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Gastroenterology 2016;151:11051112

CLINICALALIMENTARY TRACT
Association of Proton Pump Inhibitors With Reduced Risk
of Warfarin-Related Serious Upper Gastrointestinal Bleeding
Wayne A. Ray,1 Cecilia P. Chung,2,3,4 Katherine T. Murray,3,5,6 Walter E. Smalley,1,4,7
James R. Daugherty,1 William D. Dupont,8 and C. Michael Stein2,3
1
Department of Health Policy, 2Department of Medicine, Division of Rheumatology, Vanderbilt University School of Medicine,

CLINICAL AT
Nashville, Tennessee; 3Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee;
4
Veterans Administration Tennessee Valley Health Care System, Nashville, Tennessee; 5Department of Medicine, Division of
Cardiology, Vanderbilt University School of Medicine, Nashville, Tennessee; 6Department of Pharmacology, Vanderbilt
University School of Medicine, Nashville, Tennessee; 7Department of Gastroenterology, Vanderbilt University School of
Medicine, Nashville, Tennessee; and 8Department of Biostatistics, Vanderbilt University School of Medicine, Nashville,
Tennessee

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) might annually.2 However, warfarin use is limited by frequent
reduce the risk of serious warfarin-related upper gastrointes- major bleeding; in the United States, there are 29,000
tinal bleeding, but the evidence of their efcacy for this indica- warfarin-related bleeding hospitalizations each year.3
tion is limited. A gastroprotective effect of PPIs would be Serious warfarin-related bleeding commonly occurs in the
particularly important for patients who take warfarin with an- gastrointestinal tract, accounting for 26%40% of such
tiplatelet drugs or nonselective nonsteroidal anti-inammatory bleeds in large atrial brillation trials.47 Of these, many are
drugs (NSAIDs), which further increase the risk of gastrointes- upper gastrointestinal,8,9 which are thought to frequently
tinal bleeding. METHODS: This retrospective cohort study of originate from asymptomatic lesions.10
patients beginning warfarin treatment in Tennessee Medicaid Proton pump inhibitors (PPIs) reduce gastric acid pro-
and the 5% National Medicare Sample identied 97,430 new
duction, promote ulcer healing, and prevent ulcer recur-
episodes of warfarin treatment with 75,720 person-years of
rence.11 These drugs might prevent warfarin-related upper
follow-up. The study end points were hospitalizations for upper
gastrointestinal bleeding by decreasing the occurrence of
gastrointestinal bleeding potentially preventable by PPIs and for
bleeding at other sites. RESULTS: Patients who took warfarin spontaneous ulcers or promoting ulcer healing before
without PPI co-therapy had 119 hospitalizations for upper serious bleeding occurs. However, evidence is limited as to
gastrointestinal bleeding per 10,000 person-years of treatment. whether or not PPIs prevent clinically important gastroin-
The risk decreased by 24% among patients who received PPI testinal bleeding during warfarin treatment.12,13 Thus,
co-therapy (adjusted hazard ratio [HR], 0.76; 95% condence current guidelines for oral anticoagulant therapy do not
interval [CI], 0.630.91). There was no signicant reduction in recommend PPI co-therapy.1418
the risk of other gastrointestinal bleeding hospitalizations (HR, A gastroprotective effect for PPIs would be particularly
1.07; 95% CI, 0.941.22) or non-gastrointestinal bleeding hos- important for warfarin patients taking either antiplatelet
pitalizations (HR, 0.98; 95% CI, 0.841.15) in this group. Among drugs or nonselective nonsteroidal anti-inammatory agents
patients concurrently using antiplatelet drugs or NSAIDs, those (NSAIDs), which further increase the risk of serious gastro-
without PPI co-therapy had 284 upper gastrointestinal bleeding intestinal bleeding.19 Antiplatelet drugs are often indicated
hospitalizations per 10,000 person-years of warfarin treatment. for patients taking oral anticoagulants, who frequently have
The risk decreased by 45% (HR, 0.55; 95% CI, 0.390.77) with coronary artery disease treated with low-dose aspirin, and
PPI co-therapy. PPI co-therapy had no signicant protective who may require a P2Y12 inhibitor for an acute coronary
effect for warfarin patients not using antiplatelet drugs or syndrome or after a percutaneous coronary intervention.20
NSAIDs (HR, 0.86; 95% CI, 0.701.06). Findings were similar in PPIs might be particularly benecial for warfarin patients
both study populations. CONCLUSIONS: In an analysis of with concurrent antiplatelet drug or NSAID use, given that
patients beginning warfarin treatment in Tennessee Medicaid they decrease the risk of upper gastrointestinal ulcers and
and the 5% National Medicare Sample, PPI co-therapy was
bleeding induced by low-dose aspirin,21 clopidogrel,2224 and
associated with reduced risk of warfarin-related upper gastro-
NSAIDs.21,25 Although guidelines recommend PPIs for most
intestinal bleeding; the greatest reduction occurred in patients
warfarin patients taking antiplatelet drugs or NSAIDs,19,26,27
also taking antiplatelet drugs or NSAIDs.
there are no controlled studies of the efcacy of PPI
co-therapy in this high-risk group.
Keywords: Warfarin; Proton-Pump Inhibitor; Antiplatelet Drugs.

Abbreviations used in this paper: HR, hazard ratio; NSAID, nonsteroidal


anti-inammatory drug; PPI, proton pump inhibitor.

W arfarin, an oral anticoagulant that inhibits the


production of vitamin K-dependent clotting fac-
tors,1 is one of the most frequently prescribed medications
Most current article
2016 by the AGA Institute
0016-5085/$36.00
in the United States, with more than 30 million prescriptions http://dx.doi.org/10.1053/j.gastro.2016.08.054
1106 Ray et al Gastroenterology Vol. 151, No. 6

Thus, we conducted a retrospective cohort study of The exposure period was based on the dispensed days of
patients beginning warfarin treatment to assess whether the supply. The denitions of the period of use accounted for the
risk of hospitalization for upper gastrointestinal bleeding residual effects of some study drugs on the risk of bleeding.
was reduced with PPI co-therapy. We also studied the effect Warfarin treatment during follow-up was dened as the
of PPI co-therapy in warfarin patients concurrently period during which patients were likely to have increased risk
receiving antiplatelet drugs/NSAIDs. of warfarin-related bleeding complications. This period began
on the date the prescription was lled and, given the long half-
life of warfarin, ended 3 days after the end of the days of supply
Methods (Supplementary Material). All cohort follow-up and all study
analyses were restricted to periods of warfarin treatment.
Sources of Data There were 3 possible categories of concomitant PPI use
The cohort of patients beginning warfarin treatment came during warfarin treatment (Supplementary Material). PPI
CLINICAL AT

from 2 populations: Tennessee Medicaid enrollees28,29 co-therapy consisted of person-days on which the patient was
(19962011) and the longitudinal 5% National Medicare likely to be taking the PPI and for which a gastroprotective
Sample (20112013).30 Each population had computerized effect was most plausible. It was dened as the interval
les documenting members periods of enrollment and medical between the lling of a PPI prescription through the end of
care encounters for pharmacy, hospital, outpatient, and nursing days of supply. Former co-therapy consisted of person-days for
home providers, an efcient means to identify the cohort and patients who had had a PPI prescription but for which there
obtain study data.29 We studied 2 independent populations should be no PPI-related gastroprotection. Analysis of this
both to increase sample size and to examine the consistency of person-time permitted assessment of confounding by unmea-
our ndings. sured factors associated with receiving a PPI prescription.
Study medication use was identied from pharmacy les No co-therapy consisted of person-days with no lled PPI
that recorded lled prescriptions. These included the prescription in the past year.
dispensing date, drug, quantity, dose, and days of supply. Concurrent antiplatelet drug or NSAID use indicated
Throughout much of the study period, Tennessee Medicaid had whether or not these drugs were used during warfarin treat-
a relatively generous drug benet, which covered over-the- ment. For aspirin and other antiplatelet drugs, concurrent use
counter medications, such as low-dose aspirin, when these was dened as present for the interval between the prescrip-
were obtained with a prescription. Because Medicare reim- tion ll and 7 days after the end of the days of supply, given the
bursement policies were more restrictive, the pharmacy les irreversible antiplatelet effects of these medications
did not include information on low-dose aspirin and over- (Supplementary Material). For NSAIDs, concurrent use was
the-counter NSAIDs. Although some PPIs are available over- present for the interval between the prescription ll and the
the-counter, they only are recommended at low doses and for end of the days of supply.
14 day-courses up to 2 times a year.31

Cohort End Points


The cohort included persons 30 years of age or older in The primary study end point was hospitalization for upper
either population whose rst prescription for warfarin was gastrointestinal bleeding potentially preventable by PPI
lled during the study period. They could not have had any oral co-therapy (Supplementary Material). This included bleeding
anticoagulant prescription in the preceding year related to esophagitis, peptic ulcer disease, and gastritis, but
(Supplementary Table 1). They had to have complete excluded bleeding unlikely to be affected by PPIs (eg, Mallory
demographic information, full pharmacy benets and, to assure Weiss tear). We also examined hospitalizations for other
regular contact with medical care, at least 1 outpatient visit and gastrointestinal bleeding (predominantly lower gastrointestinal
1 lled prescription in the prior year. Patients could not have or gastrointestinal hemorrhages for which upper/lower site not
end-stage renal disease, serious gastrointestinal illness pre- indicated) and for bleeding at other sites (Supplementary
disposing to bleeding (eg, esophageal varices or gastrointestinal Material), which should not be affected by PPI co-therapy.
cancer), or a bleeding-related hospitalization in the past year We identied bleeding-related hospitalizations from
(Supplementary Table 1). hospital admissions with a previously validated algorithm
Patients entered the cohort on the day they lled their rst (Supplementary Material).32 The positive predictive value was
warfarin prescription. Patients left the cohort on the rst of the 99% for all bleeding-related hospitalizations, 98% for all
following: last day of the study, 365 days with no lling of a gastrointestinal bleeding, and 80% for upper gastrointestinal
warfarin prescription, lling of a prescription for a different bleeding (Supplementary Table 2). The lower positive predic-
oral anticoagulant, loss of enrollment, failure to meet the cohort tive value for upper gastrointestinal bleeding resulted from
eligibility criteria, a bleeding-related hospitalization, or death. occasional use of diagnosis codes that did not specify the
Patients who left the cohort could reenter if they subsequently gastrointestinal bleeding site.
met the eligibility criteria.
Analysis
Medication Exposure We analyzed the occurrence of endpoints during warfarin
Because the effect of study medications on the risk of treatment according to PPI co-therapy. Adjusted relative risk
bleeding is thought to be acute, each day of study follow-up was was estimated with the hazard ratio (HR), with the reference
classied according to probable study medication use, as category no PPI co-therapy. HRs were calculated from Cox
identied from lled prescriptions (Supplementary Material). regression models. Because patients at higher risk of upper
December 2016 PPI Co-Therapy and Warfarin-Related Upper Gastrointestinal Bleeds 1107

gastrointestinal bleeding are more likely to receive PPIs, the Table 1.Characteristics of New Episodes of Warfarin
models included 61 time-dependent covariates plausibly Treatment According to Proton Pump Inhibitor
related to bleeding risk (Supplementary Table 3). These Co-Therapya
included the study population (Medicaid or Medicare),
demographic characteristics, warfarin indication and treatment No PPI PPI
duration, gastrointestinal disease, risk factors for warfarin- Characteristic co-therapy co-therapy
related bleeding, medications thought to affect bleeding risk, Person-years warfarin treatmentb 52,407 14,658
cardiovascular comorbidity, alcohol abuse, liver disease, and Tennesee Medicaid 71.8 63.4
recent medical care utilization. Separate models were t for Age, y, mean 67.7 68.2
bleeding-related hospitalizations at upper gastrointestinal, Female sex 61.7 66.3
non-gastrointestinal, and other sites. Nursing home residence past year 11.7 13.3
The absolute effect of PPI co-therapy on the risk of Warfarin indication

CLINICAL AT
bleeding-related hospitalizations in the study cohort was Atrial brillation 52.7 53.2
described with the adjusted rate difference. These were esti- Deep vein thrombosis 24.7 28.7
Other cardiovascular 14.6 11.2
mated as I0*(HR  1), where I0 was the unadjusted incidence
Other or unknown 7.9 6.9
in patients without PPI co-therapy and HR the hazard ratio for
History of risk factors for upper 35.1 57.4
PPI co-therapy. CIs were calculated analogously. GI bleeding
We analyzed the effect of PPI co-therapy for patients with Peptic ulcer disease 3.9 15.6
concurrent antiplatelet drug or NSAID use (Supplementary Gastritis 3.1 10.6
Material), as well as for those with a history in the past year Blood in stool/GI bleedingc 2.6 6.1
of risk factors for upper gastrointestinal bleeding (peptic ulcer Abdominal pain 15.9 29.1
disease, gastritis, blood in stool/gastrointestinal bleeding, Anemiad 19.2 31.2
abdominal pain, or anemia). PPI effect estimates were obtained GERD/dyspepsia 22.7 57.3
from single degree of freedom contrasts. Any antiplatelet drug or NSAID 35.4 41.2
Aspirin 9.9 12.1
The study was powered (a .05, 1  b .80) to detect a
NSAID 23.0 24.7
22% reduction in the PPI co-therapy HR for the entire cohort.
P2Y12 or other antiplatelet druge 9.3 14.7
For warfarin patients with and without concurrent antiplatelet Coxib, current use 3.4 8.2
drugs or NSAIDs, the detectable reductions were 38% and 27%. Smoking 14.0 18.4
All statistical analyses were performed with SAS software, AMI, revascularization, angina 13.7 17.5
version 9.4 (SAS Institute, Cary, NC). Stroke or TIA 23.7 25.2
Heart failure 37.5 43.1
Digoxin 27.9 21.8
Loop diuretic 47.6 54.7
Results Insulin 13.9 17.4
The cohort included 97,430 new episodes of warfarin Oral hypoglycemic 23.8 27.3
treatment with 75,720 person-years of active treatment, of Alcohol abuse and related illnesses 1.8 1.9
which 52,442 were from Tennessee Medicaid and 23,278 Hospitalization 54.4 63.9
from the Medicare sample. There were 14,658 person-years ED visit, any, past 90 days 27.3 32.6
of warfarin treatment with PPI co-therapy, 52,407 person-
years with no co-therapy and 8,654 person-years with NOTE. Values are percentages unless otherwise indicated.
non-current co-therapy. The indication was atrial brillation Coxib, cycloxygenase-2 selective NSAID; ED, emergency
for more than one-half of the warfarin treatment and deep department; GI, gastrointestinal; AMI, acute myocardial
vein thrombosis for more than one-fourth (Table 1). infarction; GERD, gastroesophageal reux disease; TIA,
Warfarin patients with PPI co-therapy had greater transient ischemic attack.
a
Weighted according to person-years of warfarin treatment.
prevalence of risk factors for upper gastrointestinal Unless otherwise noted, all values are proportions. Unless
bleeding than did those without PPI co-therapy (57.4% vs otherwise stated, disease/medication variables reect diag-
35.1%, Table 1). These included history of peptic ulcer nosis/prescription ll during the preceding 365 days.
b
disease (15.6% vs 3.9%), abdominal pain (29.1% vs 15.9%), Not shown are 8,654 person-years of follow-up for non-
and anemia (31.2% vs 19.2%). Those with PPI co-therapy current PPI co-therapy.
c
were more likely to have had an antiplatelet drug or Outpatient or inpatient not meeting end-point denition
NSAID prescription in the past year (41.2% vs 35.4%), (admission not related to bleeding with secondary diagnosis,
such as blood in stool, indicating bleeding).
including aspirin, non-selective NSAIDs, and P2Y12 d
Diagnosis or prescription for iron.
inhibitors/other antiplatelet drugs. Findings were similar in e
Dipyridamole, cilostazole.
both the Tennessee Medicaid and Medicare populations
(Supplementary Table 4).
There were 3,848 bleeding-related hospitalizations population had similar incidence of hospitalizations for
during warfarin treatment, or 508 hospitalizations per bleeding at any site (Medicaid: 494 per 10,000, Medicare:
10,000 person-years. Of these, 964 (127 per 10,000 person- 541 per 10,000) or at upper gastrointestinal sites
years) were upper gastrointestinal, 1,619 (214 per 10,000) (Medicaid:130 per 10,000, Medicare 120 per 10,000).
were other gastrointestinal sites, and 1,265 (167 per Warfarin patients without PPI co-therapy had 119 hos-
10,000) were other sites. Warfarin patients from each study pitalizations for upper gastrointestinal bleeding per 10,000
1108 Ray et al Gastroenterology Vol. 151, No. 6

Table 2.Hospitalizations for Bleeding During Warfarin Treatment According to Site of the Bleeding and Proton Pump Inhibitor
Co-Therapy

Variable No PPI co-therapy Former PPI co-therapy PPI co-therapy

Person-years 52,407 8,654 14,658


Upper gastrointestinal
Bleeding hospitalizations 624 159 181
Rate/10,000 person-years 119.1 183.7 123.5
Adjusted HRa (95% CI) 1.00 (0.82 to 1.21) 0.76 (0.63 to 0.91)
RDa (95% CI) 0.3 (21.0 to 24.7) 28.7 (44.0 to 10.3)
P value .9799 .0035
Other gastrointestinal
CLINICAL AT

Bleeding hospitalizations 936 280 403


Rate/10,000 person-years 178.6 323.5 274.9
Adjusted HRa (95% CI) 1 1.10 (0.95 to 1.27) 1.07 (0.94 to 1.22)
RDa (95% CI) 17.1 (9.5 to 47.9) 13.1 (10.6 to 40.1)
P value .2195 .2927
Other major bleeds
Bleeding hospitalizations 801 205 259
Rate/10,000 person-years 152.8 236.9 176.7
Adjusted HRa (95% CI) 1.13 (0.95 to 1.33) 0.98 (0.84 to 1.15)
RDa (95% CI) 19.1 (7.4 to 50.4) 3.0 (24.8 to 22.4)
P value 0.1676 0.8014

RD adjusted rate difference per 10,000.


a
Both the HR and RD are adjusted for the study population (Medicaid or Medicare), demographic characteristics, warfarin
indication and treatment duration, gastrointestinal disease, risk factors for warfarin-related bleeding, medications thought to
affect bleeding risk, cardiovascular comorbidity, alcohol abuse, liver disease, and recent medical care utilization
(Supplementary Table 3 has detailed list of covariates).

person-years of treatment (Table 2). The risk decreased by


24% (adjusted HR, 0.76, 95% CI, 0.630.91) with PPI
co-therapy, a reduction of 29 (10 to 44) hospitalizations per
10,000 person-years. PPI co-therapy was not signicantly
associated with reduced risk of other gastrointestinal
(HR, 1.07; 95% CI, 0.941.22) or non-gastrointestinal
(HR, 0.98; 95% CI, 0.841.15) bleeding hospitalizations.
Former PPI co-therapy was not associated with reduced risk
of hospitalization for upper gastrointestinal bleeding
(HR, 1.00; 95% CI, 0.821.21). Findings were similar in
each of the study populations (Supplementary Table 5).
Warfarin patients without PPI co-therapy who also had
concurrent antiplatelet drug or NSAID use had 283 hospi-
talizations for upper gastrointestinal bleeding per 10,000
person-years of warfarin treatment (Figure 1). The risk
decreased by 45% (HR, 0.55; 95% CI, 0.390.77) with PPI
co-therapy, a reduction of 128 (66 to 173) hospitalizations Figure 1. Incidence of warfarin-related upper gastrointestinal
per 10,000 person-years. The gastroprotective effect of PPI bleeding according to PPI co-therapy. Vertical bars indicate
co-therapy did not differ signicantly according to specic 95% CIs. Stratied by concurrent use of antiplatelet drugs or
antiplatelet drug or NSAID (Table 3). In contrast, for NSAIDs. Incidence for patients with no PPI co-therapy (I0) is
unadjusted (CIs calculated assuming Poisson distribution);
warfarin patients without concurrent antiplatelet drug or
that for patients with PPI co-therapy calculated as I0*HR,
NSAID use, the HR for PPI co-therapy was 0.86 (95% CI, where HR is the adjusted hazard ratio for PPI co-therapy (CIs
0.701.06), which differed signicantly from that for calculated analogously). HRs adjusted for the study popula-
patients with concurrent antiplatelet drug or NSAID use tion (Medicaid or Medicare), demographic characteristics,
(P .0109). warfarin indication and treatment duration, gastrointestinal
In the absence of PPI co-therapy, the incidence of upper disease, risk factors for warfarin-related bleeding, medica-
gastrointestinal bleeding hospitalizations during warfarin tions thought to affect bleeding risk, cardiovascular comor-
bidity, alcohol abuse, liver disease, and recent medical care
treatment increased with both a history of risk factors for utilization (see Supplementary Table 3 for detailed list of
upper gastrointestinal bleeding and concurrent antiplatelet covariates). Numbers below the x-axis are the number of
drug or NSAID use (Figure 2). For patients with no history hospitalizations for upper gastrointestinal bleeding and the
of risk factors, hospitalizations for upper gastrointestinal person-years of warfarin treatment.
December 2016 PPI Co-Therapy and Warfarin-Related Upper Gastrointestinal Bleeds 1109

bleeding during warfarin treatment increased from 68 to


Table 3.Hospitalizations for Upper Gastrointestinal Bleeding During Warfarin Treatment According to Proton Pump Inhibitor Co-Therapy and Concurrent Use of Specic

128.2 (172.4 to 66.4)

testinal disease, risk factors for warfarin-related bleeding, medications thought to affect bleeding risk, cardiovascular comorbidity, alcohol abuse, liver disease, and recent
Both the HR and RD are adjusted for the study population (Medicaid or Medicare), demographic characteristics, warfarin indication and treatment duration, gastroin-
197.6)
9.0)
6.1)
2.5)
224 per 10,000 person-years with concurrent antiplatelet

13.5 (29.3 to 6.0)


RDa (95% CI)
drugs or NSAIDs, 156 (109 to 204) additional hospitaliza-

to
to
to
to
tions per 10,000 person-years. For patients with a history of

(193.0
(206.9
(183.9
(271.5
risk factors, hospitalizations for upper gastrointestinal
bleeding increased from 152 to 392 per 10,000 person-

129.5
134.1
119.0
136.1
years with concurrent antiplatelet drug or NSAID use,
240 (155 to 325) additional hospitalizations per 10,000
person-years.
P value

The gastroprotective effect of PPI co-therapy for


.1608

.0004

.0388
.0423
.0536
.3089
warfarin patients was only signicant for those with con-

CLINICAL AT
current antiplatelet drug or NSAID use, irrespective of the
history of risk factors for upper gastrointestinal bleeding
0.86 (0.70 to 1.06)

0.55 (0.39 to 0.77)

0.97)
0.98)
1.01)
1.54)
HRa (95% CI)

(Figure 2). For patients with concurrent antiplatelet drug or


to
to
to
to

NSAID use, but with no history of risk factors, the HR was


(0.27
(0.32
(0.29
(0.25

0.43 (95% CI, 0.220.83), whereas for those with a history


of risk factors, the HR was 0.64 (95% CI, 0.430.94). In
0.51
0.56
0.54
0.63

contrast, absent concurrent antiplatelet drug or NSAID use,


the gastroprotective effect of PPI co-therapy was smaller
Person-years UGI bleeds Rate/10,000 Person-years UGI bleeds Rate/10,000

and not statistically signicant for those either with or


109.2

196.7

185.3
201.2
173.5
282.8

without a history of risk factors for upper gastrointestinal


bleeding.
We analyzed the effects of PPI co-therapy in warfarin
patients according to concurrent antiplatelet drug or NSAID
PPI co-therapy

use and history of upper gastrointestinal bleeding risk


47

12
15
13
134

factors for the individual study populations. Findings in


each population were similar to those from the primary
analyses (Supplementary Tables 6 and 7).
In the primary analysis, all covariates could change
during warfarin treatment, since PPI co-therapy could be
2,390
12,269

648
745
749
248

initiated for gastrointestinal conditions that developed after


cohort entry. However, some covariates could be on the
medical care utilization (Supplementary Table 3 has detailed list of covariates).

causal pathway between PPI co-therapy and reduced risk


of upper gastrointestinal bleeding hospitalization. We per-
formed a sensitivity analysis in which the only time-
RD, adjusted rate difference per 10,000; UGI, upper gastrointestinal.
283.8

263.5
302.7
258.4
363.9
97.1
Antiplatelet Drugs or Nonsteroidal Anti-Inammatory Drugs

dependent covariates were PPI co-therapy, concurrent


antiplatelet drug or NSAID use, and other drugs associated
with gastrointestinal bleeding and change in clinical status
No PPI co-therapy

from baseline was limited by restricting follow-up to 1 year.


The HR for PPI co-therapy was 0.77 (95% CI, 0.610.96) for
449

175

47
71
42
15

all warfarin patients and 0.55 (95% CI, 0.360.84) for those
with concurrent antiplatelet drug or NSAID use.
We also performed an analysis in which patients could
not re-enter the cohort. The HR for PPI co-therapy was 0.75
(95% CI, 0.620.91) for all warfarin patients and 0.53 (95%
6,167

1,783
2,346
1,626
46,240

412

CI, 0.370.75) for those with concurrent antiplatelet drug


or NSAID use.
Any concurrent antiplatelet drug

Discussion
No concurrent antiplatelet drug

P2Y12/other antiplatelet only

We sought to determine whether PPI co-therapy could


reduce the risk of serious upper gastrointestinal bleeding in
patients treated with warfarin, given the frequency of this
Variable

life-threatening complication and the absence of specic


recommendations in current guidelines.1418 In this retro-
Multiple drugs
or NSAID

or NSAID
Aspirin only

spective cohort study in 2 populations of patients initiating


NSAID only

warfarin treatment, PPI co-therapy was associated with a


statistically signicant 24% reduction in the incidence of
hospitalizations for upper gastrointestinal bleeding, or 29
a
1110 Ray et al Gastroenterology Vol. 151, No. 6
CLINICAL AT

Figure 2. Incidence of warfarin-related upper gastrointestinal bleeding according to PPI co-therapy. Vertical bars indicate 95%
CIs. Stratied by concurrent use of antiplatelet drugs or NSAIDs and history of risk factors for upper gastrointestinal (GI)
bleeding (peptic ulcer, gastritis, abdominal pain, blood in stool/GI bleeding, anemia in past year). Incidence for patients with no
PPI co-therapy (I0) is unadjusted (CIs calculated assuming Poisson distribution); that for patients with PPI co-therapy
calculated as I0*HR, where HR is the adjusted hazard ratio for PPI co-therapy (CIs calculated analogously). HRs adjusted
for the study population (Medicaid or Medicare), demographic characteristics, warfarin indication and treatment duration, GI
disease, risk factors for warfarin-related bleeding, medications thought to affect bleeding risk, cardiovascular comorbidity,
alcohol abuse, liver disease, and recent medical care utilization (see Supplementary Table 3 for detailed list of covariates).
Numbers below the x-axis are the number of hospitalizations for upper GI bleeding and the person-years of warfarin treatment.

fewer hospitalizations per 10,000 person-years of warfarin co-therapy was associated with a 45% decreased risk, or
treatment. In contrast, the protective effect was not present 128 fewer hospitalizations per 10,000 person-years of
for hospitalizations for bleeding at other sites, nor was it warfarin treatment. Even for patients without a history of
present for patients who had stopped PPI co-therapy. risk factors for upper gastrointestinal bleeding, concurrent
Findings were similar in both the Tennessee Medicaid and antiplatelet drug or NSAID use more than tripled the inci-
Medicare 5% sample populations. dence of upper gastrointestinal bleeding hospitalizations,
Our ndings were generally consistent with those of but PPI co-therapy in this group was associated with a 57%
previous smaller investigations of oral anticoagulants. Three decreased risk.
case-control studies of the effects of gastroprotective We did not nd a signicant protective effect of PPI
co-therapy during treatment with a variety of medications co-therapy for warfarin patients without concurrent anti-
that increase bleeding risk, including oral anticoagulants, platelet drug or NSAID use. The benets of PPIs may be
have reported a nonsignicant protective effect for limited to patients who also take antiplatelet drugs or
PPIs.12,33,34 A recent study by Chan and colleagues13 NSAIDs, for whom they promote healing of or prevent
reported that PPI co-therapy during dabigatran treatment bleeding in otherwise asymptomatic lesions. However, the
was associated with a 47% (9%69%) reduction in magnitude of the gastroprotective effect of PPI co-therapy in
gastrointestinal bleeding. However, these previous studies other patients may be lower than that which our study was
did not present data for the high-risk group of patients for powered to detect. The point estimate of a 14% protective
whom the incidence of warfarin-related bleeding is elevated effect, with an upper 95% CI bound of 30%, indicate that
because they also take antiplatelet drugs or NSAIDs.19 our data cannot rule out clinically important gastro-
Antiplatelet drugs often are indicated for warfarin protection for these patients. Further studies are needed to
patients with coronary artery disease, acute coronary clarify the role of PPI co-therapy for warfarin patients
syndrome, or percutaneous coronary intervention.20 We without concurrent antiplatelet drug or NSAID use.
found that in the absence of PPI co-therapy, the incidence of There is a theoretical concern that PPI co-therapy could
hospitalizations for upper gastrointestinal bleeding increase warfarin concentration, given that, in vitro, some
increased nearly 3-fold with concurrent antiplatelet drug PPIs inhibit metabolism by hepatic cytochrome P450 2C19
or NSAID use. However, for these high-risk patients, PPI (CYP2C19),35 a minor pathway for warfarin metabolism.
December 2016 PPI Co-Therapy and Warfarin-Related Upper Gastrointestinal Bleeds 1111

However, there are conicting data on the clinical impor- Supplementary Material
tance of this nding. A study of 82 Japanese patients Note: To access the supplementary material accompanying
prescribed either lansoprazole (n 41) or rabeprazole this article, visit the online version of Gastroenterology at
(n 41) at the initiation of warfarin treatment after cardiac www.gastrojournal.org, and at http://dx.doi.org/10.1053/
surgery found greater risk of bleeding in the group receiving j.gastro.2016.08.054.
lansoprazole, the more potent CYP2C19 inhibitor.36 How-
ever, a subsequent study of 305 warfarin patients in
Denmark reported that initiation of a PPI was not associated References
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The limitations of this observational study generally adults in the United States from 19992012. JAMA
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effects, given that both medications are strong risk factors SPORTIF III Investigators. Stroke prevention with the oral
for gastrointestinal bleeding and were positively correlated direct thrombin inhibitor ximelagatran compared with
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some misclassication of PPI co-therapy, which if non- (SPORTIF III): randomised controlled trial. Lancet 2003;
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8. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban
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The study cohort came from 2 distinct populations:
9. Sherwood MW, Nessel CC, Hellkamp AS, et al. Gastro-
Tennessee Medicaid, a low-income population with a high
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proportion of patients enrolled because of illness; and the
with rivaroxaban or warfarin: rocket af trial. J Am Coll
5% National Medicare Sample, a national sample of Medi-
Cardiol 2015;66:22712281.
care enrollees restricted to those with fee-for-service plans
10. Cryer B. Reducing the risks of gastrointestinal bleeding
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11. Brunner G, Creutfeldt W. Omeprazole in the long-term
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population and for subgroups dened according to anti- to ranitidine. Scand J Gastroenterol 1989;24(Suppl 166):
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the study populations or sources of data. patients on antithrombotic or anti-inammatory therapy.
In summary, for patients initiating warfarin treatment in Gastroenterology 2011;141:7179.
Tennessee Medicaid and the 5% National Medicare Sample, 13. Chan EW, Lau WC, Leung WK, et al. Prevention of
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Although we cannot rule out a small gastroprotective effect College of Chest Physicians Evidence-Based Clinical
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were found for this group. 160S198S.
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15. Cairns JA, Connolly S, McMurtry S, et al. Canadian 28. Ray WA, Grifn MR. Use of Medicaid data for pharma-
Cardiovascular Society Atrial Fibrillation Guidelines 2010: coepidemiology. Am J Epidemiol 1989;129:837849.
prevention of stroke and systemic thromboembolism in 29. Ray WA. Population-based studies of adverse drug
atrial brillation and utter. Can J Cardiol 2011;27:7490. effects. N Engl J Med 2003;349:15921594.
16. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemor- 30. Baillargeon J, Holmes HM, Lin YL, et al. Concurrent use
rhagic complications of anticoagulant and thrombolytic of warfarin and antibiotics and the risk of bleeding in
treatment: American College of Chest Physicians older adults. The Am J Med 2012;125:183189.
Evidence-Based Clinicial Practice Guidelines (8th Edi- 31. US Food and Drug Administration. FDA drug safety
tion). Chest 2008;133(Suppl):257S298S. communication: low magnesium levels can be associated
17. Garcia DA, Witt DM, Hylek E, et al. Delivery of optimized with long-term use of Proton Pump Inhibitor drugs (PPIs).
anticoagulant therapy: consensus statement from the Available at: http://www.fda.gov/Drugs/DrugSafety/
anticoagulation forum. Ann Pharmacother 2008;42: ucm245011.htm. Accessed October 21, 2016.
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979988. 32. Cunningham A, Stein CM, Chung CP, et al. An auto-


18. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ mated database case denition for serious bleeding
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american heart association task force on practice 33. Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Effect of
guidelines and the heart rhythm society. J Am Coll Car- antisecretory drugs and nitrates on the risk of ulcer
diol 2014;64(21):e1e76. bleeding associated with nonsteroidal anti-inammatory
19. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/ drugs, antiplatelet agents, and anticoagulants. Am J
AHA 2008 Expert consensus document on reducing the Gastroenterol 2007;102:507515.
gastrointestinal risks of antiplatelet therapy and NSAID 34. Masso-Gonzalez EL, Garcia-Rodriguez LA. Proton pump
use. A report of the American College of Cardiology inhibitors reduce the long-term risk of recurrent upper
Foundation Task Force on Clinical Expert Consensus gastrointestinal bleeding: an observational study. Aliment
Documents. Circulation 2008;52:15021517. Pharmacol Ther 2008;28:629637.
20. Faxon DP, Eikelboom JW, Berger PB, et al. Antith- 35. Li Z, Andersson TB, Ahlstrom M, Weidolf L. Comparison
rombotic therapy in patients with atrial brillation un- of inhibitory effects of the proton pump-inhibiting drugs
dergoing coronary stenting: a North American omeprazole, esomeprazole, lansoprazole, pantoprazole,
perspective: executive summary. Circ Cardiovasc Interv and rabeprazole on human cytochrome P450 activities.
2011;4:522534. Drug Metab Dispos 2004;32:821827.
21. Rostom A, Wells G, Tugwell P, et al. Prevention of 36. Hata M, Shiono M, Akiyama K, et al. Incidence of drug
NSAID-induced gastroduodenal ulcers. Cochrane Data- interaction when using proton pump inhibitor and
base Syst Rev 2000;(4):CD002296. warfarin according to cytochrome P450 2C19 genotype
22. Ray WA, Murray KT, Grifn MR, et al. Outcomes with in Japanese. Thorac Cardiovasc Surg 2015;63:4550.
concurrent use of clopidogrel and proton-pump in- 37. Henriksen DP, Stage TB, Hansen MR, et al. The potential
hibitors: a cohort study. Ann Intern Med 2010;152: drug-drug interaction between proton pump inhibitors
337345. and warfarin. Pharmacoepidemiol Drug Saf 2015;24:
23. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or 13371340.
without omeprazole in coronary artery disease. N Engl J
Med 2010;363:19091917. Author names in bold designate shared co-rst authorship.
24. Vaduganathan M, Bhatt DL, Cryer BL, et al. Proton-pump
inhibitors reduce gastrointestinal events regardless of Received May 23, 2016. Accepted August 31, 2016.
aspirin dose in patients requiring dual antiplatelet ther- Reprint requests
apy. J Am Coll Cardiol 2016;67:16611671. Address requests for reprints to: Wayne A. Ray, PhD, Department of Health
Policy, Village at Vanderbilt, Suite 2600, 1501 21st Avenue South, Nashville,
25. Ray WA, Chung CP, Stein CM, et al. Risk of peptic ulcer Tennessee 37212. e-mail: wayne.ray@vanderbilt.edu.
hospitalizations in users of NSAIDs with gastroprotective
cotherapy versus coxibs. Gastroenterology 2007;133: Acknowledgments
The authors gratefully acknowledge the Tennessee Bureau of TennCare and
790798. the Department of Health, which provided study data. The Vanderbilt and
26. Abraham NS, El-Serag HB, Johnson ML, et al. National Tennessee Department of Health Institutional Review Boards approved the
study.
adherence to evidence-based guidelines for the pre-
scription of nonsteroidal anti-inammatory drugs. Conicts of interest
Gastroenterology 2005;129:11711178. The authors disclose no conicts.

27. Abraham NS, Hlatky M, Antman E, et al. ACCF/ACG/AHA Funding


2010 expert consensus document on the concomitant This study was supported in part by a grant from the National Heart, Lung, and
Blood Institute (HL114518). Dr Chung was funded by grants from the National
use of proton pump inhibitors and thienopyridines: A Institute of Arthritis and Musculoskeletal and Skin Diseases (K23AR064768)
focused update of the ACCF/ACG/AHA 2008 expert and the Rheumatology Research Foundation Career Development K
consensus document on reducing the gastrointestinal Supplement. Funding agencies had no role in study conduct or reporting.
The listed authors were entirely responsible for study design, data analysis,
risks of antiplatelet therapy and NSAID use. Am J Gas- manuscript preparation, and publication decisions. The rst manuscript draft
troenterol 2010;105:25332549. was written by the primary author, who vouches for the data and the analysis.
December 2016 PPI Co-Therapy and Warfarin-Related Upper Gastrointestinal Bleeds 1112.e1

Supplementary Material Overlap. From 2006 on, Tennessee Medicaid did not
provide pharmacy benets to persons eligible for Medicare,
Cohort as these could be obtained through Medicare part D. Such
Tennessee Medicaid. The study Medicaid database enrollees were excluded from the Medicaid cohort because
included enrollment, pharmacy, hospital, outpatient, and they did not meet criterion 1. Thus, the 2 cohorts should not
nursing home les, and was augmented with linkage to death overlap.
certicates1,2 and a statewide hospital discharge database.1,3 Patients entered the cohort on the date of the warfarin
Files for the period 1995 through 2011 were used. ll. Patients left the cohort on the rst of the following dates:
5% National Medicare Sample. The longitudinal 5%
national sample of Medicare enrollees is selected on the 1. End of warfarin use: 1 year with no lled warfarin
basis of the 8th and 9th digits of the health insurance prescription.
number.4 Study les included the beneciary summary le
(enrollment/demographics), Part D events le (lled pre- 2. The last day of the study, December 31, 2011 for
scriptions), MEDPAR le (inpatient/skilled nursing facility), Medicaid and December 31, 2013 for Medicare.
outpatient standard analytic le (institutional outpatient), 3. Day before lling of a prescription for a non-study
Medicare Carrier le (non-institutional outpatient), and oral anticoagulant.
hospice le. Files for the period 2010 through 2013 were
used. 4. Last day of enrollment, including either loss of
Qualifying episodes of warfarin use. The cohort enrollment or transition to a category without full
included patients beginning warfarin treatment during the pharmacy benets. For Medicare, transfer to Medi-
period from January 1, 1996 through December 31, 2011 care Part C was considered loss of enrollment.
for Tennessee Medicaid and from January 1, 2011 through 5. Day before failure to meet inclusion/exclusion
December 31, 2013 for the 5% National Medicare Sample. criteria.
To enter the cohort, patients had to meet study inclusion/
exclusion criteria (Supplementary Table 1) on the day the 6. Day of a study end point.
prescription was lled (t0). Supplementary Table 1 shows 7. Date of death.
the numbers of potential cohort members who successively
met the inclusion/exclusion criteria. Because a person who Patients who left the cohort could re-enter if they sub-
left the cohort could subsequently re-enter, we also show sequently met the study criteria. This included patients with
the number of new episodes of warfarin treatment. an end point if they subsequently had at least 1 year with no

Supplementary Table 1.Qualifying Episodes of Warfarin Use

No. of Medicaid No. of Medicare


episodes episodes
Criterion (no. of persons) (no. of persons)

Filled prescription for warfarin during study period for a patient 30 years of age or older. 92,856 (83,807) 118,832 (116,016)
For Tennessee Medicaid, the patient must be enrolled for the prior year in a category
with full pharmacy benets. For the 5% National Medicare Sample, the patient must be
enrolled in Medicare parts A, B, and D but not in part C (Medicare Advantage) in the
month the warfarin prescription was lled and in the preceding 12 calendar months.
New treatment episode. No other lled prescription for any oral anticoagulant in the 64,015 (58,503) 46,868 (46,021)
past year.
At least 1 outpatient visit (excluding laboratory claims) and 1 lled prescription 61,618 (56,471) 46,096 (45,273)
(excluding the warfarin prescription) in the past year to assure that patients have
had regular contact with medical care.
No end-stage renal disease in the past year, in order to exclude patients with use of 59,157 (54,297) 44,108 (43,335)
warfarin for dialysis.
No serious upper GI illness in the past year predisposing to frequent GI bleeding or altering 57,178 (52,516) 41,963 (41,243)
the pathology of peptic ulcer disease. This excludes persons who may have frequent care
for bleeding from other causes, such as esophageal varices or GI cancer.
No prior bleeding-related hospitalization in the past year, dened as a hospital stay meeting 56,114 (51,584) 41,316 (40,618)
the study end-point denition. We excluded these patients because it would be difcult to
determine whether subsequent bleeding hospitalizations represented a new event or
continued care for bleeding that began before warfarin treatment. The numbers of
exclusions for each type of bleeding hospitalization are shown.
Upper GI 336 (301) 164 (161)
Other GI 417 (362) 313 (300)
Other bleed 311 (269) 170 (164)
1112.e2 Ray et al Gastroenterology Vol. 151, No. 6

end point. Because a single person could have multiple end includes person-time during which PPI exposure may
points, which could violate statistical independence be misclassied because patients were taking the drug
assumptions, we performed a sensitivity analysis that on an as-needed schedule.
excluded such patients.
Concurrent antiplatelet drug/nonsteroidal anti-
inammatory drug use. The study antiplatelet drugs
Study Medication Use During Follow-Up were aspirin, P2Y12 inhibitors, and other antiplatelet drugs
The study analysis required identifying periods of (dipyridamole and cilostazole). NSAIDs comprised the
exposure to warfarin, PPIs, and antiplatelet drugs/NSAIDs. nonselective NSAIDs other than aspirin. Concurrent anti-
Because these medications are thought to alter the risk of platelet drug/NSAID use during follow-up was dichoto-
bleeding only while the patients are taking the drugs, we mized as either present or absent. For aspirin and other
tracked study medication exposure during follow-up on a antiplatelet drugs, concurrent use was present for the
day-by-day basis. interval from the lling of the prescription through 7 days
Filled prescriptions provided a surrogate measure for after the end of the days of supply, given that these medi-
drug use during follow-up. Periods of drug exposure were cations irreversibly inhibit platelets. The period of concur-
dened according to the date the prescription was lled and rent use for non-aspirin NSAIDs was the interval from the
the dispensed days of supply. The maximum days of supply lling of the prescription through the end of the days of
per prescription was 31 days for Tennessee Medicaid and supply.
90 days for Medicare. Because medication regimens often Medication use examples. Supplementary Figure 1
change during a hospital stay, we ended the prescription provides examples of the medication use denitions. For
days of supply when the patient was admitted to the hos- convenience, the examples only depict the rst 180 days of
pital. Study medication use would resume if and when the cohort follow-up. There are 7 hypothetical patients with
patient relled the medication after hospital discharge. warfarin treatment, each illustrating a common pattern of
Some of the study drugs can affect the risk of bleeding warfarin use.
for a few days after cessation of use. The denitions of the
exposure periods varied slightly according to drug, as 1. Patient starts warfarin therapy and has no other
described here. study medications. The entire follow-up period is
Warfarin treatment. The risk of warfarin-related included in the analysis as warfarin treatment.
bleeding should only be present while patients are taking 2. Patient receives two 60-day courses of warfarin
the drug. Thus, all study analyses were restricted to periods therapy separated by 60 days. The interval between
of warfarin treatment during follow-up, dened as the the warfarin courses is not considered warfarin
interval from the date the prescription was lled through 3 treatment and is excluded from the analysis. Thus,
days after the end of the days of supply. Although some patient 2 would contribute 63 63 126 person-
warfarin effects can persist for up to 5 days (eg, surgery is days of warfarin treatment to study analyses. The
not recommended within 5 days of use), our assessment of remaining 54 days of person-time for that patient
the literature is that much of the risk for increased bleeding would not be considered.
is gone by day 3.
Proton pump inhibitor co-therapy. All warfarin 3. Patient is started on warfarin and a PPI. The entire
treatment was classied into 3 categories according to 180 days of follow-up will be classied as warfarin
concomitant use of PPIs (dexlansoprazole, esomeprazole, treatment with PPI co-therapy.
lansoprazole, omeprazole, pantoprazole, and rabeprazole):
4. A patient begins warfarin, a PPI, and a P2Y12 inhibi-
 PPI co-therapy was the period during which gastro- tor. The entire 180 days of follow-up will be classied
protective effects were most plausible, dened as the as warfarin treatment with concurrent antiplatelet
interval from the lling of the prescription through the drug/NSAID use and PPI co-therapy.
end of the dispensed days of supply.
5. A patient begins warfarin and a P2Y12 inhibitor, but
 No co-therapy indicated person-time for which no PPI there is no PPI prescription within the past year. The
prescription had been lled in the past 365 days. entire 180 days of follow-up will be classied as
warfarin treatment with concurrent antiplatelet
 Former PPI co-therapy indicated person-time for per- drug/NSAID use. A PPI is started at day 61. Days
sons who had received a PPI prescription but should 160 will be classied as no PPI co-therapy and days
not have gastroprotection. This category permits 62180 as PPI co-therapy. Day 61 is classied as
assessment of confounding by unmeasured factors former PPI co-therapy
associated with being prescribed a PPI. It was dened
as the period between the end of current co-therapy 6. Patient receives 90 days of warfarin therapy with no
and the beginning of no co-therapy; or the rst day history of PPI use in the past year. Shortly after
for a new course of therapy (none past 365 days), given therapy begins, an NSAID is started. Subsequent to
the implausibility of a gastroprotective effect on that the NSAID, a PPI prescription is lled. The rst
day and the possibility that the PPI was started to treat 30 days of follow-up is classied as warfarin treat-
a gastrointestinal (GI) bleed. Non-current use also ment with neither PPI co-therapy nor concurrent
December 2016 PPI Co-Therapy and Warfarin-Related Upper Gastrointestinal Bleeds 1112.e3

antiplatelet drug/NSAID use. The next 30 days is 7. Patient has intermittent warfarin and PPI therapy.
warfarin treatment with concurrent antiplatelet The gaps in warfarin therapy are not included in the
drug/NSAID use, but with no PPI co-therapy. The study analysis. The periods where warfarin and PPI
remaining person-time is warfarin treatment with use overlap are warfarin treatment with PPI
both concurrent antiplatelet drug/NSAID use and PPI co-therapy, the other periods of warfarin therapy are
co-therapy. warfarin treatment with former PPI co-therapy.

Supplementary Figure 1. Medication use patterns for 7 hypothetical warfarin patients: (1) Long-term warfarin use, no other
study medications; (2) two 60-day warfarin courses separated by 60 days; (3) warfarin with PPI; (4) warfarin PPI P2Y12;
(5) warfarin P2Y12, PPI starts after warfarin; (6) 90-day warfarin course, NSAID after warfarin start and subsequently PPI; and
(7) intermittent warfarin and PPI therapy.
1112.e4 Ray et al Gastroenterology Vol. 151, No. 6

Serious Bleeding End Points algorithm5 with minor modications. The primary modi-
Serious bleeding end points were hospitalizations with cation was of the method for distinguishing upper and
diagnoses and procedures indicating that the hospitaliza- lower GI bleeding when the hospital discharge diagnosis
tion was primarily related to a major bleed. These hospi- was 578.1 or 578.9, which can indicate either an upper or
talizations were classied according to the probable site of lower site. Previously, we relied upon procedure codes: for
the bleeding: example, if there was a procedure code for upper GI
endoscopy, but no diagnosis compatible with upper GI
1. gastroduodenal;
bleeding, we would assign an upper site. We modied this
2. esophageal, other than gastroesophageal reux denition because an endoscopy coupled with discharge
disease; diagnoses not indicating upper GI bleeding may reect a
negative diagnostic evaluation. The revised algorithm is
3. upper GI, unspecied as to esophageal or
available from the authors on request.
gastroduodenal;
We assessed the performance of the modied algorithm
4. upper GI, angiodysplasia; for the primary study end point of upper GI bleeding. This
utilized the 239 completed chart adjudications for bleeding
5. lower GI; hospitalizations from our previous validation study.5 The
6. unspecied GI, possibly esophageal, upper, or lower; performance of algorithms for identifying any GI bleeding
did not change: positive predictive value 102/103
7. multiple GI; (99.0%); sensitivity 102/103 (99.0%). Upper GI bleeding
8. genitourinary; performance was based on 103 cases of GI bleeding
identied by both algorithms and with completed chart
9. cerebral; adjudication (Supplementary Table 2).
10. other specied site; For the published algorithm, the positive predictive
value was 77.3% and the sensitivity 87.1%. For the revised
11. unspecied site; algorithm, the positive predictive value was 80.5% and the
sensitivity was 84.6%.
12. multiple sites.
We also assigned a date of the bleeding onset. For 92%
The upper GI sites were classied as those that should of the cases of the primary end point, this was the date of
(1 and 3) or should not (2 and 4) be affected by PPI the hospital admission. When there was evidence that the
co-therapy. The primary study endpoint, upper GI bleeding, bleeding began earlier (eg, hospitalization for bleeding
was the composite of sites 1 and 3. The other GI site end peptic ulcer with preceding day emergency department
point was the composite of sites 2, 4, 5, 6, and 7. visit with hematemesis diagnosis) the date was reset: 6% to
We identied bleeding-related hospitalizations and the day before hospital admission, 1% 27 days prior, and
assigned a bleeding site using a previously validated 1% 830 days prior.

Supplementary Table 2.Performance of Modied Algorithm for Upper Gastrointestinal Bleeds

Variable Upper GI bleed, n No Upper GI bleed, n All, n

Published algorithm
Computer UGIB 34 10 44
No computer UGIB 5 54 59
All 39 64 103
Revised algorithm
Computer UGIB 33 8 41
No Computer UGIB 6 56 62
All 39 64 103

UGIB, upper GI bleed.


December 2016 PPI Co-Therapy and Warfarin-Related Upper Gastrointestinal Bleeds 1112.e5

Study covariates Supplementary Table 3. Continued


Supplementary Table 3 shows all of the study covariates,
No PPI PPI
according to PPI co-therapy status.
Covariate co-therapy co-therapy

Supplementary Table 3.Study Covariates According to AMI, revascularization, angina 13.7 17.5
Proton Pump Inhibitor Co-Therapy Stroke or TIA 23.7 25.2
Heart failure 37.5 43.1
No PPI PPI Diabetes 34.9 40.7
Covariate co-therapy co-therapy Peripheral vascular disease 11.4 13.3
Renal failure 7.6 12.4
Person-years warfarin treatment 52,407 14,658 Smoking 14.0 18.4
Demographic characteristics Hypovolemia 7.1 12.0
Age, y 67.7 68.2 Alcohol abuse and related illnesses 1.8 1.9
Female sex 61.7 66.3 Liver disease 3.0 5.2
Year Medical care utilization
19961999 20.4 2.2 GI hospitalization past 90 d 0.9 1.7
20002002 24.4 17.1 GI hospitalization past 91365 d 2.3 4.8
20032005 19.7 41.0 Other hospitalization past 90 d 22.9 25.3
20062011 12.1 8.8 Other hospitalization past 91365 d 30.5 36.8
20122013 23.4 30.9 Hospital days: GI 10 0.7 1.7
Medicaid, disability enrollment 51.1 49.2 ED visit, GI, past year 5.1 9.4
Medicaid, other enrollment 20.7 14.2 ED visit, any, past 90 d 27.3 32.6
Medicare 28.2 36.6
Nursing home residence past year 11.7 13.3
Warfarin rst 30 d of treatment 10.3 8.8 NOTE. Values are percentages unless otherwise noted.
Warfarin indication AMI, acute myocardial infarction; Coxib, cycloxygenase-2
Atrial brillation 52.7 53.2 selective NSAID; ED, emergency department; GERD,
Deep vein thrombosis 24.7 28.7 gastroesophageal reux disease; SSRI, selective serotonin
Other cardiovascular 14.6 11.2 re-uptake inhibitor; TIA, transient ischemic attack.
Other or unknown 7.9 6.9
GI disease
Peptic ulcer disease past 365 d 3.9 15.6
Gastritis 3.1 10.6
Other upper GI 3.0 12.8
Lower GI disease 15.2 26.9
Blood stool/GI bleeding past 90 d 0.8 1.9
Blood stool/GI bleeding past 91365 d 1.8 4.2
Abdomen pain past 30 d 2.2 4.4
Epigastric/abdominal pain past 90 d 3.7 7.2
Epigastric/abdominal pain 12.2 21.9
past 91365 d
GERD/dyspepsia past 365 d 22.7 57.3
Lower GI symptoms 5.0 10.5
Risk factors for warfarin-related bleeding
Non-GI warfarin-related bleeding 9.2 12.0
Anemia past 30 d 3.5 5.4
Anemia past 90 d 8.0 13.8
Anemia past 91365 d 9.4 15.5
Abnormal coagulation prole 5.9 7.9
past 365 d
Transfusion 7.1 11.0
Medications affecting GI bleeding
H2RA, any 25.7 19.5
Aspirin, current use 4.0 5.8
NSAID, current use, not new start 4.7 5.6
NSAID, current use, new start 0.3 0.3
Coxib, current use 3.4 8.2
Clopidogrel, current use 2.8 5.2
Other antiplatelet drug, current use 0.9 1.3
Other anticoagulant, current use 0.6 0.9
Corticosteroid (systemic), current use 3.6 6.8
SSRI, current use 14.6 27.7
Antibiotic, current use 8.6 12.5
Cardiovascular comorbidity
1112.e6 Ray et al Gastroenterology Vol. 151, No. 6

Additional Findings Supplementary Table 4. Continued

No PPI PPI
Characteristic co-therapy co-therapy
Supplementary Table 4.Characteristics of New Episodes of
Warfarin Treatmenta According to GERD/dyspepsia 24.8 60.9
Study Population and Proton Pump Any antiplatelet drug/NSAID 22.8 29.7
Inhibitor Co-Therapya Aspirin 0.0 0.0
Nonselective NSAID 12.9 17.9
No PPI PPI P2Y12 or other antiplatelet druge 11.6 14.3
Characteristic co-therapy co-therapy Coxib, current use 1.1 1.8
Smoking 16.7 21.2
Tennessee Medicaid AMI, revascularization, angina 10.5 14.6
Person-years warfarin treatmentb 37,626 9,289 Stroke or TIA 24.5 29.0
Tennessee Medicaid 100.0 100.0 Heart failure 36.2 43.8
Age, y 64.1 63.8 Digoxin 15.0 13.1
Female sex 62.4 66.2 Loop diuretic 39.3 48.6
Nursing home residence past year 12.6 12.6 Insulin 9.3 14.6
Warfarin indication Oral hypoglycemic 21.4 23.9
Atrial brillation 46.6 46.4 Alcohol abuse and related illnesses 0.5 0.9
Deep vein thrombosis 26.2 30.7 Hospitalization 51.7 62.7
Other cardiovascular 18.7 15.3 ED visit, any, past 90 d 25.0 30.6
Other or unknown 8.4 7.7
History risk factors for upper 34.0 56.6
GI bleeding NOTE. Values are percentages unless otherwise noted.
Peptic ulcer disease 4.3 16.6 AMI, acute myocardial infarction; Coxib, cycloxygenase-2
Gastritis 3.4 11.1 selective NSAID; ED, emergency department; GERD,
Blood in stool/GI bleedingc 2.7 6.3 gastroesophageal reux disease; TIA, transient ischemic
Abdominal pain 16.5 30.7 attack.
a
Anemiad 16.7 26.7 Weighted according to person-years of warfarin treatment.
GERD/dyspepsia 21.8 55.3 Unless otherwise noted, all values are proportions. Unless
Any antiplatelet drug/NSAID 40.4 47.9 otherwise stated, disease/medication variables reect diag-
Aspirin 13.7 19.1 nosis/prescription ll during the preceding 365 days.
b
Nonselective NSAID 27.0 28.6 Not shown are 8,654 person-years of follow-up for non-
P2Y12 or other antiplatelet druge 8.4 14.9 current PPI co-therapy.
c
Coxib, current use 4.3 11.8 Outpatient or inpatient not meeting end-point denition
Smoking 13.0 16.8 (admission not related to bleeding with secondary diagnosis,
AMI, revascularization, angina 14.9 19.2 such as blood in stool, indicating bleeding).
d
Stroke or TIA 23.4 23.0 Diagnosis or prescription for iron.
e
Heart failure 38.0 42.6 Dipyridamole, cilostazole.
Digoxin 33.0 26.9
Loop diuretic 50.9 58.2
Insulin 15.7 19.1
Oral hypoglycemic 24.8 29.3
Alcohol abuse and related illnesses 2.3 2.5
Hospitalization 55.5 64.6
ED visit, any, past 90 d 28.2 33.8
5% National Medicare Sample
Person-years warfarin treatmentb 14,781 5,369
Tennessee Medicaid 0.0 0.0
Age, y 77.0 75.9
Female sex 60.1 66.6
Nursing home residence past year 9.2 14.5
Warfarin indication
Atrial brillation 68.3 65.1
Deep vein thrombosis 20.8 25.4
Other cardiovascular 4.2 4.1
Other or unknown 6.7 5.4
History risk factors for upper 37.9 58.7
GI bleeding
Peptic ulcer disease 3.1 13.8
Gastritis 2.2 9.6
Blood in stool/GI bleedingc 2.3 5.7
Abdominal pain 14.5 26.4
Anemiad 25.7 39.0
December 2016 PPI Co-Therapy and Warfarin-Related Upper Gastrointestinal Bleeds 1112.e7

Supplementary Table 5.Hospitalizations for Bleeding During Warfarin Treatment According to Study Population, Site of the
Bleeding and Proton Pump Inhibitor Co-Therapy

Variable No PPI Co-therapy Former PPI Co-therapy PPI Co-therapy

Tennessee Medicaid
Person-years 37,626 5527 9289
Upper GI
Bleeding hospitalizations 452 107 125
Rate/10,000 120.1 193.6 134.6
HRa (95% CI) 1.05 (0.83 to 1.33) 0.78 (0.63 to 0.98)
RDa (95% CI) 6.1 (20.2 to 39.2) 25.9 (45.0 to 2.1)
P value .6779 .0349
Other GI
Bleeding hospitalizations 607 158 234
Rate/10,000 161.3 285.9 251.9
HRa (95% CI) 1.10 (0.91 to 1.34) 1.06 (0.89 to 1.26)
RDa (95% CI) 16.6 (14.6 to 54.5) 9.5 (17.9 to 42.1)
P value .3201 .5224
Other major bleeds
Bleeding hospitalizations 601 128 176
Rate/10,000 159.7 231.6 189.5
HRa (95% CI) 1.06 (0.86 to 1.31) 1.00 (0.82 to 1.21)
RDa (95% CI) 9.7 (22.1 to 48.9) 0.4 (28.2 to 33.3)
P value .5785 .9791
5% National Medicare Sample
Person-years 14,781 3127 5369
Upper GI
Bleeding hospitalizations 172 52 56
Rate/10,000 116.4 166.3 104.3
HRa (95% CI) 0.90 (0.64 to 1.26) 0.72 (0.52 to 0.99)
RDa (95% CI) 11.7 (41.5 to 30.0) 33.1 (56.2 to 1.2)
P value .5361 .0429
Other GI
Bleeding hospitalizations 329 122 169
Rate/10,000 222.6 390.1 314.7
HRa (95% CI) 1.10 (0.88 to 1.38) 1.10 (0.90 to 1.34)
RDa (95% CI) 22.6 (26.6 to 84.2) 21.2 (23.2 to 75.5)
P value .3965 .3743
Other major bleeds
Bleeding hospitalizations 200 77 83
Rate/10,000 135.3 246.2 154.6
HRa (95% CI) 1.28 (0.96 to 1.70) 0.95 (0.72 to 1.25)
RDa (95% CI) 37.4 (5.4 to 94.4) 7.2 (38.0 to 33.4)
P value .0928 .6986

RD, adjusted rate difference per 10,000.


a
Both the HR and RD are adjusted for the covariates shown in Supplementary Table 3.
Supplementary Table 6.Hospitalizations for Upper Gastrointestinal Bleeding During Warfarin Treatment According to Study Population, Proton Pump Inhibitor

1112.e8 Ray et al
Co-Therapy and Concurrent Use of Antiplatelet Drugs/Nonsteroidal Anti-Inammatory Drugs

No PPI co-therapy PPI co-therapy

Person-years Hospitalizations Rate/10,000 Person-years Hospitalizations Rate/10,000 HR (95% CI) RD (95% CI)

Tennessee Medicaid
No concurrent antiplatelet drug/NSAID 32,519 310 95.3 7430 87 117.1 0.92 (0.71 to 1.19) 7.6 (27.7 to 18.6)
Any concurrent antiplatelet drug/NSAID 5107 142 278.0 1859 38 204.4 0.56 (0.39 to 0.82) 121.3 (170.4 to 49.8)
Aspirin only 1783 47 263.5 648 12 185.3 0.51 (0.27 to 0.97) 129.5 (193.0 to 9.0)
NSAID only 1989 58 291.6 540 11 203.5 0.57 (0.30 to 1.10) 124.5 (204.9 to 30.2)
P2Y12/other antiplatelet only 941 23 244.3 437 8 183.0 0.57 (0.25 to 1.29) 104.5 (182.2 to 70.5)
Multiple drugs 393 14 355.8 233 7 299.9 0.69 (0.27 to 1.71) 111.9 (258.0 to 252.5)
5% National Medicare Sample
No concurrent antiplatelet drug/NSAID 13,722 139 101.3 4838 47 97.1 0.78 (0.55 to 1.11) 22.4 (45.8 to 10.9)
Any concurrent antiplatelet drug/NSAID 1060 33 311.4 531 9 169.4 0.49 (0.23 to 1.03) 160.0 (239.7 to 8.2)
Aspirin only
NSAID only 357 13 364.4 205 4 195.1 0.50 (0.16 to 1.55) 181.8 (305.3 to 199.4)
P2Y12/other antiplatelet only 684 19 277.7 312 5 160.2 0.49 (0.18 to 1.33) 140.7 (227.0 to 92.2)
Multiple drugs 19 1 532.5 14 0 0

Gastroenterology Vol. 151, No. 6


Supplementary Table 7.Hospitalizations for Upper Gastrointestinal Bleeding During Warfarin Treatment According to Study Population, Proton Pump Inhibitor

December 2016
Co-Therapy, History of Upper Gastrointestinal Bleeding Risk Factors,a and Concurrent Use of Antiplatelet Drugs/Nonsteroidal
Anti-Inammatory Drugs

No PPI co-therapy PPI co-therapy

Variable Person-years Hospitalizations Rate/10,000 Person-years Hospitalizations Rate/10,000 HR (95% CI) RD (95% CI)

Tennessee Medicaid
No history risk factors
No concurrent antiplatelet drug/NSAID 21,468 141 65.7 3211 22 68.5 1.02 (0.64 to 1.61) 1.1 (23.4to39.9)
Concurrent antiplatelet drug/NSAID 3375 78 231.1 823 8 97.2 0.42 (0.20 to 0.87) 134.4 (184.7 to 29.5)
History risk factors
No concurrent antiplatelet drug/NSAID 11,050 169 152.9 4219 65 154.1 0.87 (0.64 to 1.19) 19.3 (54.6 to 28.6)
Concurrent antiplatelet drug/NSAID 1733 64 369.4 1036 30 289.6 0.69 (0.44 to 1.08) 115.4 (207.3 to 28.5)
5% National Medicare Sample
No history risk factors
No concurrent antiplatelet drug/NSAID 8581 62 72.2 1999 10 50.0 0.71 (0.36 to 1.39) 21.3 (46.2 to 27.8)
Concurrent antiplatelet drug/NSAID 599 11 183.7 218 2 91.8 0.50 (0.11 to 2.24) 92.7 (163.6 to 228.2)
History risk factors
No concurrent antiplatelet drug/NSAID 5140 77 149.8 2840 37 130.3 0.81 (0.54 to 1.22) 28.5 (69.4 to 33.2)
Concurrent antiplatelet drug/NSAID 461 22 477.4 313 7 223.3 0.48 (0.20 to 1.13) 250.6 (381.6 to 59.7)

PPI Co-Therapy and Warfarin-Related Upper Gastrointestinal Bleeds 1112.e9


RD adjusted rate difference per 10,000.
a
Risk factors: Peptic ulcer, gastritis, abdominal pain, blood in stool/GI bleeding, anemia.
1112.e10 Ray et al Gastroenterology Vol. 151, No. 6

3. Ray WA. Population-based studies of adverse drug


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