ObjectiveTo assess whether corticosteroids are associated with increased risk of gastrointestinal bleeding or perforation.DesignSystematic review and meta-analysis of randomised, double-blind, controlled trials comparing a corticosteroid to placebo for any medical condition or in healthy participants. Studies with steroids given either locally, as a single dose, or in crossover studies were excluded.Data sourcesLiterature search using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews between 1983 and 22 May 2013.Outcome measureOutcome measures were the occurrence of gastrointestinal bleeding or perforation. Predefined subgroup analyses were carried out for disease severity, use of non-steroidal anti-inflammatory drugs (NSAIDs) or gastroprotective drugs, and history of peptic ulcer.Results159 studies (N=33 253) were included. In total, 804 (2.4%) patients had a gastrointestinal bleeding or perforation (2.9% and 2.0% for corticosteroids and placebo). Corticosteroids increased the risk of gastrointestinal bleeding or perforation by 40% (OR 1.43, 95% CI 1.22 to 1.66). The risk was increased for hospitalised patients (OR 1.42, 95% CI 1.22 to 1.66). For patients in ambulatory care, the increased risk was not statistically significant (OR 1.63, 95% CI 0.42 to 6.34). Only 11 gastrointestinal bleeds or perforations occurred among 8651 patients in ambulatory care (0.13%). Increased risk was still present in subgroup analyses (studies with NSAID use excluded; OR 1.44, 95% CI 1.20 to 1.71, peptic ulcer as an exclusion criterion excluded; OR 1.47, 95% CI 1.21 to 1.78, and use of gastroprotective drugs excluded; OR 1.42, 95% CI 1.21 to 1.67).ConclusionsCorticosteroid use was associated with increased risk of gastrointestinal bleeding and perforation. The increased risk was statistically significant for hospitalised patients only. For patients in ambulatory care, the total occurrence of bleeding or perforation was very low, and the increased risk was not statistically significant.

Gastrointestinal (GI) bleeding may be caused by a constitutive bleeding disposition or drug-induced inhibition of hemostasis. Platelet function in patients with ongoing GI bleeding is unknown. The aim of this study was to investigate platelet function in patients with acute GI bleeding. Patients (n = 35) presenting with acute GI bleeding (hematemesis or melena) were recruited. For comparison, 13 patients treated with aspirin and 11 patients treated with clopidogrel without GI bleeding and 27 healthy controls were studied. Platelet function was measured by whole-blood aggregation and flow cytometry. Coagulation function was measured with calibrated automated thrombography. Platelet aggregation and P-selectin expression were significantly lower after arachidonic acid stimulation in GI bleeding patients than in healthy subjects (p £ 0.05). Collageninduced P-selectin expression was significantly reduced in patients using anti-platelet drugs (p = 0.02) and in many patients not using anti-platelet drugs. Thrombin generation, measured by calibrated automated thrombography, was only reduced in patients on warfarin treatment. In conclusion, platelet function is reduced in acute GI bleeding patients and a considerable proportion appears to be related to drug use.Gastrointestinal (GI) bleeding has an incidence of 50 ⁄ 100,000 citizens per year [1], is often serious and even lethal. GI bleeding may be caused by inherited disposition, acquired bleeding diathesis, specific diseases such as Helicobacter pylori infection or oesophageal varices [2,3]. Acquired bleeding diathesis is often caused by adverse drug reaction of anti-thrombotic drugs. Both anti-coagulants and anti-platelet drugs are frequently used drugs in primary and secondary prevention of thromboembolism [4,5] and are associated with serious GI bleeding. Vitamin K antagonists, such as warfarin, interfere with the formation of functional gammacarboxylated vitamin K-dependent clotting factors (factors II, VII, IX and X) and anti-coagulants (protein C, -S and -Z) [6]. Aspirin and clopidogrel are the most commonly used anti-platelet drugs. Aspirin irreversibly acetylates cyclooxygenase (COX) -1 and inhibits thromboxane A2-mediated platelet aggregation as well as prostaglandin E 2 -mediated gastroprotection [7,8], whereas clopidogrel blocks the platelet adenosine diphosphate (ADP)-receptor P2Y 12 [9]. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used non-selective and reversible inhibitors of both COX-1 and COX-2; however, the inhibition of COX-1 varies between the agents.Platelet count and platelet function are of vital importance for normal hemostasis. To our knowledge, no investigations have been published concerning platelet function in patients with acute GI bleeding. We hypothesized that in patients with acute GI bleeding, medications with known or possible influence on hemostasis cause a decrease in platelet and ⁄ or coagulation function. The aim of this study was therefore to investigate platelet function and the level of pro-coagulant...

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Bleeding is the main adverse drug reaction of warfarin use. • Several medicines, herbal products and dietary supplements may interact with warfarin. • A high percentage of patients on warfarin receive potentially interacting substances. WHAT THIS STUDY ADDS • Potentially interacting medicines were used in more than 50% of the warfarin‐associated bleeding events reported to the Norwegian spontaneous reporting system. • Only a minority of the concomitant medicines were reported as suspected or interacting in the reporters' assessments. • There was a higher degree of under‐reporting of pharmacokinetically than of pharmacodynamically interacting medicines. AIMS To study warfarin associated bleeding events reported to the Norwegian spontaneous reporting system and evaluate the differences in assessment of potentially interacting medicines between reporters and evaluators. METHODS Data on bleeding events on warfarin were retrieved from the Norwegian spontaneous reporting system database. Key measurements were time to bleeding, use of concomitant medications and the evaluation done by reporters. RESULTS In 289 case reports a total of 1261 medicines (median 4.0 per patient, range 1–17) was used. The evaluators (authors of this article) identified 546 medicines including warfarin (median 2.0 per patient, range 1–7) that could possibly cause bleeding alone or in combination. Reporters assessed 349 medicines (median 1.0 per patient, range 1–4) as suspect. Evaluators identified 156 pharmacokinetic and 101 pharmacodynamic interactions, compared with 19 pharmacokinetic and 56 pharmacodynamic interactions reported as suspected by the reporters. Time to bleeding was stated in 224 reports. Among the early bleeding events, the reports on warfarin without interacting medicines showed the highest INR (international normalized ratio). Heparin was used in 17/21 reported bleeding events during the first week on warfarin. Among the late bleeding events, reports with pharmacokinetic interacting medicines had the highest INR. CONCLUSIONS Concomitant use of potentially interacting medicines was involved in the majority of the warfarin‐associated bleeding events reported to the Norwegian spontaneous reporting system. Reporters assessed mostly warfarin as the only contributor to bleeding. In particular, pharmacokinetically interacting medicines were not suspected as contributing to bleeding.

The aim of this study was to investigate whether the VKORC1*3 (rs7294/9041 G > A), VKORC1*4 (rs17708472/6009 C > T), and CYP4F2 (rs2108622/1347 C > T) polymorphisms were associated with elevated warfarin maintenance dose requirements in patients with myocardial infarction (n = 105) from the Warfarin Aspirin Reinfarction Study (WARIS-II). We found significant associations between elevated warfarin dose requirements and VKORC1*3 and VKORC1*4 polymorphisms (P = .001 and P = .004, resp.), whereas CYP4F2 (1347 C > T) showed a weak association on higher warfarin dose requirements (P = .09). However, analysing these variant alleles in a regression analysis together with our previously reported data on VKORC1*2, CYP2C9*2 and CYP2C9*3 polymorphisms, gave no significant associations for neither VKORC1*3, VKORC1*4 nor CYP4F2 (1347 C > T). In conclusion, in patients with myocardial infarction, the individual contribution to warfarin dose requirements from VKORC1*3, VKORC1*4, and CYP4F2 (1347 C > T) polymorphisms was negligible. Our results indicate that pharmacogenetic testing for VKORC1*2, CYP2C9*2 and CYP2C9*3 is more informative regarding warfarin dose requirements than testing for VKORC1*3, VKORC1*4, and CYP4F2 (1347 C > T) polymorphisms.

BackgroundBleeding represents the most well-known and the most feared complications caused by the use of antithrombotic agents. There is, however, limited documentation whether pre-injury use of antithrombotic agents affects outcome after head trauma. The aim of this study was to define the relationship between the use of preinjury antithrombotic agents and mortality among elderly people sustaining blunt head trauma.MethodsA retrospective cohort analysis was performed on the hospital based trauma registry at Oslo University Hospital. Patients aged 55 years or older sustaining blunt head trauma between 2004 and 2006 were included. Multivariable logistic regression analyses were used to identify independent predictors of 30-day mortality. Separate analyses were performed for warfarin use and platelet inhibitor use.ResultsOf the 418 patients admitted with a diagnosis of head trauma, 137 (32.8 %) used pre-injury antithrombotic agents (53 warfarin, 80 platelet inhibitors, and 4 both). Seventy patients died (16.7 %); 15 (28.3 %) of the warfarin users, 12 (15.0 %) of the platelet inhibitor users, and two (50 %) with combined use of warfarin and platelet inhibitors, compared to 41 (14.6 %) of the non-users. There was a significant interaction effect between warfarin use and the Triage Revised Trauma Score collected upon the patients’ arrival at the hospital. After adjusting for potential confounders, warfarin use was associated with increased 30-day mortality among patients with normal physiology (adjusted OR 8,3; 95 % CI, 2.0 to 34.8) on admission, but not among patients with physiological derangement on admission. Use of platelet inhibitors was not associated with increased mortality.ConclusionsThe use of warfarin before trauma was associated with increased 30-day mortality among a subset of patients. Use of platelet inhibitors before trauma was not associated with increased mortality. These results indicate that patients on preinjury warfarin may need closer monitoring and follow up after trauma despite normal physiology on admission to the emergency department.

The aim of this study was to evaluate the contribution of a low calcium diet to the cortical and trabecular osteoporosis seen in ovariectomized rats after 7 weeks on a low calcium diet and to investigate the effects of the bisphosphonate clodronate on this development of osteoporosis. Thirty-six mature, female Wistar rats were randomized into four groups: Ovx-B (bisphosphonate) and Ovx-C (control) were ovariectomized, and Sham-Ca (low calcium) and Sham+Ca (normal calcium) were sham operated. The first three groups were fed a low calcium diet (0.01%) and Sham+Ca normal rat chow (Ca 1.1%). The Ovx-B received 10 mg/kg s.c. clodronate daily for nine weeks, and Ovx-C, Sham-Ca, and Sham+Ca received the same volumes of saline. Bone mineral turnover measured as 85Sr-uptake was increased in all low calcium groups compared to Sham+Ca. The Sham+Ca femora had higher dry weight and ash weight than the other groups, and Ovx-C had higher dry weight compared with Ovx-B and Sham-Ca. Calcium content was lower in both Ovx groups compared to both Sham groups. Magnesium was lower in all groups compared to Sham+Ca and higher in Ovx-B compared with Ovx-C. In the femoral shaft, Sham+Ca had significantly higher ultimate bending moment, energy absorption, and deflection compared to the other three groups. Ultimate bending moment was higher in Sham-Ca than in Ovx-C. Stiffness was increased in both Sham+Ca and Ovx-B compared to Ovx-C. The maximum stress in the femoral midshaft was higher in Sham+Ca than in the other groups, and higher in Ovx-B than in Ovx-C. Histomorphometry showed increased medullary area in all low calcium groups compared to Sham+Ca and larger cortical area in Sham+Ca and Ovx-B compared to Ovx-C. Compared to Sham+Ca the trabecular bone volume was decreased to 30% in Sham-Ca and to 9% in Ovx-C, but was unchanged in Ovx-B. The low calcium diet generally increased bone mineral turnover and reduced the tibial bone volume. Femoral changes led to a reduction of cortical fracture strength and maximal stress. Ovariectomy in addition to a low calcium diet reduced femoral strength even more. Daily injections of clodronate to ovariectomized rats on a low calcium diet increased femoral shaft stiffness and maximum stress, and clodronate preserved both trabecular and cortical tibial bone volume completely.

CYP2C9 and VKORC1 genotype frequencies in myocardial infarction patients appear similar to other patient groups and have similar impact on warfarin maintenance dose.

Non-warfarin-associated bleeding events are associated with substantial mortality. Old age, cerebral bleeds, number of drugs used, and use of fibrinolytics are all independently associated with increased mortality. The recognition of the bleeding risk of commonly used drugs such as acetylsalicylic acid and heparins may be insufficient among prescribers.