Joshua Allen-Dicker, MD, MPH

Clinical question: What are the differences between factors associated with early (zero to seven days after discharge) and late (eight to 30 days after discharge) readmission?

Background: Thirty-day readmission rates are a quality metric; however, recent evidence challenges the notion that readmissions represent unnecessary and preventable healthcare use. It remains unclear whether the 30-day window post-discharge represents a homogenous period or if there are factors that contribute to readmission during that time.

Study design: Retrospective, single-center, cohort study.

Setting: Large, urban teaching hospital.

Synopsis: Based on 13,355 admissions representing 8,078 patients over a two-year period, the overall readmission rate was 19.7%, with 7.8% early (zero to seven days post-discharge) readmissions, and 11.9% late (eight to 30 days post-discharge) readmissions. Variables were categorized as indicators of acute illness burden, chronic illness burden, patient care process factors, and social determinants of health.

Several markers of acute illness burden were associated with early readmission only. Some markers of chronic illness burden were associated with late readmissions only (e.g. hemodialysis), while others were associated with readmissions throughout the 30-day period. Worse social determinants of health increased odds of readmission in both periods.

The single-center study was able to examine detailed clinical variables; however, this approach limited the generalizability of the the results.

Bottom line: Policies to reduce 30-day readmissions should reflect the different risk factors at play across that time frame.

Citation: Graham KL, Wilker EH, Howell MD, Davis RB, Marcantonio ER. Differences between early and late readmissions among patients: A cohort study. Ann Intern Med. 2015;162(11):741-749.

Clinical question: What are the differences between factors associated with early (zero to seven days after discharge) and late (eight to 30 days after discharge) readmission?

Background: Thirty-day readmission rates are a quality metric; however, recent evidence challenges the notion that readmissions represent unnecessary and preventable healthcare use. It remains unclear whether the 30-day window post-discharge represents a homogenous period or if there are factors that contribute to readmission during that time.

Study design: Retrospective, single-center, cohort study.

Setting: Large, urban teaching hospital.

Synopsis: Based on 13,355 admissions representing 8,078 patients over a two-year period, the overall readmission rate was 19.7%, with 7.8% early (zero to seven days post-discharge) readmissions, and 11.9% late (eight to 30 days post-discharge) readmissions. Variables were categorized as indicators of acute illness burden, chronic illness burden, patient care process factors, and social determinants of health.

Several markers of acute illness burden were associated with early readmission only. Some markers of chronic illness burden were associated with late readmissions only (e.g. hemodialysis), while others were associated with readmissions throughout the 30-day period. Worse social determinants of health increased odds of readmission in both periods.

The single-center study was able to examine detailed clinical variables; however, this approach limited the generalizability of the the results.

Bottom line: Policies to reduce 30-day readmissions should reflect the different risk factors at play across that time frame.

Citation: Graham KL, Wilker EH, Howell MD, Davis RB, Marcantonio ER. Differences between early and late readmissions among patients: A cohort study. Ann Intern Med. 2015;162(11):741-749.

Clinical question: What are the differences between factors associated with early (zero to seven days after discharge) and late (eight to 30 days after discharge) readmission?

Background: Thirty-day readmission rates are a quality metric; however, recent evidence challenges the notion that readmissions represent unnecessary and preventable healthcare use. It remains unclear whether the 30-day window post-discharge represents a homogenous period or if there are factors that contribute to readmission during that time.

Study design: Retrospective, single-center, cohort study.

Setting: Large, urban teaching hospital.

Synopsis: Based on 13,355 admissions representing 8,078 patients over a two-year period, the overall readmission rate was 19.7%, with 7.8% early (zero to seven days post-discharge) readmissions, and 11.9% late (eight to 30 days post-discharge) readmissions. Variables were categorized as indicators of acute illness burden, chronic illness burden, patient care process factors, and social determinants of health.

Several markers of acute illness burden were associated with early readmission only. Some markers of chronic illness burden were associated with late readmissions only (e.g. hemodialysis), while others were associated with readmissions throughout the 30-day period. Worse social determinants of health increased odds of readmission in both periods.

The single-center study was able to examine detailed clinical variables; however, this approach limited the generalizability of the the results.

Bottom line: Policies to reduce 30-day readmissions should reflect the different risk factors at play across that time frame.

Citation: Graham KL, Wilker EH, Howell MD, Davis RB, Marcantonio ER. Differences between early and late readmissions among patients: A cohort study. Ann Intern Med. 2015;162(11):741-749.

Clinical question: How can patient adherence to pharmacological thromboprophylaxis be improved?

Background: Prior studies suggest that the hospital-wide prevalence of nonadministration of VTE thromboprophylaxis orders ranges from 5% to 13%, with patient refusal listed as the most common reason for nonadministration.

Study design: Quasi-experimental, pre-post intervention, with intervention and control units.

Setting: Academic medical center in Philadelphia.

Synopsis: Researchers identified 20,208 admissions for the study; 8,293 (41%) admissions occurred prior to the intervention and 11,915 (59%) after. The three-part intervention, which was composed of (1) standardized nurse response to patient refusal, (2) integration of daily assessment of VTE into rounds, and (3) regular audit with feedback, resulted in a decrease in nonadministration rates during the intervention. Rates continued to decline in the 21-month follow-up period.

After the intervention, the rate of missed doses of pharmacological thromboprophylaxis decreased from 24.7% to 14.7% (P<0.01). This was due to a decrease in patient refusal from 18.3% to 9.4% (P<0.01).

Although there was a decrease in the missed doses of thromboprophylaxis, there was no statistically significant change in the rate of hospital-associated VTE.

Bottom line: A multifaceted intervention resulted in a decrease in the proportion of missed and refused doses of pharmacological VTE thromboprophylaxis, but this was not associated with a statistically significant change in VTE rates.

Citation: Baillie CA, Guevara JP, Boston RC, Hecht TE. A unit-based intervention aimed at improving patient adherence to pharmacological thromboprophylaxis [published online ahead of print June 2, 2015]. BMJ Qual Saf. doi:10.1136/bmjqs-2015-003992.

Clinical question: How can patient adherence to pharmacological thromboprophylaxis be improved?

Background: Prior studies suggest that the hospital-wide prevalence of nonadministration of VTE thromboprophylaxis orders ranges from 5% to 13%, with patient refusal listed as the most common reason for nonadministration.

Study design: Quasi-experimental, pre-post intervention, with intervention and control units.

Setting: Academic medical center in Philadelphia.

Synopsis: Researchers identified 20,208 admissions for the study; 8,293 (41%) admissions occurred prior to the intervention and 11,915 (59%) after. The three-part intervention, which was composed of (1) standardized nurse response to patient refusal, (2) integration of daily assessment of VTE into rounds, and (3) regular audit with feedback, resulted in a decrease in nonadministration rates during the intervention. Rates continued to decline in the 21-month follow-up period.

After the intervention, the rate of missed doses of pharmacological thromboprophylaxis decreased from 24.7% to 14.7% (P<0.01). This was due to a decrease in patient refusal from 18.3% to 9.4% (P<0.01).

Although there was a decrease in the missed doses of thromboprophylaxis, there was no statistically significant change in the rate of hospital-associated VTE.

Bottom line: A multifaceted intervention resulted in a decrease in the proportion of missed and refused doses of pharmacological VTE thromboprophylaxis, but this was not associated with a statistically significant change in VTE rates.

Citation: Baillie CA, Guevara JP, Boston RC, Hecht TE. A unit-based intervention aimed at improving patient adherence to pharmacological thromboprophylaxis [published online ahead of print June 2, 2015]. BMJ Qual Saf. doi:10.1136/bmjqs-2015-003992.

Clinical question: How can patient adherence to pharmacological thromboprophylaxis be improved?

Background: Prior studies suggest that the hospital-wide prevalence of nonadministration of VTE thromboprophylaxis orders ranges from 5% to 13%, with patient refusal listed as the most common reason for nonadministration.

Study design: Quasi-experimental, pre-post intervention, with intervention and control units.

Setting: Academic medical center in Philadelphia.

Synopsis: Researchers identified 20,208 admissions for the study; 8,293 (41%) admissions occurred prior to the intervention and 11,915 (59%) after. The three-part intervention, which was composed of (1) standardized nurse response to patient refusal, (2) integration of daily assessment of VTE into rounds, and (3) regular audit with feedback, resulted in a decrease in nonadministration rates during the intervention. Rates continued to decline in the 21-month follow-up period.

After the intervention, the rate of missed doses of pharmacological thromboprophylaxis decreased from 24.7% to 14.7% (P<0.01). This was due to a decrease in patient refusal from 18.3% to 9.4% (P<0.01).

Although there was a decrease in the missed doses of thromboprophylaxis, there was no statistically significant change in the rate of hospital-associated VTE.

Bottom line: A multifaceted intervention resulted in a decrease in the proportion of missed and refused doses of pharmacological VTE thromboprophylaxis, but this was not associated with a statistically significant change in VTE rates.

Citation: Baillie CA, Guevara JP, Boston RC, Hecht TE. A unit-based intervention aimed at improving patient adherence to pharmacological thromboprophylaxis [published online ahead of print June 2, 2015]. BMJ Qual Saf. doi:10.1136/bmjqs-2015-003992.

Clinical question: Is there a score that will predict the mortality rate in elderly patients presenting with a non-ST-elevation myocardial infarction (NSTEMI)?

Background: Although they represent only 9% of patients in clinical trials, patients over the age of 75 make up one third of patients with NSTEMI, accounting for more than half of NSTEMI-related mortality.

Study design: Retrospective cohort analysis for score calculator design, with prospective cohort validation.

Setting: The retrospective cohort was derived from a meta-analysis of 55 papers. The prospective validation arm used a cohort of patients from a randomized multicenter Italian trial.

Synopsis: The authors developed and validated a mortality predictor for patients 75 and older who present with an NSTEMI. The calculator: hemoglobin less than 10 g/dl (two points), elevated troponin levels, ECG ischemic changes, estimated glomerular filtration rate (eGFR) less than 45, previous vascular event (one point each two). The calculator predicted probabilities of death in one year ranging from 2% (score of zero) to 75% (score of six). The calculator allowed stratification into low (score: zero to one), intermediate (score: two), or high (score: three or greater) risk. High-risk patients appeared to benefit from intervention with significantly reduced risk for mortality (odds ratio 0.44).

Bottom line: A simple risk calculator stratifies elderly patients into low, intermediate, or high risk to predict mortality from NSTEMI. High-risk patients appear to achieve a mortality benefit from intervention.

Citation: Angeli F, Cavallini C, Verdecchia P, et al. A risk score for predicting 1-year mortality in patients ≥75 years of age presenting with non-ST-elevation acute coronary syndrome. Am J Cardiol. 2015;116(2):208-213.

Clinical question: Is there a score that will predict the mortality rate in elderly patients presenting with a non-ST-elevation myocardial infarction (NSTEMI)?

Background: Although they represent only 9% of patients in clinical trials, patients over the age of 75 make up one third of patients with NSTEMI, accounting for more than half of NSTEMI-related mortality.

Study design: Retrospective cohort analysis for score calculator design, with prospective cohort validation.

Setting: The retrospective cohort was derived from a meta-analysis of 55 papers. The prospective validation arm used a cohort of patients from a randomized multicenter Italian trial.

Synopsis: The authors developed and validated a mortality predictor for patients 75 and older who present with an NSTEMI. The calculator: hemoglobin less than 10 g/dl (two points), elevated troponin levels, ECG ischemic changes, estimated glomerular filtration rate (eGFR) less than 45, previous vascular event (one point each two). The calculator predicted probabilities of death in one year ranging from 2% (score of zero) to 75% (score of six). The calculator allowed stratification into low (score: zero to one), intermediate (score: two), or high (score: three or greater) risk. High-risk patients appeared to benefit from intervention with significantly reduced risk for mortality (odds ratio 0.44).

Bottom line: A simple risk calculator stratifies elderly patients into low, intermediate, or high risk to predict mortality from NSTEMI. High-risk patients appear to achieve a mortality benefit from intervention.

Citation: Angeli F, Cavallini C, Verdecchia P, et al. A risk score for predicting 1-year mortality in patients ≥75 years of age presenting with non-ST-elevation acute coronary syndrome. Am J Cardiol. 2015;116(2):208-213.

Clinical question: Is there a score that will predict the mortality rate in elderly patients presenting with a non-ST-elevation myocardial infarction (NSTEMI)?

Background: Although they represent only 9% of patients in clinical trials, patients over the age of 75 make up one third of patients with NSTEMI, accounting for more than half of NSTEMI-related mortality.

Study design: Retrospective cohort analysis for score calculator design, with prospective cohort validation.

Setting: The retrospective cohort was derived from a meta-analysis of 55 papers. The prospective validation arm used a cohort of patients from a randomized multicenter Italian trial.

Synopsis: The authors developed and validated a mortality predictor for patients 75 and older who present with an NSTEMI. The calculator: hemoglobin less than 10 g/dl (two points), elevated troponin levels, ECG ischemic changes, estimated glomerular filtration rate (eGFR) less than 45, previous vascular event (one point each two). The calculator predicted probabilities of death in one year ranging from 2% (score of zero) to 75% (score of six). The calculator allowed stratification into low (score: zero to one), intermediate (score: two), or high (score: three or greater) risk. High-risk patients appeared to benefit from intervention with significantly reduced risk for mortality (odds ratio 0.44).

Bottom line: A simple risk calculator stratifies elderly patients into low, intermediate, or high risk to predict mortality from NSTEMI. High-risk patients appear to achieve a mortality benefit from intervention.

Citation: Angeli F, Cavallini C, Verdecchia P, et al. A risk score for predicting 1-year mortality in patients ≥75 years of age presenting with non-ST-elevation acute coronary syndrome. Am J Cardiol. 2015;116(2):208-213.

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Two Cases

A 76-year-old female with a history of hypertension, diabetes, atrial fibrillation, and diverticulosis is admitted with acute onset of dizziness and several episodes of bright red blood per rectum. Her labs show a new anemia at hemoglobin level 6.9 g/dL and an international normalized ratio (INR) of 2.7. She is transfused several units of packed red blood cells and fresh frozen plasma without further bleeding. She undergoes an esophagogastroduodenoscopy (EGD) and colonoscopy, which are notable only for extensive diverticulosis. In preparing the discharge medication reconciliation, you are uncertain what to do with the patient’s anticoagulation.

An 85-year-old male with coronary artery disease status post-percutaneous coronary intervention, with placement of a drug-eluting stent several years prior, is admitted with multiple weeks of epigastric discomfort and acute onset of hematemesis. His laboratory tests are notable for a new anemia at hemoglobin level 6.5 g/dL. Urgent EGD demonstrates a bleeding ulcer, which is cauterized. He is started on a proton-pump inhibitor (PPI). He inquires as to when he can restart his home medications, including aspirin.

Overview

Gastrointestinal (GI) bleeding is a serious complication of anticoagulant and antiplatelet therapy. Risks for GI bleeding include older age, history of peptic ulcer disease, NSAID or steroid use, and the use of antiplatelet or anticoagulation therapy. The estimated incidence of GI bleeding in the general population is 48 to 160 cases (upper GI) and 21 cases (lower GI) per 1,000 adults per year, with a case-mortality rate between 5% and 14%.¹

Although there is consensus on ceasing anticoagulant and antiplatelet agents during an acute GI bleed, debate remains over the appropriate approach to restarting these agents.

Anticoagulant Resumption

A recent study published in Archives of Internal Medicine supports a quick resumption of anticoagulation following a GI bleed.2 Although previous studies on restarting anticoagulants were small and demonstrated mixed results, this retrospective cohort study examined more than 442 warfarin-associated GI bleeds. After adjusting for various clinical indicators (e.g. clinical seriousness of bleeding, requirement of transfusions), the investigators found that the decision not to resume warfarin within 90 days of an initial GI hemorrhage was associated with an increased risk of thrombosis and death. Of note, in those patients restarted on warfarin, the mean time to medication initiation was four days following the initial GI bleed. In those not restarted on warfarin, the earliest incidence of thrombosis was documented at eight days following cessation of anticoagulation.²

Though its clinical implications are limited by the retrospective design, this study is helpful in guiding management decisions. Randomized control trials and society recommendations on this topic are lacking, so the decision to resume anticoagulants rests on patient-specific estimates of the risk of recurrent bleeding and the benefits of resuming anticoagulants.

In identifying those patients most likely to benefit from restarting anticoagulation, the risk of thromboembolism should be determined using an established risk stratification framework, such as Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (see Table 1).³ According to the guidelines, patients at highest risk of thromboembolism (in the absence of anticoagulation) are those with:

• mitral valve prostheses;
• atrial fibrillation with a CHADS2 score of five to six or cerebrovascular accidents (CVA) within the last three months; and/or
• venous thromboembolism (VTE) within the last three months or history of severe thrombophilia.

Patients at the lowest risk of thromboembolism are those with:

• mechanical aortic prostheses with no other stroke risk factors;
• atrial fibrillation with a CHADS2 score of zero to two; and/or
• a single VTE that occurred >12 months prior.

There are several approaches to identifying patients at greatest risk for bleeding. Location-specific modeling for upper GI bleeds (e.g. Rockall score) and lower GI bleeds (e.g. BLEED score) focus on the clinical presentation and/or endoscopic findings. General hemorrhage risk scores (e.g. HAS-BLED, ATRIA) focus on medical comorbidities. While easy to use, the predictive value of such scores as part of anticoagulation resumption after a GI hemorrhage remains uncertain.

Based on the above methods of risk stratification, patients at higher risk of thromboembolism and lower risk of bleeding will likely benefit from waiting only a short time interval before restarting anticoagulation. Based on the trial conducted by Witt and colleagues, anticoagulation typically can be reinitiated within four days of obtaining hemostatic and hemodynamic stability.² Conversely, those at highest risk of bleeding and lower risk of thromboembolism will benefit from a delayed resumption of anticoagulation. Involvement of a specialist, such as a gastroenterologist, could help further clarify the risk of rebleeding.

The ideal approach for patients with a high risk of both bleeding and thromboembolism remains uncertain. Such cases highlight the need for an informed discussion with the patient and any involved caregivers, as well as involvement of inpatient subspecialists and outpatient longitudinal providers.

There remains a lack of evidence on the best method to restart anticoagulation. Based on small and retrospective trials, we recommend restarting warfarin at the patient’s previous home dose. The duration of inpatient monitoring following warfarin initiation should be individualized, but warfarin is not expected to impair coagulation for four to six days after initiation.

Little data is available with respect to the role of novel oral anticoagulants after a GI bleed. Given the lack of reversing agents for these drugs, we recommend exercising caution in populations with a high risk of rebleeding. Theoretically, given that these agents reach peak effect faster than warfarin, waiting an additional four days after the time frame recommended for starting warfarin is a prudent resumption strategy for novel oral anticoagulants.

click for large version

Resumption of Antiplatelet Agents

The decision to resume antiplatelet therapy should also be highly individualized. In addition to weighing the risk of bleeding (as described in the previous section), the physician must also estimate the benefits of antiplatelet therapy in decreasing the risk of cardiovascular events.

In low-risk patients on antiplatelet therapy (i.e., for primary cardiovascular prevention) reinitiation after a bleeding episode can be reasonably delayed, because the risk of rebleeding likely outweighs the potential benefit of restarting therapy.

For patients who are at intermediate risk (i.e., those on antiplatelet agents for secondary prevention of cardiovascular disease), emerging evidence argues for early reinstitution after a GI bleed. In a trial published in Annals of Internal Medicine, Sung and colleagues randomized 156 patients to aspirin or placebo therapy immediately following endoscopically obtained hemostasis for peptic ulcer bleeding.⁴ All patients received PPIs. There was no significant difference in bleeding rates between the two groups, but delayed resumption of aspirin was associated with a significant increase in all-cause mortality.

Two recent meta-analyses provide further insight into the risks of withholding aspirin therapy. The first, which included 50,279 patients on aspirin for secondary prevention, found that aspirin non-adherence or withdrawal after a GI bleed was associated with a three-fold higher risk of major adverse cardiac events.⁵ Cardiac event rates were highest in the subgroup of patients with a history of prior percutaneous coronary stenting.

A second meta-analysis evaluated patients who had aspirin held perioperatively. In a population of patients on aspirin for secondary prevention, the mean time after withholding aspirin was 8.5 days to coronary events, 14.3 days to cerebrovascular events, and 25.8 days to peripheral arterial events.⁶ Events occurred as early as five days after withdrawal of aspirin.

Patients with recent intracoronary stenting are at highest risk of thrombosis. In patients with a bare metal stent placed within six weeks, or a drug-eluting stent placed within six months, every effort should be made to minimize interruptions of dual antiplatelet therapy.

Based on the data presented above, for patients at intermediate and/or high risk of adverse cardiac events, we recommend reinstitution of aspirin as soon as possible following a GI hemorrhage, preferably within five days. PPI co-therapy is a mainstay for secondary prevention of upper GI bleeding in patients on antiplatelet therapy. Current research and guidelines have not addressed specifically the role of withholding and reinitiating aspirin in lower GI bleeding, non-peptic ulcer, or upper-GI bleeding, however, a similar strategy is likely appropriate. As with the decision for restarting anticoagulants, discussion with relevant specialists is essential to best define the risk of re-bleeding.

Back to the Cases

Given her CHADS2 score of three, the patient with a diverticular bleed has a 9.6% annual risk of stroke if she does not resume anticoagulation. Using the HAS-BLED and ATRIA scores, this patient has 2.6% to 5.8% annual risk of hemorrhage. We recommend resuming warfarin anticoagulation therapy within four days of achieving hemostasis.

For the patient with coronary artery disease with remote drug-eluting stent placement and upper GI bleed, evidence supports early resumption of appropriate antiplatelet therapy following endoscopic therapy and hemostasis. We recommend resuming aspirin during the current hospitalization and concomitant treatment with a PPI indefinitely.

Bottom Line

Following a GI bleed, the risks and benefits of restarting anticoagulant and antiplatelet agents need to be carefully considered. In patients on oral anticoagulants at high risk for thromboembolism and low risk for rebleeding, consider restarting anticoagulation within four to five days. Patients on antiplatelet agents for secondary prevention should have the medication restarted during hospitalization after endoscopically obtained hemostasis of a peptic ulcer.

In all cases, hospitalists should engage the patient, gastroenterologist, and outpatient provider to best determine when resumption of anticoagulant and/or antiplatelet agents should occur.

Dr. Allen-Dicker is a hospitalist and clinical instructor at Mount Sinai Medical Center in New York City. Dr. Briones is director of perioperative services in the division of hospital medicine and an assistant professor; Dr. Berman is a hospitalist and a clinical instructor, and Dr. Dunn is a professor of medicine and chief of the division of hospital medicine, all at Mount Sinai Medical Center.

References

1. Barkun AN, Bardou M, Kuipers EJ, et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med. 2010;152(2):101-113.
2. Witt DM, Delate T, Garcia DA, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med. 2012;172(19):1484-1491.
3. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e326S-350S.
4. Sung JJ, Lau JY, Ching JY, et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: A randomized trial. Ann Intern Med. 2010;152(1):1-9.
5. Biondi-Zoccai GG, Lotrionte M, Agostoni P, et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J. 2006;27(22):2667-2674.
6. Burger W, Chemnitius JM, Kneissl GD, Rücker G. Low-dose aspirin for secondary cardiovascular prevention – cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation – review and meta-analysis. J Intern Med. 2005;257(5):399-414.

click for large version

Two Cases

A 76-year-old female with a history of hypertension, diabetes, atrial fibrillation, and diverticulosis is admitted with acute onset of dizziness and several episodes of bright red blood per rectum. Her labs show a new anemia at hemoglobin level 6.9 g/dL and an international normalized ratio (INR) of 2.7. She is transfused several units of packed red blood cells and fresh frozen plasma without further bleeding. She undergoes an esophagogastroduodenoscopy (EGD) and colonoscopy, which are notable only for extensive diverticulosis. In preparing the discharge medication reconciliation, you are uncertain what to do with the patient’s anticoagulation.

An 85-year-old male with coronary artery disease status post-percutaneous coronary intervention, with placement of a drug-eluting stent several years prior, is admitted with multiple weeks of epigastric discomfort and acute onset of hematemesis. His laboratory tests are notable for a new anemia at hemoglobin level 6.5 g/dL. Urgent EGD demonstrates a bleeding ulcer, which is cauterized. He is started on a proton-pump inhibitor (PPI). He inquires as to when he can restart his home medications, including aspirin.

Overview

Gastrointestinal (GI) bleeding is a serious complication of anticoagulant and antiplatelet therapy. Risks for GI bleeding include older age, history of peptic ulcer disease, NSAID or steroid use, and the use of antiplatelet or anticoagulation therapy. The estimated incidence of GI bleeding in the general population is 48 to 160 cases (upper GI) and 21 cases (lower GI) per 1,000 adults per year, with a case-mortality rate between 5% and 14%.¹

Although there is consensus on ceasing anticoagulant and antiplatelet agents during an acute GI bleed, debate remains over the appropriate approach to restarting these agents.

Anticoagulant Resumption

A recent study published in Archives of Internal Medicine supports a quick resumption of anticoagulation following a GI bleed.2 Although previous studies on restarting anticoagulants were small and demonstrated mixed results, this retrospective cohort study examined more than 442 warfarin-associated GI bleeds. After adjusting for various clinical indicators (e.g. clinical seriousness of bleeding, requirement of transfusions), the investigators found that the decision not to resume warfarin within 90 days of an initial GI hemorrhage was associated with an increased risk of thrombosis and death. Of note, in those patients restarted on warfarin, the mean time to medication initiation was four days following the initial GI bleed. In those not restarted on warfarin, the earliest incidence of thrombosis was documented at eight days following cessation of anticoagulation.²

Though its clinical implications are limited by the retrospective design, this study is helpful in guiding management decisions. Randomized control trials and society recommendations on this topic are lacking, so the decision to resume anticoagulants rests on patient-specific estimates of the risk of recurrent bleeding and the benefits of resuming anticoagulants.

In identifying those patients most likely to benefit from restarting anticoagulation, the risk of thromboembolism should be determined using an established risk stratification framework, such as Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (see Table 1).³ According to the guidelines, patients at highest risk of thromboembolism (in the absence of anticoagulation) are those with:

• mitral valve prostheses;
• atrial fibrillation with a CHADS2 score of five to six or cerebrovascular accidents (CVA) within the last three months; and/or
• venous thromboembolism (VTE) within the last three months or history of severe thrombophilia.

Patients at the lowest risk of thromboembolism are those with:

• mechanical aortic prostheses with no other stroke risk factors;
• atrial fibrillation with a CHADS2 score of zero to two; and/or
• a single VTE that occurred >12 months prior.

There are several approaches to identifying patients at greatest risk for bleeding. Location-specific modeling for upper GI bleeds (e.g. Rockall score) and lower GI bleeds (e.g. BLEED score) focus on the clinical presentation and/or endoscopic findings. General hemorrhage risk scores (e.g. HAS-BLED, ATRIA) focus on medical comorbidities. While easy to use, the predictive value of such scores as part of anticoagulation resumption after a GI hemorrhage remains uncertain.

Based on the above methods of risk stratification, patients at higher risk of thromboembolism and lower risk of bleeding will likely benefit from waiting only a short time interval before restarting anticoagulation. Based on the trial conducted by Witt and colleagues, anticoagulation typically can be reinitiated within four days of obtaining hemostatic and hemodynamic stability.² Conversely, those at highest risk of bleeding and lower risk of thromboembolism will benefit from a delayed resumption of anticoagulation. Involvement of a specialist, such as a gastroenterologist, could help further clarify the risk of rebleeding.

The ideal approach for patients with a high risk of both bleeding and thromboembolism remains uncertain. Such cases highlight the need for an informed discussion with the patient and any involved caregivers, as well as involvement of inpatient subspecialists and outpatient longitudinal providers.

There remains a lack of evidence on the best method to restart anticoagulation. Based on small and retrospective trials, we recommend restarting warfarin at the patient’s previous home dose. The duration of inpatient monitoring following warfarin initiation should be individualized, but warfarin is not expected to impair coagulation for four to six days after initiation.

Little data is available with respect to the role of novel oral anticoagulants after a GI bleed. Given the lack of reversing agents for these drugs, we recommend exercising caution in populations with a high risk of rebleeding. Theoretically, given that these agents reach peak effect faster than warfarin, waiting an additional four days after the time frame recommended for starting warfarin is a prudent resumption strategy for novel oral anticoagulants.

click for large version

Resumption of Antiplatelet Agents

The decision to resume antiplatelet therapy should also be highly individualized. In addition to weighing the risk of bleeding (as described in the previous section), the physician must also estimate the benefits of antiplatelet therapy in decreasing the risk of cardiovascular events.

In low-risk patients on antiplatelet therapy (i.e., for primary cardiovascular prevention) reinitiation after a bleeding episode can be reasonably delayed, because the risk of rebleeding likely outweighs the potential benefit of restarting therapy.

For patients who are at intermediate risk (i.e., those on antiplatelet agents for secondary prevention of cardiovascular disease), emerging evidence argues for early reinstitution after a GI bleed. In a trial published in Annals of Internal Medicine, Sung and colleagues randomized 156 patients to aspirin or placebo therapy immediately following endoscopically obtained hemostasis for peptic ulcer bleeding.⁴ All patients received PPIs. There was no significant difference in bleeding rates between the two groups, but delayed resumption of aspirin was associated with a significant increase in all-cause mortality.

Two recent meta-analyses provide further insight into the risks of withholding aspirin therapy. The first, which included 50,279 patients on aspirin for secondary prevention, found that aspirin non-adherence or withdrawal after a GI bleed was associated with a three-fold higher risk of major adverse cardiac events.⁵ Cardiac event rates were highest in the subgroup of patients with a history of prior percutaneous coronary stenting.

A second meta-analysis evaluated patients who had aspirin held perioperatively. In a population of patients on aspirin for secondary prevention, the mean time after withholding aspirin was 8.5 days to coronary events, 14.3 days to cerebrovascular events, and 25.8 days to peripheral arterial events.⁶ Events occurred as early as five days after withdrawal of aspirin.

Patients with recent intracoronary stenting are at highest risk of thrombosis. In patients with a bare metal stent placed within six weeks, or a drug-eluting stent placed within six months, every effort should be made to minimize interruptions of dual antiplatelet therapy.

Based on the data presented above, for patients at intermediate and/or high risk of adverse cardiac events, we recommend reinstitution of aspirin as soon as possible following a GI hemorrhage, preferably within five days. PPI co-therapy is a mainstay for secondary prevention of upper GI bleeding in patients on antiplatelet therapy. Current research and guidelines have not addressed specifically the role of withholding and reinitiating aspirin in lower GI bleeding, non-peptic ulcer, or upper-GI bleeding, however, a similar strategy is likely appropriate. As with the decision for restarting anticoagulants, discussion with relevant specialists is essential to best define the risk of re-bleeding.

Back to the Cases

Given her CHADS2 score of three, the patient with a diverticular bleed has a 9.6% annual risk of stroke if she does not resume anticoagulation. Using the HAS-BLED and ATRIA scores, this patient has 2.6% to 5.8% annual risk of hemorrhage. We recommend resuming warfarin anticoagulation therapy within four days of achieving hemostasis.

For the patient with coronary artery disease with remote drug-eluting stent placement and upper GI bleed, evidence supports early resumption of appropriate antiplatelet therapy following endoscopic therapy and hemostasis. We recommend resuming aspirin during the current hospitalization and concomitant treatment with a PPI indefinitely.

Bottom Line

Following a GI bleed, the risks and benefits of restarting anticoagulant and antiplatelet agents need to be carefully considered. In patients on oral anticoagulants at high risk for thromboembolism and low risk for rebleeding, consider restarting anticoagulation within four to five days. Patients on antiplatelet agents for secondary prevention should have the medication restarted during hospitalization after endoscopically obtained hemostasis of a peptic ulcer.

In all cases, hospitalists should engage the patient, gastroenterologist, and outpatient provider to best determine when resumption of anticoagulant and/or antiplatelet agents should occur.

Dr. Allen-Dicker is a hospitalist and clinical instructor at Mount Sinai Medical Center in New York City. Dr. Briones is director of perioperative services in the division of hospital medicine and an assistant professor; Dr. Berman is a hospitalist and a clinical instructor, and Dr. Dunn is a professor of medicine and chief of the division of hospital medicine, all at Mount Sinai Medical Center.

References

1. Barkun AN, Bardou M, Kuipers EJ, et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med. 2010;152(2):101-113.
2. Witt DM, Delate T, Garcia DA, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med. 2012;172(19):1484-1491.
3. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e326S-350S.
4. Sung JJ, Lau JY, Ching JY, et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: A randomized trial. Ann Intern Med. 2010;152(1):1-9.
5. Biondi-Zoccai GG, Lotrionte M, Agostoni P, et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J. 2006;27(22):2667-2674.
6. Burger W, Chemnitius JM, Kneissl GD, Rücker G. Low-dose aspirin for secondary cardiovascular prevention – cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation – review and meta-analysis. J Intern Med. 2005;257(5):399-414.

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Two Cases

A 76-year-old female with a history of hypertension, diabetes, atrial fibrillation, and diverticulosis is admitted with acute onset of dizziness and several episodes of bright red blood per rectum. Her labs show a new anemia at hemoglobin level 6.9 g/dL and an international normalized ratio (INR) of 2.7. She is transfused several units of packed red blood cells and fresh frozen plasma without further bleeding. She undergoes an esophagogastroduodenoscopy (EGD) and colonoscopy, which are notable only for extensive diverticulosis. In preparing the discharge medication reconciliation, you are uncertain what to do with the patient’s anticoagulation.

An 85-year-old male with coronary artery disease status post-percutaneous coronary intervention, with placement of a drug-eluting stent several years prior, is admitted with multiple weeks of epigastric discomfort and acute onset of hematemesis. His laboratory tests are notable for a new anemia at hemoglobin level 6.5 g/dL. Urgent EGD demonstrates a bleeding ulcer, which is cauterized. He is started on a proton-pump inhibitor (PPI). He inquires as to when he can restart his home medications, including aspirin.

Overview

Gastrointestinal (GI) bleeding is a serious complication of anticoagulant and antiplatelet therapy. Risks for GI bleeding include older age, history of peptic ulcer disease, NSAID or steroid use, and the use of antiplatelet or anticoagulation therapy. The estimated incidence of GI bleeding in the general population is 48 to 160 cases (upper GI) and 21 cases (lower GI) per 1,000 adults per year, with a case-mortality rate between 5% and 14%.¹

Although there is consensus on ceasing anticoagulant and antiplatelet agents during an acute GI bleed, debate remains over the appropriate approach to restarting these agents.

Anticoagulant Resumption

A recent study published in Archives of Internal Medicine supports a quick resumption of anticoagulation following a GI bleed.2 Although previous studies on restarting anticoagulants were small and demonstrated mixed results, this retrospective cohort study examined more than 442 warfarin-associated GI bleeds. After adjusting for various clinical indicators (e.g. clinical seriousness of bleeding, requirement of transfusions), the investigators found that the decision not to resume warfarin within 90 days of an initial GI hemorrhage was associated with an increased risk of thrombosis and death. Of note, in those patients restarted on warfarin, the mean time to medication initiation was four days following the initial GI bleed. In those not restarted on warfarin, the earliest incidence of thrombosis was documented at eight days following cessation of anticoagulation.²

Though its clinical implications are limited by the retrospective design, this study is helpful in guiding management decisions. Randomized control trials and society recommendations on this topic are lacking, so the decision to resume anticoagulants rests on patient-specific estimates of the risk of recurrent bleeding and the benefits of resuming anticoagulants.

In identifying those patients most likely to benefit from restarting anticoagulation, the risk of thromboembolism should be determined using an established risk stratification framework, such as Antithrombotic Therapy and Prevention of Thrombosis, 9th edition (see Table 1).³ According to the guidelines, patients at highest risk of thromboembolism (in the absence of anticoagulation) are those with:

• mitral valve prostheses;
• atrial fibrillation with a CHADS2 score of five to six or cerebrovascular accidents (CVA) within the last three months; and/or
• venous thromboembolism (VTE) within the last three months or history of severe thrombophilia.

Patients at the lowest risk of thromboembolism are those with:

• mechanical aortic prostheses with no other stroke risk factors;
• atrial fibrillation with a CHADS2 score of zero to two; and/or
• a single VTE that occurred >12 months prior.

There are several approaches to identifying patients at greatest risk for bleeding. Location-specific modeling for upper GI bleeds (e.g. Rockall score) and lower GI bleeds (e.g. BLEED score) focus on the clinical presentation and/or endoscopic findings. General hemorrhage risk scores (e.g. HAS-BLED, ATRIA) focus on medical comorbidities. While easy to use, the predictive value of such scores as part of anticoagulation resumption after a GI hemorrhage remains uncertain.

Based on the above methods of risk stratification, patients at higher risk of thromboembolism and lower risk of bleeding will likely benefit from waiting only a short time interval before restarting anticoagulation. Based on the trial conducted by Witt and colleagues, anticoagulation typically can be reinitiated within four days of obtaining hemostatic and hemodynamic stability.² Conversely, those at highest risk of bleeding and lower risk of thromboembolism will benefit from a delayed resumption of anticoagulation. Involvement of a specialist, such as a gastroenterologist, could help further clarify the risk of rebleeding.

The ideal approach for patients with a high risk of both bleeding and thromboembolism remains uncertain. Such cases highlight the need for an informed discussion with the patient and any involved caregivers, as well as involvement of inpatient subspecialists and outpatient longitudinal providers.

There remains a lack of evidence on the best method to restart anticoagulation. Based on small and retrospective trials, we recommend restarting warfarin at the patient’s previous home dose. The duration of inpatient monitoring following warfarin initiation should be individualized, but warfarin is not expected to impair coagulation for four to six days after initiation.

Little data is available with respect to the role of novel oral anticoagulants after a GI bleed. Given the lack of reversing agents for these drugs, we recommend exercising caution in populations with a high risk of rebleeding. Theoretically, given that these agents reach peak effect faster than warfarin, waiting an additional four days after the time frame recommended for starting warfarin is a prudent resumption strategy for novel oral anticoagulants.

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Resumption of Antiplatelet Agents

The decision to resume antiplatelet therapy should also be highly individualized. In addition to weighing the risk of bleeding (as described in the previous section), the physician must also estimate the benefits of antiplatelet therapy in decreasing the risk of cardiovascular events.

In low-risk patients on antiplatelet therapy (i.e., for primary cardiovascular prevention) reinitiation after a bleeding episode can be reasonably delayed, because the risk of rebleeding likely outweighs the potential benefit of restarting therapy.

For patients who are at intermediate risk (i.e., those on antiplatelet agents for secondary prevention of cardiovascular disease), emerging evidence argues for early reinstitution after a GI bleed. In a trial published in Annals of Internal Medicine, Sung and colleagues randomized 156 patients to aspirin or placebo therapy immediately following endoscopically obtained hemostasis for peptic ulcer bleeding.⁴ All patients received PPIs. There was no significant difference in bleeding rates between the two groups, but delayed resumption of aspirin was associated with a significant increase in all-cause mortality.

Two recent meta-analyses provide further insight into the risks of withholding aspirin therapy. The first, which included 50,279 patients on aspirin for secondary prevention, found that aspirin non-adherence or withdrawal after a GI bleed was associated with a three-fold higher risk of major adverse cardiac events.⁵ Cardiac event rates were highest in the subgroup of patients with a history of prior percutaneous coronary stenting.

A second meta-analysis evaluated patients who had aspirin held perioperatively. In a population of patients on aspirin for secondary prevention, the mean time after withholding aspirin was 8.5 days to coronary events, 14.3 days to cerebrovascular events, and 25.8 days to peripheral arterial events.⁶ Events occurred as early as five days after withdrawal of aspirin.

Patients with recent intracoronary stenting are at highest risk of thrombosis. In patients with a bare metal stent placed within six weeks, or a drug-eluting stent placed within six months, every effort should be made to minimize interruptions of dual antiplatelet therapy.

Based on the data presented above, for patients at intermediate and/or high risk of adverse cardiac events, we recommend reinstitution of aspirin as soon as possible following a GI hemorrhage, preferably within five days. PPI co-therapy is a mainstay for secondary prevention of upper GI bleeding in patients on antiplatelet therapy. Current research and guidelines have not addressed specifically the role of withholding and reinitiating aspirin in lower GI bleeding, non-peptic ulcer, or upper-GI bleeding, however, a similar strategy is likely appropriate. As with the decision for restarting anticoagulants, discussion with relevant specialists is essential to best define the risk of re-bleeding.

Back to the Cases

Given her CHADS2 score of three, the patient with a diverticular bleed has a 9.6% annual risk of stroke if she does not resume anticoagulation. Using the HAS-BLED and ATRIA scores, this patient has 2.6% to 5.8% annual risk of hemorrhage. We recommend resuming warfarin anticoagulation therapy within four days of achieving hemostasis.

For the patient with coronary artery disease with remote drug-eluting stent placement and upper GI bleed, evidence supports early resumption of appropriate antiplatelet therapy following endoscopic therapy and hemostasis. We recommend resuming aspirin during the current hospitalization and concomitant treatment with a PPI indefinitely.

Bottom Line

Following a GI bleed, the risks and benefits of restarting anticoagulant and antiplatelet agents need to be carefully considered. In patients on oral anticoagulants at high risk for thromboembolism and low risk for rebleeding, consider restarting anticoagulation within four to five days. Patients on antiplatelet agents for secondary prevention should have the medication restarted during hospitalization after endoscopically obtained hemostasis of a peptic ulcer.

In all cases, hospitalists should engage the patient, gastroenterologist, and outpatient provider to best determine when resumption of anticoagulant and/or antiplatelet agents should occur.

Dr. Allen-Dicker is a hospitalist and clinical instructor at Mount Sinai Medical Center in New York City. Dr. Briones is director of perioperative services in the division of hospital medicine and an assistant professor; Dr. Berman is a hospitalist and a clinical instructor, and Dr. Dunn is a professor of medicine and chief of the division of hospital medicine, all at Mount Sinai Medical Center.

References

1. Barkun AN, Bardou M, Kuipers EJ, et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med. 2010;152(2):101-113.
2. Witt DM, Delate T, Garcia DA, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med. 2012;172(19):1484-1491.
3. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e326S-350S.
4. Sung JJ, Lau JY, Ching JY, et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: A randomized trial. Ann Intern Med. 2010;152(1):1-9.
5. Biondi-Zoccai GG, Lotrionte M, Agostoni P, et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J. 2006;27(22):2667-2674.
6. Burger W, Chemnitius JM, Kneissl GD, Rücker G. Low-dose aspirin for secondary cardiovascular prevention – cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation – review and meta-analysis. J Intern Med. 2005;257(5):399-414.