CDAD). We found that C. difficile infection was more common in both populations of patients receiving PPIs (although the relative risk was much higher in the UHC database) (Table 5). The rate of CDAD in DH patients who received PPIs was 2.6 times higher than in patients who did not receive these acid suppressive agents.
The role of acid suppression in increasing risk for community‐acquired pneumonia is not entirely clear. Theories regarding the loss of an important host defense and bacterial proliferation head the list.6, 8, 27 Gastric and duodenal bacterial overgrowth is significantly more common in patients receiving PPIs than in patients receiving histamine type‐2 (H2) blockers.28 Previous studies have identified an increased rate of hospital‐acquired pneumonia and recurrent community‐acquired pneumonia27 in patients receiving any form of acid suppression therapy, but the risk appears to be greater in patients receiving PPIs than in those receiving H2 receptor antagonists (H2RAs).9 Significantly more patients in the UHC population who were taking PPIs had a concurrent diagnosis of pneumonia, consistent with previous studies alerting to this association6, 8, 9, 27 and consistent with the nonsignificant trend observed in the DH population.
Our study has a number of limitations. Our database comes from a single university‐affiliated public hospital with residents and hospitalists writing orders for all medications. The hospitals in the UHC are also teaching hospitals. Accordingly, our results might not generalize to other settings or reflect prescribing patterns in private, nonteaching hospital environments. Because our study was retrospective, we could not confirm the decision‐making process supporting the prescription of PPIs. Similarly, we could not temporarily relate the existence of the indication with the time the PPI was prescribed. Our list of appropriate indications for prescribing PPIs was developed by reviewing a number of references, and other studies have used slightly different lists (albeit the more commonly recognized indications are the same), but it may be argued that the list either includes or misses diagnoses in error.
While there is considerable debate about the use of PPIs for stress ulcer prophylaxis,29 we specifically chose not to include this as one of our valid indications for PPIs for 4 reasons. First, the American Society of Health‐System Pharmacists (ASHP) Report does not recommend prophylaxis for non‐ICU patients, and only recommends prophylaxis for those ICU patients with a coagulopathy, those requiring mechanical ventilation for more than 48 hours, those with a history of gastrointestinal ulceration or bleeding in the year prior to admission, and those with 2 or more of the following indications: sepsis, ICU stay >1 week, occult bleeding lasting 6 or more days, receiving high‐dose corticosteroids, and selected surgical situations.30 At the time the guideline was written, the authors note that there was insufficient data on PPIs to make any recommendations on their use, but no subsequent guidelines have been issued.30 Second, a review by Mohebbi and Hesch published in 2009, and a meta‐analysis by Lin and colleagues published in 2010, summarize subsequent randomized trials that suggest that PPIs and H2 blockers are, at best, similarly effective at preventing upper gastrointestinal (GI) bleeding among critically ill patients.31, 32 Third, the NICE guidelines do not include stress ulcer prophylaxis as an appropriate indication for PPIs except in the prevention and treatment of NSAID [non‐steroidal anti‐inflammatory drug]‐associated ulcers.19 Finally, H2RAs are currently the only medications with an FDA‐approved indication for stress ulcer prophylaxis. We acknowledge that PPIs may be a reasonable and acceptable choice for stress ulcer prophylaxis in patients who meet indications, but we were unable to identify such patients in either of our administrative databases.
In our Denver Health population, only 31% of our patients spent any time in the intensive care unit, and only a fraction of these would have both an accepted indication for stress ulcer prophylaxis by the ASHP guidelines and an intolerance or contraindication to an H2RA or sulcralfate. While our administrative database lacked the detail necessary to identify this small group of patients, the number of patients who might have been misclassified as not having a valid PPI indication was likely very small. Similar to the findings of previous studies,15, 18, 23, 29 prophylaxis against gastrointestinal bleeding was the stated justification for prescribing the PPI in 56% of the DH patient charts reviewed. It is impossible for us to estimate the number of patients in our administrative database for whom stress ulcer prophylaxis was justified by existing guidelines, as it would be necessary to gather a number of specific clinical details for each patient including: 1) ICU stay; 2) presence of coagulopathy; 3) duration of mechanical ventilation; 4) presence of sepsis; 5) duration of ICU stay; 6) presence of occult bleeding for >6 days; and 7) use of high‐dose corticosteroids. This level of clinical detail would likely only be available through a prospective study design, as has been suggested by other authors.33 Further research into the use, safety, and effectiveness of PPIs specifically for stress ulcer prophylaxis is warranted.
In conclusion, we found that 73% of nearly 1 million Medicine patients discharged from academic medical centers received a PPI without a valid indication during their hospitalization. The implications of our findings are broad. PPIs are more expensive31 than H2RAs and there is increasing evidence that they have significant side effects. In both databases we examined, the rate of C. difficile infection was higher in patients receiving PPIs than others. The prescribing habits of physicians in these university hospital settings appear to be far out of line with published guidelines and evidence‐based practice. Reducing inappropriate prescribing of PPIs would be an important educational and quality assurance project in most institutions.
- IMS Health Web site. Available at: http://www.imshealth.com/deployedfiles/ims/Global/Content/Corporate/Press%20Room/Top‐line%20Market%20Data/2009%20Top‐line%20Market%20Data/Top%20Therapy%20Classes%20by%20U.S.Sales.pdf. Accessed May 1,2011.
- Comparison of omeprazole and cimetidine in reflux oesophagitis: symptomatic, endoscopic, and histological evaluations.Gut.1990;31(9):968–972. , , , et al.
- Omeprazole before endoscopy in patients with gastrointestinal bleeding.N Engl J Med.2007;356(16):1631–1640. , , , et al.
- Use of gastric acid‐suppressive agents and the risk of community‐acquired Clostridium difficile‐associated disease.JAMA.2005;294(23):2989–2995. , , , .
- Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.JAMA.2009;301(9):937–944. , , , et al.
- Risk of community‐acquired pneumonia and use of gastric acid‐suppressive drugs.JAMA.2004;292(16):1955–1960. , , , , , .
- Long‐term proton pump inhibitor therapy and risk of hip fracture.JAMA2006;296(24):2947–2953. , , , .
- Use of proton pump inhibitors and the risk of community‐acquired pneumonia: a population‐based case‐control study.Arch Intern Med.2007;167(9):950–955. , , , , , .
- Acid‐suppressive medication use and the risk for hospital‐acquired pneumonia.JAMA.2009;301(20):2120–2128. , , , .
- US Food and Drug Administration (FDA) Website. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsfor HumanMedicalProducts/ucm245275.htm. Accessed March 2,2011.
- Inappropriate prescribing of proton pump inhibitors in primary care.Postgrad Med J.2007;83(975):66–68. , , , .
- Stress ulcer prophylaxis in hospitalized patients not in intensive care units.Am J Health Syst Pharm.2007;64(13):1396–1400. , .
- Predictors of inappropriate utilization of intravenous proton pump inhibitors.Aliment Pharmacol Ther.2007;25(5):609–615. , , , .
- Overuse of acid‐suppressive therapy in hospitalized patients.Am J Gastroenterol.2000;95(11):3118–3122. , , .
- Patterns and predictors of proton pump inhibitor overuse among academic and non‐academic hospitalists.Intern Med2010;49(23):2561–2568. , , , , , .
- Hospital use of acid‐suppressive medications and its fall‐out on prescribing in general practice: a 1‐month survey.Aliment Pharmacol Ther.2003;17(12):1503–1506. , , , et al.
- Overuse and inappropriate prescribing of proton pump inhibitors in patients with Clostridium difficile‐associated disease.QJM.2008;101(6):445–448. , , .
- Acid suppressive therapy use on an inpatient internal medicine service.Ann Pharmacother.2006;40(7–8):1261–1266. , , , .
- National Institute of Clinical Excellence (NICE), National Health Service (NHS), Dyspepsia: Management of dyspepsia in adults in primary care. Web site. Available at: http://www.nice.org.uk/nicemedia/live/10950/29460/29460.pdf. Accessed May 1,2011.
- When should stress ulcer prophylaxis be used in the ICU?Curr Opin Crit Care.2009;15(2):139–143. , , .
- An evaluation of the use of proton pump inhibitors.Pharm World Sci2001;23(3):116–117. , .
- Overuse of proton pump inhibitors.J Clin Pharm Ther.2000;25(5):333–340. , , .
- Pattern of intravenous proton pump inhibitors use in ICU and non‐ICU setting: a prospective observational study.Saudi J Gastroenterol.2010;16(4):275–279. , , , .
- Overuse of PPIs in patients at admission, during treatment, and at discharge in a tertiary Spanish hospital.Curr Clin Pharmacol.2010;5(4):288–297. , , , et al.
- Systematic review of the risk of enteric infection in patients taking acid suppression.Am J Gastroenterol.2007;102(9):2047–2056. , , .
- Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection.Arch Intern Med.2010;170(9):784–790. , , , et al.
- Recurrent community‐acquired pneumonia in patients starting acid‐suppressing drugs.Am J Med.2010;123(1):47–53. , , , , .
- Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study.Gut.1996;39(1):54–59. , , , et al.
- Why do physicians prescribe stress ulcer prophylaxis to general medicine patients?South Med J2010;103(11):1103–1110. , , , .
- ASHP therapeutic guidelines on stress ulcer prophylaxis.ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on November 14, 1998.Am J Health Syst Pharm.1999;56(4):347–379.
- Stress ulcer prophylaxis in the intensive care unit.Proc (Bayl Univ Med Cent).2009;22(4):373–376. , .
- The efficacy and safety of proton pump inhibitors vs histamine‐2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta‐analysis.Crit Care Med.2010;38(4):1197–1205. , , , , .
- Proton pump inhibitors for the prevention of stress‐related mucosal disease in critically‐ill patients: a meta‐analysis.J Med Assoc Thai.2009;92(5):632–637. , , .
- Proton pump inhibitors for prophylaxis of nosocomial upper gastrointestinal tract bleeding: effect of standardized guidelines on prescribing practice.Arch Intern Med.2010;170(9):779–783. , , , .
Proton pump inhibitors (PPIs) are the third most commonly prescribed class of medication in the United States, with $13.6 billion in yearly sales.1 Despite their effectiveness in treating acid reflux2 and their mortality benefit in the treatment of patients with gastrointestinal bleeding,3 recent literature has identified a number of risks associated with PPIs, including an increased incidence of Clostridium difficile infection,4 decreased effectiveness of clopidogrel in patients with acute coronary syndrome,5 increased risk of community‐ and hospital‐acquired pneumonia, and an increased risk of hip fracture.69 Additionally, in March of 2011, the US Food and Drug Administration (FDA) issued a warning regarding the potential for PPIs to cause low magnesium levels which can, in turn, cause muscle spasms, an irregular heartbeat, and convulsions.10
Inappropriate PPI prescription practice has been demonstrated in the primary care setting,11 as well as in small studies conducted in the hospital setting.1216 We hypothesized that many hospitalized patients receive these medications without having an accepted indication, and examined 2 populations of hospitalized patients, including administrative data from 6.5 million discharges from US university hospitals, to look for appropriate diagnoses justifying their use.
METHODS
We performed a retrospective review of administrative data collected between January 1, 2008 and December 31, 2009 from 2 patient populations: (a) those discharged from Denver Health (DH), a university‐affiliated public safety net hospital in Denver, CO; and (b) patients discharged from 112 academic health centers and 256 of their affiliated hospitals that participate in the University HealthSystem Consortium (UHC). The Colorado Multiple Institution Review Board reviewed and approved the conduct of this study.
Inclusion criteria for both populations were age >18 or <90 years, and hospitalization on a Medicine service. Prisoners and women known to be pregnant were excluded. In both cohorts, if patients had more than 1 admission during the 2‐year study period, only data from the first admission were used.
We recorded demographics, admitting diagnosis, and discharge diagnoses together with information pertaining to the name, route, and duration of administration of all PPIs (ie, omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole). We created a broadly inclusive set of valid indications for PPIs by incorporating diagnoses that could be identified by International Classification of Diseases, Ninth Revision.
(ICD‐9) codes from a number of previously published sources including the National Institute of Clinical Excellence (NICE) guidelines issued by the National Health Service (NHS) of the United Kingdom in 200012, 1721 (Table 1).
Indication | ICD‐9 Code |
---|---|
| |
Helicobacter pylori | 041.86 |
Abnormality of secretion of gastrin | 251.5 |
Esophageal varices with bleeding | 456.0 |
Esophageal varices without mention of bleeding | 456.1 |
Esophageal varices in diseases classified elsewhere | 456.2 |
Esophagitis | 530.10530.19 |
Perforation of esophagus | 530.4 |
Gastroesophageal laceration‐hemorrhage syndrome | 530.7 |
Esophageal reflux | 530.81 |
Barrett's esophagus | 530.85 |
Gastric ulcer | 531.0031.91 |
Duodenal ulcer | 532.00532.91 |
Peptic ulcer, site unspecified | 533.00533.91 |
Gastritis and duodenitis | 535.00535.71 |
Gastroparesis | 536.3 |
Dyspepsia and other specified disorders of function of stomach | 536.8 |
Hemorrhage of gastrointestinal tract, unspecified | 578.9 |
To assess the accuracy of the administrative data from DH, we also reviewed the Emergency Department histories, admission histories, progress notes, electronic pharmacy records, endoscopy reports, and discharge summaries of 123 patients randomly selected (ie, a 5% sample) from the group of patients identified by administrative data to have received a PPI without a valid indication, looking for any accepted indication that might have been missed in the administrative data.
All analyses were performed using SAS Enterprise Guide 4.1 (SAS Institute, Cary, NC). A Student t test was used to compare continuous variables and a chi‐square test was used to compare categorical variables. Bonferroni corrections were used for multiple comparisons, such that P values less than 0.01 were considered to be significant for categorical variables.
RESULTS
Inclusion criteria were met by 9875 patients in the Denver Health database and 6,592,100 patients in the UHC database. The demographics and primary discharge diagnoses for these patients are summarized in Table 2.
DH (N = 9875) | UHC (N = 6,592,100) | ||||
---|---|---|---|---|---|
Received a PPI | No PPI | Received a PPI | No PPI | ||
| |||||
No. (%) | 3962 (40) | 5913 (60) | 918,474 (14) | 5,673,626 (86) | |
Age (mean SD) | 53 15 | 51 16 | 59 17 | 55 18 | |
Gender (% male) | 2197 (55) | 3438 (58) | 464,552 (51) | 2,882,577 (51) | |
Race (% white) | 1610 (41) | 2425 (41) | 619,571 (67) | 3,670,450 (65) | |
Top 5 primary discharge diagnoses | |||||
Chest pain | 229 (6) | 462 (8) | Coronary atherosclerosis | 35,470 (4) | 186,321 (3) |
Alcohol withdrawal | 147 (4) | 174 (3) | Acute myocardial infarction | 26,507 (3) | 132,159 (2) |
Pneumonia, organism unspecified | 142 (4) | 262 (4) | Heart failure | 21,143 (2) | 103,751 (2) |
Acute pancreatitis | 132 (3) | 106 (2) | Septicemia | 20,345 (2) | 64,915 (1) |
Obstructive chronic bronchitis with (acute) exacerbation | 89 (2) | 154 (3) | Chest pain | 16,936 (2) | 107,497 (2) |
Only 39% and 27% of the patients in the DH and UHC databases, respectively, had a valid indication for PPIs on the basis of discharge diagnoses (Table 3). In the DH data, if admission ICD‐9 codes were also inspected for valid PPI indications, 1579 (40%) of patients receiving PPIs had a valid indication (admission ICD‐9 codes were not available for patients in the UHC database). Thirty‐one percent of Denver Health patients spent time in the intensive care unit (ICU) during their hospital stay and 65% of those patients received a PPI without a valid indication, as compared to 59% of patients who remained on the General Medicine ward (Table 3).
DH (N = 9875) | UHC (N = 6,592,100) | |
---|---|---|
| ||
Patients receiving PPIs (% of total) | 3962 (40) | 918,474 (14) |
Any ICU stay, N (% of all patients) | 1238 (31) | |
General Medicine ward only, N (% of all patients) | 2724 (69) | |
Patients with indication for PPI (% of all patients receiving PPIs)* | 1540 (39) | 247,142 (27) |
Any ICU stay, N (% of all ICU patients) | 434 (35) | |
General Medicine ward only, N (% of all ward patients) | 1106 (41) | |
Patients without indication for PPI (% of those receiving PPIs)* | 2422 (61) | 671,332 (73) |
Any ICU stay, N (% of all ICU patients) | 804 (65) | |
General Medicine ward only, N (% of all ward patients) | 1618 (59) |
Higher rates of concurrent C. difficile infections were observed in patients receiving PPIs in both databases; a higher rate of concurrent diagnosis of pneumonia was seen in patients receiving PPIs in the UHC population, with a nonsignificant trend towards the same finding in DH patients (Table 4).
Denver Health | UHC | |||||
---|---|---|---|---|---|---|
Concurrent diagnosis | (+) PPI 3962 | () PPI 5913 | P | (+) PPI 918,474 | () PPI 5,673,626 | P |
| ||||||
C. difficile | 46 (1.16) | 26 (0.44) | <0.0001 | 12,113 (1.32) | 175 (0.0031) | <0.0001 |
Pneumonia | 400 (10.1) | 517 (8.7) | 0.0232 | 75,274 (8.2) | 300,557 (5.3) | <0.0001 |
Chart review in the DH population found valid indications for PPIs in 19% of patients who were thought not have a valid indication on the basis of the administrative data (Table 5). For 56% of those in whom no valid indication was confirmed, physicians identified prophylaxis as the justification.
Characteristic | N (%) |
---|---|
| |
Valid indication found on chart review only | 23 (19) |
No valid indication after chart review | 100 (81) |
Written indication: prophylaxis | 56 (56) |
No written documentation of indication present in the chart | 33 (33) |
Written indication: continue home medication | 9 (9) |
Intubated with or without written indication of prophylaxis | 16 (16) |
DISCUSSION
The important finding of this study was that the majority of patients in 2 large groups of Medicine patients hospitalized in university‐affiliated hospitals received PPIs without having a valid indication. To our knowledge, the more than 900,000 UHC patients who received a PPI during their hospitalization represent the largest inpatient population evaluated for appropriateness of PPI prescriptions.
Our finding that 41% of the patients admitted to the DH Medicine service received a PPI during their hospital stay is similar to what has been observed by others.9, 14, 22 The rate of PPI prescription was lower in the UHC population (14%) for unclear reasons. By our definition, 61% lacked an adequate diagnosis to justify the prescription of the PPI. After performing a chart review on a randomly selected 5% of these records, we found that the DH administrative database had failed to identify 19% of patients who had a valid indication for receiving a PPI. Adjusting the administrative data accordingly still resulted in 50% of DH patients not having a valid indication for receiving a PPI. This is consistent with the 54% recorded by Batuwitage and colleagues11 in the outpatient setting by direct chart review, as well as a range of 60%‐75% for hospitalized patients in other studies.12, 13, 15, 23, 24
Stomach acidity is believed to provide an important host defense against lower gastrointestinal tract infections including Salmonella, Campylobacter, and Clostridium difficile.25 A recent study by Howell et al26 showed a doseresponse effect between PPI use and C. difficile infection, supporting a causal connection between loss of stomach acidity and development of Clostridium difficile‐associated diarrhea (CDAD). We found that C. difficile infection was more common in both populations of patients receiving PPIs (although the relative risk was much higher in the UHC database) (Table 5). The rate of CDAD in DH patients who received PPIs was 2.6 times higher than in patients who did not receive these acid suppressive agents.
The role of acid suppression in increasing risk for community‐acquired pneumonia is not entirely clear. Theories regarding the loss of an important host defense and bacterial proliferation head the list.6, 8, 27 Gastric and duodenal bacterial overgrowth is significantly more common in patients receiving PPIs than in patients receiving histamine type‐2 (H2) blockers.28 Previous studies have identified an increased rate of hospital‐acquired pneumonia and recurrent community‐acquired pneumonia27 in patients receiving any form of acid suppression therapy, but the risk appears to be greater in patients receiving PPIs than in those receiving H2 receptor antagonists (H2RAs).9 Significantly more patients in the UHC population who were taking PPIs had a concurrent diagnosis of pneumonia, consistent with previous studies alerting to this association6, 8, 9, 27 and consistent with the nonsignificant trend observed in the DH population.
Our study has a number of limitations. Our database comes from a single university‐affiliated public hospital with residents and hospitalists writing orders for all medications. The hospitals in the UHC are also teaching hospitals. Accordingly, our results might not generalize to other settings or reflect prescribing patterns in private, nonteaching hospital environments. Because our study was retrospective, we could not confirm the decision‐making process supporting the prescription of PPIs. Similarly, we could not temporarily relate the existence of the indication with the time the PPI was prescribed. Our list of appropriate indications for prescribing PPIs was developed by reviewing a number of references, and other studies have used slightly different lists (albeit the more commonly recognized indications are the same), but it may be argued that the list either includes or misses diagnoses in error.
While there is considerable debate about the use of PPIs for stress ulcer prophylaxis,29 we specifically chose not to include this as one of our valid indications for PPIs for 4 reasons. First, the American Society of Health‐System Pharmacists (ASHP) Report does not recommend prophylaxis for non‐ICU patients, and only recommends prophylaxis for those ICU patients with a coagulopathy, those requiring mechanical ventilation for more than 48 hours, those with a history of gastrointestinal ulceration or bleeding in the year prior to admission, and those with 2 or more of the following indications: sepsis, ICU stay >1 week, occult bleeding lasting 6 or more days, receiving high‐dose corticosteroids, and selected surgical situations.30 At the time the guideline was written, the authors note that there was insufficient data on PPIs to make any recommendations on their use, but no subsequent guidelines have been issued.30 Second, a review by Mohebbi and Hesch published in 2009, and a meta‐analysis by Lin and colleagues published in 2010, summarize subsequent randomized trials that suggest that PPIs and H2 blockers are, at best, similarly effective at preventing upper gastrointestinal (GI) bleeding among critically ill patients.31, 32 Third, the NICE guidelines do not include stress ulcer prophylaxis as an appropriate indication for PPIs except in the prevention and treatment of NSAID [non‐steroidal anti‐inflammatory drug]‐associated ulcers.19 Finally, H2RAs are currently the only medications with an FDA‐approved indication for stress ulcer prophylaxis. We acknowledge that PPIs may be a reasonable and acceptable choice for stress ulcer prophylaxis in patients who meet indications, but we were unable to identify such patients in either of our administrative databases.
In our Denver Health population, only 31% of our patients spent any time in the intensive care unit, and only a fraction of these would have both an accepted indication for stress ulcer prophylaxis by the ASHP guidelines and an intolerance or contraindication to an H2RA or sulcralfate. While our administrative database lacked the detail necessary to identify this small group of patients, the number of patients who might have been misclassified as not having a valid PPI indication was likely very small. Similar to the findings of previous studies,15, 18, 23, 29 prophylaxis against gastrointestinal bleeding was the stated justification for prescribing the PPI in 56% of the DH patient charts reviewed. It is impossible for us to estimate the number of patients in our administrative database for whom stress ulcer prophylaxis was justified by existing guidelines, as it would be necessary to gather a number of specific clinical details for each patient including: 1) ICU stay; 2) presence of coagulopathy; 3) duration of mechanical ventilation; 4) presence of sepsis; 5) duration of ICU stay; 6) presence of occult bleeding for >6 days; and 7) use of high‐dose corticosteroids. This level of clinical detail would likely only be available through a prospective study design, as has been suggested by other authors.33 Further research into the use, safety, and effectiveness of PPIs specifically for stress ulcer prophylaxis is warranted.
In conclusion, we found that 73% of nearly 1 million Medicine patients discharged from academic medical centers received a PPI without a valid indication during their hospitalization. The implications of our findings are broad. PPIs are more expensive31 than H2RAs and there is increasing evidence that they have significant side effects. In both databases we examined, the rate of C. difficile infection was higher in patients receiving PPIs than others. The prescribing habits of physicians in these university hospital settings appear to be far out of line with published guidelines and evidence‐based practice. Reducing inappropriate prescribing of PPIs would be an important educational and quality assurance project in most institutions.
Proton pump inhibitors (PPIs) are the third most commonly prescribed class of medication in the United States, with $13.6 billion in yearly sales.1 Despite their effectiveness in treating acid reflux2 and their mortality benefit in the treatment of patients with gastrointestinal bleeding,3 recent literature has identified a number of risks associated with PPIs, including an increased incidence of Clostridium difficile infection,4 decreased effectiveness of clopidogrel in patients with acute coronary syndrome,5 increased risk of community‐ and hospital‐acquired pneumonia, and an increased risk of hip fracture.69 Additionally, in March of 2011, the US Food and Drug Administration (FDA) issued a warning regarding the potential for PPIs to cause low magnesium levels which can, in turn, cause muscle spasms, an irregular heartbeat, and convulsions.10
Inappropriate PPI prescription practice has been demonstrated in the primary care setting,11 as well as in small studies conducted in the hospital setting.1216 We hypothesized that many hospitalized patients receive these medications without having an accepted indication, and examined 2 populations of hospitalized patients, including administrative data from 6.5 million discharges from US university hospitals, to look for appropriate diagnoses justifying their use.
METHODS
We performed a retrospective review of administrative data collected between January 1, 2008 and December 31, 2009 from 2 patient populations: (a) those discharged from Denver Health (DH), a university‐affiliated public safety net hospital in Denver, CO; and (b) patients discharged from 112 academic health centers and 256 of their affiliated hospitals that participate in the University HealthSystem Consortium (UHC). The Colorado Multiple Institution Review Board reviewed and approved the conduct of this study.
Inclusion criteria for both populations were age >18 or <90 years, and hospitalization on a Medicine service. Prisoners and women known to be pregnant were excluded. In both cohorts, if patients had more than 1 admission during the 2‐year study period, only data from the first admission were used.
We recorded demographics, admitting diagnosis, and discharge diagnoses together with information pertaining to the name, route, and duration of administration of all PPIs (ie, omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole). We created a broadly inclusive set of valid indications for PPIs by incorporating diagnoses that could be identified by International Classification of Diseases, Ninth Revision.
(ICD‐9) codes from a number of previously published sources including the National Institute of Clinical Excellence (NICE) guidelines issued by the National Health Service (NHS) of the United Kingdom in 200012, 1721 (Table 1).
Indication | ICD‐9 Code |
---|---|
| |
Helicobacter pylori | 041.86 |
Abnormality of secretion of gastrin | 251.5 |
Esophageal varices with bleeding | 456.0 |
Esophageal varices without mention of bleeding | 456.1 |
Esophageal varices in diseases classified elsewhere | 456.2 |
Esophagitis | 530.10530.19 |
Perforation of esophagus | 530.4 |
Gastroesophageal laceration‐hemorrhage syndrome | 530.7 |
Esophageal reflux | 530.81 |
Barrett's esophagus | 530.85 |
Gastric ulcer | 531.0031.91 |
Duodenal ulcer | 532.00532.91 |
Peptic ulcer, site unspecified | 533.00533.91 |
Gastritis and duodenitis | 535.00535.71 |
Gastroparesis | 536.3 |
Dyspepsia and other specified disorders of function of stomach | 536.8 |
Hemorrhage of gastrointestinal tract, unspecified | 578.9 |
To assess the accuracy of the administrative data from DH, we also reviewed the Emergency Department histories, admission histories, progress notes, electronic pharmacy records, endoscopy reports, and discharge summaries of 123 patients randomly selected (ie, a 5% sample) from the group of patients identified by administrative data to have received a PPI without a valid indication, looking for any accepted indication that might have been missed in the administrative data.
All analyses were performed using SAS Enterprise Guide 4.1 (SAS Institute, Cary, NC). A Student t test was used to compare continuous variables and a chi‐square test was used to compare categorical variables. Bonferroni corrections were used for multiple comparisons, such that P values less than 0.01 were considered to be significant for categorical variables.
RESULTS
Inclusion criteria were met by 9875 patients in the Denver Health database and 6,592,100 patients in the UHC database. The demographics and primary discharge diagnoses for these patients are summarized in Table 2.
DH (N = 9875) | UHC (N = 6,592,100) | ||||
---|---|---|---|---|---|
Received a PPI | No PPI | Received a PPI | No PPI | ||
| |||||
No. (%) | 3962 (40) | 5913 (60) | 918,474 (14) | 5,673,626 (86) | |
Age (mean SD) | 53 15 | 51 16 | 59 17 | 55 18 | |
Gender (% male) | 2197 (55) | 3438 (58) | 464,552 (51) | 2,882,577 (51) | |
Race (% white) | 1610 (41) | 2425 (41) | 619,571 (67) | 3,670,450 (65) | |
Top 5 primary discharge diagnoses | |||||
Chest pain | 229 (6) | 462 (8) | Coronary atherosclerosis | 35,470 (4) | 186,321 (3) |
Alcohol withdrawal | 147 (4) | 174 (3) | Acute myocardial infarction | 26,507 (3) | 132,159 (2) |
Pneumonia, organism unspecified | 142 (4) | 262 (4) | Heart failure | 21,143 (2) | 103,751 (2) |
Acute pancreatitis | 132 (3) | 106 (2) | Septicemia | 20,345 (2) | 64,915 (1) |
Obstructive chronic bronchitis with (acute) exacerbation | 89 (2) | 154 (3) | Chest pain | 16,936 (2) | 107,497 (2) |
Only 39% and 27% of the patients in the DH and UHC databases, respectively, had a valid indication for PPIs on the basis of discharge diagnoses (Table 3). In the DH data, if admission ICD‐9 codes were also inspected for valid PPI indications, 1579 (40%) of patients receiving PPIs had a valid indication (admission ICD‐9 codes were not available for patients in the UHC database). Thirty‐one percent of Denver Health patients spent time in the intensive care unit (ICU) during their hospital stay and 65% of those patients received a PPI without a valid indication, as compared to 59% of patients who remained on the General Medicine ward (Table 3).
DH (N = 9875) | UHC (N = 6,592,100) | |
---|---|---|
| ||
Patients receiving PPIs (% of total) | 3962 (40) | 918,474 (14) |
Any ICU stay, N (% of all patients) | 1238 (31) | |
General Medicine ward only, N (% of all patients) | 2724 (69) | |
Patients with indication for PPI (% of all patients receiving PPIs)* | 1540 (39) | 247,142 (27) |
Any ICU stay, N (% of all ICU patients) | 434 (35) | |
General Medicine ward only, N (% of all ward patients) | 1106 (41) | |
Patients without indication for PPI (% of those receiving PPIs)* | 2422 (61) | 671,332 (73) |
Any ICU stay, N (% of all ICU patients) | 804 (65) | |
General Medicine ward only, N (% of all ward patients) | 1618 (59) |
Higher rates of concurrent C. difficile infections were observed in patients receiving PPIs in both databases; a higher rate of concurrent diagnosis of pneumonia was seen in patients receiving PPIs in the UHC population, with a nonsignificant trend towards the same finding in DH patients (Table 4).
Denver Health | UHC | |||||
---|---|---|---|---|---|---|
Concurrent diagnosis | (+) PPI 3962 | () PPI 5913 | P | (+) PPI 918,474 | () PPI 5,673,626 | P |
| ||||||
C. difficile | 46 (1.16) | 26 (0.44) | <0.0001 | 12,113 (1.32) | 175 (0.0031) | <0.0001 |
Pneumonia | 400 (10.1) | 517 (8.7) | 0.0232 | 75,274 (8.2) | 300,557 (5.3) | <0.0001 |
Chart review in the DH population found valid indications for PPIs in 19% of patients who were thought not have a valid indication on the basis of the administrative data (Table 5). For 56% of those in whom no valid indication was confirmed, physicians identified prophylaxis as the justification.
Characteristic | N (%) |
---|---|
| |
Valid indication found on chart review only | 23 (19) |
No valid indication after chart review | 100 (81) |
Written indication: prophylaxis | 56 (56) |
No written documentation of indication present in the chart | 33 (33) |
Written indication: continue home medication | 9 (9) |
Intubated with or without written indication of prophylaxis | 16 (16) |
DISCUSSION
The important finding of this study was that the majority of patients in 2 large groups of Medicine patients hospitalized in university‐affiliated hospitals received PPIs without having a valid indication. To our knowledge, the more than 900,000 UHC patients who received a PPI during their hospitalization represent the largest inpatient population evaluated for appropriateness of PPI prescriptions.
Our finding that 41% of the patients admitted to the DH Medicine service received a PPI during their hospital stay is similar to what has been observed by others.9, 14, 22 The rate of PPI prescription was lower in the UHC population (14%) for unclear reasons. By our definition, 61% lacked an adequate diagnosis to justify the prescription of the PPI. After performing a chart review on a randomly selected 5% of these records, we found that the DH administrative database had failed to identify 19% of patients who had a valid indication for receiving a PPI. Adjusting the administrative data accordingly still resulted in 50% of DH patients not having a valid indication for receiving a PPI. This is consistent with the 54% recorded by Batuwitage and colleagues11 in the outpatient setting by direct chart review, as well as a range of 60%‐75% for hospitalized patients in other studies.12, 13, 15, 23, 24
Stomach acidity is believed to provide an important host defense against lower gastrointestinal tract infections including Salmonella, Campylobacter, and Clostridium difficile.25 A recent study by Howell et al26 showed a doseresponse effect between PPI use and C. difficile infection, supporting a causal connection between loss of stomach acidity and development of Clostridium difficile‐associated diarrhea (CDAD). We found that C. difficile infection was more common in both populations of patients receiving PPIs (although the relative risk was much higher in the UHC database) (Table 5). The rate of CDAD in DH patients who received PPIs was 2.6 times higher than in patients who did not receive these acid suppressive agents.
The role of acid suppression in increasing risk for community‐acquired pneumonia is not entirely clear. Theories regarding the loss of an important host defense and bacterial proliferation head the list.6, 8, 27 Gastric and duodenal bacterial overgrowth is significantly more common in patients receiving PPIs than in patients receiving histamine type‐2 (H2) blockers.28 Previous studies have identified an increased rate of hospital‐acquired pneumonia and recurrent community‐acquired pneumonia27 in patients receiving any form of acid suppression therapy, but the risk appears to be greater in patients receiving PPIs than in those receiving H2 receptor antagonists (H2RAs).9 Significantly more patients in the UHC population who were taking PPIs had a concurrent diagnosis of pneumonia, consistent with previous studies alerting to this association6, 8, 9, 27 and consistent with the nonsignificant trend observed in the DH population.
Our study has a number of limitations. Our database comes from a single university‐affiliated public hospital with residents and hospitalists writing orders for all medications. The hospitals in the UHC are also teaching hospitals. Accordingly, our results might not generalize to other settings or reflect prescribing patterns in private, nonteaching hospital environments. Because our study was retrospective, we could not confirm the decision‐making process supporting the prescription of PPIs. Similarly, we could not temporarily relate the existence of the indication with the time the PPI was prescribed. Our list of appropriate indications for prescribing PPIs was developed by reviewing a number of references, and other studies have used slightly different lists (albeit the more commonly recognized indications are the same), but it may be argued that the list either includes or misses diagnoses in error.
While there is considerable debate about the use of PPIs for stress ulcer prophylaxis,29 we specifically chose not to include this as one of our valid indications for PPIs for 4 reasons. First, the American Society of Health‐System Pharmacists (ASHP) Report does not recommend prophylaxis for non‐ICU patients, and only recommends prophylaxis for those ICU patients with a coagulopathy, those requiring mechanical ventilation for more than 48 hours, those with a history of gastrointestinal ulceration or bleeding in the year prior to admission, and those with 2 or more of the following indications: sepsis, ICU stay >1 week, occult bleeding lasting 6 or more days, receiving high‐dose corticosteroids, and selected surgical situations.30 At the time the guideline was written, the authors note that there was insufficient data on PPIs to make any recommendations on their use, but no subsequent guidelines have been issued.30 Second, a review by Mohebbi and Hesch published in 2009, and a meta‐analysis by Lin and colleagues published in 2010, summarize subsequent randomized trials that suggest that PPIs and H2 blockers are, at best, similarly effective at preventing upper gastrointestinal (GI) bleeding among critically ill patients.31, 32 Third, the NICE guidelines do not include stress ulcer prophylaxis as an appropriate indication for PPIs except in the prevention and treatment of NSAID [non‐steroidal anti‐inflammatory drug]‐associated ulcers.19 Finally, H2RAs are currently the only medications with an FDA‐approved indication for stress ulcer prophylaxis. We acknowledge that PPIs may be a reasonable and acceptable choice for stress ulcer prophylaxis in patients who meet indications, but we were unable to identify such patients in either of our administrative databases.
In our Denver Health population, only 31% of our patients spent any time in the intensive care unit, and only a fraction of these would have both an accepted indication for stress ulcer prophylaxis by the ASHP guidelines and an intolerance or contraindication to an H2RA or sulcralfate. While our administrative database lacked the detail necessary to identify this small group of patients, the number of patients who might have been misclassified as not having a valid PPI indication was likely very small. Similar to the findings of previous studies,15, 18, 23, 29 prophylaxis against gastrointestinal bleeding was the stated justification for prescribing the PPI in 56% of the DH patient charts reviewed. It is impossible for us to estimate the number of patients in our administrative database for whom stress ulcer prophylaxis was justified by existing guidelines, as it would be necessary to gather a number of specific clinical details for each patient including: 1) ICU stay; 2) presence of coagulopathy; 3) duration of mechanical ventilation; 4) presence of sepsis; 5) duration of ICU stay; 6) presence of occult bleeding for >6 days; and 7) use of high‐dose corticosteroids. This level of clinical detail would likely only be available through a prospective study design, as has been suggested by other authors.33 Further research into the use, safety, and effectiveness of PPIs specifically for stress ulcer prophylaxis is warranted.
In conclusion, we found that 73% of nearly 1 million Medicine patients discharged from academic medical centers received a PPI without a valid indication during their hospitalization. The implications of our findings are broad. PPIs are more expensive31 than H2RAs and there is increasing evidence that they have significant side effects. In both databases we examined, the rate of C. difficile infection was higher in patients receiving PPIs than others. The prescribing habits of physicians in these university hospital settings appear to be far out of line with published guidelines and evidence‐based practice. Reducing inappropriate prescribing of PPIs would be an important educational and quality assurance project in most institutions.
- IMS Health Web site. Available at: http://www.imshealth.com/deployedfiles/ims/Global/Content/Corporate/Press%20Room/Top‐line%20Market%20Data/2009%20Top‐line%20Market%20Data/Top%20Therapy%20Classes%20by%20U.S.Sales.pdf. Accessed May 1,2011.
- Comparison of omeprazole and cimetidine in reflux oesophagitis: symptomatic, endoscopic, and histological evaluations.Gut.1990;31(9):968–972. , , , et al.
- Omeprazole before endoscopy in patients with gastrointestinal bleeding.N Engl J Med.2007;356(16):1631–1640. , , , et al.
- Use of gastric acid‐suppressive agents and the risk of community‐acquired Clostridium difficile‐associated disease.JAMA.2005;294(23):2989–2995. , , , .
- Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.JAMA.2009;301(9):937–944. , , , et al.
- Risk of community‐acquired pneumonia and use of gastric acid‐suppressive drugs.JAMA.2004;292(16):1955–1960. , , , , , .
- Long‐term proton pump inhibitor therapy and risk of hip fracture.JAMA2006;296(24):2947–2953. , , , .
- Use of proton pump inhibitors and the risk of community‐acquired pneumonia: a population‐based case‐control study.Arch Intern Med.2007;167(9):950–955. , , , , , .
- Acid‐suppressive medication use and the risk for hospital‐acquired pneumonia.JAMA.2009;301(20):2120–2128. , , , .
- US Food and Drug Administration (FDA) Website. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsfor HumanMedicalProducts/ucm245275.htm. Accessed March 2,2011.
- Inappropriate prescribing of proton pump inhibitors in primary care.Postgrad Med J.2007;83(975):66–68. , , , .
- Stress ulcer prophylaxis in hospitalized patients not in intensive care units.Am J Health Syst Pharm.2007;64(13):1396–1400. , .
- Predictors of inappropriate utilization of intravenous proton pump inhibitors.Aliment Pharmacol Ther.2007;25(5):609–615. , , , .
- Overuse of acid‐suppressive therapy in hospitalized patients.Am J Gastroenterol.2000;95(11):3118–3122. , , .
- Patterns and predictors of proton pump inhibitor overuse among academic and non‐academic hospitalists.Intern Med2010;49(23):2561–2568. , , , , , .
- Hospital use of acid‐suppressive medications and its fall‐out on prescribing in general practice: a 1‐month survey.Aliment Pharmacol Ther.2003;17(12):1503–1506. , , , et al.
- Overuse and inappropriate prescribing of proton pump inhibitors in patients with Clostridium difficile‐associated disease.QJM.2008;101(6):445–448. , , .
- Acid suppressive therapy use on an inpatient internal medicine service.Ann Pharmacother.2006;40(7–8):1261–1266. , , , .
- National Institute of Clinical Excellence (NICE), National Health Service (NHS), Dyspepsia: Management of dyspepsia in adults in primary care. Web site. Available at: http://www.nice.org.uk/nicemedia/live/10950/29460/29460.pdf. Accessed May 1,2011.
- When should stress ulcer prophylaxis be used in the ICU?Curr Opin Crit Care.2009;15(2):139–143. , , .
- An evaluation of the use of proton pump inhibitors.Pharm World Sci2001;23(3):116–117. , .
- Overuse of proton pump inhibitors.J Clin Pharm Ther.2000;25(5):333–340. , , .
- Pattern of intravenous proton pump inhibitors use in ICU and non‐ICU setting: a prospective observational study.Saudi J Gastroenterol.2010;16(4):275–279. , , , .
- Overuse of PPIs in patients at admission, during treatment, and at discharge in a tertiary Spanish hospital.Curr Clin Pharmacol.2010;5(4):288–297. , , , et al.
- Systematic review of the risk of enteric infection in patients taking acid suppression.Am J Gastroenterol.2007;102(9):2047–2056. , , .
- Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection.Arch Intern Med.2010;170(9):784–790. , , , et al.
- Recurrent community‐acquired pneumonia in patients starting acid‐suppressing drugs.Am J Med.2010;123(1):47–53. , , , , .
- Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study.Gut.1996;39(1):54–59. , , , et al.
- Why do physicians prescribe stress ulcer prophylaxis to general medicine patients?South Med J2010;103(11):1103–1110. , , , .
- ASHP therapeutic guidelines on stress ulcer prophylaxis.ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on November 14, 1998.Am J Health Syst Pharm.1999;56(4):347–379.
- Stress ulcer prophylaxis in the intensive care unit.Proc (Bayl Univ Med Cent).2009;22(4):373–376. , .
- The efficacy and safety of proton pump inhibitors vs histamine‐2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta‐analysis.Crit Care Med.2010;38(4):1197–1205. , , , , .
- Proton pump inhibitors for the prevention of stress‐related mucosal disease in critically‐ill patients: a meta‐analysis.J Med Assoc Thai.2009;92(5):632–637. , , .
- Proton pump inhibitors for prophylaxis of nosocomial upper gastrointestinal tract bleeding: effect of standardized guidelines on prescribing practice.Arch Intern Med.2010;170(9):779–783. , , , .
- IMS Health Web site. Available at: http://www.imshealth.com/deployedfiles/ims/Global/Content/Corporate/Press%20Room/Top‐line%20Market%20Data/2009%20Top‐line%20Market%20Data/Top%20Therapy%20Classes%20by%20U.S.Sales.pdf. Accessed May 1,2011.
- Comparison of omeprazole and cimetidine in reflux oesophagitis: symptomatic, endoscopic, and histological evaluations.Gut.1990;31(9):968–972. , , , et al.
- Omeprazole before endoscopy in patients with gastrointestinal bleeding.N Engl J Med.2007;356(16):1631–1640. , , , et al.
- Use of gastric acid‐suppressive agents and the risk of community‐acquired Clostridium difficile‐associated disease.JAMA.2005;294(23):2989–2995. , , , .
- Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.JAMA.2009;301(9):937–944. , , , et al.
- Risk of community‐acquired pneumonia and use of gastric acid‐suppressive drugs.JAMA.2004;292(16):1955–1960. , , , , , .
- Long‐term proton pump inhibitor therapy and risk of hip fracture.JAMA2006;296(24):2947–2953. , , , .
- Use of proton pump inhibitors and the risk of community‐acquired pneumonia: a population‐based case‐control study.Arch Intern Med.2007;167(9):950–955. , , , , , .
- Acid‐suppressive medication use and the risk for hospital‐acquired pneumonia.JAMA.2009;301(20):2120–2128. , , , .
- US Food and Drug Administration (FDA) Website. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsfor HumanMedicalProducts/ucm245275.htm. Accessed March 2,2011.
- Inappropriate prescribing of proton pump inhibitors in primary care.Postgrad Med J.2007;83(975):66–68. , , , .
- Stress ulcer prophylaxis in hospitalized patients not in intensive care units.Am J Health Syst Pharm.2007;64(13):1396–1400. , .
- Predictors of inappropriate utilization of intravenous proton pump inhibitors.Aliment Pharmacol Ther.2007;25(5):609–615. , , , .
- Overuse of acid‐suppressive therapy in hospitalized patients.Am J Gastroenterol.2000;95(11):3118–3122. , , .
- Patterns and predictors of proton pump inhibitor overuse among academic and non‐academic hospitalists.Intern Med2010;49(23):2561–2568. , , , , , .
- Hospital use of acid‐suppressive medications and its fall‐out on prescribing in general practice: a 1‐month survey.Aliment Pharmacol Ther.2003;17(12):1503–1506. , , , et al.
- Overuse and inappropriate prescribing of proton pump inhibitors in patients with Clostridium difficile‐associated disease.QJM.2008;101(6):445–448. , , .
- Acid suppressive therapy use on an inpatient internal medicine service.Ann Pharmacother.2006;40(7–8):1261–1266. , , , .
- National Institute of Clinical Excellence (NICE), National Health Service (NHS), Dyspepsia: Management of dyspepsia in adults in primary care. Web site. Available at: http://www.nice.org.uk/nicemedia/live/10950/29460/29460.pdf. Accessed May 1,2011.
- When should stress ulcer prophylaxis be used in the ICU?Curr Opin Crit Care.2009;15(2):139–143. , , .
- An evaluation of the use of proton pump inhibitors.Pharm World Sci2001;23(3):116–117. , .
- Overuse of proton pump inhibitors.J Clin Pharm Ther.2000;25(5):333–340. , , .
- Pattern of intravenous proton pump inhibitors use in ICU and non‐ICU setting: a prospective observational study.Saudi J Gastroenterol.2010;16(4):275–279. , , , .
- Overuse of PPIs in patients at admission, during treatment, and at discharge in a tertiary Spanish hospital.Curr Clin Pharmacol.2010;5(4):288–297. , , , et al.
- Systematic review of the risk of enteric infection in patients taking acid suppression.Am J Gastroenterol.2007;102(9):2047–2056. , , .
- Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection.Arch Intern Med.2010;170(9):784–790. , , , et al.
- Recurrent community‐acquired pneumonia in patients starting acid‐suppressing drugs.Am J Med.2010;123(1):47–53. , , , , .
- Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study.Gut.1996;39(1):54–59. , , , et al.
- Why do physicians prescribe stress ulcer prophylaxis to general medicine patients?South Med J2010;103(11):1103–1110. , , , .
- ASHP therapeutic guidelines on stress ulcer prophylaxis.ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on November 14, 1998.Am J Health Syst Pharm.1999;56(4):347–379.
- Stress ulcer prophylaxis in the intensive care unit.Proc (Bayl Univ Med Cent).2009;22(4):373–376. , .
- The efficacy and safety of proton pump inhibitors vs histamine‐2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta‐analysis.Crit Care Med.2010;38(4):1197–1205. , , , , .
- Proton pump inhibitors for the prevention of stress‐related mucosal disease in critically‐ill patients: a meta‐analysis.J Med Assoc Thai.2009;92(5):632–637. , , .
- Proton pump inhibitors for prophylaxis of nosocomial upper gastrointestinal tract bleeding: effect of standardized guidelines on prescribing practice.Arch Intern Med.2010;170(9):779–783. , , , .
Copyright © 2011 Society of Hospital Medicine