High-dimensional versus conventional propensity scores in a comparative effectiveness study of coxibs and reduced upper gastrointestinal complications

Purpose

High-dimensional propensity score (hd-PS) adjustment has been proposed as a tool to improve control for confounding in pharmacoepidemiological studies using longitudinal claims databases. We investigated whether hd-PS matching improved confounding by indication in a study of Cox-2 inhibitors (coxibs) and traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) and their association with the risk of upper gastrointestinal complications (UGIC).

Methods

In a cohort study of new users of coxibs and tNSAIDs we compared the effectiveness of these drugs to reduce UGIC using hd-PS matching and conventional propensity score (PS) matching in the German Pharmacoepidemiological Research Database.

Results

The unadjusted rate ratio (RR) of UGIC for coxib users versus tNSAID users was 1.21 [95 % confidence interval (CI) 0.91–1.61]. The conventional PS matched cohort based on 79 investigator-identified covariates resulted in a RR of 0.84 (0.56–1.26). The use of the hd-PS algorithm based on 900 empirical covariates further decreased the RR to 0.62 (0.43–0.91).

Conclusions

A comparison of hd-PS matching versus conventional PS matching resulted in improved point estimates for studying an intended treatment effect of coxibs versus tNSAIDs when benchmarked against results from randomized controlled trials.     

Clinical use and pharmacological properties of selective COX-2 inhibitors

Selective COX-2 inhibitors (coxibs) are approved for the relief of acute pain and symptoms of chronic inflammatory conditions such as osteoarthritis (OA) and rheumatoid arthritis (RA). They have similar pharmacological properties but a slightly improved gastrointestinal (GI) safety profile if compared to traditional nonsteroidal anti-inflammatory drugs (tNSAIDs). However, long-term use of coxibs can be associated with an increased risk for cardiovascular (CV) adverse events (AEs). For this reason, two coxibs were withdrawn from the market. Currently celecoxib, etoricoxib, and lumiracoxib are used. These three coxibs differ in their chemical structure and selectivity for COX-2, which might explain some of their pharmacological features. Following oral administration, the less lipophilic celecoxib has a lower bioavailability (20–40%) than the other two coxibs (74–100%). All are eliminated by hepatic metabolism involving mainly CYP2C9 (celecoxib, lumiracoxib) and CYP3A4 (etoricoxib). Elimination half-life varies from 5 to 8 h (lumiracoxib), 11 to 16 h (celecoxib) and 19 to 32 h (etoricoxib). In patients with liver disease, plasma levels of celecoxib and etoricoxib are increased about two-fold. Clinical efficacies of the coxibs are comparable to tNSAIDs. There is an ongoing discussion about whether the slightly better GI tolerability (which is lost if acetylsalicylic acid is coadministered) of the coxibs is offset by their elevated risks for CV AEs (also seen with tNSAIDs other than naproxen), which apparently increase with dose and duration of exposure. In addition, the higher costs for coxibs (if compared to tNSAIDs, even when a “gastroprotective” proton pump inhibitor is coadministered) should be taken into consideration, if a coxib will be selected for certain patients with a high risk for GI complications. For such treatment, the lowest effective dose should be used for a limited time. Monitoring of kidney function and blood pressure appears advisable. It is hoped that further controlled studies can better define the therapeutic place of the coxibs.     

Variability in the Response to Non‐Steroidal Anti‐Inflammatory Drugs: Mechanisms and Perspectives

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are a chemically heterogeneous group of compounds that provide unmistakable and significant health benefits in the treatment of pain and inflammation. They include traditional NSAIDs (tNSAIDs), which act by inhibiting both cyclooxygenase (COX)‐1 and COX‐2 and selective COX‐2 inhibitors (coxibs). The development of biomarkers predictive of the impact of NSAIDs on COX‐1 and COX‐2 activities in vitro, ex vivo and in vivo has been essential to read out the clinical consequences of selective and non‐selective inhibition of COX isozymes in human beings. The analgesic and anti‐inflammatory effects of NSAIDs are COX‐2‐dependent effects, unrelated to COX‐2 selectivity. The intensity and duration of these effects are influenced by dose and half‐life of the NSAID. However, the inhibition of COX‐1 in cells of the gastrointestinal (GI) system and COX‐2 in vascular cells translates into increased risk of serious GI adverse events and atherothrombosis and hypertension, respectively. The COX‐2 selectivity of NSAIDs can predict, at least in part, the GI toxicity. In contrast, the CV effects are largely COX‐2‐dependent effects, unrelated to COX‐2 selectivity but are dose dependent. The reduction in the dose is recommended and presumably will limit the number of patients exposed to a CV or a GI hazard by NSAIDs and coxibs. It will not, however, eliminate the risk on an individual level because there is a marked variability in how different people react to these drugs, based on their genetic background. The challenge of the next future will be to develop biomarkers useful to identify the individuals who react abnormally to COX inhibition.     

Risk factors for NSAID-associated upper GI clinical events in a long-term prospective study of 34 701 arthritis patients

Aliment Pharmacol Ther 2010; 32: 1240–1248

Summary

Background Nonsteroidal anti‐inflammatory drugs (NSAID)‐related GI effects vary based on patient characteristics. Aims To assess risk factors for NSAID‐associated upper GI clinical events and dyspepsia. Methods Patients ≥50 years with osteoarthritis or rheumatoid arthritis were randomized to etoricoxib or diclofenac in a prespecified intent‐to‐treat analysis of three double‐blind randomized trials. Potential risk factors for upper GI clinical events (bleeding, perforation, obstruction, or ulcer), complicated events (perforation, obstruction, bleeding) and discontinuations due to dyspepsia were assessed with Cox proportional hazard models. Results Significant predictors of clinical events and complicated events included age ≥65 years [hazards ratios (HRs) = 2.25 (1.84–2.76), 4.09 (2.82–5.92)], prior event [HRs = 2.57 (1.94–3.39), 3.23 (2.09–5.00)], low‐dose aspirin [HRs = 2.34 (1.87–2.92), 3.41 (2.33–5.00)] and corticosteroid [HRs = 1.85 (1.41–2.43), 2.09 (1.29–3.38)]. Predictors of discontinuation due to dyspepsia included prior dyspepsia [HR = 1.78 (1.44–2.00)], prior event [HR = 1.78 (1.40–2.27)] and age ≥65 years [HR = 1.35 (1.16–1.57)]. Conclusions Assessment for age ≥65 years, prior upper GI clinical events and low‐dose aspirin use are key in identifying patients who should either avoid NSAIDs or employ management strategies to reduce NSAID‐associated upper GI events. Prior dyspepsia or upper GI clinical events and age ≥65 years also predict an increased risk of developing dyspepsia severe enough to necessitate discontinuation of NSAIDs.     

Comparative cardiovascular safety of traditional nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory and analgesic effects. Unfortunately, these drugs are not without toxicity, namely on the gastric mucosa, but also on the cardiovascular system. In this context, the marketing of the coxibs, a new series of NSAIDs that selectively inhibit COX-2, resulted in a large debate around their cardiovascular safety, because they may increase the incidence of myocardial infarction and stroke. The recent suspension of a large, randomised, controlled trial comparing celecoxib, naproxen and placebo in Alzheimer patients (the ADAPT trial) because of an apparent elevated cardiovascular risk in the naproxen group revived the debate on the cardiovascular safety of these drugs, but this time with special emphasis on the effect of traditional nonselective NSAIDs (tNSAIDs). In this paper that reviews and discusses the cardiovascular safety profile of tNSAIDs, essentially naproxen and ibuprofen in view of the most recent experimental and clinical data, the authors note that the published data are quite discordant and one cannot conclude that there is clear evidence to support a cardiovascular hazard from the administration of naproxen or non-naproxen NSAIDs unless additional information is provided. In addition, the results of retrospective case-control studies have to be interpreted very carefully because of the risk of confounding factors that are not always taken into account when subjects were classified either as cases or controls. Thus, in the absence of clear cut data, physicians will have to use traditional NSAIDs (or coxibs) in patients with a high cardiovascular risk on the basis of their common sense rather than on evidence-based medicine. For these patients, one should not forget that an inadequate long-term control of cardiovascular risk factors such as a hypertension, dyslipidaemia, diabetes, smoking and weight excess is more deleterious in terms of cardiovascular mortality than the administration of NSAIDs itself.     

COXIBs, CINODs and H₂S-releasing NSAIDs: current perspectives in the development of safer non steroidal anti-inflammatory drugs

Traditional nonsteroidal anti-inflammatory drugs, tNSAIDs, are effective medication for prevention of ischemic events and treatment of pain, fever and inflammation. However their use associates with a significant risk to develop gastrointestinal and cardiovascular complications. Low doses of acetyl salicylic acid (ASA) and effective doses of tNSAIDs associate with a 2-6 fold increase in the risk of gastrointestinal bleeding. ASA and tNSAIDs inhibit cyclooxygenases (COXs). The COX exists at least in two isoforms, COX-1 and COX-2. Selective inhibitors of COX-2, the coxibs, spares the gastrointestinal tract while exert anti-inflammatory and analgesic effects. However, coxibs increase the risk of thrombo-embolic events. Nitric oxide (NO) and hydrogen sulfide (H?S), are potent vasodilatory agents that maintain mucosal integrity in the gastrointestinal tract. Hybrid molecules generated by coupling a NO or H?S releasing moiety to ASA or tNSAIDs has resulted into new classes of NSAIDs. These agents, the NO-releasing NSAIDs, or CINOD, and the H?S releasing NSAIDs are currently investigated as a potential alternative to tNSAIDs and coxibs. Naproxcinod has been the first, and so far the only, CINOD investigated in clinical trials. These studies have shown a slightly improvement in gastrointestinal tolerability in comparison to naproxen in surrogate endpoints (number of gastric and duodenal ulcers) and a significant reduction in the risk of destabilization of blood pressure control in patients with osteoarthosis taking anti-hypertensive medications in comparison to either naproxen and rofecoxib. The lack of outcome studies, however, has precluded the approval of naproxcinod by the Food and Drug Administration leading to a voluntary withdrawn of an application to the EMEA in May 2011. NSAIDs that releases H?S as a mechanism supporting an intrinsic gastrointestinal and cardiovascular safety are being investigated in preclinical models. Either naproxen and diclofenac hybrids have been reported to cause less gastrointestinal injury than parent NSAIDs. These novel chemical entities exert a variety of beneficial effects in rodent models of cardiovascular and metabolic disorders through a mechanism that might involve the release of H?S and/or by exerting anti-oxidant effects. The beneficial role these mechanisms in clinical settings await a proof-of-concept study.     

Benzodiazepine and Z-Drug Use and the Risk of Developing Dementia

BackgroundBenzodiazepines (BZDs) and Z-drugs (BZDRs) are among the most prescribed medications for anxiety and insomnia, especially among older adults. Our objective was to investigate the association between the use of BZDRs and the risk of dementia.MethodsA community-based retrospective cohort study was conducted based on the data available from 2002 to 2015 in Catalan Health Service. This cohort included all BZDR users (N = 83 138) and nonusers (N = 84 652) older than 45 years. A minimum 5-year lag window and an adjustment for psychiatric problems were applied for the data analysis.ResultsThe hazard ratio (HR) for the risk of incident dementia among BZDR users was 1.22 (95% CI = 1.15 to 1.31). This risk was not significant after adjusting the data confounding factors (HR = 1.01; 95% CI = 0.94 to 1.08). We observed a higher risk with short-to-intermediate half-life BZDs (HR = 1.11; 95% CI = 1.04 to 1.20) and Z-drugs (HR = 1.20; 95% CI = 1.07 to 1.33) than for intermediate-to-long half-life BZDs (HR = 1.01; 95% CI = 0.94 to 1.08). We demonstrated a higher risk of incident dementia (HR = 1.23; 95% CI = 1.07 to 1.41 and odds ratio = 1.38; 95% CI = 1.27 to 1.50, respectively) in patients who received 91 to 180 defined daily doses (DDDs) and >180 DDDs compared with patients who received <90 DDD. Regarding patient sex, the risk of dementia was higher in women than in men.ConclusionWe found that the incidence of dementia was not higher among all BZDR users. Short half-life BZDs and Z-drugs increased the risk of dementia at the highest doses, especially in female patients, showing a dose-response relationship.