Anticoagulation Hub

NASHVILLE, TENN. – About 25% of patients with ischemic stroke who receive thrombolytic therapy get it in the field before hospital transfer with the “drip-and-ship” paradigm.

While there were only modest differences in clinical outcomes between these patients and those treated when admitted to an emergency department, drip-and-ship may actually increase the overall use of tissue plasminogen activator (TPA), Dr. Kevin N. Sheth said at the International Stroke Conference, sponsored by the American Heart Association.

The retrospective analysis, which was simultaneously published in Stroke (2015 Feb. 11 [doi:10.1161/STROKEAHA.114.007506]), plumbed the Get With the Guidelines registry for data to describe trends in the use of TPA and drip-and-ship administration across the United States over time. The study involved 1,440 hospitals and 44,667 patients who had an ischemic stroke during 2003-2010 and received TPA. Of these, 10,475 (23.5%) received it in the field before optional admission and within 3 hours of symptom onset.

Baseline characteristics were similar between the treatment groups. The patients’ mean age was 70 years, and the sex distribution was evenly split. More than 75% of each group was white.

The National Institutes of Health Stroke Scale (NIHSS) score was significantly higher among those who presented for hospital treatment (12.9 vs. 11). However, these patients were seen before TPA administration, while the drip-and-ship group had already been treated, a temporal difference that could have accounted for the score finding, cautioned Dr. Sheth, director of the neuroscience ICU and chief of clinical research at Yale University, New Haven, Conn.

In hospitals that employed drip-and-ship, there were significantly higher rates of stroke patients treated each year as well as more beds. Those hospitals also were more often teaching facilities and were designated as a primary stroke center.

Drip-and-ship frequency remained fairly steady over the study period – about 25% of all eligible patients had it in both 2003 and 2010. Among those treated at the hospital, the frequency of TPA administration within 3 hours of stroke onset rose sharply over the study period, from about 11% in 2003 to 25% in 2010. In contrast, the percentage of timely thrombolysis in drip-and-ship patients moved very little, from about 5% to 9% over the same period.

Overall inpatient mortality was 10%, but was slightly higher among drip-and-ship patients (10.93% vs. 9.67). Symptomatic intracranial hemorrhage occurred in 5.79% of those treated via drip-and-ship and 5.22% of those treated in the hospital. Nearly the same percentage of patients were discharged walking independently (38.4% vs. 38.8%) and discharged home (40.3% vs. 40.6%).

Among the hospital-treated patients, fewer than 4% (1,200) underwent endovascular therapy; this occurred in 707 (7%) of drip-and-ship patients. Those who got endovascular treatment had higher median NIHSS scores at TPA administration than did those who did not (17 vs. 12, respectively). Endovascular treatment was significantly associated with higher mortality (20% vs. 10%) and intracranial hemorrhage (11% vs. 5%).

In a multivariate analysis that adjusted for NIHSS score, in-hospital mortality was significantly more likely in drip-and-ship patients (odds ratio, 1.23). Those patients also were significantly less likely to be independently walking at discharge (OR, 0.66) or discharge to home (OR, 0.66). Intracranial hemorrhage was significantly more likely in drip-and-ship patients (OR, 1.4), as was a hospital stay of longer than 4 days (OR, 1.20).

“These are very modest differences clinically,” Dr. Sheth said, adding that selection bias or unmeasured confounding could have influenced the findings.

Dr. Sheth is a member of the Get with the Guidelines (GWTG) Stroke Clinical Workgroup, and he is a coinvestigator and executive committee member for Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals (GAMES-RP), a phase II trial to prevent swelling in patients with large stroke, funded by Remedy Pharmaceuticals.

[email protected]

On Twitter @alz_gal

NASHVILLE, TENN. – About 25% of patients with ischemic stroke who receive thrombolytic therapy get it in the field before hospital transfer with the “drip-and-ship” paradigm.

While there were only modest differences in clinical outcomes between these patients and those treated when admitted to an emergency department, drip-and-ship may actually increase the overall use of tissue plasminogen activator (TPA), Dr. Kevin N. Sheth said at the International Stroke Conference, sponsored by the American Heart Association.

The retrospective analysis, which was simultaneously published in Stroke (2015 Feb. 11 [doi:10.1161/STROKEAHA.114.007506]), plumbed the Get With the Guidelines registry for data to describe trends in the use of TPA and drip-and-ship administration across the United States over time. The study involved 1,440 hospitals and 44,667 patients who had an ischemic stroke during 2003-2010 and received TPA. Of these, 10,475 (23.5%) received it in the field before optional admission and within 3 hours of symptom onset.

Baseline characteristics were similar between the treatment groups. The patients’ mean age was 70 years, and the sex distribution was evenly split. More than 75% of each group was white.

The National Institutes of Health Stroke Scale (NIHSS) score was significantly higher among those who presented for hospital treatment (12.9 vs. 11). However, these patients were seen before TPA administration, while the drip-and-ship group had already been treated, a temporal difference that could have accounted for the score finding, cautioned Dr. Sheth, director of the neuroscience ICU and chief of clinical research at Yale University, New Haven, Conn.

In hospitals that employed drip-and-ship, there were significantly higher rates of stroke patients treated each year as well as more beds. Those hospitals also were more often teaching facilities and were designated as a primary stroke center.

Drip-and-ship frequency remained fairly steady over the study period – about 25% of all eligible patients had it in both 2003 and 2010. Among those treated at the hospital, the frequency of TPA administration within 3 hours of stroke onset rose sharply over the study period, from about 11% in 2003 to 25% in 2010. In contrast, the percentage of timely thrombolysis in drip-and-ship patients moved very little, from about 5% to 9% over the same period.

Overall inpatient mortality was 10%, but was slightly higher among drip-and-ship patients (10.93% vs. 9.67). Symptomatic intracranial hemorrhage occurred in 5.79% of those treated via drip-and-ship and 5.22% of those treated in the hospital. Nearly the same percentage of patients were discharged walking independently (38.4% vs. 38.8%) and discharged home (40.3% vs. 40.6%).

Among the hospital-treated patients, fewer than 4% (1,200) underwent endovascular therapy; this occurred in 707 (7%) of drip-and-ship patients. Those who got endovascular treatment had higher median NIHSS scores at TPA administration than did those who did not (17 vs. 12, respectively). Endovascular treatment was significantly associated with higher mortality (20% vs. 10%) and intracranial hemorrhage (11% vs. 5%).

In a multivariate analysis that adjusted for NIHSS score, in-hospital mortality was significantly more likely in drip-and-ship patients (odds ratio, 1.23). Those patients also were significantly less likely to be independently walking at discharge (OR, 0.66) or discharge to home (OR, 0.66). Intracranial hemorrhage was significantly more likely in drip-and-ship patients (OR, 1.4), as was a hospital stay of longer than 4 days (OR, 1.20).

“These are very modest differences clinically,” Dr. Sheth said, adding that selection bias or unmeasured confounding could have influenced the findings.

Dr. Sheth is a member of the Get with the Guidelines (GWTG) Stroke Clinical Workgroup, and he is a coinvestigator and executive committee member for Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals (GAMES-RP), a phase II trial to prevent swelling in patients with large stroke, funded by Remedy Pharmaceuticals.

[email protected]

On Twitter @alz_gal

NASHVILLE, TENN. – About 25% of patients with ischemic stroke who receive thrombolytic therapy get it in the field before hospital transfer with the “drip-and-ship” paradigm.

While there were only modest differences in clinical outcomes between these patients and those treated when admitted to an emergency department, drip-and-ship may actually increase the overall use of tissue plasminogen activator (TPA), Dr. Kevin N. Sheth said at the International Stroke Conference, sponsored by the American Heart Association.

The retrospective analysis, which was simultaneously published in Stroke (2015 Feb. 11 [doi:10.1161/STROKEAHA.114.007506]), plumbed the Get With the Guidelines registry for data to describe trends in the use of TPA and drip-and-ship administration across the United States over time. The study involved 1,440 hospitals and 44,667 patients who had an ischemic stroke during 2003-2010 and received TPA. Of these, 10,475 (23.5%) received it in the field before optional admission and within 3 hours of symptom onset.

Baseline characteristics were similar between the treatment groups. The patients’ mean age was 70 years, and the sex distribution was evenly split. More than 75% of each group was white.

The National Institutes of Health Stroke Scale (NIHSS) score was significantly higher among those who presented for hospital treatment (12.9 vs. 11). However, these patients were seen before TPA administration, while the drip-and-ship group had already been treated, a temporal difference that could have accounted for the score finding, cautioned Dr. Sheth, director of the neuroscience ICU and chief of clinical research at Yale University, New Haven, Conn.

In hospitals that employed drip-and-ship, there were significantly higher rates of stroke patients treated each year as well as more beds. Those hospitals also were more often teaching facilities and were designated as a primary stroke center.

Drip-and-ship frequency remained fairly steady over the study period – about 25% of all eligible patients had it in both 2003 and 2010. Among those treated at the hospital, the frequency of TPA administration within 3 hours of stroke onset rose sharply over the study period, from about 11% in 2003 to 25% in 2010. In contrast, the percentage of timely thrombolysis in drip-and-ship patients moved very little, from about 5% to 9% over the same period.

Overall inpatient mortality was 10%, but was slightly higher among drip-and-ship patients (10.93% vs. 9.67). Symptomatic intracranial hemorrhage occurred in 5.79% of those treated via drip-and-ship and 5.22% of those treated in the hospital. Nearly the same percentage of patients were discharged walking independently (38.4% vs. 38.8%) and discharged home (40.3% vs. 40.6%).

Among the hospital-treated patients, fewer than 4% (1,200) underwent endovascular therapy; this occurred in 707 (7%) of drip-and-ship patients. Those who got endovascular treatment had higher median NIHSS scores at TPA administration than did those who did not (17 vs. 12, respectively). Endovascular treatment was significantly associated with higher mortality (20% vs. 10%) and intracranial hemorrhage (11% vs. 5%).

In a multivariate analysis that adjusted for NIHSS score, in-hospital mortality was significantly more likely in drip-and-ship patients (odds ratio, 1.23). Those patients also were significantly less likely to be independently walking at discharge (OR, 0.66) or discharge to home (OR, 0.66). Intracranial hemorrhage was significantly more likely in drip-and-ship patients (OR, 1.4), as was a hospital stay of longer than 4 days (OR, 1.20).

“These are very modest differences clinically,” Dr. Sheth said, adding that selection bias or unmeasured confounding could have influenced the findings.

Dr. Sheth is a member of the Get with the Guidelines (GWTG) Stroke Clinical Workgroup, and he is a coinvestigator and executive committee member for Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals (GAMES-RP), a phase II trial to prevent swelling in patients with large stroke, funded by Remedy Pharmaceuticals.

[email protected]

On Twitter @alz_gal

Rudolph Virchow clearly demonstrated the association between malignancy and venous thromboembolic events. VTE – deep vein thrombosis and pulmonary embolism – affect between 15% and 38% of patients with gynecologic malignancies after surgery.

The rate of pulmonary embolism (PE) in this patient population can be as high as 6.8%, with the case fatality rate being 11%-12% (Obstet. Gynecol. 2012;119:155-67). Other factors associated with the development of VTE include prior VTE, older age, African American race, prolonged operative time, obesity, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of VTE in women undergoing gynecologic surgery is quadrupled in the presence of malignancy(Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE compared to matched controls (Gynecol. Oncol. 2007;106:439-45).

Additionally, cancer patients are typically older, have longer and more complex surgeries, and the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).

Although the treatment of VTE is fairly similar between patients with malignancy and those without cancer, treatment of a VTE in patients with cancer can be further complicated by higher VTE recurrence rates and increased risk of bleeding. Furthermore, issues related to the malignant disease process such as prognosis, presence and location of metastasis, and life expectancy should be taken into consideration when managing VTE in this patient population.

Generally, in the setting of an acute or recurrent VTE, initial therapy with a parenteral anticoagulant (heparin or low-molecular-weight heparins [LMWH]) should be immediately instituted in patients with a gynecologic malignancy, unless there is evidence of active bleeding or any other contraindication for the use of an anticoagulant.

Other factors associated with cancer such as immobilization, the presence of metastases, and impaired renal function with a creatinine clearance less than 30 mL/min, may increase the risk of bleeding complications but are not absolute contraindications to anticoagulation (Thromb. Haemost. 2008;100:435-9). The initial treatment phase, which last for 5-10 days, is then followed by a longer treatment phase lasting 3-6 months.

In the majority of cases, LMWH is the preferred agent for both the initial and prolonged treatment phase assuming adequate renal function. Based on evidence from a meta-analysis of 16 randomized controlled trials in cancer patients receiving initial anticoagulation for VTE, LMWH is associated with a 30% reduction in mortality without an increased risk of bleeding in comparison to unfractionated heparin (Cochrane Database. Syst. Rev. 2014;6:CD006649).

When compared with the vitamin K antagonist warfarin, LMWH appears to be associated with a significantly reduced rate of recurrent VTE (hazard ratio, 0.47; 95% confidence interval 0.32-0.71). However, this was not associated with a survival advantage (N. Engl. J. Med. 2003;349:146-53).

There are no trials comparing the different formulations of LMWH. In our practice, we routinely use the LMWH enoxaparin dosed at 1 mg/kg subcutaneously twice daily. Other well-studied LMWHs include dalteparin and tinzaparin.

LMWHs are primarily renally excreted, thus, in patients with compromised renal function, the biological half-life of the medication may be prolonged, leading to potential bleeding complications. The majority of LMWH trials excluded patients with creatinine clearance less than 30 mL/min, therefore, in patients with compromised renal function, one option would be to decrease the daily dose by as much as 50% and closely monitor antifactor XA levels. Alternatively, the use of unfractionated heparin in the acute setting followed by warfarin with close monitoring of the patient’s international normalized ratio could prove less cumbersome and ultimately safer for these patients. However, given the limitations of the currently available data we would not recommend the routine use of newer oral anticoagulation agents.

Patients with a malignancy are at increased risk for the development of a recurrent VTE even in the setting of anticoagulation. Some of the risks factors for this phenomenon include presence of central venous catheters, interruption of therapy for procedures, and immobilization. In cases of recurrent VTE, consideration should be given to extending the duration of treatment beyond the initial planned 3-6 months. Other patients that may benefit from extended therapy include those with continued immobility or active cancer burden.

LMWH is also the preferred agent for extended therapy based on very limited evidence from experimental studies suggesting that LMWH may have antineoplastic effects and thus a survival advantage. However, in the setting of a recurrent VTE, there is very limited data on which to base the choice of extended treatment. Options include switching the therapeutic agent, increasing the dose or frequency of administration, or placement of an inferior vena cava filter. Consultation with a hematologist may also be warranted in this and more complicated scenarios.

Ultimately, LMWH appears to be the best available therapy for patients with a gynecologic malignancy. However, the decision to anticoagulate should be carefully planned out, taking into consideration the individual patient’s disease burden and associated comorbidities in order to select the most appropriate treatment option.

Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant financial disclosures.

Rudolph Virchow clearly demonstrated the association between malignancy and venous thromboembolic events. VTE – deep vein thrombosis and pulmonary embolism – affect between 15% and 38% of patients with gynecologic malignancies after surgery.

The rate of pulmonary embolism (PE) in this patient population can be as high as 6.8%, with the case fatality rate being 11%-12% (Obstet. Gynecol. 2012;119:155-67). Other factors associated with the development of VTE include prior VTE, older age, African American race, prolonged operative time, obesity, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of VTE in women undergoing gynecologic surgery is quadrupled in the presence of malignancy(Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE compared to matched controls (Gynecol. Oncol. 2007;106:439-45).

Additionally, cancer patients are typically older, have longer and more complex surgeries, and the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).

Although the treatment of VTE is fairly similar between patients with malignancy and those without cancer, treatment of a VTE in patients with cancer can be further complicated by higher VTE recurrence rates and increased risk of bleeding. Furthermore, issues related to the malignant disease process such as prognosis, presence and location of metastasis, and life expectancy should be taken into consideration when managing VTE in this patient population.

Generally, in the setting of an acute or recurrent VTE, initial therapy with a parenteral anticoagulant (heparin or low-molecular-weight heparins [LMWH]) should be immediately instituted in patients with a gynecologic malignancy, unless there is evidence of active bleeding or any other contraindication for the use of an anticoagulant.

Other factors associated with cancer such as immobilization, the presence of metastases, and impaired renal function with a creatinine clearance less than 30 mL/min, may increase the risk of bleeding complications but are not absolute contraindications to anticoagulation (Thromb. Haemost. 2008;100:435-9). The initial treatment phase, which last for 5-10 days, is then followed by a longer treatment phase lasting 3-6 months.

In the majority of cases, LMWH is the preferred agent for both the initial and prolonged treatment phase assuming adequate renal function. Based on evidence from a meta-analysis of 16 randomized controlled trials in cancer patients receiving initial anticoagulation for VTE, LMWH is associated with a 30% reduction in mortality without an increased risk of bleeding in comparison to unfractionated heparin (Cochrane Database. Syst. Rev. 2014;6:CD006649).

When compared with the vitamin K antagonist warfarin, LMWH appears to be associated with a significantly reduced rate of recurrent VTE (hazard ratio, 0.47; 95% confidence interval 0.32-0.71). However, this was not associated with a survival advantage (N. Engl. J. Med. 2003;349:146-53).

There are no trials comparing the different formulations of LMWH. In our practice, we routinely use the LMWH enoxaparin dosed at 1 mg/kg subcutaneously twice daily. Other well-studied LMWHs include dalteparin and tinzaparin.

LMWHs are primarily renally excreted, thus, in patients with compromised renal function, the biological half-life of the medication may be prolonged, leading to potential bleeding complications. The majority of LMWH trials excluded patients with creatinine clearance less than 30 mL/min, therefore, in patients with compromised renal function, one option would be to decrease the daily dose by as much as 50% and closely monitor antifactor XA levels. Alternatively, the use of unfractionated heparin in the acute setting followed by warfarin with close monitoring of the patient’s international normalized ratio could prove less cumbersome and ultimately safer for these patients. However, given the limitations of the currently available data we would not recommend the routine use of newer oral anticoagulation agents.

Patients with a malignancy are at increased risk for the development of a recurrent VTE even in the setting of anticoagulation. Some of the risks factors for this phenomenon include presence of central venous catheters, interruption of therapy for procedures, and immobilization. In cases of recurrent VTE, consideration should be given to extending the duration of treatment beyond the initial planned 3-6 months. Other patients that may benefit from extended therapy include those with continued immobility or active cancer burden.

LMWH is also the preferred agent for extended therapy based on very limited evidence from experimental studies suggesting that LMWH may have antineoplastic effects and thus a survival advantage. However, in the setting of a recurrent VTE, there is very limited data on which to base the choice of extended treatment. Options include switching the therapeutic agent, increasing the dose or frequency of administration, or placement of an inferior vena cava filter. Consultation with a hematologist may also be warranted in this and more complicated scenarios.

Ultimately, LMWH appears to be the best available therapy for patients with a gynecologic malignancy. However, the decision to anticoagulate should be carefully planned out, taking into consideration the individual patient’s disease burden and associated comorbidities in order to select the most appropriate treatment option.

Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant financial disclosures.

Rudolph Virchow clearly demonstrated the association between malignancy and venous thromboembolic events. VTE – deep vein thrombosis and pulmonary embolism – affect between 15% and 38% of patients with gynecologic malignancies after surgery.

The rate of pulmonary embolism (PE) in this patient population can be as high as 6.8%, with the case fatality rate being 11%-12% (Obstet. Gynecol. 2012;119:155-67). Other factors associated with the development of VTE include prior VTE, older age, African American race, prolonged operative time, obesity, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of VTE in women undergoing gynecologic surgery is quadrupled in the presence of malignancy(Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE compared to matched controls (Gynecol. Oncol. 2007;106:439-45).

Additionally, cancer patients are typically older, have longer and more complex surgeries, and the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).

Although the treatment of VTE is fairly similar between patients with malignancy and those without cancer, treatment of a VTE in patients with cancer can be further complicated by higher VTE recurrence rates and increased risk of bleeding. Furthermore, issues related to the malignant disease process such as prognosis, presence and location of metastasis, and life expectancy should be taken into consideration when managing VTE in this patient population.

Generally, in the setting of an acute or recurrent VTE, initial therapy with a parenteral anticoagulant (heparin or low-molecular-weight heparins [LMWH]) should be immediately instituted in patients with a gynecologic malignancy, unless there is evidence of active bleeding or any other contraindication for the use of an anticoagulant.

Other factors associated with cancer such as immobilization, the presence of metastases, and impaired renal function with a creatinine clearance less than 30 mL/min, may increase the risk of bleeding complications but are not absolute contraindications to anticoagulation (Thromb. Haemost. 2008;100:435-9). The initial treatment phase, which last for 5-10 days, is then followed by a longer treatment phase lasting 3-6 months.

In the majority of cases, LMWH is the preferred agent for both the initial and prolonged treatment phase assuming adequate renal function. Based on evidence from a meta-analysis of 16 randomized controlled trials in cancer patients receiving initial anticoagulation for VTE, LMWH is associated with a 30% reduction in mortality without an increased risk of bleeding in comparison to unfractionated heparin (Cochrane Database. Syst. Rev. 2014;6:CD006649).

When compared with the vitamin K antagonist warfarin, LMWH appears to be associated with a significantly reduced rate of recurrent VTE (hazard ratio, 0.47; 95% confidence interval 0.32-0.71). However, this was not associated with a survival advantage (N. Engl. J. Med. 2003;349:146-53).

There are no trials comparing the different formulations of LMWH. In our practice, we routinely use the LMWH enoxaparin dosed at 1 mg/kg subcutaneously twice daily. Other well-studied LMWHs include dalteparin and tinzaparin.

LMWHs are primarily renally excreted, thus, in patients with compromised renal function, the biological half-life of the medication may be prolonged, leading to potential bleeding complications. The majority of LMWH trials excluded patients with creatinine clearance less than 30 mL/min, therefore, in patients with compromised renal function, one option would be to decrease the daily dose by as much as 50% and closely monitor antifactor XA levels. Alternatively, the use of unfractionated heparin in the acute setting followed by warfarin with close monitoring of the patient’s international normalized ratio could prove less cumbersome and ultimately safer for these patients. However, given the limitations of the currently available data we would not recommend the routine use of newer oral anticoagulation agents.

Patients with a malignancy are at increased risk for the development of a recurrent VTE even in the setting of anticoagulation. Some of the risks factors for this phenomenon include presence of central venous catheters, interruption of therapy for procedures, and immobilization. In cases of recurrent VTE, consideration should be given to extending the duration of treatment beyond the initial planned 3-6 months. Other patients that may benefit from extended therapy include those with continued immobility or active cancer burden.

LMWH is also the preferred agent for extended therapy based on very limited evidence from experimental studies suggesting that LMWH may have antineoplastic effects and thus a survival advantage. However, in the setting of a recurrent VTE, there is very limited data on which to base the choice of extended treatment. Options include switching the therapeutic agent, increasing the dose or frequency of administration, or placement of an inferior vena cava filter. Consultation with a hematologist may also be warranted in this and more complicated scenarios.

Ultimately, LMWH appears to be the best available therapy for patients with a gynecologic malignancy. However, the decision to anticoagulate should be carefully planned out, taking into consideration the individual patient’s disease burden and associated comorbidities in order to select the most appropriate treatment option.

Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant financial disclosures.

SNOWMASS, COLO. – U.S. cardiologists are glaringly out of touch with the guidelines on maintenance aspirin dosing in patients with acute coronary syndrome, American College of Cardiology President Dr. Patrick T. O’Gara said at the Annual Cardiovascular Conference at Snowmass.

The latest AHA/ACC guidelines state that maintenance aspirin therapy at 81 mg/day to be continued indefinitely is preferred over 325 mg/day in patients with ACS, regardless of whether they have received a coronary stent or noninvasive medical management (Circulation 2014 Dec 23;130(25):e344-426).

“This statement has been out there in the guidelines for several years now. Yet the last time we interrogated the NCDR [National Cardiovascular Data Registry], 70% of patients with ACS were discharged on 325 mg/day of aspirin in the U.S.,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.

The recommendation in the guidelines is based on several solid studies, including OASIS 7, which in more than 25,000 randomized patients showed no difference in outcomes when aspirin at 75-100 mg/day was compared with 300-325 mg/day, but an increased incidence of bleeding at the higher dose (N. Engl. J. Med. 2010;363:930-42).

“Aspirin at 81 mg/day is not inferior with respect to clinical efficacy and it’s superior with respect to its safety outcome. But here in the United States we are still very much wedded to using 325 mg of aspirin. I’m not exactly sure of the reasons for that. Maybe it’s a catch up phenomenon,” Dr. O’Gara commented.

In the setting of percutaneous coronary intervention with a bare metal or drug-eluting stent for patients with either non–ST-elevation ACS or ST-elevation MI, the AHA/ACC guidelines give a class I recommendation for at least 12 months of dual-antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ inhibitor. Either ticagrelor (Brilinta) at 90 mg twice daily or prasugrel (Effient) once daily at 10 mg is recommended over clopidogrel at 75 mg/day in patients who can take those medications safely; this guidance is based on ticagrelor’s superior efficacy compared with clopidogrel as shown in TRITON TIMI-38 (N. Engl. J. Med. 2007;357:2001-15) and prasugrel’s superiority in the PLATO trial (N. Engl. J. Med. 2009;361:1045-57).

The AHA/ACC guidelines give a relatively tepid level IIb recommendation that continuation of DAPT beyond 12 months may be considered in stent recipients. Many observers expect a stronger endorsement in the next iteration of the guidelines on the strength of the recent DAPT study, which showed that 30 months of DAPT was better than 12 in terms of major adverse cardiac and cerebrovascular events (N. Engl. J. Med. 2014;371:2155-66).

“Interestingly enough, the mechanism of benefit had less to do with prevention of stent thrombosis than it did with prevention of recurrent MI and stroke. This renders into much sharper focus the question of whether we’re treating the patient or we’re treating the stent. This result would imply that we’re treating the patient,” Dr. O’Gara observed.

The guidelines also include a bail-out option which states that if the risk of bleeding outweighs the anticipated benefit, it’s reasonable to discontinue DAPT before 12 months.

“I don’t know a single practitioner who’s not had to withdraw one or both elements of DAPT because of bleeding or because of the need for unanticipated noncardiac surgery. It’s a fact of life, and sometimes you have to just hope for the best,” the cardiologist said.

He reported having no financial conflicts of interest.

[email protected]

SNOWMASS, COLO. – U.S. cardiologists are glaringly out of touch with the guidelines on maintenance aspirin dosing in patients with acute coronary syndrome, American College of Cardiology President Dr. Patrick T. O’Gara said at the Annual Cardiovascular Conference at Snowmass.

The latest AHA/ACC guidelines state that maintenance aspirin therapy at 81 mg/day to be continued indefinitely is preferred over 325 mg/day in patients with ACS, regardless of whether they have received a coronary stent or noninvasive medical management (Circulation 2014 Dec 23;130(25):e344-426).

“This statement has been out there in the guidelines for several years now. Yet the last time we interrogated the NCDR [National Cardiovascular Data Registry], 70% of patients with ACS were discharged on 325 mg/day of aspirin in the U.S.,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.

The recommendation in the guidelines is based on several solid studies, including OASIS 7, which in more than 25,000 randomized patients showed no difference in outcomes when aspirin at 75-100 mg/day was compared with 300-325 mg/day, but an increased incidence of bleeding at the higher dose (N. Engl. J. Med. 2010;363:930-42).

“Aspirin at 81 mg/day is not inferior with respect to clinical efficacy and it’s superior with respect to its safety outcome. But here in the United States we are still very much wedded to using 325 mg of aspirin. I’m not exactly sure of the reasons for that. Maybe it’s a catch up phenomenon,” Dr. O’Gara commented.

In the setting of percutaneous coronary intervention with a bare metal or drug-eluting stent for patients with either non–ST-elevation ACS or ST-elevation MI, the AHA/ACC guidelines give a class I recommendation for at least 12 months of dual-antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ inhibitor. Either ticagrelor (Brilinta) at 90 mg twice daily or prasugrel (Effient) once daily at 10 mg is recommended over clopidogrel at 75 mg/day in patients who can take those medications safely; this guidance is based on ticagrelor’s superior efficacy compared with clopidogrel as shown in TRITON TIMI-38 (N. Engl. J. Med. 2007;357:2001-15) and prasugrel’s superiority in the PLATO trial (N. Engl. J. Med. 2009;361:1045-57).

The AHA/ACC guidelines give a relatively tepid level IIb recommendation that continuation of DAPT beyond 12 months may be considered in stent recipients. Many observers expect a stronger endorsement in the next iteration of the guidelines on the strength of the recent DAPT study, which showed that 30 months of DAPT was better than 12 in terms of major adverse cardiac and cerebrovascular events (N. Engl. J. Med. 2014;371:2155-66).

“Interestingly enough, the mechanism of benefit had less to do with prevention of stent thrombosis than it did with prevention of recurrent MI and stroke. This renders into much sharper focus the question of whether we’re treating the patient or we’re treating the stent. This result would imply that we’re treating the patient,” Dr. O’Gara observed.

The guidelines also include a bail-out option which states that if the risk of bleeding outweighs the anticipated benefit, it’s reasonable to discontinue DAPT before 12 months.

“I don’t know a single practitioner who’s not had to withdraw one or both elements of DAPT because of bleeding or because of the need for unanticipated noncardiac surgery. It’s a fact of life, and sometimes you have to just hope for the best,” the cardiologist said.

He reported having no financial conflicts of interest.

[email protected]

SNOWMASS, COLO. – U.S. cardiologists are glaringly out of touch with the guidelines on maintenance aspirin dosing in patients with acute coronary syndrome, American College of Cardiology President Dr. Patrick T. O’Gara said at the Annual Cardiovascular Conference at Snowmass.

The latest AHA/ACC guidelines state that maintenance aspirin therapy at 81 mg/day to be continued indefinitely is preferred over 325 mg/day in patients with ACS, regardless of whether they have received a coronary stent or noninvasive medical management (Circulation 2014 Dec 23;130(25):e344-426).

“This statement has been out there in the guidelines for several years now. Yet the last time we interrogated the NCDR [National Cardiovascular Data Registry], 70% of patients with ACS were discharged on 325 mg/day of aspirin in the U.S.,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.

The recommendation in the guidelines is based on several solid studies, including OASIS 7, which in more than 25,000 randomized patients showed no difference in outcomes when aspirin at 75-100 mg/day was compared with 300-325 mg/day, but an increased incidence of bleeding at the higher dose (N. Engl. J. Med. 2010;363:930-42).

“Aspirin at 81 mg/day is not inferior with respect to clinical efficacy and it’s superior with respect to its safety outcome. But here in the United States we are still very much wedded to using 325 mg of aspirin. I’m not exactly sure of the reasons for that. Maybe it’s a catch up phenomenon,” Dr. O’Gara commented.

In the setting of percutaneous coronary intervention with a bare metal or drug-eluting stent for patients with either non–ST-elevation ACS or ST-elevation MI, the AHA/ACC guidelines give a class I recommendation for at least 12 months of dual-antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ inhibitor. Either ticagrelor (Brilinta) at 90 mg twice daily or prasugrel (Effient) once daily at 10 mg is recommended over clopidogrel at 75 mg/day in patients who can take those medications safely; this guidance is based on ticagrelor’s superior efficacy compared with clopidogrel as shown in TRITON TIMI-38 (N. Engl. J. Med. 2007;357:2001-15) and prasugrel’s superiority in the PLATO trial (N. Engl. J. Med. 2009;361:1045-57).

The AHA/ACC guidelines give a relatively tepid level IIb recommendation that continuation of DAPT beyond 12 months may be considered in stent recipients. Many observers expect a stronger endorsement in the next iteration of the guidelines on the strength of the recent DAPT study, which showed that 30 months of DAPT was better than 12 in terms of major adverse cardiac and cerebrovascular events (N. Engl. J. Med. 2014;371:2155-66).

“Interestingly enough, the mechanism of benefit had less to do with prevention of stent thrombosis than it did with prevention of recurrent MI and stroke. This renders into much sharper focus the question of whether we’re treating the patient or we’re treating the stent. This result would imply that we’re treating the patient,” Dr. O’Gara observed.

The guidelines also include a bail-out option which states that if the risk of bleeding outweighs the anticipated benefit, it’s reasonable to discontinue DAPT before 12 months.

“I don’t know a single practitioner who’s not had to withdraw one or both elements of DAPT because of bleeding or because of the need for unanticipated noncardiac surgery. It’s a fact of life, and sometimes you have to just hope for the best,” the cardiologist said.

He reported having no financial conflicts of interest.

[email protected]

Patients with atrial fibrillation who had CHA₂DS₂-VASc scores of 1 were at lower risk of ischemic stroke than previously reported, according to a retrospective analysis of hospital registry data. The research appeared online January 19 in the Journal of American College of Cardiology.

Depending on the definition of stroke used, risk was 0.1% to 0.2% in women and 0.5% to 0.7% in men – so low that oral anticoagulants (OACs) would not be expected to benefit patients of either sex, said Dr. Leif Friberg at the Karolinska Institute in Stockholm and his associates. Past studies had potentially overestimated the risk of stroke in this population, which “may have led to unnecessary, and potentially harmful, OAC treatment of low-risk patients,” they said.

European and U.S. guidelines both recommend using the CHA₂DS₂-VASc (heart failure, hypertension, age ≥75, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65-74 years, female) scoring system to assess stroke risk in patients with atrial fibrillation (AF). But past studies have reported a threefold variation (ranging from 0.6% to greater than 2.0%) in stroke risk among AF patients with CHA₂DS₂-VASc scores of 1 who were not receiving OAC, the researchers noted. Anticoagulation therapy is likely to benefit AF patients whose annual risk of stroke exceeds 1%, but not patients whose risk is only 0.6%, they added.

Their study, which included 140,420 patients in Sweden with nonvalvular AF, assessed the effect of varying definitions of stroke on estimates of stroke risk. Using a broad definition that included ischemic stroke, transient ischemic attack (TIA), and pulmonary embolism led to a 44% greater annual risk of stroke than if only ischemic strokes were considered, the investigators reported. They disagreed with classifying pulmonary embolism events and TIAs as strokes, as some past studies have done. “Primary prevention of pulmonary embolism among patients with AF has, to the best of our knowledge, not been studied and is not an approved indication for OAC treatment,” they said. “We also did not find it relevant to count TIA as an endpoint in studies that describe stroke risk. As a diagnosis, TIA is difficult to validate.”

Several Swedish foundations supported the study. Dr. Friberg reported no relevant financial conflicts of interest.

Patients with atrial fibrillation who had CHA₂DS₂-VASc scores of 1 were at lower risk of ischemic stroke than previously reported, according to a retrospective analysis of hospital registry data. The research appeared online January 19 in the Journal of American College of Cardiology.

Depending on the definition of stroke used, risk was 0.1% to 0.2% in women and 0.5% to 0.7% in men – so low that oral anticoagulants (OACs) would not be expected to benefit patients of either sex, said Dr. Leif Friberg at the Karolinska Institute in Stockholm and his associates. Past studies had potentially overestimated the risk of stroke in this population, which “may have led to unnecessary, and potentially harmful, OAC treatment of low-risk patients,” they said.

European and U.S. guidelines both recommend using the CHA₂DS₂-VASc (heart failure, hypertension, age ≥75, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65-74 years, female) scoring system to assess stroke risk in patients with atrial fibrillation (AF). But past studies have reported a threefold variation (ranging from 0.6% to greater than 2.0%) in stroke risk among AF patients with CHA₂DS₂-VASc scores of 1 who were not receiving OAC, the researchers noted. Anticoagulation therapy is likely to benefit AF patients whose annual risk of stroke exceeds 1%, but not patients whose risk is only 0.6%, they added.

Their study, which included 140,420 patients in Sweden with nonvalvular AF, assessed the effect of varying definitions of stroke on estimates of stroke risk. Using a broad definition that included ischemic stroke, transient ischemic attack (TIA), and pulmonary embolism led to a 44% greater annual risk of stroke than if only ischemic strokes were considered, the investigators reported. They disagreed with classifying pulmonary embolism events and TIAs as strokes, as some past studies have done. “Primary prevention of pulmonary embolism among patients with AF has, to the best of our knowledge, not been studied and is not an approved indication for OAC treatment,” they said. “We also did not find it relevant to count TIA as an endpoint in studies that describe stroke risk. As a diagnosis, TIA is difficult to validate.”

Several Swedish foundations supported the study. Dr. Friberg reported no relevant financial conflicts of interest.

Patients with atrial fibrillation who had CHA₂DS₂-VASc scores of 1 were at lower risk of ischemic stroke than previously reported, according to a retrospective analysis of hospital registry data. The research appeared online January 19 in the Journal of American College of Cardiology.

Depending on the definition of stroke used, risk was 0.1% to 0.2% in women and 0.5% to 0.7% in men – so low that oral anticoagulants (OACs) would not be expected to benefit patients of either sex, said Dr. Leif Friberg at the Karolinska Institute in Stockholm and his associates. Past studies had potentially overestimated the risk of stroke in this population, which “may have led to unnecessary, and potentially harmful, OAC treatment of low-risk patients,” they said.

European and U.S. guidelines both recommend using the CHA₂DS₂-VASc (heart failure, hypertension, age ≥75, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65-74 years, female) scoring system to assess stroke risk in patients with atrial fibrillation (AF). But past studies have reported a threefold variation (ranging from 0.6% to greater than 2.0%) in stroke risk among AF patients with CHA₂DS₂-VASc scores of 1 who were not receiving OAC, the researchers noted. Anticoagulation therapy is likely to benefit AF patients whose annual risk of stroke exceeds 1%, but not patients whose risk is only 0.6%, they added.

Their study, which included 140,420 patients in Sweden with nonvalvular AF, assessed the effect of varying definitions of stroke on estimates of stroke risk. Using a broad definition that included ischemic stroke, transient ischemic attack (TIA), and pulmonary embolism led to a 44% greater annual risk of stroke than if only ischemic strokes were considered, the investigators reported. They disagreed with classifying pulmonary embolism events and TIAs as strokes, as some past studies have done. “Primary prevention of pulmonary embolism among patients with AF has, to the best of our knowledge, not been studied and is not an approved indication for OAC treatment,” they said. “We also did not find it relevant to count TIA as an endpoint in studies that describe stroke risk. As a diagnosis, TIA is difficult to validate.”

Several Swedish foundations supported the study. Dr. Friberg reported no relevant financial conflicts of interest.

Edoxaban, a selective factor Xa-inhibitor, has been approved by the Food and Drug Administration for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, with a statement in the boxed warning that it should not be used in patients with normal renal function.

The warning reflects the results of a subgroup analysis in the pivotal trial, which found that the 60-mg dose was superior to warfarin in terms of reducing the stroke risk in mildly renally impaired patients, but was worse in patients with normal renal function. This was the main focus of a meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Panel meeting in October, in which the panel voted 9-1 to recommend approval of edoxaban for this indication, but had mixed opinions on whether approval should be limited to patients with mild to moderate renal impairment.

The approved prescribing information recommends that a patient’s creatinine clearance should be checked before edoxaban is prescribed. “Patients with creatinine clearance greater than 95 mL/min have an increased risk of stroke, compared to similar patients given warfarin,” and should be treated with another anticoagulant, the FDA said in the Jan. 9 statement announcing the approval. The recommended dose for those with a creatinine clearance between 50 mL/min and 95 mL/min is 60 mg once a day; for those with a creatinine clearance of 15-50 mL/min, the recommended dose is 30 mg once a day, according to the prescribing information.

Edoxaban, the fourth novel oral anticoagulant drug approved by the FDA, will be marketed as Savaysa by Daiichi Sankyo. It was also approved to treat deep vein thrombosis and pulmonary embolism following 5-10 days of initial therapy with a parenteral anticoagulant. The recommended dose for this indication is 60 mg once a day. For patients with a creatinine clearance of 15-50 mL/min, or who weigh up to 60 kg (about 132 pounds), or who are taking “certain P-glycoprotein inhibitors,” the 30-mg/day dose is recommended.

Approval for the nonvalvular AF indication was based on ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation) study, comparing once-daily edoxaban (60 mg and 30 mg) to warfarin in 21,015 patients with nonvalvular AF, at a moderate to high risk of thromboembolic events (N. Engl. J. Med. 2013;369:2093-104). Over a median of almost 3 years, both doses were noninferior to warfarin in the primary efficacy endpoint, the occurrence of first stroke or of a systemic embolic event. Overall, major bleeding events were significantly lower among those on the 60-mg and 30-mg doses, compared with those on warfarin. However, the rate of ischemic stroke was higher relative to warfarin in patients with a creatinine clearance over 95 mL/min.

About half of the edoxaban dose is eliminated by the kidneys, and patients with a creatinine clearance above 95 mL/min have lower plasma edoxaban levels, according to a statement in the clinical trials section of the prescribing information, which adds: “Given the clear relationship of dose and blood levels to effectiveness in the ENGAGE AF-TIMI 48 study, it could be anticipated that patients with better renal function would show a smaller effect of Savaysa, compared to warfarin than would patients with mildly impaired renal function, and this was in fact observed.”

Approval of the DVT and PE indication was based on the Hokusai-VTE study of about 8,200 people comparing edoxaban to warfarin, which found that the edoxaban 60 mg once a day was noninferior to warfarin in the rate of symptomatic venous thromboembolism (3.2% vs. 3.5% in those on warfarin). The rate of major or clinically relevant nonmajor bleeding events was 8.5% among those on edoxaban vs. 10.3% in those on warfarin (N. Engl. J. Med. 2013;369:1406-15).

Bleeding and anemia were the most common adverse events among patients with nonvalvular atrial fibrillation in clinical trials, and “as with other FDA-approved anticlotting drugs, bleeding, including life-threatening bleeding, is the most serious risk with Savaysa,” the FDA statement said. Among those treated for DVT and PE, the most common adverse events were bleeding, rash, abnormal liver function tests, and anemia.

Savaysa is the fourth novel oral anticoagulant to be cleared by the FDA, after dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis).

Serious adverse events associated with edoxaban should be reported to the FDA’s MedWatch program or at 800-332-1088.

[email protected]

Edoxaban, a selective factor Xa-inhibitor, has been approved by the Food and Drug Administration for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, with a statement in the boxed warning that it should not be used in patients with normal renal function.

The warning reflects the results of a subgroup analysis in the pivotal trial, which found that the 60-mg dose was superior to warfarin in terms of reducing the stroke risk in mildly renally impaired patients, but was worse in patients with normal renal function. This was the main focus of a meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Panel meeting in October, in which the panel voted 9-1 to recommend approval of edoxaban for this indication, but had mixed opinions on whether approval should be limited to patients with mild to moderate renal impairment.

The approved prescribing information recommends that a patient’s creatinine clearance should be checked before edoxaban is prescribed. “Patients with creatinine clearance greater than 95 mL/min have an increased risk of stroke, compared to similar patients given warfarin,” and should be treated with another anticoagulant, the FDA said in the Jan. 9 statement announcing the approval. The recommended dose for those with a creatinine clearance between 50 mL/min and 95 mL/min is 60 mg once a day; for those with a creatinine clearance of 15-50 mL/min, the recommended dose is 30 mg once a day, according to the prescribing information.

Edoxaban, the fourth novel oral anticoagulant drug approved by the FDA, will be marketed as Savaysa by Daiichi Sankyo. It was also approved to treat deep vein thrombosis and pulmonary embolism following 5-10 days of initial therapy with a parenteral anticoagulant. The recommended dose for this indication is 60 mg once a day. For patients with a creatinine clearance of 15-50 mL/min, or who weigh up to 60 kg (about 132 pounds), or who are taking “certain P-glycoprotein inhibitors,” the 30-mg/day dose is recommended.

Approval for the nonvalvular AF indication was based on ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation) study, comparing once-daily edoxaban (60 mg and 30 mg) to warfarin in 21,015 patients with nonvalvular AF, at a moderate to high risk of thromboembolic events (N. Engl. J. Med. 2013;369:2093-104). Over a median of almost 3 years, both doses were noninferior to warfarin in the primary efficacy endpoint, the occurrence of first stroke or of a systemic embolic event. Overall, major bleeding events were significantly lower among those on the 60-mg and 30-mg doses, compared with those on warfarin. However, the rate of ischemic stroke was higher relative to warfarin in patients with a creatinine clearance over 95 mL/min.

About half of the edoxaban dose is eliminated by the kidneys, and patients with a creatinine clearance above 95 mL/min have lower plasma edoxaban levels, according to a statement in the clinical trials section of the prescribing information, which adds: “Given the clear relationship of dose and blood levels to effectiveness in the ENGAGE AF-TIMI 48 study, it could be anticipated that patients with better renal function would show a smaller effect of Savaysa, compared to warfarin than would patients with mildly impaired renal function, and this was in fact observed.”

Approval of the DVT and PE indication was based on the Hokusai-VTE study of about 8,200 people comparing edoxaban to warfarin, which found that the edoxaban 60 mg once a day was noninferior to warfarin in the rate of symptomatic venous thromboembolism (3.2% vs. 3.5% in those on warfarin). The rate of major or clinically relevant nonmajor bleeding events was 8.5% among those on edoxaban vs. 10.3% in those on warfarin (N. Engl. J. Med. 2013;369:1406-15).

Bleeding and anemia were the most common adverse events among patients with nonvalvular atrial fibrillation in clinical trials, and “as with other FDA-approved anticlotting drugs, bleeding, including life-threatening bleeding, is the most serious risk with Savaysa,” the FDA statement said. Among those treated for DVT and PE, the most common adverse events were bleeding, rash, abnormal liver function tests, and anemia.

Savaysa is the fourth novel oral anticoagulant to be cleared by the FDA, after dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis).

Serious adverse events associated with edoxaban should be reported to the FDA’s MedWatch program or at 800-332-1088.

[email protected]

Edoxaban, a selective factor Xa-inhibitor, has been approved by the Food and Drug Administration for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, with a statement in the boxed warning that it should not be used in patients with normal renal function.

The warning reflects the results of a subgroup analysis in the pivotal trial, which found that the 60-mg dose was superior to warfarin in terms of reducing the stroke risk in mildly renally impaired patients, but was worse in patients with normal renal function. This was the main focus of a meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Panel meeting in October, in which the panel voted 9-1 to recommend approval of edoxaban for this indication, but had mixed opinions on whether approval should be limited to patients with mild to moderate renal impairment.

The approved prescribing information recommends that a patient’s creatinine clearance should be checked before edoxaban is prescribed. “Patients with creatinine clearance greater than 95 mL/min have an increased risk of stroke, compared to similar patients given warfarin,” and should be treated with another anticoagulant, the FDA said in the Jan. 9 statement announcing the approval. The recommended dose for those with a creatinine clearance between 50 mL/min and 95 mL/min is 60 mg once a day; for those with a creatinine clearance of 15-50 mL/min, the recommended dose is 30 mg once a day, according to the prescribing information.

Edoxaban, the fourth novel oral anticoagulant drug approved by the FDA, will be marketed as Savaysa by Daiichi Sankyo. It was also approved to treat deep vein thrombosis and pulmonary embolism following 5-10 days of initial therapy with a parenteral anticoagulant. The recommended dose for this indication is 60 mg once a day. For patients with a creatinine clearance of 15-50 mL/min, or who weigh up to 60 kg (about 132 pounds), or who are taking “certain P-glycoprotein inhibitors,” the 30-mg/day dose is recommended.

Approval for the nonvalvular AF indication was based on ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation) study, comparing once-daily edoxaban (60 mg and 30 mg) to warfarin in 21,015 patients with nonvalvular AF, at a moderate to high risk of thromboembolic events (N. Engl. J. Med. 2013;369:2093-104). Over a median of almost 3 years, both doses were noninferior to warfarin in the primary efficacy endpoint, the occurrence of first stroke or of a systemic embolic event. Overall, major bleeding events were significantly lower among those on the 60-mg and 30-mg doses, compared with those on warfarin. However, the rate of ischemic stroke was higher relative to warfarin in patients with a creatinine clearance over 95 mL/min.

About half of the edoxaban dose is eliminated by the kidneys, and patients with a creatinine clearance above 95 mL/min have lower plasma edoxaban levels, according to a statement in the clinical trials section of the prescribing information, which adds: “Given the clear relationship of dose and blood levels to effectiveness in the ENGAGE AF-TIMI 48 study, it could be anticipated that patients with better renal function would show a smaller effect of Savaysa, compared to warfarin than would patients with mildly impaired renal function, and this was in fact observed.”

Approval of the DVT and PE indication was based on the Hokusai-VTE study of about 8,200 people comparing edoxaban to warfarin, which found that the edoxaban 60 mg once a day was noninferior to warfarin in the rate of symptomatic venous thromboembolism (3.2% vs. 3.5% in those on warfarin). The rate of major or clinically relevant nonmajor bleeding events was 8.5% among those on edoxaban vs. 10.3% in those on warfarin (N. Engl. J. Med. 2013;369:1406-15).

Bleeding and anemia were the most common adverse events among patients with nonvalvular atrial fibrillation in clinical trials, and “as with other FDA-approved anticlotting drugs, bleeding, including life-threatening bleeding, is the most serious risk with Savaysa,” the FDA statement said. Among those treated for DVT and PE, the most common adverse events were bleeding, rash, abnormal liver function tests, and anemia.

Savaysa is the fourth novel oral anticoagulant to be cleared by the FDA, after dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis).

Serious adverse events associated with edoxaban should be reported to the FDA’s MedWatch program or at 800-332-1088.

[email protected]

CHICAGO – Patients with atrial fibrillation who frequently have a supratherapeutic international normalized ratio are at sharply increased risk for developing dementia, according to a large observational study.

“We postulate that the mechanism is an accumulation of microbleeds in the brain,” Dr. T. Jared Bunch said at the American Heart Association Scientific Sessions.

“In patients with hypertension, a condition that’s extremely common with atrial fibrillation, these repetitive small bleeds are preferentially in the hippocampus, where memory is stored,” added Dr. Bunch, who is medical director for heart rhythm services at the Intermountain Medical Center Heart Institute in Salt Lake City.

He presented a study of 1,031 patients with atrial fibrillation (AF) in Intermountain’s centralized anticoagulation service. All were on dual therapy with warfarin plus aspirin or, much less commonly, another antiplatelet agent. At baseline, their average age was in the early- to mid-70s, and none of the subjects had a history of stroke or any notes in their medical record suggestive of early cognitive decline. At this dedicated anticoagulation center, their INR was measured on a weekly or biweekly basis, as a result of which their average time spent in the therapeutic range of 2.0-3.0 was relatively high at nearly 70%.

The increased risk of dementia in patients with AF has previously been recognized. The association is stronger in patients under age 75 than in those who are older. But the mechanism has been unknown. Dr. Bunch and coinvestigators decided to test their hypothesis that the mechanism involves microbleeds secondary to long-term overanticoagulation by dividing the patients into three groups based upon their percentage of INR measurements above 3.0 during a mean follow-up of more than 4 and up to a maximum of 10 years: 240 patients had a supratherapeutic INR 25% of the time or more; 374 did so less than 10% of the time; and 417 had an elevated INR 10%-24% of the time.

The incidence of dementia diagnosed by a consultant neurologist during follow-up was 5.8% in the group with an INR above 3.0 at least 25% of the time, more than twice the 2.7% rate in patients with a high INR less than 10% of the time. In the middle group, the incidence of dementia was 4.1%. In a multivariate Cox regression analysis, having an INR above 3.0 on at least 25% of occasions was independently associated with a 2.59-fold increased risk of developing dementia, making it by far the most potent risk factor in their analysis.

The next step in their research will be to perform serial brain imaging and volumetric scans, Dr. Bunch said. Also, he and his coworkers are 3 years into an ongoing study looking at the incidence of dementia in AF patients on the various novel oral anticoagulants, where INR is a nonissue. Their hypothesis is the dementia risk will be lower than in patients on warfarin. Dr. Bunch has particularly high hopes for AF patients on apixaban (Eliquis) because it’s known to have a reduced risk of large bleeds, stroke, and GI bleeding; the hope is it will cause fewer cerebral microbleeds as well.

In an interview, the cardiologist said he believes his study showing an increased risk of dementia in AF patients with supratherapeutic INRs on warfarin plus antiplatelet therapy holds several important lessons for AF patients and physicians alike.

For patients, the message is don’t just start taking aspirin on your own because you’ve read it’s good for your heart or may reduce cancer risk; consult your physician.

And for physicians, it’s important to ask all patients on warfarin if they’re using aspirin; many don’t ask. Also, periodically reconsider the need for dual therapy with warfarin and aspirin.

“We find the risks of stroke and bleeding change dynamically over time, so the initial therapy for stroke prevention may not be the ideal therapy after 5-10 years,” Dr. Bunch said.

Lastly, for patients who are overanticoagulated on a substantial percentage of their INR measurements, it’s essential to consider a change in strategy. Either follow their INRs more closely and adjust warfarin dosing accordingly, or switch to one of the novel, more predictable oral anticoagulants, he concluded.

This study was funded internally by Intermountain Healthcare. Dr. Bunch reported having no financial conflicts.

[email protected]

CHICAGO – Patients with atrial fibrillation who frequently have a supratherapeutic international normalized ratio are at sharply increased risk for developing dementia, according to a large observational study.

“We postulate that the mechanism is an accumulation of microbleeds in the brain,” Dr. T. Jared Bunch said at the American Heart Association Scientific Sessions.

“In patients with hypertension, a condition that’s extremely common with atrial fibrillation, these repetitive small bleeds are preferentially in the hippocampus, where memory is stored,” added Dr. Bunch, who is medical director for heart rhythm services at the Intermountain Medical Center Heart Institute in Salt Lake City.

He presented a study of 1,031 patients with atrial fibrillation (AF) in Intermountain’s centralized anticoagulation service. All were on dual therapy with warfarin plus aspirin or, much less commonly, another antiplatelet agent. At baseline, their average age was in the early- to mid-70s, and none of the subjects had a history of stroke or any notes in their medical record suggestive of early cognitive decline. At this dedicated anticoagulation center, their INR was measured on a weekly or biweekly basis, as a result of which their average time spent in the therapeutic range of 2.0-3.0 was relatively high at nearly 70%.

The increased risk of dementia in patients with AF has previously been recognized. The association is stronger in patients under age 75 than in those who are older. But the mechanism has been unknown. Dr. Bunch and coinvestigators decided to test their hypothesis that the mechanism involves microbleeds secondary to long-term overanticoagulation by dividing the patients into three groups based upon their percentage of INR measurements above 3.0 during a mean follow-up of more than 4 and up to a maximum of 10 years: 240 patients had a supratherapeutic INR 25% of the time or more; 374 did so less than 10% of the time; and 417 had an elevated INR 10%-24% of the time.

The incidence of dementia diagnosed by a consultant neurologist during follow-up was 5.8% in the group with an INR above 3.0 at least 25% of the time, more than twice the 2.7% rate in patients with a high INR less than 10% of the time. In the middle group, the incidence of dementia was 4.1%. In a multivariate Cox regression analysis, having an INR above 3.0 on at least 25% of occasions was independently associated with a 2.59-fold increased risk of developing dementia, making it by far the most potent risk factor in their analysis.

The next step in their research will be to perform serial brain imaging and volumetric scans, Dr. Bunch said. Also, he and his coworkers are 3 years into an ongoing study looking at the incidence of dementia in AF patients on the various novel oral anticoagulants, where INR is a nonissue. Their hypothesis is the dementia risk will be lower than in patients on warfarin. Dr. Bunch has particularly high hopes for AF patients on apixaban (Eliquis) because it’s known to have a reduced risk of large bleeds, stroke, and GI bleeding; the hope is it will cause fewer cerebral microbleeds as well.

In an interview, the cardiologist said he believes his study showing an increased risk of dementia in AF patients with supratherapeutic INRs on warfarin plus antiplatelet therapy holds several important lessons for AF patients and physicians alike.

For patients, the message is don’t just start taking aspirin on your own because you’ve read it’s good for your heart or may reduce cancer risk; consult your physician.

And for physicians, it’s important to ask all patients on warfarin if they’re using aspirin; many don’t ask. Also, periodically reconsider the need for dual therapy with warfarin and aspirin.

“We find the risks of stroke and bleeding change dynamically over time, so the initial therapy for stroke prevention may not be the ideal therapy after 5-10 years,” Dr. Bunch said.

Lastly, for patients who are overanticoagulated on a substantial percentage of their INR measurements, it’s essential to consider a change in strategy. Either follow their INRs more closely and adjust warfarin dosing accordingly, or switch to one of the novel, more predictable oral anticoagulants, he concluded.

This study was funded internally by Intermountain Healthcare. Dr. Bunch reported having no financial conflicts.

[email protected]

CHICAGO – Patients with atrial fibrillation who frequently have a supratherapeutic international normalized ratio are at sharply increased risk for developing dementia, according to a large observational study.

“We postulate that the mechanism is an accumulation of microbleeds in the brain,” Dr. T. Jared Bunch said at the American Heart Association Scientific Sessions.

“In patients with hypertension, a condition that’s extremely common with atrial fibrillation, these repetitive small bleeds are preferentially in the hippocampus, where memory is stored,” added Dr. Bunch, who is medical director for heart rhythm services at the Intermountain Medical Center Heart Institute in Salt Lake City.

He presented a study of 1,031 patients with atrial fibrillation (AF) in Intermountain’s centralized anticoagulation service. All were on dual therapy with warfarin plus aspirin or, much less commonly, another antiplatelet agent. At baseline, their average age was in the early- to mid-70s, and none of the subjects had a history of stroke or any notes in their medical record suggestive of early cognitive decline. At this dedicated anticoagulation center, their INR was measured on a weekly or biweekly basis, as a result of which their average time spent in the therapeutic range of 2.0-3.0 was relatively high at nearly 70%.

The increased risk of dementia in patients with AF has previously been recognized. The association is stronger in patients under age 75 than in those who are older. But the mechanism has been unknown. Dr. Bunch and coinvestigators decided to test their hypothesis that the mechanism involves microbleeds secondary to long-term overanticoagulation by dividing the patients into three groups based upon their percentage of INR measurements above 3.0 during a mean follow-up of more than 4 and up to a maximum of 10 years: 240 patients had a supratherapeutic INR 25% of the time or more; 374 did so less than 10% of the time; and 417 had an elevated INR 10%-24% of the time.

The incidence of dementia diagnosed by a consultant neurologist during follow-up was 5.8% in the group with an INR above 3.0 at least 25% of the time, more than twice the 2.7% rate in patients with a high INR less than 10% of the time. In the middle group, the incidence of dementia was 4.1%. In a multivariate Cox regression analysis, having an INR above 3.0 on at least 25% of occasions was independently associated with a 2.59-fold increased risk of developing dementia, making it by far the most potent risk factor in their analysis.

The next step in their research will be to perform serial brain imaging and volumetric scans, Dr. Bunch said. Also, he and his coworkers are 3 years into an ongoing study looking at the incidence of dementia in AF patients on the various novel oral anticoagulants, where INR is a nonissue. Their hypothesis is the dementia risk will be lower than in patients on warfarin. Dr. Bunch has particularly high hopes for AF patients on apixaban (Eliquis) because it’s known to have a reduced risk of large bleeds, stroke, and GI bleeding; the hope is it will cause fewer cerebral microbleeds as well.

In an interview, the cardiologist said he believes his study showing an increased risk of dementia in AF patients with supratherapeutic INRs on warfarin plus antiplatelet therapy holds several important lessons for AF patients and physicians alike.

For patients, the message is don’t just start taking aspirin on your own because you’ve read it’s good for your heart or may reduce cancer risk; consult your physician.

And for physicians, it’s important to ask all patients on warfarin if they’re using aspirin; many don’t ask. Also, periodically reconsider the need for dual therapy with warfarin and aspirin.

“We find the risks of stroke and bleeding change dynamically over time, so the initial therapy for stroke prevention may not be the ideal therapy after 5-10 years,” Dr. Bunch said.

Lastly, for patients who are overanticoagulated on a substantial percentage of their INR measurements, it’s essential to consider a change in strategy. Either follow their INRs more closely and adjust warfarin dosing accordingly, or switch to one of the novel, more predictable oral anticoagulants, he concluded.

This study was funded internally by Intermountain Healthcare. Dr. Bunch reported having no financial conflicts.

[email protected]

CHICAGO – Implementation of preoperative venous thromboembolism prophylaxis requires a highly individualized approach and a little boost from information technology, one expert suggested.

“What may not be appreciated by some vascular surgeons is that for certain procedures we do, our patients actually have a high VTE [venous thromboembolism] risk. I know people think, ‘We use heparin, so our patients aren’t at high risk,’ but they actually are,” Dr. Melina Kibbe said at a symposium on vascular surgery sponsored by Northwestern University.

The VTE risk is 4.2% for open thoracoabdominal aortic aneurysm repair and 2.2% for thoracic endovascular aortic repair in the American College of Surgeons National Surgical Quality Improvement Program database. That may be an underestimation, however, because the NSQIP database captures only symptomatic events documented by imaging and those events occurring in the first 30 days after surgery.

Patrice Wendling/Frontline Medical News

Smaller studies looking at the problem prospectively suggest the VTE risk is closer to 2%-12% after open aortic surgery and 5.3% after endovascular aortic repair, she said.

Add to that the U.S. Surgeon General’s 2008 call to action to prevent VTE and the Institute of Medicine’s stance that failure to provide VTE prophylaxis qualifies as a medical error, and it would be tempting for vascular surgeons to prescribe pharmacologic prophylaxis for all of their patients, or at least do so based on the type of procedure.

“But VTE formation is really secondary to patient-specific and procedure-related factors,” said Dr. Kibbe, a professor of vascular surgery at Northwestern University in Chicago.

She highlighted five current VTE risk assessment models (RAMs) and the potential returns when RAMs are incorporated into clinical decision support systems.

• Kucher model. One of the earlier and most straightforward RAMs is the Kucher model. It assessed eight weighted risk factors (advanced age, obesity, bed rest, hormone replacement therapy/oral contraceptives, major surgery, cancer, prior VTE, and hypercoagulability) and provided surgeons with electronic alerts regarding prophylaxis.

VTE rates dropped from 8.2% to 4.9% in the high-risk category (score ≥ 4) with the use of the simple physician reminders (N. Engl. J. Med. 2005;352:969-77). Prospective validation showed that VTE increased proportionally with higher scores, Dr. Kibbe said. On the other hand, the model lacked sensitivity at low VTE risk, because 20% of patients with a score of 4 or less actually had VTEs.

“So, while it was simple, it only works well for the high-risk category,” she said.

• Rogers model. One of the most vigorously studied and developed RAMs is the Rogers model (J. Am. Coll. Surg. 2007;204:1211-21). It identified 15 variables (including lab values, patient characteristics, disease states, work relative-value unit, and type of operation) that were independently associated with VTE formation among 183,609 patients undergoing general, vascular, or thoracic procedures at 142 Veterans Health Administration and private hospitals. Each variable is assigned a value from 0 to 9 and added together to create a Rogers score.

Validation showed that VTE risk correlates with the Rogers score, rising from 0.11% for patients with a low score (< 7) to 1.32% for those with a high score (> 10), Dr. Kibbe said. Criticisms of the model are that it is complex, VTE incidence in the entire cohort was low at just 0.63%, the type of VTE prophylaxis used was unclear, and the model lacks prospective validation in a vascular surgery cohort.

• Caprini model. The most commonly used RAM is the 2005 Caprini model (Dis. Mon. 2005;51:70-8), which assigns a weighted score based on more than 30 VTE risk factors compiled by the authors. It has been prospectively validated in numerous studies and shown to accurately stratify 30-day VTE risk at 0.5% for patients at very low risk, 1.5% for low risk, 3% for moderate risk, and 6% for high risk.

The Caprini model, however, was not developed with the same rigor as the Rogers RAM, some of the risk factors have been shown not to be a risk for VTE, and it is complex, Dr. Kibbe observed.

• Pannucci model. The Pannucci model was created specifically to counteract the complexity of the Rogers and Caprini RAMs and incorporates only seven risk factors (personal history of VTE, current cancer, age ≥ 60 years, body mass index ≥ 40 kg/m², male sex, sepsis/septic shock/systemic inflammatory response syndrome, and family history of VTE) into a weighted index for 90-day VTE risk (Chest 2014;145:567-73). The model was developed using a statewide database and a derivation cohort made up of 20% vascular surgery patients.

Both the derivation and validation cohorts identified an 18-fold variation in VTE risk from the lowest- to highest-risk surgical population, showing that the model stratifies patients correctly. Further prospective validation is needed, Dr. Kibbe said.

• Scarborough model. Finally, in an attempt to develop a RAM specific to vascular surgery patients, Dr. John Scarborough and colleagues examined 6,035 patients undergoing open AAA repair in the NSQIP database. The 30-day VTE rate was 2.4% for the entire cohort. Eight independent perioperative risk factors were identified and used to create a nonweighted scoring system (J. Am. Coll. Surg. 2012;214:620-6).

Overall, 65% of patients had 0-1 risk factor and a VTE incidence of 1.5%, while 15% had 3 or more risk factors and a VTE incidence of 6.1%. The Scarborough model has good risk stratification, Dr. Kibbe said, but it is limited by the aforementioned criticisms regarding the NSQIP database, and it also needs prospective validation.

“We all know that proper VTE prophylaxis is very important for our patients; but we need mechanisms by which the attention given to this need for prophylaxis, which is a lot, is turned into proper implementation,” she said.

For Dr. Kibbe and her colleagues, proper implementation meant developing a RAM that was incorporated into the electronic medical record system for all surgical patients at the Jesse Brown VA Medical Center in Chicago. Clinicians were prompted to complete the RAM upon placing orders for preanesthesia testing clearance, and the clinical decision support system would provide a recommended prophylaxis regimen and easily selected electronic orders that could be signed.

A pre- and postimplementation analysis involving 400 consecutive patients revealed an 82% increase in patients with preoperative VTE prophylaxis ordered (22% vs. 40%), a 75% decrease in inappropriate cancellation of orders more than 12 hours before surgery (37% vs. 9%), and a nearly sevenfold increase in the number of patients receiving pharmacologic and mechanical prophylaxis (5% vs. 32%), she said. There was an 80% and 36% decline in DVT rates at 30 and 90 days postoperative, but event rates were too low to detect a significant difference (J. Vasc. Surg. 2010;51:648-54).

Dr. Kibbe reported having no financial disclosures.

[email protected]

CHICAGO – Implementation of preoperative venous thromboembolism prophylaxis requires a highly individualized approach and a little boost from information technology, one expert suggested.

“What may not be appreciated by some vascular surgeons is that for certain procedures we do, our patients actually have a high VTE [venous thromboembolism] risk. I know people think, ‘We use heparin, so our patients aren’t at high risk,’ but they actually are,” Dr. Melina Kibbe said at a symposium on vascular surgery sponsored by Northwestern University.

The VTE risk is 4.2% for open thoracoabdominal aortic aneurysm repair and 2.2% for thoracic endovascular aortic repair in the American College of Surgeons National Surgical Quality Improvement Program database. That may be an underestimation, however, because the NSQIP database captures only symptomatic events documented by imaging and those events occurring in the first 30 days after surgery.

Patrice Wendling/Frontline Medical News

Smaller studies looking at the problem prospectively suggest the VTE risk is closer to 2%-12% after open aortic surgery and 5.3% after endovascular aortic repair, she said.

Add to that the U.S. Surgeon General’s 2008 call to action to prevent VTE and the Institute of Medicine’s stance that failure to provide VTE prophylaxis qualifies as a medical error, and it would be tempting for vascular surgeons to prescribe pharmacologic prophylaxis for all of their patients, or at least do so based on the type of procedure.

“But VTE formation is really secondary to patient-specific and procedure-related factors,” said Dr. Kibbe, a professor of vascular surgery at Northwestern University in Chicago.

She highlighted five current VTE risk assessment models (RAMs) and the potential returns when RAMs are incorporated into clinical decision support systems.

• Kucher model. One of the earlier and most straightforward RAMs is the Kucher model. It assessed eight weighted risk factors (advanced age, obesity, bed rest, hormone replacement therapy/oral contraceptives, major surgery, cancer, prior VTE, and hypercoagulability) and provided surgeons with electronic alerts regarding prophylaxis.

VTE rates dropped from 8.2% to 4.9% in the high-risk category (score ≥ 4) with the use of the simple physician reminders (N. Engl. J. Med. 2005;352:969-77). Prospective validation showed that VTE increased proportionally with higher scores, Dr. Kibbe said. On the other hand, the model lacked sensitivity at low VTE risk, because 20% of patients with a score of 4 or less actually had VTEs.

“So, while it was simple, it only works well for the high-risk category,” she said.

• Rogers model. One of the most vigorously studied and developed RAMs is the Rogers model (J. Am. Coll. Surg. 2007;204:1211-21). It identified 15 variables (including lab values, patient characteristics, disease states, work relative-value unit, and type of operation) that were independently associated with VTE formation among 183,609 patients undergoing general, vascular, or thoracic procedures at 142 Veterans Health Administration and private hospitals. Each variable is assigned a value from 0 to 9 and added together to create a Rogers score.

Validation showed that VTE risk correlates with the Rogers score, rising from 0.11% for patients with a low score (< 7) to 1.32% for those with a high score (> 10), Dr. Kibbe said. Criticisms of the model are that it is complex, VTE incidence in the entire cohort was low at just 0.63%, the type of VTE prophylaxis used was unclear, and the model lacks prospective validation in a vascular surgery cohort.

• Caprini model. The most commonly used RAM is the 2005 Caprini model (Dis. Mon. 2005;51:70-8), which assigns a weighted score based on more than 30 VTE risk factors compiled by the authors. It has been prospectively validated in numerous studies and shown to accurately stratify 30-day VTE risk at 0.5% for patients at very low risk, 1.5% for low risk, 3% for moderate risk, and 6% for high risk.

The Caprini model, however, was not developed with the same rigor as the Rogers RAM, some of the risk factors have been shown not to be a risk for VTE, and it is complex, Dr. Kibbe observed.

• Pannucci model. The Pannucci model was created specifically to counteract the complexity of the Rogers and Caprini RAMs and incorporates only seven risk factors (personal history of VTE, current cancer, age ≥ 60 years, body mass index ≥ 40 kg/m², male sex, sepsis/septic shock/systemic inflammatory response syndrome, and family history of VTE) into a weighted index for 90-day VTE risk (Chest 2014;145:567-73). The model was developed using a statewide database and a derivation cohort made up of 20% vascular surgery patients.

Both the derivation and validation cohorts identified an 18-fold variation in VTE risk from the lowest- to highest-risk surgical population, showing that the model stratifies patients correctly. Further prospective validation is needed, Dr. Kibbe said.

• Scarborough model. Finally, in an attempt to develop a RAM specific to vascular surgery patients, Dr. John Scarborough and colleagues examined 6,035 patients undergoing open AAA repair in the NSQIP database. The 30-day VTE rate was 2.4% for the entire cohort. Eight independent perioperative risk factors were identified and used to create a nonweighted scoring system (J. Am. Coll. Surg. 2012;214:620-6).

Overall, 65% of patients had 0-1 risk factor and a VTE incidence of 1.5%, while 15% had 3 or more risk factors and a VTE incidence of 6.1%. The Scarborough model has good risk stratification, Dr. Kibbe said, but it is limited by the aforementioned criticisms regarding the NSQIP database, and it also needs prospective validation.

“We all know that proper VTE prophylaxis is very important for our patients; but we need mechanisms by which the attention given to this need for prophylaxis, which is a lot, is turned into proper implementation,” she said.

For Dr. Kibbe and her colleagues, proper implementation meant developing a RAM that was incorporated into the electronic medical record system for all surgical patients at the Jesse Brown VA Medical Center in Chicago. Clinicians were prompted to complete the RAM upon placing orders for preanesthesia testing clearance, and the clinical decision support system would provide a recommended prophylaxis regimen and easily selected electronic orders that could be signed.

A pre- and postimplementation analysis involving 400 consecutive patients revealed an 82% increase in patients with preoperative VTE prophylaxis ordered (22% vs. 40%), a 75% decrease in inappropriate cancellation of orders more than 12 hours before surgery (37% vs. 9%), and a nearly sevenfold increase in the number of patients receiving pharmacologic and mechanical prophylaxis (5% vs. 32%), she said. There was an 80% and 36% decline in DVT rates at 30 and 90 days postoperative, but event rates were too low to detect a significant difference (J. Vasc. Surg. 2010;51:648-54).

Dr. Kibbe reported having no financial disclosures.

[email protected]

CHICAGO – Implementation of preoperative venous thromboembolism prophylaxis requires a highly individualized approach and a little boost from information technology, one expert suggested.

“What may not be appreciated by some vascular surgeons is that for certain procedures we do, our patients actually have a high VTE [venous thromboembolism] risk. I know people think, ‘We use heparin, so our patients aren’t at high risk,’ but they actually are,” Dr. Melina Kibbe said at a symposium on vascular surgery sponsored by Northwestern University.

The VTE risk is 4.2% for open thoracoabdominal aortic aneurysm repair and 2.2% for thoracic endovascular aortic repair in the American College of Surgeons National Surgical Quality Improvement Program database. That may be an underestimation, however, because the NSQIP database captures only symptomatic events documented by imaging and those events occurring in the first 30 days after surgery.

Patrice Wendling/Frontline Medical News

Smaller studies looking at the problem prospectively suggest the VTE risk is closer to 2%-12% after open aortic surgery and 5.3% after endovascular aortic repair, she said.

Add to that the U.S. Surgeon General’s 2008 call to action to prevent VTE and the Institute of Medicine’s stance that failure to provide VTE prophylaxis qualifies as a medical error, and it would be tempting for vascular surgeons to prescribe pharmacologic prophylaxis for all of their patients, or at least do so based on the type of procedure.

“But VTE formation is really secondary to patient-specific and procedure-related factors,” said Dr. Kibbe, a professor of vascular surgery at Northwestern University in Chicago.

She highlighted five current VTE risk assessment models (RAMs) and the potential returns when RAMs are incorporated into clinical decision support systems.

• Kucher model. One of the earlier and most straightforward RAMs is the Kucher model. It assessed eight weighted risk factors (advanced age, obesity, bed rest, hormone replacement therapy/oral contraceptives, major surgery, cancer, prior VTE, and hypercoagulability) and provided surgeons with electronic alerts regarding prophylaxis.

VTE rates dropped from 8.2% to 4.9% in the high-risk category (score ≥ 4) with the use of the simple physician reminders (N. Engl. J. Med. 2005;352:969-77). Prospective validation showed that VTE increased proportionally with higher scores, Dr. Kibbe said. On the other hand, the model lacked sensitivity at low VTE risk, because 20% of patients with a score of 4 or less actually had VTEs.

“So, while it was simple, it only works well for the high-risk category,” she said.

• Rogers model. One of the most vigorously studied and developed RAMs is the Rogers model (J. Am. Coll. Surg. 2007;204:1211-21). It identified 15 variables (including lab values, patient characteristics, disease states, work relative-value unit, and type of operation) that were independently associated with VTE formation among 183,609 patients undergoing general, vascular, or thoracic procedures at 142 Veterans Health Administration and private hospitals. Each variable is assigned a value from 0 to 9 and added together to create a Rogers score.

Validation showed that VTE risk correlates with the Rogers score, rising from 0.11% for patients with a low score (< 7) to 1.32% for those with a high score (> 10), Dr. Kibbe said. Criticisms of the model are that it is complex, VTE incidence in the entire cohort was low at just 0.63%, the type of VTE prophylaxis used was unclear, and the model lacks prospective validation in a vascular surgery cohort.

• Caprini model. The most commonly used RAM is the 2005 Caprini model (Dis. Mon. 2005;51:70-8), which assigns a weighted score based on more than 30 VTE risk factors compiled by the authors. It has been prospectively validated in numerous studies and shown to accurately stratify 30-day VTE risk at 0.5% for patients at very low risk, 1.5% for low risk, 3% for moderate risk, and 6% for high risk.

The Caprini model, however, was not developed with the same rigor as the Rogers RAM, some of the risk factors have been shown not to be a risk for VTE, and it is complex, Dr. Kibbe observed.

• Pannucci model. The Pannucci model was created specifically to counteract the complexity of the Rogers and Caprini RAMs and incorporates only seven risk factors (personal history of VTE, current cancer, age ≥ 60 years, body mass index ≥ 40 kg/m², male sex, sepsis/septic shock/systemic inflammatory response syndrome, and family history of VTE) into a weighted index for 90-day VTE risk (Chest 2014;145:567-73). The model was developed using a statewide database and a derivation cohort made up of 20% vascular surgery patients.

Both the derivation and validation cohorts identified an 18-fold variation in VTE risk from the lowest- to highest-risk surgical population, showing that the model stratifies patients correctly. Further prospective validation is needed, Dr. Kibbe said.

• Scarborough model. Finally, in an attempt to develop a RAM specific to vascular surgery patients, Dr. John Scarborough and colleagues examined 6,035 patients undergoing open AAA repair in the NSQIP database. The 30-day VTE rate was 2.4% for the entire cohort. Eight independent perioperative risk factors were identified and used to create a nonweighted scoring system (J. Am. Coll. Surg. 2012;214:620-6).

Overall, 65% of patients had 0-1 risk factor and a VTE incidence of 1.5%, while 15% had 3 or more risk factors and a VTE incidence of 6.1%. The Scarborough model has good risk stratification, Dr. Kibbe said, but it is limited by the aforementioned criticisms regarding the NSQIP database, and it also needs prospective validation.

“We all know that proper VTE prophylaxis is very important for our patients; but we need mechanisms by which the attention given to this need for prophylaxis, which is a lot, is turned into proper implementation,” she said.

For Dr. Kibbe and her colleagues, proper implementation meant developing a RAM that was incorporated into the electronic medical record system for all surgical patients at the Jesse Brown VA Medical Center in Chicago. Clinicians were prompted to complete the RAM upon placing orders for preanesthesia testing clearance, and the clinical decision support system would provide a recommended prophylaxis regimen and easily selected electronic orders that could be signed.

A pre- and postimplementation analysis involving 400 consecutive patients revealed an 82% increase in patients with preoperative VTE prophylaxis ordered (22% vs. 40%), a 75% decrease in inappropriate cancellation of orders more than 12 hours before surgery (37% vs. 9%), and a nearly sevenfold increase in the number of patients receiving pharmacologic and mechanical prophylaxis (5% vs. 32%), she said. There was an 80% and 36% decline in DVT rates at 30 and 90 days postoperative, but event rates were too low to detect a significant difference (J. Vasc. Surg. 2010;51:648-54).

Dr. Kibbe reported having no financial disclosures.

[email protected]

CHICAGO – The ORBIT-AF bleeding risk score is a simple, user-friendly new tool for assessing the risk of major bleeding in patients with atrial fibrillation on oral anticoagulation, Emily C. O’Brien, Ph.D., announced at the American Heart Association scientific sessions.

This novel score offers significant advantages over existing bleeding risk scores, including HAS-BLED and ATRIA. Those scores were developed on the basis of small numbers of bleeding events, they show inconsistent performance, and their calculation requires data that’s often not readily accessible in busy daily practice, according to Dr. O’Brien of the Duke Clinical Research Institute in Durham, N.C.

Bruce Jancin/Frontline Medical News

The new score was derived from the ORBIT-AF registry, the largest prospective U.S. registry of patients with atrial fibrillation (AF).

The score was constructed using data on 7,411 AF patients in community practice settings at 173 U.S. sites. All subjects were on oral anticoagulant therapy at baseline. During 2 years of prospective follow-up, 581 patients (7.8%) experienced a major bleeding event as defined by International Society on Thrombosis and Haemostasis criteria.

After sifting through numerous potential candidate variables, Dr. O’Brien and coinvestigators settled upon five they identified as the most potent and practical baseline predictors of major bleeding risk while on oral anticoagulation. Then they packaged them in a convenient acronym: ORBIT, for Older than 74, Renal insufficiency with an estimated glomerular filtration rate below 60 mL/minute per/1.73 m², Bleeding history, Insufficient hemoglobin/hematocrit or anemia, and Treatment with an antiplatelet agent. The two strongest predictors – renal insufficiency and bleeding history– were awarded two points each; the others are worth one point each.

The observed major bleeding rate among patients enrolled in the ORBIT-AF registry rose with an increasing risk score. The same was true upon application of the ORBIT bleeding score to an independent study sample comprised of participants in the ROCKET-AF randomized clinical trial.

Dr. O’Brien also compared the performance of the ORBIT bleeding score to that of two existing bleeding risk scores – HAS-BLED and ATRIA – in the ORBIT-AF and ROCKET-AF cohorts. The simpler, more user friendly ORBIT bleeding score had a C-statistic of 0.67, similar to the 0.64 for HAS-BLED and 0.66 for ATRIA.

Thus, the ORBIT bleeding score is a practical new tool for use alongside the CHA2DS2-VASc stroke risk score to support clinical decision making regarding whether or not to place an individual AF patient on oral anticoagulation, Dr. O’Brien concluded.

She reported having no financial conflicts regarding this study. The ORBIT-AF registry is sponsored by Janssen.

[email protected]

CHICAGO – The ORBIT-AF bleeding risk score is a simple, user-friendly new tool for assessing the risk of major bleeding in patients with atrial fibrillation on oral anticoagulation, Emily C. O’Brien, Ph.D., announced at the American Heart Association scientific sessions.

This novel score offers significant advantages over existing bleeding risk scores, including HAS-BLED and ATRIA. Those scores were developed on the basis of small numbers of bleeding events, they show inconsistent performance, and their calculation requires data that’s often not readily accessible in busy daily practice, according to Dr. O’Brien of the Duke Clinical Research Institute in Durham, N.C.

Bruce Jancin/Frontline Medical News

The new score was derived from the ORBIT-AF registry, the largest prospective U.S. registry of patients with atrial fibrillation (AF).

The score was constructed using data on 7,411 AF patients in community practice settings at 173 U.S. sites. All subjects were on oral anticoagulant therapy at baseline. During 2 years of prospective follow-up, 581 patients (7.8%) experienced a major bleeding event as defined by International Society on Thrombosis and Haemostasis criteria.

After sifting through numerous potential candidate variables, Dr. O’Brien and coinvestigators settled upon five they identified as the most potent and practical baseline predictors of major bleeding risk while on oral anticoagulation. Then they packaged them in a convenient acronym: ORBIT, for Older than 74, Renal insufficiency with an estimated glomerular filtration rate below 60 mL/minute per/1.73 m², Bleeding history, Insufficient hemoglobin/hematocrit or anemia, and Treatment with an antiplatelet agent. The two strongest predictors – renal insufficiency and bleeding history– were awarded two points each; the others are worth one point each.

The observed major bleeding rate among patients enrolled in the ORBIT-AF registry rose with an increasing risk score. The same was true upon application of the ORBIT bleeding score to an independent study sample comprised of participants in the ROCKET-AF randomized clinical trial.

Dr. O’Brien also compared the performance of the ORBIT bleeding score to that of two existing bleeding risk scores – HAS-BLED and ATRIA – in the ORBIT-AF and ROCKET-AF cohorts. The simpler, more user friendly ORBIT bleeding score had a C-statistic of 0.67, similar to the 0.64 for HAS-BLED and 0.66 for ATRIA.

Thus, the ORBIT bleeding score is a practical new tool for use alongside the CHA2DS2-VASc stroke risk score to support clinical decision making regarding whether or not to place an individual AF patient on oral anticoagulation, Dr. O’Brien concluded.

She reported having no financial conflicts regarding this study. The ORBIT-AF registry is sponsored by Janssen.

[email protected]

CHICAGO – The ORBIT-AF bleeding risk score is a simple, user-friendly new tool for assessing the risk of major bleeding in patients with atrial fibrillation on oral anticoagulation, Emily C. O’Brien, Ph.D., announced at the American Heart Association scientific sessions.

This novel score offers significant advantages over existing bleeding risk scores, including HAS-BLED and ATRIA. Those scores were developed on the basis of small numbers of bleeding events, they show inconsistent performance, and their calculation requires data that’s often not readily accessible in busy daily practice, according to Dr. O’Brien of the Duke Clinical Research Institute in Durham, N.C.

Bruce Jancin/Frontline Medical News

The new score was derived from the ORBIT-AF registry, the largest prospective U.S. registry of patients with atrial fibrillation (AF).

The score was constructed using data on 7,411 AF patients in community practice settings at 173 U.S. sites. All subjects were on oral anticoagulant therapy at baseline. During 2 years of prospective follow-up, 581 patients (7.8%) experienced a major bleeding event as defined by International Society on Thrombosis and Haemostasis criteria.

After sifting through numerous potential candidate variables, Dr. O’Brien and coinvestigators settled upon five they identified as the most potent and practical baseline predictors of major bleeding risk while on oral anticoagulation. Then they packaged them in a convenient acronym: ORBIT, for Older than 74, Renal insufficiency with an estimated glomerular filtration rate below 60 mL/minute per/1.73 m², Bleeding history, Insufficient hemoglobin/hematocrit or anemia, and Treatment with an antiplatelet agent. The two strongest predictors – renal insufficiency and bleeding history– were awarded two points each; the others are worth one point each.

The observed major bleeding rate among patients enrolled in the ORBIT-AF registry rose with an increasing risk score. The same was true upon application of the ORBIT bleeding score to an independent study sample comprised of participants in the ROCKET-AF randomized clinical trial.

Dr. O’Brien also compared the performance of the ORBIT bleeding score to that of two existing bleeding risk scores – HAS-BLED and ATRIA – in the ORBIT-AF and ROCKET-AF cohorts. The simpler, more user friendly ORBIT bleeding score had a C-statistic of 0.67, similar to the 0.64 for HAS-BLED and 0.66 for ATRIA.

Thus, the ORBIT bleeding score is a practical new tool for use alongside the CHA2DS2-VASc stroke risk score to support clinical decision making regarding whether or not to place an individual AF patient on oral anticoagulation, Dr. O’Brien concluded.

She reported having no financial conflicts regarding this study. The ORBIT-AF registry is sponsored by Janssen.

[email protected]

CHICAGO – Patients with atrial fibrillation who start treatment with a new oral anticoagulant may spend more on their medication than if they were prescribed generic warfarin, but their overall health care costs may wind up being about the same, based on an analysis of health care expense records for more than 4,500 U.S. patients.

“Despite higher anticoagulant costs, total all-cause and atrial fibrillation–related costs remain comparable” between patients prescribed warfarin and those who received the new oral anticoagulant rivaroxaban (Xarelto), said Concetta Crivera, Pharm.D., at the American Heart Association Scientific Sessions. Higher drug costs for daily treatment with rivaroxaban were offset by reduced hospital lengths of stays and hence reduced hospitalization costs, said Dr. Crivera, director of cardiovascular health economics and outcomes research at Janssen in Raritan, N.J., the company that markets rivaroxaban along with Bayer.

Mitchel L. Zoler/Frontline Medical News

“I can believe that hospitalized days would be reduced because patients treated with rivaroxaban or any of the other new oral anticoagulants don’t need to remain in the hospital while you wait for their international normalized ratio to enter the therapeutic range,” which is what happens with patients treated with warfarin, commented Dr. Jeffrey Weitz, professor of medicine and director of the Juravinski Hospital and Cancer Centre of McMaster University in Hamilton, Ont.

The new findings by Dr. Crivera “are not definitive on their own, but they add to a growing body of data that indicate that all the new oral anticoagulants are cost effective,” said Dr. Weitz, who specializes in thrombosis and anticoagulants. “The worst time for a patient on warfarin is when they start treatment. You do a disservice to patients with new-onset atrial fibrillation by using warfarin, because some patients will get into the therapeutic range but others never will. That’s why the new oral anticoagulants are better, because everybody gets into therapeutic range,” he said in an interview.

Dr. Crivera and her associates conducted a retrospective study of health records for 2,253 patients with nonvalvular atrial fibrillation (AF) who started anticoagulation treatment with rivaroxaban during the period of November 2011 (when the drug received U.S. marketing approval) through December 2012. The data came from the patient records of Humana, a U.S. HMO and insurer that covers both commercially insured patients and those covered by Medicare. The researchers matched each of the patients initiating rivaroxaban treatment with a similar patient from the Humana database with nonvalvular AF who started on warfarin during the same period. The average age of patients in the study was about 74 years, and patients in the two groups were closely matched for their demographic and clinical characteristics, including comorbidities. Data on health care use were available for patients for an average of about 4 months following their start of anticoagulant treatment.

The analysis showed that during the first months on treatment, patients prescribed rivaroxaban averaged 2.11 days of hospitalization for an AF-related episode, compared with 3.02 days for those prescribed warfarin, a statistically significant difference. Hospitalizations for any cause averaged a total of 2.71 days in the rivaroxaban group and 3.87 days in the patients on warfarin, also a significant difference, Dr. Crivera reported.

This difference in days hospitalized translated into reduced hospitalization costs, a roughly $2,000 average difference per patient in actual hospitalization costs in favor of the rivaroxaban patients for all-cause hospitalizations, and an average $1,300 difference per patient for hospitalization costs directly related to AF.

Although the rivaroxaban patients spent an average of $2,700 more per patient on pharmaceuticals for all causes, and an average $2,200 more for AF-related drugs, the total average all-cause and AF-related costs for drugs, hospitalizations, outpatient visits, and emergency department visits were similar in the two subgroups: an average total of $17,590 per patient for the rivaroxaban patients and $18,676 for warfarin patients for all causes, and an average of $7,394 for the rivaroxaban patients and $7,319 for those on warfarin for AF-related care. The between-group differences for both sets of total costs were not statistically significant.

The study was sponsored by Janssen, which along with Bayer markets rivaroxaban (Xarelto). Dr. Crivera is a Janssen employee. Dr. Weitz has been an adviser or a consultant to Janssen and Bayer and to Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Pfizer, and Portola.

[email protected]

On Twitter @mitchelzoler

CHICAGO – Patients with atrial fibrillation who start treatment with a new oral anticoagulant may spend more on their medication than if they were prescribed generic warfarin, but their overall health care costs may wind up being about the same, based on an analysis of health care expense records for more than 4,500 U.S. patients.

“Despite higher anticoagulant costs, total all-cause and atrial fibrillation–related costs remain comparable” between patients prescribed warfarin and those who received the new oral anticoagulant rivaroxaban (Xarelto), said Concetta Crivera, Pharm.D., at the American Heart Association Scientific Sessions. Higher drug costs for daily treatment with rivaroxaban were offset by reduced hospital lengths of stays and hence reduced hospitalization costs, said Dr. Crivera, director of cardiovascular health economics and outcomes research at Janssen in Raritan, N.J., the company that markets rivaroxaban along with Bayer.

Mitchel L. Zoler/Frontline Medical News

“I can believe that hospitalized days would be reduced because patients treated with rivaroxaban or any of the other new oral anticoagulants don’t need to remain in the hospital while you wait for their international normalized ratio to enter the therapeutic range,” which is what happens with patients treated with warfarin, commented Dr. Jeffrey Weitz, professor of medicine and director of the Juravinski Hospital and Cancer Centre of McMaster University in Hamilton, Ont.

The new findings by Dr. Crivera “are not definitive on their own, but they add to a growing body of data that indicate that all the new oral anticoagulants are cost effective,” said Dr. Weitz, who specializes in thrombosis and anticoagulants. “The worst time for a patient on warfarin is when they start treatment. You do a disservice to patients with new-onset atrial fibrillation by using warfarin, because some patients will get into the therapeutic range but others never will. That’s why the new oral anticoagulants are better, because everybody gets into therapeutic range,” he said in an interview.

Dr. Crivera and her associates conducted a retrospective study of health records for 2,253 patients with nonvalvular atrial fibrillation (AF) who started anticoagulation treatment with rivaroxaban during the period of November 2011 (when the drug received U.S. marketing approval) through December 2012. The data came from the patient records of Humana, a U.S. HMO and insurer that covers both commercially insured patients and those covered by Medicare. The researchers matched each of the patients initiating rivaroxaban treatment with a similar patient from the Humana database with nonvalvular AF who started on warfarin during the same period. The average age of patients in the study was about 74 years, and patients in the two groups were closely matched for their demographic and clinical characteristics, including comorbidities. Data on health care use were available for patients for an average of about 4 months following their start of anticoagulant treatment.

The analysis showed that during the first months on treatment, patients prescribed rivaroxaban averaged 2.11 days of hospitalization for an AF-related episode, compared with 3.02 days for those prescribed warfarin, a statistically significant difference. Hospitalizations for any cause averaged a total of 2.71 days in the rivaroxaban group and 3.87 days in the patients on warfarin, also a significant difference, Dr. Crivera reported.

This difference in days hospitalized translated into reduced hospitalization costs, a roughly $2,000 average difference per patient in actual hospitalization costs in favor of the rivaroxaban patients for all-cause hospitalizations, and an average $1,300 difference per patient for hospitalization costs directly related to AF.

Although the rivaroxaban patients spent an average of $2,700 more per patient on pharmaceuticals for all causes, and an average $2,200 more for AF-related drugs, the total average all-cause and AF-related costs for drugs, hospitalizations, outpatient visits, and emergency department visits were similar in the two subgroups: an average total of $17,590 per patient for the rivaroxaban patients and $18,676 for warfarin patients for all causes, and an average of $7,394 for the rivaroxaban patients and $7,319 for those on warfarin for AF-related care. The between-group differences for both sets of total costs were not statistically significant.

The study was sponsored by Janssen, which along with Bayer markets rivaroxaban (Xarelto). Dr. Crivera is a Janssen employee. Dr. Weitz has been an adviser or a consultant to Janssen and Bayer and to Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Pfizer, and Portola.

[email protected]

On Twitter @mitchelzoler

CHICAGO – Patients with atrial fibrillation who start treatment with a new oral anticoagulant may spend more on their medication than if they were prescribed generic warfarin, but their overall health care costs may wind up being about the same, based on an analysis of health care expense records for more than 4,500 U.S. patients.

“Despite higher anticoagulant costs, total all-cause and atrial fibrillation–related costs remain comparable” between patients prescribed warfarin and those who received the new oral anticoagulant rivaroxaban (Xarelto), said Concetta Crivera, Pharm.D., at the American Heart Association Scientific Sessions. Higher drug costs for daily treatment with rivaroxaban were offset by reduced hospital lengths of stays and hence reduced hospitalization costs, said Dr. Crivera, director of cardiovascular health economics and outcomes research at Janssen in Raritan, N.J., the company that markets rivaroxaban along with Bayer.

Mitchel L. Zoler/Frontline Medical News

“I can believe that hospitalized days would be reduced because patients treated with rivaroxaban or any of the other new oral anticoagulants don’t need to remain in the hospital while you wait for their international normalized ratio to enter the therapeutic range,” which is what happens with patients treated with warfarin, commented Dr. Jeffrey Weitz, professor of medicine and director of the Juravinski Hospital and Cancer Centre of McMaster University in Hamilton, Ont.

The new findings by Dr. Crivera “are not definitive on their own, but they add to a growing body of data that indicate that all the new oral anticoagulants are cost effective,” said Dr. Weitz, who specializes in thrombosis and anticoagulants. “The worst time for a patient on warfarin is when they start treatment. You do a disservice to patients with new-onset atrial fibrillation by using warfarin, because some patients will get into the therapeutic range but others never will. That’s why the new oral anticoagulants are better, because everybody gets into therapeutic range,” he said in an interview.

Dr. Crivera and her associates conducted a retrospective study of health records for 2,253 patients with nonvalvular atrial fibrillation (AF) who started anticoagulation treatment with rivaroxaban during the period of November 2011 (when the drug received U.S. marketing approval) through December 2012. The data came from the patient records of Humana, a U.S. HMO and insurer that covers both commercially insured patients and those covered by Medicare. The researchers matched each of the patients initiating rivaroxaban treatment with a similar patient from the Humana database with nonvalvular AF who started on warfarin during the same period. The average age of patients in the study was about 74 years, and patients in the two groups were closely matched for their demographic and clinical characteristics, including comorbidities. Data on health care use were available for patients for an average of about 4 months following their start of anticoagulant treatment.

The analysis showed that during the first months on treatment, patients prescribed rivaroxaban averaged 2.11 days of hospitalization for an AF-related episode, compared with 3.02 days for those prescribed warfarin, a statistically significant difference. Hospitalizations for any cause averaged a total of 2.71 days in the rivaroxaban group and 3.87 days in the patients on warfarin, also a significant difference, Dr. Crivera reported.

This difference in days hospitalized translated into reduced hospitalization costs, a roughly $2,000 average difference per patient in actual hospitalization costs in favor of the rivaroxaban patients for all-cause hospitalizations, and an average $1,300 difference per patient for hospitalization costs directly related to AF.

Although the rivaroxaban patients spent an average of $2,700 more per patient on pharmaceuticals for all causes, and an average $2,200 more for AF-related drugs, the total average all-cause and AF-related costs for drugs, hospitalizations, outpatient visits, and emergency department visits were similar in the two subgroups: an average total of $17,590 per patient for the rivaroxaban patients and $18,676 for warfarin patients for all causes, and an average of $7,394 for the rivaroxaban patients and $7,319 for those on warfarin for AF-related care. The between-group differences for both sets of total costs were not statistically significant.

The study was sponsored by Janssen, which along with Bayer markets rivaroxaban (Xarelto). Dr. Crivera is a Janssen employee. Dr. Weitz has been an adviser or a consultant to Janssen and Bayer and to Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Pfizer, and Portola.

[email protected]

On Twitter @mitchelzoler

CHICAGO – Atrial fibrillation patients treated with an anticoagulant plus four or more other medications had significantly more bleeding complications than did those on fewer medications in a retrospective study.

“This is the first study examining polypharmacy in patients with nonvalvular atrial fibrillation,” Dr. Jonathan P. Piccini said at the American Heart Association Scientific Sessions. The main consequence is, “We should do everything we can to reduce the number of medications a patient receives,” he said.

His exploratory, retrospective analysis of data from more than 14,000 patients enrolled in an anticoagulant treatment trial showed that atrial fibrillation patients on an oral anticoagulant and taking a total of 10 or more medications concurrently had a 46% increased rate of a major bleed or clinically relevant nonmajor bleed. Patients taking five to nine medications had a 17% increased rate for this primary bleeding endpoint. Both increases were statistically significant, reported Dr. Piccini, a cardiologist at Duke University in Durham, N.C. Major bleeds alone were 90% higher in patients on at least 10 drugs and 47% higher in patients on 5-9 total drugs, compared with those on 4 or fewer, also statistically significant differences.

“Increasing medication use was associated with an increased risk of bleeding but not stroke,” he said. In addition, because the data came from a large trial that had compared the new oral anticoagulant rivaroxaban (Xarelto) with warfarin, the analysis was able to show that this polypharmacy effect was similar regardless of which anticoagulant patients took.

Polypharmacy was common among the 14,264 patients (average age, 73 years) enrolled in the trial, as 51% were on 5-9 drugs and 13% were on 10 or more drugs, with a minority of 36% forming the comparator group taking 4 or fewer medications.

The analysis used data collected from 14,264 patients enrolled in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial, which was designed as a pivotal trial comparing the safety and efficacy of the new oral anticoagulant rivaroxaban with warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (N. Engl. J. Med. 2011;365:883-91). Dr. Piccini and his associates assessed various measures of bleeding as well as strokes, vascular deaths, and all-cause deaths in the patients by their number of concomitant medications based on data collected at baseline when patients entered the trial. The relative hazard rates the investigators calculated were adjusted for all “clinically important covariates,” but Dr. Piccini acknowledged that residual confounding accounted for by the adjustments likely remained.

All-cause death was also significantly increased in patients taking at least 10 (a 43% increase) or 5-9 drugs (a 25% increase), compared with patients on 4 or fewer drugs. But the rate of stroke or nonstroke embolism was not significantly increased among patients on five or more drugs. The combined rate of stroke, nonstroke embolism, and vascular death was a statistically significant 25% higher in patients on at least 10 drugs, compared with those on 4 or fewer drugs, but there was no significant increase in patients on 5-9 drugs.

The link between higher numbers of concomitant medications and an increased bleeding rate likely has two explanations, Dr. Piccini said. It could happen because the drugs themselves promote bleeding, and because the need to prescribe multiple drugs is a marker for patients who are sicker and have more comorbidities and a higher underlying risk of bleeding.

ROCKET AF was sponsored by Janssen and Bayer. Dr. Piccini has been a consultant to and has received research funding from Janssen, Bayer, and several other companies.

[email protected]

On Twitter @mitchelzoler

CHICAGO – Atrial fibrillation patients treated with an anticoagulant plus four or more other medications had significantly more bleeding complications than did those on fewer medications in a retrospective study.

“This is the first study examining polypharmacy in patients with nonvalvular atrial fibrillation,” Dr. Jonathan P. Piccini said at the American Heart Association Scientific Sessions. The main consequence is, “We should do everything we can to reduce the number of medications a patient receives,” he said.

His exploratory, retrospective analysis of data from more than 14,000 patients enrolled in an anticoagulant treatment trial showed that atrial fibrillation patients on an oral anticoagulant and taking a total of 10 or more medications concurrently had a 46% increased rate of a major bleed or clinically relevant nonmajor bleed. Patients taking five to nine medications had a 17% increased rate for this primary bleeding endpoint. Both increases were statistically significant, reported Dr. Piccini, a cardiologist at Duke University in Durham, N.C. Major bleeds alone were 90% higher in patients on at least 10 drugs and 47% higher in patients on 5-9 total drugs, compared with those on 4 or fewer, also statistically significant differences.

“Increasing medication use was associated with an increased risk of bleeding but not stroke,” he said. In addition, because the data came from a large trial that had compared the new oral anticoagulant rivaroxaban (Xarelto) with warfarin, the analysis was able to show that this polypharmacy effect was similar regardless of which anticoagulant patients took.

Polypharmacy was common among the 14,264 patients (average age, 73 years) enrolled in the trial, as 51% were on 5-9 drugs and 13% were on 10 or more drugs, with a minority of 36% forming the comparator group taking 4 or fewer medications.

The analysis used data collected from 14,264 patients enrolled in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial, which was designed as a pivotal trial comparing the safety and efficacy of the new oral anticoagulant rivaroxaban with warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (N. Engl. J. Med. 2011;365:883-91). Dr. Piccini and his associates assessed various measures of bleeding as well as strokes, vascular deaths, and all-cause deaths in the patients by their number of concomitant medications based on data collected at baseline when patients entered the trial. The relative hazard rates the investigators calculated were adjusted for all “clinically important covariates,” but Dr. Piccini acknowledged that residual confounding accounted for by the adjustments likely remained.

All-cause death was also significantly increased in patients taking at least 10 (a 43% increase) or 5-9 drugs (a 25% increase), compared with patients on 4 or fewer drugs. But the rate of stroke or nonstroke embolism was not significantly increased among patients on five or more drugs. The combined rate of stroke, nonstroke embolism, and vascular death was a statistically significant 25% higher in patients on at least 10 drugs, compared with those on 4 or fewer drugs, but there was no significant increase in patients on 5-9 drugs.

The link between higher numbers of concomitant medications and an increased bleeding rate likely has two explanations, Dr. Piccini said. It could happen because the drugs themselves promote bleeding, and because the need to prescribe multiple drugs is a marker for patients who are sicker and have more comorbidities and a higher underlying risk of bleeding.

ROCKET AF was sponsored by Janssen and Bayer. Dr. Piccini has been a consultant to and has received research funding from Janssen, Bayer, and several other companies.

[email protected]

On Twitter @mitchelzoler

CHICAGO – Atrial fibrillation patients treated with an anticoagulant plus four or more other medications had significantly more bleeding complications than did those on fewer medications in a retrospective study.

“This is the first study examining polypharmacy in patients with nonvalvular atrial fibrillation,” Dr. Jonathan P. Piccini said at the American Heart Association Scientific Sessions. The main consequence is, “We should do everything we can to reduce the number of medications a patient receives,” he said.

His exploratory, retrospective analysis of data from more than 14,000 patients enrolled in an anticoagulant treatment trial showed that atrial fibrillation patients on an oral anticoagulant and taking a total of 10 or more medications concurrently had a 46% increased rate of a major bleed or clinically relevant nonmajor bleed. Patients taking five to nine medications had a 17% increased rate for this primary bleeding endpoint. Both increases were statistically significant, reported Dr. Piccini, a cardiologist at Duke University in Durham, N.C. Major bleeds alone were 90% higher in patients on at least 10 drugs and 47% higher in patients on 5-9 total drugs, compared with those on 4 or fewer, also statistically significant differences.

“Increasing medication use was associated with an increased risk of bleeding but not stroke,” he said. In addition, because the data came from a large trial that had compared the new oral anticoagulant rivaroxaban (Xarelto) with warfarin, the analysis was able to show that this polypharmacy effect was similar regardless of which anticoagulant patients took.

Polypharmacy was common among the 14,264 patients (average age, 73 years) enrolled in the trial, as 51% were on 5-9 drugs and 13% were on 10 or more drugs, with a minority of 36% forming the comparator group taking 4 or fewer medications.

The analysis used data collected from 14,264 patients enrolled in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial, which was designed as a pivotal trial comparing the safety and efficacy of the new oral anticoagulant rivaroxaban with warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (N. Engl. J. Med. 2011;365:883-91). Dr. Piccini and his associates assessed various measures of bleeding as well as strokes, vascular deaths, and all-cause deaths in the patients by their number of concomitant medications based on data collected at baseline when patients entered the trial. The relative hazard rates the investigators calculated were adjusted for all “clinically important covariates,” but Dr. Piccini acknowledged that residual confounding accounted for by the adjustments likely remained.

All-cause death was also significantly increased in patients taking at least 10 (a 43% increase) or 5-9 drugs (a 25% increase), compared with patients on 4 or fewer drugs. But the rate of stroke or nonstroke embolism was not significantly increased among patients on five or more drugs. The combined rate of stroke, nonstroke embolism, and vascular death was a statistically significant 25% higher in patients on at least 10 drugs, compared with those on 4 or fewer drugs, but there was no significant increase in patients on 5-9 drugs.

The link between higher numbers of concomitant medications and an increased bleeding rate likely has two explanations, Dr. Piccini said. It could happen because the drugs themselves promote bleeding, and because the need to prescribe multiple drugs is a marker for patients who are sicker and have more comorbidities and a higher underlying risk of bleeding.

ROCKET AF was sponsored by Janssen and Bayer. Dr. Piccini has been a consultant to and has received research funding from Janssen, Bayer, and several other companies.

[email protected]

On Twitter @mitchelzoler