Literature Review

Background: Recent trials (ARISE, ProCESS) showed EGDT provided no mortality benefit over usual care. Questions remain about the effectiveness of intensive monitoring protocols, as well as the evolution of what constitutes usual care. The ProMISe trial seeks to test the hypothesis that EGDT impacts mortality in a cost-effective way.

Study design: Pragmatic, open, multicenter, parallel group RCT.

Setting: English National Health Service hospitals that did not routinely use EGDT that included continuous ScvO2 monitoring.

Synopsis: The authors enrolled 1,260 adult patients with early severe sepsis or septic shock; they randomized patients to either usual care or EGDT for six hours. Data was collected prospectively on the EGDT group and retrospectively on the usual care group.

By intention-to-treat analysis, all-cause mortality at 90 days was not significantly different (unadjusted RR 1.01, 95% CI, 0.85-1.20; adjusted OR 0.95, 95% CI, 0.74-1.24, P=0.73). EGDT patients received more intensive therapy, their quality of life scores were similar, and their average costs were higher, though not statistically significant. The probability that EGDT was cost effective was calculated to be below 20%.

Usual care patients had lower-than-expected mortality (29% vs. 40%), limiting the treatment effect of EGDT and limiting extrapolation to groups with higher mortality. Comparison to older studies is limited by the evolution in usual care for sepsis, with earlier recognition and antibiotic administration and greater use of vasoactive drugs. This study adds significant information about quality of life and cost to the discussion about EGDT.

Bottom line: The ProMISe study completes a powerful trio of papers suggesting that EGDT might be an expensive option that offers no clinical benefit over usual care.

Citation: Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372:1301-1311.

Background: Recent trials (ARISE, ProCESS) showed EGDT provided no mortality benefit over usual care. Questions remain about the effectiveness of intensive monitoring protocols, as well as the evolution of what constitutes usual care. The ProMISe trial seeks to test the hypothesis that EGDT impacts mortality in a cost-effective way.

Study design: Pragmatic, open, multicenter, parallel group RCT.

Setting: English National Health Service hospitals that did not routinely use EGDT that included continuous ScvO2 monitoring.

Synopsis: The authors enrolled 1,260 adult patients with early severe sepsis or septic shock; they randomized patients to either usual care or EGDT for six hours. Data was collected prospectively on the EGDT group and retrospectively on the usual care group.

By intention-to-treat analysis, all-cause mortality at 90 days was not significantly different (unadjusted RR 1.01, 95% CI, 0.85-1.20; adjusted OR 0.95, 95% CI, 0.74-1.24, P=0.73). EGDT patients received more intensive therapy, their quality of life scores were similar, and their average costs were higher, though not statistically significant. The probability that EGDT was cost effective was calculated to be below 20%.

Usual care patients had lower-than-expected mortality (29% vs. 40%), limiting the treatment effect of EGDT and limiting extrapolation to groups with higher mortality. Comparison to older studies is limited by the evolution in usual care for sepsis, with earlier recognition and antibiotic administration and greater use of vasoactive drugs. This study adds significant information about quality of life and cost to the discussion about EGDT.

Bottom line: The ProMISe study completes a powerful trio of papers suggesting that EGDT might be an expensive option that offers no clinical benefit over usual care.

Citation: Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372:1301-1311.

Background: Recent trials (ARISE, ProCESS) showed EGDT provided no mortality benefit over usual care. Questions remain about the effectiveness of intensive monitoring protocols, as well as the evolution of what constitutes usual care. The ProMISe trial seeks to test the hypothesis that EGDT impacts mortality in a cost-effective way.

Study design: Pragmatic, open, multicenter, parallel group RCT.

Setting: English National Health Service hospitals that did not routinely use EGDT that included continuous ScvO2 monitoring.

Synopsis: The authors enrolled 1,260 adult patients with early severe sepsis or septic shock; they randomized patients to either usual care or EGDT for six hours. Data was collected prospectively on the EGDT group and retrospectively on the usual care group.

By intention-to-treat analysis, all-cause mortality at 90 days was not significantly different (unadjusted RR 1.01, 95% CI, 0.85-1.20; adjusted OR 0.95, 95% CI, 0.74-1.24, P=0.73). EGDT patients received more intensive therapy, their quality of life scores were similar, and their average costs were higher, though not statistically significant. The probability that EGDT was cost effective was calculated to be below 20%.

Usual care patients had lower-than-expected mortality (29% vs. 40%), limiting the treatment effect of EGDT and limiting extrapolation to groups with higher mortality. Comparison to older studies is limited by the evolution in usual care for sepsis, with earlier recognition and antibiotic administration and greater use of vasoactive drugs. This study adds significant information about quality of life and cost to the discussion about EGDT.

Bottom line: The ProMISe study completes a powerful trio of papers suggesting that EGDT might be an expensive option that offers no clinical benefit over usual care.

Citation: Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372:1301-1311.

Clinical question: Is there increased risk of bleeding or cardiovascular events when using NSAIDs while on antithrombotic therapy for secondary cardiovascular prevention?

Background: NSAIDs are among the most commonly used medications, despite the fact that individual NSAIDs have been associated with increased cardiovascular risk, and despite guidelines recommending against the use of NSAIDs in patients with cardiovascular disease. The risk of using NSAIDs with antithrombotic medications after first MI has not yet been examined.

Study design: Retrospective registry study.

Setting: Patients registered in official medical, pharmacy, and civil databases in Denmark, with unique individual identifier numbers allowing for database cross-reference.

Synopsis: The authors enrolled 61,971 patients of a possible 88,662 who were 30 years or older and admitted for a first-time MI starting 30 days following discharge, and tracked them for endpoint events and prescriptions. NSAID prescriptions were identified for 20,931 patients. Patients were placed in cohorts by their specific antithrombotic regimen (monotherapy, or combination therapy with aspirin, clopidogrel, or vitamin K antagonist) and specific NSAID use, accounting for changes in prescription combinations for a given individual.

Antithrombotic use between the NSAID and non-NSAID groups was equal. NSAID use, regardless of duration, was associated with increased risk of admission or death from bleeding (HR 2.02, 95% CI 1.81-2.26). NSAID use was also associated with increased cardiovascular endpoints (HR 1.40, 95% CI 1.30-1.49), including with the most common antithrombotic regimens.

This study is limited by its observational design, lack of more detailed database information, and use of prescription data. Differences in mortality were not separately presented. This study implies that even short exposures to NSAIDs while on antithrombotic therapy may be problematic.

Bottom line: NSAID use is associated with significant bleeding and cardiovascular events in patients who are on antithrombotic medications following their first MI.

Citation: Schjerning Olsen AM, Gislason GH, McGettigan P, et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA. 2015;313(8):805-814.

Clinical question: Is there increased risk of bleeding or cardiovascular events when using NSAIDs while on antithrombotic therapy for secondary cardiovascular prevention?

Background: NSAIDs are among the most commonly used medications, despite the fact that individual NSAIDs have been associated with increased cardiovascular risk, and despite guidelines recommending against the use of NSAIDs in patients with cardiovascular disease. The risk of using NSAIDs with antithrombotic medications after first MI has not yet been examined.

Study design: Retrospective registry study.

Setting: Patients registered in official medical, pharmacy, and civil databases in Denmark, with unique individual identifier numbers allowing for database cross-reference.

Synopsis: The authors enrolled 61,971 patients of a possible 88,662 who were 30 years or older and admitted for a first-time MI starting 30 days following discharge, and tracked them for endpoint events and prescriptions. NSAID prescriptions were identified for 20,931 patients. Patients were placed in cohorts by their specific antithrombotic regimen (monotherapy, or combination therapy with aspirin, clopidogrel, or vitamin K antagonist) and specific NSAID use, accounting for changes in prescription combinations for a given individual.

Antithrombotic use between the NSAID and non-NSAID groups was equal. NSAID use, regardless of duration, was associated with increased risk of admission or death from bleeding (HR 2.02, 95% CI 1.81-2.26). NSAID use was also associated with increased cardiovascular endpoints (HR 1.40, 95% CI 1.30-1.49), including with the most common antithrombotic regimens.

This study is limited by its observational design, lack of more detailed database information, and use of prescription data. Differences in mortality were not separately presented. This study implies that even short exposures to NSAIDs while on antithrombotic therapy may be problematic.

Bottom line: NSAID use is associated with significant bleeding and cardiovascular events in patients who are on antithrombotic medications following their first MI.

Citation: Schjerning Olsen AM, Gislason GH, McGettigan P, et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA. 2015;313(8):805-814.

Clinical question: Is there increased risk of bleeding or cardiovascular events when using NSAIDs while on antithrombotic therapy for secondary cardiovascular prevention?

Background: NSAIDs are among the most commonly used medications, despite the fact that individual NSAIDs have been associated with increased cardiovascular risk, and despite guidelines recommending against the use of NSAIDs in patients with cardiovascular disease. The risk of using NSAIDs with antithrombotic medications after first MI has not yet been examined.

Study design: Retrospective registry study.

Setting: Patients registered in official medical, pharmacy, and civil databases in Denmark, with unique individual identifier numbers allowing for database cross-reference.

Synopsis: The authors enrolled 61,971 patients of a possible 88,662 who were 30 years or older and admitted for a first-time MI starting 30 days following discharge, and tracked them for endpoint events and prescriptions. NSAID prescriptions were identified for 20,931 patients. Patients were placed in cohorts by their specific antithrombotic regimen (monotherapy, or combination therapy with aspirin, clopidogrel, or vitamin K antagonist) and specific NSAID use, accounting for changes in prescription combinations for a given individual.

Antithrombotic use between the NSAID and non-NSAID groups was equal. NSAID use, regardless of duration, was associated with increased risk of admission or death from bleeding (HR 2.02, 95% CI 1.81-2.26). NSAID use was also associated with increased cardiovascular endpoints (HR 1.40, 95% CI 1.30-1.49), including with the most common antithrombotic regimens.

This study is limited by its observational design, lack of more detailed database information, and use of prescription data. Differences in mortality were not separately presented. This study implies that even short exposures to NSAIDs while on antithrombotic therapy may be problematic.

Bottom line: NSAID use is associated with significant bleeding and cardiovascular events in patients who are on antithrombotic medications following their first MI.

Citation: Schjerning Olsen AM, Gislason GH, McGettigan P, et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA. 2015;313(8):805-814.

Clinical question: Is anticoagulation beneficial for patients with atrial fibrillation (Afib) and low CHA2DS2-VASc score (0 for men, 1 for women) or for those with one additional stroke risk factor?

Background: Guidelines nearly universally recommend anticoagulation for patients with a CHA2DS2-VASc of >2, but differ on recommendation for patients with a CHA2DS2-VASc of 1.

Study design: Cohort study.

Setting: Multiple national registries in Denmark.

Synopsis: Based on analysis, patients with very low stroke risk using the CHA2DS2-VASc score (0 for men, 1 for women) had particularly low stroke risk and did not appear to benefit from additional therapy with aspirin or warfarin, both at one year and at full follow-up (mean 5.9 years).

The addition of one stroke risk factor increased stroke risk without treatment significantly (three-fold increase). Hazard ratios favored treatment with warfarin in these patients, most notably with a reduction in all-cause mortality (though this was more significant at one year than at full follow-up).

Bottom line: Although guidelines differ on treatment strategy for patients with Afib and one stroke risk factor (i.e., CHA2DS2-VASc score of 1 for men, 2 for women), this study supports treatment with warfarin.

Citation: Lip GY, Skjöth F, Rasmussen LH, Larsen TB. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc score. J Am Coll Cardiol. 2015;65(14):1385-1394.

Clinical question: Is anticoagulation beneficial for patients with atrial fibrillation (Afib) and low CHA2DS2-VASc score (0 for men, 1 for women) or for those with one additional stroke risk factor?

Background: Guidelines nearly universally recommend anticoagulation for patients with a CHA2DS2-VASc of >2, but differ on recommendation for patients with a CHA2DS2-VASc of 1.

Study design: Cohort study.

Setting: Multiple national registries in Denmark.

Synopsis: Based on analysis, patients with very low stroke risk using the CHA2DS2-VASc score (0 for men, 1 for women) had particularly low stroke risk and did not appear to benefit from additional therapy with aspirin or warfarin, both at one year and at full follow-up (mean 5.9 years).

The addition of one stroke risk factor increased stroke risk without treatment significantly (three-fold increase). Hazard ratios favored treatment with warfarin in these patients, most notably with a reduction in all-cause mortality (though this was more significant at one year than at full follow-up).

Bottom line: Although guidelines differ on treatment strategy for patients with Afib and one stroke risk factor (i.e., CHA2DS2-VASc score of 1 for men, 2 for women), this study supports treatment with warfarin.

Citation: Lip GY, Skjöth F, Rasmussen LH, Larsen TB. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc score. J Am Coll Cardiol. 2015;65(14):1385-1394.

Clinical question: Is anticoagulation beneficial for patients with atrial fibrillation (Afib) and low CHA2DS2-VASc score (0 for men, 1 for women) or for those with one additional stroke risk factor?

Background: Guidelines nearly universally recommend anticoagulation for patients with a CHA2DS2-VASc of >2, but differ on recommendation for patients with a CHA2DS2-VASc of 1.

Study design: Cohort study.

Setting: Multiple national registries in Denmark.

Synopsis: Based on analysis, patients with very low stroke risk using the CHA2DS2-VASc score (0 for men, 1 for women) had particularly low stroke risk and did not appear to benefit from additional therapy with aspirin or warfarin, both at one year and at full follow-up (mean 5.9 years).

The addition of one stroke risk factor increased stroke risk without treatment significantly (three-fold increase). Hazard ratios favored treatment with warfarin in these patients, most notably with a reduction in all-cause mortality (though this was more significant at one year than at full follow-up).

Bottom line: Although guidelines differ on treatment strategy for patients with Afib and one stroke risk factor (i.e., CHA2DS2-VASc score of 1 for men, 2 for women), this study supports treatment with warfarin.

Citation: Lip GY, Skjöth F, Rasmussen LH, Larsen TB. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc score. J Am Coll Cardiol. 2015;65(14):1385-1394.

Clinical question: Is ticagrelor for secondary prevention indicated for more than one year after myocardial infarction (MI)?

Background: The efficacy and safety of ticagrelor combined with low-dose aspirin more than one year after MI for secondary prevention has not previously been established.

Study design: Randomized, double-blinded, placebo-controlled, clinical trial.

Setting: Multi-center across 31 countries.

Synopsis: Investigators randomized 21,162 patients one to three years after first MI to a 90 mg, twice daily dose; a 60 mg, twice daily dose; or placebo. Patients also received low-dose aspirin (75 mg to 100 mg). Interestingly, a number of patients had been off dual antiplatelet therapy prior to the start of the trial, because most patients were enrolled closer to two years after primary MI. The manufacturer of ticagrelor sponsored the trial.

The study authors’ analysis showed that treating 10,000 patients with the 90 mg dose would prevent 40 cardiac events (cardiovascular death, MI, or stroke), while the 60 mg dose would prevent 42 events; however, the 90 mg dose would cause 41 major bleeding events and the 60 mg dose 31 major bleeding events. Fatal bleeding was less than 1% in all groups, though patients with increased bleeding risk were excluded.

In addition, patients on either dose of ticagrelor had a significantly higher rate of dyspnea, which resulted in increases in drug discontinuation.

Bottom line: Use of ticagrelor with aspirin for secondary prevention greater than one year after myocardial infarction reduced rates of cardiovascular death, MI, and stroke but increased the risk of major bleeding.

Citation: Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372:1791-1800.

Clinical question: Is ticagrelor for secondary prevention indicated for more than one year after myocardial infarction (MI)?

Background: The efficacy and safety of ticagrelor combined with low-dose aspirin more than one year after MI for secondary prevention has not previously been established.

Study design: Randomized, double-blinded, placebo-controlled, clinical trial.

Setting: Multi-center across 31 countries.

Synopsis: Investigators randomized 21,162 patients one to three years after first MI to a 90 mg, twice daily dose; a 60 mg, twice daily dose; or placebo. Patients also received low-dose aspirin (75 mg to 100 mg). Interestingly, a number of patients had been off dual antiplatelet therapy prior to the start of the trial, because most patients were enrolled closer to two years after primary MI. The manufacturer of ticagrelor sponsored the trial.

The study authors’ analysis showed that treating 10,000 patients with the 90 mg dose would prevent 40 cardiac events (cardiovascular death, MI, or stroke), while the 60 mg dose would prevent 42 events; however, the 90 mg dose would cause 41 major bleeding events and the 60 mg dose 31 major bleeding events. Fatal bleeding was less than 1% in all groups, though patients with increased bleeding risk were excluded.

In addition, patients on either dose of ticagrelor had a significantly higher rate of dyspnea, which resulted in increases in drug discontinuation.

Bottom line: Use of ticagrelor with aspirin for secondary prevention greater than one year after myocardial infarction reduced rates of cardiovascular death, MI, and stroke but increased the risk of major bleeding.

Citation: Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372:1791-1800.

Clinical question: Is ticagrelor for secondary prevention indicated for more than one year after myocardial infarction (MI)?

Background: The efficacy and safety of ticagrelor combined with low-dose aspirin more than one year after MI for secondary prevention has not previously been established.

Study design: Randomized, double-blinded, placebo-controlled, clinical trial.

Setting: Multi-center across 31 countries.

Synopsis: Investigators randomized 21,162 patients one to three years after first MI to a 90 mg, twice daily dose; a 60 mg, twice daily dose; or placebo. Patients also received low-dose aspirin (75 mg to 100 mg). Interestingly, a number of patients had been off dual antiplatelet therapy prior to the start of the trial, because most patients were enrolled closer to two years after primary MI. The manufacturer of ticagrelor sponsored the trial.

The study authors’ analysis showed that treating 10,000 patients with the 90 mg dose would prevent 40 cardiac events (cardiovascular death, MI, or stroke), while the 60 mg dose would prevent 42 events; however, the 90 mg dose would cause 41 major bleeding events and the 60 mg dose 31 major bleeding events. Fatal bleeding was less than 1% in all groups, though patients with increased bleeding risk were excluded.

In addition, patients on either dose of ticagrelor had a significantly higher rate of dyspnea, which resulted in increases in drug discontinuation.

Bottom line: Use of ticagrelor with aspirin for secondary prevention greater than one year after myocardial infarction reduced rates of cardiovascular death, MI, and stroke but increased the risk of major bleeding.

Citation: Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372:1791-1800.

Clinical question: In patients with a first unprovoked VTE, is it safe to use a normalized D-dimer test to stop anticoagulation therapy?

Background: The risk of VTE recurrence after stopping anticoagulation is higher in patients who have elevated D-dimer levels after treatment. It is unknown whether we can use normalized D-dimer levels to guide the decision about whether or not to stop anticoagulation.

Study design: Prospective cohort study.

Setting: Thirteen university-affiliated centers.

Synopsis: Study authors screened 410 adult patients who had a first unprovoked VTE and completed three to seven months of anticoagulation therapy with D-dimer tests. In patients with negative D-dimer tests, anticoagulation was stopped, and D-dimer tests were repeated after a month. In those with two consecutive negative D-dimer tests, anticoagulation was stopped indefinitely; these patients were followed for an average of 2.2 years. Among those 319 patients, there was an overall recurrent VTE rate of 6.7% per patient year. Subgroup analysis was performed among men, women not on estrogen therapy, and women on estrogen therapy; recurrence rates per patient year were 9.7%, 5.4%, and 0%, respectively.

This study used a point-of-care D-dimer test that was either positive or negative; it is unclear if the results can be generalized to all D-dimer tests. Additionally, although the study found a lower recurrence VTE rate among women, the study was not powered for the subgroups.

Bottom line: The high rate of recurrent VTE among men makes the D-dimer test an unsafe marker to use in deciding whether or not to stop anticoagulation for an unprovoked VTE. Among women, D-dimer test can potentially be used to guide length of treatment, but, given the limitations of the study, more evidence is needed.

Citation: Kearon C, Spencer FA, O’Keeffe D, et al. D-Dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy. Ann Intern Med. 2015;162(1):27-34.

Clinical question: In patients with a first unprovoked VTE, is it safe to use a normalized D-dimer test to stop anticoagulation therapy?

Background: The risk of VTE recurrence after stopping anticoagulation is higher in patients who have elevated D-dimer levels after treatment. It is unknown whether we can use normalized D-dimer levels to guide the decision about whether or not to stop anticoagulation.

Study design: Prospective cohort study.

Setting: Thirteen university-affiliated centers.

Synopsis: Study authors screened 410 adult patients who had a first unprovoked VTE and completed three to seven months of anticoagulation therapy with D-dimer tests. In patients with negative D-dimer tests, anticoagulation was stopped, and D-dimer tests were repeated after a month. In those with two consecutive negative D-dimer tests, anticoagulation was stopped indefinitely; these patients were followed for an average of 2.2 years. Among those 319 patients, there was an overall recurrent VTE rate of 6.7% per patient year. Subgroup analysis was performed among men, women not on estrogen therapy, and women on estrogen therapy; recurrence rates per patient year were 9.7%, 5.4%, and 0%, respectively.

This study used a point-of-care D-dimer test that was either positive or negative; it is unclear if the results can be generalized to all D-dimer tests. Additionally, although the study found a lower recurrence VTE rate among women, the study was not powered for the subgroups.

Bottom line: The high rate of recurrent VTE among men makes the D-dimer test an unsafe marker to use in deciding whether or not to stop anticoagulation for an unprovoked VTE. Among women, D-dimer test can potentially be used to guide length of treatment, but, given the limitations of the study, more evidence is needed.

Citation: Kearon C, Spencer FA, O’Keeffe D, et al. D-Dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy. Ann Intern Med. 2015;162(1):27-34.

Clinical question: In patients with a first unprovoked VTE, is it safe to use a normalized D-dimer test to stop anticoagulation therapy?

Background: The risk of VTE recurrence after stopping anticoagulation is higher in patients who have elevated D-dimer levels after treatment. It is unknown whether we can use normalized D-dimer levels to guide the decision about whether or not to stop anticoagulation.

Study design: Prospective cohort study.

Setting: Thirteen university-affiliated centers.

Synopsis: Study authors screened 410 adult patients who had a first unprovoked VTE and completed three to seven months of anticoagulation therapy with D-dimer tests. In patients with negative D-dimer tests, anticoagulation was stopped, and D-dimer tests were repeated after a month. In those with two consecutive negative D-dimer tests, anticoagulation was stopped indefinitely; these patients were followed for an average of 2.2 years. Among those 319 patients, there was an overall recurrent VTE rate of 6.7% per patient year. Subgroup analysis was performed among men, women not on estrogen therapy, and women on estrogen therapy; recurrence rates per patient year were 9.7%, 5.4%, and 0%, respectively.

This study used a point-of-care D-dimer test that was either positive or negative; it is unclear if the results can be generalized to all D-dimer tests. Additionally, although the study found a lower recurrence VTE rate among women, the study was not powered for the subgroups.

Bottom line: The high rate of recurrent VTE among men makes the D-dimer test an unsafe marker to use in deciding whether or not to stop anticoagulation for an unprovoked VTE. Among women, D-dimer test can potentially be used to guide length of treatment, but, given the limitations of the study, more evidence is needed.

Citation: Kearon C, Spencer FA, O’Keeffe D, et al. D-Dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy. Ann Intern Med. 2015;162(1):27-34.

Clinical question: Do patients hospitalized with acute COPD exacerbations have improved outcomes with noninvasive ventilation (NIV) compared to those treated with invasive mechanical ventilation (IMV)?

Background: Previous studies have shown that in select patients, NIV has a mortality benefit over IMV for acute COPD exacerbations requiring hospitalization. NIV may also decrease complication rates and reduce length of stay; however, the previous prospective studies have been small.

Study design: Retrospective cohort study.

Setting: 420 structurally and geographically diverse U.S. hospitals.

Synopsis: Using the Premier Healthcare Informatics database, this study looked at 25,628 patients over 40 years old who were hospitalized with COPD exacerbations. Compared with patients who were initially treated with IMV, patients treated with NIV demonstrated lower mortality rates with an odds ratio of 0.54, lower risk of hospital-acquired pneumonia with an odds ratio of 0.53, and a 32% cost reduction. They also had shorter lengths of stay.

This was a retrospective study using a limited data set, and the authors did not have access to potentially confounding factors between the two groups, including vital signs and blood gases. Additionally, the advantages of NIV were attenuated among patients with pneumonia present on admission, patients with high burden of comorbid diseases, and patients older than 85 years.

Bottom line: Treatment of acute COPD exacerbations with NIV is associated with lower mortality, lower costs, and shorter length of stay as compared with IMV.

Citation: Lindenauer PK, Stefan MS, Shieh MS, Pekow PS, Rothberg MB, Hill NS. Outcomes associated with invasive and noninvasive ventilation among patients hospitalized with exacerbations of chronic obstructive pulmonary disease. JAMA Intern Med. 2014;174(12):1982-1993.

Clinical question: Do patients hospitalized with acute COPD exacerbations have improved outcomes with noninvasive ventilation (NIV) compared to those treated with invasive mechanical ventilation (IMV)?

Background: Previous studies have shown that in select patients, NIV has a mortality benefit over IMV for acute COPD exacerbations requiring hospitalization. NIV may also decrease complication rates and reduce length of stay; however, the previous prospective studies have been small.

Study design: Retrospective cohort study.

Setting: 420 structurally and geographically diverse U.S. hospitals.

Synopsis: Using the Premier Healthcare Informatics database, this study looked at 25,628 patients over 40 years old who were hospitalized with COPD exacerbations. Compared with patients who were initially treated with IMV, patients treated with NIV demonstrated lower mortality rates with an odds ratio of 0.54, lower risk of hospital-acquired pneumonia with an odds ratio of 0.53, and a 32% cost reduction. They also had shorter lengths of stay.

This was a retrospective study using a limited data set, and the authors did not have access to potentially confounding factors between the two groups, including vital signs and blood gases. Additionally, the advantages of NIV were attenuated among patients with pneumonia present on admission, patients with high burden of comorbid diseases, and patients older than 85 years.

Bottom line: Treatment of acute COPD exacerbations with NIV is associated with lower mortality, lower costs, and shorter length of stay as compared with IMV.

Citation: Lindenauer PK, Stefan MS, Shieh MS, Pekow PS, Rothberg MB, Hill NS. Outcomes associated with invasive and noninvasive ventilation among patients hospitalized with exacerbations of chronic obstructive pulmonary disease. JAMA Intern Med. 2014;174(12):1982-1993.

Clinical question: Do patients hospitalized with acute COPD exacerbations have improved outcomes with noninvasive ventilation (NIV) compared to those treated with invasive mechanical ventilation (IMV)?

Background: Previous studies have shown that in select patients, NIV has a mortality benefit over IMV for acute COPD exacerbations requiring hospitalization. NIV may also decrease complication rates and reduce length of stay; however, the previous prospective studies have been small.

Study design: Retrospective cohort study.

Setting: 420 structurally and geographically diverse U.S. hospitals.

Synopsis: Using the Premier Healthcare Informatics database, this study looked at 25,628 patients over 40 years old who were hospitalized with COPD exacerbations. Compared with patients who were initially treated with IMV, patients treated with NIV demonstrated lower mortality rates with an odds ratio of 0.54, lower risk of hospital-acquired pneumonia with an odds ratio of 0.53, and a 32% cost reduction. They also had shorter lengths of stay.

This was a retrospective study using a limited data set, and the authors did not have access to potentially confounding factors between the two groups, including vital signs and blood gases. Additionally, the advantages of NIV were attenuated among patients with pneumonia present on admission, patients with high burden of comorbid diseases, and patients older than 85 years.

Bottom line: Treatment of acute COPD exacerbations with NIV is associated with lower mortality, lower costs, and shorter length of stay as compared with IMV.

Citation: Lindenauer PK, Stefan MS, Shieh MS, Pekow PS, Rothberg MB, Hill NS. Outcomes associated with invasive and noninvasive ventilation among patients hospitalized with exacerbations of chronic obstructive pulmonary disease. JAMA Intern Med. 2014;174(12):1982-1993.

Clinical question: Can the Bova risk model stratify patients with acute PE into stages of increasing risk for 30-day pulmonary embolism (PE)-related complications?

Background: The Bova score is based on four variables assessed at the time of PE diagnosis: heart rate, systolic blood pressure, cardiac troponin, and a marker of right ventricular (RV) dysfunction. In the original study, the Bova risk model was derived from 2,874 normotensive patients with PE. This study performed a retrospective validation of this model on a different cohort of patients.

Study design: Retrospective cohort study.

Setting: Academic urban ED in Madrid, Spain.

Synopsis: Investigators included 1,083 patients with normotensive PE, and the Bova risk score classified 80% into class I, 15% into class II, and 5% into class III—correlating 30-day PE-related complication rates were 4.4%, 18%, and 42%, respectively. When dichotomized into low risk (class I and II) versus intermediate to high risk (class III), the model had a specificity of 97%, a positive predictive value of 42%, and a positive likelihood ratio of 7.9 for predicting 30-day PE-related complications.

The existing risk assessment models, the pulmonary embolism severity index (PESI) and the simplified PESI (sPESI), have been extensively validated but were specifically developed to identity patients with low risk for mortality. The Bova risk model could be used in a stepwise fashion, with the PESI or sPESI model, to further assess intermediate-risk patients.

This model was derived and validated at one single center, so the results may not be generalizable. Additionally, the variables were collected prospectively, but this validation analysis was performed retrospectively.

Bottom line: The Bova risk model accurately stratifies patients with normotensive PE into stages of increasing risk for developing 30-day PE-related complications.

Citation: Fernández C, Bova C, Sanchez O, et al. Validation of a model for identification of patients at intermediate to high risk for complications associated with acute symptomatic pulmonary embolism [published online ahead of print January 29, 2015]. Chest.

Clinical question: Can the Bova risk model stratify patients with acute PE into stages of increasing risk for 30-day pulmonary embolism (PE)-related complications?

Background: The Bova score is based on four variables assessed at the time of PE diagnosis: heart rate, systolic blood pressure, cardiac troponin, and a marker of right ventricular (RV) dysfunction. In the original study, the Bova risk model was derived from 2,874 normotensive patients with PE. This study performed a retrospective validation of this model on a different cohort of patients.

Study design: Retrospective cohort study.

Setting: Academic urban ED in Madrid, Spain.

Synopsis: Investigators included 1,083 patients with normotensive PE, and the Bova risk score classified 80% into class I, 15% into class II, and 5% into class III—correlating 30-day PE-related complication rates were 4.4%, 18%, and 42%, respectively. When dichotomized into low risk (class I and II) versus intermediate to high risk (class III), the model had a specificity of 97%, a positive predictive value of 42%, and a positive likelihood ratio of 7.9 for predicting 30-day PE-related complications.

The existing risk assessment models, the pulmonary embolism severity index (PESI) and the simplified PESI (sPESI), have been extensively validated but were specifically developed to identity patients with low risk for mortality. The Bova risk model could be used in a stepwise fashion, with the PESI or sPESI model, to further assess intermediate-risk patients.

This model was derived and validated at one single center, so the results may not be generalizable. Additionally, the variables were collected prospectively, but this validation analysis was performed retrospectively.

Bottom line: The Bova risk model accurately stratifies patients with normotensive PE into stages of increasing risk for developing 30-day PE-related complications.

Citation: Fernández C, Bova C, Sanchez O, et al. Validation of a model for identification of patients at intermediate to high risk for complications associated with acute symptomatic pulmonary embolism [published online ahead of print January 29, 2015]. Chest.

Clinical question: Can the Bova risk model stratify patients with acute PE into stages of increasing risk for 30-day pulmonary embolism (PE)-related complications?

Background: The Bova score is based on four variables assessed at the time of PE diagnosis: heart rate, systolic blood pressure, cardiac troponin, and a marker of right ventricular (RV) dysfunction. In the original study, the Bova risk model was derived from 2,874 normotensive patients with PE. This study performed a retrospective validation of this model on a different cohort of patients.

Study design: Retrospective cohort study.

Setting: Academic urban ED in Madrid, Spain.

Synopsis: Investigators included 1,083 patients with normotensive PE, and the Bova risk score classified 80% into class I, 15% into class II, and 5% into class III—correlating 30-day PE-related complication rates were 4.4%, 18%, and 42%, respectively. When dichotomized into low risk (class I and II) versus intermediate to high risk (class III), the model had a specificity of 97%, a positive predictive value of 42%, and a positive likelihood ratio of 7.9 for predicting 30-day PE-related complications.

The existing risk assessment models, the pulmonary embolism severity index (PESI) and the simplified PESI (sPESI), have been extensively validated but were specifically developed to identity patients with low risk for mortality. The Bova risk model could be used in a stepwise fashion, with the PESI or sPESI model, to further assess intermediate-risk patients.

This model was derived and validated at one single center, so the results may not be generalizable. Additionally, the variables were collected prospectively, but this validation analysis was performed retrospectively.

Bottom line: The Bova risk model accurately stratifies patients with normotensive PE into stages of increasing risk for developing 30-day PE-related complications.

Citation: Fernández C, Bova C, Sanchez O, et al. Validation of a model for identification of patients at intermediate to high risk for complications associated with acute symptomatic pulmonary embolism [published online ahead of print January 29, 2015]. Chest.

Clinical question: Do minor and minimal head injuries in patients on warfarin lead to significant intracranial bleed?

Background: Warfarin use is common, and many of these patients sustain minor and minimal head injuries. When presenting to the ED, these patients pose a clinical dilemma regarding whether to obtain neuroimaging and/or admit.

Study design: Retrospective cohort study.

Setting: Two urban tertiary care EDs in Ottawa, Canada, over a two-year period.

Synopsis: Using the Canadian National Ambulatory Care Reporting System database and the associated coding data, 259 patients were identified that fit the inclusion criteria GCS ≥13 and INR >1.5. This study showed that the rate of intracranial bleeds in this group of patients was high (15.9%); for minor and minimal head injury groups, the rate was 21.9% and 4.8%, respectively. Additionally, loss of consciousness was associated with higher rates of intracranial bleeding.

The risk of intracranial bleed after a head injury while on warfarin is considerably high, particularly for those patients with minor head injury (21.9%), which is about three times the rate previously reported. Hospitalists evaluating these patients should consider obtaining neuroimaging.

Nonetheless, these rates may be overestimating the true prevalence due to the following: 1) Coding data may overlook minor and minimal head injuries in the presence of more serious injuries, and 2) patients with minimal head injuries may not seek medical care.

Bottom line: Patients sustaining minor head injury while on warfarin have a high rate of intracranial bleed.

Reference: Alrajhi KN, Perry JJ, Forster AJ. Intracranial bleeds after minor and minimal head injury in patients on warfarin. J Emer Med. 2015;48(2):137-142.

Clinical question: Do minor and minimal head injuries in patients on warfarin lead to significant intracranial bleed?

Background: Warfarin use is common, and many of these patients sustain minor and minimal head injuries. When presenting to the ED, these patients pose a clinical dilemma regarding whether to obtain neuroimaging and/or admit.

Study design: Retrospective cohort study.

Setting: Two urban tertiary care EDs in Ottawa, Canada, over a two-year period.

Synopsis: Using the Canadian National Ambulatory Care Reporting System database and the associated coding data, 259 patients were identified that fit the inclusion criteria GCS ≥13 and INR >1.5. This study showed that the rate of intracranial bleeds in this group of patients was high (15.9%); for minor and minimal head injury groups, the rate was 21.9% and 4.8%, respectively. Additionally, loss of consciousness was associated with higher rates of intracranial bleeding.

The risk of intracranial bleed after a head injury while on warfarin is considerably high, particularly for those patients with minor head injury (21.9%), which is about three times the rate previously reported. Hospitalists evaluating these patients should consider obtaining neuroimaging.

Nonetheless, these rates may be overestimating the true prevalence due to the following: 1) Coding data may overlook minor and minimal head injuries in the presence of more serious injuries, and 2) patients with minimal head injuries may not seek medical care.

Bottom line: Patients sustaining minor head injury while on warfarin have a high rate of intracranial bleed.

Reference: Alrajhi KN, Perry JJ, Forster AJ. Intracranial bleeds after minor and minimal head injury in patients on warfarin. J Emer Med. 2015;48(2):137-142.

Clinical question: Do minor and minimal head injuries in patients on warfarin lead to significant intracranial bleed?

Background: Warfarin use is common, and many of these patients sustain minor and minimal head injuries. When presenting to the ED, these patients pose a clinical dilemma regarding whether to obtain neuroimaging and/or admit.

Study design: Retrospective cohort study.

Setting: Two urban tertiary care EDs in Ottawa, Canada, over a two-year period.

Synopsis: Using the Canadian National Ambulatory Care Reporting System database and the associated coding data, 259 patients were identified that fit the inclusion criteria GCS ≥13 and INR >1.5. This study showed that the rate of intracranial bleeds in this group of patients was high (15.9%); for minor and minimal head injury groups, the rate was 21.9% and 4.8%, respectively. Additionally, loss of consciousness was associated with higher rates of intracranial bleeding.

The risk of intracranial bleed after a head injury while on warfarin is considerably high, particularly for those patients with minor head injury (21.9%), which is about three times the rate previously reported. Hospitalists evaluating these patients should consider obtaining neuroimaging.

Nonetheless, these rates may be overestimating the true prevalence due to the following: 1) Coding data may overlook minor and minimal head injuries in the presence of more serious injuries, and 2) patients with minimal head injuries may not seek medical care.

Bottom line: Patients sustaining minor head injury while on warfarin have a high rate of intracranial bleed.

Reference: Alrajhi KN, Perry JJ, Forster AJ. Intracranial bleeds after minor and minimal head injury in patients on warfarin. J Emer Med. 2015;48(2):137-142.

Clinical question: Does a high-calorie, high-protein formula enriched with supplements of arginine, zinc, and antioxidants improve pressure ulcer healing?

Background: Malnutrition is thought to be a major factor in the development and poor healing of pressure ulcers. Trials evaluating whether or not the addition of antioxidants, arginine, and zinc to nutritional formulas improves pressure ulcer healing have been small and inconsistent.

Study design: Multicenter, randomized, controlled, blinded trial.

Setting: Long-term care facilities and patients receiving home care services.

Synopsis: Two hundred patients with stage II, III, or IV pressure ulcers receiving standardized wound care were randomly assigned to a control formula or an experimental formula enriched with arginine, zinc, and antioxidants. At eight weeks, the experimental formula group had an 18.7% (CI, 5.7% to 31.8%, P=0.017) mean reduction in pressure ulcer size compared with the control formula group, although both groups showed efficacy in wound healing.

Nutrition is an important part of wound healing and should be incorporated into the plan of care for the hospitalized patient with pressure ulcers. Hospitalists should be mindful that this study was conducted in non-acute settings, with a chronically ill patient population; more research needs to be done to investigate the effect of these specific immune-modulating nutritional supplements in acutely ill hospitalized patients, given the inconclusive safety profile of certain nutrients such as arginine in severe sepsis.

Bottom line: Enhanced nutritional support with an oral nutritional formula enriched with arginine, zinc, and antioxidants improves pressure ulcer healing in malnourished patients already receiving standard wound care.

Citation: Cereda E, Klersy C, Serioli M, Crespi A, D’Andrea F, OligoElement Sore Trial Study Group. A nutritional formula enriched with arginine, zinc, and antioxidants for the healing of pressure ulcers: a randomized trial. Ann Intern Med. 2015;162(3):167-174.

Clinical question: Does a high-calorie, high-protein formula enriched with supplements of arginine, zinc, and antioxidants improve pressure ulcer healing?

Background: Malnutrition is thought to be a major factor in the development and poor healing of pressure ulcers. Trials evaluating whether or not the addition of antioxidants, arginine, and zinc to nutritional formulas improves pressure ulcer healing have been small and inconsistent.

Study design: Multicenter, randomized, controlled, blinded trial.

Setting: Long-term care facilities and patients receiving home care services.

Synopsis: Two hundred patients with stage II, III, or IV pressure ulcers receiving standardized wound care were randomly assigned to a control formula or an experimental formula enriched with arginine, zinc, and antioxidants. At eight weeks, the experimental formula group had an 18.7% (CI, 5.7% to 31.8%, P=0.017) mean reduction in pressure ulcer size compared with the control formula group, although both groups showed efficacy in wound healing.

Nutrition is an important part of wound healing and should be incorporated into the plan of care for the hospitalized patient with pressure ulcers. Hospitalists should be mindful that this study was conducted in non-acute settings, with a chronically ill patient population; more research needs to be done to investigate the effect of these specific immune-modulating nutritional supplements in acutely ill hospitalized patients, given the inconclusive safety profile of certain nutrients such as arginine in severe sepsis.

Bottom line: Enhanced nutritional support with an oral nutritional formula enriched with arginine, zinc, and antioxidants improves pressure ulcer healing in malnourished patients already receiving standard wound care.

Citation: Cereda E, Klersy C, Serioli M, Crespi A, D’Andrea F, OligoElement Sore Trial Study Group. A nutritional formula enriched with arginine, zinc, and antioxidants for the healing of pressure ulcers: a randomized trial. Ann Intern Med. 2015;162(3):167-174.

Clinical question: Does a high-calorie, high-protein formula enriched with supplements of arginine, zinc, and antioxidants improve pressure ulcer healing?

Background: Malnutrition is thought to be a major factor in the development and poor healing of pressure ulcers. Trials evaluating whether or not the addition of antioxidants, arginine, and zinc to nutritional formulas improves pressure ulcer healing have been small and inconsistent.

Study design: Multicenter, randomized, controlled, blinded trial.

Setting: Long-term care facilities and patients receiving home care services.

Synopsis: Two hundred patients with stage II, III, or IV pressure ulcers receiving standardized wound care were randomly assigned to a control formula or an experimental formula enriched with arginine, zinc, and antioxidants. At eight weeks, the experimental formula group had an 18.7% (CI, 5.7% to 31.8%, P=0.017) mean reduction in pressure ulcer size compared with the control formula group, although both groups showed efficacy in wound healing.

Nutrition is an important part of wound healing and should be incorporated into the plan of care for the hospitalized patient with pressure ulcers. Hospitalists should be mindful that this study was conducted in non-acute settings, with a chronically ill patient population; more research needs to be done to investigate the effect of these specific immune-modulating nutritional supplements in acutely ill hospitalized patients, given the inconclusive safety profile of certain nutrients such as arginine in severe sepsis.

Bottom line: Enhanced nutritional support with an oral nutritional formula enriched with arginine, zinc, and antioxidants improves pressure ulcer healing in malnourished patients already receiving standard wound care.

Citation: Cereda E, Klersy C, Serioli M, Crespi A, D’Andrea F, OligoElement Sore Trial Study Group. A nutritional formula enriched with arginine, zinc, and antioxidants for the healing of pressure ulcers: a randomized trial. Ann Intern Med. 2015;162(3):167-174.

Clinical question: Is there an association between hospital volume and hospital readmission rates?

Background: There is an established association between high patient volume and reduced complications or mortality after surgical procedures; however, readmission represents a different type of quality metric than mortality or complications. Studies on the association between hospital patient volume and readmission rates have been controversial.

Study design: Retrospective, cross-sectional study.

Setting: Acute care hospitals.

Synopsis: The study included 6,916,644 admissions to 4,651 hospitals, where patients were assigned to one of five cohorts: medicine, surgery/gynecology, cardiorespiratory, cardiovascular, and neurology. The hospital with the highest volume group had a hospital-wide mean standardized readmission rate of 15.9%, while the hospital with the lowest volume group had a readmission rate of 14.7%. This was a 1.2 percentage point absolute difference between the two hospitals (95% confidence interval 0.9 to 1.5). This trend continued when specialty cohorts were examined, with the exception of the procedure-heavy cardiovascular cohort.

Results showed a trend toward decreased readmission rates in lower-volume hospitals; however, it is unclear why this trend exists. Possible reasons include different patient populations and different practitioner-to-patient ratios in low-volume hospitals.

Limitations of this study are the inclusion of only patients 65 years and older and the fact that all admissions per patient were included, which may bias the results against hospitals with many frequently admitted patients.

Bottom line: Hospitals with high patient volumes are associated with higher readmission rates, except in procedure-heavy patient groups.

Citation: Horwitz LI, Lin Z, Herrin J, et al.Association of hospital volume with readmission rates: a retrospective cross-sectional study. BMJ. 2015;350:h447.

Clinical question: Is there an association between hospital volume and hospital readmission rates?

Background: There is an established association between high patient volume and reduced complications or mortality after surgical procedures; however, readmission represents a different type of quality metric than mortality or complications. Studies on the association between hospital patient volume and readmission rates have been controversial.

Study design: Retrospective, cross-sectional study.

Setting: Acute care hospitals.

Synopsis: The study included 6,916,644 admissions to 4,651 hospitals, where patients were assigned to one of five cohorts: medicine, surgery/gynecology, cardiorespiratory, cardiovascular, and neurology. The hospital with the highest volume group had a hospital-wide mean standardized readmission rate of 15.9%, while the hospital with the lowest volume group had a readmission rate of 14.7%. This was a 1.2 percentage point absolute difference between the two hospitals (95% confidence interval 0.9 to 1.5). This trend continued when specialty cohorts were examined, with the exception of the procedure-heavy cardiovascular cohort.

Results showed a trend toward decreased readmission rates in lower-volume hospitals; however, it is unclear why this trend exists. Possible reasons include different patient populations and different practitioner-to-patient ratios in low-volume hospitals.

Limitations of this study are the inclusion of only patients 65 years and older and the fact that all admissions per patient were included, which may bias the results against hospitals with many frequently admitted patients.

Bottom line: Hospitals with high patient volumes are associated with higher readmission rates, except in procedure-heavy patient groups.

Citation: Horwitz LI, Lin Z, Herrin J, et al.Association of hospital volume with readmission rates: a retrospective cross-sectional study. BMJ. 2015;350:h447.

Clinical question: Is there an association between hospital volume and hospital readmission rates?

Background: There is an established association between high patient volume and reduced complications or mortality after surgical procedures; however, readmission represents a different type of quality metric than mortality or complications. Studies on the association between hospital patient volume and readmission rates have been controversial.

Study design: Retrospective, cross-sectional study.

Setting: Acute care hospitals.

Synopsis: The study included 6,916,644 admissions to 4,651 hospitals, where patients were assigned to one of five cohorts: medicine, surgery/gynecology, cardiorespiratory, cardiovascular, and neurology. The hospital with the highest volume group had a hospital-wide mean standardized readmission rate of 15.9%, while the hospital with the lowest volume group had a readmission rate of 14.7%. This was a 1.2 percentage point absolute difference between the two hospitals (95% confidence interval 0.9 to 1.5). This trend continued when specialty cohorts were examined, with the exception of the procedure-heavy cardiovascular cohort.

Results showed a trend toward decreased readmission rates in lower-volume hospitals; however, it is unclear why this trend exists. Possible reasons include different patient populations and different practitioner-to-patient ratios in low-volume hospitals.

Limitations of this study are the inclusion of only patients 65 years and older and the fact that all admissions per patient were included, which may bias the results against hospitals with many frequently admitted patients.

Bottom line: Hospitals with high patient volumes are associated with higher readmission rates, except in procedure-heavy patient groups.

Citation: Horwitz LI, Lin Z, Herrin J, et al.Association of hospital volume with readmission rates: a retrospective cross-sectional study. BMJ. 2015;350:h447.