Chances of Getting Internal Bleeding From Baby Aspirin if You're 25

• Loading metrics

Open Admission

Peer-reviewed

Enquiry Article

Bleeding Risk with Long-Term Low-Dose Aspirin: A Systematic Review of Observational Studies

• Luis A. García Rodríguez,
• Mar Martín-Pérez,
• Charles H. Hennekens,
• Peter M. Rothwell,
• Angel Lanas

x

• Published: August four, 2016
• https://doi.org/10.1371/journal.pone.0160046

Figures

Abstract

Background

Low-dose aspirin has proven effectiveness in secondary and chief prevention of cardiovascular events, just is as well associated with an increased adventure of major bleeding events. For primary prevention, this absolute take a chance must be carefully weighed against the benefits of aspirin; such assessments are currently express past a lack of data from general populations.

Methods

Systematic searches of Medline and Embase were conducted to identify observational studies published betwixt 1946 and iv March 2015 that reported the risks of gastrointestinal (GI) bleeding or intracranial hemorrhage (ICH) with long-term, low-dose aspirin (75–325 mg/twenty-four hour period). Pooled estimates of the relative risk (RR) for haemorrhage events with aspirin versus not-use were calculated using random-effects models, based on reported estimates of RR (including odds ratios, hazard ratios, incidence rate ratios and standardized incidence ratios) in 39 articles.

Findings

The incidence of GI bleeding with low-dose aspirin was 0.48–3.64 cases per thousand person-years, and the overall pooled estimate of the RR with low-dose aspirin was i.4 (95% confidence interval [CI]: i.2–one.7). For upper and lower GI bleeding, the RRs with low-dose aspirin were 2.3 (2.0–two.6) and i.8 (ane.1–3.0), respectively. Neither aspirin dose nor duration of use had consistent furnishings on RRs for upper GI haemorrhage. The estimated RR for ICH with low-dose aspirin was 1.4 (1.2–1.seven) overall. Aspirin was associated with increased bleeding risks when combined with non-steroidal anti-inflammatory drugs, clopidogrel and selective serotonin reuptake inhibitors compared with monotherapy. By contrast, concomitant use of proton pump inhibitors decreased upper GI haemorrhage risks relative to aspirin monotherapy.

Conclusions

The risks of major bleeding with depression-dose aspirin in real-world settings are of a like magnitude to those reported in randomized trials. These data will help inform clinical judgements regarding the use of low-dose aspirin in prevention of cardiovascular events.

Citation: García Rodríguez LA, Martín-Pérez M, Hennekens CH, Rothwell PM, Lanas A (2016) Bleeding Chance with Long-Term Low-Dose Aspirin: A Systematic Review of Observational Studies. PLoS Ane eleven(8): e0160046. https://doi.org/10.1371/journal.pone.0160046

Editor: Tobias Eckle, University of Colorado Denver, UNITED STATES

Received: Apr 5, 2016; Accepted: May 30, 2016; Published: Baronial 4, 2016

Copyright: © 2016 García Rodríguez et al. This is an open admission article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in whatever medium, provided the original writer and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: The authors received no specific funding for this work. Medical writing support was provided by Oxford Pharmagenesis, Oxford, UK, with funding from Bayer Pharma AG. The funders had no part in report blueprint, data collection and analysis, determination to publish, or preparation of the manuscript.

Competing interests: Drs García Rodríguez and Martín-Pérez work at CEIFE, which has received enquiry grants from Bayer Pharma AG. Dr García Rodríguez has been paid as a consultant for Bayer Pharma AG (Deutschland). Professor Lanas has received research grants from, and has been paid equally a consultant for, Bayer Pharma AG. Professor Hennekens is funded past the Charles E. Schmidt College of Medicine at Florida Atlantic University. He serves as an independent scientist in an advisory role to investigators and sponsors as: Chair or Fellow member of Information and Safety Monitoring Boards for Amgen, AstraZeneca, Bayer, Bristol Myers-Squibb, British Heart Foundation, Cadila, Canadian Institutes of Health Enquiry, DalCor, Genzyme, Lilly, Regeneron, Sanofi, Sunovion and the Wellcome Foundation; advisor to Aralez/Pozen, the Us (U.Due south.) Food and Drug Administration, UpToDate, and legal counsel for Pfizer and Takeda. Professor Hennekens receives royalties for authorship or editorship of 3 textbooks and every bit coinventor on patents for inflammatory markers and CV disease that are held by Brigham and Women's Hospital; has an investment management relationship with the West-Bacon Grouping within SunTrust Investment Services, which has discretionary investment authority and does not ain whatsoever common or preferred stock in whatsoever pharmaceutical or medical device visitor. Professor Rothwell is a member of the Executive Committee of the ARRIVE trial and has received honoraria from Bayer for advisory boards. This does non alter the authors' adherence to all PLOS 1 policies on sharing data and materials.

Introduction

Aspirin (acetylsalicylic acid; ASA) is one of the earth'southward near widely used drugs [one], with substantial clinical evidence demonstrating its analgesic, antipyretic, and anti-inflammatory properties [ii]. Aspirin also exhibits antiplatelet activity by irreversibly inhibiting production of the eicosanoid thromboxane A₂ (TXA_two), a powerful promoter of platelet aggregation [3, 4]. This property underlies the effectiveness of aspirin in the prevention of occlusive cardiovascular (CV) events, including myocardial infarction [v, half-dozen], stroke [7, 8], and transient ischaemic attack [9, x], every bit demonstrated in randomized trials of primary and secondary prevention. More recently, post-hoc analyses of randomized trials have shown that aspirin reduces the incidence and bloodshed of colorectal cancer. Observational studies have besides suggested possible benefits on other cancers [11]. The use of low-dose aspirin is, withal, associated with several adverse furnishings, the most clinically relevant of which are major extracranial bleeding events, specifically GI haemorrhage [12]. In improver, aspirin increases the take chances of the serious but rare upshot, intracranial (including intracerebral) hemorrhage (ICH) [13].

In the secondary prevention of cardiovascular affliction (CVD), the absolute benefits of aspirin far outweigh the absolute risks of major bleeding events [xiv]. In master prevention, nevertheless, the net benefit of aspirin is smaller than for secondary prevention [half dozen]. Thus, recent clinical guidelines recommend that for principal prevention, clinicians assess the residual betwixt the risk of occlusive CV events and the gamble of major bleeding events on an individual basis [14–17].

In improver to establishing the level of bleeding chance associated with low-dose aspirin apply, there is a need to identify the factors that influence the risk of bleeding with aspirin therapy and the magnitudes of these effects on the gamble. For instance, many patients will exist taking concomitant medications that have been shown to increase the gamble of GI bleeding when taken alone, including anticoagulants, other antiplatelet agents, and not-steroidal anti-inflammatory drugs (NSAIDs) [18], while other patients may take a history of peptic ulcer, which is known to increase the adventure of upper GI bleeding (UGIB) considerably [nineteen].

Data from both randomized controlled trials (RCTs) and observational studies are required to assess the risks associated with depression-dose aspirin, given the notable differences between these study types in the populations included, levels of monitoring, and, therefore, reported outcomes. Indeed, a large proportion of patients who take aspirin in the real world (such every bit elderly patients, patients with a history of ulcers or GI complaints, and those who are likewise taking other gastrotoxic drugs) are excluded from some RCTs, and there is a lack of robust data from real life clinical do. A recent systematic review of RCTs and observational studies investigated the bleeding chance with aspirin therapy, and age and the presence of Helicobacter pylori were identified as factors that may increase the risk of GI bleeding events in individuals taking aspirin; however, this review included simply a minor number of observational studies, all of which were conducted in the Great britain [20].

In the present systematic review, information from a large number of observational studies, conducted across multiple countries, were assessed in order to determine the risks of the most clinically relevant adverse effect, GI haemorrhage, and the serious just rare event, ICH, in patients taking low-dose aspirin in real-world settings. The influence of risk factors, including age and concomitant medications, on the clan between low-dose aspirin and bleeding events was also assessed.

Methods

Search Strategy

Systematic searches of Medline and Embase were performed for terms relating to epidemiology, aspirin, and aspirin condom (specifically GI bleeding and ICH) in the titles and abstracts of papers published betwixt 1946 and 4 March 2015 (meet S1 File for details of the search strategy. No published protocol was followed). The search was restricted to studies conducted in humans and to publications written in English language. Reviews, editorials, comments, clinical trials and pediatric studies were excluded, as were studies using only aspirin doses college than 325 mg per day. The results were supplemented by a PubMed search for publications only available online that were non identified by Medline or Embase. In addition, i relevant article published after completion of the searches was included.

After removal of duplicates, the identified references were manually screened on the basis of titles and abstracts. Observational studies identified as containing potentially relevant information were subsequently reviewed as full-text articles. Manufactures were included but if they reported measures of association (odds ratio [OR], relative take chances [RR], hazard ratio [HR], incidence rate ratio [IRR], or standardized incidence ratio [SIR]) betwixt aspirin employ and the chance of major bleeding events, specifically events reported as GI bleeding or ICH; a full listing of exclusion criteria is detailed in S2 File. A flow chart of the systematic literature search is shown in Fig one.

Data Extraction

Details of study design, written report population, data source, aspirin dose(south), and indication were extracted from the articles. If available, information on the frequency and duration of aspirin use was also retrieved. The outcomes recorded were the incidences of GI bleeding and ICH and measures of their clan (OR, RR, 60 minutes, IRR, SIR) with low-dose aspirin (75–325 mg per twenty-four hours). In addition, several factors were examined for their potential predictive effects on the gamble of bleeding, such as historic period, history of peptic ulcer, and H. pylori infection; when available, the incidences of GI haemorrhage and ICH and the measures of association for these factors were recorded. The effects of medications taken concomitantly with low-dose aspirin (including proton pump inhibitors [PPIs], clopidogrel, and not-steroidal anti-inflammatory drugs [NSAIDs]) on the take a chance of bleeding were also documented.

Statistical Assay

Pooled estimates of the RRs for GI bleeding and ICH with low-dose aspirin versus non-use were calculated by random-effects models. This model weights individual studies by sample size and variance (both within- and between-study variance) and yields a pooled betoken estimate and 95% confidence interval (CI). Heterogeneity was assessed using the I ^two statistic. Pooled estimates of the RR with low-dose aspirin in case–control and cohort studies were compared; pooled estimates of the overall RR of low-dose aspirin in all studies were also calculated. All statistical analyses were performed using STATA 12 (Stata Corp, College Station, TX).

Results

Summary of Studies Included

A total of 39 articles met the inclusion criteria for the review (S1 Table). Among these observational studies, at that place were 23 example–control studies, including one example–crossover report [21], and 16 cohort studies, one of which was a long-term, post-trial follow-up of a randomized trial [22]. Notably, some of the case–control studies identified were nested in well-defined cohorts [23–29].

Twenty-three studies reported data from European countries (seven each from Spain and the UK), 9 from the U.s., and 7 from Asia (S1 Table). All except five studies were published since the beginning of 2000 and nigh half (18 studies) were published since the beginning of 2010. When specified, the duration of aspirin utilise ranged from 1 month to more than xx years, and reported follow-up was 4–14 years. Studies evaluated daily and/or regular use of aspirin. The criteria for participants to exist considered 'current users' of aspirin varied among studies: the maximum time period betwixt stopping aspirin use and the study alphabetize date ranged from 7 to 90 days.

Risk of Gastrointestinal Bleeding with Low-Dose Aspirin

All gastrointestinal bleeding.

Eight studies reported measures of the RR for all GI bleeding events, with low-dose aspirin compared with non-use: two case–control studies [18, 30], one case–crossover study [21], and five accomplice studies (S1 Table) [22, 31–34]. Two studies showed no increment in the risk of GI bleeding with low-dose aspirin [22, 31], whereas six studies showed a pregnant increase compared with non-use [18, 21, thirty, 32–34]. The highest risk was reported in Japanese patients prescribed depression-dose aspirin for CVD for more than i year, although the confidence intervals were wide [33]. With the exception of this study, the RRs were similar in cohort and case–control studies. The range of the estimates of the RRs for GI bleeding with low-dose aspirin was 0.99–4.64, with virtually studies reporting values between 0.99 and i.6.

The pooled estimates of the RR for GI haemorrhage with low-dose aspirin were 1.7 (95% CI: 1.2–2.v) for instance–command studies and ane.3 (95% CI: 1.0–one.7) for cohort studies (Fig 2). In that location was significant heterogeneity among cohort studies (I ² = 86.4%) and less heterogeneity amongst example–control studies (I ² = 59.0%). The overall pooled estimate of the RR for GI haemorrhage with depression-dose aspirin, for all eight studies, was i.4 (95% CI: one.2–one.vii) (Fig two), although in that location was significant heterogeneity among studies (I ² = 79.7%).

Fig 2. Adventure of gastrointestinal bleeding with low-dose aspirin.

Data are shown as adjusted OR, adjusted RR (unless otherwise stated), adjusted IRR, or multivariate HR, plus 95% CIs, for the risk of any gastrointestinal bleeding with low-dose aspirin vs no aspirin. A test for heterogeneity (I ^two statistic) is provided. ^aCase-crossover study; ^badjusted OR; ^cadjusted RR; ^dadjusted IRR; ^{due east}multivariate 60 minutes. CI, conviction interval; HR, hazard ratio; IRR, incidence rate ratio; OR, odds ratio; RR, relative risk.

https://doi.org/x.1371/journal.pone.0160046.g002

The overall incidence (as cases per 1000 person-years) of GI bleeding with low-dose aspirin were reported in ii accomplice studies conducted in the Us, ane of which involved only men (1.39 events per yard person-years) and the other of which involved only women (1.67 events per thousand person-years) [31, 32] (Fig iii).

Fig 3. Incidence (cases per 1000 person-years) of gastrointestinal bleeding with depression-dose aspirin.

^aIncidences for all GI bleeding as reported in the original studies, without specification of location inside the tract; ^bincidences specifically for upper GI bleeding every bit reported in the original studies; ^cincidences specifically for lower GI bleeding equally reported in the original studies. GI, gastrointestinal; LGIB, lower gastrointestinal bleeding; UGIB, upper gastrointestinal bleeding.

https://doi.org/10.1371/journal.pone.0160046.g003

Upper gastrointestinal bleeding.

Most studies reporting GI bleeding evaluated the effects of low-dose aspirin on UGIB. Of the 24 studies, 17 were case–control studies [eighteen, 23–26, 29, 35–45] and seven were cohort studies [31–33, 46–49]. Depression-dose aspirin was associated with a significant increment in the gamble of UGIB compared with non-use in most studies. In the case–command studies, the bulk of RRs for UGIB with low-dose aspirin were in the range 1.4–4.0 and the pooled estimate was 2.3 (95% CI: 2.0–2.7) (Fig 4). RRs in the cohort studies fell within a similar range (1.ii–4.5), with a pooled estimate of 2.0 (95% CI: one.5–2.vii). The overall pooled guess of the RR for UGIB with depression-dose aspirin, for all 24 studies, was 2.3 (95% CI: 2.0–2.6). There was significant heterogeneity amid both case–command (I ² = 76.two%) and accomplice studies (I ² = fourscore.vii%) and among all studies (I ² = 80.5%). Three case–control studies reported risks higher than those in the other studies, but these three studies all involved relatively few cases of UGIB (northward < 300) and controls, and the CIs were wide [37, 42, 44].

Fig 4. Risk of upper gastrointestinal bleeding with depression-dose aspirin: case–command studies and cohort studies.

For instance–control studies, data are shown as adapted or multivariate ORs or RRs, plus 95% CIs, for the risk of upper gastrointestinal bleeding with depression-dose aspirin vs no aspirin. For accomplice studies, data are shown as multivariate ORs, SIR, multivariate Hr, or multivariate RRs, plus 95% CIs, for the risk of upper gastrointestinal haemorrhage with depression-dose aspirin vs no aspirin. A test for heterogeneity (I ⁱⁱ statistic) is provided. ^aData for duodenal bleeding and gastric haemorrhage (defined equally bleeds located in the upper gastrointestinal tract, at sites other than the duodenum) [≤ 250 and 251–325 mg per day]; ^bInformation for apparently, enteric-coated, and buffered aspirin; ^cData for dissimilar alcohol consumption categories (current drinker/never drinker/ex-drinker); ^dInformation for gastric ulcer and duodenal ulcer bleeding (defined as the presence of melena, haematemesis or haematochezia with a substantial decrease in haemoglobin and a peptic ulcer identified endoscopically); ^eastwardData for primary and secondary prevention; ^fChance of erosive esophagitis; ^gAcute divers every bit regular or sporadic aspirin use for 5–30 days before endoscopy; ^hChronic defined as regular aspirin use for more than ane month before endoscopy; ⁱOR; ^jRR; ^gSIR; ^lHour. CI, confidence interval; Hr, hazard ratio; OR, odds ratio; RR, relative risk; SIR, standardized incidence ratio.

https://doi.org/10.1371/journal.pone.0160046.g004

One study compared the RR for UGIB with low-dose aspirin in the master and secondary prevention of CVD [29]. The RR for UGIB with low-dose aspirin alone compared with non-use was higher in the chief than in the secondary prevention cohort (adapted RR [95% CI]: 1.90 [ane.59–2.26] and ane.40 [1.xiv–i.72], respectively). However, the baseline absolute risk of UGIB was higher in the secondary than in the chief prevention cohort; patients in the secondary accomplice were older and were more than likely to take a history of ulcers and to use concomitant medications, such every bit NSAIDs, clopidogrel, and oral anticoagulants. Indeed, the analysis showed that the absolute increment in take a chance of UGIB with low-dose aspirin was college in the secondary prevention cohort than in the primary prevention cohort.

Eight studies evaluated the furnishings of aspirin dose or dosing regimen on the adventure of UGIB (Fig 5) [23, 24, 26, 31, 32, 36, 41, 48]. Two studies reported an increment in the risk of UGIB with increasing frequency of doses [31, 32] and a 3rd demonstrated a clear dose-dependency for UGIB with low-dose aspirin in a Castilian case–control study [41]. Other studies reported piffling divergence in RRs for different low-dose aspirin regimens [24, 26, 36, 48]. RRs for some doses (e.thou. 300 mg) showed marked differences betwixt the studies.

Fig five. Risk of upper gastrointestinal bleeding with low-dose aspirin: effects of dose and frequency of use.

Data are shown as adjusted RR, adjusted OR, or SIR, plus 95% CIs, for the take chances of upper gastrointestinal haemorrhage with depression-dose aspirin vs no aspirin. ^aI dose equals one 325 mg tablet; ^badapted RR; ^cAdjusted OR; ^dSIR. CI, confidence interval; OR, odds ratio; RR, relative gamble; SIR standardized incidence ratio.

https://doi.org/10.1371/journal.pone.0160046.g005

Two studies suggested that the duration of continuous low-dose aspirin handling upward to 10 or 20 years has little effect on the RR of UGIB, when adjusted for treatment dose [31, 32]. Similarly, another study reported an increase in the RR of UGIB with low-dose aspirin monotherapy, irrespective of whether patients had received treatment for less than or more than one twelvemonth [26]. However, it has also been shown that the risk of UGIB with low-dose aspirin is greatest during the first 2 months of therapy, and decreases with increasing handling elapsing [24], with a similar upshot besides being observed in another study [41].

The furnishings of contempo or past apply or discontinuation of low-dose aspirin, compared with current apply, on the hazard of UGIB were assessed in v studies [23, 24, 26, 35, 41]. All five studies showed a lower take chances of UGIB with recent or by use compared with current use of depression-dose aspirin. Ane study reported recent discontinuation of low-dose aspirin (i.e. use ending 15–180 days before the index date) in 11.2% of cases and xiii.1% of controls [23]. The data suggested that the risk of UGIB was reduced in those who had recently discontinued depression-dose aspirin when compared with patients who continued treatment (adapted RR: 0.71 [95% CI: 0.42–1.20]). Among the patients who had discontinued, the risk of UGIB was higher for those who had discontinued aspirin for safety-related reasons (RR compared with continued use: two.xviii [95% CI: 0.80–5.95]) than for patients who had discontinued for non-safety related reasons, primarily non-adherence (RR: 0.52 [95% CI: 0.28–0.99]).

Four studies reported overall incidences of UGIB with low-dose aspirin, which were in the range of 0.70–iii.64 cases per 1000 person-years (Fig three). Incidences were similar in studies conducted in the The states [31, 32] and the United kingdom of great britain and northern ireland [23] and higher in a Danish cohort report [48].

Lower gastrointestinal bleeding.

Six studies evaluated the risk of LGIB associated with the use of depression-dose aspirin compared with non-utilize: ii case–control studies [eighteen, fifty] and iv cohort studies [31–33, 51]. RRs for LGIB with low-dose aspirin varied from 0.8 to 5.0 (S1 Fig), with a pooled gauge of 1.viii (95% CI: 1.one–3.0). At that place was significant heterogeneity amid studies (I ² = 81.1%). The highest chance was reported in a Japanese report involving patients with CVD prescribed low-dose aspirin for more 1 year (OR 5.03 [95% CI: 0.59–43.16]) [33]; however, few (n < 10) cases of bleeding were observed, so the CI was wide and the finding not statistically significant. A second Japanese report reported a significantly increased run a risk of LGIB with depression-dose (100 mg) aspirin (OR 3.7 [95% CI: 1.3–10.nine]), although again, relatively few cases of bleeding (n = 44) were observed [50]. In a contempo Spanish case–control study (> 1000 observed cases of bleeding), depression-dose aspirin was associated with a 2.vii-fold increased risk of LGIB (including bleeds in both the modest and large bowel) compared with not-use [eighteen].

Ii cohort studies involving men enrolled in the Wellness Professionals Follow-upwardly Study examined the effects of aspirin on LGIB [31, 51]. One reported a significant increase in the adventure of diverticular bleeding with depression-dose aspirin (two–5.9 tablets of 325 mg per week; multivariate HR: 2.32 [95% CI: 1.34–4.02]) compared with no aspirin [51]. However, no significant increase in take chances was observed with either 0.1–1.9 or ≥ six aspirin tablets per week (multivariate HR 1.58 [95% CI: 0.88–two.82] and i.65 [95% CI: 0.84–iii.26], respectively). The other cohort study reported no significant increase in hazard of LGIB with two–5 tablets per week or whatever of the other doses studied (0.5–1.five, half-dozen–fourteen, or > xiv tablets per week) [31]. Similarly, none of these aspirin doses was associated with a significant increase in risk of LGIB in women enrolled in the Nurses' Health Study [32].The duration of continuous aspirin use also had no meaning effect on adventure of LGIB in either of these studies [31, 32].

Three studies reported overall incidence of LGIB among patients receiving depression-dose aspirin (Fig 3); the incidences were like across the studies (0.48–0.74 cases per thousand person-years) [31, 32, 51].

Chance of Intracranial Hemorrhage with Low-Dose Aspirin

Seven studies reported the risk of ICH associated with low-dose aspirin therapy: 3 cohort studies [34, 46, 52], three case–control studies [27, 28, 53], and ane case-crossover study [21]. In virtually studies, depression-dose aspirin was non associated with a significantly increased risk of ICH (Fig 6). Estimates of RRs for ICH with low-dose aspirin were 0.82–1.71 across the studies, and for most studies the 95% CI included 1.0. The pooled estimates of the RR for ICH with low-dose aspirin were 1.0 (95% CI: 0.eight–1.2) for instance–control studies and i.5 (95% CI: ane.4–i.7) for cohort studies, and i.4 (95% CI ane.2–1.seven) overall. Heterogeneity was high among all studies (I ² = 92.0%) and among case–control studies (I ^two = 71.vii%), but there was less heterogeneity among cohort studies (I ² < 0.05%). One study reported the overall incidence of ICH with low-dose aspirin (8.0 cases per 1000 person-years) in a accomplice of patients with non-valvular atrial fibrillation [52].

Fig half-dozen. Risk of intracranial (including intracerebral) hemorrhage with low-dose aspirin.

Data are shown as adapted OR, multivariate HR or adjusted IRR, plus 95% CIs, for the risk of intracranial (including intracerebral) hemorrhage with low-dose aspirin vs no aspirin. A test for heterogeneity (I ² statistic) is provided. ^aIntracerebral hemorrhage/hemorrhagic stroke; ^bIntracranial hemorrhage; ^cExample-crossover study; ^dadjusted OR; ^eastmultivariate HR; ^fadjusted IRR. CI, confidence interval; 60 minutes, adventure ratio; ICH, intracerebral hemorrhage; IRR, incidence rate ratio; OR, odds ratio; SAH, subarachnoid hemorrhage.

https://doi.org/10.1371/journal.pone.0160046.g006

Potential Predictive Factors

Age.

4 studies reported increasing incidences of major bleeding events (including all GI haemorrhage and ICH [34] and UGIB [23, 25, 48]) with increasing historic period (S2 Fig). The incidence of UGIB was like across the three studies that reported this issue and was generally higher in men than in women. The magnitude of the increase in UGIB incidence with age was more than pronounced in two studies than in the third study. One of these two studies showed an increase of 3.24 cases per k person-years in men aged ≥ lxx years compared with men anile 16–59 years [48], and the other demonstrated an increase of 2.22 cases per 1000 person-years in men aged ≥ 80 years compared with men anile 40–59 years [25].

Information on the effects of age on the RR of major bleeding events with low-dose aspirin were available from eight studies: two assessing all major bleeding events (GI bleeding and ICH) [21, 34], 2 evaluating major GI bleeding [31, 32], three reporting data for UGIB [24, 29, 48], and 1 assessing ICH [53]. There was no clear evidence that the RR of bleeding with low-dose aspirin increases with increasing age (S3 and S4 Figs).

Peptic ulcer and Helicobacter pylori infection.

Both a history of peptic ulcer and H. pylori infection were associated with a significant increment in the gamble of UGIB (S2 Table) [35, 42–45, 54]. Still, the combination of low-dose aspirin utilize and H.Pylori infection was not associated with a significant increment in the hazard of duodenal or gastric ulcer haemorrhage compared with either variable alone in one study [43]. In some other study, in that location was no increase in the risk of UGIB across the sum of the independent effects of the two variables [45].

Concomitant medications.

Some studies evaluated the effects of PPIs on the hazard of major bleeding events when taken in combination with aspirin (S3 Table)[18, 23, 34, 36, 40, 47]. In one written report, the combination of PPI plus depression-dose aspirin was not associated with an increased gamble of UGIB compared with non-utilise of both agents, in dissimilarity to the use of low-dose aspirin alone [eighteen]. In addition, another study showed that omeprazole plus low-dose aspirin was associated with a reduced gamble of UGIB compared with patients taking depression-dose aspirin alone [xl].

Several studies suggested that the use of low-dose aspirin in combination with other NSAIDs leads to an increased run a risk of bleeding events compared with utilize of depression-dose aspirin alone (S4 Table) [23, 26, 40]. Ane study reported a substantially increased risk of upper gastrointestinal complications (bleeding or perforation) with aspirin and loftier-dose NSAID compared with non-use of both drugs beyond the sum of their independent effects, simply no such interaction was observed with aspirin and low/medium-dose NSAIDs. The NSAIDs assessed in this report included ibuprofen, diclofenac, and mefenamic acid [24].

A higher risk of UGIB with low-dose aspirin plus clopidogrel compared with low-dose aspirin lone has likewise been demonstrated (S4 Tabular array) [23, 26, 35]. Clopidogrel plus low-dose aspirin was not associated with an increased risk of intracerebral hemorrhage compared with non-use of both agents [27]. In addition, when low-dose aspirin was used in combination with other anticoagulant medications, the risk of major bleeding was increased compared with non-apply or the monotherapies (S4 Table) [24, 27, 34, 35].

One study reported a small-scale, simply non significant, increase in the risk of UGIB with selective serotonin reuptake inhibitor (SSRI) use compared with non-use in patients not receiving aspirin [26] (S5 Table). Ane study reported a greater number of hospitalizations for UGIB with current use of SSRIs compared with the expected number for non-SSRI users (observed to expected ratio: 3.6), and the risk of hospitalization was increased further with SSRI plus low-dose aspirin (S5 Table) [55]. Another study, withal, showed no pregnant difference in the incidence of major bleeding events between SSRI users and individuals receiving both low-dose aspirin and an SSRI [34].

Discussion

This systematic review of 39 observational studies provides an indication of the magnitudes of the risk of major bleeding events associated with long-term, depression-dose aspirin therapy in the real world.

Furnishings of Depression-Dose Aspirin on the Gamble of Major Bleeding Events

The incidence of all GI bleeding events with low-dose aspirin varied between 0.5 and 3.half-dozen cases per 1000 person-years. The lower terminate of this range concurs with results from the 2009 meta-analysis of RCTs past the Antithrombotic Trialists' Collaboration (ATTC), which calculated an incidence of 0.5 cases of major extracranial haemorrhage events per grand person-years [6]. A contempo review estimated the incidence of all GI bleeding events in the U.k. population, using results from trials included in the ATTC analysis, likewise as those from a small number of Britain observational studies [20]. The estimated range of 0.79–iv.92 cases per 1000 person-years in men aged from 50–84 years is comparable to the range of incidence values presented in this review.

The majority of studies reported an increased RR of GI bleeding with low-dose aspirin compared with non-use, which is consistent with findings from previous meta-analyses of RCTs [6]. The pooled judge of the RR for all GI bleeding (presumably from the whole GI tract) with low-dose aspirin was one.4, with pooled estimates of i.3 and 1.seven in the cohort and case–control studies, respectively. In the contempo analysis of observational studies conducted in the United kingdom of great britain and northern ireland, the risk of all GI bleeding events with low-dose aspirin was slightly higher than in this review, with a total adventure ratio of 1.88 in cohort studies and a total OR of 2.41 in instance–control studies [xx]. The same article also provided an overview of RCTs that reported RRs for any GI bleeding events with low-dose aspirin. These RRs were lower than those for observational studies (range 1.31–1.96). Similarly, the 2009 ATTC meta-analysis reported an RR of 1.54 (95% CI: i.xxx–i.82) for major extracranial bleeds with low-dose aspirin in six primary prevention trials [half-dozen], and a recent systematic review conducted for the United states of america Preventive Services Task Force (USPSTF) reported an OR of 1.59 (95% CI: one.32–ane.91) for major GI bleeding with aspirin (fifty–500 mg per day) in seven CVD primary prevention trials and an IRR of 1.55 (5.58 and three.lx events per one thousand person-years in aspirin users and non-users, respectively) for the same outcome in cohort data [56]. Given the general understanding betwixt the data from accomplice studies and those from RCTs and the greater susceptibility of some instance–command studies to recall bias, the lower estimate of risk derived from the accomplice studies and RCTs of less than a twofold increment in GI bleeding with aspirin compared with non-use, seems likely to exist the most reliable and is consistent with our findings.

In the present review, the RRs for UGIB with low-dose aspirin were college than those for all GI bleeding events (ranging from i.4 to 8.2 for example–command studies and from ane.21 to 4.51 for cohort studies). These findings are as expected given the well-established adverse effects of aspirin on the upper GI mucosa, which include directly cytotoxic effects on the epithelium, as well as dumb platelet assemblage [57].

The association between depression-dose aspirin and the run a risk of haemorrhage was less potent for LGIB than for UGIB, with wide variation in the data. Notably, data from three studies showed there was a significantly increased chance of bleeding in individuals treated with low-dose aspirin (RRs: two.iii–3.7), and two studies showed a not-significant increase in the gamble of LGIB (RRs: one.thirteen–5.03), compared with not-utilise. The pooled assay suggested that low-dose aspirin increases the run a risk of LGIB by less than twofold. Indeed, there is prove for aspirin causing mucosal injury in the small-scale bowel equally well every bit in the upper GI tract, in addition to its antiplatelet result [58, 59]. Thus, more studies are warranted to constitute the magnitude of risk of LGIB with low-dose aspirin.

In the instance–control studies included in the nowadays review, there was a lack of a meaning issue of low-dose aspirin on the risk of ICH. However, the iii cohort studies included in this assay all reported increased relative risks of ICH with aspirin compared with non-use. Thus, the overall pooled guess of RR for ICH with low-dose aspirin was 1.4, suggesting a trend towards a small increased gamble of ICH with aspirin. These findings are consistent with those from the 2009 meta-analysis past the ATTC, which showed a non-significant increase in the incidence of hemorrhagic stroke in patients taking depression-dose aspirin for primary prevention (rate ratio: i.32 [95% CI: 1.00–one.75]) [6] and the recent systematic review performed for the USPSTF, which reported an OR of 1.33 (95% CI: 1.03–one.71) for hemorrhagic stroke with aspirin in CVD main prevention trials [56]. In considering these findings, it should be borne in listen that, although life-threatening, ICH is a rare event in individuals under the age of 70 years [60].

Only one of the studies that reported risks of ICH provided figures for its incidence, and this report was performed in a cohort of patients with not-valvular atrial fibrillation. Equally would exist expected, the incidence of ICH was very loftier in both aspirin-treated and untreated groups (eight.0 and 5.iii cases per 1000 person-years, respectively). Several contempo observational studies have estimated the incidence of ICH in patient groups more representative of the general population. One study calculated an incidence of sub-arachnoid hemorrhage of 0.11 per 1000 person-years in the Danish population [61], while some other reported the incidences of intracerebral and subarachnoid hemorrhage in the Uk population to be 0.xv and 0.11 cases per 1000 person-years, respectively [60]. Combined information from two earlier population studies estimated an overall ICH incidence of 0.16 per g person-years between 1981 and 2006 in England and Wales [62]. These figures are in understanding with the incidence of hemorrhagic stroke reported in the ATTC meta-analysis of primary prevention studies (0.18 and 0.13 cases per chiliad person-years in aspirin treated and untreated groups, respectively) [half dozen].

Bear on of Aspirin Dose and Elapsing of Treatment on Haemorrhage Hazard

Two accomplice studies included in the nowadays review, which investigated a wide range of aspirin dosing regimens (0.5–>fourteen tablets (325 mg) per week), showed an increased chance of UGIB with more than frequent dosing [31, 32]. Studies investigating a possible correlation betwixt dose and risk of bleeding did not discover whatever consequent effects [23, 24, 26, 36, 41, 48], suggesting that the risk of bleeding associated with the utilize of aspirin within the defined 'low-dose' range may not vary essentially according to dose.

Increasing the duration of aspirin use was not associated with increased RRs of bleeding. Indeed, one written report included in this review reported smaller hazard estimates when aspirin was used for more than than five years, compared with brusque-term aspirin use [24]. Some other report reported no significant effect of the elapsing of aspirin employ on the risk of GI bleeding, and it was postulated that long-term aspirin apply is associated with mucosal adaptations that protect against haemorrhage events [32]. These findings, together with the demonstration of increased benefits of aspirin with longer-term use [63], support the hypothesis of a more favourable do good–run a risk ratio for longer-term use of aspirin in primary prevention.

Influence of Patient Factors on the Take a chance of Bleeding Associated with Depression-Dose Aspirin

Age.

The studies included in the present review showed fairly consistent RRs for GI bleeding with low-dose aspirin compared with non-use in individuals of different ages. However, the incidence of major bleeding events increased with age, as expected; thus, the absolute risk of bleeding in individuals receiving low-dose aspirin increased with age. Indeed, the 2009 meta-assay of randomized trials past the ATTC identified age as the most important predictor of the run a risk of bleeding associated with depression-dose aspirin, with an approximate doubling of the accented risk of bleeding with depression-dose aspirin for every 10-twelvemonth increase in age [half dozen]. It is important to note that any increase in the absolute risk of aspirin-associated bleeding with historic period would have to be balanced against a possible increased absolute do good of aspirin in older patients [63].

H. pylori infection.

The presence of H. pylori infection has been postulated to increase the hazard of peptic ulcer haemorrhage in individuals taking low-dose aspirin [45]. Although the studies reviewed here showed an association between H. pylori infection and GI bleeding, patients taking low-dose aspirin who had H. pylori infection were non generally at significantly increased take chances of ulcer bleeding compared with non-infected individuals taking low-dose aspirin or infected individuals not taking aspirin. A recent review proposed that screening for and eradication of H. pylori infection could essentially decrease aspirin-related GI damage [20]. The ongoing Helicobacter Eradication Aspirin Trial (HEAT), which is due to be completed in April 2017, is assessing whether eradication of H. pylori has the potential to prevent peptic ulcer bleeding in aspirin users [64].

Use of concomitant medications.

The ability of PPIs to reduce the take a chance of aspirin-associated GI haemorrhage has been observed previously [65] and was besides evident in the studies reviewed hither [66]. The nowadays review also showed that the risk of GI bleeding was increased in individuals taking low-dose aspirin in combination with other NSAIDs, as expected. Some studies directly compared the use of low-dose aspirin plus NSAIDs with low-dose aspirin alone, with calculated RRs for GI bleeding of 2.vi–3.8. The observed inter-study variation is well-nigh likely to be attributable to differences in the types and doses of NSAIDs used in the studies.

This review as well indicated increases in the risk of UGIB with concomitant therapy with low-dose aspirin and clopidogrel compared with depression-dose aspirin alone. The use of SSRIs in combination with aspirin was also associated with an increased risk of UGIB compared with aspirin alone, although the number of studies analyzed was small. In that location was reported to be no increase in take a chance of ICH with the combination of low-dose aspirin and clopidogrel versus depression-dose aspirin alone. Notwithstanding, a split up study reported an increased risk of both intracerebral and subarachnoid haemorrhage with concomitant use of aspirin and dipyridamole compared with aspirin alone. Further studies are needed to help to clarify which drugs at which doses affect the risks of major bleeding events when given with depression-dose aspirin therapy.

Study Strengths and Limitations

A cardinal force of this review is that it collates data from a big number (northward = 39) of observational studies, which reverberate the effects of aspirin in the existent world. Limitations include the fact that observational studies are more than prone to bias from confounding factors than RCTs and the identified betwixt-study heterogeneity, reflecting the differences in pattern, aspirin treatment regimen, bleeding definitions, outcomes recorded and calculated and the more diverse patient populations. As a result of this, the pooled estimates of bleeding risk comprise a level of uncertainty. Nevertheless, despite these factors, at that place was understanding between many of the studies and our findings are generally consistent with results from RCTs.

Future Implications for the Use of Low-Dose Aspirin in Primary Prevention

These findings contribute to the body of evidence regarding aspirin's relative benefits and risks in primary prevention. Ongoing and future trials will provide farther information on the do good–chance profile of depression-dose aspirin in the prevention of CVD events, peculiarly in the primary prevention of CVD events. The Aspirin to Reduce Chance of Initial Vascular Events (ARRIVE) trial is assessing the benefits and risks of low-dose aspirin for chief prevention in individuals at moderate risk of CV events [67]. Other trials are investigating the benefit–hazard profile of aspirin in specific patient groups, including elderly patients (Aspirin in Reducing Events in the Elderly [ASPREE] trial) [68] and individuals with diabetes (A Study of Cardiovascular Events in Diabetes [ASCEND]) [69].

In add-on to the efficacy in reducing the take a chance of CVD events and the potential increase in risk of major bleeding events, the increasing evidence for the chemopreventive effects of aspirin, most notably in colorectal cancers, merits consideration in clinical decision-making regarding the use of low-dose aspirin for principal prevention, particularly given the overlap in the risk factors for CVD and cancer [70]. In a recent recommendation statement, the USPSTF recommends low-dose aspirin for the master prevention of CVD and colorectal cancer in adults aged 50–59 years who have a x-year CVD risk of ≥ 10%, are not at increased hazard of bleeding, accept a life expectancy of at least 10 years, and are willing to have depression-dose aspirin daily for at least 10 years [71]. For adults aged sixty–69 years with a ten-twelvemonth CVD run a risk of >10%, the USPSTF recommends that the decision to use depression-dose aspirin to prevent CVD and colorectal cancer be made on an private basis, after consideration of the balance betwixt benefits and risks [71]. Data such equally those presented here will inform such controlling regarding the benefit–risk profile of aspirin.

Conclusions

There was an approximately 40% increased risk of all GI haemorrhage with low-dose aspirin in the observational studies reviewed here, a finding very similar to that reported in randomized trials [6, twenty]. When UGIB was studied separately, there was an approximately twofold increased risk of bleeding with depression-dose aspirin. Neither aspirin dose nor the duration of treatment had consistent furnishings on the RR for GI bleeding. The overall chance of ICH was as well increased past approximately forty% with long-term low-dose aspirin, which is as well like to the estimates from randomized trials, although an increment in risk was not consistently reported in all studies. In users of low-dose aspirin, the absolute risk of bleeding, only not the RR for bleeding compared with non-use, increased with historic period.

Ongoing and hereafter studies will provide further information on the benefit–risk profile of low-dose aspirin in the prevention of CV events, peculiarly in principal prevention of CVD. In the meantime, past providing estimates of bleeding risks in a real-globe setting, the data presented in this review should assist clinicians in making individual clinical judgments [72] on whether to prescribe low-dose aspirin for the prevention of CVD events.

Supporting Information

S1 Fig. Gamble of LGIB with depression-dose aspirin.

Data are shown as OR, adjusted or multivariate RR or adjusted Hour, plus 95% CIs, for the risk of lower gastrointestinal bleeding with depression-dose aspirin vs no aspirin. A test for heterogeneity (reported as I ² statistics, derived from X ² on 5 degrees of freedom [case–control and cohort studies combined] is provided. ^aUnivariate OR. ^bRR. ^cOR. ^dadjusted Hour. CI, confidence interval; d.f., degrees of liberty; Hour, run a risk ratio; LGIB, lower gastrointestinal bleeding; OR, odds ratio; RR, relative take chances.

https://doi.org/10.1371/periodical.pone.0160046.s002

(EPS)

S2 Fig. Effect of age on the incidence of major bleeding events with low-dose aspirin.

Incidence values are shown for UGIB, except for De Berardis 2012 (gastrointestinal bleeds and ICH). GI, gastrointestinal; ICH, intracranial (including intracerebral) hemorrhage; UGIB, upper gastrointestinal haemorrhage.

https://doi.org/ten.1371/periodical.pone.0160046.s003

(EPS)

S3 Fig. Effect of age on the take chances of major bleeding events (all GI bleeding and ICH) with low-dose aspirin.

Information are shown as adjusted IRR, crude or adjusted OR or Hr, plus 95% CIs, for the risk of major bleeds with low-dose aspirin vs no aspirin. ^aMajor gastrointestinal bleeds only. ^badjusted IRR. ^cOR. ^d60 minutes. CI, confidence interval; GI, gastrointestinal; Hour, risk ratio; ICH, intracranial (including intracerebral) hemorrhage; IRR, incidence charge per unit ratio; OR, odds ratio.

https://doi.org/10.1371/journal.pone.0160046.s004

(EPS)

S4 Fig. Effect of historic period on the risk of major bleeding events (UGIB) with low-dose aspirin.

Data are shown as adapted RR or SIR, plus 95% CIs, for the risk of UGIB with depression-dose aspirin vs no aspirin. ^aSIR. ^badjusted RR. CI, conviction interval; IRR, incidence rate ratio; RR, relative risk; SIR, standardized incidence ratio; UGIB, upper gastrointestinal haemorrhage.

https://doi.org/ten.1371/journal.pone.0160046.s005

(EPS)

S2 Tabular array. Effect of Helicobacter pylori infection on the risk of UGIB.

Values are adjusted or multivariate odds ratios unless otherwise indicated. ^aAdjusted RR. ^bNSAIDs included aspirin. CI, confidence interval; D, duodenal ulcer; G, gastric ulcer; UGIB, upper gastrointestinal bleeding.

https://doi.org/10.1371/journal.pone.0160046.s009

(DOCX)

S3 Table. Effect of proton pump inhibitor utilize on the take a chance of major bleeding events.

^aIncidence charge per unit ratio. CI, conviction interval; LGIB, lower gastrointestinal haemorrhage; OR, odds ratio; PPI, proton pump inhibitor; RR, relative gamble; UGIB, upper gastrointestinal bleeding.

https://doi.org/x.1371/journal.pone.0160046.s010

(DOCX)

S4 Table. Chance of major haemorrhage events with concomitant medications: clopidogrel, NSAIDs, and anticoagulants.

Values are adjusted or multivariate OR, RR, or HR unless otherwise indicated. ^aStandardized incidence ratio. ^bNo aspirin, no clopidogrel, no vitamin K antagonist, and no dipyridamole. ^cSecondary prevention accomplice. ^dIncidence rate ratio. CI, confidence interval; coxib, cyclo-oxygenase 2 inhibitor; Hour, chance ratio; LGIB, lower gastrointestinal bleeding; OR, odds ratio; RR, relative take a chance; UGIB, upper gastrointestinal bleeding.

https://doi.org/ten.1371/journal.pone.0160046.s011

(DOCX)

S5 Table. Effect of SSRI use on the take chances of major bleeding events.

^aRatio of observed chance to expected risk. ^bIncidence charge per unit ratio. CI, conviction interval; coxib, cyclo-oxygenase 2 inhibitor; 60 minutes, hazard ratio; LGIB, lower gastrointestinal bleeding; OR, odds ratio; RR, relative hazard; SSRI, selective serotonin reuptake inhibitor; UGIB, upper gastrointestinal bleeding.

https://doi.org/10.1371/journal.pone.0160046.s012

(DOCX)

Acknowledgments

Medical writing support was provided past Emma Moorhouse and Lucy Ambrose of Oxford Pharmagenesis, Oxford, U.k., with funding from Bayer Pharma AG.

Author Contributions

1. Conceived and designed the experiments: LGR.
2. Performed the experiments: LGR CH AL MMP PR.
3. Analyzed the data: LGR CH AL MMP PR.
4. Contributed reagents/materials/analysis tools: LGR MMP.
5. Wrote the paper: LGR CH AL MMP PR.

References

1. 1. Vane JR, Botting RM. The machinery of activity of aspirin. Thromb Res. 2003;110(5–half dozen):255–8. pmid:14592543
   • View Article
   • PubMed/NCBI
   • Google Scholar
2. 2. Collier HO. A pharmacological analysis of aspirin. Adv Pharmacol. 1969;7:333–405. pmid:4984754
   • View Article
   • PubMed/NCBI
   • Google Scholar
3. 3. Patrono C, Ciabattoni One thousand, Pinca E, Pugliese F, Castrucci M, De Salvo A, et al. Depression dose aspirin and inhibition of thromboxane B2 production in good for you subjects. Thromb Res. 1980;17(3–iv):317–27. pmid:7368167
   • View Article
   • PubMed/NCBI
   • Google Scholar
4. 4. Warner TD, Nylander S, Whatling C. Anti-platelet therapy: cyclo-oxygenase inhibition and the utilise of aspirin with particular regard to dual anti-platelet therapy. Br J Clin Pharmacol. 2011;72(4):619–33. pmid:21320154
   • View Article
   • PubMed/NCBI
   • Google Scholar
5. 5. Baigent C, Collins R, Appleby P, Parish South, Sleight P, Peto R. ISIS-2: 10 year survival amid patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Report of Infarct Survival) Collaborative Group. BMJ. 1998;316(7141):1337 43.
   • View Article
   • Google Scholar
6. half-dozen. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. Aspirin in the primary and secondary prevention of vascular affliction: collaborative meta-assay of individual participant information from randomised trials. Lancet. 2009;373(9678):1849–lx. pmid:19482214
   • View Commodity
   • PubMed/NCBI
   • Google Scholar
7. 7. Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. Northward Engl J Med. 2001;345(20):1444–51. pmid:11794192
   • View Article
   • PubMed/NCBI
   • Google Scholar
8. 8. Gorelick Atomic number 82, Richardson D, Kelly Thousand, Ruland Due south, Hung E, Harris Y, et al. Aspirin and ticlopidine for prevention of recurrent stroke in blackness patients: a randomized trial. Jama. 2003;289(22):2947–57. pmid:12799402
   • View Article
   • PubMed/NCBI
   • Google Scholar
9. 9. Ikeda Y, Shimada Thou, Teramoto T, Uchiyama S, Yamazaki T, Oikawa S, et al. Depression-dose aspirin for main prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic take a chance factors: a randomized clinical trial. JAMA. 2014;312(23):2510–20. pmid:25401325
   • View Article
   • PubMed/NCBI
   • Google Scholar
10. x. de Gaetano Chiliad. Low-dose aspirin and vitamin E in people at cardiovascular take chances: a randomised trial in general practise. Collaborative Group of the Primary Prevention Projection. Lancet. 2001;357(9250):89–95. pmid:11197445
    • View Article
    • PubMed/NCBI
    • Google Scholar
11. eleven. Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparing of bear witness from observational studies versus randomised trials. Lancet Oncol. 2012;thirteen(v):518–27. pmid:22440112
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
12. 12. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. Bmj. 2000;321(7270):1183–7. pmid:11073508
    • View Article
    • PubMed/NCBI
    • Google Scholar
13. 13. He J, Whelton PK, Vu B, Klag MJ. Aspirin and gamble of hemorrhagic stroke: a meta-assay of randomized controlled trials. Jama. 1998;280(22):1930–five. pmid:9851479
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
14. fourteen. Halvorsen South, Andreotti F, 10 Berg JM, Cattaneo One thousand, Coccheri S, Marchioli R, et al. Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology working group on thrombosis. J Am Coll Cardiol. 2014;64(3):319–27. pmid:25034070
    • View Article
    • PubMed/NCBI
    • Google Scholar
15. 15. Vandvik PO, Lincoff AM, Gore JM, Gutterman DD, Sonnenberg FA, Alonso-Coello P, et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Breast Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e637S–68S. pmid:22315274
    • View Article
    • PubMed/NCBI
    • Google Scholar
16. 16. Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, et al. Guidelines for the main prevention of stroke: a argument for healthcare professionals from the American Heart Association/American Stroke Clan. Stroke. 2014;45(12):3754–832. pmid:25355838
    • View Article
    • PubMed/NCBI
    • Google Scholar
17. 17. Force USPST. Aspirin for the prevention of cardiovascular affliction: U.S. Preventive Services Task Forcefulness recommendation argument. Ann Intern Med. 2009;150(6):396–404. pmid:19293072
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
18. 18. Lanas A, Carrera-Lasfuentes P, Arguedas Y, Garcia Due south, Bujanda L, Calvet X, et al. Risk of Upper and Lower Gastrointestinal Bleeding in Patients Taking Nonsteroidal Anti-inflammatory Drugs, Antiplatelet Agents, or Anticoagulants. Clin Gastroenterol Hepatol. 2015;thirteen(five):906–12 e2. pmid:25460554
    • View Article
    • PubMed/NCBI
    • Google Scholar
19. 19. Hernandez-Diaz S, Garcia Rodriguez LA. Cardioprotective aspirin users and their backlog risk of upper gastrointestinal complications. BMC medicine. 2006;4:22. pmid:16987411
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
20. xx. Thorat MA, Cuzick J. Prophylactic use of aspirin: systematic review of harms and approaches to mitigation in the general population. Eur J Epidemiol. 2015;xxx(ane):5–18. pmid:25421783
    • View Article
    • PubMed/NCBI
    • Google Scholar
21. 21. Wu IC, Lin MY, Yu FJ, Hsieh HM, Chiu KF, Wu MT. A short-term effect of depression-dose aspirin on major hemorrhagic risks in primary prevention: a case-crossover pattern. PLoS 1. 2014;9(5):e98326. pmid:24879431
    • View Article
    • PubMed/NCBI
    • Google Scholar
22. 22. Cook NR, Lee IM, Zhang SM, Moorthy MV, Buring JE. Alternating-day, low-dose aspirin and cancer risk: Long-term observational follow-up of a randomized trial. Annals of Internal Medicine. 2013;159 (2):77–85. pmid:23856681
    • View Article
    • PubMed/NCBI
    • Google Scholar
23. 23. Cea Soriano L, Rodriguez LA. Adventure of Upper Gastrointestinal Bleeding in a Cohort of New Users of Depression-Dose ASA for Secondary Prevention of Cardiovascular Outcomes. Front Pharmacol. 2010;1:126. pmid:21811460
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
24. 24. de Abajo FJ, Garcia Rodriguez LA. Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as obviously and enteric-coated formulations. BMC Clinical Pharmacology. 2001;1(1).
    • View Commodity
    • Google Scholar
25. 25. de Abajo FJ, Gil MJ, Bryant 5, Timoner J, Oliva B, Garcia-Rodriguez LA. Upper gastrointestinal haemorrhage associated with NSAIDs, other drugs and interactions: A nested instance-control report in a new general practice database. European Periodical of Clinical Pharmacology. 2013;69 (3):691–701. pmid:22955795
    • View Article
    • PubMed/NCBI
    • Google Scholar
26. 26. Garcia Rodriguez LA, Lin KJ, Hernandez-Diaz S, Johansson S. Take a chance of upper gastrointestinal haemorrhage with low-dose acetylsalicylic acid alone and in combination with clopidogrel and other medications. Circulation. 2011;123 (10):1108–15. pmid:21357821
    • View Article
    • PubMed/NCBI
    • Google Scholar
27. 27. Garcia Rodriguez LA, Gaist D, Morton J, Cookson C, Gonzalez-Perez A. Antithrombotic drugs and risk of hemorrhagic stroke in the general population. Neurology. 2013;81(six):566–74. pmid:23843464
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
28. 28. Hasan DM, Mahaney KB, Brownish RD Jr., Meissner I, Piepgras DG, Huston J, et al. Aspirin every bit a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke. 2011;42(11):3156–62. pmid:21980208
    • View Article
    • PubMed/NCBI
    • Google Scholar
29. 29. Lin KJ, De Caterina R, Garcia Rodriguez LA. Low-dose aspirin and upper gastrointestinal bleeding in primary versus secondary cardiovascular prevention a population-based, nested instance-control written report. Apportionment: Cardiovascular Quality and Outcomes. 2014;7 (1):seventy–7. pmid:24254886
    • View Article
    • PubMed/NCBI
    • Google Scholar
30. 30. Absorb WJ, McLaughlin JK. Over the counter non-steroidal anti-inflammatory drugs and risk of gastrointestinal bleeding. Periodical of epidemiology and biostatistics. 2000;five (ii):137–42. pmid:10890286
    • View Article
    • PubMed/NCBI
    • Google Scholar
31. 31. Huang ES, Strate LL, Ho WW, Lee SS, Chan AT. A prospective report of aspirin use and the hazard of gastrointestinal haemorrhage in men. PLoS One. 2010;v(12):e15721. pmid:21209949
    • View Article
    • PubMed/NCBI
    • Google Scholar
32. 32. Huang ES, Strate LL, Ho WW, Lee SS, Chan AT. Long-term employ of aspirin and the risk of gastrointestinal bleeding. American Periodical of Medicine. 2011;124 (5):426–33. pmid:21531232
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
33. 33. Hirata Y, Kataoka H, Shimura T, Mizushima T, Mizoshita T, Tanida S, et al. Incidence of gastrointestinal bleeding in patients with cardiovascular affliction: Buffered aspirin versus enteric-coated aspirin. Scandinavian Journal of Gastroenterology. 2011;46 (vii–8):803–9. pmid:21501103
    • View Article
    • PubMed/NCBI
    • Google Scholar
34. 34. De Berardis G, Lucisano Thou, D'Ettorre A, Pellegrini F, Lepore Five, Tognoni G, et al. Association of aspirin apply with major bleeding in patients with and without diabetes. JAMA. 2012;307(21):2286–94. pmid:22706834
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
35. 35. Hallas J, Dall M, Andries A, Andersen BS, Aalykke C, Hansen JM, et al. Use of single and combined antithrombotic therapy and run a risk of serious upper gastrointestinal haemorrhage: Population based case-control study. British Medical Journal. 2006;333 (7571):726–8. pmid:16984924
    • View Article
    • PubMed/NCBI
    • Google Scholar
36. 36. Ibanez L, Vidal Ten, Vendrell 50, Moretti U, Laporte JR. Upper gastrointestinal haemorrhage associated with antiplatelet drugs. Aliment Pharmacol Ther. 2006;23(two):235–42. pmid:16393302
    • View Article
    • PubMed/NCBI
    • Google Scholar
37. 37. Kaufman DW, Kelly JP, Sheehan JE, Laszlo A, Wiholm Exist, Alfredsson L, et al. Nonsteroidal anti-inflammatory drug use in relation to major upper gastrointestinal bleeding. Clinical Pharmacology and Therapeutics. 1993;53 (4):485–94. pmid:8477566
    • View Article
    • PubMed/NCBI
    • Google Scholar
38. 38. Kaufman DW, Kelly JP, Wiholm BE, Laszlo A, Sheehan JE, Koff RS, et al. The risk of acute major upper gastrointestinal haemorrhage amid users of aspirin and ibuprofen at various levels of booze consumption. American Journal of Gastroenterology. 1999;94 (eleven):3189–96. pmid:10566713
    • View Article
    • PubMed/NCBI
    • Google Scholar
39. 39. Kelly JP, Kaufman DW, Jurgelon JM, Sheehan J, Koff RS, Shapiro S. Take a chance of aspirin-associated major upper-gastrointestinal haemorrhage with enteric-coated or buffered production. Lancet. 1996;348 (9039):1413–vi. pmid:8937281
    • View Article
    • PubMed/NCBI
    • Google Scholar
40. 40. Lanas A, Bajador E, Serrano P, Fuentes J, Carreno S, Guardia J, et al. Nitrovasodilators, depression-dose aspirin, other nonsteroidal antiinflammatory drugs, and the hazard of upper gastrointestinal bleeding. N Engl J Med. 2000;343(12):834–9. pmid:10995862
    • View Article
    • PubMed/NCBI
    • Google Scholar
41. 41. Lanas A, Garcia-Rodriguez LA, Approach MT, Gomollon F, Feu F, Gonzalez-Perez A, et al. Take chances of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut. 2006;55 (12):1731–viii. pmid:16687434
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
42. 42. Sakamoto C, Sugano K, Ota S, Sakaki Northward, Takahashi Southward, Yoshida Y, et al. Instance-control study on the association of upper gastrointestinal haemorrhage and nonsteroidal anti-inflammatory drugs in Japan. Eur J Clin Pharmacol. 2006;62(ix):765–72. pmid:16821007
    • View Article
    • PubMed/NCBI
    • Google Scholar
43. 43. Santolaria S, Lanas A, Benito R, Perez-Aisa M, Montoro M, Sainz R. Helicobacter pylori infection is a protective gene for bleeding gastric ulcers but not for bleeding duodenal ulcers in NSAID users. Aliment Pharmacol Ther. 1999;thirteen(11):1511–eight. pmid:10571609
    • View Article
    • PubMed/NCBI
    • Google Scholar
44. 44. Stack WA, Atherton JC, Hawkey GM, Logan RF, Hawkey CJ. Interactions between Helicobacter pylori and other adventure factors for peptic ulcer bleeding. Aliment Pharmacol Ther. 2002;16(3):497–506. pmid:11876703
    • View Article
    • PubMed/NCBI
    • Google Scholar
45. 45. Sostres C, Carrera-Lasfuentes P, Benito R, Roncales P, Arruebo One thousand, Arroyo MT, et al. Peptic Ulcer Bleeding Risk. The Role of Helicobacter Pylori Infection in NSAID/Low-Dose Aspirin Users. American Periodical of Gastroenterology. 2015;110(v):684–9. pmid:25895518
    • View Article
    • PubMed/NCBI
    • Google Scholar
46. 46. Leung WY, Then WY, Stewart D, Lui A, Tong PC, Ko GT, et al. Lack of benefits for prevention of cardiovascular illness with aspirin therapy in blazon 2 diabetic patients—a longitudinal observational written report. Cardiovascular Diabetology. 2009;8 (pp 57)(1475).
    • View Article
    • Google Scholar
47. 47. Pilotto A, Franceschi M, Leandro Thou, Paris F, Niro Five, Longo MG, et al. The risk of upper gastrointestinal bleeding in elderly users of aspirin and other not-steroidal anti-inflammatory drugs: the role of gastroprotective drugs. Aging Clin Exp Res. 2003;15(half-dozen):494–ix. pmid:14959953
    • View Article
    • PubMed/NCBI
    • Google Scholar
48. 48. Sorensen HT, Mellemkjaer L, Blot WJ, Nielsen GL, Steffensen FH, McLaughlin JK, et al. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am J Gastroenterol. 2000;95(9):2218–24. pmid:11007221
    • View Article
    • PubMed/NCBI
    • Google Scholar
49. 49. Taha AS, Angerson WJ, Knill-Jones RP, Blatchford O. Upper gastrointestinal mucosal abnormalities and claret loss complicating low-dose aspirin and antithrombotic therapy. Aliment Pharmacol Ther. 2006;23(4):489–95. pmid:16441469
    • View Article
    • PubMed/NCBI
    • Google Scholar
50. fifty. Yamada A, Sugimoto T, Kondo S, Ohta M, Watabe H, Maeda South, et al. Cess of the chance factors for colonic diverticular hemorrhage. Dis Colon Rectum. 2008;51(1):116–20. pmid:18085336
    • View Article
    • PubMed/NCBI
    • Google Scholar
51. 51. Strate LL, Liu YL, Huang ES, Giovannucci EL, Chan AT. Use of aspirin or nonsteroidal anti-inflammatory drugs increases risk for diverticulitis and diverticular haemorrhage. Gastroenterology. 2011;140(5):1427–33. pmid:21320500
    • View Article
    • PubMed/NCBI
    • Google Scholar
52. 52. Ho CW, Ho MH, Chan PH, Hai JJ, Cheung E, Yeung CY, et al. Ischemic stroke and intracranial hemorrhage with aspirin, dabigatran, and warfarin: Affect of quality of anticoagulation control. Stroke. 2015;46 (1):23–30. pmid:25406148
    • View Article
    • PubMed/NCBI
    • Google Scholar
53. 53. Thrift AG, McNeil JJ, Forbes A, Donnan GA. Adventure of primary intracerebral haemorrhage associated with aspirin and non-steroidal anti-inflammatory drugs: case-control study. BMJ. 1999;318(7186):759–64. pmid:10082697
    • View Article
    • PubMed/NCBI
    • Google Scholar
54. 54. Nakayama Yard, Iwakiri R, Hara M, Ootani H, Shimoda R, Tsunada Due south, et al. Low-dose aspirin is a prominent cause of bleeding ulcers in patients who underwent emergency endoscopy. J Gastroenterol. 2009;44(9):912–8. pmid:19436943
    • View Article
    • PubMed/NCBI
    • Google Scholar
55. 55. Dalton So, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH. Apply of selective serotonin reuptake inhibitors and take chances of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med. 2003;163(1):59–64. pmid:12523917
    • View Article
    • PubMed/NCBI
    • Google Scholar
56. 56. Whitlock E, Burda B, Williams Due south, Guiguis-Blake J, Evans C. Haemorrhage Risks With Aspirin Use for Principal Prevention in Adults: A Systematic Testify Review for the U.Southward. Preventive Services Task Strength. Typhoon Bear witness Summary: Harms of Aspirin Use Draft Bear witness Review for Aspirin to Forbid Cardiovascular Disease and Cancer. 2015. Available: http://www.uspreventiveservicestaskforce.org/Page/Document/draft-evidence-summary-harms-of-aspirin-use/aspirin-to-foreclose-cardiovascular-disease-and-cancer. Accessed 23 September 2015.
57. 57. Iwamoto J, Saito Y, Honda A, Matsuzaki Y. Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy. World J Gastroenterol. 2013;19(11):1673–82. pmid:23555156
    • View Article
    • PubMed/NCBI
    • Google Scholar
58. 58. Endo H, Hosono Thou, Inamori M, Nozaki Y, Yoneda 1000, Fujita K, et al. Characteristics of small-scale bowel injury in symptomatic chronic low-dose aspirin users: the feel of two medical centers in sheathing endoscopy. J Gastroenterol. 2009;44(6):544–ix. pmid:19373431
    • View Article
    • PubMed/NCBI
    • Google Scholar
59. 59. Shiotani A, Haruma K, Nishi R, Fujita 1000, Kamada T, Honda K, et al. Randomized, double-bullheaded, airplane pilot report of geranylgeranylacetone versus placebo in patients taking low-dose enteric-coated aspirin. Depression-dose aspirin-induced small bowel damage. Scand J Gastroenterol. 2010;45(three):292–eight. pmid:19968611
    • View Article
    • PubMed/NCBI
    • Google Scholar
60. threescore. Gaist D, Wallander MA, Gonzalez-Perez A, Garcia-Rodriguez LA. Incidence of hemorrhagic stroke in the full general population: validation of data from The Wellness Improvement Network. Pharmacoepidemiol Drug Saf. 2013;22(2):176–82. pmid:23229888
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
61. 61. Pottegard A, Garcia Rodriguez LA, Poulsen FR, Hallas J, Gaist D. Antithrombotic drugs and subarachnoid haemorrhage take chances. A nationwide case-control study in Denmark. Thromb Haemost. 2015;114(5).
    • View Article
    • Google Scholar
62. 62. Lovelock CE, Molyneux AJ, Rothwell PM, Oxford Vascular South. Change in incidence and aetiology of intracerebral haemorrhage in Oxfordshire, UK, between 1981 and 2006: a population-based study. Lancet Neurol. 2007;6(6):487–93. pmid:17509483
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
63. 63. Cuzick J, Thorat MA, Bosetti C, Brownish PH, Fire J, Cook NR, et al. Estimates of benefits and harms of rubber employ of aspirin in the full general population. Ann Oncol. 2015;26(ane):47–57. pmid:25096604
    • View Article
    • PubMed/NCBI
    • Google Scholar
64. 64. Helicobacter Eradication Aspirin Trial (HEAT). Available: https://clinicaltrials.gov/ct2/show/NCT01506986. Accessed 23 July 2015.
65. 65. Mo C, Dominicus G, Lu ML, Zhang L, Wang YZ, Lord's day X, et al. Proton pump inhibitors in prevention of low-dose aspirin-associated upper gastrointestinal injuries. World J Gastroenterol. 2015;21(17):5382–92. pmid:25954113
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
66. 66. Lanas A, Wu P, Medin J, Mills EJ. Low doses of acetylsalicylic acid increment risk of gastrointestinal haemorrhage in a meta-analysis. Clin Gastroenterol Hepatol. 2011;9(ix):762–viii e6. pmid:21699808
    • View Commodity
    • PubMed/NCBI
    • Google Scholar
67. 67. Bayer HealthCare. Bachelor: http://www.go far-study.com/en/study.cfm. Accessed 23 July 2015.
68. 68. National institute on crumbling. Available: https://world wide web.nia.nih.gov/alzheimers/clinical-trials/aspirin-reducing-events-elderly-aspree. Accessed 23 July 2015.
69. 69. Ascend. Bachelor: https://world wide web.ctsu.ox.ac.uk/ascend/. Accessed 23 July 2015.
70. 70. Battistoni A, Mastromarino V, Volpe M. Reducing Cardiovascular and Cancer Chance: How to Address Global Primary Prevention in Clinical Do. Clin Cardiol. 2015.
    • View Article
    • Google Scholar
71. 71. Bibbins-Domingo Chiliad, Forcefulness USPST. Aspirin Apply for the Master Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016.
    • View Article
    • Google Scholar
72. 72. Hennekens CH, DeMets DL. Prevention: Aspirin in primary prevention needs individual judgements. Nat Rev Cardiol. 2014;11(viii):438–forty. pmid:24958081
    • View Article
    • PubMed/NCBI
    • Google Scholar

daysontst.blogspot.com

Source: https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0160046

Share this post