Concomitant Use Of Low-dose Aspirin Research Articles

A narrative review of the cardiovascular risks associated with concomitant aspirin and NSAID use.

The concomitant use of low-dose aspirin for cardioprotection and non-steroidal anti-inflammatory agents for pain relief is prevalent, particularly in the elderly for whom cardiovascular disease and pain are common co-morbidities. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are known to interfere with the antiplatelet effect of aspirin through competitive binding with COX-1. While the clinical significance of this interference is still unclear, this review sought to assess the body of literature which has evaluated the potential attenuation of the anti-platelet effect of aspirin when dosed concomitantly with an NSAID. This review supports that the pharmacodynamic interaction between aspirin and non-selective NSAIDs occurs, but finds that the interaction varies amongst agents, and is highly dependent on numerous factors including: dose timing, dose of aspirin, and dose of the NSAID in question. Recent findings suggest that patient factors, such as body weight may also be indicators of aspirin's cardiovascular effectiveness. Ultimately, the clinical decision making for concomitant NSAID and low-dose aspirin regimens remains at the patient level.

Utilization of gastroprotective strategies for nonsteroidal anti-inflammatory drug-induced gastrointestinal events in a major teaching hospital.

Background and purposeClinical guidelines recommend the prescribing of gastroprotective strategies in nonsteroidal anti-inflammatory drug (NSAID) users with risk factors for gastrointestinal (GI) ulcer or ulcer complications. However, these guidelines are not often translated into clinical practice. Therefore, the aim of this study was to investigate the utilization of gastroprotective strategies for NSAID-induced upper GI events in at-risk users in a major teaching hospital.Patients and methodsA cross-sectional, observational, pharmacy-based study was conducted in a major Asian institution with both primary and secondary health care services. This study involved the screening of prescriptions for regular NSAIDs, and patients who met the inclusion criteria were recruited and interviewed using a questionnaire.ResultsOf the 409 participants recruited, 83.1% had at least one GI risk factor, of whom 70.3% did not receive appropriate gastroprotection. The most common GI risk factor was the use of high-dose NSAIDs (69.2%), followed by participants aged 65 years and older (22%) and concomitant use of low-dose aspirin (11.7%). Appropriate gastroprotective strategies utilized consisted of the use of a cyclooxygenase (COX)-2 inhibitor alone or a nonselective NSAID plus a proton pump inhibitor (PPI) in the moderate-risk group and a COX-2 inhibitor plus a PPI in the high-risk group. Gastroprotective strategies were underutilized in 67.1% of at-risk participants and overutilized in 59.4% of those without risk factors. Co-prescription of a histamine-2 receptor antagonist at lower-than-recommended doses constituted 59% of the inappropriate gastroprotective agents used. Logistic regression analysis revealed patients aged 65 years and older (odds ratio, 1.89; 95% CI =1.15–3.09) as a predictor for the prescribing of gastroprotection by the clinicians.ConclusionApproximately 70% of at-risk NSAID users, mainly on high-dose NSAIDs, were not prescribed appropriate gastroprotective strategies. Further measures are warranted to improve the safe prescribing of regular NSAIDs.

Systematic review with meta‐analysis: the gastrointestinal benefits of COX‐2 selective inhibitors with concomitant use of low‐dose aspirin

It is uncertain whether concurrent use of low-dose aspirin removes the gastrointestinal benefit displayed by COX-2 selective inhibitors (coxibs) when compared to traditional nonsteroidal anti-inflammatory drugs (NSAIDs). To evaluate the gastrointestinal risks associated with coxibs and traditional NSAIDs and the interaction with concurrent use of low-dose aspirin. We searched MEDLINE, EMBASE and the Cochrane Library through April 2016 to identify randomised trials comparing the gastrointestinal risk between coxibs and traditional NSAIDs in patients taking or not taking low-dose aspirin. Results were combined using random effects meta-analysis. Subgroup analyses by concurrent use of aspirin were undertaken. Eleven trials (84 150 participants) were included. The overall relative risk (RR) of coxibs vs. traditional NSAIDs for complicated gastrointestinal events was 0.54 (95% CI, confidence interval 0.32-0.92), with a significant subgroup difference (P = 0.04) according to concurrent use of aspirin (used: RR = 0.96, 95% CI 0.66-1.24; not used: RR = 0.33, 95% CI 0.14-0.83). The overall RR for clinical gastrointestinal events was 0.59 (95% CI 0.47-0.75), with a significant subgroup difference according to aspirin usage (P = 0.008; used: RR = 0.77, 95% CI 0.62-0.95; not used: RR = 0.50, 95% CI 0.39-0.64). Overall coxibs were associated with significantly lower risk of symptomatic ulcers (RR = 0.60, 95% CI 0.50-0.72) and endoscopic ulcers (RR = 0.29, 95% CI 0.16-0.53) than traditional NSAIDs; a significant subgroup difference was shown for endoscopic ulcers (P = 0.05) but not for symptomatic ulcers (P = 0.27). Concomitant use of low-dose aspirin reduces but does not completely eliminate the gastrointestinal benefit of coxibs over traditional NSAIDs.

Gastric and renal effects of COX-2 selective and non-selective NSAIDs in rats receiving low-dose aspirin therapy.

The consumption of low-dose aspirin (LDA) to prevent cardiovascular disease continues to increase worldwide. Consequently, the number of chronic LDA users seeking dental procedures that require complementary acute anti-inflammatory medication has also grown. Considering the lack of literature evaluating this interaction, we analyzed the gastric and renal effects caused by a selective COX-2 inhibitor (etoricoxib) and a non-selective COX-2 inhibitor (ibuprofen) nonsteroidal anti-inflammatory drug (NSAID) in rats receiving chronic LDA therapy. Male Wistar rats were divided into six experimental groups (carboxymethylcellulose (CMC) - vehicle; LDA; LDA + ibuprofen; ibuprofen; LDA + etoricoxib; and etoricoxib) and submitted to long-term LDA therapy with a subsequent NSAID administration for three days by gavage. After the experimental period, we analyzed gastric and renal tissues and quantified serum creatinine levels. The concomitant use of LDA with either NSAID induced the highest levels of gastric damage when compared to the CMC group (F = 20.26, p < 0.05). Treatment with either LDA or etoricoxib alone was not associated with gastric damage. No significant damage was observed on kidney morphology and function (F = 0.5418, p > 0.05). These results suggest that even the acute use of an NSAID (regardless of COX-2 selectivity) can induce gastric damage when combined with the long-term use of low-dose aspirin in an animal model. Additional studies, including clinical assessments, are thus needed to clarify this interaction, and clinicians should be careful of prescribing NSAIDs to patients using LDA.

Mo1545 Efficacy of Albis® for the Prevention of Peptic Ulcer by Concomitant Use of Low-Dose Aspirin: a Prospective, Randomized, Placebo-Controlled Study

Mo1545 Efficacy of Albis® for the Prevention of Peptic Ulcer by Concomitant Use of Low-Dose Aspirin: a Prospective, Randomized, Placebo-Controlled Study

Difference between the frequencies of antisecretory drug prescriptions in users of buffered vs. enteric-coated low-dose aspirin therapies

To provide further insights on the risks of gastrointestinal (GI) complications in individuals using low-dose aspirin (LDA), we investigated the concomitant use of LDA and antisecretory drugs. Additionally, we examined the frequency distributions of prescribing sequences for LDA and antisecretory drugs. Data from a computerized prescription order entry system was analyzed at the National Cerebral and Cardiovascular Center of Japan. LDA use in combination with H2-receptor antagonists (H2RAs) and proton pomp inhibitors (PPIs) was examined over the period from January 2001 to December 2010. Prescription sequence symmetry analyses were used to identify LDA-induced H2RAs or PPIs users. In December 2010, PPIs accounted for 9.9% of the prescriptions for buffered LDA users and 16.1% of those for enteric-coated LDA users. Incident use of PPIs occurred more frequently among enteric-coated LDA users than buffered LDA users (17.6% vs. 11.0%, respectively). Prescription sequence symmetry analyses of PPI use revealed significant associations with enteric-coated LDA use, resulting in adjusted sequence ratios of 1.82 (95%CI, 1.11 - 3.03) and 1.87 (95% CI, 1.26 - 2.83) at intervals of 182 and 365 days, respectively. Enteric-coated LDA users tended to initiate PPI therapy on the same date more frequently than buffered LDA users (35.1% vs. 10.8%, respectively). Our findings do not support the notion that entericcoated LDA products confer a lower risk for GI complications than buffered formulations, but may conversely imply that the risk of GI complications associated with buffered LDA is lower than that of enteric-coated LDA.

W1735 Sulforaphane Stimulates Histamine-Mediated Gastric Acid Secretion and Ameliorates Monochloramine-Induced Gastric Mucosal Injury

Background: Alpha 1 protease inhibitor (A1-PI) is the major circulating serine protease inhibitor. It is are critical factor in various inflammatory conditions, in particular in A1-PI deficiency in humans. Here, we analyzed the mucosal and systemic A1-PI levels with respect to two major etiological risk factors for gastroduodenal diseases, H. pylori infection and intake of low-dose aspirin. Patients and Methods: The study included 20 volunteers (H. pylori-positive and -negative: n=10) who received 2x50mg aspirin/day for 7 days. H. pyloripositive subjects underwent eradication therapy and repeated the protocol. Blood and tissue samples were obtained at day 0, 1, 3 and 7, and A1-PI levels were subsequently determined by ELISA. Results: Basal mucosal A1-PI expression were between 30 75 pg/10μg total protein in H. pylori-negative subjects, and found to be similar in antral, corpus and duodenal mucosa. In H. pylori-infected subjects, A1-PI levels were significantly increased in antrum (mean: 111 vs. 37.4 pg/10μg protein; p=0.019), whereas corresponding corpus, duodenum and serum levels were unchanged. Immunohistochemistry demonstrated that infiltrating immune cells and antral surface epithelium contributed to elevated A1-PI expression in H. pylori-infected subjects. The concomitant use of low-dose aspirin in all three groups was associated with no alterations of mucosal A1-PI levels, but a 2-fold induction of peripheral A1-PI levels that were identified in both H. pylori-infected (p=0.004) and -noninfected subjects (p=0.009). Conclusions: H. pylori infection leads to an induction of antral A1-PI levels, while low dose aspirin specifically increases circulating A1-PI levels, thus suggesting an effect of aspirin on hepatocytes. Both these anti-inflammatory mechanisms expand the pathophysiological importance of A1-PI to the gastrointestinal tract beyond its established role in A1-PI deficiency.

Helicobacter pylori infection and short-term intake of low-dose aspirin have different effects on alpha-1 antitrypsin/alpha-1 peptidase inhibitor (α1-PI) levels in antral mucosa and peripheral blood

Objective. Alpha-1 protease inhibitor (α1-PI) is the major circulating serine protease inhibitor. The purpose of the study was to investigate α1-PI expression in gastroduodenal mucosa and blood with respect to two major etiological risk factors for gastroduodenal diseases, Helicobacter pylori infection and intake of low-dose aspirin. Material and methods. Twenty volunteers (H. pylori-positive and -negative: n=10) received 2×50 mg aspirin/day for 7 days. H. pylori-positive subjects underwent eradication therapy and repeated the protocol. Blood and tissue samples were obtained on days 0, 1, 3 and 7; α1-PI levels were determined by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and analyzed for histopathological findings. Results. Mucosal α1-PI expression was between 30 and 75 pg/10 µg total protein in H. pylori-negative subjects, and found to be similar in antral, corpus and duodenal mucosa. In H. pylori-infected subjects, α1-PI levels were significantly increased in the antrum (mean: 111 versus 37.4 pg/10 µg protein; p=0.019), whereas corresponding levels in the corpus, duodenum and sera were unchanged. Alpha-1-PI transcript levels were similarly induced in H. pylori-infected subjects (0.13±0.15 versus 0.027±0.043 a.u. (arbitrary units), p=0.018). Immunohistochemistry demonstrated that infiltrating immune cells and antral surface epithelium contributed to elevated α1-PI expression in H. pylori-infected subjects. The concomitant use of low-dose aspirin did not change mucosal α1-PI levels, but led to a 2-fold increase in α1-PI levels in sera independently of the H. pylori status (p<0.009). Conclusions. Antral α1-PI expression is specifically induced by H. pylori infection, suggesting a pathophysiological role of this protease inhibitor in the upper gastrointestinal tract, whereas low-dose aspirin led to an increase in systemic α1-PI levels.

How to Advise Aspirin Use in Patients Who Need NSAIDs

NSAIDs are widely used all over the world. NSAID use is rising due to increasing availability without a prescription, use of aspirin for prevention of thrombotic disorders and the ageing population. Aspirin is used as an analgesic drug in many countries, but the main current indication is low-dose aspirin for the prevention of cardiovascular events. However, NSAIDs and aspirin use account for approximately 20-25% of all reported drug adverse events. Most of those are gastrointestinal including dyspepsia, hemorrhage, perforation and even death. The COX-2- selective inhibitors (coxibs) have demonstrated equivalent efficacy to nonspecific NSAIDs in the management of arthritis and pain but have less gastrointestinal adverse events, although coxibs and probably all NSAIDs, significantly increase risk of serious thromboembolic events. Concomitant use of low-dose aspirin is present in more than 20% of all patients taking either NSAIDs or coxibs, thus increasing the risk of gastrointestinal side effects. Furthermore, at present, it is not known whether aspirin decreases the cardiovascular risks of COX-2 inhibitors or NSAIDs. Appropriate strategies for gastrointestinal risk reduction with NSAIDs and aspirin must consider the overall health status of our patients including the presence of cardiovascular and gastrointestinal risk factors. Use of the lowest possible dose of these drugs, gastroprotectants, especially proton pump inhibitors and Helicobacter pylori eradication will reduce the risk of gastrointestinal side effects in patients taking low-dose aspirin and NSAIDs or coxibs.

Under-utilization of gastroprotective drugs in patients with NSAID-related ulcers

To determine the proportion of patients with a risk of NSAID gastropathy receiving adequate gastroprotection. This observational study was performed between November 2001 and December 2003. We selected patients who were hospitalized with perforated and bleeding gastroduodenal ulcers attributable to NSAID use and controls without ulcers. Data were collected on their sociodemographic characteristics, actual and recent medication, comorbidity and medical history. For each patient and control the number of different risk factors associated with NSAID gastropathy was calculated. A composite risk factor (CRF) was obtained from the sum of all separate risk factors. During the observational period a total of 388 patients using NSAID were included in the study, 104 patient cases and 284 matched community-based controls. The mean CRF was significantly higher in patient cases than in controls (cases mean CRF 3.31 (SD 1.67) and controls mean CRF 2.76 (SD 1.45), p = 0.002). A total of 148 (38%) patients used an adequate preventive strategy. Significant variables for using a preventive strategy were concomitant use of steroids (corrected odds ratio 4.22, 95% CI 2.11 8.47, p < 0.001), a history of gastroduodenal ulcers (corrected odds ratio 2.90, 95% CI 1.51 - 5.56, p = 0.001) and concomitant use of low-dose aspirin (corrected odds ratio 1.96,95% CI 1.18 3.25, p= 0.01). Among patients with 4 or more risk factors associated with NSAID gastropathy, 47% still did not use adequate gastroprotection. Gastroprotective drugs are greatly under-utilized in patients with a risk of NSAID gastropathy.

Recent FDA Warning of the Concomitant Use of Aspirin and Ibuprofen and the Effects on Platelet Aggregation

Recent FDA Warning of the Concomitant Use of Aspirin and Ibuprofen and the Effects on Platelet Aggregation

Lessons in drug development

To the Editor: There are indeed many implications arising from the recent problems surrounding the use of cyclooxygenase (COX) 2 inhibitors. However, it is an over simplification to suggest that less selective non-steroidal anti-inflammatory drugs (NSAIDs) do not increase cardiovascular risk with long term use.1 The literature is certainly complex and at times conflicting in its overall message confounded by difficulties between studies of the patients’ baseline cardiovascular risk, age, drug dosage, concomitant use of low-dose aspirin, duration of dosing, possible use of over the counter analgesic remedies and different underlying pathologies. Nevertheless some (reasonably) firm conclusions can be made: 1. Many studies have shown increased cardiac events,2,3 primarily thrombotic in nature, in patients taking COX 2 inhibitors compared to placebo or nonselective COX inhibitors. 2. Some studies have suggested that some COX 2 inhibitors are worse than others e.g., rofecoxib compared to celecoxib4,5 perhaps related to their degree of COX selectivity. Lumiracoxib seems not to be associated with increased cardiac risk.6 3. Many studies also show increased cardiovascular risk with the COX 1 inhibitors7–9 at times comparable to the increased risk associated with COX 2 inhibitors. 4. Patients still die from gastrointestinal complications – more so with the less selective NSAIDs. The imbalance created by the COX 2 mediated suppression of the vasodilator prostaglandin and the lack of suppression of the vasoconstrictor thromboxane A2 (the major COX 1 product of platelets causing platelet aggregration and vasoconstriction) has been suggested to explain the increased thrombotic complications, but this in itself does not explain the increased risk seen with non selective drugs. Other cardiac effects may do so. All NSAIDs are associated with worsening of hypertension control and probably increased risk of developing hypertension. In addition, fluid retention, renal dysfunction and increased edema will increase the likelihood of developing or worsening heart failure. Lessons in drug development to be learned should include rigorous evaluation or reevaluation of the risks vs benefits of all NSAIDs, not just the COX 2 group. In the perioperative setting this should include sensible guidelines on duration of therapy, caution in elderly patients especially those with heart disease, hypertension or heart failure, possible use of concomitant low-dose aspirin, and an understanding that nonselective COX inhibitors are not necessarily safer.

Celecoxib versus a Non-Selective NSAID Plus Proton-Pump Inhibitor

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used worldwide. However, associated adverse gastrointestinal effects (NSAID gastropathy) such as bleeding, perforation and obstruction result in considerable morbidity, mortality, and expense. Although it is essential to employ gastroprotective strategies to minimize these complications in patients at risk, controversy remains on whether celecoxib alone or a non-selective NSAID in conjunction with a proton-pump inhibitor (PPI) is a superior choice. Recent concerns regarding potential cardiovascular toxicities associated with cox-2 selective inhibitors may favor non-selective NSAID/PPI co-therapy as the preferred choice. Concomitant use of low-dose aspirin with any NSAID increases the risk of gastrointestinal complications and diminishes the improved gastrointestinal safety profile of celecoxib; whereas use of ibuprofen plus PPI regimens may negate aspirin's antiplatelet benefits. Evidence shows that concurrent use of a non-selective NSAID (such as naproxen) plus a PPI is as effective in preventing NSAID gastropathy as celecoxib, and may be more cost-effective. Patients failing or intolerant to this therapy would be candidates for celecoxib at the lowest effective dose for the shortest duration of time. Potential benefits from using low-dose celecoxib with a PPI in patients previously experiencing bleeding ulcers while taking NSAIDs remains to be proven. An evidence-based debate is presented to assist clinicians with the difficult decision-making process of preventing NSAID gastropathy while minimizing other complications.

Selective Cyclooxygenase-2 Inhibitors Development in Cardiovascular Medicine

At the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. Since its approval in 1999, Vioxx, a selective cyclooxygenase-2 (COX-2) inhibitor, has been Merck & Co’s leading drug for control of acute pain and chronic pain associated with osteoarthritis, rheumatoid arthritis, and menstruation. Last year, worldwide sales of rofecoxib reached US $2.5 billion, and it is estimated that the drug was prescribed ≈10 million times per month in the United States.1 Thus, given the number of patients involved and the serious nature of the side effects, the withdrawal raised serious concerns about the safety of other selective COX-2 inhibitors, collectively called coxibs, that are on the market and those currently under development. Celecoxib (Celebrex) and rofecoxib were the first 2 coxibs approved by the US Food and Drug Administration (FDA) and launched in 1999 by Pfizer and Merck & Co, respectively. Since then, a second generation of these drugs has emerged onto the market. Valdecoxib (Bextra) was approved by the FDA and launched in 2002. In that same year, the European regulatory authority approved 2 other coxibs: etoricoxib (Arcoxia) and parecoxib sodium (Dynastat), the prodrug of valdecoxib. Today, etoricoxib and a fifth coxib, lumiracoxib (Prexige), are under consideration for FDA approval. In view of the rapid development in this area, the main concern is whether the reported cardiovascular effects of rofecoxib are a class effect applicable to all coxibs that were initially designed to reduce the gastric toxicity of nonselective COX inhibitors. Although most of the data accumulated so far would suggest a class effect related to the general mode of action of all coxibs and the physiological role of COX-2, recent in vitro data would theoretically support the hypothesis that the cardiovascular side …

Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: A historical cohort analysis

Etodolac is a generic nonsteroidal anti-inflammatory drug (NSAID). Previous in vitro studies have shown that etodolac is a selective inhibitor of cyclooxygenase (COX)-2 with selectivity in between that of other COX-2 inhibitors such as celecoxib and rofecoxib. However, there are no outcomes data assessing clinically significant upper gastrointestinal (CSUGI) events with etodolac. A historical cohort study was performed at the Dallas Veterans Affairs Medical Center in which 16,286 veteran patients (5596 patient-years) received etodolac or naproxen during a 3-year period without concurrent use of other ulcerogenic drugs other than low-dose aspirin. The primary outcome was the CSUGI event rate of the etodolac and naproxen groups without concomitant low-dose aspirin. The incidence of CSUGI events was .78% and .24% for naproxen and etodolac, respectively. In the NSAID-naive subset, the incidence of CSUGI events was .99% and .24% for naproxen and etodolac, respectively. Compared with naproxen, etodolac was associated with a reduction in upper gastrointestinal events, corresponding to an odds ratio of .39 (95% confidence interval, .20-.76; P = .006). Concomitantly used low-dose aspirin increased event rates with naproxen 2-fold and etodolac 9-fold. Hence, there was no significant difference in gastrointestinal event rates between etodolac and naproxen when low-dose aspirin was taken concomitantly. Etodolac is a generic COX-2 selective inhibitor that reduces CSUGI events compared with the nonselective NSAID naproxen. However, concomitant use of low-dose aspirin negates the gastrointestinal safety advantages of etodolac.