ABSTRACT
Aims:
To determine the long-term incidence and outcome of gastrointestinal (GI) bleeding in users of aspirin with (dual antiplatelet therapy, DAPT) or without clopidogrel.
Settings and Design:
Prospective hospital based 12-year study.
Methods and Material:
There were 1047 patients on either aspirin 150 md/day alone (n = 574, 54.8%) or aspirin 75 md/day + clopidogrel 75 md/day (n = 473, 45.2%) were followed up for any incident GI bleed, rebleed and mortality. Those simultaneously using other drugs known to cause GI bleeding were excluded. Comorbidities, concomitant use of proton pump inhibitors and statins were noted.
Results:
GI bleed occurred in 11.8% after 8,683 person years of follow up. 56 (45%) patients had lower GI source of bleed [colon 9 (7%), small gut 47 (38%)] and 68 (55%) had upper GI source [duodenum 39 (32.3%), stomach 28 (22.6%) and oesophagus 1 (0.1%)]. Whereas stomach and duodenum were the chief sites in the first year, small gut predominated in later years. The cumulative bleeding rate after 1, 5 and 10 years was 5%, 8% and 11%, respectively, higher in the DAPT group. Bleeding stopped spontaneously in 98% on drug withdrawal, and 7.3% patients rebled in the next 6.2 years. The overall mortality was 33.1% but only 1.6% was due to the bleed being significantly lower in the DAPT group. On multivariate analysis coronary interventions, diabetes mellitus, renal and multiorgan dysfunction were the significant predictors of GI bleed and mortality.
Conclusions:
Though the incidence and mortality are low, GI bleed increases with longer use of antiplatelet agents predominantly from the lower GI tract.
Keywords: Aspirin, clopidogrel, dual antiplatelet therapy, gastrointestinal bleed, inflammation
Introduction
The Global Burden of Disease study[1] has shown the rising trend of cardiovascular and cerebrovascular diseases, the major causes of morbidity and mortality world over partly due to the aging population. Aspirin and other antiplatelet agents (of which clopidogrel has been the longest in use) are the key drugs used for their primary and secondary prophylaxis. As people live longer with these chronic ailments, long term use of such drugs mandates more data on their side effects [especially gastrointestinal (GI) bleeding which is expected to rise] to ensure safe use. Majority of western studies have reported GI bleed rates of 0.7%–1.3% for aspirin and 1.2%–2% for aspirin + clopidogrel combination (dual antiplatelet therapy, DAPT) within maximum follow up of 1–2 years.[2,3] Data on long term (>10 years) incidence of GI bleed are sparse, reported as 2.1% in males after 14 years[4] and 1.75% in females after 24 years of aspirin use.[5] Data are sparser from the eastern world.[6] The present study was aimed to delineate the long term incidence of GI bleed, rebleed, treatment outcome and mortality as also any difference therein among the patient groups receiving the above medications for various indications. With rising elderly population in resource limited Indian settings, many primary care providers will have to deal with problems in this patient group early in their course. The outcome of our study might give guidelines for them in such patient management.
Subjects and Methods
Type and duration of study: Prospective single centre observational study from January 2007 to December 2018.
Study participants: (a) Inclusion criteria: Patients receiving either aspirin 150 md/day alone or a combination of aspirin 75 md/day + clopidogrel 75 md/day for various indications [Table 1]. Only these medicines were chosen as they have been in use for very long giving the opportunity to generate valid long-term data. Concomitant use of proton pump inhibitors (PPI) and statins were noted as also the associated comorbidities. As atorvastatin is supplied free by the hospital, all the patients were taking this statin only. (b) Exclusion criteria: Patients receiving only low dose aspirin 75 mg/day (to keep the groups comparable and avoid the bias of using lower drug dosage) and those simultaneously taking other drugs known to cause GI bleeding (NSAID, COX-2 inhibitors, anticoagulants, selective serotonin reuptake inhibitors, other antiplatelet agents, corticosteroids) on regular basis.
Table 1.
Patient characteristics with univariate analysis of differences
| Variables | Total patient number (n=1047) | Bleeder (n=124, 11.8%) | Non bleeder (n=923, 88.2%) | P [overall bleeder vs non bleeder] | ||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|||||||
| Overall | E (n=55, 44.4%) | DAPT (n=69, 55.6%)* | Overall | E (n=519, 56.2%) | DAPT (n=404, 43.8%) | |||
| Age (years)@ | 59.21+11.23 (45-80) | 60.21+9.87 (48-76) | 61.04+8.54 (48-76) | 59.78+12.15 (49-80) | 57.59+10.78 (45-76) | 57.42+10.23 (45-76) | 57.78+9.84 (47-73) | 0.01 |
| Males | 687 (66%) | 87 (70%) | 38 (69%) | 49 (71%) | 600 (65%) | 330 (63.6%) | 270 (66.8%) | 0.1 |
| BMI (kg/m2)@ | 20.2+2.1 (18.7-23.8) | 21.5+1.8 (18.8- 23.5) | 21.2+1.4 (19.1- 23.1) | 21.8+1.6 (19.2- 23.8) | 19.8+0.8 (18.8- 21.9) | 20.1+1.6 (18.1- 22.6) | 19.6+1.8 (18.8-23.1) | 0.5 |
| Follow up (years)@ | 7.9+2.8 (5-12) | 7.8+2.6 (5-12) | 8.1+2.8 (5-12) | 7.6+3.1 (5-12) | 7.9+2.8 (5-12) | 8.2+2.7 (5-12) | 7.8+2.6 (5-12) | 0.1 |
| Indications | ||||||||
| Angina | 430 (41.1%) | 43 (34.7%) | 19 (34.5%) | 24 (34.8%) | 387 (41.9%) | 207 (39.9%) | 180 (44.5%) | 0.14 |
| PCI with stenting | 118 (11.3%) | 26 (21%) | 2 (3.6%) | 24 (34.8%)* | 92 (9.9%) | 5 (1%) | 87 (21.5%)* | 0.00002 |
| CABG | 147 (14%) | 35 (28.2%) | 2 (3.6%) | 33 (47.8%)* | 112 (12.1%) | 4 (0.8%) | 108 (26.7%)* | 0.00003 |
| PVD | 56 (5.3%) | 1 (1.2%) | 1 (1.8%) | 0 | 55 (5.9%) | 34 (6.5%) | 21 (5.2%) | 0.02 |
| Ischemic CVD | 181 (17.3%) | 15 (12.1%) | 7 (12.7%) | 8 (11.6%) | 166 (18%) | 91 (17.5%) | 75 (18.6%) | 0.13 |
| Cardiomyopathy | 115 (11%) | 4 (3.2%) | 2 (3.6%) | 2 (2.9%) | 111 (12%) | 51 (9.8%) | 60 (14.8%)* | 0.005 |
| Comorbidities | ||||||||
| Smoking | 444 (42.4%) | 72 (58%) | 37 (67.3%) | 35 (50.7%) | 372 (40.3%) | 206 (39.7%) | 166 (41.1%) | 0.0002 |
| Alcohol consumption | 227 (21.7%) | 43 (34.7%) | 22 (40%) | 21 (30.4%) | 184 (19.9%) | 100 (19.3%) | 84 (20.8%) | 0.0003 |
| Diabetes mellitus | 403 (38.5%) | 72 (58%) | 34 (61.8%) | 38 (55.1%) | 331 (35.8%) | 181 (34.9%) | 150 (37.1%) | 0.0000 |
| Hypertension | 671 (64.1%) | 90 (72.6%) | 45 (81.8%) | 45 (65.2%) | 581 (62.9%) | 315 (60.7%) | 266 (65.8%) | 0.04 |
| Dyslipidemias | 361 (34.5%) | 60 (48.4%) | 33 (60%) | 37 (53.6%) | 301 (32.6%) | 160 (30.8%) | 141 (34.9%) | 0.0007 |
| Previous GI bleed | 25 (2.4%) | 10 (8.1%) | 4 (7.3%) | 6 (8.7%) | 15 (1.6%) | 9 (1.7%) | 6 (1.5%) | 0.0000 |
| Chronic liver disease | 6 (0.6%) | 4 (3.2%) | 1 (1.8%) | 3 (4.3%) | 2 (0.2%) | 2 (0.4%) | 0 | 0.0004 |
| Chronic renal disease | 96 (9.2%) | 19 (15.3%) | 10 (18.2%) | 9 (13%) | 77 (8.3%) | 42 (8.1%) | 35 (8.7%) | 0.02 |
| COPD | 96 (9.2%) | 26 (21%) | 12 (21.8%) | 14 (20.2%) | 70 (7.6%) | 42 (8.1%) | 28 (6.9%) | 0.0003 |
| Multiorgan dysfunction | 35 (3.3%) | 15 (12.1%) | 7 (12.7%) | 8 (11.6%) | 20 (2.1%) | 10 (1.9%) | 10 (2.5%) | 0.0000 |
| Concommitant use of | ||||||||
| PPI | 100 | 124 (100%) | 55 (100%) | 69 (100%) | 923 (100%) | 519 (100%) | 404 (100%) | ns |
| Statins | 931 (88%) | 100 (80.6%) | 48 (87.3%) | 50 (75.4%) | 831 (90%) | 462 (89%) | 369 (91.3%) | 0.0002 |
| Mortality | ||||||||
| 30 day | 2 (0.2%) | 2 (1.6%) | 0 | 2 (2.9%) | 0 | 0 | 0 | 0.005 |
| 1 year | 5 (0.5%) | 5 (4%) | 4 (7.3%) | 1 (1.5%) | 0 | 0 | 0 | 0.0000 |
| At last follow up | 226 (21.6%) | 41 (33.1%) | 30 (54.5%) | 11 (15.9%)* | 185 (20%) | 138 (26.6%) | 47 (11.6%)* | 0.001 |
@Values represented as mean+standard deviation (Range), *Difference significant at P<0.05 between E vs DAPT groups. E=Ecosprin, DAPT=Dual antiplatelet therapy, PCI=percutaneous coronary intervention, CABG=coronary artery bypass grafting, PVD=peripheral vascular disease, CVA=cerebrovascular accident, COPD=Chronic obstructive pulmonary disease, GI=gastrointestinal
Follow up: The patients were followed up for any incident GI bleed, rebleed and mortality. As all the patients get their quota of medicines free of cost every month from this hospital, they were automatically followed up monthly. At every visit they were asked about symptoms of anaemia (weakness fatigue), dyspepsia/pain abdomen and any incidence of hematemesis or melena. The haemoglobin level was checked routinely every 6 months or before if mandated by anaemia, GI bleed and other comorbidities. Stool guaiac test was done if anaemia was found in absence of overt GI bleed. Other appropriate tests were also done as mandated by the comorbidities.
Treatment: Those with overt GI bleed or anaemia with positive stool guaiac test (in absence of overt GI bleed) underwent upper GI endoscopy first within 12 hours followed by colonoscopy if endoscopy was normal. If both were negative, a small gut source was assumed (small gut enteroscopy or capsule endoscopy was not done routinely except when bleeding was persistent or significant without response to therapy). Upper GI bleed was defined as any bleed occurring from oesophagus, stomach and up to the ampulla of Vater in the second part of duodenum. Any source beyond that was labelled as lower GI bleed. Intravenous (IV) pantoprazole 80-mg bolus, followed by a continuous infusion of 8 mg/hour was started before endoscopy and continued later for 72 hours, if an upper GI source of bleed was found. Blood transfusion was given if (a) haemoglobin was <8 gm% or higher if mandated by comorbidities (b) there was acute drop in haemoglobin of 3 gm/dl from baseline or (c) significant hypotension. The treatment of other comorbidities were continued as necessary.
In patients receiving aspirin only, the drug was discontinued for at least three days and up to seven days if bleed did not stop. It was reintroduced at a dose of 75 mg/day after bleeding stopped. For those receiving aspirin and clopidogrel, the latter was first discontinued for up to five days with continuation of aspirin. If bleed stopped, only aspirin was continued. If bleed continued, then aspirin was also stopped and reintroduced first after stoppage of bleed in the same dose. Restarting clopidogrel after two weeks depended on the indication of therapy (especially for acute coronary syndrome with stenting or coronary artery bypass grafting) and the duration of combination drug use (less than 1 year). The patients were subsequently followed up for any rebleed or mortality from any cause. In case of rebleed, repeat endoscopy was done (with endotherapy, if needed). Adverse cardiovascular and cerebrovascular events on drug discontinuation if any was also noted.
Statistics
Continuous and discrete variables were expressed as mean + standard deviation and percentage, respectively, and compared by Student’s t-test and Chi-square test, respectively. Univariate analysis of the individual risk factors associated with GI bleed and mortality was done by calculating the respective odds ratio (OR) followed by Cox-Proportional regression analysis to find the independent predictors of survival, where variables in univariate analysis with P ≤ 0.10 were entered into the stepwise forward multivariable model to calculate the hazards ratio (HR). All statistical analysis was done with SPSS version 13 (Chicago Inc). A two-sided P < 0.05 was considered significant.
We conducted this study in compliance with the principles of the Helsinki Declaration of 1975, as revised in 2000. The study protocol was reviewed and approved by the institutional ethics committee and written informed consent was obtained from all patients to be included in the study.
Results
A total of 1629 patients were recruited. For various reasons, 582 patients were excluded (437 taking other drugs known to cause GI bleed, 105 for missing data and 40 for inadequate follow up), and finally 1047 patients were included. The results are summarized in Tables 1–3 and Figures 1 and 2. The mean duration of atorvastatin use was 8.4 (6–10) years in dose of 10–20 mg/day. After mean follow up of 7.9 (5–12) years (8,683 person years), GI bleed occurred 11.8% patients but mortality due to the bleed happened in only 2 (4.8%, all in the first month after coronary interventions) though overall mortality in bleeders was significantly higher than in non bleeders (p < 0.001). Bleeding was significantly higher yet the mortality was significantly lower in both bleeders and non bleeders in the DAPT group compared to aspirin alone. Among the patients with coronary intervention, the use of DAPT was significantly higher compared to aspirin both in bleeders and non bleeders but its use was significantly higher among bleeders than non bleeders (46% vs 21.1%, P < 0.05). All the comorbidities were significantly higher among bleeders though the use of the two drug groups was not different among both bleeders and non bleeders having these comorbidities.
Table 3.
Risk factors for mortality
| Item | Univariate OR (CI) | Multivariate HR (CI) |
|---|---|---|
| Age | 0.83 (0.61-1.11) | 0.95 (0.85-1.05) |
| Sex (Males, Females) | 1.1 (1.03-1.17), 0.68 (0.52-0.89)* |
1.03 (0.68-1.57), 0.79 (0.54-1.06) |
| Body mass index | 0.8 (0.56-1.1) | 0.86 (0.69-1.06) |
| Ecosprin | 1.63 (1.20-2.21)* | 0.82 (0.58-1.05) |
| Ecosprin+Clopidogrel | 0.6 (0.45-0.82)* | 0.26 (0.08-0.82)* |
| Proton pump inhibitor | 1 | 1 |
| Statins | 0.97 (0.6-1.56) | 0.6 (0.36-1.01) |
| Angina | 0.93 (0.68-1.31) | 0.83 (0.59-1.09) |
| Percutaneous coronary intervention with stenting | 1.98 (1.29-3.09)* | 1.57 (1.12-1.89)* |
| Coronary artery bypass grafting | 2.1 (1.45-3.01)* | 2.38 (1.13-4.23)* |
| Peripheral vascular disease | 0.87 (0.69-1.12) | 1.11 (0.79-1.31) |
| Ischemic cerebrovascular disease | 1.31 (0.91-1.89) | 1.03 (0.85-1.23) |
| Cardiomyopathy | 1.64 (1.06-2.54)* | 0.91 (0.69-1.03) |
| Smoking | 0.96 (0.71-1.29) | 1.18 (0.82-1.7) |
| Alcohol consumption | 1.15 (0.81-1.63) | 0.77 (0.5-1.17) |
| Diabetes mellitus | 1.29 (0.96-1.75) | 1.73 (1.01-2.95)* |
| Hypertension | 1.08 (0.79-1.47) | 1.08 (0.77-1.5) |
| Dyslipidemias | 1.29 (0.95-1.75) | 1.79 (1.23-2.59) |
| Chronic liver disease | 2.31 (1.27-3.41)* | 0.75 (0.36-1.16) |
| Chronic renal disease | 8.03 (6.77-9.51)* | 5.45 (1.31-10.62)* |
| Chronic obstructive airway disease | 3.97 (1.77-8.21)* | 7.79 (1.97-14.82)* |
| Multiorgan dysfunction | 5.49 (4.82-6.26)* | 1.17 (1.01-1.31)* |
OR=odds ratio, HR=hazards ratio, CI=confidence intervals, *P<0.05
Figure 1.
Cumulative incidence of GI bleed in[1] Aspirin,[2] DAPT group
Figure 2.
Cumulative incidence of mortality in[1] DAPT,[2] Aspirin group
Table 2.
Risk factors for gastrointestinal bleed
| Item | Univariate OR (CI) | Multivariate HR (CI) |
|---|---|---|
| Age | 2.71 (1.18-4.02)* | 1.93 (1.14-3.78)* |
| Sex (Males, Females) | 1.05 (0.83-1.19), 0.89 (0.68-1.18) | 0.95 (0.84-1.06), 0.93 (0.78-1.15) |
| Body mass index | 0.73 (0.45-0.24) | 0.82 (0.63-1.04) |
| Ecosprin | 1.31 (0.9-1.9) | 1.09 (0.86-1.37) |
| Ecosprin+Clopidogrel | 1.16 (0.8-1.68) | 1.04 (0.86-1.25) |
| Proton pump inhibitor | 1 | 1 |
| Statins | 0.17 (0.05-0.55) | 0.23 (0.07-0.78) |
| Angina | 1.25 (1.21-1.31)* | 1.12 (0.89-1.3) |
| Percutaneous coronary intervention with stenting | 11.52 (7.38-17.97)* | 3.57 (1.23-7.14)* |
| Coronary artery bypass grafting | 6.96 (4.65-10.47)* | 3.38 (1.12-6.76)* |
| Peripheral vascular disease | 1.07 (0.89-1.15) | 1.10 (0.87-1.34) |
| Ischemic cerebrovascular disease | 0.87 (0.68-1.02) | 0.74 (0.48-1.16) |
| Cardiomyopathy | 0.84 (0.45-1.29) | 0.91 (0.78-1.07) |
| Smoking | 0.73 (0.43-1.06) | 0.87 (0.68-1.15) |
| Alcohol consumption | 1.08 (0.7-1.7) | 0.88 (0.66-1.14) |
| Diabetes mellitus | 1.35 (0.93-1.96) | 1.73 (1.01-2.95)* |
| Hypertension | 0.85 (0.58-1.23) | 0.91 (0.78-1.08) |
| Dyslipidemias | 1.17 (0.8-1.7) | 1.03 (0.84-1.24) |
| Chronic liver disease | 8.65 (7.21-10.23)* | 1.14 (0.95-1.39)* |
| Chronic renal disease | 29.53 (7.32-78.14)* | 2.97 (1.84-4.8)* |
| Chronic obstructive airway disease | 0.89 (0.77-1.12)* | 0.82 (0.58-1.10)* |
| Multiorgan dysfunction | 11.55 (9.45-14.12)* | 3.21 (1.54-6.71)* |
OR=odds ratio, HR=hazards ratio, CI=confidence intervals, *P<0.05
Only hematemesis occurred in 3 (2.2%), melena + hematemesis in 5 (4.1%), melena in 107 (86.7%) and haematochezia in 9 (7%) patients. 56 (45%) patients had lower GI source of bleed [colon 9 (7%), small gut 47 (38%)] and 68 (55%) had upper GI source [duodenum 39 (32.3%), stomach 28 (22.6%) and oesophagus 1 (0.1%)]. Lesions found in the upper GI tract were gastroduodenitis (diffuse erythema of stomach and duodenum with scattered blood clots) in 32 (26%), gastric ulcers and erosions in 17 (14%), duodenal ulcers and erosions in 19 (15%) patients. Colonic lesions were diverticulum in 4 (3%), haemorrhoids in 3 (2.4%) and ulcers in 2 (1.6%) patients. Capsule endoscopy was done in only 9 (23.6%) patients with suspected small gut bleed which revealed jejunal ulcer in 7 (5.6%) and angioectasias in the other 2 (1.6%).
Whereas the stomach and duodenum were the chief sites of bleed in the first year of therapy (54/68 = 79%), small gut and colon predominated in later years (50/56 = 89%). Though the use of DAPT was numerically higher in patients with lower GI bleed (35/56 = 62.5% vs 34/68 = 50%) and aspirin alone in upper GI bleed (34/68 = 50% vs 21/56 = 37.5%) but the differences was not statistically significant. The past history of GI bleed was present in 5 (4%) patients.
Cumulative bleeding rate after 1, 5 and 10 years was 5%, 8% and 11%, respectively. On drug withdrawal bleeding stopped spontaneously in 120 (97%) patients within 1–5 days of conservative therapy, 2 patients died of continuous bleed, one within 12 hours of percutaneous coronary intervention (PCI) and another within 48 hours of coronary artery bypass grafting (CABG). The other 2 patients needed endoscopic intervention by oesophageal variceal band ligation which was their source of bleed. Nine (7.3%) patients rebled in the next 4.5 years at interval of 1–2 years after the index bleed.
Discussion
To the best of our knowledge this is the first study from the eastern world reporting long term (>10 years) incidence and outcome of GI bleeding in Indian patients receiving antiplatelet agents. It shows that the overall incidence and mortality is low, and the use of DAPT is associated with more GI bleed but less mortality compared to aspirin alone. Most bleed are also manageable with temporary drug discontinuation without the risk of serious adverse events. Majority of bleed related adverse events occur in the first 30 days of coronary interventions.
Short term outcome: Large randomized controlled trials show 28 day and 1 year follow up bleeding rates of 0.6% and 4.8% for DAPT compared to 0.6% and 3.8% for aspirin alone respectively.[2] Others report overall GI bleeding rate of 2.3%,[7] 2.8%[8] and 1- and 2-year cumulative incidences of upper GI bleed without the use of an antisecretory drug to be 4.5% and 9.2%, respectively.[9] Most events occur in first 30 days.[7-9] These support our results.
Long term outcome: Our study also showed that though the incidence of GI bleed rises slowly with long term use of the drugs but mortality is mostly associated with the comorbidities and not from the GI bleed only [Table 3]. The major comorbidities associated with bleed and mortality were ischemic cardiovascular diseases and their interventions, chronic kidney disease and multiorgan failure. The comorbidities were higher among bleeders who also had higher mortality though not from GI bleed. The use of the two drug groups were also not different among both the bleeders and non bleeders with these comorbidities. The cumulative bleeding rate was 8% after 5 years and 11% after 10 years.
Studies on long term outcome are scarce. In addition to the studies quoted above,[4,5] two other population based studies reported risk of GI bleed to be 6.6% for DAPT vs 4.1% for aspirin (12 years follow up, majority also used other NSAID)[10] and 4.6% for DAPT vs 1.5% for aspirin alone per year (5 years follow up of elderly patients surviving myocardial infarction, overall GI bleed rate of 6.7%).[11] A retrospective Chinese study over 6 years on elderly patients above 75 years age who underwent PCI reported a GI bleed rate of 16.5% with no rebleed after reintroduction of drugs.[6] Western studies appear to have lower incidence of GI bleed in the long term (i.e. it falls off in later years) but our results are more in conformity with the Chinese study.
Source of bleed: Upper GI tract was the commonest source in the first year but lower GI tract increasingly took over in later years. This is expected as the upper GI tract is the first site to be exposed to the drugs continually in the initial months, whereas the longer lower GI tract bears the brunt of cumulative effect in later years. A systematic review of observational studies on bleeding risk with long term low dose aspirin use showed the relative risk for upper and lower GI bleeding to be 2.3 and 1.8, respectively (overall relative risk 1.4), the association being less strong for lower GI bleed. Bleeding risks increased when it was combined with clopidogrel.[12]
Treatment outcome: The other important observation of our study was that the majority of GI bleeds responded to conservative therapy with short term drug discontinuation which did not affect the primary disease adversely. Only two adverse cardiac events were observed. Much higher rates are reported in western studies.[13] This has great public health importance for resource limited countries like India as it spares the need for expensive investigations (especially for lower GI bleed) and therapeutic modalities. These patients can be managed at the primary care level in emergency just by stopping the medicines and adding a PPI. Other appropriate investigations as outlined above can be done later in higher centres according to availability without risk of serious adverse outcomes.
The use of PPI did not appear to have an effect on the occurrence or outcome of GI bleed in our study as all our patients were already on PPI before the onset of GI bleed. A previous study reported slightly higher GI bleed rate in patients on DAPT not on PPI.[9] A systematic review[12] and another meta-analysis[14] showed that the PPIs are effective in preventing low dose aspirin-associated upper GI ulcers and bleeding and concomitant use of PPI and DAPT did not increase the risk of adverse cardiovascular events as in our study. PPI, however, either do not have any effect on or may even exacerbate lower GI bleed.[15] But statins had protective effect on GI bleed but not mortality in our study. Though initial studies[16,17] supported our results (with the possible explanation being increase in prostaglandin E by statins), later studies assume it to be due to “healthy user” bias.[18]
The strength of our study lies in the large patient number with their robust follow up data. The main limitation was the inability to demonstrate the exact site and lesion causing suspected small intestinal bleed in all such patients due to limited availability of small gut endoscopy though bleed stopped in majority on drug withdrawal for short time interval.
Conclusion
Our study, the first of its kind from the eastern world, shows that though the long-term incidence and related mortality is low compared to the western world, GI bleed rate increases with longer use of antiplatelet agents predominantly from the lower GI tract. But these can be managed by temporary drug discontinuation in the first few days without serious adverse outcome thereby sparing the need for expensive investigations. Patients after coronary interventions should be closely monitored in the first month when most short-term mortality from GI bleed occur. Comorbidities need attention for long term mortality. Statins have a protective effect on GI bleed but not mortality. Further such studies involving other antiplatelet agents, anticoagulants and NSAID may be conducted in future.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgements
Dr. A. Majumdar, Head, Dept of Cardiology for his support on the cardiology aspect of patient management and data collection and Drs. T. Agarwala, P. Manjubhargav, DNB Trainees, Dept of Medicine, B. R. Singh Hospital for data collection and maintaining records.
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