Managing the Adverse Effects of Nonsteroidal Anti-inflammatory Drugs

Paola Patrignani; Stefania Tacconelli; Annalisa Bruno; Carlos Sostres; Angel Lanas


Expert Rev Clin Pharmacol. 2011;4(5):605-621. 

In This Article

Managing GI Toxicity

From a clinical point of view, the main goal in the management of patients receiving NSAIDs is the prevention of GI complications rather than acute mucosal lesions, including erosions or even ulcers, since they are often asymptomatic and most do not complicate.[77] Other important clinical objective is the treatment and prevention of NSAID-induced dyspepsia. The correlation between dyspepsia and the presence of NSAID-induced lesions is poor, but dyspepsia is clinically relevant since up to 10% of patients stop taking NSAIDs because of that.[78]

Not all patients have the same risk of developing GI complications. Risk factors for ulcer complications in patients taking NSAIDs include: history of previous ulcer complications, history of previous noncomplicated ulcer, advanced age (>60 years), concomitant use of other NSAIDs, corticosteroids, antiplatelet or anticoagulant drugs, and significant CV disability.[79–83] Concomitant use of low-dose aspirin for the prevention of CV events is frequent in patients taking NSAIDs. In clinical trials, this proportion reaches at 20% of patients requiring NSAIDs. This aspect complicates the management of these patients, since it is unclear and unknown whether the use of NSAIDs/coxibs might interfere with the cardioprotective effect of low-dose aspirin. The addition of low-dose aspirin to tNSAIDs or coxibs increases the risk of GI events (estimated annual GI risk is 5.6–7.5% GI events/year). Because of that, patients who combine a NSAID with low dose-aspirin are a high-risk group for GI bleeding. Evidence from observational studies and randomized trials showed that the risk of coxib plus aspirin is lower than tNSAIDs plus aspirin, but both were increased by aspirin. Low-dose aspirin further increases the risk of upper GI bleeds in NSAID users and negates the GI benefits of coxibs over the nonselective NSAIDs.[28,84] Furthermore, owing to the association of tNSAID and coxib use with increased CV risk, the baseline CV risk should also be taken into account in the management of patients who need NSAIDs.

In Box 1, the prevention strategies to use in patients with GI risk factors who need NSAIDs are reported. Under a cost-effective perspective, patients with one or more risk factors should receive prevention strategies. In the following section, we describe the current approached for the management of patients who need NSAIDs.

Targeting Modifiable Risk Factors

There are some risk factors (e.g., age) than cannot be modified. However most risk factors associated with the development of GI complications in patients who need NSAIDs can be modified. In general, we should look for the lowest effective NSAID dose and patients should take the medication for the lowest possible period of time. The risk of GI complications seems higher during the first month of therapy, but then it is constant over the entire period of treatment. Furthermore, the increased risk of CV events with the use of coxibs and probably tNSAIDs may be time-dependent.[64,65,85] Although many of the differences of GI risk observed among the different NSAIDs are driven by the dose used, there is agreement that ibuprofen, diclofenac, and aceclofenac are associated with the lowest relative risk (RR) of GI complications in clinical practice and, if possible, these tNSAIDs should be preferred to other NSAIDs. In this way, ketorolac and piroxicam are associated with the highest risk of GI complications.[86,87] In addition, if possible, the use of concomitant therapy with low-dose aspirin, corticosteroids, anticoagulants or even non-aspirin antiplatelet therapy should be avoided, since all they have been shown to further increase the risk of bleeding.[28,75,84] H. pylori infection eradication will reduce the incidence of peptic ulcers in, at least, a subset of NSAID users. This therapeutic approach will be discussed in another section.

The Addition of Gastroprotectants to NSAIDs

Patients with GI risk factors, who require nonselective NSAIDs, should receive a gastroprotectant. Misoprostol is a synthetic prostaglandin that stimulates mucus secretion in the upper GI tract. Several clinical trials have shown that the incidence of endoscopically diagnosed ulcers associated with NSAID use can be reduced by co-therapy with misoprostol.[88] A 6 month, randomized, double-blind, placebo-controlled trial involving 8843 rheumatoid arthritis patients receiving NSAIDs demonstrated that misoprostol reduced NSAID-associated upper GI complications (Misoprostol Ulcer Complications Outcomes Safety Assessment trial [MUCOSA]).[89] The study showed that misoprostol 200 µg four times a day significantly reduced symptomatic ulcers (adjusted RR: 0.36; 95% CI: 0.20–0.67) and serious GI complications (adjusted RR: 0.57; 95% CI: 0.36–0.91). However, misoprostol use in clinical practice is limited by its poor tolerability. In the MUCOSA trial, 27.5% of misoprostol-treated patients withdrew prematurely from the study due to adverse events, most of which were GI complaints.[90] The required dosing schedule of three-to-four-times daily may also be inconvenient for patients, thereby adversely affecting treatment outcomes. Besides GI symptoms, the major problem with using misoprostol is that it is contraindicated in women of child-bearing age because of abortion risk.

H2-receptor antagonists are gastroprotectans acting by a reversible interference and blockage of histamine receptors in the parietal cell which reduces acid secretion. When compared with placebo, different endoscopic studies have shown that ranitidine reduces the incidence of duodenal ulcers, but not gastric ulcers. High-dose famotidine has been shown to prevent both gastric and duodenal ulcers associated with NSAID use.[91] A meta-analysis showed that H2-receptor antagonists did not significantly reduce the risk of symptomatic ulcers among patients receiving NSAIDs (adjusted RR: 1.46; 95% CI: 0.06–35.3).[88,92]

Proton pump inhibitors (PPIs) block gastric acid secretion by inhibiting the H+/K+ ATPase and are significantly more effective than H2-receptor antagonists for treatment and prevention of acid-related diseases.[93] PPIs seem to be the best candidates to hinder the acidic mechanism of NSAID-induced gastroduodenal lesions. In fact, PPIs are largely used worldwide for the prevention of NSAID-induced gastropathy. PPIs inhibit gastric acid secretion and raise intragastric pH, decreasing the damaging potential of NSAIDs. PPIs inhibit the final step of acid secretion, the gastric acid pump. Epidemiological evidence has shown a parallel increase in the use of PPIs in the community with a decrease in the incidence of peptic ulcers and ulcer complications.[94] In one study misoprostol was compared with lansoprazole in patients on long-term NSAID use.[95] Each active treatment had an equivalent success rate of 69%. Other studies have confirmed that omeprazole 20 mg/day was more effective than ranitidine and low-dose misoprostol in the primary or secondary prevention of gastric and duodenal ulcers in NSAID users.[78,96,97] More recently, omeprazole 20 mg/day was shown to be more effective than H. pylori eradication in the prevention of ulcer bleeding recurrence in patients receiving naproxen for 6 months.[98] Different epidemiological studies have shown that PPIs reduce the risk of peptic ulcer bleeding in NSAID users.[99–101]

Proton pump inhibitor use has also been associated with adverse effects. Intestinal infection, including Clostridium difficile infection and pneumonia risk may be increased in patients taking these drugs.[102]C. difficile infection may become a clinical challenge and this side effect is currently being taken very seriously by several health authority bodies.[103–105] An increased risk of hip fracture has also been associated with PPI use although there are contradictory results.[106–109] A recent study by Ho et al.[110] found that concomitant use of clopidogrel and PPI after hospital discharge for acute coronary syndrome (ACS) was associated with an increased risk of CV adverse outcomes than use of clopidogrel without PPI, suggesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS. Several other studies have been conducted in order to answer this question. The recently published Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) clinical trial has shown no differences in CV outcomes among patients taking a combined compound of clopidogrel–omeprazol plus aspirin, versus clopidogrel and aspirin alone. The primary GI end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction or perforation. The primary CV end point was a composite of death from CV causes, nonfatal MI, revascularization or stroke. A total of 3873 patients were randomly assigned and 3761 were included in analyses. A total of 109 patients had a CV event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole: 0.99; 95% CI: 0.68–1.44; p = 0.96).[111]

Prescribing Coxibs Instead of tNSAIDs

Coxibs were as effective as conventional agents in reducing pain and improving physical functioning in people with arthritis, and are associated with fewer GI events. A meta-analysis of 112 large-scale randomized clinical trials revealed that the risk of symptomatic ulcers and serious GI complications associated with coxibs (celecoxib, rofecoxib, etoricoxib and lumiracoxib) were lower than that of nonspecific NSAIDs (adjusted RR: 0.49; 95% CI: 0.38–0.62 and 0.55; 95% CI: 0.38–0.80, respectively).[92] Another meta-analysis of all available and published randomized clinical trials published by the Cochrane Collaboration concluded that compared with nonselective NSAIDs, coxibs (celecoxib, valdecoxib, etoricoxib, limiracoxib and rofecoxib) produced significantly fewer gastroduodenal ulcers (RR: 0.26; 95% CI: 0.23–0.30) and ulcer complications (RR: 0.39; 95% CI: 0.31–0.50), as well as fewer treatment withdrawals caused by GI symptoms. The coadministration of acetylsalicylic acid reduces the GI benefits of COX-2 over tNSAIDs in subgroup analyses.[112] Data from the newest coxibs (lumiracoxib, withdrawn from the market because of liver toxicity, and etoricoxib) confirm this safety profile in the GI tract,[28,113] although the Multinational Etoricoxib and Diclofenac Arthritis Long-term program did not show differences between diclofenac and etoricoxib in the incidence of upper GI complications. In the Celecoxib Long-Term Arthritis Safety Study study, patients treated with high-dose celecoxib 400 mg twice daily had significantly fewer upper GI ulcer complications than those treated with nonselective NSAIDs (0.44 vs 1.27%; p = 0.04)[80] in patients not taking aspirin. However, the GI benefits of celecoxib was lost with the addition of low dose-aspirin, as the annualized incidence rates of upper GI ulcer complications were 2.01 and 2.12%, respectively (p = 0.92) with aspirin use.

When prescribing all these agents, caution should be focused on patients with CV diseases. In Europe, coxibs are contraindicated in patients with previous CV events and etoricoxib in uncontrolled hypertension. Whether this population may benefit from the potential introduction of NO–naproxen into the market in the future remains to be seen. Nevertheless, this compound seems to have a favorable profile in patients with hypertension and to induce less gastroduodenal and intestinal mucosal damage than naproxen.[76,88,114]

Combining Gastroprotectants & Coxibs

Another strategy in order to prevent NSAID-induced GI complications is the combination of a PPI plus a COX-2 selective NSAID, especially in the high-risk patients. Available evidence indicates that patients with previous ulcer bleeding who take either a non-selective NSAID plus a PPI or a COX-2 selective NSAID alone still have a low but significant rate of ulcer rebleeding after 6 months of therapy.[115,116] In one of those studies, 287 patients with recent ulcer bleeding received H. pylori eradication.[115] After ulcer healing, patients were randomized to take celecoxib 200 mg twice daily versus co-therapy consisting of omeprazole 20 mg once daily plus diclofenac 75 mg twice daily. After 6 months, the celecoxib arm had a 4.9% probability of recurrent ulcer bleeding, whereas patients on diclofenac plus omeprazole showed a 6.4% probability of recurrence (p = nonsignificant). As demonstrated recently, the combination of a PPI + COX-2 selective NSAID provides the safest option in patients at the highest risk of developing a GI complication. A recent small randomized controlled trial has evaluated the combination of celecoxib plus PPI to prevent GI events in high-risk patients with previous ulcer story. After 12 months of therapy, patients taking celecoxib 200 mg twice a day plus esomeprazole 20 mg/day had no recurrent ulcer bleeding events whereas 8.9% (p < 0.001) of patients taking the same of dose of celecoxib and placebo had a recurrence ulcer bleeding event.[117] This combination should be cost effective,[118] providing a 50% additional reduction in the incidence of upper GI complications already obtained with any of these strategies (tNSAIDs plus PPI vs coxib) alone. A recent study by Latimer et al. showed that prescribing a PPI for people with OA who are taking either a nonselective NSAID or coxibs is cost effective.[119]

Compliance with guidelines and prescription according to them are one problems we face in order to reduce the risk of GI complications in patients taking NSAIDs. A very recent cross-sectional study conducted in 1 day in over 17,000 patients suffering from OA showed that in over 50% of patients, the prescription of NSAIDs was not in accordance with current guidelines or recommendations made by regulatory agencies.[120] Adherence to the prescribed preventive therapy is an additional problem. A study by Sturkenboom et al.[121] showed that over 30% of patients were nonadherent and the lowest rate of nonadherence was associated with the first NSAID prescription (9%), increasing to 61% for patients with three or more prescriptions. Non-adherence patients had a higher risk of GI events compared with those who are fully adherent. Another study by Van Soest et al.[122] showed that the risk of GI complications in NSAID users increased 16% for every 10% decrease in adherence. Patients with proportion of NSAIDs treatment days covered by gastroprotective agents of 20–80% and <20% had higher risk of GI complications than patients with >80% of days covered: fourfold (95% CI: 1.2–13) and 2.5-fold (95% CI: 1.0–6.7), respectively.[119] Predictors of nonadherence include a high average daily dose of NSAIDs and long-term use of NSAIDs (>90 days). Predictors of adherence include use of low-dose aspirin, anticoagulant use and history of upper GI events, among others.[123]

Eradication of H. pylori

Eradication therapy is one of the mainstays of treatment in ulcer patients with H. pylori infection. However, the role of H. pylori eradication in patients receiving NSAIDs (including aspirin) has been controversial.[87,124] A meta-analysis of observational studies[125] showed synergism for the development of peptic ulcer and ulcer bleeding between H. pylori infection and NSAID use. Randomized controlled trials have shown that H. pylori eradication in naive NSAID users is associated with a significant reduction of the incidence of endoscopic ulcers in patients starting NSAIDs.[126,127] However, the benefit is less evident in patients already on long-term NSAIDs or in those who had an ulcer history or history of ulcer complications, where co-therapy with a PPI seems necessary.[98] Among patients with previous ulcer history, those treated with naproxen 500 mg twice daily plus omeprazole 20 mg/daily had recurrent rates of ulcer bleeding of 4.4 versus 18.8% (p = 0.005) in those who were treated with naproxen (same dose) and underwent H. pylori eradication after 6 months of follow-up. The results showed a clear advantage of PPIs over eradication therapy in this population. High-risk patients receiving low-dose aspirin may also use PPIs after eradication treatment to prevent ulcer recurrence.[128] Testing for and eradicating H. pylori in patients with a history of ulcer disease is recommended before starting chronic antiplatelet therapy. Post hoc analysis of the Vioxx GI Outcomes Research (VIGOR) study suggested that the GI benefits of coxib therapy are greater in patients without H. pylori infection than those with the infection.[78] It is unclear whether the strategy to eradicate H. pylori infection in all infected patients who start NSAID therapy will be cost effective.


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