ContextConventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated
with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because
of inhibition of cyclooxygenase (COX)-1. Whether COX-2–specific inhibitors
are associated with fewer clinical GI toxic effects is unknown.ObjectiveTo determine whether celecoxib, a COX-2–specific inhibitor, is
associated with a lower incidence of significant upper GI toxic effects and
other adverse effects compared with conventional NSAIDs.DesignThe Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind,
randomized controlled trial conducted from September 1998 to March 2000.SettingThree hundred eighty-six clinical sites in the United States and Canada.ParticipantsA total of 8059 patients (≥18 years old) with osteoarthritis (OA)
or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received
at least 1 dose of study drug. A total of 4573 patients (57%) received treatment
for 6 months.InterventionsPatients were randomly assigned to receive celecoxib, 400 mg twice per
day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987);
ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per
day (n = 1996). Aspirin use for cardiovascular prophylaxis (≤325 mg/d)
was permitted.Main Outcome MeasuresIncidence of prospectively defined symptomatic upper GI ulcers and ulcer
complications (bleeding, perforation, and obstruction) and other adverse effects
during the 6-month treatment period.ResultsFor all patients, the annualized incidence rates of upper GI ulcer complications
alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76%
vs 1.45% (P = .09) and 2.08% vs 3.54% (P = .02), respectively. For patients not taking aspirin, the annualized
incidence rates of upper GI ulcer complications alone and combined with symptomatic
ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P
= .04) and 1.40% vs 2.91% (P = .02). For patients
taking aspirin, the annualized incidence rates of upper GI ulcer complications
alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01%
vs 2.12% (P = .92) and 4.70% vs 6.00% (P = .49). Fewer celecoxib-treated patients than NSAID-treated patients
experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal
toxicity. No difference was noted in the incidence of cardiovascular events
between celecoxib and NSAIDs, irrespective of aspirin use.ConclusionsIn this study, celecoxib, at dosages greater than those indicated clinically,
was associated with a lower incidence of symptomatic ulcers and ulcer complications
combined, as well as other clinically important toxic effects, compared with
NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest
among patients not taking aspirin concomitantly.

https://jamanetwork.com/journals/jama/articlepdf/193062/JOC01227.pdf

Gastrointestinal Toxicity With Celecoxib vs Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis: The CLASS Study: A Randomized Controlled Trial

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(09)60938-7.pdf

Peptic ulcer disease

Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects

This document has been developed by the American College of Cardiology Foundation (ACCF) Task Force on Clinical Expert Consensus Documents, the American College of Gastroenterology (ACG), and the American Heart Association (AHA). Expert consensus documents (ECDs) are intended to inform practitioners, payers, and other interested parties of the opinion of the ACCF and document cosponsors concerning evolving areas of clinical practice and/or technologies that are widely available or new to the practice community. Topics chosen for coverage by ECDs are so designed because the evidence base, the experience with technology, and/or the clinical practice are not considered sufficiently well developed to be evaluated by the formal American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines process. Often the topic is the subject of ongoing investigation. Thus, the reader should view ECDs as the best attempt of the ACCF and other cosponsors to inform and guide clinical practice in areas where rigorous evidence may not be available or the evidence to date is not widely accepted. When feasible, ECDs include indications or contraindications. Topics covered by ECDs may be addressed subsequently by the ACC/AHA Practice Guidelines Committee as new evidence evolves and is evaluated.

The Task Force on ECDs makes every …

/pdf/accf-acg-aha-2008-expert-consensus-document-on-reducing-the-3t3a5cdta8.pdf

ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents

Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(96)01254-8.pdf

Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product

Agranulocytosis and aplastic anaemia are rare but serious conditions known to be caused by numerous drugs. Most of what is known or suspected about the aetiology is based on case reports, with only a few formal epidemiological studies that provide quantitative estimates of risk. Updated results have been obtained from a combined analysis of data from 3 case-control studies that used similar methods: the International Agranulocytosis and Aplastic Anemia Study (IAAAS), conducted in Israel and Europe; a study conducted in the northeast US; and a study conducted in Thailand. Totals of 362 cases of agranulocytosis, 454 cases of aplastic anaemia and 6458 controls were included in the analyses. The IAAAS and Thai study were population-based, providing estimates of the incidence of the 2 dyscrasias. The overall annual incidence of agranulocytosis in the ambulatory population was 3.4/10(6) in the IAAAS and 0.8/10(6) in Thailand; by contrast the incidence of aplastic anaemia was 2.0/10(6) in the IAAAS and 4.1/10(6) in Thailand. A total of 21 compounds were significantly associated with an increased risk of agranulocytosis in the IAAAS and US studies. Excess risks ranged from 0.06 to 13 cases/10(6) users/wk; the most strongly associated drugs were procainamide, anti-thyroid drugs and sulphasalazine. An association with drugs that had previously been suspected was also seen in Thailand. The overall aetiologic fractions of agranulocytosis due to drug use were 62% in the IAAAS, 72% in the US and 70% in Thailand. Eleven drugs were significantly associated with an increased risk of aplastic anaemia, with excess risks ranging from 1.4 to 60 cases/10(6) users in a 5-month period. The most strongly associated drugs were penicillamine, gold and carbamazepine. Aetiologic fractions were 27% in the IAAAS, 17% in the US and 2% in Thailand, which paralleled the prevalence of use of associated drugs in the 3 populations. The present results confirm that agranulocytosis is largely a drug-induced disease, with similar proportions accounted for in 3 disparate geographic regions. By contrast, although many of the expected associations were observed for aplastic anaemia, most of the aetiology is not explained by drugs. For all associated drugs, the excess risks are sufficiently low that blood dyscrasias should not figure prominently in the balancing of risks and benefits.

Drugs in the aetiology of agranulocytosis and aplastic anaemia

Two hypotheses were examined in the combined data from 3 case-control studies of aplastic anaemia, conducted in Thailand, Europe/Israel and the US: 1. Cases exposed to drugs associated with a significantly increased risk of aplastic anaemia are more likely to present with thrombocytopenia (e.g. petechiae, easy bruising); and 2. cases exposed to these drugs are more likely to recover quickly than non-exposed cases. After excluding all cases who lacked information on timing of symptoms and those whose symptoms began > or = 180 d before hospital admission, 392 cases remained for analysis. A total of 51 (13%) had been exposed to one of the significantly associated drugs; the remaining 341 (87%) had not. Among the former, 31% reported thrombocytopenia either before or at the same time as non-bleeding symptoms (e.g. pallor, fatigue); the corresponding proportion among the non-exposed was 53%. Data on time to recovery (return of the 3 blood cell lines to normal levels) were not available for the Thai cases; among the others, the median time to recovery for the non-fatal cases was 7 and 6 months in the 29 exposed and the 83 non-exposed cases, respectively. The data do not support either hypothesis: the two groups of aplastic anaemia cases appeared to be similar in both the presenting symptoms and the recovery time.

Jan M. Jurgelon

Papers

Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product

Drugs in the aetiology of agranulocytosis and aplastic anaemia

An epidemiological study of aplastic anaemia: relationship of drug exposures to clinical features and outcome.