Luis A. García-Rodríguez

Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations

Background: The risks and benefits of coxibs, non-steroidal anti-inflammatory drugs (NSAIDs), and aspirin treatment are under intense debate. Objective: To determine the risk of peptic ulcer upper gastrointestinal bleeding (UGIB) associated with the use of coxibs, traditional NSAIDs, aspirin or combinations of these drugs in clinical practice. Methods: A hospital-based, case–control study in the general community of patients from the National Health System in Spain. The study included 2777 consecutive patients with endoscopy-proved major UGIB because of the peptic lesions and 5532 controls matched by age, hospital and month of admission. Adjusted relative risk (adj RR) of UGIB determined by conditional logistic regression analysis is provided. Results: Use of non-aspirin-NSAIDs increased the risk of UGIB (adj RR 5.3; 95% confidence interval (CI) 4.5 to 6.2). Among non-aspirin-NSAIDs, aceclofenac (adj RR 3.1; 95% CI 2.3 to 4.2) had the lowest RR, whereas ketorolac (adj RR 14.4; 95% CI 5.2 to 39.9) had the highest. Rofecoxib treatment increased the risk of UGIB (adj RR 2.1; 95% CI 1.1 to 4.0), whereas celecoxib, paracetamol or concomitant use of a proton pump inhibitor with an NSAID presented no increased risk. Non-aspirin antiplatelet treatment (clopidogrel/ticlopidine) had a similar risk of UGIB (adj RR 2.8; 95% CI 1.9 to 4.2) to cardioprotective aspirin at a dose of 100 mg/day (adj RR 2.7; 95% CI 2.0 to 3.6) or anticoagulants (adj RR 2.8; 95% CI 2.1 to 3.7). An apparent interaction was found between low-dose aspirin and use of non-aspirin-NSAIDs, coxibs or thienopyridines, which increased further the risk of UGIB in a similar way. Conclusions: Coxib use presents a lower RR of UGIB than non-selective NSAIDs. However, when combined with low-dose aspirin, the differences between non-selective NSAIDs and coxibs tend to disappear. Treatment with either non-aspirin antiplatelet or cardioprotective aspirin has a similar risk of UGIB.

Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice.

OBJECTIVES:Changing patterns in medical practice may contribute to temporal changes in the incidence of upper and lower gastrointestinal (GI) complications. There are limited data on the incidence of lower GI complications in clinical practice and most studies that have been done have serious methodological limitations to inferring the actual burden of this problem. The aims of this study were to analyze time trends of hospitalizations resulting from GI complications originating both from the upper and lower GI tract in the general population, and to determine the risk factors, severity, and clinical impact of these GI events.METHODS:This was a population-based study of patients hospitalized because of GI complications in 10 general hospitals between 1996 and 2005 in Spain. We report the age- and gender-specific rates, estimate the regression coefficients of the upper and lower GI event trends, and evaluate the severity and associated risk factors. GI hospitalization charts were validated by an independent review of large random samples of unspecific and specific codes distributed among all hospitals and study years.RESULTS:Upper GI complications fell from 87/100,000 persons in 1996 to 47/100,000 persons in 2005, whereas lower GI complications increased from 20/100,000 to 33/100,000. Overall, mortality rates decreased, but the case fatality remained constant over time. Lower GI events had a higher mortality rate (8.8 vs. 5.5%), a longer hospitalization (11.6±13.9 vs. 7.9±8.8 days), and higher resource utilization than did upper GI events. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) without concomitant proton pump inhibitor was more frequently recorded among upper GI complications than among lower GI complications. When comparing upper GI events with lower GI events, we found that male gender (adjusted odds ratio (OR): 1.94; 95% confidence interval (CI): 1.70–2.21), and recorded NSAID use (OR: 1.92; 95% CI: 1.60–2.30) were associated to a greater extent with upper GI events, whereas older age (OR: 0.83; 95% CI: 0.77–0.89), number of comorbidities (OR: 0.91; 95% CI: 0.86–0.96), and having a diagnosis in recent years (OR: 0.92; 95% CI: 0.90–0.94) were all associated to a greater extent with lower GI events than with upper GI events after adjusting for age, sex, hospitalization, and discharge year.CONCLUSIONS:Over the past decade, there has been a progressive change in the overall picture of GI events leading to hospitalization, with a clear decreasing trend in upper GI events and a significant increase in lower GI events, causing the rates of these two GI complications to converge. Overall, mortality has also decreased, but the in-hospital case fatality of upper or lower GI complication events has remained constant. It will be a challenge to improve future care in this area unless we develop new strategies to reduce the number of events originating in the lower GI tract, as well as reducing their associated mortality.

Effect of Antisecretory Drugs and Nitrates on the Risk of Ulcer Bleeding Associated With Nonsteroidal Anti-Inflammatory Drugs, Antiplatelet Agents, and Anticoagulants

OBJECTIVES:After the withdrawal of some cyclooxygenase-2 (COX-2) selective inhibitors, traditional nonsteroidal anti-inflammatory drug (NSAID) use has increased, but without additional prevention strategies against upper gastrointestinal (GI) complications in many cases. Here, we report the effect of antisecretory drugs and nitrates on the risk of upper GI peptic ulcer bleeding (UGIB) associated with nonselective NSAIDs, aspirin, antiplatelet agents, and anticoagulants.METHODS:This case–control study matched 2,777 consecutive patients with UGIB (confirmed by endoscopy) with 5,532 controls (2:1). Adjusted relative risks (RR) of UGIB are reported.RESULTS:Proton pump inhibitors (PPIs) (RR 0.33, 95% confidence interval [CI] 0.27–0.39), H2-receptor antagonists (H2-RAs) (RR 0.65, 95% CI 0.50–0.85), and nitrates (RR 0.52, 95% CI 0.38–0.70) reduced UGIB risk. PPI use was associated with greater reductions among both traditional NSAID (RR 0.13, 95% CI 0.09–0.19 vs RR 0.30, 95% CI 0.17–0.53 with H2-RAs; RR 0.48, 95% CI 0.19–1.24 with nitrates) and low-dose aspirin users (RR 0.32, 95% CI 0.22–0.51 vs RR 0.40, 95% CI 0.19–0.73 with H2-RA; RR 0.69, 95% CI 0.36–1.04 with nitrates), and among patients taking clopidogrel (RR 0.19, 95% CI 0.07–0.49). For patients taking anticoagulants, use of nitrates, H2-RA, or PPIs was not associated with a significant effect on UGIB risk.CONCLUSION:Antisecretory agent or nitrate treatment is associated with reduced UGIB RR in patients taking NSAID or aspirin. Only PPI therapy was associated with a marked, consistent risk reduction among patients receiving all types of agents (including nonaspirin antiplatelet agents). Protection was not apparent in patients taking anticoagulants.

Risk of Upper Gastrointestinal Tract Bleeding Associated With Selective Serotonin Reuptake Inhibitors and Venlafaxine Therapy: Interaction With Nonsteroidal Anti-inflammatory Drugs and Effect of Acid-Suppressing Agents

CONTEXT Selective serotonin reuptake inhibitors have been reported to increase the risk of upper gastrointestinal tract bleeding. The wide use of these drugs makes such potential risk a public health concern, and identification of factors that may increase or minimize such risk is necessary. OBJECTIVES To test the association of selective serotonin reuptake inhibitors and venlafaxine hydrochloride therapy with upper gastrointestinal tract bleeding, to identify subgroups of patients at particularly increased risk, and to explore whether acid-suppressing agents may be effective in minimizing risk. DESIGN Nested case-control study. SETTING General practice database from the United Kingdom. PARTICIPANTS One thousand three hundred twenty-one patients with upper gastrointestinal tract bleeding referred to a consultant or hospital and 10 000 control subjects matched for age, sex, and calendar year of the index date. Main Outcome Measure Risk of bleeding associated with selective serotonin reuptake inhibitors and effect of acid-suppressing agents. RESULTS The percentage of current users of selective serotonin reuptake inhibitors (5.3%) or venlafaxine (1.1%) among case subjects was significantly higher than in matched control subjects (3.0% and 0.3%; adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2-2.1, and OR, 2.9; 95% CI, 1.5-5.6, respectively). An interaction with nonsteroidal anti-inflammatory drugs (OR, 4.8; 95% CI, 2.8-8.3) was observed, in particular among those not using acid-suppressing agents (OR, 9.1; 95% CI, 4.8-17.3) compared with users of these drugs (OR, 1.3; 95% CI, 0.5-3.3). In addition, an interaction with antiplatelet drugs in nonusers of acid-suppressing agents was suggested (OR, 4.7; 95% CI, 2.6-8.3) compared with users of these drugs (OR, 0.8; 95% CI, 0.3-2.5). CONCLUSIONS Antidepressants with a relevant blockade action on the serotonin reuptake mechanism increase the risk of upper gastrointestinal tract bleeding. The increased risk may be of particular relevance when these drugs are associated with nonsteroidal anti-inflammatory drugs. Our study findings also provide evidence that use of acid-suppressing agents limits such increased risk.

Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drugs

The use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with upper gastrointestinal bleeding and perforation (UGIB), acute liver injury, acute renal injury, heart failure, and adverse reproductive outcomes. This article summarizes the effects of various factors, such as NSAID dose, duration of treatment, patient age, and ulcer history, on the incidences of these adverse side effects. We used the UK General Practice Research Database to study further the principal safety concern related to NSAIDs, namely, UGIB.

Antithrombotic drugs and risk of hemorrhagic stroke in the general population

Objective: To investigate the relationship between hemorrhagic stroke and use of antiplatelets and warfarin using data from The Health Improvement Network. Methods: A total of 1,797 incident cases of intracerebral hemorrhage (ICH) and 1,340 of subarachnoid hemorrhage (SAH) were ascertained. Density-based sampling was used to select 10,000 controls free from hemorrhagic stroke. Risk of hemorrhagic stroke was evaluated in current users and nonusers of antiplatelets and warfarin. Unconditional logistic regression models were used to adjust for age, sex, calendar year, alcohol, body mass index, hypertension, and health services utilization. Results: Aspirin use was not associated with an increased risk of ICH (odds ratio [OR] 1.06, 95% confidence interval [CI] 0.93–1.21), but was associated with a decreased risk of SAH (OR 0.82, 95% CI 0.67–1.00), compared with no therapy. Aspirin use ≥3 years was associated with a decreased risk of SAH (OR 0.63, 95% CI 0.45–0.90) compared with no therapy. Warfarin use was associated with a greatly increased risk of ICH (OR 2.82, 95% CI 2.26–3.53) and a moderately increased risk of SAH (OR 1.67, 95% CI 1.15–2.43) compared with no therapy. International normalized ratio values ≥3 carried a marked risk of ICH (OR 7.01, 95% CI 4.10–11.99). Conclusion: Aspirin is not associated with a risk of ICH compared with no therapy. Chronic low-dose aspirin treatment may have a protective effect on the risk of SAH. Warfarin users in this study cohort were at a much higher risk of ICH than those receiving no therapy, with a marked association with international normalized ratio >3.

Risk of Upper and Lower Gastrointestinal Bleeding in Patients Taking Nonsteroidal Anti-inflammatory Drugs, Antiplatelet Agents, or Anticoagulants

BACKGROUND & AIMS Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin is associated with increased risk of upper gastrointestinal bleeding. There is little evidence on the risk of lower gastrointestinal bleeding with NSAIDs, antiplatelet agents (APAs), or anticoagulants. We aimed to quantify the relative risk (RR) of upper and lower gastrointestinal bleeding associated with use of NSAIDs, APAs, or anticoagulants. METHODS We performed a case-control study that used data collected from consecutive patients hospitalized for gastrointestinal bleeding (563 upper, mean age, 63.6 ± 16.7 years and 415 lower, mean age, 70.8 ± 13.8 years), confirmed by endoscopy or other diagnostic procedures. Unhospitalized patients were used as controls (n = 1008) and matched for age, hospital, and month of admission. Drug use was considered current when taken within 7 days or less before hospitalization. RRs and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis. RESULTS Use of anticoagulants, low-dose aspirin, and other drugs (non-aspirin-APA, 82.3% thienopiridines) was associated with upper and lower gastrointestinal bleeding; the risk was 2-fold higher for anticoagulants (RR, 4.2; 95% CI, 2.9-6.2) than for low-dose aspirin (RR, 2.1; 95% CI, 1.4-3.3) or other non-aspirin-APA drugs (RR, 2.0; 95% CI, 1.6-2.6). NSAID use was also associated with increased risk of gastrointestinal bleeding and greater for upper (RR, 2.6; 95% CI, 2.0-3.5) than lower gastrointestinal bleeding (RR, 1.4; 95% CI, 1.0-1.9). Use of proton pump inhibitors was associated with reduced risk of upper, but not lower, gastrointestinal bleeding. CONCLUSIONS Anticoagulants, low-dose aspirin, NSAIDs, and other non-aspirin-APA drugs are associated with increased risk of upper and lower gastrointestinal bleeding. Use of anticoagulants appears to be the strongest risk factor for gastrointestinal bleeding.

The safety of rosuvastatin in comparison with other statins in over 100 000 statin users in UK primary care

To compare mortality and the incidence of hospitalization for myopathy, rhabdomyolysis, acute renal failure and acute liver injury in patients receiving rosuvastatin and those taking other statins.

Mortality after hemorrhagic stroke Data from general practice (The Health Improvement Network)

Objective: To investigate short-term case fatality and long-term mortality after intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) using data from The Health Improvement Network database. Methods: Thirty-day case fatality was stratified by age, sex, and calendar year after ICH and SAH using logistic regression. Cox proportional hazards regression analyses were used to estimate the risk of death during the first year of follow-up and survivors at 1 year. Results: Case fatality after ICH was 42.0%, compared with 28.7% after SAH. It increased with age (ICH: 29.7% for 20–49 years, 54.6% for 80–89 years; SAH: 20.3% for 20–49 years, 56.7% for 80–89 years; both p-trend < 0.001), and decreased over the period 2000–2001 to 2006–2008 (ICH: from 53.1% to 35.8%, p-trend < 0.001; SAH: from 33.3% to 24.7%, p-trend = 0.02). Risk of death was significantly higher among stroke patients during the first year of follow-up compared with controls (ICH: hazard ratio [HR] 2.60, 95% confidence interval [CI] 2.09–3.24, p < 0.01; SAH: HR 2.87, 95% CI 2.07–3.97, p < 0.01) and remained elevated among survivors at 1 year (ICH: HR 2.02, 95% CI 1.75–2.32, p < 0.01; SAH: HR 1.32, 95% CI 1.02–1.69, p = 0.03). Conclusions: More than one-third of individuals die in the first month after hemorrhagic stroke, and patients younger than 50 years are more likely to die after ICH than SAH. Short-term case fatality has decreased over time. Patients who survive hemorrhagic stroke have a continuing elevated risk of death compared with matched individuals from the general population.

Prevalence, incidence, morbidity and treatment patterns in a cohort of patients diagnosed with anxiety in UK primary care

BACKGROUND Anxiety disorders are common and can cause substantial quality of life impairment. OBJECTIVE The aim of this study was to investigate the frequency of anxiety in UK primary care. Treatment patterns and factors associated with an anxiety diagnosis were also assessed. METHODS The Health Improvement Network was used to identify all patients aged 10-79 years with a new diagnosis of anxiety in 2002-04 (n = 40 873) and age-, sex- and calendar-year-matched controls (n = 50 000). A nested case-control analysis was used to quantify potential risk factors for anxiety by multivariate logistic regression. RESULTS The prevalence of anxiety was 7.2% and the incidence was 9.7 per 1000 person-years. Incidence and prevalence were highest in women and young adults (20-29 years). Anxiety was associated with heavy alcohol use, smoking and addiction problems as well as stress, sleep and depression disorders. Anxiety patients used health care services more frequently than controls. Among patients diagnosed with anxiety, 63% were treated pharmacologically. Antidepressants accounted for almost 80% of prescriptions. CONCLUSIONS The prevalence and incidence of anxiety are high in UK primary care and are almost twice as high in women than in men. Anxiety is associated with other psychiatric morbidity as well as frequent health care use. Antidepressants are the most commonly used pharmacological treatment.