Postoperative nonsteroidal anti-inflammatory drug prophylaxis for elbow heterotopic ossification: a systematic review and meta-analysis comparing COX-2 selective and nonselective inhibitors.

The aim of this study was to assess the efficacy of non-selective and selective non-steroidal anti-inflammatory drugs (NSAIDs) in preventing heterotopic ossification (HO) after total hip arthroplasty (THA). A thorough and systematic literature search was conducted and 29 studies were found that met inclusion criteria. Data were extracted and statistical analysis was carried out generating forest plots. Non-selective NSAIDs showed a significant decrease in the odds for forming HO after THA (odds ratio (OR) -1.35, confidence interval (CI) -1.83 to -0.86) when compared with placebo. Selective NSAIDs also showed a significant decrease in the odds for forming HO after THA when compared with placebo (OR -1.58, CI -2.41 to -0.75). When comparing non-selective NSAIDs with selective NSAIDs, there was no significant change in the odds for forming HO after THA (OR 0.22, CI -0.36 to 0.79). Our meta-analyses of all available data suggest that both non-selective and selective NSAIDs are effective HO prophylaxis and can be used routinely after THA for pain control as well as prevention of HO. Indomethacin may serve as the benchmark among non-selective NSAIDs and celecoxib among selective NSAIDs. There was no difference in the incidence of HO between non-selective and selective NSAIDs, allowing physicians to choose either based on the clinical scenario and patient-specific factors. Cite this article: Bone Joint J 2018;100-B:915-22.

Risk of Cardiovascular Events in Patients Receiving Celecoxib: A Meta-Analysis of Randomized Clinical Trials

Whether selective non-steroidal anti-inflammatory drugs (NSAIDs) has equally efficacy with non-selective NSAIDs in preventing heterotopic ossification (HO) after total hip arthroplasty (THA) was controversial. The purpose of this meta-analysis was to assess the efficacy and safety of selective NSAID versus non-selective NSAIDs for the prevention of HO after THA. PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, Google Search Engine, and China National Knowledge Infrastructure databases was searched for randomized controlled trials (RCTs) were comparing selective NSAID versus non-selective NSAIDs for preventing HO after THA. The primary outcomes were overall HO incidence, Brooker classification HO incidence, gastrointestinal side effects, the occurrence of excessive bleeding and discontinuation caused by gastrointestinal side effects (DGSE). Data were analyzed using Stata 12.0. A total of 8 RCTs involving 1636 patients were included in the meta-analysis. There was no significant difference between the nonselective NSAIDs group and the selective NSAIDs group in the overall incidence of HO (relative risk, RR = 0.91, 95% confidence intervals, CI 0.78-1.06, P = .203), Brooker I HO (RR = 1.02, 95% CI 0.85-1.23, P = .794), Brooker II HO (RR = 1.00, 95% CI 0.66-1.52, P = .996). Brooker III HO (RR = 0.98, 95% CI 0.37-2.62, P = .971). And the occurrence of excessive bleeding (RR = 0.67, 95% CI 0.24-1.92, P = .458). The selective NSAIDs group was associated with a significant decrease in gastrointestinal side effects (RR = 0.35, 95% CI 0.18-0.71, P = .004) and discontinuation caused by gastrointestinal side effects compared with the nonselective NSAIDs group (RR = 0.28, 95% CI 0.11-0.66, P = .004). The available evidence indicates selective NSAIDs were as effective as non-selective NSAIDs in preventing HO after THA. And selective NSAIDs were associated with less gastrointestinal side effects than non-selective NSAIDs. Considering the limitation of current meta-analysis, more RCTs need to identify the optimal NSAIDs drug for HO after THA.

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3⇓). Figure 1. Comparison of effects of different selective COX-2 inhibitors vs placebo on myocardial infarction. Event numbers and person-years of exposure, with corresponding mean annual event rates in parentheses, are presented for patients allocated to selective COX-2 inhibitor or placebo. Event rate ratios for pooled data with 95% CIs are indicated by a diamond; rate ratios for individual selective COX-2 inhibitors, with 99% CIs, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX-2 inhibitor compared with placebo. As noted, there was a significant increase in the rate ratio for myocardial infarction with COX-2 inhibitors compared with placebo. Similar analyses (data not shown) include rate ratios of 1.42 (1.13 to 1.78; P =0.003) for vascular events, 1.02 (0.71 to 1.47; P …

Do non-steroidal anti-inflammatory drugs cause osteoarthritis progression, a systematic review and meta analysis

Recent placebo-controlled clinical trials suggest excessive adverse cardiovascular (CV) events associated with cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs), developed to reduce gastrointestinal irritation associated with nonselective NSAIDs. Subsequent retrospective analyses of observational series and non-CV clinical trials suggest that CV events may occur with modest excess with all NSAIDs, nonselective and COX-2 selective, compared with nonuse of these drugs, may be dose related, and do not differ substantially in frequency among various NSAIDs. However, inadequacy of study designs, controls, and events has precluded definition of the risk-benefit relationship of COX-2 selective and nonselective NSAIDs. Resolution of this problem requires several different types of studies, necessarily including appropriately designed randomized, controlled trials comparing commonly employed nonselective and COX-2 selective NSAIDs in patients expected to benefit (ie, those with symptomatically severe arthritis) who also have coronary occlusive disease so that achievable noninferiority trial size has power sufficient to resolve relatively small differences in adverse CV (and gastrointestinal) event rates. This article explores the goals and possible designs of trials appropriate for defining risk-benefit relationship that must be known for optimal application of NSAID therapy.

Heterotopic ossification (HO) is a frequent complication after total hip arthroplasty (THA). Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used as routine prophylaxis for HO after THA. However, the efficacy of NSAIDs on HO, particularly selective NSAIDs versus nonselective NSAIDs, is uncertain.We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and clinicaltrials.gov to identify randomized controlled trials with respect to HO after THA. Two reviewers extracted the data and estimated the risk of bias. For the ordered data, we followed the Bayesian framework to calculate the odds ratio (OR) with a 95% credible interval (CrI). For the dichotomous data, the OR and 95% confidence interval (CI) were calculated using Stata version 12.0. The subgroup analyses and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach were used.A total of 1856 articles were identified, and 21 studies (5995 patients) were included. In the NSAIDs versus placebo analysis, NSAIDs could decrease the incidence of HO, according to the Brooker scale (OR = 2.786, 95% CrI 1.879–3.993) and Delee scale (OR = 9.987, 95% CrI 5.592–16.17). In the selective NSAIDs versus nonselective NSAIDs analysis, there was no significant difference (OR = 0.7989, 95% CrI 0.5506–1.125) in the prevention of HO. NSAIDs could increase discontinuation caused by gastrointestinal side effects (DGSE) (OR = 1.28, 95% CI 1.00–1.63, P = 0.046) more than a placebo. Selective NSAIDs could decrease DGSE (OR = 0.48, 95% CI 0.24–0.97, P = 0.042) compared with the nonselective NSAIDs. There was no significant difference with respect to discontinuation caused by nongastrointestinal side effects (DNGSE) in NSAIDs versus a placebo (OR = 1.16, 95% CI 0.88–1.53, P = 0.297) and in selective NSAIDs versus nonselective NSAIDs (OR = 0.83, 95% CI 0.50–1.37, P = 0.462).NSAIDs might reduce the incidence of HO and increase DGSE in the short-term.

The impact of nonsteroidal anti-inflammatory drugs on blood pressure, with an emphasis on newer agents

Your editor has been looking forward to the approval of the new injectable cyclooxygenase 2 (COX-2) nonsteroidal anti-inflammatory drug (NSAID) parecoxib for use in the perioperative period as a substitute for the non-selective injectable NSAID ketorolac, which inhibits platelet aggregation. Additionally, I have taken comfort that as I grow older and eventually may need pain relief for my stiff joints, I could depend on the oral COX-2 NSAIDs for safe and effective pain control. Now both of those options appear to be clouded. The Food and Drug Administration (FDA) has issued an advisory opinion because of recently released data from controlled clinical trials that show that COX-2 selective agents (rofecoxib, celecoxib, and valdecoxib) may be associated with an increased risk of serious cardiovascular events, such as myocardial infarction and stroke, especially when they are used for long periods or perhaps in very high-risk settings, such as immediately after heart surgery. Rofecoxib (Vioxx) was voluntarily removed from the market by its manufacturer after data from a long-term gastrointestinal cancer prevention study indicated an increased risk of cardiovascular morbidity and mortality that may not have been apparent in its original premarketing short-term analgesic studies. It may ultimately return to the marketplace with limited indications if it can be determined that its risks are no greater than those of the other selective COX-2 inhibitors. Preliminary data from a clinical trial suggest that long-term use of the nonselective NSAID naproxen might be associated with an increased cardiovascular risk compared with a placebo. However, these results are preliminary and conflict with other data from studies of the same drug. Until scientifically proven otherwise, we should consider nonselective NSAIDs to be no problem in this regard. The FDA recommends that practitioners who prescribe celecoxib (Celebrex) or valdecoxib (Bextra) should consider this emerging information when weighing the benefits against risks for individual patients. Patients who are at high risk of gastrointestinal bleeding, have a history of intolerance to nonselective NSAIDs, or are not doing well with nonselective NSAIDs may be appropriate candidates for COX-2 selective agents. The individual patient risk for cardiovascular events and other risks commonly associated with NSAIDs should be taken into account for each prescribing situation. I believe the practitioner must thoroughly discuss the benefits and risks with each patient before prescribing COX-2 NSAIDs. There should be written documentation similar to informed consent in the medical record attesting to the fact that the patient is willing to accept the drug under those circumstances. The FDA also advises consumers that all over-the-counter pain medications, including NSAIDs, should be used in strict accordance with the labeled directions. If an over-the-counter NSAID is needed for longer than 10 days, the FDA suggests that a physician should be consulted. As with all drugs, the ratio of the benefits compared with the risks must be considered when prescribing to individual patients. A huge body of data shows that long-term use of nonselective NSAIDs, such as ibuprofen, increases the risk of death from gastrointestinal bleeding, and this was the primary impetus for developing COX-2 inhibitors. The practitioner must now weigh that risk of death from gastrointestinal bleeding from non-selective NSAIDs against the risk of myocardial infarction or stroke with the COX-2 selective NSAIDS when deciding which analgesic to prescribe. It may turn out that the COX-2 inhibitors are much less likely to cause adverse cardiovascular events than life-threatening gastrointestinal bleeding associated with nonselective NSAIDs. Unfortunately, those studies may be much more difficult to conduct, particularly in the wake of all the television advertisements from trial lawyers who hope to get rich on their excessively large share of class action suit settlements while thousands or hundreds of thousands of individuals who claim harm from the drug each receive only a few dollars from perhaps a couple of million dollars that a court might award. In the meantime, it is important for the FDA-required postmarketing studies on the safety and efficacy of newly marketed drugs to be conducted. Drug companies are often vilified in the press for making huge profits, yet imagine how much money, time, and effort the company spent to get rofecoxib on the market, only to lose it all before its investment could be returned as profit. The manufacturer pays for many of the postmarketing studies. Of course, independent research by academic scientists is also valuable in discovering new information, both good and bad, about these drugs. Taking a second look at new drugs and techniques is as important as performing the original investigations, and both companies and independent scientists should be applauded for their efforts.

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Optimal strategies for the prevention of heterotopic ossification after total hip arthroplasty: A network meta-analysis

Selective and Nonselective Nonsteroidal Anti-inflammatory Drugs in Perianesthesia Pain Management

Celecoxib Plus Aspirin Versus Naproxen and Lansoprazole Plus Aspirin: A Randomized, Double-Blind, Endoscopic Trial

Cyclooxygenase-2 (COX-2) plays a key role in inflammation, making it a prime target for nonsteroidal anti-inflammatory drugs (NSAIDs). This study uses molecular docking to compare the binding affinities of four nonselective NSAIDs (aspirin, ibuprofen, diclofenac, naproxen) and three selective COX-2 inhibitors (celecoxib, rofecoxib, etoricoxib) to COX-2. Simulations with AutoDock4 and AutoDock Vina revealed distinct differences in binding profiles and selectivity. Selective COX-2 inhibitors exhibited stronger binding affinities, with etoricoxib achieving -11.22 kcal/mol (AutoDock4), driven by key hydrogen bonds and π interactions. Nonselective NSAIDs, such as diclofenac (-8.08 kcal/mol), showed moderate affinity but lacked specificity, targeting both COX isoforms and increasing gastrointestinal side effects. AutoDock4 provided detailed conformational analysis, while AutoDock Vina complemented with faster but less detailed results. This research highlights the structural interactions underlying NSAID efficacy and side effects, offering valuable insights for drug design. Selective inhibitors provide improved safety profiles for long-term use, while nonselective NSAIDs remain effective for short-term treatments. These findings emphasize the importance of computational tools in optimizing NSAID selectivity and efficacy, paving the way for developing safer anti-inflammatory therapies.

Occult GI Bleeding in NSAID Users—The Base of the Iceberg!