Risk of Gastrointestinal Bleeding Increases With Combinations of Antithrombotic Agents and Patient Age

Risk of Gastrointestinal Bleeding Increases With Combinations of Antithrombotic Agents and Patient Age

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Clinical Gastroenterology and Hepatology 2019;-:-–-

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Risk of Gastrointestinal Bleeding Increases With Combinations of Antithrombotic Agents and Patient Age Q35

Neena S. Abraham,*,‡,§ Peter A. Noseworthy,‡,k Jonathan Inselman,‡ Jeph Herrin,¶ Xiaoxi Yao,‡ Lindsey R. Sangaralingham,‡ Gabriella Cornish,* Che Ngufor,‡ and Nilay D. Shah‡,§,#

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*Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona; ‡Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, §Division of Health Care Policy and Research, kCardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; ¶Division of Cardiology, Yale School of Medicine, New Haven, Connecticut; # OptumLabs, Cambridge, Massachusetts

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BACKGROUND & AIMS:

The safety of different antithrombotic strategies for patients with 1 or more indication for antithrombotic drugs has not been determined. We investigated the risk and time frame for gastrointestinal bleeding (GIB) in patients prescribed different antithrombotic regimens. We proposed that risk would increase over time and with combination regimens, especially among elderly patients.

METHODS:

We performed a retrospective analysis of nationwide claims data from privately insured and Medicare Advantage enrollees who received anticoagulant and/or antiplatelet agents from October 1, 2010, through May 31, 2017. Patients were stratified by their prescriptions (anticoagulant alone, antiplatelet alone, or a combination) and by their primary diagnosis (atrial fibrillation, ischemic heart disease, or venous thromboembolism). The 1-year GIB risk was estimated using parametric time-to-event survival models and expressed as annualized risk and number needed to harm (NNH).

RESULTS:

Our final analysis included 311,211 patients (mean ages, 67 years for monotherapy and 69.8 years for combination antithrombotic therapy). There was no significant difference in the proportion of patients with bleeding after anticoagulant or antiplatelet monotherapy (w3.5%/ year). Combination antithrombotic therapy increased GIB risk compared with anticoagulant (NNH, 29) or antiplatelet (NNH, 31) monotherapy, regardless of the patients’ diagnosis or time point analyzed. Advancing age was associated with increasing 1-year probability of GIB. Patients prescribed combination therapy were at the greatest risk for GIB, especially after the age of 75 years (GIB occurred in 10%–17.5% of patients/y).

CONCLUSIONS:

In an analysis of nationwide insurance and Medicare claims data, we found GIB to occur in a higher proportion of patients prescribed combinations of anticoagulant and antiplatelet agents compared with monotherapy. Among all drug exposure categories and cardiovascular conditions, the risk of GIB increased with age, especially among patients older than 75 years.

Keywords: Anticoagulant; Antiplatelet; Ischemic Heart Disease; Venous Thromboembolism; Atrial Fibrillation.

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astrointestinal bleeding (GIB) in cardiac patients is common in an aging and increasingly comorbid population.1,2 Choosing among drug strategies is challenging in the absence of head-to-head safety studies among comparable patients, given a myriad of treatment options, combinations, and increasing patient complexity and comorbidity. Published studies tend to focus on a single cardiovascular risk group when studying adverse events,1,3–7 an approach that does not reflect the clinical reality of patients with more than 1 underlying cardiovascular condition requiring antithrombotic therapy. In addition, there are limited data on GIB risk in the era

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Abbreviations used in this paper: ACTIVE, Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; AF, atrial fibrillation; ASA, acetylsalicylic acid; AVERROES, Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; CV, cardiovascular; DOAC, direct oral anticoagulant; GIB, gastrointestinal bleeding; IHD, ischemic heart disease; NNH, number needed to harm; NSAID, nonsteroidal anti-inflammatory drug; OTC, over-the-counter; PPI, proton pump inhibitor; VTE, venous thromboembolism. © 2019 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2019.05.017

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of direct oral anticoagulants (DOACs) and secondgeneration antiplatelet agents.3,6,7 We sought to fill this knowledge gap by providing a richer exploration of GI bleeding risk (ie, safety) among patients with multiple comorbid cardiovascular conditions, in whom multiple antithrombotic strategies are indicated.6,8–10 We quantified the risk and time frame of GIB among persons with 1 or more indications (atrial fibrillation, ischemic heart disease, and/or venous thromboembolism) for antithrombotic medications (antiplatelet and/or anticoagulant drugs) prescribed as monotherapy or in combination. We hypothesized that GIB risk would increase over time when combination antithrombotic drug regimens are prescribed and patients age 75 years and older would be at greatest risk.

Methods Data Source We evaluated data from the OptumLabs Data Warehouse (Cambridge, MA), which includes claims data for privately insured and Medicare Advantage enrollees in a large private, US health plan.1,5 The database contains longitudinal health information including physician, hospital, and prescription drug services on enrollees of diverse ages, ethnicities, and geographic regions across the United States. Medical claims include International Classification of Diseases, 9th and 10th revisions, Clinical Modification, diagnosis codes and procedure codes, Current Procedural Terminology, version 4, procedure codes, Healthcare Common Procedure Coding System procedure codes, site of service codes, and provider specialty codes. Because this study involved analysis of pre-existing, de-identified data, it was exempt from Institutional Review Board approval.

Patient Identification and Stratification We identified patients 18 years of age and older with an index prescription of an anticoagulant (vitamin K antagonist or DOAC) and/or an antiplatelet agent (second- or third-generation thienopyridine agent) either as monotherapy or in combination from October 1, 2010, to May 31, 2017. The date of first filled prescription was the index date and was used to assign patients to their exposure strata (anticoagulant, antiplatelet, or anticoagulant and antiplatelet). We excluded patients with evidence of a dispensed prescription in the 12 months before the index date to ensure a new-user cohort. All patients required 12 months of continuous enrollment in the medical and pharmacy plan before the index prescription; this period of time was considered the baseline period for assessment of past medical history. We excluded patients with a current cancer diagnosis who may be at risk for a malignancy-associated GIB. Eligible patients then were stratified by cardiovascular (CV)

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What You Need to Know Background Antithrombotic drugs are prescribed to patients with atrial fibrillation, ischemic heart disease, and venous thromboembolism. Clinicians tend to underestimate gastrointestinal bleeding risk among complex patients with 1 or more indications for treatment.

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Findings Among cardiovascular subgroups the risk of bleeding was similar (3.5%/y) if 1 agent was prescribed. Among patients age 75 years and older, regardless of the cardiovascular indication, risk increased from 10% to 17.5% per year on combination therapy. Implications for patient care We quantify the impact of going from single to combination therapy with risk estimates that are higher than previous studies examining only 1 at-risk patient population. An age of 75 years and older markedly increases risk across all antithrombotic strategies. diagnosis of atrial fibrillation (AF), ischemic heart disease (IHD), and/or venous thromboembolism (VTE) at the time of the index prescription; combinations of these 3 conditions were treated as separate strata. The first occurrence of the diagnostic code of interest during the first 90 days of observation after index prescription determined the cardiovascular condition stratification category.

Exposures and Primary Outcome Exposure was considered continuous from the index date until the occurrence of an outcome or until censoring because of the end of enrollment (including owing to mortality), switch to another treatment strategy, or treatment termination as defined by the absence of a new prescription by the end of the 30 days after the last identified prescription fill date for the index medication. The last date of follow-up evaluation was May 31, 2017. The primary outcome of interest was a GI bleed as previously defined,1,5,11 expressed as upper GIB, lower GIB, and the composite outcome of total GIB (Supplementary Table 1). Each event was identified using in-patient hospital claims for relevant primary and secondary discharge diagnoses.

Variables of Interest Baseline demographic characteristics, CHA2DS2-VASC score (hypertension, age 75 y, diabetes mellitus, stroke/transient ischemic attack/thromboembolic event), and concomitant prescribed pharmacologic risk factors (acetylsalicylic acid [ASA], nonsteroidal anti-

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inflammatory drugs [NSAIDs], selective serotonin reuptake inhibitors, and gastroprotective agents) were assessed as potential confounding variables. Comorbid conditions were identified by administrative codes in the primary or secondary position on any claim during the baseline period and overall comorbidity burden was assessed using the Charlson–Deyo index.

Statistical Analysis We estimated separate models for each of the antithrombotic drug exposures by CV condition group using a parametric time-to-event survival model with a Weibull distribution.12 This model then was used to predict the GIB risk of each patient averaged over each treatment group at multiple time points within the first 6 months of the prescription and at 1 year. For each prescription strategy, the 1-year risk ratio and 95% CIs were calculated, as was the absolute risk reduction and the number needed to harm (NNH) at 1 year. The analytic data set was created and manipulated using SAS 9.3 (SAS Institute, Inc, Cary, NC) and Stata 15.1 (Stata Corp, College Station, TX).

Sensitivity Analyses We examined the effect of age and treatment regimen on annualized GIB by including an interaction term in the model. The comparative safety of the antithrombotic prescription was examined in 5 age stratum: 18 to 44, 45 to 64, 55 to 64, 65 to 74, and 75 and older. Two address potential underascertainment of over-the-counter (OTC) ASA and proton pump inhibitor (PPI) cohort members were assigned randomly to an increased prevalence of ASA and PPI use (20%, 40%, 60%, and 80%), and the magnitude of effect on the annualized GIB (total, upper, and lower) was calculated.

Results Baseline Characteristics We identified 311,211 eligible patients (Figure 1). At index, 164,649 patients were prescribed an anticoagulant agent, 142,433 patients were prescribed a non-ASA/ NSAID antiplatelet agent, and 4129 patients were prescribed an anticoagulant concomitantly with a non-ASA/ NSAID antiplatelet agent. The mean patient age ranged from 67 years in patients prescribed anticoagulant or antiplatelet monotherapy to 70 years for those prescribed combination therapy with an anticoagulant and concomitant antiplatelet (Table 1). The duration of therapy was shortest for patients prescribed combination antithrombotic therapy (111 days), and longest for patients prescribed antiplatelet monotherapy (291 days). We observed a male sex predominance (67%–70% male), more than 30% were 75 years and older and most

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were Caucasian (74%). A CHA2DS2-VASC score higher than 4 was noted among 55.4% and 81.3% prescribed anticoagulant or combination antithrombotic therapy, respectively. The Charlson–Deyo comorbidity index suggested the majority had a relatively low, noncardiac comorbidity burden. Anticoagulant therapy was the primary strategy for patients with AF alone. However, both AF and IHD patients commonly were prescribed combination anticoagulant and antiplatelet therapy (56.8%). Among patients with AF with IHD and VTE, combination antithrombotic therapy was most prevalent (11.0%), with fewer prescribed anticoagulant monotherapy (6.0%). Patients with IHD predominantly were prescribed antiplatelet therapy (84.4%). Among those patients with IHD and VTE, the addition of an anticoagulant to antiplatelet therapy (13.9%) was more common than anticoagulant monotherapy (9.88%) or antiplatelet monotherapy (3.14%). Patients with VTE or VTE and AF predominantly were prescribed anticoagulant monotherapy, as expected. DOACs were prescribed as the index anticoagulant prescription in 42.7% of patients in this new-user cohort, with the greatest prevalence among patients aged 18 to 64 years (Supplementary Table 2). Among patients receiving DOACs, an apixaban prescription was prescribed to 10.3% of patients aged 18 to 64, to 15.4% of patients aged 65 to 74, and to 17.4% of patients aged 75 years and older (Supplementary Table 3). Chronic kidney disease was noted in approximately 16% and a past medical history of GIB was present in 22% to 23% of patients. A concomitant prescription of ASA or NSAIDs was noted in 13.6% of patients prescribed an anticoagulant, in 15.6% of patients prescribed antiplatelets, and in 12.5% of patients prescribed combination antithrombotic therapy. Gastroprotective agents, including PPIs and histamine blockers, were prescribed in 23% to 33% of patients whereas prescription of selective serotonin reuptake inhibitors was approximately 12%.

Annual Risk of Gastrointestinal Bleeding, Absolute Risk Reduction, and the Number Needed to Harm Overall, there were 13,979 GIB events during the period of observation, of which 9929 (3.22%) were upper and 3937 (1.28%) were lower events, and 113 (0.81%) were impossible to classify. Figure 2 shows the 1-year total GIB risk per patient based on prescription and cardiovascular indication, as well as the absolute risk reduction of 2 compared strategies and the subsequent NNH. Among all conditions, the prescription of combination antithrombotic therapy is associated with a higher risk of GIB at 1 year when compared with monotherapy. The same was true at all other time points examined (Supplementary Table 4).

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Figure 1. Study flow diagram. GIB, gastrointestinal bleeding.

In Figure 2, patients with both AF and IHD prescribed combination antithrombotic therapy have a higher 1year GIB risk at 7.4% (95% CI, 6.3–8.4) than those patients prescribed anticoagulant therapy alone. Only 29 patients with AF þ IHD would need to be prescribed combination antithrombotic therapy to incur 1 additional GIB. In this cardiovascular subgroup (ie, AF þ IHD) the risk of GIB is similar between anticoagulant monotherapy (4.0%; 95% CI, 3.8–4.2) and antiplatelet monotherapy (4.2; 95% CI, 3.9–4.5), as is the protective benefit of monotherapy over combination antithrombotic

therapy. Only 31 patients would need to be prescribed combination antithrombotic therapy as opposed to antiplatelet monotherapy to incur 1 additional clinically significant GIB. Among patients with concurrent AF, IHD, and VTE the prescription strategy with the lowest GIB risk per patient-year is anticoagulant monotherapy, and the strategy with the greatest GIB risk is combination antithrombotic therapy. As few as 20 patients with AF þ IHD þ VTE would need to be prescribed combination antithrombotic therapy to result in 1 additional GIB, with

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Table 1. All Patients Full cohort Characteristics Demographics and risk scores Mean age, y (SD) Age group, y 18–44 45–54 55–64 65–74 75 Sex Female Male Race/ethnicity White Black Other Charlson–Deyo score 0–1 2–3 4 Condition(s) at treatment episode start AF AF þ IHD AF þ IHD þ VTE IHD IHD þ VTE VTE VTE þ AF Previous treatment episode Baseline comorbidities Alcoholism Carotid revascularization procedures Chronic liver disease Chronic kidney disease Chronic heart failure Diabetes treatment No diabetes Diabetes not treated Diabetes treated with metformin only Diabetes treated with other noninsulin medications Diabetes treated with insulin History of GIB History of ischemic heart disease History of PCI Hypertension Peripheral arterial disease Rheumatologic diseases Sleep apnea Smoking Thyroid disease Valvular disease Viral hepatitis Concomitant drug exposure Aspirin and/or NSAID Antihypertensive drugs Antiarrhythmics Gastroprotective agents, proton pump inhibitor, H2 blocker Selective serotonin reuptake inhibitors

Anticoagulant (N ¼ 164,649)

Antiplatelets (N ¼ 142,433)

Anticoagulants and antiplatelets (N ¼ 4129)

67.0 (14.1)

67.0 (11.7)

12,909 (7.84%) 17,665 (10.73%) 32,268 (19.60%) 44,416 (26.98%) 57,391 (34.86%)

4838 (3.40%) 17,032 (11.96%) 35,515 (24.93%) 43,874 (30.80%) 41,174 (28.91%)

122 (2.95%) 314 (7.60%) 795 (19.25%) 1280 (31.00%) 1618 (39.19%)

80,376 (48.82%) 84,273 (51.18%)

56,781 (39.87%) 85,652 (60.13%)

1566 (37.93%) 2563 (62.07%)

124,302 (75.50%) 16,288 (9.89%) 24,059 (14.61%)

100,544 (70.59%) 16,124 (11.32%) 25,765 (18.09%)

3109 (75.30%) 377 (9.13%) 643 (15.57%)

99,315 (60.32%) 33,288 (20.22%) 32,046 (19.46%)

62,989 (44.22%) 39,456 (27.70%) 39,988 (28.07%)

3344 (80.99%) 308 (7.46%) 477 (11.55%)

69.8 (11.5)

35,637 48,308 9811 14,372 16,263 35,789 4469 40,867

(21.64%) (29.34%) (5.96%) (8.73%) (9.88%) (21.74%) (2.71%) (24.82%)

795 16,482 1417 118,826 4474 399 40 29,259

(0.56%) (11.57%) (0.99%) (83.43%) (3.14%) (0.28%) (0.03%) (20.54%)

(1.45%) (56.82%) (10.97%) (15.94%) (13.93%) (0.85%) w 3221 (78.01%)

9368 4275 11,089 22,907 51,288

(5.69%) (2.60%) (6.73%) (13.91%) (31.15%)

7766 8058 9502 19,663 37,531

(5.45%) (5.66%) (6.67%) (13.81%) (26.35%)

230 308 282 857 2151

106,627 (64.76%) 28,313 (17.20%) 7982 (4.85%) 11,040 (6.71%) 10,687 (6.49%) 37,187 (22.59%) 75,065 (45.59%) 11,493 (6.98%) 136,172 (82.70%) 19,862 (12.06%) 12,307 (7.47%) 22,956 (13.94%) 51,850 (31.49%) 47,278 (28.71%) 69,973 (42.50%) 2940 (1.79%)

78,970 (55.44%) 25,079 (17.61%) 8794 (6.17%) 14,145 (9.93%) 15,445 (10.84%) 32,389 (22.74%) 116,024 (81.46%) 76,828 (53.94%) 129,527 (90.94%) 33,409 (23.46%) 9229 (6.48%) 15,688 (11.01%) 64,788 (45.49%) 36,950 (25.94%) 53,818 (37.78%) 2762 (1.94%)

22,311 114,977 18,083 38,382 20,793

22,237 113,978 3646 36,514 17,341

(13.55%) (69.83%) (10.98%) (23.31%) (12.63%)

(15.61%) (80.02%) (2.56%) (25.64%) (12.17%)

60 2346 453 658 575 35

(5.57%) (7.46%) (6.83%) (20.76%) (52.09%)

2045 (49.53%) 929 (22.50%) 241 (5.84%) 427 (10.34%) 487 (11.79%) 919 (22.26%) 3592 (86.99%) 2481 (60.09%) 3854 (93.34%) 1225 (29.67%) 330 (7.99%) 608 (14.73%) 1935 (46.86%) 1155 (27.97%) 2315 (56.07%) 70 (1.70%) 516 3716 675 1352 532

(12.50%) (90.00%) (16.35%) (32.74%) (12.88%)

AF, atrial fibrillation; AP, ______; IHD, ischemic heart disease; NSAID, nonsteroidal anti-inflammatory drug; PCI, percutaneous coronary implantation; VTE, venous Q21 thromboembolism.

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its 10% per patient-year risk of GIB. A similar pattern was observed among patients with IHD. If prescribed combination antithrombotic therapy with an anticoagulant and antiplatelet, a patient’s 1-year probability of GIB increased to 10% from 3.5% with anticoagulant or antiplatelet monotherapies. The prescription of combination antithrombotic therapy was associated with a much higher GIB risk among patients with IHD and VTE. With an estimated 1 year GIB risk per patient of 7.5%, 41 patients with IHD and VTE would need to be prescribed this strategy instead of antiplatelet monotherapy, or 31 patients instead of anticoagulant therapy, to incur 1 additional GIB. Stratification by lower GIB (Supplementary Figure 1) and upper GIB (Supplementary Figure 2) showed a similar pattern across all cardiovascular strata and drug regimens.

Sensitivity Analysis: Impact of Advancing Age on Gastrointestinal Bleeding Risk Across all cardiovascular subgroups, older age was associated with a greater probability of GI bleeds within 1 year of the index prescription (Figures 3 and 4). The patients’ prescribed concomitant anticoagulants and antiplatelets were at the greatest risk, especially after the age of 75. Among patients with AF (Figure 3), anticoagulant monotherapy strategies were the safest regimens across all age ranges regardless of whether the patient had additional cardiovascular conditions at the time of the index prescription (ie, IHD or IHD and VTE). Among patients older than age 65 years with AF, combination antithrombotic therapy was associated with twice the rate of GIB within 1 year when compared with anticoagulant monotherapy (10%–11% and 5%/y, respectively). The same pattern was seen among the elderly with AF and IHD, and AF with IHD and VTE. In the latter

Figure 2. Annual risk of gastrointestinal (GI) bleeding, absolute risk reduction (ARR), and number needed to harm (NNH). AC, __________; AF, atrial fibrillation; AP, ______; IHD, ischemic heart disease; VTE, venous thromboembolism.

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group, combination antithrombotic therapy in patients 75 years and older was associated with more than a 17% probability of GIB per year, as compared with a 9% probability of GIB per year among similar patients prescribed anticoagulant monotherapy (Figure 3). Increased risk with combination antithrombotic therapy and advancing age also was seen among patients with IHD, IHD and VTE, VTE, and VTE and AF (Figure 4).

Sensitivity Analysis: Impact of Potential Overthe-Counter Acetylsalicylic Acid and Proton Pump Inhibitor Use OTC drug use is not captured in traditional prescription drug claims data. To explore how risk estimates might change with the addition of OTC ASA and PPI, we conducted exploratory sensitivity analyses. In Supplementary Tables 5 and 6 we highlight the annualized estimates of GIB assuming different clinical thresholds of OTC ASA or OTC PPI use from 20% to 80%. As shown in Supplementary Tables 5 and 6, no significant difference in GIB rates were seen because the prevalence of ASA or PPI use was varied from 20% to 80%. There was also no meaningful difference in location of the GI bleed when OTC drug risk was varied among all CV subgroups prescribed any prescription strategy.

Discussion The goal of this study was to quantify the safety, as assessed by rates of GIB, of a variety of common antithrombotic regimens among patients with 1 or more cardiovascular conditions. The use of a large national administrative claims database of commercially insured and Medicare Advantage patients during a time period with increasing use of DOACs and second-generation antiplatelet agents permitted a broad exploration of the real-world risk of antithrombotic polypharmacy among American cardiovascular patients. We showed that the use of antithrombotic polypharmacy was associated with a much higher risk of GIB than monotherapies. Our estimates of GIB among cardiovascular patients with 1 or more indication for antiplatelet or anticoagulant therapy show a 2.5% to 10% annual risk per patient depending on the indication for antithrombotic therapy and the choice of monotherapy or combination antithrombotic therapy. These estimates remained stable over multiple time points within the first 6 months of antithrombotic prescription over all cardiovascular patient strata and prescription strategies examined. Typically, comparative effectiveness and safety studies have been used to estimate the benefits and risks associated with each of the antithrombotic agents.3,7,13,14 However, because we were interested specifically in quantifying the risk of GIB among patients taking various antithrombotic regimens for varying indications, a

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Figure 3. Age-stratified analysis. AC, __________; AF, atrial fibrillation; AP, ______; GI, gastrointestinal; IHD, ischemic heart disease; VTE, venous thromboembolism.

comparative effectiveness study would not be suitable because it would require limiting our investigation to a homogenous population to ensure accurate assessment of benefit among patients with similar CV conditions and indications for drug therapy. Online calculators/risk prediction tools such as the Stroke Prevention in Atrial Fibrillation Risk Tool already exist to compare the comparative benefits of commonly used medication regimens for the atrial fibrillation population (http:// www.sparctool.com/). Similarly, the antiplatelet therapy clinical prediction score was developed to help identify patients with greater expected benefit vs harm

from prolonged dual-antiplatelet therapy.15 In this study, we have extended the safety literature by performing a methodologically rigorous study that allows for examination of antithrombotic-related GIB risk as a drug class, regardless of the indication for which these agents are prescribed. The results of this study highlight the importance of careful consideration of risk-benefit before adding antiplatelet and anticoagulant drugs to a patient’s cardiovascular regimen, particularly in patients older than age 75. In the current study, AF patients had similar bleeding rates whether they were prescribed anticoagulant or

Figure 4. Age-stratified analysis. AC, __________; AF, atrial fibrillation; AP, ______; GI, gastrointestinal; IHD, ischemic heart disease; VTE, venous thromboembolism.

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antiplatelet therapy. This is consistent with the results from the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,16 which showed a reduction in the risk of systemic embolism without a significant increase in GIB complications (hazard ratio, 0.86; 95% CI, 0.38–1.90) when apixaban (5 mg/d) was used as compared with aspirin (81–324 mg/d). In the AVERROES trial, a reduced dose of apixaban (2.5 mg/d) was used in the very elderly (age, 80 y), in patients with low body weight (60 kg), or individuals with impaired renal excretion (serum creatinine level, 1.5 mg/dL). Dose reduction among the elderly and in patients with renal impairment, as directed in the Food and Drug Administration drug labeling, has been shown to reduce gastrointestinal and other major bleeding complications significantly.17–19 Both underdosing and overdosing commonly are observed in practice and is associated with suboptimal stroke and bleeding risks.20 The risk-benefit profile of AF patients with concurrent IHD may favor anticoagulant monotherapy, which has been shown to be effective in patients with IHD.14 Our data suggest that combination antithrombotic therapy substantially increases GIB risk when compared with anticoagulant monotherapy (NNH, 29) or antiplatelet monotherapy (NNH, 31). Dual-antiplatelet therapy (ASA þ clopidogrel) increased GIB risk without improvement in stroke prevention in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) trial.21 The ACTIVE W trial8 further showed the superiority of oral anticoagulant therapy to dual-antiplatelet therapy (ASA þ clopidogrel) in reducing vascular events, with an increase in minor bleeds. Taken together, the results of our study, the ACTIVE trial, ACTIVE W trial, and the AVERROES trial suggest that anticoagulant therapy with appropriately dosed anticoagulant may be the most favorable approach for AF patients, with and without IHD, who are at moderate to severe risk of bleeding. This conclusion also is supported by the 2018 American Heart Association White Paper updating recommendations for antithrombotic therapy in AF patients after percutaneous coronary intervention.22 The authors endorse considering the ischemic/thrombotic and bleeding risk profiles of patient when choosing the duration of a dual-antithrombotic regimen. A doubletherapy regimen (anticoagulant plus single thienopyridine antiplatelet agent) should be considered for most patients except for those at high bleeding risk; and triple antithrombotic therapy (anticoagulant plus ASA and thienopyridine agent) should be used only for a limited period of time in very select cases when there is a very high ischemic and low bleeding risk (eg, for 1 month after percutaneous intervention with coronary stent placement). Modification of antithrombotic strategies to minimize bleeding risk is encouraged in susceptible patients, including prescription of clopidogrel as the

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thienopyridine antiplatelet of choice in most patients, with the use of ticagrelor reserved for patients with a high ischemic/thrombotic and low bleeding risk. These recommendations are consistent with prior clinical data showing high bleeding rates with both prasugrel and ticagrelor; with the most common bleeding location being gastrointestinal.23–25 In these aforementioned studies,23–25 there was an observed absolute increase in major bleeding that is greatest in the elderly (1.2%) when compared with younger patients (0.7%). This study further highlights the risk of antithrombotic GIB among elderly patients, underscoring the necessity of careful consideration of risk when individualizing therapy.1,5 Across all cardiovascular conditions and all antithrombotic regimens, advancing age was associated with the greatest risk of GIB at 1 year (up to 10%/y). Patients aged 75 years and older prescribed dualantithrombotic therapy experienced a doubling of their probability of GIB (up to 17.5%/y) in some cardiovascular subgroups.

Strengths and Weaknesses As with any observational study, detected associations may not be causal and treatment choices may be influenced by factors that also influence outcomes. However, this study focused specifically on describing the rates of bleed rather than conducting a comparative effectiveness study. Second, we were not able to capture the rates of over-the-counter medication use (ASA or PPI) in pharmacy claims data. However, the sensitivity analyses performed to better understand the magnitude of effect of underascertainment of OTC ASA and PPI use (Supplementary Table 5) confirm no meaningful differences in the GIB rates (total, upper, and lower) when a wider threshold of clinical exposure is applied, highlighting the robustness of our estimates. Third, this study focused on evaluating outcomes at 1 year and it is possible that treatment effects may differ for different time frames, especially with a longer follow-up period. However, we expect that including 1-year outcomes are meaningful for clinicians because they consider starting these treatments for patients with cardiovascular disease. Against these limitations, this study also had important strengths worth considering. Outcomes were captured in a large, nationally representative, cohort of patients across all adult age groups and diverse backgrounds. This heterogeneous population provides meaningful information for patients and clinicians with broad applicability. In addition, this study evaluated the risk of GIB in an era with increasing use of DOACs and second-generation antiplatelet agents.

Implications for Health Care Professionals and Patients There are some key findings from this study for both patients and clinicians. First, although it is known that

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Q16

871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928

-

929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986

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GIB on Antithrombotic Therapy

combination therapy increases the harms associated with these medications, this study quantifies the impact of single and combination therapy over a wide range of ages, and at multiple time points during the initial year of exposure. Just as importantly, this study showed that anticoagulant and antiplatelet monotherapies have similar GIB rates. It has been assumed that antiplatelets may be safer compared with anticoagulants and may be a preferred strategy for patients at moderate-to-high bleeding risks; however, this study shows that these risks may be similar, and in some individuals the use of appropriately dosed anticoagulant monotherapy may be the most favorable approach for AF patients, with and without IHD, who are at moderate to severe risk of bleeding. This is an important consideration because patients and clinicians decide on optimal treatment strategies.

Conclusions In this study, we describe the rates of GIB among various treatment strategies for patients with cardiovascular disease. Combination therapy with both antiplatelets and anticoagulants are associated with significantly higher 30- to 180-day risk of GIB, and 1-year risk of GIB compared with either antiplatelet or anticoagulant monotherapy. The 30- to 180-day and 1-year risks of GIB associated with antiplatelet or anticoagulants are similar. Among all drug exposure categories and cardiovascular conditions, the risk of GIB increases with advancing age. This risk is most pronounced among patients older than 75 years, in whom the risk of GIB doubles when compared with patients who are younger.

Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at https://doi.org/10.1016/j.cgh.2019.05.017.

9

5. Abraham NS, Singh S, Alexander GC, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ 2015;350:h1857. 6. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012;126:1185–1193. 7. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol 2013; 62:981–989. 8. Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903–1912. 9. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494–502. 10. Steg PG, James SK, Atar D, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33:2569–2619. 11. Abraham NS, Hartman C, Richardson P, et al. Risk of lower and upper gastrointestinal bleeding, transfusions, and hospitalizations with complex antithrombotic therapy in elderly patients. Circulation 2013;128:1869–1877. 12. Carroll KJ. On the use and utility of the Weibull model in the analysis of survival data. Control Clin Trials 2003; 24:682–701. 13. Noseworthy PA, Yao X, Abraham NS, et al. Direct comparison of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in nonvalvular atrial fibrillation. Chest 2016; 150:1302–1312. 14. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002;347:969–974. 15. Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315:1735–1749. 16. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–817. 17. Abraham NS, Castillo DL. Novel anticoagulants: bleeding risk and management strategies. Curr Opin Gastroenterol 2013; 29:676–683.

References 1. Abraham NS, Noseworthy PA, Yao X, et al. Gastrointestinal safety of direct oral anticoagulants: a large population-based study. Gastroenterology 2017;152:1014–1022.e1.

18. Yao X, Tangri N, Gersh BJ, et al. Renal outcomes in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol 2017;70:2621–2632.

2. Abraham NS. New clinical paradigms for treating and preventing antiplatelet gastrointestinal bleeding. Curr Opin Gastroenterol 2017;33:467–472.

19. Del-Carpio Munoz F, Yao X, Abraham NS, et al. Dabigatran versus warfarin in relation to renal function in patients with atrial fibrillation. J Am Coll Cardiol 2016;68:129–131.

3. Yao X, Abraham NS, Alexander GC, et al. Effect of adherence to oral anticoagulants on risk of stroke and major bleeding among patients with atrial fibrillation. J Am Heart Assoc 2016;5.

20. Yao X, Shah ND, Sangaralingham LR, et al. Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol 2017; 69:2779–2790.

4. Noseworthy PA, Yao X, Gersh BJ, et al. Baseline characteristics and event rates among anticoagulated patients with atrial fibrillation in practice and pivotal NOAC trials. Data Brief 2017; 14:563–565.

21. The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066–2078.

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987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044

10

1045 1046 1047 1048 1049 1050 1051 1052 Q17 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102

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22. Angiolillo DJ, Goodman SG, Bhatt DL, et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention - a North American perspective–2018 update. Circulation 2018; 138:527–536. 23. Husted S, James S, Becker RC, et al. Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes. A Substudy From the Prospective Randomized PLATelet Inhibition and Patient Outcomes (PLATO) trial 2012;5:680–688. 24. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–1057. 25. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–2015.

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Reprint requests Address requests for reprints to: Neena S. Abraham, MD, MSCE, FACG, FASGE, AGAF, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259. e-mail: [email protected]; fax: (xxx) xxx-xxxx. Conflicts of interest The authors disclose no conflicts.

Q2 Q3

Q4 Funding This project was supported by grant R01HS025402 (N.S.A.) from the Agency Q34 for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. The design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication were solely the responsibility of the authors listed. Jeph Herrin and Jonathan Inselman had full access to all the data in the study and take Q5 responsibility for the integrity of the data and the accuracy of the analysis.

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1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160

-

1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 Q22 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218

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GIB on Antithrombotic Therapy

10.e1

Supplementary Figure 1. Annual risk of lower gastrointestinal bleeding (LGIB). AC, _____; AF, atrial fibrillation; AP, ____; ARR, __________; NNH, number needed to harm; IHD, ischemic heart disease; VTE, venous thromboembolism.

Supplementary Figure 2. Annual risk of upper gastrointestinal bleeding (UGIB). AC, _____; AF, atrial fibrillation; AP, ____; ARR, __________; NNH, number needed to harm; IHD, ischemic heart disease; VTE, venous thromboembolism.

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Q23

1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276

10.e2

1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334

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No.

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Q24

Supplementary Table 1. ICD 9th and 10th Revisions Diagnostic Codes Used Upper GI bleed Code Code version 456.2 530.7 530.82 531.0 531.00

9 9 9 9 9

531.01 531.1 531.10

9 9 9

531.11

Code description

9

Esophageal varices diseases classified elsewhere Gastroesophageal laceration–hemorrhage syndrome Esophageal hemorrhage Acute gastric ulcer with hemorrhage Acute gastric ulcer with hemorrhage w/o mention of obstruction Acute gastric ulcer with hemorrhage and obstruction Acute gastric ulcer with perforation Acute gastric ulcer with perforation w/o mention of obstruction Acute gastric ulcer with perforation and obstruction

531.2

9

531.20

9

531.21

9

531.3

9

531.30

9

531.31

9

531.4

9

531.40

9

531.41

9

531.5

9

531.50

9

531.51

9

531.6

9

531.60

9

531.61

9

532.0 532.00

9 9

532.01 532.1 532.10

9 9 9

532.11 532.2 532.20

9 9 9

532.21

9

532.3

9

532.30

9

532.31

9

Lower GI bleed Code Code version

Code description

562.02 562.03 562.12 562.13 568.81

9 9 9 9 9

569.3 569.85 K55.21

9 9 10

Hemorrhage of rectum and anus Angiodysplasia of intestine with hemorrhage Angiodysplasia of colon with hemorrhage

K57.01

10

Acute gastric ulcer with hemorrhage and perforation

K57.11

10

Acute gastric ulcer with hemorrhage and perforation w/o mention of obstruction Acute gastric ulcer with hemorrhage, perforation, and obstruction Acute gastric ulcer without mention of hemorrhage/ perforation Acute gastric ulcer w/o mention of hemorrhage, perforation, or obstruction Acute gastric ulcer w/o mention of hemorrhage or perforation with obstruction Chronic unspecified gastric ulcer with hemorrhage

K57.13

10

K57.21

10

K57.31

10

K57.33

10

K57.41

10

K57.51

10

K57.53

10

K57.91

10

K57.93

10 10

Diverticulitis of small intestine with perforation Q25 and ABSC with bleed Diverticulosis of small intestine w/o perforation ABSC with bleed Diverticulitis of small intestine w/o perforation ABSC with bleed Diverticulitis of large intestine with perforation and ABSC with bleed Diverticulosis of large intestine w/o perforation/ ABSC with bleed Diverticulitis of large intestine w/o perforation/ ABSC with bleed Diverticulitis of small and large intestine with perforation and ABSC with bleed Diverticulosis of small and large intestine w/o perforation/ABSC with bleed Diverticulitis of small and large intestine w/o perforation/ABSC with bleed Diverticulosis part unspecified w/o perforation or ABSC with bleed Diverticulitis part unspecified w/o perforation or ABSC with bleed Hemorrhage of anus and rectum

10

Hemoperitoneum

Chronic unspecified gastric ulcer with hemorrhage w/o mention of obstruction Chronic unspecified gastric ulcer with hemorrhage and obstruction Chronic unspecified gastric ulcer with perforation

Chronic unspecified gastric ulcer with perforation w/o K62.5 mention of obstruction Chronic unspecified gastric ulcer with perforation and K66.1 obstruction Chronic unspecified gastric ulcer with hemorrhage and perforation Chronic unspecified gastric ulcer with hemorrhage and perforation w/o obstruction Chronic unspecified gastric ulcer with hemorrhage perforation and obstruction Acute duodenal ulcer with hemorrhage Acute duodenal ulcer with hemorrhage w/o mention of obstruction Acute duodenal ulcer with hemorrhage and obstruction Acute duodenal ulcer with perforation Acute duodenal ulcer with perforation w/o mention of obstruction Acute duodenal ulcer with perforation and obstruction Acute duodenal ulcer with hemorrhage and perforation Acute duodenal ulcer with hemorrhage and perforation w/ o mention of obstruction Acute duodenal ulcer with hemorrhage, perforation, and obstruction Acute duodenal ulcer without mention of hemorrhage/ perforation Acute duodenal ulcer w/o mention of hemorrhage, perforation, or obstruction Acute duodenal ulcer w/o mention of hemorrhage or perforation with obstruction

Diverticulosis of small intestine w/hemorrhage Diverticulitis of small intestine with hemorrhage Diverticulosis of colon with hemorrhage Diverticulitis of colon with hemorrhage Hemoperitoneum

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1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392

-

1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 1450

2019

GIB on Antithrombotic Therapy

Supplementary Table 1. Continued Upper GI bleed Code Code version 532.4 532.40

9 9

532.41

9

532.5 532.50

9 9

532.51

9

532.6

9

532.60

9

532.61

9

533.0 533.00

9 9

533.01

9

533.1 533.10

9 9

533.11

9

533.2

9

533.20

9

533.21

9

533.3

9

533.30

9

533.31

9

533.4

9

533.40

9

533.41

9

533.5

9

533.50

9

533.51

9

533.6

9

533.60

9

533.61

9

534.0 534.00

9 9

534.01

9

Code description

Lower GI bleed Code Code version

Code description

Chronic unspecified duodenal ulcer with hemorrhage Chronic unspecified duodenal ulcer with hemorrhage w/o mention of obstruction Chronic/unspecified duodenal ulcer with hemorrhage and obstruction Chronic unspecified duodenal ulcer with perforation Chronic unspecified duodenal ulcer with perforation w/o mention of obstruction Chronic unspecified duodenal ulcer with perforation and obstruction Chronic unspecified duodenal ulcer with hemorrhage and perforation Chronic unspecified duodenal ulcer with hemorrhage and perforation w/o obstruction Chronic unspecified duodenal ulcer with hemorrhage, perforation, and obstruction Acute peptic ulcer unspecified site with hemorrhage Acute peptic ulcer unspecified site with hemorrhage w/o mention of obstruction Acute peptic ulcer unspecified site with hemorrhage and obstruction Acute peptic ulcer unspecified site with perforation Acute peptic ulcer unspecified site with perforation w/o mention of obstruction Acute peptic ulcer unspecified site with perforation and obstruction Acute peptic ulcer unspecified site with hemorrhage and perforation Acute peptic ulcer unspecified site with hemorrhage and perforation w/o obstruction Acute peptic ulcer unspecified site with hemorrhage, perforation, and obstruction Acute peptic ulcer unspecified site w/o mention of hemorrhage or perforation Acute peptic ulcer unspecified site w/o hemorrhage, perforation, or obstruction Acute peptic ulcer unspecified site w/o hemorrhage and perforation with obstruction Chronic unspecified peptic ulcer unspecified site with hemorrhage Chronic unspecified peptic ulcer unspecified site with hemorrhage w/o obstruction Chronic unspecified peptic ulcer unspecified site with hemorrhage and obstruction Chronic unspecified peptic ulcer unspecified site with perforation Chronic unspecified peptic ulcer unspecified site with perforation w/o obstruction Chronic unspecified peptic ulcer unspecified site with perforation and obstruction Chronic unspecified peptic ulcer unspecified site with hemorrhage and perforation Chronic unspecified peptic ulcer with hemorrhage and perforation w/o obstruction Chronic unspecified peptic ulcer unspecified site with hemorrhage, perforation, and obstruction Acute gastrojejunal ulcer with hemorrhage Acute gastrojejunal ulcer with hemorrhage w/o mention of obstruction Acute gastrojejunal ulcer with hemorrhage and obstruction

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10.e3

1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501 1502 1503 1504 1505 1506 1507 1508

10.e4

1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553 1554 1555 1556 1557 1558 1559 1560 1561 1562 1563 1564 1565 1566

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Supplementary Table 1. Continued Upper GI bleed Code Code version 534.1 534.10

9 9

534.11 534.2

9 9

534.20

9

534.21

9

534.3

9

534.30

9

534.31

9

534.4 534.40

9 9

534.41

9

534.5 534.50

9 9

534.51

9

534.6

9

534.60

9

534.61

9

535.0 535.00 535.01 535.1 535.10 535.11 535.2 535.20

9 9 9 9 9 9 9 9

535.21 535.3 535.30 535.31 535.4 535.40 535.41 535.5 535.50

9 9 9 9 9 9 9 9 9

535.51

9

535.6 535.60 535.61 537.83

9 9 9 9

537.84

9

Code description

Lower GI bleed Code Code version

Code description

Acute gastrojejunal ulcer with perforation Acute gastrojejunal ulcer with perforation w/o mention of obstruction Acute gastrojejunal ulcer with perforation and obstruction Acute gastrojejunal ulcer with hemorrhage and perforation Acute gastrojejunal ulcer with hemorrhage and perforation w/o obstruction Acute gastrojejunal ulcer with hemorrhage perforation and obstruction Acute gastrojejunal ulcer w/o mention of hemorrhage or perforation Acute gastrojejunal ulcer w/o mention of hemorrhage, perforation, or obstruction Acute gastrojejunal ulcer w/o hemorrhage or perforation with obstruction Chronic unspecified gastrojejunal ulcer with hemorrhage Chronic unspecified gastrojejunal ulcer with hemorrhage w/o mention of obstruction Chronic unspecified gastrojejunal ulcer with hemorrhage and obstruction Chronic unspecified gastrojejunal ulcer with perforation Chronic unspecified gastrojejunal ulcer with perforation w/o mention of obstruction Chronic unspecified gastrojejunal ulcer with perforation and obstruction Chronic unspecified gastrojejunal ulcer with hemorrhage and perforation Chronic unspecified gastrojejunal ulcer with hemorrhage and perforation w/o obstruction Chronic unspecified gastrojejunal ulcer with hemorrhage, perforation, and obstruction Acute gastritis Acute gastritis without mention of hemorrhage Acute gastritis with hemorrhage Atrophic gastritis Atrophic gastritis without mention of hemorrhage Atrophic gastritis with hemorrhage Gastric mucosal hypertrophy Gastric mucosal hypertrophy without mention of hemorrhage Gastric mucosal hypertrophy with hemorrhage Alcoholic gastritis Alcoholic gastritis without mention of hemorrhage Alcoholic gastritis with hemorrhage Other specified gastritis Other specified gastritis without mention of hemorrhage Other specified gastritis with hemorrhage Unspecified gastritis and gastroduodenitis Unspecified gastritis and gastroduodenitis w/o mention of hemorrhage Unspecified gastritis and gastroduodenitis with hemorrhage Duodenitis Duodenitis without mention of hemorrhage Duodenitis with hemorrhage Angiodysplasia of stomach and duodenum with hemorrhage Dieulafoy lesion of stomach and duodenum

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1567 1568 1569 1570 1571 1572 1573 1574 1575 1576 1577 1578 1579 1580 1581 1582 1583 1584 1585 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605 1606 1607 1608 1609 1610 1611 1612 1613 1614 1615 1616 1617 1618 1619 1620 1621 1622 1623 1624

-

1625 1626 1627 1628 1629 1630 1631 1632 1633 1634 1635 1636 1637 1638 1639 1640 1641 1642 1643 1644 1645 1646 1647 1648 1649 1650 1651 1652 1653 1654 1655 1656 1657 1658 1659 1660 1661 1662 1663 1664 1665 1666 1667 1668 1669 1670 1671 1672 1673 1674 1675 1676 1677 1678 1679 1680 1681 1682

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GIB on Antithrombotic Therapy

Supplementary Table 1. Continued Upper GI bleed Code Code version 578. K22.6 K25.0 K25.1 K25.2 K25.3 K25.4 K25.5 K25.6

9 10 10 10 10 10 10 10 10

K26.0 K26.1 K26.2

10 10 10

K26.3 K26.4 K26.5 K26.6

10 10 10 10

K27.0 K27.1 K27.2

10 10 10

K27.3

10

K27.4

10

K27.5

10

K27.6

10

K28.0 K28.1 K28.2

10 10 10

K28.3

10

K28.4

10

K28.5

10

K28.6

10

K29.00 K29.01 K29.30 K29.31 K29.40 K29.41 K29.50 K29.51 K29.60 K29.61 K29.70 K29.71 K29.80 K29.81 K29.90

10 10 10 10 10 10 10 10 10 10 10 10 10 10 10

Code description

Lower GI bleed Code Code version

Code description

Gastrointestinal hemorrhage Gastroesophageal laceration–hemorrhage syndrome Acute gastric ulcer with hemorrhage Acute gastric ulcer with perforation Acute gastric ulcer with both hemorrhage and perforation Acute gastric ulcer without hemorrhage or perforation Chronic or unspecified gastric ulcer with hemorrhage Chronic or unspecified gastric ulcer with perforation Chronic or unspecified gastric ulcer with both hemorrhage and perforation Acute duodenal ulcer with hemorrhage Acute duodenal ulcer with perforation Acute duodenal ulcer with both hemorrhage and perforation Acute duodenal ulcer without hemorrhage or perforation Chronic or unspecified duodenal ulcer with hemorrhage Chronic or unspecified duodenal ulcer with perforation Chronic or unspecified duodenal ulcer with both hemorrhage and perforation Acute peptic ulcer site unspecified with hemorrhage Acute peptic ulcer site unspecified with perforation Acute peptic ulcer site unspecified with both hemorrhage and perforation Acute peptic ulcer site unspecified w/o hemorrhage or perforation Chronic or unspecified peptic ulcer site unspecified with hemorrhage Chronic or unspecified peptic ulcer site unspecified with perforation Chronic or unspecified peptic ulcer site unspecified with both hemorrhage and perforation Acute gastrojejunal ulcer with hemorrhage Acute gastrojejunal ulcer with perforation Acute gastrojejunal ulcer with both hemorrhage and perforation Acute gastrojejunal ulcer without hemorrhage or perforation Chronic or unspecified gastrojejunal ulcer with hemorrhage Chronic or unspecified gastrojejunal ulcer with perforation Chron or unspecified gastrojejunal ulcer with both hemorrhage and perforation Acute gastritis without bleeding Acute gastritis with bleeding Chronic superficial gastritis without bleeding Chronic superficial gastritis with bleeding Chronic atrophic gastritis without bleeding Chronic atrophic gastritis with bleeding Unspecified chronic gastritis without bleeding Unspecified chronic gastritis with bleeding Other gastritis without bleeding Other gastritis with bleeding Gastritis unspecified without bleeding Gastritis unspecified with bleeding Duodenitis without bleeding Duodenitis with bleeding Gastroduodenitis unspecified without bleeding

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10.e5

1683 1684 1685 1686 1687 1688 1689 1690 1691 1692 1693 1694 1695 1696 1697 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 1724 1725 1726 1727 1728 1729 1730 1731 1732 1733 1734 1735 1736 1737 1738 1739 1740

10.e6

1741 1742 1743 1744 1745 1746 1747 1748 1749 1750 1751 1752 1753 1754 1755 1756 1757 1758 1759 1760 1761 1762 1763 1764 1765 1766 1767 1768 1769 1770 1771 1772 1773 1774 1775 1776 1777 1778 1779 1780 1781 1782 1783 1784 1785 1786 1787 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798

Abraham et al

Clinical Gastroenterology and Hepatology Vol.

-,

No.

-

Supplementary Table 1. Continued Upper GI bleed Code Code version K29.91 K31.811 K31.82

10 10 10

Lower GI bleed Code Code version

Code description

Code description

Gastroduodenitis unspecified with bleeding Angiodysplasia stomach and duodenum with bleeding Dieulafoy lesion hemorrhagic stomach and duodenum

GI, gastrointestinal; ICD, International Classification of Diseases; w/o, without.

Supplementary Table 2. Direct Oral Anticoagulant at Index Prescription Age group, y 18–64 65–74 75 Total

N

%

28,277 20,055 23,676 72,008

44.1 43.9 40.1 42.7

Supplementary Table 3. Apixaban at Index Prescription Age group, y 18–64 65–74 75 Total

FLA 5.6.0 DTD  YJCGH56519_proof  5 July 2019  7:36 pm  ce DVC

N

%

6589 7040 10,283 23,912

10.3 15.4 17.4 14.2

1799 1800 1801 1802 1803 1804 1805 1806 1807 1808 1809 1810 1811 1812 1813 1814 1815 1816 1817 1818 1819 1820 1821 1822 1823 1824 1825 1826 1827 1828 1829 1830 1831 1832 1833 1834 1835 1836 1837 1838 1839 1840 1841 1842 1843 1844 1845 1846 1847 1848 1849 1850 1851 1852 1853 1854 1855 1856

-

1857 1858 1859 1860 1861 1862 1863 1864 1865 1866 1867 1868 1869 1870 1871 1872 1873 1874 1875 1876 1877 1878 1879 1880 1881 1882 1883 1884 1885 1886 1887 1888 1889 1890 1891 1892 1893 1894 1895 1896 1897 1898 1899 1900 1901 1902 1903 1904 1905 1906 1907 1908 1909 1910 1911 1912 1913 1914

2019

GIB on Antithrombotic Therapy

10.e7 Q26

Supplementary Table 4. Estimated GI Bleeding Risk by Time Points Condition Anticoagulants AF AF þ IHD AF þ IHD þ VTE IHD IHD þ VTE VTE VTE þ AF Antiplatelets AF AF þ IHD AF þ IHD þ VTE IHD IHD þ VTE VTE VTE þ AF Anticoagulants and antiplatelets AF AF þ IHD AF þ IHD þ VTE IHD IHD þ VTE VTE VTE þ AF

Estimated 30day GI bleed riska

Estimated 60day GI bleed riska

0.44 0.55 0.63 0.44 0.54 0.42 0.49

(0.37–0.51) (0.48–0.61) (0.47–0.79) (0.33–0.55) (0.43–0.65) (0.35–0.48) (0.28–0.69)

0.77 0.95 1.1 0.77 0.94 0.73 0.85

(0.68–0.86) (0.87–1.04) (0.89–1.31) (0.63–0.92) (0.79–1.09) (0.64–0.82) (0.58–1.12)

1.06 1.32 1.52 1.07 1.3 1.01 1.18

(0.96–1.17) (1.22–1.42) (1.28–1.76) (0.9–1.24) (1.13–1.48) (0.9–1.11) (0.86–1.49)

1.34 1.66 1.91 1.35 1.64 1.27 1.48

(1.22–1.46) (1.55–1.77) (1.64–2.18) (1.16–1.53) (1.45–1.84) (1.15–1.38) (1.13–1.83)

1.85 2.29 2.63 1.86 2.26 1.75 2.04

(1.71–1.99) (2.16–2.42) (2.32–2.95) (1.64–2.08) (2.04–2.49) (1.62–1.89) (1.63–2.46)

0.56 0.57 0.72 0.46 0.66 0.49

(0.04–1.08) (0.46–0.69) (0.28–1.17) (0.43–0.5) (0.42–0.89) (-0.19 to 1.18) w

0.98 1 1.26 0.81 1.14 0.86

(0.29–1.66) (0.84–1.15) (0.68–1.84) (0.76–0.86) (0.83–1.46) (-0.05 to 1.76) w

1.35 1.38 1.74 1.12 1.58 1.19

(0.55–2.15) (1.2–1.55) (1.06–2.43) (1.06–1.18) (1.22–1.95) (0.12–2.25) w

1.7 1.73 2.19 1.41 1.99 1.49

(0.8–2.6) (1.53–1.93) (1.43–2.95) (1.34–1.48) (1.58–2.4) (0.3–2.68) w

2.34 2.39 3.02 1.95 2.74 2.06

(1.29–3.4) (2.16–2.62) (2.13–3.91) (1.87–2.03) (2.26–3.22) (0.67–3.45) w

1.04 1.35 1.46 1

w (0.63–1.44) (0.29–2.41) (0.54–2.38) (0.19–1.82) w w

1.8 2.34 2.53 1.74

w (1.26–2.34) (0.95–3.73) (1.33–3.73) (0.67–2.81) w w

Estimated 90day GI bleed riska

2.48 3.22 3.48 2.41

w (1.85–3.11) (1.6–4.85) (2.08–4.88) (1.15–3.66) w w

Estimated 120day GI bleed riska

3.11 4.04 4.36 3.02

w (2.41–3.82) (2.23–5.85) (2.8–5.92) (1.62–4.42) w w

AF, atrial fibrillation; GI, gastrointestinal; IHD, ischemic heart disease; VTE, venous thromboembolism. a Estimated GI bleed incidence rate per patient (%) at each time point, by Weibull model, adjusted for all covariates in the model.

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Estimated 180day GI bleed riska

4.28 5.53 5.97 4.15

w (3.46–5.1) (3.43–7.64) (4.16–7.78) (2.52–5.78) w w

1915 1916 1917 1918 1919 1920 1921 1922 1923 1924 1925 1926 1927 1928 1929 1930 1931 1932 1933 1934 1935 1936 1937 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 1948 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972

1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 10.e8

Supplementary Table 5. OTC ASA Sensitivity Analysis Total GIB

AF þ IHD AF þ IHD þ VTE IHD IHD þ VTE VTE VTE þ AF Antiplatelets AF

20% Aspirin estimated 1-year GI bleed riska

40% Aspirin estimated 1-year GI bleed riska

60% Aspirin estimated 1-year GI bleed riska

80% Aspirin estimated 1-year GI bleed riska

20% Aspirin estimated 1-year GI bleed riska

40% Aspirin estimated 1-year GI bleed riska

60% Aspirin estimated 1-year GI bleed riska

80% Aspirin estimated 1-year GI bleed riska

20% Aspirin estimated 1-year GI bleed riska

40% Aspirin estimated 1-year GI bleed riska

60% Aspirin estimated 1-year GI bleed riska

80% Aspirin estimated 1-year GI bleed riska

3.22 (3.04–3.41) 3.98 (3.8–4.15) 4.56 (4.15–4.97) 3.27 (2.98–3.56) 3.94 (3.64–4.24) 3.08 (2.9–3.26) 3.53 (2.99–4.07)

3.22 (3.04–3.41) 3.98 (3.8–4.15) 4.56 (4.15–4.97) 3.27 (2.98–3.56) 3.94 (3.64–4.24) 3.08 (2.9–3.26) 3.53 (2.99–4.07)

3.22 (3.04–3.41) 3.98 (3.8–4.15) 4.56 (4.15–4.97) 3.27 (2.98–3.56) 3.94 (3.64–4.24) 3.08 (2.9–3.26) 3.53 (2.99–4.07)

3.22 (3.04–3.41) 3.98 (3.8–4.15) 4.56 (4.15–4.97) 3.27 (2.98–3.56) 3.94 (3.64–4.24) 3.08 (2.9–3.26) 3.53 (2.99–4.07)

1.09 (0.98–1.19) 1.35 (1.24–1.45) 1.54 (1.3–1.79) 1.12 (0.95–1.3) 1.27 (1.1–1.45) 1.19 (1.07–1.3) 1.2 (0.88–1.52)

1.09 (0.98–1.19) 1.35 (1.25–1.45) 1.54 (1.3–1.79) 1.12 (0.95–1.3) 1.27 (1.1–1.45) 1.19 (1.07–1.3) 1.2 (0.88–1.52)

1.09 (0.98–1.19) 1.35 (1.25–1.45) 1.54 (1.3–1.79) 1.12 (0.95–1.3) 1.27 (1.1–1.45) 1.19 (1.07–1.3) 1.2 (0.88–1.52)

1.09 (0.98–1.19) 1.35 (1.25–1.45) 1.54 (1.3–1.79) 1.12 (0.95–1.3) 1.27 (1.1–1.45) 1.19 (1.07–1.3) 1.2 (0.88–1.52)

2.17 (2.01–2.32) 2.68 (2.53–2.82) 3.09 (2.74–3.43) 2.19 (1.95–2.43) 2.72 (2.47–2.97) 1.94 (1.79–2.08) 2.38 (1.93–2.83)

2.17 (2.01–2.32) 2.68 (2.53–2.82) 3.09 (2.74–3.43) 2.19 (1.95–2.43) 2.72 (2.47–2.98) 1.94 (1.79–2.08) 2.38 (1.93–2.83)

2.17 (2.01–2.32) 2.68 (2.53–2.82) 3.09 (2.74–3.43) 2.19 (1.95–2.43) 2.72 (2.47–2.98) 1.94 (1.79–2.08) 2.38 (1.93–2.83)

2.17 (2.01–2.32) 2.68 (2.53–2.82) 3.09 (2.74–3.43) 2.19 (1.95–2.43) 2.72 (2.47–2.98) 1.94 (1.79–2.08) 2.38 (1.93–2.83)

4.11 (2.73–5.49) 4.16 (3.85–4.46) 5.23 (4.07–6.39) 3.41 (3.31–3.51) 4.73 (4.11–5.35) 3.61 (1.78–5.44) 2.78 (-2.31 to 7.87)

4.11 (2.73–5.49) 4.16 (3.85–4.46) 5.23 (4.07–6.39) 3.41 (3.31–3.52) 4.73 (4.11–5.35) 3.61 (1.78–5.43) 2.79 (-2.31 to 7.89)

4.11 (2.73–5.49) 4.16 (3.85–4.46) 5.23 (4.07–6.39) 3.41 (3.31–3.52) 4.73 (4.11–5.35) 3.61 (1.78–5.44) 2.79 (-2.31 to 7.89)

1.31 (0.51–2.1) 1.12 (0.96–1.28) 1.61 (0.95–2.27) 0.81 (0.76–0.87) 0.97 (0.68–1.26) 1.35 (0.22–2.49) w

1.31 (0.52–2.1) 1.12 (0.96–1.28) 1.61 (0.95–2.27) 0.81 (0.76–0.87) 0.97 (0.68–1.25) 1.35 (0.22–2.49) w

1.31 (0.51–2.1) 1.12 (0.96–1.28) 1.61 (0.96–2.27) 0.81 (0.76–0.87) 0.97 (0.68–1.25) 1.36 (0.22–2.49) w

1.31 (0.51–2.1) 1.12 (0.96–1.28) 1.61 (0.95–2.27) 0.81 (0.76–0.87) 0.97 (0.68–1.26) 1.35 (0.22–2.49) w

2.85 (1.69–4.01) 3.09 (2.83–3.36) 3.71 (2.72–4.7) 2.62 (2.53–2.71) 3.79 (3.23–4.36) 2.31 (0.83–3.78) 2.86 (-2.31 to 8.02)

2.85 (1.69–4.01) 3.09 (2.83–3.36) 3.71 (2.72–4.7) 2.62 (2.53–2.71) 3.79 (3.23–4.35) 2.31 (0.83–3.78) 2.85 (-2.31 to 8.01)

2.85 (1.69–4.01) 3.09 (2.83–3.36) 3.71 (2.72–4.7) 2.62 (2.53–2.71) 3.79 (3.23–4.36) 2.31 (0.83–3.78) 2.85 (-2.31 to 8.02)

2.85 (1.69–4.01) 3.09 (2.83–3.36) 3.71 (2.72–4.7) 2.62 (2.53–2.71) 3.79 (3.23–4.35) 2.31 (0.83–3.79) 2.85 (-2.31 to 8.01)

4.1 (2.73–5.48) AF þ IHD 4.16 (3.85–4.46) AF þ IHD þ VTE 5.23 (4.07–6.39) IHD 3.41 (3.31–3.52) IHD þ VTE 4.73 (4.11–5.35) VTE 3.6 (1.77–5.43) VTE þ AF 2.8 (-2.31 to 7.9)

Clinical Gastroenterology and Hepatology Vol.

FLA 5.6.0 DTD  YJCGH56519_proof  5 July 2019  7:36 pm  ce DVC

Anticoagulants AF

Upper GIB Abraham et al

Condition

Lower GIB

-,

No. -

2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 2055 2056 2057 2058 2059 2060 2061 2062 2063 2064 2065 2066 2067 2068 2069 2070 2071 2072 2073 2074 2075 2076 2077 2078 2079 2080 2081 2082 2083 2084 2085 2086 2087 2088

2089 2090 2091 2092 2093 2094 2095 2096 2097 2098 2099 2100 2101 2102 2103 2104 2105 2106 2107 2108 2109 2110 2111 2112 2113 2114 2115 2116 2117 2118 2119 2120 2121 2122 2123 2124 2125 2126 2127 2128 2129 2130 2131 2132 2133 2134 2135 2136 2137 2138 2139 2140 2141 2142 2143 2144 2145 2146 -

w 7.36 (6.3–8.41) 9.56 (6.85–12.27) 10.2 (7.89–12.51) 6.92 (4.84–8.99) w w

w 7.35 (6.3–8.41) 9.58 (6.87–12.29) 10.2 (7.89–12.52) 6.92 (4.85–9) w w

w 7.36 (6.3–8.41) 9.58 (6.87–12.29) 10.2 (7.89–12.52) 6.92 (4.84–8.99) w w

w 2.63 (1.98–3.28) 2.35 (0.95–3.75) 2.77 (1.51–4.03) 3.04 (1.63–4.44) w w

w 2.62 (1.97–3.27) 2.34 (0.94–3.74) 2.76 (1.5–4.02) 3.04 (1.64–4.45) w w

w 2.62 (1.97–3.27) 2.36 (0.95–3.77) 2.76 (1.51–4.02) 3.04 (1.64–4.45) w w

w 2.62 (1.97–3.27) 2.36 (0.95–3.76) 2.77 (1.51–4.02) 3.04 (1.64–4.45) w w

w 4.95 (4.06– 5.83) 7.46 (5.03–9.89) 7.75 (5.7–9.8) 4.14 (2.51–5.77) w w

w 4.94 (4.06–5.83) 7.47 (5.04–9.9) 7.75 (5.7–9.8) 4.15 (2.51–5.78) w w

w 4.94 (4.06–5.83) 7.46 (5.03–9.9) 7.75 (5.7–9.8) 4.15 (2.52–5.78) w w

w 4.94 (4.06–5.82) 7.47 (5.04–9.91) 7.74 (5.69–9.79) 4.14 (2.51–5.78) w w

2019

AF, atrial fibrillation; GIB, gastrointestinal bleeding; IHD, ischemic heart disease; VTE, venous thromboembolism. a Estimated GI bleed incidence rate per patient (%) by Weibull model, adjusted for all covariates in the model.

GIB on Antithrombotic Therapy

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Anticoagulants and antiplatelets AF w AF þ IHD 7.36 (6.3–8.41) AF þ IHD þ VTE 9.56 (6.85–12.27) IHD 10.22 (7.9–12.53) IHD þ VTE 6.91 (4.84–8.98) VTE w VTE þ AF w

10.e9

2147 2148 2149 2150 2151 2152 2153 2154 2155 2156 2157 2158 2159 2160 2161 2162 2163 2164 2165 2166 2167 2168 2169 2170 2171 2172 2173 2174 2175 2176 2177 2178 2179 2180 2181 2182 2183 2184 2185 2186 2187 2188 2189 2190 2191 2192 2193 2194 2195 2196 2197 2198 2199 2200 2201 2202 2203 2204

2205 2206 2207 2208 2209 2210 2211 2212 2213 2214 2215 2216 2217 2218 2219 2220 2221 2222 2223 2224 2225 2226 2227 2228 2229 2230 2231 2232 2233 2234 2235 2236 2237 2238 2239 2240 2241 2242 2243 2244 2245 2246 2247 2248 2249 2250 2251 2252 2253 2254 2255 2256 2257 2258 2259 2260 2261 2262 10.e10

Supplementary Table 6. OTC PPI Sensitivity Analysis Total GIB

AF þ IHD AF þ IHD þ VTE IHD IHD þ VTE VTE VTE þ AF Antiplatelets AF AF þ IHD AF þ IHD þ VTE IHD IHD þ VTE VTE VTE þ AF

20% PPI estimated 1-year GI bleed riska

40% PPI estimated 1-year GI bleed riska

60% PPI estimated 1-year GI bleed riska

80% PPI estimated 1-year GI bleed riska

20% PPI estimated 1-year GI bleed riska

40% PPI estimated 1-year GI bleed riska

60% PPI estimated 1-year GI bleed riska

80% PPI estimated 1-year GI bleed riska

20% PPI estimated 1-year GI bleed riska

40% PPI estimated 1-year GI bleed riska

60% PPI estimated 1-year GI bleed riska

80% PPI estimated 1-year GI bleed riska

3.17 (2.99–3.35) 3.97 (3.8–4.15) 4.64 (4.22–5.05) 3.26 (2.97–3.55) 3.98 (3.68–4.28) 3.07 (2.9–3.25) 3.56 (3.01–4.1)

3.17 (2.99–3.35) 3.98 (3.8–4.15) 4.64 (4.22–5.05) 3.26 (2.97–3.55) 3.99 (3.68–4.29) 3.08 (2.9–3.25) 3.56 (3.01–4.1)

3.17 (2.99–3.35) 3.97 (3.8–4.15) 4.64 (4.22–5.05) 3.26 (2.97–3.55) 3.99 (3.69–4.29) 3.07 (2.9–3.25) 3.56 (3.01–4.1)

3.17 (2.99–3.35) 3.97 (3.8–4.15) 4.64 (4.22–5.05) 3.26 (2.97–3.55) 3.99 (3.69–4.29) 3.07 (2.9–3.25) 3.56 (3.01–4.1)

1.08 (0.97–1.19) 1.35 (1.24–1.45) 1.55 (1.3–1.79) 1.12 (0.95–1.3) 1.28 (1.1–1.45) 1.19 (1.07–1.3) 1.2 (0.88–1.52)

1.08 (0.97–1.19) 1.35 (1.24–1.45) 1.55 (1.3–1.8) 1.12 (0.95–1.3) 1.28 (1.1–1.45) 1.19 (1.07–1.3) 1.2 (0.88–1.52)

1.08 (0.97–1.19) 1.35 (1.24–1.45) 1.55 (1.3–1.79) 1.12 (0.95–1.3) 1.28 (1.1–1.45) 1.19 (1.07–1.3) 1.2 (0.88–1.52)

1.08 (0.97–1.19) 1.35 (1.24–1.45) 1.55 (1.3–1.79) 1.12 (0.95–1.3) 1.28 (1.1–1.45) 1.19 (1.07–1.3) 1.2 (0.88–1.52)

2.12 (1.97–2.27) 2.67 (2.53–2.82) 3.16 (2.81–3.5) 2.18 (1.94–2.42) 2.76 (2.51–3.02) 1.93 (1.79–2.08) 2.4 (1.95–2.85)

2.17 (2.01–2.32) 2.68 (2.53–2.82) 3.09 (2.74–3.43) 2.19 (1.95–2.43) 2.72 (2.47–2.98) 1.94 (1.79–2.08) 2.38 (1.93–2.83)

2.17 (2.01–2.32) 2.68 (2.53–2.82) 3.09 (2.74–3.43) 2.19 (1.95–2.43) 2.72 (2.47–2.98) 1.94 (1.79–2.08) 2.38 (1.93–2.83)

2.17 (2.01–2.32) 2.68 (2.53–2.82) 3.09 (2.74–3.43) 2.19 (1.95–2.43) 2.72 (2.47–2.98) 1.94 (1.79–2.08) 2.38 (1.93–2.83)

4.07 (2.7–5.45) 4.2 (3.89–4.5) 5.34 (4.17–6.51) 3.41 (3.3–3.51) 4.75 (4.12–5.37) 3.6 (1.77–5.43) 2.77 (-2.32 to 7.86)

4.08 (2.7–5.45) 4.19 (3.89–4.5) 5.34 (4.17–6.51) 3.41 (3.3–3.51) 4.74 (4.12–5.37) 3.6 (1.77–5.43) 2.76 (-2.32 to 7.83)

4.08 (2.7–5.45) 4.19 (3.89–4.5) 5.34 (4.17–6.51) 3.41 (3.3–3.51) 4.75 (4.12–5.37) 3.6 (1.77–5.43) 2.77 (-2.32 to 7.85)

4.08 (2.7–5.45) 4.19 (3.89–4.5) 5.34 (4.17–6.51) 3.41 (3.3–3.51) 4.74 (4.12–5.37) 3.6 (1.77–5.43) 2.76 (-2.32 to 7.84)

1.3 (0.51–2.09) 1.12 (0.96–1.28) 1.62 (0.96–2.28) 0.81 (0.76–0.87) 0.97 (0.68–1.26) 1.35 (0.21–2.49) w

1.3 (0.51–2.1) 1.12 (0.96–1.28) 1.62 (0.96–2.28) 0.81 (0.76–0.87) 0.97 (0.68–1.26) 1.35 (0.22–2.49) w

1.3 (0.51–2.09) 1.12 (0.96–1.28) 1.62 (0.96–2.28) 0.81 (0.76–0.87) 0.97 (0.68–1.26) 1.35 (0.22–2.49) w

1.3 (0.51–2.1) 1.12 (0.96–1.28) 1.62 (0.96–2.28) 0.81 (0.76–0.87) 0.97 (0.68–1.26) 1.35 (0.22–2.49) w

2.82 (1.67–3.98) 3.13 (2.86–3.39) 3.81 (2.81–4.81) 2.62 (2.53–2.71) 3.81 (3.25–4.37) 2.3 (0.83–3.78) 2.83 (-2.31 to 7.97)

2.85 (1.69–4.01) 3.09 (2.83–3.36) 3.71 (2.72–4.7) 2.62 (2.53–2.71) 3.79 (3.23–4.35) 2.31 (0.83–3.78) 2.85 (-2.31 to 8.01)

2.85 (1.69–4.01) 3.09 (2.83–3.36) 3.71 (2.72–4.7) 2.62 (2.53–2.71) 3.79 (3.23–4.36) 2.31 (0.83–3.78) 2.85 (-2.31 to 8.02)

2.85 (1.69–4.01) 3.090 (2.83–3.36) 3.71 (2.72–4.7) 2.62 (2.53–2.71) 3.79 (3.23–4.35) 2.31 (0.83–3.79) 2.85 (-2.31 to 8.01)

Clinical Gastroenterology and Hepatology Vol.

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Anticoagulants AF

Upper GIB

Abraham et al

Condition

Lower GIB

-,

No. -

2263 2264 2265 2266 2267 2268 2269 2270 2271 2272 2273 2274 2275 2276 2277 2278 2279 2280 2281 2282 2283 2284 2285 2286 2287 2288 2289 2290 2291 2292 2293 2294 2295 2296 2297 2298 2299 2300 2301 2302 2303 2304 2305 2306 2307 2308 2309 2310 2311 2312 2313 2314 2315 2316 2317 2318 2319 2320

2321 2322 2323 2324 2325 2326 2327 2328 2329 2330 2331 2332 2333 2334 2335 2336 2337 2338 2339 2340 2341 2342 2343 2344 2345 2346 2347 2348 2349 2350 2351 2352 2353 2354 2355 2356 2357 2358 2359 2360 2361 2362 2363 2364 2365 2366 2367 2368 2369 2370 2371 2372 2373 2374 2375 2376 2377 2378 -

w 7.55 (6.48–8.62) 9.8 (7.06–12.54) 10.32 (8–12.65) 7.05 (4.96–9.14) w w

w 7.55 (6.48–8.61) 9.82 (7.08–12.56) 10.32 (8–12.65) 7.05 (4.96–9.14) w w

w 7.55 (6.48–8.62) 9.82 (7.08–12.56) 10.33 (8–12.65) 7.05 (4.96–9.14) w w

w 2.65 (1.99–3.3) 2.37 (0.96–3.78) 2.78 (1.52–4.04) 3.06 (1.65–4.47) w w

w 2.65 (1.99–3.3) 2.36 (0.95–3.77) 2.77 (1.51–4.03) 3.07 (1.66–4.48) w w

w 2.64 (1.99–3.3) 2.38 (0.97–3.79) 2.77 (1.51–4.03) 3.06 (1.65–4.48) w w

w 2.65 (1.99–3.3) 2.38 (0.97–3.79) 2.77 (1.51–4.03) 3.07 (1.65–4.48) w w

w 5.11 (4.21–6.01) 7.69 (5.23–10.16) 7.88 (5.81–9.94) 4.24 (2.59–5.89) w w

w 4.94 (4.06–5.83) 7.47 (5.04–9.9) 7.75 (5.7–9.8) 4.15 (2.51–5.78) w w

w 4.94 (4.06–5.83) 7.46 (5.03–9.9) 7.75 (5.7–9.8) 4.15 (2.52–5.78) w w

w 4.94 (4.06–5.82) 7.47 (5.04–9.91) 7.74 (5.69–9.79) 4.14 (2.51–5.78) w w

2019

AF, atrial fibrillation; GIB, gastrointestinal bleeding; IHD, ischemic heart disease; OTC, over-the-counter; PPI, proton pump inhibitor; VTE, venous thromboembolism. a Estimated GI bleed incidence rate per patient (%) by Weibull model, adjusted for all covariates in the model.

GIB on Antithrombotic Therapy

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Anticoagulants and antiplatelets AF w AF þ IHD 7.55 (6.48–8.62) AF þ IHD þ VTE 9.8 (7.06–12.54) IHD 10.34 (8.01–12.66) IHD þ VTE 7.04 (4.95–9.13) VTE w VTE þ AF w

10.e11

2379 2380 2381 2382 2383 2384 2385 2386 2387 2388 2389 2390 2391 2392 2393 2394 2395 2396 2397 2398 2399 2400 2401 2402 2403 2404 2405 2406 2407 2408 2409 2410 2411 2412 2413 2414 2415 2416 2417 2418 2419 2420 2421 2422 2423 2424 2425 2426 2427 2428 2429 2430 2431 2432 2433 2434 2435 2436

10.e12

2437 2438 2439 2440 2441 2442 2443 2444 2445 2446 2447 2448 2449 2450 2451 2452 2453 2454 2455 2456 2457 2458Q28 2459 2460 2461 2462 2463 2464 2465 2466 2467 2468 2469 2470 2471 2472 2473 2474 2475 2476 2477 2478 2479 2480 2481 2482 2483 2484 2485 2486 2487 2488 2489 2490 2491 2492 2493 2494

Abraham et al

Clinical Gastroenterology and Hepatology Vol.

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No.

-

Q27

Supplementary Table 7. Medications Included as Either Exposures or Covariates by Category

Antihypertensive drugs Acebutolol HCL

Anti-arrhythmics Anticoagulants Antiplatelets Adenosine

Aliskiren hemifumarate Amiodarone HCL

Aliskiren/ Bretylium tosylate hydrochlorothiazide Amlodipine bes/ Disopyramide olmesartan med phosphate Amlodipine besylate Dofetilide Amlodipine besylate/ benazepril Amlodipine besylate/ valsartan Amlodipine/valsartan Amlodipine/valsartan/ hcthiazid Atenolol

Dronedarone HCL Encainide HCL Flecainide acetate Ibutilide fumarate Lidocaine HCL

Apixaban

Cilostazol

Dabigatran etexilate mesylate Edoxaban tosylate Rivaroxaban

Clopidogrel bisulfate

Aspirin and/or NSAID Aspirin

Prasugrel HCL Warfarin sodium Ticagrelor Ticlopidine HCL Vorapaxar sulfate

Aspirin/acetaminophen/ caffeine Aspirin/acetaminophen/ cal carb Aspirin/acetaminophen/ phenacet Aspirin/apap/al hydrox/ caffeine Aspirin/apap/caffeine/ potassium Aspirin/butalbital

Esomeprazole mag trihydrate Esomeprazole mag/glycerin Esomeprazole magnesium Esomeprazole sodium esomeprazole Strontium Famotidine

Aspirin/caffeine/ dihydrocodeine

Famotidine/Ca carb/mag hydrox Famotidine/ calcium carb/ Mag Lansoprazole

Aspirin/caffeine

Azilsartan medoxomil

Moricizine HCL

Benazepril HCL

Procainamide HCL

Benazepril HCL/hctz

Propafenone HCL

Aspirin/caffeine/ butalbital Aspirin/caffeine/ dihydrocodeine Aspirin/calcium carb/ mag/prava Aspirin/calcium carb/ magnesium Aspirin/calcium carbonate

Betaxolol HCL

Quinidine sulfate

Bisoprolol/ Tocainide HCL hydrochlorothiazide Bisoprolol fumarate Bisoprolol fumarate/ hctz Bumetanide

Candesartan cilexetil Candesartan/ hydrochlorothiazide Captopril Captopril/ hydrochlorothiazide Carvedilol Carvedilol phosphate Clonidine

Cimetidine

Aspirin (calcium and Cimetidine HCL magnesium) /pravastatin Dipyridamole Aspirin/acetaminophen Dexlansoprazole

Atenolol/chlorthalidone Mexiletine HCL

Benazepril/ Quinidine gluconate hydrochlorothiazide Bepridil HCL Quinidine polygalacturonate

Gastroprotective agents, proton pump inhibitor, H2 blocker

Aspirin/calcium carbonate/mag Aspirin/chlor-mal Aspirin/codeine phosphate Aspirin/ diphenhydramine citrate Aspirin/ diphenhydramine HCL Aspirin/dipyridamole Aspirin/mag carb/al aminoacet Aspirin/mag carb/ aluminum Aspirin/mag hydrox/al hydrox Aspirin/meprobamate Aspirin/omeprazole Aspirin/salamide/apap/ caffeine

Nizatidine Omeprazole Omeprazole magnesium Omeprazole/ sodium bicarbonate Pantoprazole sodium Rabeprazole sodium Ranitidine HCL

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Selective serotonin reuptake inhibitors Citalopram hydrobromide Escitalopram oxalate Fluoxetine HCL Fluvoxamine maleate Paroxetine HCL Paroxetine mesylate Sertraline HCL

2495 2496 2497 2498 2499 2500 2501 2502 2503 2504 2505 2506 2507 2508 2509 2510 2511 2512 2513 2514 2515 2516 2517 2518 2519 2520 2521 2522 2523 2524 2525 2526 2527 2528 2529 2530 2531 2532 2533 2534 2535 2536 2537 2538 2539 2540 2541 2542 2543 2544 2545 2546 2547 2548 2549 2550 2551 2552

-

2553 2554 2555 2556 2557 2558 2559 2560 2561 2562 2563 2564 2565 2566 2567 2568 2569 2570 2571 2572 2573 2574 2575 2576 2577 2578 2579 2580 2581 2582 2583 2584 2585 2586 2587 2588 2589 2590 2591 2592 2593 2594 2595 2596 2597 2598 2599 2600 2601 2602 2603 2604 2605 2606 2607 2608 2609 2610

2019

GIB on Antithrombotic Therapy

10.e13

Supplementary Table 7. Continued

Antihypertensive drugs Clonidine HCL Clonidine HCL/ chlorthalidone Diazoxide Diltiazem HCL Diltiazem malate Doxazosin mesylate Enalapril mal/diltiazem mal Enalapril maleate Enalapril maleate/ felodipine Enalapril maleate/hctz Enalapril/ hydrochlorothiazide Enalaprilat dihydrate Eprosartan mesylate Eprosartan/ hydrochlorothiazide Esmolol HCL Ethacrynate sodium Ethacrynic acid Felodipine Fenoldopam mesylate Fosinopril sodium Fosinopril sodium/hctz Fosinopril/ hydrochlorothiazide Furosemide Guanabenz acetate Guanadrel sulfate Guanethid/ hydrochlorothiazide Guanethidine sulfate Guanfacine HCL Hydralazine HCL Hydralazine/ hydrochlorothiazide Hydralazine/reserpin/ hcthiazid Iloprost tromethamine Irbesartan

Irbesartan/ hydrochlorothiazide Isradipine

Anti-arrhythmics Anticoagulants Antiplatelets

Aspirin and/or NSAID

Gastroprotective agents, proton pump inhibitor, H2 blocker

Aspirin/salicylamide/ caffeine Aspirin/sodium bicarb/ citric acid Bromfenac sodium Butalbital/aspirin/ caffeine Carisoprodol/aspirin Carisoprodol/aspirin/ codeine Celecoxib Chlorphen/phenyleph/ Dm/aspirin Chlorphen/pseudoeph/ ibuprofen Chlorphenir/phenyleph/ aspirin Chlorpheniramine-Ppaaspirin Codeine phos/aspirin Codeine phos/ carisoprodol/Asa Dextromethorphan Hb/ Ppa/aspirin/Cp Diclofenac epolamine Diclofenac potassium Diclofenac sodium Diclofenac sodium/ misoprostol Diclofenac submicronized Diclofenac/ benzalkonium chlor Dihydrocodeine/aspirin/ caffeine Etodolac Fenoprofen calcium Fenoprofen calcium, dihydrate Flurbiprofen Flurbiprofen sodium Hydrocodone bit/aspirin Hydrocodone/ibuprofen Ibuprofen Ibuprofen/caffeine/B1/ B2/B6/B12 Ibuprofen/ diphenhydramine Ibuprofen/ diphenhydramine cit Ibuprofen/ diphenhydramine HCL Ibuprofen/famotidine Ibuprofen/hydrocodone bit

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Selective serotonin reuptake inhibitors

2611 2612 2613 2614 2615 2616 2617 2618 2619 2620 2621 2622 2623 2624 2625 2626 2627 2628 2629 2630 2631 2632 2633 2634 2635 2636 2637 2638 2639 2640 2641 2642 2643 2644 2645 2646 2647 2648 2649 2650 2651 2652 2653 2654 2655 2656 2657 2658 2659 2660 2661 2662 2663 2664 2665 2666 2667 2668

10.e14

2669 2670 2671 2672 2673 2674 2675 2676 2677 2678 2679 2680 2681 2682 2683 2684 2685 2686 2687 2688 2689 2690 2691 2692 2693 2694 2695 2696 2697 2698 2699 2700 2701 2702 2703 2704 2705 2706 2707 2708 2709 2710 2711 2712 2713 2714 2715 2716 2717 2718 2719 2720 2721 2722 2723 2724 2725 2726

Abraham et al

Clinical Gastroenterology and Hepatology Vol.

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No.

Supplementary Table 7. Continued

Antihypertensive drugs Labetalol HCL Lisinopril

Lisinopril/ hydrochlorothiazide Losartan potassium

Losartan/ hydrochlorothiazide Mecamylamine HCL Methyldopa Methyldopa/ chlorothiazide Methyldopa/ hydrochlorothiazide Metoprolol su/ hydrochlorothiazide Metoprolol succinate Metoprolol succinate/ hctz Metoprolol tartrate Moexipril HCL Moexipril HCL/hctz Nadolol Nadolol/ bendroflumethiazide Nebivolol HCL Nebivolol HCL/ valsartan Nicardipine HCL Nifedipine

Nisoldipine Nitroprusside sodium

Olmesartan medoxomil Olmesartan/amlodipin/ hcthiazid Olmesartan/ hydrochlorothiazide Penbutolol sulfate Perindopril arg/ amlodipine bes Perindopril erbumine Pindolol Prazosin HCL Propranolol HCL Quinapril HCL Quinapril HCL/hctz/ mag carb

Anti-arrhythmics Anticoagulants Antiplatelets

Aspirin and/or NSAID

Gastroprotective agents, proton pump inhibitor, H2 blocker

Ibuprofen/oxycodone HCL Ibuprofen/ pseudoephedrine HCL/Cp Ibuprofen/ phenylephrine HCL Ibuprofen/ pseudoephedrine HCL Indomethacin Indomethacin sodium Indomethacin sodium trihydrate Indomethacin, submicronized Ketoprofen Ketoprofen, micronized Ketorolac tromethamine Lansoprazole/naproxen Meclofenamate sodium Mefenamic acid Meloxicam Meloxicam, submicronized Methocarbamol/aspirin Nabumetone Nabumetone, micronized Naproxen Naproxen Nadiphenhydramine HCL Naproxen sodium Naproxen sodium/ pseudoephedrine HCL Naproxen sodium/ pseudoephedrine Naproxen/ esomeprazole mag Opium/aspirin/caffeine Opium/aspirin/caffeine/ camphor Orphenadrine/aspirin/ caffeine Oxaprozin Oxycodone HCL/aspirin Oxycodone HCL/ oxycodone Ter/Asa Oxycodone/aspirin Pentazocine HCL/ aspirin Phenylephrine HCL/ aspirin

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Selective serotonin reuptake inhibitors

-

2727 2728 2729 2730 2731 2732 2733 2734 2735 2736 2737 2738 2739 2740 2741 2742 2743 2744 2745 2746 2747 2748 2749 2750 2751 2752 2753 2754 2755 2756 2757 2758 2759 2760 2761 2762 2763 2764 2765 2766 2767 2768 2769 2770 2771 2772 2773 2774 2775 2776 2777 2778 2779 2780 2781 2782 2783 2784

-

2785 2786 2787 2788 2789 2790 2791 2792 2793 2794 2795 2796 2797 2798 2799 2800 2801 2802 2803 2804 2805 2806 2807 2808 2809 2810 2811 2812 2813 2814 2815 2816 2817 2818 2819 2820 2821 2822 2823 2824 2825 2826 2827 2828 2829 2830 2831 2832 2833 2834 2835 2836 2837 2838 2839 2840 2841 2842

2019

GIB on Antithrombotic Therapy

10.e15

Supplementary Table 7. Continued

Antihypertensive drugs

Anti-arrhythmics Anticoagulants Antiplatelets

Quinapril HCL/mag carb Quinapril/ hydrochlorothiazide Ramipril

Aspirin and/or NSAID

Gastroprotective agents, proton pump inhibitor, H2 blocker

Selective serotonin reuptake inhibitors

Phenylephrine/ ketorolac Piroxicam Pseudoephedrine HCL/ aspirin Sulindac Sumatriptan succ/ naproxen sodium Tolmetin sodium Valdecoxib

Sotalol HCL Telmisartan Telmisartan/amlodipine Telmisartan/ hydrochlorothiazide Terazosin HCL Timolol maleate Torsemide Trandolapril Trandolapril/verapamil HCL Treprostinil diolamine Valsartan Valsartan/ hydrochlorothiazide Verapamil HCL

HCL, hydrochloric acid; NSAID, nonsteroidal anti-inflammatory drug.

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Q29

2843 2844 2845 2846 2847 2848 2849 2850 2851 2852 2853 2854 2855 2856 2857 2858 2859 2860 2861 2862 2863 2864 2865 2866 2867 2868 2869 2870 2871 2872 2873 2874 2875 2876 2877 2878 2879 2880 2881 2882 2883 2884 2885 2886 2887 2888 2889 2890 2891 2892 2893 2894 2895 2896 2897 2898 2899 2900

2901 2902 2903 2904 2905 2906 2907 2908 2909 2910 2911 2912 2913 2914 2915 2916 2917 2918 2919 2920 2921 2922 2923 2924 2925 2926 2927 2928 2929 2930 2931 2932 2933 2934 2935 2936 2937 2938 2939 2940 2941 2942 2943 2944 2945 2946 2947 2948 2949 2950 2951 2952 2953 2954 2955 2956 2957 2958 CPT description

ICD-9 diagnosis

ICD-9 diagnosis description

ICD-10 diagnosis description

ICD-9 procedure

ICD-9 procedure description

ICD-10 procedure 02100X

Bypass coronary artery, 1 artery

02110X

Bypass coronary artery, 2 arteries Bypass coronary artery, 3 arteries Bypass coronary artery, 4 or more arteries Dilation CA 1 artery bifurcation Rx-Eluting Il device Pc Q30 Dilation CA 1 artery Rxeluting Il device percutaneous Dilation CA 1 site bifurcation intraluminal device percutaneous Dilation CA 1 site intraluminal device percutaneous Dilation CA 1 site bifurcation percutaneous Dilatation CA 1 site percutaneous Dilation CA 2 arteries bifurcation Rx-eluting Il device percutaneous Dilation CA 2 arteries Rxeluting Il device percutaneous

CABG vein single

410X

Acute MI

E105

Type 1 DM with circulatory complications

0040

33511

CABG vein 2

411X

E115

Type 2 DM with circulatory complications

0041

33512

CABG vein 3

412X

Other acute and subacute forms of ischemic heart disease Old MI

Procedure on single vessel, number unspecified Procedure on 2 vessels

G459

0042

Procedure on 3 vessels

02120X

33513

CABG vein 4

413X

Angina pectoris

I20X

Transient cerebral ischemic attack unspecified Angina pectoris

0043

02130X

33514

CABG vein 5

414X

I21X

Acute myocardial infarction

0044

33516

CABG vein 6þ

4295

Other forms of chronic ischemic heart disease Chordae tendineae rupture

I22X

Subsequent STEMI and NSTEMI MI

0045

Procedure on 4 or more vessels Procedure on vessel bifurcation Insertion of 1 vascular stent

33517

CABG artery-vein single

4296

Papillary muscle rupture

I23X

0046

Insertion of 2 vascular stents

02703D6

33518

CABG artery-vein 2

42971

I24X

0047

CABG artery vein 3

42979

Insertion of 3 vascular stents Supersaturated O2 therapy

02703DZ

33519

Acquired cardiac septal defect Other certain sequelae MI NEC

Certain current complications after acute MI Other acute ischemic heart diseases Chronic ischemic heart disease

33521

CABG artery-vein 4

431

Intracerebral hemorrhage

I61

006

CABG artery-vein 5

434

Cerebral artery occlusion

I63

33523

CABG artery-vein 6þ

4359

Transient cerebral ischemia NOS

I631

Cerebral infarct embolism of precerebral artery

0061

33533

CABG arterial single

436

Acute but ill-defined cerebrovascular disease

I632

Cerebral infarction unspecified occlusion/ stent precerebral artery

0062

33534

CABG arterial 2

440X

Aortic atherosclerosis

I633

0063

33535

CABG arterial 3

443X

Other peripheral vascular disease

I634

Cerebral infarction thrombosis cerebral artery Cerebral infarction embolism cerebral artery

Procedures on blood vessels Insertion of drug-eluting stent of superficial femoral artery Percutaneous angioplasty/ atherectomy precerebral vessel Percutaneous angioplasty/ atherectomy intracranial vessel Percutaneous insertion carotid artery stent(s)

02703ZZ

33522

Nontraumatic intracerebral hemorrhage Cerebral infarction

I25X

0049

0060

0064

Percutaneous insertion of other precerebral arterial stent

0270346 027034Z

02703Z6

0271346

027134Z

02713D6 Dilation CA 2 site bifurcation intraluminal device percutaneous 02713DZ Dilation CA 2 site intraluminal device percutaneous 02713Z6 Dilation CA 2 site bifurcation percutaneous

-,

33510

ICD-10 procedure description

Clinical Gastroenterology and Hepatology Vol.

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ICD-10 diagnosis

Abraham et al

CPT

10.e16

Supplementary Table 8. Ischemic Heart Disease and Percutaneous Coronary Implantation Codes

No. -

2959 2960 2961 2962 2963 2964 2965 2966 2967 2968 2969 2970 2971 2972 2973 2974 2975 2976 2977 2978 2979 2980 2981 2982 2983 2984 2985 2986 2987 2988 2989 2990 2991 2992 2993 2994 2995 2996 2997 2998 2999 3000 3001 3002 3003 3004 3005 3006 3007 3008 3009 3010 3011 3012 3013 3014 3015 3016

3017 3018 3019 3020 3021 3022 3023 3024 3025 3026 3027 3028 3029 3030 3031 3032 3033 3034 3035 3036 3037 3038 3039 3040 3041 3042 3043 3044 3045 3046 3047 3048 3049 3050 3051 3052 3053 3054 3055 3056 3057 3058 3059 3060 3061 3062 3063 3064 3065 3066 3067 3068 3069 3070 3071 3072 3073 3074 V4581

Aortocoronary bypass

I635

4110F

Internal mammary artery used for CABG Percutaneous cardiac angioplasty 1 artery

V4582

Postsurgical PTCA status

I679

92920

92921

92925

92928

92929

92933 Q32

92934

92937

92938

92941

92943

0065

I702

Atherosclerosis native artery extreme

0067

I731

Thromboangiitis obliterans

0068

I739

Peripheral vascular disease unspecified

0069

T8221X

Breakdown mechanical CABG initial

360X

Insert coronary stent

02723Z6 Dilation CA 3 arteries bifurcation percutaneous

Z951

Presence aortocoronary bypass graft

361X

Bypass anastomosis for heart revascularization

02723ZZ Dilation CA 3 sites percutaneous

Z955

Presence coronary angioplasty implant and graft

0273346 Dilation CA 4/> arteries bifurcation Rx-eluting Il device percutaneous

Coronary angioplasty status

027334Z Dilation CA 4/> arteries Rxeluting Il device percutaneous 02733D6 Dilation CA 4/> site bifurcation with Il device percutaneous 02733DZ Dilation CA 4/> site with Il device percutaneous

Z9861

0066

Percutaneous insertion of intracranial vascular stent PTCA or coronary atherectomy Intravascular measurement intrathoracic artery Intravascular measurement peripheral artery Intravascular pressure measurement, NOS

02713ZZ Dilation CA 2 sites percutaneous 0272346 Dilation CA 3 arteries bifurcation Rx-eluting Il device percutaneous 027234Z Dilation CA 3 arteries Rxeluting Il device percutaneous 02723D6 Dilation CA 3 arteries bifurcation intraluminal device percutaneous 02723DZ Dilation CA 3 arteries intraluminal device percutaneous

02733Z6 Dilation CA 4/> arteries bifurcation percutaneous

02733ZZ Dilation CA 4/> arteries percutaneous 02C03ZZ Extirpation matter CA 1 artery percutaneous

Q31 Q33

GIB on Antithrombotic Therapy

FLA 5.6.0 DTD  YJCGH56519_proof  5 July 2019  7:36 pm  ce DVC

92924

Percutaneous cardiac angioplasty additional artery Percutaneous cardiac angioplasty/ atherectomy, 1 artery Percutaneous cardiac angioplasty/ athrectomy additional Percutaneous cardiac stent with angioplasty 1 vessel Percutaneous cardiac stent with angioplasty additional Percutaneous cardiac stent/ atherectomy /angioplasty Percutaneous cardiac stent/ atherectomy /angioplasty Percutaneous revascularization bypass graft 1 vessel Percutaneous revascularization bypass graft additional Percutaneous cardiac revascularization MI 1 vessel Percutaneous cardiac revascularization chronic 1 vessel

Cerebral infarction unspecified occlusion/ stent cerebral artery Cerebrovascular disease unspecified

2019

CABG arterial 4þ

-

33536

10.e17

3075 3076 3077 3078 3079 3080 3081 3082 3083 3084 3085 3086 3087 3088 3089 3090 3091 3092 3093 3094 3095 3096 3097 3098 3099 3100 3101 3102 3103 3104 3105 3106 3107 3108 3109 3110 3111 3112 3113 3114 3115 3116 3117 3118 3119 3120 3121 3122 3123 3124 3125 3126 3127 3128 3129 3130 3131 3132

3133 3134 3135 3136 3137 3138 3139 3140 3141 3142 3143 3144 3145 3146 3147 3148 3149 3150 3151 3152 3153 3154 3155 3156 3157 3158 3159 3160 3161 3162 3163 3164 3165 3166 3167 3168 3169 3170 3171 3172 3173 3174 3175 3176 3177 3178 3179 3180 3181 3182 3183 3184 3185 3186 3187 3188 3189 3190 CPT

92975

92980 92981

92982

Coronary artery dilation

92984 92995 92996

Coronary artery dilation Coronary atherectomy Coronary atherectomy

ICD-9 diagnosis description

ICD-10 diagnosis

ICD-10 diagnosis description

ICD-9 procedure

ICD-9 procedure description

ICD-10 procedure

ICD-10 procedure description

02C13ZZ Extirpation matter CA 2 arteries percutaneous 02C23ZZ Extirpation matter CA 3 arteries percutaneous 02C33ZZ Extirpation matter CA 4/> arteries percutaneous 03BB0ZZ Excision right radial artery open approach 06BQ4ZZ Excision Lt Gt saphenous vein percutaneous endo 5A1221Z Performance cardiac output continuous

CA, _______; CABG, coronary artery bypass graft; CPT, Current Procedural Terminology; DM, diabetes mellitus; endo, _________; ICD-9, International Classification of Diseases, 9th revision; ICD-10, International Classification of Diseases, 10th revision; Lt Gt, ______; MI, myocardial infarction; NEC, _________; NOS, _________; NSTEMI MI, ____________; PTCA, ________; STEMI, ______.

Clinical Gastroenterology and Hepatology Vol.

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92977

Percutaneous card revascularization chronic additional Dissolve clot heart vessel Dissolve clot heart vessel Insert intracoronary stent Insert intracoronary stent

ICD-9 diagnosis

Abraham et al

92944

CPT description

10.e18

Supplementary Table 8. Continued

-,

No. -

3191 3192 3193 3194 3195 3196 3197 3198 3199 3200 3201 3202 3203 3204 3205 3206 3207 3208 3209 3210 3211 3212 3213 3214 3215 3216 3217 3218 3219 3220 3221 3222 3223 3224 3225 3226 3227 3228 3229 3230 3231 3232 3233 3234 3235 3236 3237 3238 3239 3240 3241 3242 3243 3244 3245 3246 3247 3248

-

3249 3250 3251 3252 3253 3254 3255 3256 3257 3258 3259 3260 3261 3262 3263 3264 3265 3266 3267 3268 3269 3270 3271 3272 3273 3274 3275 3276 3277 3278 3279 3280 3281 3282 3283 3284 3285 3286 3287 3288 3289 3290 3291 3292 3293 3294 3295 3296 3297 3298 3299 3300 3301 3302 3303 3304 3305 3306 3307 3308 3309 3310 3311

2019

GIB on Antithrombotic Therapy

Supplementary Table 9. Antiplatelets at Index Prescription Drug

N

%

Cilostazol Clopidogrel Dipyridamole Prasugrel Ticagrelor Ticlopidine Vorapaxar

6930 111,736 4044 12,404 7247 61 11

4.87 78.45 2.84 8.71 5.09 0.04 0.01

FLA 5.6.0 DTD  YJCGH56519_proof  5 July 2019  7:36 pm  ce DVC

10.e19 3312 3313 3314 3315 3316 3317 3318 3319 3320 3321 3322 3323 3324 3325 3326 3327 3328 3329 3330 3331 3332 3333 3334 3335 3336 3337 3338 3339 3340 3341 3342 3343 3344 3345 3346 3347 3348 3349 3350 3351 3352 3353 3354 3355 3356 3357 3358 3359 3360 3361 3362 3363 3364 3365 3366 3367 3368 3369 3370 3371 3372 3373 3374