Thrombosis

SAN FRANCISCO – After 3 months of ticagrelor (Brilinta) plus aspirin following cardiac stenting, stopping the aspirin but continuing the ticagrelor resulted in less bleeding with no increase in ischemic events in a randomized trial with more than 7,000 drug-eluting stent patients at high risk for both.

“This was a superior therapy” to staying on both drugs, the more usual approach, said lead investigator Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York.

“We can’t say this is for all comers, but for patients whose physician felt comfortable putting them on aspirin and ticagrelor,” who tolerated it well for the first 3 months, and who had clinical and angiographic indications of risk, “I think these patients can be peeled away” from aspirin, she said in a presentation at the Transcatheter Cardiovascular Therapeutics annual meeting that coincided with publication of the trial, dubbed TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention).

Interventional cardiologists have long sought the sweet spot for dual-antiplatelet therapy (DAPT) after stenting; the idea is to maximize thrombosis prevention while minimizing bleeding risk. The trial supports the trend in recent years towards shorter DAPT. Often, however, it’s the P2Y12 inhibitor – ticagrelor, clopidogrel (Plavix), or prasugrel (Effient) – that goes first, not the aspirin.

Responding to an audience question about why the trial didn’t include an aspirin monotherapy arm, Dr. Mehran said that aspirin alone wouldn’t have been sufficient in high-risk patients “in whom you have almost 70% acute coronary syndrome.” She added that her team has data showing that aspirin itself doesn’t have much effect on blood thrombogenicity.

The 7,119 patients in TWILIGHT were on ticagrelor 90 mg twice daily and aspirin 81-100 mg daily for 3 months, then evenly randomized to continued treatment or ticagrelor plus an aspirin placebo for a year.

Subjects had to have at least one clinical and angiographic finding that put them at high risk for bleeding or an ischemic event, such as chronic kidney disease, acute coronary syndrome, diabetes, or a bifurcated target lesion treated with two stents.

One year after randomization, 4% in the ticagrelor monotherapy group versus 7.1% in the ticagrelor plus aspirin arm reached the primary end point, actionable (type 2), severe (type 3), or fatal (type 5) bleeding on the Bleeding Academic Research Consortium scale (hazard ratio, 0.56; 95% confidence interval, 0.45 - 0.68, P less than .001).

The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (HR, 0.99; 95% CI, 0.78-1.25; P less than .001 for noninferiority).

There were more ischemic strokes in the ticagrelor monotherapy arm (0.5% versus 0.2%). All-cause mortality (1.3% versus 1%) and stent thrombosis (0.6% versus 0.4%) were more frequent in the ticagrelor/aspirin group, but the differences were not statistically significant.

The two groups were well balanced. The mean age was 65 years, 23.8% of the patients were female, 37% had diabetes, and 65% had percutaneous coronary intervention for an acute coronary syndrome. Almost two-thirds had multivessel disease. Mean stent length was about 40 mm. The trial excluded patients with prior strokes.

Almost 2,000 patients originally enrolled in the trial never made it to randomization because they had a major bleeding or ischemic event in the 3-month run up, or dyspnea or some other reaction to ticagrelor.

The recent STOPDAPT-2 trial had a similar outcome – less bleeding with no increase in ischemic events – with clopidogrel monotherapy after a month-long run in of dual therapy with aspirin, versus continued treatment with both, in patients at low risk for ischemic events after stenting (JAMA. 2019 Jun 25;321[24]:2414-27).

Another recent study, GLOBAL LEADERS, concluded that 1 month of DAPT followed by ticagrelor monotherapy for 23 months was not superior to 12 months of DAPT followed by a year of aspirin. There was a numerical advantage for solo ticagrelor on death, myocardial infarction, and bleeding, but it did not reach statistical significance (Lancet. 2018 Sep 15;392[10151]:940-9).

The work was funded by ticagrelor’s maker, AstraZeneca. Dr. Mehran reported consulting and other relationships with Abbott, Janssen, and other companies.

[email protected]

SOURCE: Mehran A et al. N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419.

SAN FRANCISCO – After 3 months of ticagrelor (Brilinta) plus aspirin following cardiac stenting, stopping the aspirin but continuing the ticagrelor resulted in less bleeding with no increase in ischemic events in a randomized trial with more than 7,000 drug-eluting stent patients at high risk for both.

“This was a superior therapy” to staying on both drugs, the more usual approach, said lead investigator Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York.

“We can’t say this is for all comers, but for patients whose physician felt comfortable putting them on aspirin and ticagrelor,” who tolerated it well for the first 3 months, and who had clinical and angiographic indications of risk, “I think these patients can be peeled away” from aspirin, she said in a presentation at the Transcatheter Cardiovascular Therapeutics annual meeting that coincided with publication of the trial, dubbed TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention).

Interventional cardiologists have long sought the sweet spot for dual-antiplatelet therapy (DAPT) after stenting; the idea is to maximize thrombosis prevention while minimizing bleeding risk. The trial supports the trend in recent years towards shorter DAPT. Often, however, it’s the P2Y12 inhibitor – ticagrelor, clopidogrel (Plavix), or prasugrel (Effient) – that goes first, not the aspirin.

Responding to an audience question about why the trial didn’t include an aspirin monotherapy arm, Dr. Mehran said that aspirin alone wouldn’t have been sufficient in high-risk patients “in whom you have almost 70% acute coronary syndrome.” She added that her team has data showing that aspirin itself doesn’t have much effect on blood thrombogenicity.

The 7,119 patients in TWILIGHT were on ticagrelor 90 mg twice daily and aspirin 81-100 mg daily for 3 months, then evenly randomized to continued treatment or ticagrelor plus an aspirin placebo for a year.

Subjects had to have at least one clinical and angiographic finding that put them at high risk for bleeding or an ischemic event, such as chronic kidney disease, acute coronary syndrome, diabetes, or a bifurcated target lesion treated with two stents.

One year after randomization, 4% in the ticagrelor monotherapy group versus 7.1% in the ticagrelor plus aspirin arm reached the primary end point, actionable (type 2), severe (type 3), or fatal (type 5) bleeding on the Bleeding Academic Research Consortium scale (hazard ratio, 0.56; 95% confidence interval, 0.45 - 0.68, P less than .001).

The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (HR, 0.99; 95% CI, 0.78-1.25; P less than .001 for noninferiority).

There were more ischemic strokes in the ticagrelor monotherapy arm (0.5% versus 0.2%). All-cause mortality (1.3% versus 1%) and stent thrombosis (0.6% versus 0.4%) were more frequent in the ticagrelor/aspirin group, but the differences were not statistically significant.

The two groups were well balanced. The mean age was 65 years, 23.8% of the patients were female, 37% had diabetes, and 65% had percutaneous coronary intervention for an acute coronary syndrome. Almost two-thirds had multivessel disease. Mean stent length was about 40 mm. The trial excluded patients with prior strokes.

Almost 2,000 patients originally enrolled in the trial never made it to randomization because they had a major bleeding or ischemic event in the 3-month run up, or dyspnea or some other reaction to ticagrelor.

The recent STOPDAPT-2 trial had a similar outcome – less bleeding with no increase in ischemic events – with clopidogrel monotherapy after a month-long run in of dual therapy with aspirin, versus continued treatment with both, in patients at low risk for ischemic events after stenting (JAMA. 2019 Jun 25;321[24]:2414-27).

Another recent study, GLOBAL LEADERS, concluded that 1 month of DAPT followed by ticagrelor monotherapy for 23 months was not superior to 12 months of DAPT followed by a year of aspirin. There was a numerical advantage for solo ticagrelor on death, myocardial infarction, and bleeding, but it did not reach statistical significance (Lancet. 2018 Sep 15;392[10151]:940-9).

The work was funded by ticagrelor’s maker, AstraZeneca. Dr. Mehran reported consulting and other relationships with Abbott, Janssen, and other companies.

[email protected]

SOURCE: Mehran A et al. N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419.

SAN FRANCISCO – After 3 months of ticagrelor (Brilinta) plus aspirin following cardiac stenting, stopping the aspirin but continuing the ticagrelor resulted in less bleeding with no increase in ischemic events in a randomized trial with more than 7,000 drug-eluting stent patients at high risk for both.

“This was a superior therapy” to staying on both drugs, the more usual approach, said lead investigator Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York.

“We can’t say this is for all comers, but for patients whose physician felt comfortable putting them on aspirin and ticagrelor,” who tolerated it well for the first 3 months, and who had clinical and angiographic indications of risk, “I think these patients can be peeled away” from aspirin, she said in a presentation at the Transcatheter Cardiovascular Therapeutics annual meeting that coincided with publication of the trial, dubbed TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention).

Interventional cardiologists have long sought the sweet spot for dual-antiplatelet therapy (DAPT) after stenting; the idea is to maximize thrombosis prevention while minimizing bleeding risk. The trial supports the trend in recent years towards shorter DAPT. Often, however, it’s the P2Y12 inhibitor – ticagrelor, clopidogrel (Plavix), or prasugrel (Effient) – that goes first, not the aspirin.

Responding to an audience question about why the trial didn’t include an aspirin monotherapy arm, Dr. Mehran said that aspirin alone wouldn’t have been sufficient in high-risk patients “in whom you have almost 70% acute coronary syndrome.” She added that her team has data showing that aspirin itself doesn’t have much effect on blood thrombogenicity.

The 7,119 patients in TWILIGHT were on ticagrelor 90 mg twice daily and aspirin 81-100 mg daily for 3 months, then evenly randomized to continued treatment or ticagrelor plus an aspirin placebo for a year.

Subjects had to have at least one clinical and angiographic finding that put them at high risk for bleeding or an ischemic event, such as chronic kidney disease, acute coronary syndrome, diabetes, or a bifurcated target lesion treated with two stents.

One year after randomization, 4% in the ticagrelor monotherapy group versus 7.1% in the ticagrelor plus aspirin arm reached the primary end point, actionable (type 2), severe (type 3), or fatal (type 5) bleeding on the Bleeding Academic Research Consortium scale (hazard ratio, 0.56; 95% confidence interval, 0.45 - 0.68, P less than .001).

The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (HR, 0.99; 95% CI, 0.78-1.25; P less than .001 for noninferiority).

There were more ischemic strokes in the ticagrelor monotherapy arm (0.5% versus 0.2%). All-cause mortality (1.3% versus 1%) and stent thrombosis (0.6% versus 0.4%) were more frequent in the ticagrelor/aspirin group, but the differences were not statistically significant.

The two groups were well balanced. The mean age was 65 years, 23.8% of the patients were female, 37% had diabetes, and 65% had percutaneous coronary intervention for an acute coronary syndrome. Almost two-thirds had multivessel disease. Mean stent length was about 40 mm. The trial excluded patients with prior strokes.

Almost 2,000 patients originally enrolled in the trial never made it to randomization because they had a major bleeding or ischemic event in the 3-month run up, or dyspnea or some other reaction to ticagrelor.

The recent STOPDAPT-2 trial had a similar outcome – less bleeding with no increase in ischemic events – with clopidogrel monotherapy after a month-long run in of dual therapy with aspirin, versus continued treatment with both, in patients at low risk for ischemic events after stenting (JAMA. 2019 Jun 25;321[24]:2414-27).

Another recent study, GLOBAL LEADERS, concluded that 1 month of DAPT followed by ticagrelor monotherapy for 23 months was not superior to 12 months of DAPT followed by a year of aspirin. There was a numerical advantage for solo ticagrelor on death, myocardial infarction, and bleeding, but it did not reach statistical significance (Lancet. 2018 Sep 15;392[10151]:940-9).

The work was funded by ticagrelor’s maker, AstraZeneca. Dr. Mehran reported consulting and other relationships with Abbott, Janssen, and other companies.

[email protected]

SOURCE: Mehran A et al. N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419.

Background: Active cancer places patients at increased risk for VTE. Ambulatory patients can be risk stratified using the validated Khorana score to assess risk for VTE, a complication resulting in significant morbidity, mortality, and health care costs.

There was no significant difference in overall survival, with 87% of deaths were related to cancer or cancer progression.

Bottom line: VTE is significantly lower with the use of apixaban, compared with placebo, in intermediate- to high-risk ambulatory patients with active cancer who are initiating chemotherapy.

Citation: Carrier M et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2018 Dec 4. doi: 10.1056/NEJMoa1814468.
 

Dr. Trammell Velasquez is an associate professor of medicine in the division of general and hospital medicine at UT Health San Antonio and a hospitalist at South Texas Veterans Health Care System.

Background: Active cancer places patients at increased risk for VTE. Ambulatory patients can be risk stratified using the validated Khorana score to assess risk for VTE, a complication resulting in significant morbidity, mortality, and health care costs.

There was no significant difference in overall survival, with 87% of deaths were related to cancer or cancer progression.

Bottom line: VTE is significantly lower with the use of apixaban, compared with placebo, in intermediate- to high-risk ambulatory patients with active cancer who are initiating chemotherapy.

Citation: Carrier M et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2018 Dec 4. doi: 10.1056/NEJMoa1814468.
 

Dr. Trammell Velasquez is an associate professor of medicine in the division of general and hospital medicine at UT Health San Antonio and a hospitalist at South Texas Veterans Health Care System.

Background: Active cancer places patients at increased risk for VTE. Ambulatory patients can be risk stratified using the validated Khorana score to assess risk for VTE, a complication resulting in significant morbidity, mortality, and health care costs.

There was no significant difference in overall survival, with 87% of deaths were related to cancer or cancer progression.

Bottom line: VTE is significantly lower with the use of apixaban, compared with placebo, in intermediate- to high-risk ambulatory patients with active cancer who are initiating chemotherapy.

Citation: Carrier M et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2018 Dec 4. doi: 10.1056/NEJMoa1814468.
 

Dr. Trammell Velasquez is an associate professor of medicine in the division of general and hospital medicine at UT Health San Antonio and a hospitalist at South Texas Veterans Health Care System.

When on call for admissions, a hospitalist receives a request from a colleague to admit an octogenarian man with an acute uncomplicated deep vein thrombosis to start heparin, bridging to warfarin. The patient has no evidence of postphlebitic syndrome, pulmonary embolism, or right-sided heart strain. The hospitalist asks her colleague if he had considered treating the patient in the ambulatory setting using a direct-acting oral anticoagulant (DOAC). After all, this would save the patient an unnecessary hospitalization, weekly international normalized ratio checks, and other important lifestyle changes. In response, the colleague voices concern that the “new drugs don’t have antidotes.”

DOACs have several benefits over vitamin K antagonists (VKAs) and heparins. DOACs have quicker onset of action, can be taken by mouth, in general do not require dosage adjustment, and have fewer dietary and lifestyle modifications, compared with VKAs and heparins. In atrial fibrillation, DOACs have been shown to have lower all-cause and bleeding-related mortality than warfarin (see Table 1).¹ Observational studies also suggest less risk of major bleeding with DOACs over warfarin but no difference in overall mortality when used to treat venous thromboembolism (see Table 2).² Because of these combined advantages, DOACs are increasingly prescribed, accounting for approximately half of all oral anticoagulant prescriptions in 2014.³

Although DOACs have been shown to be as good if not superior to VKAs and heparins in these circumstances, there are situations where a DOAC should not be used. There is limited data on the safety of DOACs in patients with mechanical heart valves, liver failure, and chronic kidney disease with a creatinine clearance less than 30 mL/min.⁴ Therefore, warfarin is still the preferred agent in these settings. There is some data that apixaban may be safe in patients with a creatinine clearance of greater than 10 mL/min, but long-term safety studies have not been performed in patients with end-stage renal disease on hemodialysis.⁵ Finally, in patients requiring concomitant inducers or inhibitors of the P-glycoprotein or cytochrome P450 enzymes like antiepileptics and protease inhibitors, VKAs and heparins are favored.⁴

Notwithstanding their advantages, when DOACs first hit the market there were concerns that reversal agents were not available. In the August issue of the Journal of Hospital Medicine’s Clinical Guideline Highlights for the Hospitalist, Emily Gottenborg, MD, and Gregory Misky, MD, summarized guideline recommendations for reversal of the newer agents.⁶ This includes use of idarucizumab for patients on dabigatran and use of prothrombin complex concentrate (PCC) or recombinant coagulation factor Xa (andexanet alfa) for patients on apixaban or rivaroxaban for the treatment of life-threatening bleeding.

Idarucizumab is a monoclonal antibody developed to reverse the effects of dabigatran, the only DOAC that directly inhibits thrombin. In 2017, researchers reported on a cohort of subjects receiving idarucizumab for uncontrolled bleeding or who were on dabigatran and about to undergo an urgent procedure.⁷ Of those with uncontrolled bleeding, two-thirds had confirmed bleeding cessation within 24 hours. Periprocedural hemostasis was achieved in 93.4% of patients undergoing urgent procedures. However, it should be noted that use of idarucizumab conferred an increase risk (6.3%) of thrombosis within 90 days. Based on these findings, guidelines recommend use of idarucizumab in patients experiencing life-threatening bleeding, balanced against the risk of thrombosis.⁸

In 2018, the Food and Drug Administration approved recombinant coagulation factor Xa for treatment of life-threatening or uncontrolled bleeding in patients on apixaban or rivaroxaban.⁹ The approval came after a study by the ANNEXA-4 investigators showed that recombinant coagulation factor Xa quickly and effectively achieved hemostasis.¹⁰ Full study results were published in April 2019, demonstrating 82% of patients receiving the drug attained clinical hemostasis.¹¹ However, as with idarucizumab, up to 10% of patients had a thrombotic event in the follow-up period. Use of recombinant coagulation factor Xa for treatment of life-threatening bleeding related to betrixaban and edoxaban is considered off label but is recommended by guidelines.⁸ Studies on investigational reversal agents for betrixaban and edoxaban are ongoing.

Both unactivated and activated PCC contain clotting factor X. Their use to control bleeding related to DOAC use is based on observational studies. In a systematic review of the nonrandomized studies, the efficacy of PCC to stem major bleeding was 69% and the risk for thromboembolism was 4%.¹² There are no head-to-head studies comparing use of recombinant coagulation factor Xa and PCC. Therefore, guidelines are to use either recombinant factor Xa or PCC for the treatment of life-threatening bleeding related to DOAC use.⁷

As thrombosis risk heightens after use of any reversal agent, the recommendations are to resume anticoagulation within 90 days if the patient is at moderate or high risk for recurrent thromboembolism.⁸

After discussion with the hospitalist about the new agents available to reverse anticoagulation, the colleague decided to place the patient on a DOAC and keep the patient in his nursing home. Thankfully, the patient did not thereafter experience sustained bleeding necessitating use of these reversal agents. More importantly for the patient, he was able to stay in the comfort of his home.

Dr. Tuck is associate section chief for hospital medicine at the Veterans Affairs Medical Center in Washington, D.C.

References

1. Gómez-Outes A et al. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2016;68:2508-21.

2. Jun M et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population-based, observational study. BMJ. 2017;359:j4323.

3. Barnes GD et al. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128:(1300-5).e2.

4. Reddy P et al. Practical approach to VTE management in hospitalized patients. Am J Ther. 2017;24(4):e442-67.

5. Kimachi M et al. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease. Cochrane Database Syst Rev. 2017 Nov 6;11:CD011373.

6. Gottenborg E et al. Clinical guideline highlights for the hospitalist: The management of anticoagulation in the hospitalized adult. J Hosp Med. 2019; 14(8):499-500.

7. Pollack CV Jr et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med. 2017;377(5):431-41.

8. Witt DM et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-91.

9. Malarky M et al. FDA accelerated approval letter. Retrieved July 15, 2019. https://www.fda.gov/media/113285/download

10. Connolly SJ et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-41.

11. Connolly SJ et al. Full study report of andexanet alfa for bleeding associated with factor xa inhibitors. N Engl J Med. 2019;380(14):1326-35.

12. Piran S et al. Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: A meta-analysis. Blood Adv. 2019;3(2):158-67.

When on call for admissions, a hospitalist receives a request from a colleague to admit an octogenarian man with an acute uncomplicated deep vein thrombosis to start heparin, bridging to warfarin. The patient has no evidence of postphlebitic syndrome, pulmonary embolism, or right-sided heart strain. The hospitalist asks her colleague if he had considered treating the patient in the ambulatory setting using a direct-acting oral anticoagulant (DOAC). After all, this would save the patient an unnecessary hospitalization, weekly international normalized ratio checks, and other important lifestyle changes. In response, the colleague voices concern that the “new drugs don’t have antidotes.”

DOACs have several benefits over vitamin K antagonists (VKAs) and heparins. DOACs have quicker onset of action, can be taken by mouth, in general do not require dosage adjustment, and have fewer dietary and lifestyle modifications, compared with VKAs and heparins. In atrial fibrillation, DOACs have been shown to have lower all-cause and bleeding-related mortality than warfarin (see Table 1).¹ Observational studies also suggest less risk of major bleeding with DOACs over warfarin but no difference in overall mortality when used to treat venous thromboembolism (see Table 2).² Because of these combined advantages, DOACs are increasingly prescribed, accounting for approximately half of all oral anticoagulant prescriptions in 2014.³

Although DOACs have been shown to be as good if not superior to VKAs and heparins in these circumstances, there are situations where a DOAC should not be used. There is limited data on the safety of DOACs in patients with mechanical heart valves, liver failure, and chronic kidney disease with a creatinine clearance less than 30 mL/min.⁴ Therefore, warfarin is still the preferred agent in these settings. There is some data that apixaban may be safe in patients with a creatinine clearance of greater than 10 mL/min, but long-term safety studies have not been performed in patients with end-stage renal disease on hemodialysis.⁵ Finally, in patients requiring concomitant inducers or inhibitors of the P-glycoprotein or cytochrome P450 enzymes like antiepileptics and protease inhibitors, VKAs and heparins are favored.⁴

Notwithstanding their advantages, when DOACs first hit the market there were concerns that reversal agents were not available. In the August issue of the Journal of Hospital Medicine’s Clinical Guideline Highlights for the Hospitalist, Emily Gottenborg, MD, and Gregory Misky, MD, summarized guideline recommendations for reversal of the newer agents.⁶ This includes use of idarucizumab for patients on dabigatran and use of prothrombin complex concentrate (PCC) or recombinant coagulation factor Xa (andexanet alfa) for patients on apixaban or rivaroxaban for the treatment of life-threatening bleeding.

Idarucizumab is a monoclonal antibody developed to reverse the effects of dabigatran, the only DOAC that directly inhibits thrombin. In 2017, researchers reported on a cohort of subjects receiving idarucizumab for uncontrolled bleeding or who were on dabigatran and about to undergo an urgent procedure.⁷ Of those with uncontrolled bleeding, two-thirds had confirmed bleeding cessation within 24 hours. Periprocedural hemostasis was achieved in 93.4% of patients undergoing urgent procedures. However, it should be noted that use of idarucizumab conferred an increase risk (6.3%) of thrombosis within 90 days. Based on these findings, guidelines recommend use of idarucizumab in patients experiencing life-threatening bleeding, balanced against the risk of thrombosis.⁸

In 2018, the Food and Drug Administration approved recombinant coagulation factor Xa for treatment of life-threatening or uncontrolled bleeding in patients on apixaban or rivaroxaban.⁹ The approval came after a study by the ANNEXA-4 investigators showed that recombinant coagulation factor Xa quickly and effectively achieved hemostasis.¹⁰ Full study results were published in April 2019, demonstrating 82% of patients receiving the drug attained clinical hemostasis.¹¹ However, as with idarucizumab, up to 10% of patients had a thrombotic event in the follow-up period. Use of recombinant coagulation factor Xa for treatment of life-threatening bleeding related to betrixaban and edoxaban is considered off label but is recommended by guidelines.⁸ Studies on investigational reversal agents for betrixaban and edoxaban are ongoing.

Both unactivated and activated PCC contain clotting factor X. Their use to control bleeding related to DOAC use is based on observational studies. In a systematic review of the nonrandomized studies, the efficacy of PCC to stem major bleeding was 69% and the risk for thromboembolism was 4%.¹² There are no head-to-head studies comparing use of recombinant coagulation factor Xa and PCC. Therefore, guidelines are to use either recombinant factor Xa or PCC for the treatment of life-threatening bleeding related to DOAC use.⁷

As thrombosis risk heightens after use of any reversal agent, the recommendations are to resume anticoagulation within 90 days if the patient is at moderate or high risk for recurrent thromboembolism.⁸

After discussion with the hospitalist about the new agents available to reverse anticoagulation, the colleague decided to place the patient on a DOAC and keep the patient in his nursing home. Thankfully, the patient did not thereafter experience sustained bleeding necessitating use of these reversal agents. More importantly for the patient, he was able to stay in the comfort of his home.

Dr. Tuck is associate section chief for hospital medicine at the Veterans Affairs Medical Center in Washington, D.C.

References

1. Gómez-Outes A et al. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2016;68:2508-21.

2. Jun M et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population-based, observational study. BMJ. 2017;359:j4323.

3. Barnes GD et al. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128:(1300-5).e2.

4. Reddy P et al. Practical approach to VTE management in hospitalized patients. Am J Ther. 2017;24(4):e442-67.

5. Kimachi M et al. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease. Cochrane Database Syst Rev. 2017 Nov 6;11:CD011373.

6. Gottenborg E et al. Clinical guideline highlights for the hospitalist: The management of anticoagulation in the hospitalized adult. J Hosp Med. 2019; 14(8):499-500.

7. Pollack CV Jr et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med. 2017;377(5):431-41.

8. Witt DM et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-91.

9. Malarky M et al. FDA accelerated approval letter. Retrieved July 15, 2019. https://www.fda.gov/media/113285/download

10. Connolly SJ et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-41.

11. Connolly SJ et al. Full study report of andexanet alfa for bleeding associated with factor xa inhibitors. N Engl J Med. 2019;380(14):1326-35.

12. Piran S et al. Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: A meta-analysis. Blood Adv. 2019;3(2):158-67.

When on call for admissions, a hospitalist receives a request from a colleague to admit an octogenarian man with an acute uncomplicated deep vein thrombosis to start heparin, bridging to warfarin. The patient has no evidence of postphlebitic syndrome, pulmonary embolism, or right-sided heart strain. The hospitalist asks her colleague if he had considered treating the patient in the ambulatory setting using a direct-acting oral anticoagulant (DOAC). After all, this would save the patient an unnecessary hospitalization, weekly international normalized ratio checks, and other important lifestyle changes. In response, the colleague voices concern that the “new drugs don’t have antidotes.”

DOACs have several benefits over vitamin K antagonists (VKAs) and heparins. DOACs have quicker onset of action, can be taken by mouth, in general do not require dosage adjustment, and have fewer dietary and lifestyle modifications, compared with VKAs and heparins. In atrial fibrillation, DOACs have been shown to have lower all-cause and bleeding-related mortality than warfarin (see Table 1).¹ Observational studies also suggest less risk of major bleeding with DOACs over warfarin but no difference in overall mortality when used to treat venous thromboembolism (see Table 2).² Because of these combined advantages, DOACs are increasingly prescribed, accounting for approximately half of all oral anticoagulant prescriptions in 2014.³

Although DOACs have been shown to be as good if not superior to VKAs and heparins in these circumstances, there are situations where a DOAC should not be used. There is limited data on the safety of DOACs in patients with mechanical heart valves, liver failure, and chronic kidney disease with a creatinine clearance less than 30 mL/min.⁴ Therefore, warfarin is still the preferred agent in these settings. There is some data that apixaban may be safe in patients with a creatinine clearance of greater than 10 mL/min, but long-term safety studies have not been performed in patients with end-stage renal disease on hemodialysis.⁵ Finally, in patients requiring concomitant inducers or inhibitors of the P-glycoprotein or cytochrome P450 enzymes like antiepileptics and protease inhibitors, VKAs and heparins are favored.⁴

Notwithstanding their advantages, when DOACs first hit the market there were concerns that reversal agents were not available. In the August issue of the Journal of Hospital Medicine’s Clinical Guideline Highlights for the Hospitalist, Emily Gottenborg, MD, and Gregory Misky, MD, summarized guideline recommendations for reversal of the newer agents.⁶ This includes use of idarucizumab for patients on dabigatran and use of prothrombin complex concentrate (PCC) or recombinant coagulation factor Xa (andexanet alfa) for patients on apixaban or rivaroxaban for the treatment of life-threatening bleeding.

Idarucizumab is a monoclonal antibody developed to reverse the effects of dabigatran, the only DOAC that directly inhibits thrombin. In 2017, researchers reported on a cohort of subjects receiving idarucizumab for uncontrolled bleeding or who were on dabigatran and about to undergo an urgent procedure.⁷ Of those with uncontrolled bleeding, two-thirds had confirmed bleeding cessation within 24 hours. Periprocedural hemostasis was achieved in 93.4% of patients undergoing urgent procedures. However, it should be noted that use of idarucizumab conferred an increase risk (6.3%) of thrombosis within 90 days. Based on these findings, guidelines recommend use of idarucizumab in patients experiencing life-threatening bleeding, balanced against the risk of thrombosis.⁸

In 2018, the Food and Drug Administration approved recombinant coagulation factor Xa for treatment of life-threatening or uncontrolled bleeding in patients on apixaban or rivaroxaban.⁹ The approval came after a study by the ANNEXA-4 investigators showed that recombinant coagulation factor Xa quickly and effectively achieved hemostasis.¹⁰ Full study results were published in April 2019, demonstrating 82% of patients receiving the drug attained clinical hemostasis.¹¹ However, as with idarucizumab, up to 10% of patients had a thrombotic event in the follow-up period. Use of recombinant coagulation factor Xa for treatment of life-threatening bleeding related to betrixaban and edoxaban is considered off label but is recommended by guidelines.⁸ Studies on investigational reversal agents for betrixaban and edoxaban are ongoing.

Both unactivated and activated PCC contain clotting factor X. Their use to control bleeding related to DOAC use is based on observational studies. In a systematic review of the nonrandomized studies, the efficacy of PCC to stem major bleeding was 69% and the risk for thromboembolism was 4%.¹² There are no head-to-head studies comparing use of recombinant coagulation factor Xa and PCC. Therefore, guidelines are to use either recombinant factor Xa or PCC for the treatment of life-threatening bleeding related to DOAC use.⁷

As thrombosis risk heightens after use of any reversal agent, the recommendations are to resume anticoagulation within 90 days if the patient is at moderate or high risk for recurrent thromboembolism.⁸

After discussion with the hospitalist about the new agents available to reverse anticoagulation, the colleague decided to place the patient on a DOAC and keep the patient in his nursing home. Thankfully, the patient did not thereafter experience sustained bleeding necessitating use of these reversal agents. More importantly for the patient, he was able to stay in the comfort of his home.

Dr. Tuck is associate section chief for hospital medicine at the Veterans Affairs Medical Center in Washington, D.C.

References

1. Gómez-Outes A et al. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2016;68:2508-21.

2. Jun M et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population-based, observational study. BMJ. 2017;359:j4323.

3. Barnes GD et al. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128:(1300-5).e2.

4. Reddy P et al. Practical approach to VTE management in hospitalized patients. Am J Ther. 2017;24(4):e442-67.

5. Kimachi M et al. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease. Cochrane Database Syst Rev. 2017 Nov 6;11:CD011373.

6. Gottenborg E et al. Clinical guideline highlights for the hospitalist: The management of anticoagulation in the hospitalized adult. J Hosp Med. 2019; 14(8):499-500.

7. Pollack CV Jr et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med. 2017;377(5):431-41.

8. Witt DM et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-91.

9. Malarky M et al. FDA accelerated approval letter. Retrieved July 15, 2019. https://www.fda.gov/media/113285/download

10. Connolly SJ et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-41.

11. Connolly SJ et al. Full study report of andexanet alfa for bleeding associated with factor xa inhibitors. N Engl J Med. 2019;380(14):1326-35.

12. Piran S et al. Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: A meta-analysis. Blood Adv. 2019;3(2):158-67.

Hospitalized patients with inflammatory bowel diseases (IBD) are most likely to be readmitted for venous thromboembolism (VTE) within 60 days of discharge, according to a new study that analyzed 5 years of U.S. readmissions data.

“Given increased thrombotic risk postdischarge, as well as overall safety of VTE prophylaxis, extending prophylaxis for those at highest risk may have significant benefits,” wrote Adam S. Faye, MD, of Columbia University, and coauthors. The study was published in Clinical Gastroenterology and Hepatology.

To determine which IBD patients would be most in need of postdischarge VTE prophylaxis, as well as when to administer it, the researchers analyzed 2010-2014 data from the Nationwide Readmissions Database (NRD). They found a total of 872,122 index admissions for IBD patients; 4% of those patients had a prior VTE. Of the index admissions, 1,160 led to a VTE readmission within 90 days. Readmitted patients had a relatively equal proportion of ulcerative colitis (n = 522) and Crohn’s disease (n = 638).

More than 90% of VTE readmissions occurred within 60 days of discharge; the risk was highest over the first 10 days and then decreased in each ensuing 10-day period until a slight increase at the 81- to 90-day period. All patients over age 30 had higher rates of readmission than those of patients under age 18, with the highest risk in patients between the ages of 66 and 80 years (risk ratio 4.04; 95% confidence interval, 2.54-6.44, P less than .01). Women were at lower risk (RR 0.82; 95% CI, 0.73-0.92, P less than .01). Higher risks of readmission were also associated with being on Medicare (RR 1.39; 95% CI, 1.23-1.58, P less than .01) compared with being on private insurance and being cared for at a large hospital (RR 1.26; 95% CI, 1.04-1.52, P = .02) compared with a small hospital.

The highest risk of VTE readmission was associated with a prior history of VTE (RR 2.89; 95% CI, 2.40-3.48, P less than .01), having two or more comorbidities (RR 2.57; 95% CI, 2.11-3.12, P less than .01) and having a Clostridioides difficile infection as of index admission (RR 1.90; 95% CI, 1.51-2.38, P less than .01). In addition, increased risk was associated with being discharged to a nursing or care facility (RR 1.85; 95% CI, 1.56-2.20, P less than .01) or home with health services (RR 2.05; 95% CI, 1.78-2.38, P less than .01) compared with a routine discharge.

In their multivariable analysis, similar factors such as a history of VTE (adjusted RR 2.41; 95% CI, 1.99-2.90, P less than .01), two or more comorbidities (aRR 1.78; 95% CI, 1.44-2.20, P less than .01) and C. difficile infection (aRR 1.47; 95% CI, 1.17-1.85, P less than.01) continued to be associated with higher risk of VTE readmission.

SOURCE: Faye AS et al. Clin Gastroenterol Hepatol. 2019 July 20. doi: 10.1016/j.cgh.2019.07.028.

Hospitalized patients with inflammatory bowel diseases (IBD) are most likely to be readmitted for venous thromboembolism (VTE) within 60 days of discharge, according to a new study that analyzed 5 years of U.S. readmissions data.

“Given increased thrombotic risk postdischarge, as well as overall safety of VTE prophylaxis, extending prophylaxis for those at highest risk may have significant benefits,” wrote Adam S. Faye, MD, of Columbia University, and coauthors. The study was published in Clinical Gastroenterology and Hepatology.

To determine which IBD patients would be most in need of postdischarge VTE prophylaxis, as well as when to administer it, the researchers analyzed 2010-2014 data from the Nationwide Readmissions Database (NRD). They found a total of 872,122 index admissions for IBD patients; 4% of those patients had a prior VTE. Of the index admissions, 1,160 led to a VTE readmission within 90 days. Readmitted patients had a relatively equal proportion of ulcerative colitis (n = 522) and Crohn’s disease (n = 638).

More than 90% of VTE readmissions occurred within 60 days of discharge; the risk was highest over the first 10 days and then decreased in each ensuing 10-day period until a slight increase at the 81- to 90-day period. All patients over age 30 had higher rates of readmission than those of patients under age 18, with the highest risk in patients between the ages of 66 and 80 years (risk ratio 4.04; 95% confidence interval, 2.54-6.44, P less than .01). Women were at lower risk (RR 0.82; 95% CI, 0.73-0.92, P less than .01). Higher risks of readmission were also associated with being on Medicare (RR 1.39; 95% CI, 1.23-1.58, P less than .01) compared with being on private insurance and being cared for at a large hospital (RR 1.26; 95% CI, 1.04-1.52, P = .02) compared with a small hospital.

The highest risk of VTE readmission was associated with a prior history of VTE (RR 2.89; 95% CI, 2.40-3.48, P less than .01), having two or more comorbidities (RR 2.57; 95% CI, 2.11-3.12, P less than .01) and having a Clostridioides difficile infection as of index admission (RR 1.90; 95% CI, 1.51-2.38, P less than .01). In addition, increased risk was associated with being discharged to a nursing or care facility (RR 1.85; 95% CI, 1.56-2.20, P less than .01) or home with health services (RR 2.05; 95% CI, 1.78-2.38, P less than .01) compared with a routine discharge.

In their multivariable analysis, similar factors such as a history of VTE (adjusted RR 2.41; 95% CI, 1.99-2.90, P less than .01), two or more comorbidities (aRR 1.78; 95% CI, 1.44-2.20, P less than .01) and C. difficile infection (aRR 1.47; 95% CI, 1.17-1.85, P less than.01) continued to be associated with higher risk of VTE readmission.

SOURCE: Faye AS et al. Clin Gastroenterol Hepatol. 2019 July 20. doi: 10.1016/j.cgh.2019.07.028.

Hospitalized patients with inflammatory bowel diseases (IBD) are most likely to be readmitted for venous thromboembolism (VTE) within 60 days of discharge, according to a new study that analyzed 5 years of U.S. readmissions data.

“Given increased thrombotic risk postdischarge, as well as overall safety of VTE prophylaxis, extending prophylaxis for those at highest risk may have significant benefits,” wrote Adam S. Faye, MD, of Columbia University, and coauthors. The study was published in Clinical Gastroenterology and Hepatology.

To determine which IBD patients would be most in need of postdischarge VTE prophylaxis, as well as when to administer it, the researchers analyzed 2010-2014 data from the Nationwide Readmissions Database (NRD). They found a total of 872,122 index admissions for IBD patients; 4% of those patients had a prior VTE. Of the index admissions, 1,160 led to a VTE readmission within 90 days. Readmitted patients had a relatively equal proportion of ulcerative colitis (n = 522) and Crohn’s disease (n = 638).

More than 90% of VTE readmissions occurred within 60 days of discharge; the risk was highest over the first 10 days and then decreased in each ensuing 10-day period until a slight increase at the 81- to 90-day period. All patients over age 30 had higher rates of readmission than those of patients under age 18, with the highest risk in patients between the ages of 66 and 80 years (risk ratio 4.04; 95% confidence interval, 2.54-6.44, P less than .01). Women were at lower risk (RR 0.82; 95% CI, 0.73-0.92, P less than .01). Higher risks of readmission were also associated with being on Medicare (RR 1.39; 95% CI, 1.23-1.58, P less than .01) compared with being on private insurance and being cared for at a large hospital (RR 1.26; 95% CI, 1.04-1.52, P = .02) compared with a small hospital.

The highest risk of VTE readmission was associated with a prior history of VTE (RR 2.89; 95% CI, 2.40-3.48, P less than .01), having two or more comorbidities (RR 2.57; 95% CI, 2.11-3.12, P less than .01) and having a Clostridioides difficile infection as of index admission (RR 1.90; 95% CI, 1.51-2.38, P less than .01). In addition, increased risk was associated with being discharged to a nursing or care facility (RR 1.85; 95% CI, 1.56-2.20, P less than .01) or home with health services (RR 2.05; 95% CI, 1.78-2.38, P less than .01) compared with a routine discharge.

In their multivariable analysis, similar factors such as a history of VTE (adjusted RR 2.41; 95% CI, 1.99-2.90, P less than .01), two or more comorbidities (aRR 1.78; 95% CI, 1.44-2.20, P less than .01) and C. difficile infection (aRR 1.47; 95% CI, 1.17-1.85, P less than.01) continued to be associated with higher risk of VTE readmission.

SOURCE: Faye AS et al. Clin Gastroenterol Hepatol. 2019 July 20. doi: 10.1016/j.cgh.2019.07.028.

Background: Despite multiple guidelines that support outpatient management of acute PE in the appropriate patient population, the rate of hospital admission for patients eligible for outpatient management remains high. One explanation is that physicians may have difficulty identifying which patients meet discharge criteria.

Dr. Bordin-Wosk is an assistant clinical professor in the division of hospital medicine at the University of California, San Diego.

Background: Despite multiple guidelines that support outpatient management of acute PE in the appropriate patient population, the rate of hospital admission for patients eligible for outpatient management remains high. One explanation is that physicians may have difficulty identifying which patients meet discharge criteria.

Dr. Bordin-Wosk is an assistant clinical professor in the division of hospital medicine at the University of California, San Diego.

Background: Despite multiple guidelines that support outpatient management of acute PE in the appropriate patient population, the rate of hospital admission for patients eligible for outpatient management remains high. One explanation is that physicians may have difficulty identifying which patients meet discharge criteria.

Dr. Bordin-Wosk is an assistant clinical professor in the division of hospital medicine at the University of California, San Diego.

Background: With increased use of anticoagulants, the amount of related ADEs has also increased. ADEs may be preventable through improved communication during transitions of care. The key communication elements are not standardized.

The following items are the 15 RDEs that require documentation: (1) current anticoagulants; (2) indications; (3) new or previous user; (4) if new, start date, (5) short-term or long-term use; (6) if short term, intended duration; (7) last two doses given; (8) next dose due; (9) latest renal function; (10) provision of patient education materials; (11) assessment of patient/caregiver understanding; (12) future anticoagulation provider; and if warfarin, (13) the target range, (14) at least 2-3 consecutive international normalized ratio results, and (15) next INR level.

Bottom line: Standardized communication during transitions of care regarding anticoagulation may reduce anticoagulant ADEs. Objective evidence showing reduction of ADEs after implementation of the list is needed.

Citation: Triller D et al. Defining minimum necessary anticoagulation-related communication at discharge: Consensus of the Care Transitions Task Force of the New York State Anticoagulation Coalition. Jt Comm J Qual Patient Saf. 2018;44(11):630-40.

Dr. Vuong is an associate physician in the division of hospital medicine at the University of California, San Diego.

Background: With increased use of anticoagulants, the amount of related ADEs has also increased. ADEs may be preventable through improved communication during transitions of care. The key communication elements are not standardized.

The following items are the 15 RDEs that require documentation: (1) current anticoagulants; (2) indications; (3) new or previous user; (4) if new, start date, (5) short-term or long-term use; (6) if short term, intended duration; (7) last two doses given; (8) next dose due; (9) latest renal function; (10) provision of patient education materials; (11) assessment of patient/caregiver understanding; (12) future anticoagulation provider; and if warfarin, (13) the target range, (14) at least 2-3 consecutive international normalized ratio results, and (15) next INR level.

Bottom line: Standardized communication during transitions of care regarding anticoagulation may reduce anticoagulant ADEs. Objective evidence showing reduction of ADEs after implementation of the list is needed.

Citation: Triller D et al. Defining minimum necessary anticoagulation-related communication at discharge: Consensus of the Care Transitions Task Force of the New York State Anticoagulation Coalition. Jt Comm J Qual Patient Saf. 2018;44(11):630-40.

Dr. Vuong is an associate physician in the division of hospital medicine at the University of California, San Diego.

Background: With increased use of anticoagulants, the amount of related ADEs has also increased. ADEs may be preventable through improved communication during transitions of care. The key communication elements are not standardized.

The following items are the 15 RDEs that require documentation: (1) current anticoagulants; (2) indications; (3) new or previous user; (4) if new, start date, (5) short-term or long-term use; (6) if short term, intended duration; (7) last two doses given; (8) next dose due; (9) latest renal function; (10) provision of patient education materials; (11) assessment of patient/caregiver understanding; (12) future anticoagulation provider; and if warfarin, (13) the target range, (14) at least 2-3 consecutive international normalized ratio results, and (15) next INR level.

Bottom line: Standardized communication during transitions of care regarding anticoagulation may reduce anticoagulant ADEs. Objective evidence showing reduction of ADEs after implementation of the list is needed.

Citation: Triller D et al. Defining minimum necessary anticoagulation-related communication at discharge: Consensus of the Care Transitions Task Force of the New York State Anticoagulation Coalition. Jt Comm J Qual Patient Saf. 2018;44(11):630-40.

Dr. Vuong is an associate physician in the division of hospital medicine at the University of California, San Diego.

PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.

“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.

This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.

Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.

“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.

The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.

The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.

The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.

In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.

“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.

POP AGE is hailed as ‘a wake up call’

In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”

“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.

Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.

“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”

So is POP AGE a practice-changing study?

“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”

“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.

Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
 

[email protected]

SOURCE: Gimbel ME. ESC 2019, Abstract 84.


 

PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.

“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.

This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.

Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.

“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.

The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.

The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.

The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.

In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.

“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.

POP AGE is hailed as ‘a wake up call’

In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”

“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.

Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.

“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”

So is POP AGE a practice-changing study?

“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”

“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.

Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
 

[email protected]

SOURCE: Gimbel ME. ESC 2019, Abstract 84.


 

PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.

“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.

This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.

Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.

“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.

The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.

The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.

The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.

In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.

“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.

POP AGE is hailed as ‘a wake up call’

In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”

“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.

Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.

“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”

So is POP AGE a practice-changing study?

“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”

“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.

Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
 

[email protected]

SOURCE: Gimbel ME. ESC 2019, Abstract 84.


 

Case

A 78-year-old woman with end-stage renal disease (ESRD) is hospitalized with cellulitis and is incidentally found to be in atrial fibrillation. She does not have a history of mitral stenosis, nor does she have a prosthetic valve. She does have a history of hypertension, diabetes, and prior stroke without residual deficits.

After counseling her about the risk of stroke associated with atrial fibrillation (AFib) she makes it clear she is interested in pharmacologic therapy to minimize her risk of stroke and asks what medication you would recommend for anticoagulation.

Brief overview of the issue

Anticoagulation for AFib is indicated for stroke prophylaxis in patients with an elevated risk of stroke. The CHA₂DS₂-VASc score is useful in calculating an individual patient’s risk of stroke and as a decision tool to determine who would benefit from anticoagulation, and it is recommended in the American Heart Association guidelines.¹

Low-risk patients (CHA₂DS₂-VASc score of 0 in men or 1 in women) should not be started on anticoagulation for stroke prophylaxis. For anyone with a risk factor, other than being female, anticoagulation is indicated and should be considered.

The guideline recommends anticoagulant therapy, not antiplatelet agents. For most of the recent past, this has meant a vitamin K antagonist (warfarin) or sometimes a low-molecular-weight heparin injected subcutaneously. Over the past decade, however, with the approval of multiple direct oral anticoagulants (DOACs), nonwarfarin oral anticoagulation has grown in popularity as the prophylactic medication of choice.²

While the data for patients with preserved renal function is robust, there is far less data to guide decision making for patients with end-stage renal disease.

Overview of the data

Until the introduction of DOACs, warfarin was the main agent used for stroke prophylaxis in patients with end-stage kidney disease and AFib. Professional guidelines favored warfarin for these patients who were mostly excluded from DOAC trials. Specialized conferences also looked at this issue.

The Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference, which reviewed chronic kidney disease and arrhythmias, noted that there were no randomized controlled trials that examined the efficacy and safety of anticoagulation in chronic kidney disease patients with estimated creatinine clearance less than 30 mL/min. They remarked that there was insufficient high-quality evidence to recommend warfarin for the prevention of stroke in patients with AFib and dialysis-dependent chronic kidney disease.

Since, according to other trials, DOACs had better safety profiles in other populations, the conference noted that lower-dose apixaban (2.5 mg orally twice daily) or rivaroxaban (15 mg daily) may be considered in this population until clinical safety data were available. Furthermore, the conference recommended that these patients be treated with a multidisciplinary approach in regards to anticoagulation and have an annual reevaluation of treatment goals, along with a risk-benefit assessment.³

Since the publication of the 2018 AHA guidelines and the guidance document that resulted from the KDIGO conference, additional research has been published comparing anticoagulation with a DOAC versus warfarin for AFib in patients with ESRD.

“Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States” was an observational, retrospective, cohort study that compared outcomes in dialysis patients who took warfarin for AFib with those who took apixaban.⁴ Patients’ data was taken from the U.S. Renal Data System database and were included in the final analysis if they had ESRD, a recent diagnosis of AFib or atrial flutter, and a new prescription for either warfarin or apixaban. Outcome measures were stroke or systemic embolism, major bleeding (critical site, transfusion, or death), gastrointestinal bleeding, intracranial bleeding, or death. Drug usage and compliance were assessed using Medicare Part D prescription information.

A total of 25,523 patients met the inclusion/exclusion criteria and had taken either warfarin (n = 23,172) or apixaban (n = 2,351). To account for selection bias in these cohorts, a subset of the warfarin patients was selected based on prognostic score matching. The prognostic score was calculated from the baseline characteristics (which included age, stroke history, diabetes, smoking, antiplatelet medication, liver disease, prior bleeding, and CHA₂DS₂-VASc score). Kaplan-Meier and Cox regression analysis were used to give hazard ratios and 95% confidence intervals for each outcome measure. Prespecified subgroup analyses were conducted to compare apixaban doses, where 44% were prescribed 5 mg b.i.d. and 56% were prescribed 2.5 mg b.i.d..

In the study, patients in the apixaban group had a significantly lower risk of major bleeding as compared with the warfarin group (HR, 0.72; 95% CI, 0.59-0.87; P less than .001) with overall high rates of major bleeding in both groups at 19.7 and 22.9 per 100 patient-years in the apixaban group and warfarin group, respectively. There was no difference in the rate of stroke/systemic embolism between patients receiving apixaban and warfarin (HR, 0.88; 95% CI, 0.69-1.12; P = .29). There was a nonsignificant trend toward decreased risk of GI bleeding in the apixaban group and no significant differences between the groups in the rates of intracranial bleeding. Apixaban was also associated with a nonsignificant trend toward lower risk of mortality (HR, 0.85; 95% CI, 0.71-1.01; P = .06).

Notably, censoring rates because of expired prescriptions or a 1-month gap between prescriptions were high in both groups and the majority of censoring occurred within the first 12 months. Additionally, in dose specific analyses, patients receiving the 5-mg, twice-daily dose were found to have statistically significant decreases in risk of stroke/systemic embolism (P = .035) and mortality (P = .005) as compared with the 2.5-mg, twice-daily dose without significant differences in GI or intracranial bleeding.

There are three ongoing, open-label, randomized, controlled trials examining anticoagulation for nonvalvular AFib in patients with ESRD on hemodialysis with two comparing apixaban to warfarin (or derivative) and the other warfarin versus no anticoagulation.⁵ All trials are in adult patients with documented AFib and CHA₂DS₂-VASc score of at least 2. AKADIA (Germany based) plans to enroll 222 patients and compares a vitamin K antagonist (INR goal, 2-3) with 2.5-mg b.i.d. apixaban patients with ESRD on hemodialysis for at least 3 months with primary outcome of major and clinically relevant nonmajor bleeding and secondary outcome of thromboembolic events, as well as apixaban levels pre- and post hemodialysis.

RENAL-AF (U.S. based) plans to enrolled 762 patients and compares 5-mg b.i.d. apixaban (with 2.5 mg for selected patients) with warfarin in people of chronic hemodialysis with primary outcome of days to first major or clinically relevant nonmajor bleeding event and secondary outcome of stroke, systemic embolism, mortality, adherence and plasma apixaban levels. AVKDIAL (France based) plans to enroll 855 patients and compares no anticoagulation with vitamin K antagonists in patients on hemodialysis for at least 1 month, with primary outcome of cumulative incidence of severe bleeding and thrombosis.

Application of the data to our original case

Our patient is Medicare age with ESRD and newly diagnosed nonvalvular AFib. Recent data suggests apixaban could be used for stroke prevention instead of the prior standard of care, warfarin. This approach is supported in the 2019 guidelines.¹

Patients with ESRD have an increased risk of bleeding and apixaban was shown to have less bleeding complications than warfarin in this analysis. However, only standard-dose apixaban was associated with a statistically significant lower risk of stroke/systemic embolism, major bleeding, and death. Reduced-dose apixaban had a lower risk of major bleeding but no difference for stroke/systemic embolism or death. Reduced-dose apixaban is used for patients who have two out of the following three criteria: aged at least 80 years, weight of at least 60 kg, and creatinine of at least 1.5 mg/dL. Therefore, many Medicare-age patients with ESRD would not be indicated for the dose of apixaban that was shown to improve the most important outcomes of stroke/SE and death.

It may still be beneficial to use apixaban in this patient since it appears to work as well as warfarin for stroke/systemic embolism prevention with less bleeding complications.

Bottom line

For patients who have decided to pursue an anticoagulation strategy for stroke prevention in AFib and have end-stage renal disease, either warfarin or apixaban are sensible options.

Dr. Farber is a medical instructor at Duke University Health System in Durham, N.C. Dr. Stafford is a medical instructor at Duke University. Dr. Sata is assistant professor of medicine at Duke University. Dr. Abdo and Dr. Menon are hospitalists at Duke University. Dr. Brooks is assistant professor of medicine at Duke University. Dr. Wachter is associate medical director at Duke Regional Hospital and assistant professor of medicine at Duke University. Dr. Sharma is associate medical director for clinical education in hospital medicine at Duke Regional Hospital and assistant professor of medicine at Duke University.

References

1. January CT et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2019;139. doi: 1161/CIR.0000000000000665.

2. Lippi G et al. Direct oral anticoagulants: Analysis of worldwide use and popularity using Google Trends. Ann Transl Med. 2017 Aug; 5(16):322. doi: 10.21037/atm.2017.06.65.

3. Turakhia MP et al. Chronic kidney disease and arrhythmias: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Eur Heart J. 2018 Jun 21;39(24):2314-25. doi: 10.1093/eurheartj/ehy060.

4. Siontis KC et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation. 2018 Oct 9;138(15):1519-29. doi: 10.1161/CIRCULATIONAHA.118.035418.

5. Nigwekar SU et al. Long-term anticoagulation for patient receiving dialysis: Tilting the benefit-to-risk ratio? Circulation. 2018 Oct 9;138(15):1530-3. doi: 10.1161/CIRCULATIONAHA.118.037091.

Key points

• According to 2019 American Heart Association guidelines, warfarin or apixaban are reasonable options for stroke prevention for patients who have end-stage renal disease and who plan for anticoagulation because of atrial fibrillation.
• Recent observational data suggests that apixaban may be safer than warfarin in this population.
• Several randomized, controlled trials are ongoing that may help determine the optimal agent to use in this setting.
• Until more definitive data is available, a reasonable approach is to discuss the risks and benefits of various treatment strategies with patients, and engage a multidisciplinary team (cardiologist, nephrologist, primary care provider, pharmacist) in the decision making process.

Additional reading

January CT et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2019;139. doi: 1161/CIR.0000000000000665.

Nigwekar SU et al. Long-term anticoagulation for patient receiving dialysis: Tilting the benefit to risk ratio? Circulation. 2018 Oct 9;138(15):1530-3. doi: 10.1161/CIRCULATIONAHA.118.037091.

Garlo KG et al. Demystifying the benefits and harms of anticoagulation for atrial fibrillation in chronic kidney disease. Clin J Am Soc Nephrol 2019;14:125-36. doi: 10.2215/CJN.06430518.

Quiz

Two days ago you admitted a 72-year-old woman with end-stage renal disease on dialysis who had developed new-onset atrial fibrillation causing a mild acute diastolic congestive heart failure exacerbation. Transthoracic ECG showed a preserved left ventricular ejection fraction and no significant valvular disease. After two sessions of dialysis in the hospital and initiation of a beta-blocker for control of her heart rate, she is stable and ready for discharge. Her discharge weight is 75 kg.

Which of the following recommendations should you make to this patient regarding anticoagulation for prevention of stroke and systemic embolism from atrial fibrillation?

A. Take warfarin with a international normalized ratio goal of 2.5.

B. Take apixaban 2.5 mg twice a day.

C. Take apixaban 5 mg twice a day.

D. Discuss the risks/benefits of various treatment approaches with the patient, and involve the hospital pharmacist as well as the patient’s nephrologist, cardiologist, and/or primary care provider in the decision making process to reach a consensus and to ensure a safe follow-up plan.

The best answer is D. While A, B, and C are all reasonable approaches based on the available data and current guidelines, the best approach is to involve the patient and the multidisciplinary team in the decision making process. When more clinical trial data becomes available in the future, the optimal approach to managing patients such as this one may become clearer, but until then it makes sense to take into account individual patient characteristics and patient preferences.

Case

A 78-year-old woman with end-stage renal disease (ESRD) is hospitalized with cellulitis and is incidentally found to be in atrial fibrillation. She does not have a history of mitral stenosis, nor does she have a prosthetic valve. She does have a history of hypertension, diabetes, and prior stroke without residual deficits.

After counseling her about the risk of stroke associated with atrial fibrillation (AFib) she makes it clear she is interested in pharmacologic therapy to minimize her risk of stroke and asks what medication you would recommend for anticoagulation.

Brief overview of the issue

Anticoagulation for AFib is indicated for stroke prophylaxis in patients with an elevated risk of stroke. The CHA₂DS₂-VASc score is useful in calculating an individual patient’s risk of stroke and as a decision tool to determine who would benefit from anticoagulation, and it is recommended in the American Heart Association guidelines.¹

Low-risk patients (CHA₂DS₂-VASc score of 0 in men or 1 in women) should not be started on anticoagulation for stroke prophylaxis. For anyone with a risk factor, other than being female, anticoagulation is indicated and should be considered.

The guideline recommends anticoagulant therapy, not antiplatelet agents. For most of the recent past, this has meant a vitamin K antagonist (warfarin) or sometimes a low-molecular-weight heparin injected subcutaneously. Over the past decade, however, with the approval of multiple direct oral anticoagulants (DOACs), nonwarfarin oral anticoagulation has grown in popularity as the prophylactic medication of choice.²

While the data for patients with preserved renal function is robust, there is far less data to guide decision making for patients with end-stage renal disease.

Overview of the data

Until the introduction of DOACs, warfarin was the main agent used for stroke prophylaxis in patients with end-stage kidney disease and AFib. Professional guidelines favored warfarin for these patients who were mostly excluded from DOAC trials. Specialized conferences also looked at this issue.

The Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference, which reviewed chronic kidney disease and arrhythmias, noted that there were no randomized controlled trials that examined the efficacy and safety of anticoagulation in chronic kidney disease patients with estimated creatinine clearance less than 30 mL/min. They remarked that there was insufficient high-quality evidence to recommend warfarin for the prevention of stroke in patients with AFib and dialysis-dependent chronic kidney disease.

Since, according to other trials, DOACs had better safety profiles in other populations, the conference noted that lower-dose apixaban (2.5 mg orally twice daily) or rivaroxaban (15 mg daily) may be considered in this population until clinical safety data were available. Furthermore, the conference recommended that these patients be treated with a multidisciplinary approach in regards to anticoagulation and have an annual reevaluation of treatment goals, along with a risk-benefit assessment.³

Since the publication of the 2018 AHA guidelines and the guidance document that resulted from the KDIGO conference, additional research has been published comparing anticoagulation with a DOAC versus warfarin for AFib in patients with ESRD.

“Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States” was an observational, retrospective, cohort study that compared outcomes in dialysis patients who took warfarin for AFib with those who took apixaban.⁴ Patients’ data was taken from the U.S. Renal Data System database and were included in the final analysis if they had ESRD, a recent diagnosis of AFib or atrial flutter, and a new prescription for either warfarin or apixaban. Outcome measures were stroke or systemic embolism, major bleeding (critical site, transfusion, or death), gastrointestinal bleeding, intracranial bleeding, or death. Drug usage and compliance were assessed using Medicare Part D prescription information.

A total of 25,523 patients met the inclusion/exclusion criteria and had taken either warfarin (n = 23,172) or apixaban (n = 2,351). To account for selection bias in these cohorts, a subset of the warfarin patients was selected based on prognostic score matching. The prognostic score was calculated from the baseline characteristics (which included age, stroke history, diabetes, smoking, antiplatelet medication, liver disease, prior bleeding, and CHA₂DS₂-VASc score). Kaplan-Meier and Cox regression analysis were used to give hazard ratios and 95% confidence intervals for each outcome measure. Prespecified subgroup analyses were conducted to compare apixaban doses, where 44% were prescribed 5 mg b.i.d. and 56% were prescribed 2.5 mg b.i.d..

In the study, patients in the apixaban group had a significantly lower risk of major bleeding as compared with the warfarin group (HR, 0.72; 95% CI, 0.59-0.87; P less than .001) with overall high rates of major bleeding in both groups at 19.7 and 22.9 per 100 patient-years in the apixaban group and warfarin group, respectively. There was no difference in the rate of stroke/systemic embolism between patients receiving apixaban and warfarin (HR, 0.88; 95% CI, 0.69-1.12; P = .29). There was a nonsignificant trend toward decreased risk of GI bleeding in the apixaban group and no significant differences between the groups in the rates of intracranial bleeding. Apixaban was also associated with a nonsignificant trend toward lower risk of mortality (HR, 0.85; 95% CI, 0.71-1.01; P = .06).

Notably, censoring rates because of expired prescriptions or a 1-month gap between prescriptions were high in both groups and the majority of censoring occurred within the first 12 months. Additionally, in dose specific analyses, patients receiving the 5-mg, twice-daily dose were found to have statistically significant decreases in risk of stroke/systemic embolism (P = .035) and mortality (P = .005) as compared with the 2.5-mg, twice-daily dose without significant differences in GI or intracranial bleeding.

There are three ongoing, open-label, randomized, controlled trials examining anticoagulation for nonvalvular AFib in patients with ESRD on hemodialysis with two comparing apixaban to warfarin (or derivative) and the other warfarin versus no anticoagulation.⁵ All trials are in adult patients with documented AFib and CHA₂DS₂-VASc score of at least 2. AKADIA (Germany based) plans to enroll 222 patients and compares a vitamin K antagonist (INR goal, 2-3) with 2.5-mg b.i.d. apixaban patients with ESRD on hemodialysis for at least 3 months with primary outcome of major and clinically relevant nonmajor bleeding and secondary outcome of thromboembolic events, as well as apixaban levels pre- and post hemodialysis.

RENAL-AF (U.S. based) plans to enrolled 762 patients and compares 5-mg b.i.d. apixaban (with 2.5 mg for selected patients) with warfarin in people of chronic hemodialysis with primary outcome of days to first major or clinically relevant nonmajor bleeding event and secondary outcome of stroke, systemic embolism, mortality, adherence and plasma apixaban levels. AVKDIAL (France based) plans to enroll 855 patients and compares no anticoagulation with vitamin K antagonists in patients on hemodialysis for at least 1 month, with primary outcome of cumulative incidence of severe bleeding and thrombosis.

Application of the data to our original case

Our patient is Medicare age with ESRD and newly diagnosed nonvalvular AFib. Recent data suggests apixaban could be used for stroke prevention instead of the prior standard of care, warfarin. This approach is supported in the 2019 guidelines.¹

Patients with ESRD have an increased risk of bleeding and apixaban was shown to have less bleeding complications than warfarin in this analysis. However, only standard-dose apixaban was associated with a statistically significant lower risk of stroke/systemic embolism, major bleeding, and death. Reduced-dose apixaban had a lower risk of major bleeding but no difference for stroke/systemic embolism or death. Reduced-dose apixaban is used for patients who have two out of the following three criteria: aged at least 80 years, weight of at least 60 kg, and creatinine of at least 1.5 mg/dL. Therefore, many Medicare-age patients with ESRD would not be indicated for the dose of apixaban that was shown to improve the most important outcomes of stroke/SE and death.

It may still be beneficial to use apixaban in this patient since it appears to work as well as warfarin for stroke/systemic embolism prevention with less bleeding complications.

Bottom line

For patients who have decided to pursue an anticoagulation strategy for stroke prevention in AFib and have end-stage renal disease, either warfarin or apixaban are sensible options.

Dr. Farber is a medical instructor at Duke University Health System in Durham, N.C. Dr. Stafford is a medical instructor at Duke University. Dr. Sata is assistant professor of medicine at Duke University. Dr. Abdo and Dr. Menon are hospitalists at Duke University. Dr. Brooks is assistant professor of medicine at Duke University. Dr. Wachter is associate medical director at Duke Regional Hospital and assistant professor of medicine at Duke University. Dr. Sharma is associate medical director for clinical education in hospital medicine at Duke Regional Hospital and assistant professor of medicine at Duke University.

References

1. January CT et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2019;139. doi: 1161/CIR.0000000000000665.

2. Lippi G et al. Direct oral anticoagulants: Analysis of worldwide use and popularity using Google Trends. Ann Transl Med. 2017 Aug; 5(16):322. doi: 10.21037/atm.2017.06.65.

3. Turakhia MP et al. Chronic kidney disease and arrhythmias: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Eur Heart J. 2018 Jun 21;39(24):2314-25. doi: 10.1093/eurheartj/ehy060.

4. Siontis KC et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation. 2018 Oct 9;138(15):1519-29. doi: 10.1161/CIRCULATIONAHA.118.035418.

5. Nigwekar SU et al. Long-term anticoagulation for patient receiving dialysis: Tilting the benefit-to-risk ratio? Circulation. 2018 Oct 9;138(15):1530-3. doi: 10.1161/CIRCULATIONAHA.118.037091.

Key points

• According to 2019 American Heart Association guidelines, warfarin or apixaban are reasonable options for stroke prevention for patients who have end-stage renal disease and who plan for anticoagulation because of atrial fibrillation.
• Recent observational data suggests that apixaban may be safer than warfarin in this population.
• Several randomized, controlled trials are ongoing that may help determine the optimal agent to use in this setting.
• Until more definitive data is available, a reasonable approach is to discuss the risks and benefits of various treatment strategies with patients, and engage a multidisciplinary team (cardiologist, nephrologist, primary care provider, pharmacist) in the decision making process.

Additional reading

January CT et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2019;139. doi: 1161/CIR.0000000000000665.

Nigwekar SU et al. Long-term anticoagulation for patient receiving dialysis: Tilting the benefit to risk ratio? Circulation. 2018 Oct 9;138(15):1530-3. doi: 10.1161/CIRCULATIONAHA.118.037091.

Garlo KG et al. Demystifying the benefits and harms of anticoagulation for atrial fibrillation in chronic kidney disease. Clin J Am Soc Nephrol 2019;14:125-36. doi: 10.2215/CJN.06430518.

Quiz

Two days ago you admitted a 72-year-old woman with end-stage renal disease on dialysis who had developed new-onset atrial fibrillation causing a mild acute diastolic congestive heart failure exacerbation. Transthoracic ECG showed a preserved left ventricular ejection fraction and no significant valvular disease. After two sessions of dialysis in the hospital and initiation of a beta-blocker for control of her heart rate, she is stable and ready for discharge. Her discharge weight is 75 kg.

Which of the following recommendations should you make to this patient regarding anticoagulation for prevention of stroke and systemic embolism from atrial fibrillation?

A. Take warfarin with a international normalized ratio goal of 2.5.

B. Take apixaban 2.5 mg twice a day.

C. Take apixaban 5 mg twice a day.

D. Discuss the risks/benefits of various treatment approaches with the patient, and involve the hospital pharmacist as well as the patient’s nephrologist, cardiologist, and/or primary care provider in the decision making process to reach a consensus and to ensure a safe follow-up plan.

The best answer is D. While A, B, and C are all reasonable approaches based on the available data and current guidelines, the best approach is to involve the patient and the multidisciplinary team in the decision making process. When more clinical trial data becomes available in the future, the optimal approach to managing patients such as this one may become clearer, but until then it makes sense to take into account individual patient characteristics and patient preferences.

Case

A 78-year-old woman with end-stage renal disease (ESRD) is hospitalized with cellulitis and is incidentally found to be in atrial fibrillation. She does not have a history of mitral stenosis, nor does she have a prosthetic valve. She does have a history of hypertension, diabetes, and prior stroke without residual deficits.

After counseling her about the risk of stroke associated with atrial fibrillation (AFib) she makes it clear she is interested in pharmacologic therapy to minimize her risk of stroke and asks what medication you would recommend for anticoagulation.

Brief overview of the issue

Anticoagulation for AFib is indicated for stroke prophylaxis in patients with an elevated risk of stroke. The CHA₂DS₂-VASc score is useful in calculating an individual patient’s risk of stroke and as a decision tool to determine who would benefit from anticoagulation, and it is recommended in the American Heart Association guidelines.¹

Low-risk patients (CHA₂DS₂-VASc score of 0 in men or 1 in women) should not be started on anticoagulation for stroke prophylaxis. For anyone with a risk factor, other than being female, anticoagulation is indicated and should be considered.

The guideline recommends anticoagulant therapy, not antiplatelet agents. For most of the recent past, this has meant a vitamin K antagonist (warfarin) or sometimes a low-molecular-weight heparin injected subcutaneously. Over the past decade, however, with the approval of multiple direct oral anticoagulants (DOACs), nonwarfarin oral anticoagulation has grown in popularity as the prophylactic medication of choice.²

While the data for patients with preserved renal function is robust, there is far less data to guide decision making for patients with end-stage renal disease.

Overview of the data

Until the introduction of DOACs, warfarin was the main agent used for stroke prophylaxis in patients with end-stage kidney disease and AFib. Professional guidelines favored warfarin for these patients who were mostly excluded from DOAC trials. Specialized conferences also looked at this issue.

The Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference, which reviewed chronic kidney disease and arrhythmias, noted that there were no randomized controlled trials that examined the efficacy and safety of anticoagulation in chronic kidney disease patients with estimated creatinine clearance less than 30 mL/min. They remarked that there was insufficient high-quality evidence to recommend warfarin for the prevention of stroke in patients with AFib and dialysis-dependent chronic kidney disease.

Since, according to other trials, DOACs had better safety profiles in other populations, the conference noted that lower-dose apixaban (2.5 mg orally twice daily) or rivaroxaban (15 mg daily) may be considered in this population until clinical safety data were available. Furthermore, the conference recommended that these patients be treated with a multidisciplinary approach in regards to anticoagulation and have an annual reevaluation of treatment goals, along with a risk-benefit assessment.³

Since the publication of the 2018 AHA guidelines and the guidance document that resulted from the KDIGO conference, additional research has been published comparing anticoagulation with a DOAC versus warfarin for AFib in patients with ESRD.

“Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States” was an observational, retrospective, cohort study that compared outcomes in dialysis patients who took warfarin for AFib with those who took apixaban.⁴ Patients’ data was taken from the U.S. Renal Data System database and were included in the final analysis if they had ESRD, a recent diagnosis of AFib or atrial flutter, and a new prescription for either warfarin or apixaban. Outcome measures were stroke or systemic embolism, major bleeding (critical site, transfusion, or death), gastrointestinal bleeding, intracranial bleeding, or death. Drug usage and compliance were assessed using Medicare Part D prescription information.

A total of 25,523 patients met the inclusion/exclusion criteria and had taken either warfarin (n = 23,172) or apixaban (n = 2,351). To account for selection bias in these cohorts, a subset of the warfarin patients was selected based on prognostic score matching. The prognostic score was calculated from the baseline characteristics (which included age, stroke history, diabetes, smoking, antiplatelet medication, liver disease, prior bleeding, and CHA₂DS₂-VASc score). Kaplan-Meier and Cox regression analysis were used to give hazard ratios and 95% confidence intervals for each outcome measure. Prespecified subgroup analyses were conducted to compare apixaban doses, where 44% were prescribed 5 mg b.i.d. and 56% were prescribed 2.5 mg b.i.d..

In the study, patients in the apixaban group had a significantly lower risk of major bleeding as compared with the warfarin group (HR, 0.72; 95% CI, 0.59-0.87; P less than .001) with overall high rates of major bleeding in both groups at 19.7 and 22.9 per 100 patient-years in the apixaban group and warfarin group, respectively. There was no difference in the rate of stroke/systemic embolism between patients receiving apixaban and warfarin (HR, 0.88; 95% CI, 0.69-1.12; P = .29). There was a nonsignificant trend toward decreased risk of GI bleeding in the apixaban group and no significant differences between the groups in the rates of intracranial bleeding. Apixaban was also associated with a nonsignificant trend toward lower risk of mortality (HR, 0.85; 95% CI, 0.71-1.01; P = .06).

Notably, censoring rates because of expired prescriptions or a 1-month gap between prescriptions were high in both groups and the majority of censoring occurred within the first 12 months. Additionally, in dose specific analyses, patients receiving the 5-mg, twice-daily dose were found to have statistically significant decreases in risk of stroke/systemic embolism (P = .035) and mortality (P = .005) as compared with the 2.5-mg, twice-daily dose without significant differences in GI or intracranial bleeding.

There are three ongoing, open-label, randomized, controlled trials examining anticoagulation for nonvalvular AFib in patients with ESRD on hemodialysis with two comparing apixaban to warfarin (or derivative) and the other warfarin versus no anticoagulation.⁵ All trials are in adult patients with documented AFib and CHA₂DS₂-VASc score of at least 2. AKADIA (Germany based) plans to enroll 222 patients and compares a vitamin K antagonist (INR goal, 2-3) with 2.5-mg b.i.d. apixaban patients with ESRD on hemodialysis for at least 3 months with primary outcome of major and clinically relevant nonmajor bleeding and secondary outcome of thromboembolic events, as well as apixaban levels pre- and post hemodialysis.

RENAL-AF (U.S. based) plans to enrolled 762 patients and compares 5-mg b.i.d. apixaban (with 2.5 mg for selected patients) with warfarin in people of chronic hemodialysis with primary outcome of days to first major or clinically relevant nonmajor bleeding event and secondary outcome of stroke, systemic embolism, mortality, adherence and plasma apixaban levels. AVKDIAL (France based) plans to enroll 855 patients and compares no anticoagulation with vitamin K antagonists in patients on hemodialysis for at least 1 month, with primary outcome of cumulative incidence of severe bleeding and thrombosis.

Application of the data to our original case

Our patient is Medicare age with ESRD and newly diagnosed nonvalvular AFib. Recent data suggests apixaban could be used for stroke prevention instead of the prior standard of care, warfarin. This approach is supported in the 2019 guidelines.¹

Patients with ESRD have an increased risk of bleeding and apixaban was shown to have less bleeding complications than warfarin in this analysis. However, only standard-dose apixaban was associated with a statistically significant lower risk of stroke/systemic embolism, major bleeding, and death. Reduced-dose apixaban had a lower risk of major bleeding but no difference for stroke/systemic embolism or death. Reduced-dose apixaban is used for patients who have two out of the following three criteria: aged at least 80 years, weight of at least 60 kg, and creatinine of at least 1.5 mg/dL. Therefore, many Medicare-age patients with ESRD would not be indicated for the dose of apixaban that was shown to improve the most important outcomes of stroke/SE and death.

It may still be beneficial to use apixaban in this patient since it appears to work as well as warfarin for stroke/systemic embolism prevention with less bleeding complications.

Bottom line

For patients who have decided to pursue an anticoagulation strategy for stroke prevention in AFib and have end-stage renal disease, either warfarin or apixaban are sensible options.

Dr. Farber is a medical instructor at Duke University Health System in Durham, N.C. Dr. Stafford is a medical instructor at Duke University. Dr. Sata is assistant professor of medicine at Duke University. Dr. Abdo and Dr. Menon are hospitalists at Duke University. Dr. Brooks is assistant professor of medicine at Duke University. Dr. Wachter is associate medical director at Duke Regional Hospital and assistant professor of medicine at Duke University. Dr. Sharma is associate medical director for clinical education in hospital medicine at Duke Regional Hospital and assistant professor of medicine at Duke University.

References

1. January CT et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2019;139. doi: 1161/CIR.0000000000000665.

2. Lippi G et al. Direct oral anticoagulants: Analysis of worldwide use and popularity using Google Trends. Ann Transl Med. 2017 Aug; 5(16):322. doi: 10.21037/atm.2017.06.65.

3. Turakhia MP et al. Chronic kidney disease and arrhythmias: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Eur Heart J. 2018 Jun 21;39(24):2314-25. doi: 10.1093/eurheartj/ehy060.

4. Siontis KC et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation. 2018 Oct 9;138(15):1519-29. doi: 10.1161/CIRCULATIONAHA.118.035418.

5. Nigwekar SU et al. Long-term anticoagulation for patient receiving dialysis: Tilting the benefit-to-risk ratio? Circulation. 2018 Oct 9;138(15):1530-3. doi: 10.1161/CIRCULATIONAHA.118.037091.

Key points

• According to 2019 American Heart Association guidelines, warfarin or apixaban are reasonable options for stroke prevention for patients who have end-stage renal disease and who plan for anticoagulation because of atrial fibrillation.
• Recent observational data suggests that apixaban may be safer than warfarin in this population.
• Several randomized, controlled trials are ongoing that may help determine the optimal agent to use in this setting.
• Until more definitive data is available, a reasonable approach is to discuss the risks and benefits of various treatment strategies with patients, and engage a multidisciplinary team (cardiologist, nephrologist, primary care provider, pharmacist) in the decision making process.

Additional reading

January CT et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2019;139. doi: 1161/CIR.0000000000000665.

Nigwekar SU et al. Long-term anticoagulation for patient receiving dialysis: Tilting the benefit to risk ratio? Circulation. 2018 Oct 9;138(15):1530-3. doi: 10.1161/CIRCULATIONAHA.118.037091.

Garlo KG et al. Demystifying the benefits and harms of anticoagulation for atrial fibrillation in chronic kidney disease. Clin J Am Soc Nephrol 2019;14:125-36. doi: 10.2215/CJN.06430518.

Quiz

Two days ago you admitted a 72-year-old woman with end-stage renal disease on dialysis who had developed new-onset atrial fibrillation causing a mild acute diastolic congestive heart failure exacerbation. Transthoracic ECG showed a preserved left ventricular ejection fraction and no significant valvular disease. After two sessions of dialysis in the hospital and initiation of a beta-blocker for control of her heart rate, she is stable and ready for discharge. Her discharge weight is 75 kg.

Which of the following recommendations should you make to this patient regarding anticoagulation for prevention of stroke and systemic embolism from atrial fibrillation?

A. Take warfarin with a international normalized ratio goal of 2.5.

B. Take apixaban 2.5 mg twice a day.

C. Take apixaban 5 mg twice a day.

D. Discuss the risks/benefits of various treatment approaches with the patient, and involve the hospital pharmacist as well as the patient’s nephrologist, cardiologist, and/or primary care provider in the decision making process to reach a consensus and to ensure a safe follow-up plan.

The best answer is D. While A, B, and C are all reasonable approaches based on the available data and current guidelines, the best approach is to involve the patient and the multidisciplinary team in the decision making process. When more clinical trial data becomes available in the future, the optimal approach to managing patients such as this one may become clearer, but until then it makes sense to take into account individual patient characteristics and patient preferences.

In patients with atrial fibrillation (AFib) who have undergone transcatheter aortic valve replacement (TAVR) and had a CHA2DS2-VASc score of at least 2, oral anticoagulant (OAC) therapy alone was not linked to reduced stroke risk.

By contrast, antiplatelet therapy was linked to a reduced risk of stroke in those AFib-TAVR patients, regardless of whether an oral anticoagulant was on board, according to results of a substudy of the randomized PARTNER II (Placement of Aortic Transcatheter Valve II) trial and its associated registries.

“Anticoagulant therapy was associated with a reduced risk of stroke and the composite of death or stroke when used concomitantly with uninterrupted antiplatelet therapy following TAVR,” concluded authors of the analysis, led by Ioanna Kosmidou, MD, PhD, of Columbia University in New York.

Taken together, these findings suggest OAC alone is “not sufficient” to prevent cerebrovascular events after TAVR in patients with AFib, Dr. Kosmidou and colleagues reported in JACC: Cardiovascular Interventions.

The analysis of the PARTNER II substudy included a total of 1,621 patients with aortic stenosis treated with TAVR who had a history of AFib and an absolute indication for anticoagulation as evidenced by a CHA2DS2-VASc score of at least 2.

Despite the absolute indication for anticoagulation, more than 40% of these patients were not prescribed an OAC upon discharge, investigators wrote, though the rate of nonprescribing decreased over the 5-year enrollment period of 2011-2015.

OAC therapy alone was not linked to reduced stroke risk in this cohort, investigators said. After 2 years, the rate of stroke was 6.6% for AFib-TAVR patients on anticoagulant therapy, and 5.6% for those who were not on anticoagulant therapy, a nonsignificant difference at P = 0.53, according to the reported data.

By contrast, uninterrupted antiplatelet therapy reduced both risk of stroke and risk of the composite endpoint of stroke and death at 2 years “irrespective of concomitant anticoagulation,” Dr. Kosmidou and coinvestigators wrote in the report.

The stroke rates were 5.4% for antiplatelet therapy plus OAC, versus 11.1% for those receiving neither antithrombotic treatment (P = 0.03), while the rates of stroke or death were 29.7% and 40.1%, respectively (P = 0.01), according to investigators.

After adjustment, stroke risk was not significantly reduced for OAC when compared with no OAC or antiplatelet therapy (HR, 0.61; P = .16), whereas stroke risk was indeed reduced for antiplatelet therapy alone (HR, 0.32; P = .002) and antiplatelet therapy with oral anticoagulation (HR, 0.44; P = .018).

The PARTNER II study was funded by Edwards Lifesciences. Senior author Martin B. Leon, MD, and several other study coauthors reported disclosures related to Edwards Lifesciences, in addition to Abbott Vascular, Cordis, Medtronic, Boston Scientific, and other companies. Dr. Kosmidou reported no disclosures.

SOURCE: Kosmidou I et al. JACC Cardiovasc Interv. 2019;12:1580-9.

In patients with atrial fibrillation (AFib) who have undergone transcatheter aortic valve replacement (TAVR) and had a CHA2DS2-VASc score of at least 2, oral anticoagulant (OAC) therapy alone was not linked to reduced stroke risk.

By contrast, antiplatelet therapy was linked to a reduced risk of stroke in those AFib-TAVR patients, regardless of whether an oral anticoagulant was on board, according to results of a substudy of the randomized PARTNER II (Placement of Aortic Transcatheter Valve II) trial and its associated registries.

“Anticoagulant therapy was associated with a reduced risk of stroke and the composite of death or stroke when used concomitantly with uninterrupted antiplatelet therapy following TAVR,” concluded authors of the analysis, led by Ioanna Kosmidou, MD, PhD, of Columbia University in New York.

Taken together, these findings suggest OAC alone is “not sufficient” to prevent cerebrovascular events after TAVR in patients with AFib, Dr. Kosmidou and colleagues reported in JACC: Cardiovascular Interventions.

The analysis of the PARTNER II substudy included a total of 1,621 patients with aortic stenosis treated with TAVR who had a history of AFib and an absolute indication for anticoagulation as evidenced by a CHA2DS2-VASc score of at least 2.

Despite the absolute indication for anticoagulation, more than 40% of these patients were not prescribed an OAC upon discharge, investigators wrote, though the rate of nonprescribing decreased over the 5-year enrollment period of 2011-2015.

OAC therapy alone was not linked to reduced stroke risk in this cohort, investigators said. After 2 years, the rate of stroke was 6.6% for AFib-TAVR patients on anticoagulant therapy, and 5.6% for those who were not on anticoagulant therapy, a nonsignificant difference at P = 0.53, according to the reported data.

By contrast, uninterrupted antiplatelet therapy reduced both risk of stroke and risk of the composite endpoint of stroke and death at 2 years “irrespective of concomitant anticoagulation,” Dr. Kosmidou and coinvestigators wrote in the report.

The stroke rates were 5.4% for antiplatelet therapy plus OAC, versus 11.1% for those receiving neither antithrombotic treatment (P = 0.03), while the rates of stroke or death were 29.7% and 40.1%, respectively (P = 0.01), according to investigators.

After adjustment, stroke risk was not significantly reduced for OAC when compared with no OAC or antiplatelet therapy (HR, 0.61; P = .16), whereas stroke risk was indeed reduced for antiplatelet therapy alone (HR, 0.32; P = .002) and antiplatelet therapy with oral anticoagulation (HR, 0.44; P = .018).

The PARTNER II study was funded by Edwards Lifesciences. Senior author Martin B. Leon, MD, and several other study coauthors reported disclosures related to Edwards Lifesciences, in addition to Abbott Vascular, Cordis, Medtronic, Boston Scientific, and other companies. Dr. Kosmidou reported no disclosures.

SOURCE: Kosmidou I et al. JACC Cardiovasc Interv. 2019;12:1580-9.

In patients with atrial fibrillation (AFib) who have undergone transcatheter aortic valve replacement (TAVR) and had a CHA2DS2-VASc score of at least 2, oral anticoagulant (OAC) therapy alone was not linked to reduced stroke risk.

By contrast, antiplatelet therapy was linked to a reduced risk of stroke in those AFib-TAVR patients, regardless of whether an oral anticoagulant was on board, according to results of a substudy of the randomized PARTNER II (Placement of Aortic Transcatheter Valve II) trial and its associated registries.

“Anticoagulant therapy was associated with a reduced risk of stroke and the composite of death or stroke when used concomitantly with uninterrupted antiplatelet therapy following TAVR,” concluded authors of the analysis, led by Ioanna Kosmidou, MD, PhD, of Columbia University in New York.

Taken together, these findings suggest OAC alone is “not sufficient” to prevent cerebrovascular events after TAVR in patients with AFib, Dr. Kosmidou and colleagues reported in JACC: Cardiovascular Interventions.

The analysis of the PARTNER II substudy included a total of 1,621 patients with aortic stenosis treated with TAVR who had a history of AFib and an absolute indication for anticoagulation as evidenced by a CHA2DS2-VASc score of at least 2.

Despite the absolute indication for anticoagulation, more than 40% of these patients were not prescribed an OAC upon discharge, investigators wrote, though the rate of nonprescribing decreased over the 5-year enrollment period of 2011-2015.

OAC therapy alone was not linked to reduced stroke risk in this cohort, investigators said. After 2 years, the rate of stroke was 6.6% for AFib-TAVR patients on anticoagulant therapy, and 5.6% for those who were not on anticoagulant therapy, a nonsignificant difference at P = 0.53, according to the reported data.

By contrast, uninterrupted antiplatelet therapy reduced both risk of stroke and risk of the composite endpoint of stroke and death at 2 years “irrespective of concomitant anticoagulation,” Dr. Kosmidou and coinvestigators wrote in the report.

The stroke rates were 5.4% for antiplatelet therapy plus OAC, versus 11.1% for those receiving neither antithrombotic treatment (P = 0.03), while the rates of stroke or death were 29.7% and 40.1%, respectively (P = 0.01), according to investigators.

After adjustment, stroke risk was not significantly reduced for OAC when compared with no OAC or antiplatelet therapy (HR, 0.61; P = .16), whereas stroke risk was indeed reduced for antiplatelet therapy alone (HR, 0.32; P = .002) and antiplatelet therapy with oral anticoagulation (HR, 0.44; P = .018).

The PARTNER II study was funded by Edwards Lifesciences. Senior author Martin B. Leon, MD, and several other study coauthors reported disclosures related to Edwards Lifesciences, in addition to Abbott Vascular, Cordis, Medtronic, Boston Scientific, and other companies. Dr. Kosmidou reported no disclosures.

SOURCE: Kosmidou I et al. JACC Cardiovasc Interv. 2019;12:1580-9.

The direct oral anticoagulants (DOACs) apixaban and rivaroxaban are now among the options for thromboprophylaxis in high-risk cancer outpatients with low risk for bleeding and drug interactions, according to a practice guideline update from the American Society of Clinical Oncology.

Sebastian Kaulitzki/Thinkstock

Rivaroxaban also has been added as an option for initial anticoagulation for venous thromboembolism (VTE), and both rivaroxaban and edoxaban are now options for long-term anticoagulation, Nigel S. Key, MB ChB, and colleagues wrote in the updated guideline on the prophylaxis and treatment of VTE – including deep vein thrombosis (DVT) and pulmonary embolism (PE) – in cancer patients (J Clin Oncol. 2019 Aug 5. doi: 10.1200/JCO.19.19.01461).

The addition of DOACs as options for VTE prophylaxis and treatment represents the most notable change to the guideline.

“Oral anticoagulants that target thrombin (direct thrombin inhibitor, dabigatran) or activated factor X (antifactor Xa inhibitors, rivaroxaban, apixaban, and edoxaban) are now approved for treatment of DVT or PE as well as for DVT prophylaxis following orthopedic surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation,” the guideline panel wrote.

A systematic review of PubMed and the Cochrane Library for randomized controlled trials (RCTs) and meta-analyses of RCTs published from Aug. 1, 2014, through Dec. 4, 2018, identified 35 publications on VTE prophylaxis and treatment, including 2 RCTs of DOACs for prophylaxis and 2 others of DOAC treatment, as well as 8 publications on VTE risk assessment. A multidisciplinary expert panel appointed by ASCO and cochaired by Dr. Key of the University of North Carolina, Chapel Hill, used this evidence to develop the updated guideline.

The work was guided by “the ‘signals’ approach that is designed to identify only new, potentially practice-changing data – signals – that might translate into revised practice recommendations,” the authors explained.

DOAC-related updates

VTE prophylaxis. Based in part on findings from the recently published AVERT trial of apixaban in patients initiating a new course of chemotherapy and from the CASSINI trial of rivaroxaban in patients with solid tumors or lymphoma starting systemic antineoplastic therapy, the panel added both agents as thromboprophylactic options that can be offered to high-risk cancer outpatients with no significant risk factors for bleeding or drug interactions (N Engl J Med. 2019;380:711-19; N Engl J Med. 2019;380:720-8).

Low-molecular-weight heparin (LMWH) also remains an option in such patients; consideration of therapy should involve discussion with the patient about relative benefits and harms, drug costs, and “the uncertainty surrounding duration of prophylaxis in this setting,” they wrote.

Anticoagulation for VTE. Options for initial anticoagulation include LMWH, unfractionated heparin (UFH), fondaparinux, and now rivaroxaban, with the latter added based on findings from two RCTs – the SELECT-D trial and the Hokusai VTE-Cancer study – and multiple meta-analyses (J Clin Oncol. 2018;36:2017-23; N Engl J Med. 2018;378:615-24).

Long-term anticoagulation can involve treatment with LMWH, edoxaban, or rivaroxaban for at least 6 months, all of which have improved efficacy versus vitamin K agonists (VKAs), the panel noted. However, VKAs may be used if LMWH and DOACs are not accessible.

Importantly, the literature indicates an increased risk of major bleeding with DOACs, particularly in patients with gastrointestinal malignancies and potentially in those with genitourinary malignancies. “Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding,” the panel wrote.
 

Additional updates

CNS metastases. The anticoagulation recommendations were also updated to include patients with metastatic central nervous system malignancies (those with primary CNS malignancies were included previously). Both those with primary and metastatic CNS malignancy should be offered anticoagulation for established VTE as described for patients with other types of cancer. However, the panel stressed that “uncertainties remain about choice of agents and selection of patients most likely to benefit.”

“Patients with intracranial tumors are at increased risk for thrombotic complications and intracranial hemorrhage (ICH), but the presence of a stable or active primary intracranial malignancy or brain metastases is not an absolute contraindication to anticoagulation,” they wrote.

Limited evidence suggests that therapeutic anticoagulation does not increase ICH risk in patients with brain metastases, but it may increase risk in those with primary brain tumors, the panel added.

Additionally, preliminary data from a retrospective cohort of patients with metastatic brain disease and venous thrombosis suggest that DOACs may be associated with a lower risk of ICH than is LMWH in this population.

Long-term postoperative LMWH. Extended prophylaxis with LMWH for up to 4 weeks is recommended after major open or laparoscopic abdominal or pelvic surgery in cancer patients with high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. Lower-risk surgical settings require case-by-case decision making about appropriate thromboprophylaxis duration, according to the update.

A 2014 RCT looking at thromboprophylaxis duration in 225 patients undergoing laparoscopic surgery for colorectal cancer prompted the addition of laparoscopic surgery to this recommendation. In that study, VTE occurred by 4 weeks in nearly 10% of patients receiving 1 week of prophylaxis and in no patients in the 4-week arm. Major bleeding occurred in one versus zero patients in the thromboprophylaxis arms, respectively (Ann Surg. April 2014;259[4]:665-9).
 

Reaffirmed recommendations

Based on the latest available data, the panel reaffirmed that most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis for the duration of their hospitalization and that thromboprophylaxis should not be routinely recommended for all outpatients with cancer.

The panel also reaffirmed the need for thromboprophylaxis starting preoperatively and continuing for at least 7-10 days in patients undergoing major cancer surgery, the need for periodic assessment of VTE risk in cancer patients, and the importance of patient education about the signs and symptoms of VTE.
 

Perspective and future directions

In an interview, David H. Henry, MD, said he was pleased to see ASCO incorporate the latest DOAC data into the VTE guideline.

The AVERT and CASSINI studies, in particular, highlight the value of using the Khorana Risk Score, which considers cancer type, blood counts, and body mass index to predict the risk of thrombosis in cancer patients and to guide decisions regarding prophylaxis, said Dr. Henry, vice chair of the department of medicine and clinical professor of medicine at Penn Medicine’s Abramson Cancer Center, Philadelphia.

The DOACs also represent “a nice new development in the treatment setting,” he said, adding that it’s been long known – since the 2003 CLOT trial – that cancer patients with VTE had much lower recurrence rates with LMWH versus warfarin (Coumadin).

“Now fast forward to the modern era ... and DOACs now appear to be a good idea,” he said.

Dr. Henry also addressed the recommendation for expanded postoperative LMWH use.

“That I found interesting; I’m not sure what took them so long,” he said, explaining that National Comprehensive Cancer Network and European Society of Medical Oncology recommendations have long stated that, for patients with abdominal cancers who undergo abdominopelvic surgery, DVT prophylaxis should continue for 4 weeks.

Dr. Henry said that a survey at his center showed that those recommendations were “very poorly followed,” with surgeons giving 4 weeks of prophylaxis in just 5% of cases.

“The good news from our survey was that not many people had a VTE, despite not many people following the recommendations, but I must say I think our surgeons are catching on,” he said.

Overall, the updated guideline highlights the importance of considering the “cancer variable” when it comes to VTE prevention and treatment.

“We’ve known forever that when we diagnose a DVT or PE in the outpatient setting – and this is independent of cancer – that you should treat it. Add the cancer variable and we now know that we should worry and try to prevent the VTE in certain high-risk patients, and there are some drugs to do it with,” he said, adding that “you should worry about the person you’ve just provoked [with surgery] as well.”

An important question not addressed in the guideline update is the indefinite use of DOACs in cancer patients with ongoing risk, he said.

“When we see DVT or PE, we usually treat for 3 months – that’s the industry standard – and at the end of 3 months ... you do a time out and you say to yourself, ‘Was this person provoked?’ ” he said.

For example, if they took a long flight or if pregnancy was a factor, treatment can usually be safely stopped. However, in a cancer patient who still has cancer, the provocation continues, and the patient may require indefinite treatment.

Questions that remain involve defining “indefinite” and include whether (and which of) these drugs can be used indefinitely in such patients, Dr. Henry said.

Dr. Key reported receiving honoraria from Novo Nordisk, research funding to his institution from Baxter Biosciences, Grifols, and Pfizer, and serving as a consultant or advisor for Genentech, Roche, Uniqure, Seattle Genetics, and Shire Human Genetic Therapies. Numerous disclosures were also reported by other expert panel members.

[email protected]

The direct oral anticoagulants (DOACs) apixaban and rivaroxaban are now among the options for thromboprophylaxis in high-risk cancer outpatients with low risk for bleeding and drug interactions, according to a practice guideline update from the American Society of Clinical Oncology.

Sebastian Kaulitzki/Thinkstock

Rivaroxaban also has been added as an option for initial anticoagulation for venous thromboembolism (VTE), and both rivaroxaban and edoxaban are now options for long-term anticoagulation, Nigel S. Key, MB ChB, and colleagues wrote in the updated guideline on the prophylaxis and treatment of VTE – including deep vein thrombosis (DVT) and pulmonary embolism (PE) – in cancer patients (J Clin Oncol. 2019 Aug 5. doi: 10.1200/JCO.19.19.01461).

The addition of DOACs as options for VTE prophylaxis and treatment represents the most notable change to the guideline.

“Oral anticoagulants that target thrombin (direct thrombin inhibitor, dabigatran) or activated factor X (antifactor Xa inhibitors, rivaroxaban, apixaban, and edoxaban) are now approved for treatment of DVT or PE as well as for DVT prophylaxis following orthopedic surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation,” the guideline panel wrote.

A systematic review of PubMed and the Cochrane Library for randomized controlled trials (RCTs) and meta-analyses of RCTs published from Aug. 1, 2014, through Dec. 4, 2018, identified 35 publications on VTE prophylaxis and treatment, including 2 RCTs of DOACs for prophylaxis and 2 others of DOAC treatment, as well as 8 publications on VTE risk assessment. A multidisciplinary expert panel appointed by ASCO and cochaired by Dr. Key of the University of North Carolina, Chapel Hill, used this evidence to develop the updated guideline.

The work was guided by “the ‘signals’ approach that is designed to identify only new, potentially practice-changing data – signals – that might translate into revised practice recommendations,” the authors explained.

DOAC-related updates

VTE prophylaxis. Based in part on findings from the recently published AVERT trial of apixaban in patients initiating a new course of chemotherapy and from the CASSINI trial of rivaroxaban in patients with solid tumors or lymphoma starting systemic antineoplastic therapy, the panel added both agents as thromboprophylactic options that can be offered to high-risk cancer outpatients with no significant risk factors for bleeding or drug interactions (N Engl J Med. 2019;380:711-19; N Engl J Med. 2019;380:720-8).

Low-molecular-weight heparin (LMWH) also remains an option in such patients; consideration of therapy should involve discussion with the patient about relative benefits and harms, drug costs, and “the uncertainty surrounding duration of prophylaxis in this setting,” they wrote.

Anticoagulation for VTE. Options for initial anticoagulation include LMWH, unfractionated heparin (UFH), fondaparinux, and now rivaroxaban, with the latter added based on findings from two RCTs – the SELECT-D trial and the Hokusai VTE-Cancer study – and multiple meta-analyses (J Clin Oncol. 2018;36:2017-23; N Engl J Med. 2018;378:615-24).

Long-term anticoagulation can involve treatment with LMWH, edoxaban, or rivaroxaban for at least 6 months, all of which have improved efficacy versus vitamin K agonists (VKAs), the panel noted. However, VKAs may be used if LMWH and DOACs are not accessible.

Importantly, the literature indicates an increased risk of major bleeding with DOACs, particularly in patients with gastrointestinal malignancies and potentially in those with genitourinary malignancies. “Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding,” the panel wrote.
 

Additional updates

CNS metastases. The anticoagulation recommendations were also updated to include patients with metastatic central nervous system malignancies (those with primary CNS malignancies were included previously). Both those with primary and metastatic CNS malignancy should be offered anticoagulation for established VTE as described for patients with other types of cancer. However, the panel stressed that “uncertainties remain about choice of agents and selection of patients most likely to benefit.”

“Patients with intracranial tumors are at increased risk for thrombotic complications and intracranial hemorrhage (ICH), but the presence of a stable or active primary intracranial malignancy or brain metastases is not an absolute contraindication to anticoagulation,” they wrote.

Limited evidence suggests that therapeutic anticoagulation does not increase ICH risk in patients with brain metastases, but it may increase risk in those with primary brain tumors, the panel added.

Additionally, preliminary data from a retrospective cohort of patients with metastatic brain disease and venous thrombosis suggest that DOACs may be associated with a lower risk of ICH than is LMWH in this population.

Long-term postoperative LMWH. Extended prophylaxis with LMWH for up to 4 weeks is recommended after major open or laparoscopic abdominal or pelvic surgery in cancer patients with high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. Lower-risk surgical settings require case-by-case decision making about appropriate thromboprophylaxis duration, according to the update.

A 2014 RCT looking at thromboprophylaxis duration in 225 patients undergoing laparoscopic surgery for colorectal cancer prompted the addition of laparoscopic surgery to this recommendation. In that study, VTE occurred by 4 weeks in nearly 10% of patients receiving 1 week of prophylaxis and in no patients in the 4-week arm. Major bleeding occurred in one versus zero patients in the thromboprophylaxis arms, respectively (Ann Surg. April 2014;259[4]:665-9).
 

Reaffirmed recommendations

Based on the latest available data, the panel reaffirmed that most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis for the duration of their hospitalization and that thromboprophylaxis should not be routinely recommended for all outpatients with cancer.

The panel also reaffirmed the need for thromboprophylaxis starting preoperatively and continuing for at least 7-10 days in patients undergoing major cancer surgery, the need for periodic assessment of VTE risk in cancer patients, and the importance of patient education about the signs and symptoms of VTE.
 

Perspective and future directions

In an interview, David H. Henry, MD, said he was pleased to see ASCO incorporate the latest DOAC data into the VTE guideline.

The AVERT and CASSINI studies, in particular, highlight the value of using the Khorana Risk Score, which considers cancer type, blood counts, and body mass index to predict the risk of thrombosis in cancer patients and to guide decisions regarding prophylaxis, said Dr. Henry, vice chair of the department of medicine and clinical professor of medicine at Penn Medicine’s Abramson Cancer Center, Philadelphia.

The DOACs also represent “a nice new development in the treatment setting,” he said, adding that it’s been long known – since the 2003 CLOT trial – that cancer patients with VTE had much lower recurrence rates with LMWH versus warfarin (Coumadin).

“Now fast forward to the modern era ... and DOACs now appear to be a good idea,” he said.

Dr. Henry also addressed the recommendation for expanded postoperative LMWH use.

“That I found interesting; I’m not sure what took them so long,” he said, explaining that National Comprehensive Cancer Network and European Society of Medical Oncology recommendations have long stated that, for patients with abdominal cancers who undergo abdominopelvic surgery, DVT prophylaxis should continue for 4 weeks.

Dr. Henry said that a survey at his center showed that those recommendations were “very poorly followed,” with surgeons giving 4 weeks of prophylaxis in just 5% of cases.

“The good news from our survey was that not many people had a VTE, despite not many people following the recommendations, but I must say I think our surgeons are catching on,” he said.

Overall, the updated guideline highlights the importance of considering the “cancer variable” when it comes to VTE prevention and treatment.

“We’ve known forever that when we diagnose a DVT or PE in the outpatient setting – and this is independent of cancer – that you should treat it. Add the cancer variable and we now know that we should worry and try to prevent the VTE in certain high-risk patients, and there are some drugs to do it with,” he said, adding that “you should worry about the person you’ve just provoked [with surgery] as well.”

An important question not addressed in the guideline update is the indefinite use of DOACs in cancer patients with ongoing risk, he said.

“When we see DVT or PE, we usually treat for 3 months – that’s the industry standard – and at the end of 3 months ... you do a time out and you say to yourself, ‘Was this person provoked?’ ” he said.

For example, if they took a long flight or if pregnancy was a factor, treatment can usually be safely stopped. However, in a cancer patient who still has cancer, the provocation continues, and the patient may require indefinite treatment.

Questions that remain involve defining “indefinite” and include whether (and which of) these drugs can be used indefinitely in such patients, Dr. Henry said.

Dr. Key reported receiving honoraria from Novo Nordisk, research funding to his institution from Baxter Biosciences, Grifols, and Pfizer, and serving as a consultant or advisor for Genentech, Roche, Uniqure, Seattle Genetics, and Shire Human Genetic Therapies. Numerous disclosures were also reported by other expert panel members.

[email protected]

The direct oral anticoagulants (DOACs) apixaban and rivaroxaban are now among the options for thromboprophylaxis in high-risk cancer outpatients with low risk for bleeding and drug interactions, according to a practice guideline update from the American Society of Clinical Oncology.

Sebastian Kaulitzki/Thinkstock

Rivaroxaban also has been added as an option for initial anticoagulation for venous thromboembolism (VTE), and both rivaroxaban and edoxaban are now options for long-term anticoagulation, Nigel S. Key, MB ChB, and colleagues wrote in the updated guideline on the prophylaxis and treatment of VTE – including deep vein thrombosis (DVT) and pulmonary embolism (PE) – in cancer patients (J Clin Oncol. 2019 Aug 5. doi: 10.1200/JCO.19.19.01461).

The addition of DOACs as options for VTE prophylaxis and treatment represents the most notable change to the guideline.

“Oral anticoagulants that target thrombin (direct thrombin inhibitor, dabigatran) or activated factor X (antifactor Xa inhibitors, rivaroxaban, apixaban, and edoxaban) are now approved for treatment of DVT or PE as well as for DVT prophylaxis following orthopedic surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation,” the guideline panel wrote.

A systematic review of PubMed and the Cochrane Library for randomized controlled trials (RCTs) and meta-analyses of RCTs published from Aug. 1, 2014, through Dec. 4, 2018, identified 35 publications on VTE prophylaxis and treatment, including 2 RCTs of DOACs for prophylaxis and 2 others of DOAC treatment, as well as 8 publications on VTE risk assessment. A multidisciplinary expert panel appointed by ASCO and cochaired by Dr. Key of the University of North Carolina, Chapel Hill, used this evidence to develop the updated guideline.

The work was guided by “the ‘signals’ approach that is designed to identify only new, potentially practice-changing data – signals – that might translate into revised practice recommendations,” the authors explained.

DOAC-related updates

VTE prophylaxis. Based in part on findings from the recently published AVERT trial of apixaban in patients initiating a new course of chemotherapy and from the CASSINI trial of rivaroxaban in patients with solid tumors or lymphoma starting systemic antineoplastic therapy, the panel added both agents as thromboprophylactic options that can be offered to high-risk cancer outpatients with no significant risk factors for bleeding or drug interactions (N Engl J Med. 2019;380:711-19; N Engl J Med. 2019;380:720-8).

Low-molecular-weight heparin (LMWH) also remains an option in such patients; consideration of therapy should involve discussion with the patient about relative benefits and harms, drug costs, and “the uncertainty surrounding duration of prophylaxis in this setting,” they wrote.

Anticoagulation for VTE. Options for initial anticoagulation include LMWH, unfractionated heparin (UFH), fondaparinux, and now rivaroxaban, with the latter added based on findings from two RCTs – the SELECT-D trial and the Hokusai VTE-Cancer study – and multiple meta-analyses (J Clin Oncol. 2018;36:2017-23; N Engl J Med. 2018;378:615-24).

Long-term anticoagulation can involve treatment with LMWH, edoxaban, or rivaroxaban for at least 6 months, all of which have improved efficacy versus vitamin K agonists (VKAs), the panel noted. However, VKAs may be used if LMWH and DOACs are not accessible.

Importantly, the literature indicates an increased risk of major bleeding with DOACs, particularly in patients with gastrointestinal malignancies and potentially in those with genitourinary malignancies. “Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding,” the panel wrote.
 

Additional updates

CNS metastases. The anticoagulation recommendations were also updated to include patients with metastatic central nervous system malignancies (those with primary CNS malignancies were included previously). Both those with primary and metastatic CNS malignancy should be offered anticoagulation for established VTE as described for patients with other types of cancer. However, the panel stressed that “uncertainties remain about choice of agents and selection of patients most likely to benefit.”

“Patients with intracranial tumors are at increased risk for thrombotic complications and intracranial hemorrhage (ICH), but the presence of a stable or active primary intracranial malignancy or brain metastases is not an absolute contraindication to anticoagulation,” they wrote.

Limited evidence suggests that therapeutic anticoagulation does not increase ICH risk in patients with brain metastases, but it may increase risk in those with primary brain tumors, the panel added.

Additionally, preliminary data from a retrospective cohort of patients with metastatic brain disease and venous thrombosis suggest that DOACs may be associated with a lower risk of ICH than is LMWH in this population.

Long-term postoperative LMWH. Extended prophylaxis with LMWH for up to 4 weeks is recommended after major open or laparoscopic abdominal or pelvic surgery in cancer patients with high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. Lower-risk surgical settings require case-by-case decision making about appropriate thromboprophylaxis duration, according to the update.

A 2014 RCT looking at thromboprophylaxis duration in 225 patients undergoing laparoscopic surgery for colorectal cancer prompted the addition of laparoscopic surgery to this recommendation. In that study, VTE occurred by 4 weeks in nearly 10% of patients receiving 1 week of prophylaxis and in no patients in the 4-week arm. Major bleeding occurred in one versus zero patients in the thromboprophylaxis arms, respectively (Ann Surg. April 2014;259[4]:665-9).
 

Reaffirmed recommendations

Based on the latest available data, the panel reaffirmed that most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis for the duration of their hospitalization and that thromboprophylaxis should not be routinely recommended for all outpatients with cancer.

The panel also reaffirmed the need for thromboprophylaxis starting preoperatively and continuing for at least 7-10 days in patients undergoing major cancer surgery, the need for periodic assessment of VTE risk in cancer patients, and the importance of patient education about the signs and symptoms of VTE.
 

Perspective and future directions

In an interview, David H. Henry, MD, said he was pleased to see ASCO incorporate the latest DOAC data into the VTE guideline.

The AVERT and CASSINI studies, in particular, highlight the value of using the Khorana Risk Score, which considers cancer type, blood counts, and body mass index to predict the risk of thrombosis in cancer patients and to guide decisions regarding prophylaxis, said Dr. Henry, vice chair of the department of medicine and clinical professor of medicine at Penn Medicine’s Abramson Cancer Center, Philadelphia.

The DOACs also represent “a nice new development in the treatment setting,” he said, adding that it’s been long known – since the 2003 CLOT trial – that cancer patients with VTE had much lower recurrence rates with LMWH versus warfarin (Coumadin).

“Now fast forward to the modern era ... and DOACs now appear to be a good idea,” he said.

Dr. Henry also addressed the recommendation for expanded postoperative LMWH use.

“That I found interesting; I’m not sure what took them so long,” he said, explaining that National Comprehensive Cancer Network and European Society of Medical Oncology recommendations have long stated that, for patients with abdominal cancers who undergo abdominopelvic surgery, DVT prophylaxis should continue for 4 weeks.

Dr. Henry said that a survey at his center showed that those recommendations were “very poorly followed,” with surgeons giving 4 weeks of prophylaxis in just 5% of cases.

“The good news from our survey was that not many people had a VTE, despite not many people following the recommendations, but I must say I think our surgeons are catching on,” he said.

Overall, the updated guideline highlights the importance of considering the “cancer variable” when it comes to VTE prevention and treatment.

“We’ve known forever that when we diagnose a DVT or PE in the outpatient setting – and this is independent of cancer – that you should treat it. Add the cancer variable and we now know that we should worry and try to prevent the VTE in certain high-risk patients, and there are some drugs to do it with,” he said, adding that “you should worry about the person you’ve just provoked [with surgery] as well.”

An important question not addressed in the guideline update is the indefinite use of DOACs in cancer patients with ongoing risk, he said.

“When we see DVT or PE, we usually treat for 3 months – that’s the industry standard – and at the end of 3 months ... you do a time out and you say to yourself, ‘Was this person provoked?’ ” he said.

For example, if they took a long flight or if pregnancy was a factor, treatment can usually be safely stopped. However, in a cancer patient who still has cancer, the provocation continues, and the patient may require indefinite treatment.

Questions that remain involve defining “indefinite” and include whether (and which of) these drugs can be used indefinitely in such patients, Dr. Henry said.

Dr. Key reported receiving honoraria from Novo Nordisk, research funding to his institution from Baxter Biosciences, Grifols, and Pfizer, and serving as a consultant or advisor for Genentech, Roche, Uniqure, Seattle Genetics, and Shire Human Genetic Therapies. Numerous disclosures were also reported by other expert panel members.

[email protected]