Re-starting anticoagulation and antiplatelets after gastrointestinal bleeding: A systematic review

Anticoagulants and antithrombotics

Each year, there is an increasing number of patients being prescribed anti-thrombotic and anticoagulant therapies. Unfortunately, these therapies tend to place patients at an increased risk of developing GIBs. Current research indicates that 4% of individuals on anticoagulants experience GIBs at some point during treatment.⁷ The decision to restart anticoagulation and antithrombotic therapy in patients post-GIB is a challenging task for many physicians; this makes risk stratification and shared decision making essential in the judgement to restart therapy.⁸

Anticoagulants mechanism

Anticoagulants act as blood thinners by preventing the synthesis of clotting factors or by directly blocking them. Warfarin works via competitive inhibition of the enzyme vitamin K epoxide reductase to decrease the synthesis of vitamin K-dependent clotting factors II, VII, IX, X, and proteins C and S that aid in coagulation.⁹ Prescribing warfarin to patients requires careful monitoring and assessment by physicians due to various factors, such as the patient’s genes, laboratory values, and a diet rich in vitamin K. These factors may affect the proper dosage of warfarin.⁹ Warfarin is administered orally and inhibits multiple clotting factors, whereas direct oral anticoagulants (DOACs) work by blocking one specific clotting factor. Examples of DOACs are dabigatran, rivaroxaban, apixaban, and edoxaban.¹⁰

Antithrombotic mechanism

Antithrombotics, such as aspirin, prohibits the aggregation of platelets in the vasculature and reduce the risk of thrombosis.¹¹ Aspirin works by permanently inhibiting COX-1 and COX-2. Aspirin as an antithrombotic drug, rather than an anti-inflammatory drug, requires a much smaller dosage to inhibit COX-1; aspirin at higher doses inhibits COX-2 and acts as an anti-inflammatory agent.¹¹ By inhibiting COX-1, arachidonic acid cannot be converted to thromboxane A₂, a prostanoid that works to stimulate platelet aggregation. Aspirin is therefore a powerful antithrombotic drug that works to inhibit the synthesis of platelet modulators.¹¹ Other known antithrombotics work in similarly to inhibit platelet aggregation. Therefore, antithrombotics work as blood thinners and reduce the risk of thromboembolic events and ischemic stroke.

Physicians who decide to restart patients on anticoagulants must also decide the best time to do so. We sought to determine if there was a timeframe in which restarting anticoagulants and anti-thrombolytics best reduced the risk of rebleed while also protecting patients from a thrombotic event.

Inclusion criteria

The following inclusion criteria were used: articles written in English, articles conducted on humans, articles published between 1992 and 2022, articles relevant to our interest, articles that are full-text, peer-reviewed, and include case-control, meta-analysis, observational, and cohort studies.

Exclusion criteria

Exclusion criteria used were articles not written in English, articles published before 1992, systematic reviews, case reports, or review articles. All duplicates and non-full-text articles were also excluded. The process of inclusion and exclusion of articles is illustrated in Figure 1.

Figure 1. Flow of article analysis and extraction for this systematic review.

Bias

The studies were assessed for bias. It was determined that there was a medium risk for bias as the studies were primarily conducted based on medical reports and insurance claims. The risk of bias of the individual studies were assessed using the Grading of Recommendations, Assessments, Development and Evaluation (GRADE). GRADE is a tool that evaluates flaws like imprecision, indirectness, and publications.

Oral anticoagulants

The decision to resume anticoagulants and antithrombotic post-GIB is crucial when confronted with patients with a history of thrombotic events, mechanical heart valves, and atrial fibrillation, despite the associated risk of recurrent bleeding.¹² The clinical impacts of thromboembolism and recurrent GIB are not equivalent and need to be accounted for when determining whether to resume anticoagulant and antithrombotic therapy. Little et al. reports that the case-fatality rate and institutionalization due to a thromboembolic event at three months post-GIB was 41% (Europe) and 57% (U.S.).¹² In contrast, the case-fatality rate of oral anticoagulants (OAC)-caused recurrent GIB was between 8-13%.¹² Research has shown that while there is an increase in the risk of recurrent bleeding, there is a decreased risk of thrombolytic events and all-cause mortality.

According to multiple studies, an average of 60% of patients who suffered a GIB were resumed on OACs as a preventive measure.^12,13 Up to half of the patients resuming OACs post-GIB were restarted on the same drug and dosage, and around 40% of patients were switched to a drug that was not an OAC.¹⁴ Restarting OACs in patients who suffered atrial fibrillation and bleeding events were associated with a significant decrease in thromboembolism and did not significantly increase the risk of recurrent bleeding. This then contributed to a reduction of all-cause mortality in patients.^13,15–18 Proietti et al., found a decreased risk of thromboembolic events in patients who restarted OACs versus. those who did not, with a relative risk reduction of 44%.¹⁹ There was also a significant reduction in all-cause mortality and thromboembolic event (hazard ratio (HR) 0.35; 95% confidence interval (CI); HR 0.76; 95% CI) in patients who were restarted on OACs.¹⁹

Sostres et al., compared patients who resumed OACs versus those who did not after a GIB, they found that of the 811 patients that stopped therapy, 17.8% of patients experienced a thromboembolic event during the follow-up period, while 24.9% had a recurrent GIB.²⁰ There was a significant difference in those that resumed therapy versus those who did not, with patients who resumed having a lower risk of an ischemic event (HR 0.626; 95% CI) and a decreased mortality (HR.0606), although they did have a higher risk of rebleeding (HR 2.184; 95% CI).²⁰ Rebleeding during the time following the initial GIB is a likely event. Candeloro et al. explored the status of recurrent GIB in patients who restarted and discontinued OACs post GIB and found that the rebleeds tend to occur where the original bleed stemmed from Ref. 18. Proietti et al., found that recurrent GIBs occurred in 10.2% of patients who resumed OACs compared to 5% of patients who did not restart.¹⁹ Similarly, Tapaskar et al., found that 10.1% of patients who resumed OACs post-GIB had recurrent GIB compared to 5.3% of patients who discontinued OACs.²¹ Across those studies, there was an average of a 5% increase in risk for GI bleed; both studies found these results insignificant.

Warfarin

Several studies have been conducted to assess the resumption of warfarin post-GIB, as it is infamously known for its unpredictability. Witt et al., found that at least 35% of patients resumed warfarin after a GIB.²² Smit and Gelder showed that after significant bleeding, 47% of warfarin users were restarted on their therapy, and there was a decrease in thromboembolic events and all-cause mortality. In a study population of 1825, Chai-Adisaksopha et al. reported a significant reduction in thromboembolic events in patients who resumed warfarin therapy post-GIB.²³ Across multiple studies, there was an average of 6% decrease in thrombolytic events for those who resumed warfarin therapy.^12,22–24 Resumption of warfarin was associated with a significant reduction in all-cause mortality in patients.^22–26 Chai-Adisaksopha et al. reported that death occurred in 24.6% of patients who resumed warfarin, whereas, in patients who did not resume warfarin, death occurred in 39.2% of patients.²³ Similarly, Little et al. observed that the all-cause mortality rate was 21.5% in patients who resumed warfarin compared to 31.6% who did not.¹²

Across all studies, only one patient death was reported which was associated with a massive gastrointestinal bleed in a patient who resumed warfarin.²⁵ On average, rebleeding occurred in 11.6% of patients restarted on warfarin and 5.7% of patients who were not restarted; however, the studies found that these differences were not statistically significant.^{17,19,22–24,26,27} Although it is assumed that patients who do not resume anticoagulants are at a lower risk of rebleeding and bleeding-related complications, Majeed et al. demonstrated that these patients would require closer monitoring and shorter follow-up (92 weeks) as compared to those who were restarted on VKAs (142 weeks, p < 0.001).²⁶ The rate of recurrent bleed is high whether the patient is resumed on anticoagulants or not, with bleeding occurring at a median of 24 weeks in those that were resumed on anticoagulants and 23 weeks in patients that were not.²⁶

Direct oral anticoagulants

Some physicians decide to switch treatment plans, such as changing from warfarin to DOAC post-GIB.^18,28 Little et al. found that apixaban was the DOAC of choice in most cases.¹² There was a 3% increase in patients who experienced a recurrent GIB after the resumption of DOACs.^12,27 Proietti et al. focused on dabigatran and found that patients who were started on dabigatran had a reduced risk for recurrent GIB compared to those who started on warfarin.¹⁸ Smit and Gelder reported that 49% of dabigatran users restarted anticoagulation after significant bleeding, and the risk of ischemic stroke and all-cause mortality decreased.²⁹ There was some conflict on the overall effectiveness of DOAC’s competence post-GIBs. Sengupta et al. found that patients with a history of venous thromboembolism who were restarted on DOAC had a risk of 2.7% for a thromboembolic event compared to 2.2% in patients whose DOAC was held 90 days post-GIB.³⁰ In that same year, however, Proietti et al. found a reduced risk of thromboembolic events and all-cause mortality in patients who restarted on DOACs after a GIB.¹⁹

Patients who restarted on DOACs within 30 days of the index bleed were not associated with a recurrent bleed.³⁰ Sengupta et al. reported no difference in readmission for a recurrent GIB in patients started on DOACs compared to those who were not restarted on DOACs.³⁰ Other studies, however, have reported recurrent GIB issues associated with rivaroxaban.^17,27,30 Valanejad et al. demonstrated that rivaroxaban was the only DOAC that increased the risk of recurrent GIB.²⁷ Overall, most research reports that the resumption of DOACs reduces the risk of thromboembolism and all-cause mortality with a selective increase in recurrent GIBs.^12,17,19,28 The results were relatively similar when comparing DOACs with warfarin use, but a benefit of the DOACs with resuming treatment post-GIB is the predictability and reduced monitoring that is typically associated with DOACs as compared to warfarin.

Heparin

Heparin is a low molecular weight anti-coagulant typically used as a bridging therapy. Individuals with a history of thrombolytic events, cancer, and who were younger tended to be restarted on heparin post-GIB by the first outpatient hemodialysis session.³¹ Heparin doses tend to be decreased post-GIB, and Shen et. al found no significant association between recurrent GIB (HR.78, 95% CI) and death (HR 1.01, 95%) compared to those who did not resume heparin therapy [39]. Resumption of heparin in both studies reduced thrombolytic events while non-significantly contributing to recurrent GIB.^18,31

Antithrombotic therapy

Antithrombotic therapy resumption post-GIB was also a point of interest. Studies showed that antithrombotic were paired with anti-coagulants and proton-pump inhibitors and were typically not given alone.^{16,18,20,21,30,32} Of the patients on antithrombotics, 8.5% were discontinued to reduce rebleeding risk, while 6.8% of patients were switched to a different antithrombotic.¹⁸ Patients restarted on antithrombotics with anticoagulants, and a small few alone, had a higher risk of rebleed than those just resuming OAC.¹⁶ Patients on dual antithrombotic therapy were also associated with lower mortality (15.9%) than those that were not (29.3%; p = 0.009).²⁰ Sostres et al., also reported that patients who did not resume anticoagulant and/or antithrombotic therapy within 90 days after the initial bleed had higher all-cause mortality and higher risk of thromboembolism.²⁰ Tapaskar et al., however, reported that they were unable to identify the significance of resuming or discontinuing antithrombotic in patients post-GIB.²¹ Sengupta et al. did discover that patients who were taking thienopyridines were more likely to have a recurrent GIB.³⁰ Ultimately, anticoagulants were better than antithrombotic in terms of thromboembolic and mortality outcomes with less incidences of recurrent bleeds.

Timing to resume anticoagulants

Studies have noted that resuming anticoagulation is optimal around 90 days. However, other studies have indicated that thrombotic events occur within these days, leaving with a greater increase in mortality.^16,20,27,33 Narrowing down this time frame is optimal. The type and severity of the GIB plays a role in the clinician’s decision on when to resume anticoagulants.³³ Hafiz et al. suggested a prophylactic dose of anticoagulants be administered before graduating to a full dose to balance the risk of a thromboembolic event.³³ They also indicated that resuming antithrombotic therapy within seven days of the initial bleeding event has an overall beneficial effect.³³ Sostres et al. found that 98.5% of patients reinstated therapy within the first 30 days (median of 6 and mean of 7.6 ± 6.4 days), suggesting that the first week might be the optimal time for resuming anticoagulant or antithrombotic therapy.²⁰ However, they also stress that clinicians should use risk stratification tools and make decisions case-by-case.²⁰

Other studies have shown that as compared to patients that were resumed on therapy at least seven days after the index bleed, patients that were resumed on therapy within the first seven days were associated with a higher rate of rebleeding (30.6% p = 0.044) and a lower rate of ischemic events (13.6%; p = 0.025).^20,22,25 Patients who resumed after day 7 had a lower rebleeding rate than those who restarted anticoagulants within the first seven days.²⁵ Mortality during follow-up of patients was lowest when warfarin was restarted between 15-90 days post-GIB.²² Lee et al. suggests the optimal timing for resumption of warfarin lies between 14-20 days after the initial bleeding event after a SEE has been performed to ensure that the patient is hemodynamically stable.²⁴ Majed et al. however, suggested that the risk of rebleeding within the first three weeks after the index bleed is very high and that risk reduces significantly by the sixth week. Hence, the optimal time for resumption lies between the third and sixth week after the initial bleed.²⁶ The time frame varies greatly between <7 days up to 90 days, ultimately showing a decrease in thrombolytic events. Most research points toward 15-30 days post GIB as an optimal window as to when to resume therapy, but it is still clear that this needs to be assessed based on the patient’s presentation and medical history.

Limitations to resuming anticoagulants and antithrombotic therapies

While we found a greater benefit in resuming anticoagulant and antithrombotic therapies post-GIB, there are still factors to consider as to why physicians wouldn’t resume these therapies. Physicians tend to hesitate resumption in patients with upper, lower, and unknown-source GIB, diabetes, renal disease, coronary artery disease, and history of falls, specifically for warfarin due to either medication adherence or increase chance in rebleeds and other adverse events.^27,34 Older patients or patients with dementia and living in a long-term care facility were also less likely to be placed on OACs post GIB.²⁴ Patients who underwent blood transfusion during hospitalization and required monitoring in intensive care units and previous GIB bleeds, were usually given alternate medication to prevent thromboembolism.^19,30 Quershi et al. reported that on top of the previously mentioned factors, 19% of patients could not follow-up treatment with an anticoagulant clinic and had insurance issues.²⁵ The physician’s preference was also indicated in 18% of the cases not to restart anticoagulation.²⁵ While this paper addresses some of the reasons for resuming anticoagulant and antithrombotic therapy, specific reasons should be addressed in further research.

Limitations to the study

The studies did present with some limitations in that they were largely retrospective investigations using health insurance claims. Retrieving reports from health insurance claims do run the risk of being inaccurate. This also limits the study population, depending on the origin of the study, due to patient who are not covered under insurance, as their population could be an important factor to consider in rates of rebleeds or thrombolytic events.