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Keywords:

  • NSAIDs;
  • Analgesics;
  • Quality indicators;
  • Patient safety

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Objective

To develop systematically validated quality indicators (QIs) addressing analgesic safety.

Methods

A comprehensive literature review of existing quality measures, clinical guidelines, and evidence supporting potential QIs concerning nonselective (traditional) nonsteroidal anti-inflammatory drugs (NSAIDs) and newer cyclooxygenase 2–selective NSAIDs was undertaken. An expert panel then validated or refuted potential indicators utilizing a proven methodology.

Results

Eleven potential QIs were proposed. After panel review, 8 were judged to be valid; an additional 10 were proposed by the panel, of which 7 were rated as valid. Quality indicators focused upon informing patients about risk, NSAID choice and gastrointestinal prophylaxis, and side effect monitoring.

Conclusion

The 15 validated indicators were combined, where appropriate, to yield 10 validated processes of care indicators for the safe use of NSAIDs. These indicators developed by literature review and finalized by our expert panel process can serve as a basis to compare the quality of analgesic use provided by health care providers and delivery systems.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Prescription and over-the-counter analgesics, such as nonsteroidal antiinflammatory drugs (NSAIDs), aspirin, and acetaminophen, are among the most frequently used therapeutic agents in the United States (1–5). These medications assist in controlling the pain and inflammation associated with arthritis and related disorders. Despite their efficacy and popularity, this group of therapies can lead to significant adverse events, principally affecting the gastrointestinal (GI) tract and kidney. These toxicities are of greatest concern among users of advanced age or with comorbidities (6–13).

Various professional organizations and committees have promulgated guidelines designed to translate knowledge about analgesic safety into clinical practice (14–24). Such guidelines have been derived from a synthesis of expert opinion and a review of the existing literature.

As part of the Arthritis Foundation Quality Indicator Project, we sought to develop 10 systematically validated (25) quality indicators (QIs) that would synthesize previous guidelines and use the current literature to address issues of analgesic safety. These indicators focused on 3 domains: 1) informing patients about risk, 2) NSAID choice and GI prophylaxis in patients at higher risk of GI side effects, and 3) side effect monitoring.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The methods for developing NSAID and analgesic QIs, including initial indicator development, literature review, and QI validation, are detailed in a related manuscript (25). Briefly, we comprehensively reviewed existing quality measures and clinical guidelines on analgesic use, selecting those focused on processes of care and having the potential to significantly impact patient outcomes. We next conducted a systematic literature review of the Medline database (from 1980 through 2001) for evidence supporting potential QIs concerning nonselective (traditional) NSAIDs, such as ibuprofen and naproxen, as well as newer cyclooxygenase 2 (COX-2)–selective NSAIDs, such as celecoxib and rofecoxib. The structured literature search identified 1,569 titles, from which 189 relevant articles were identified. On the basis of the published literature, 11 potential quality indicators were proposed. Full search terms and results of the literature review are available (see Appendix A, available at http://www.interscience.wiley.com/jpages/0004–3591:1/suppmat/index.html). An expert panel then considered evidence and validated or refuted the indicators as per previous validation methodology (26).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Of the 11 initial NSAID and analgesic QIs created for panel review, 8 were judged to be valid by the expert panel process; an additional 10 indicators were proposed by the panel, of which 7 were rated as valid. Where appropriate, validated indicators were combined to produce a final list of 10 indicators (Table 1). A list of the original indicators and voting results is available (see Appendix A, available at http://www.interscience.wiley.com/jpages/0004–3591:1/suppmat/index.html).

Table 1. The Arthritis Foundation's quality indicators for analgesic use*
  • *

    NSAID = nonsteroidal antiinflammatory drug; COX = cyclooxygenase; PPI = proton pump inhibitor; CBC = complete blood count.

  • Risk factors for gastrointestinal bleeding for indicators 4–7 defined as any of the following: age ≥75 years, peptic ulcer disease, gastrointestinal bleeding, or glucocorticoid use.

  • Risk factors for gastrointestinal bleeding for indicator 9 defined as any of the following: age ≥75 years, peptic ulcer disease, gastrointestinal bleeding, glucocorticoid use, or coumadin use.

  • §

    Risk factors for renal insufficiency defined as any of the following: age ≥75 years, diabetes mellitus, hypertension, angiotensin converting enzyme inhibitor use, or diuretic use.

Informing patients about risks1. IF a patient is prescribed an NSAID (nonselective or selective), THEN the patient should be advised of the associated gastrointestinal bleeding risks and renal risks and the gastrointestinal risks should be documented.
 2. IF a patient is prescribed low-dose (≤325 mg/day) aspirin, THEN the patient should be advised of the associated gastrointestinal bleeding risks.
 3. If a patient is prescribed acetaminophen AND the patient has risk factors for liver disease OR if the patient is treated with high-dose (≥4 gm/day) acetaminophen, THEN the patient should be advised of the associated risk of liver toxicity.
Gastrointestinal prophylaxis4. IF a patient is treated with a nonselective NSAID, AND the patient has risk factors for gastrointestinal bleeding, THEN the patient should be treated concomitantly with either misoprostol or a PPI.
 5. IF a patient is treated with a COX-2–selective NSAID AND the patient takes low-dose aspirin daily AND the patient has risk factors for gastrointestinal bleeding, THEN the patient should be treated concomitantly with either misoprostol or a PPI.
 6. IF a patient is treated with low-dose aspirin daily AND the patient has 2 or more risk factors for gastrointestinal bleeding, THEN the patient should be treated concomitantly with either misoprostol or a PPI.
Selection of NSAID7. IF a patient who is NOT treated with low-dose aspirin, has risk factors for gastrointestinal bleeding, and is prescribed an NSAID, THEN the patient should receive EITHER a nonselective NSAID plus a gastroprotective agent (PPI or misoprostol) OR a COX-selective NSAID.
 8. IF a patient who takes coumadin is prescribed an NSAID, THEN the NSAID should be either COX-2–selective or a nonacetylated salicylate.
Monitoring9. IF a patient is treated with daily NSAIDs (selective or nonselective) and has risk factors for gastrointestinal bleeding, THEN a CBC should be performed at baseline and during the first year after initiating therapy.
 10. IF a patient is treated with daily NSAIDs (selective or nonselective) AND the patient has risk factors for developing renal insufficiency,§ THEN a serum creatinine should be assessed at baseline and at least once in the first year following the initiation of therapy.

Informing patients about the risks of NSAIDs and acetaminophen

The first 3 QIs deal with informing patients about risks.

QI 1: IF a patient is prescribed an NSAID (nonselective or selective), THEN the patient should be advised of the associated gastrointestinal (GI) bleeding and renal risks and the GI risks should be documented BECAUSE the risks are increased compared with nonusers.

QI 2: IF a patient is prescribed low-dose (≤325 mg/day) aspirin, THEN the patient should be advised of the associated GI bleeding risks BECAUSE the risks are increased compared with nonusers.

QI 3: IF a patient is prescribed acetaminophen AND the patient has risk factors for liver disease OR if the patient is treated with high-dose (≥4 gm/day) acetaminophen, THEN the patient should be advised of the associated risk of liver toxicity BECAUSE these risks are increased compared with nonusers.

GI risks of nonselective NSAIDs

A number of metaanalyses (10, 11, 27, 28) have evaluated the relationship between the use of aspirin (>325 mg/day) and other nonaspirin, nonselective NSAIDs and the risk for clinically defined adverse GI events (Table 2). Exposure to NSAIDs has been associated with a 2.7–5.4-fold increased risk of various GI adverse events in these various studies.

Table 2. Meta-analyses of nonselective NSAID use with GI endpoints*
Author, year (ref.)EndpointNo. studies pooledGI risk OR or RR (95% CI)
  • *

    NSAID = nonsteroidal antiinflammatory drug; GI = gastrointestinal; OR = odds ratio; RR = relative risk; 95% CI = 95% confidence interval; PUBs = perforations, ulcers, or GI bleeds; RCT = randomized controlled trial.

  • GI tract disease indicates hematemesis, melena, peptic ulcer, ulcer perforation, or death attributable to these outcomes (RR adjusted for study design and methodologic strength).

  • GI AEs indicates bleeding, perforation, or other adverse GI events resulting in hospitalization or death.

  • §

    UGIB indicates bleeding, perforation, or other serious upper GI tract events resulting in hospitalization or visit to a specialist.

Ofman et al, 2002 (28)PUBs16 placebo RCT5.4 (1.8–16.0)
  9 cohort2.7 (2.1–3.5)
  23 case-control3.0 (2.5–3.7)
Bollini et al, 1992 (27)GI tract disease34 studies (7 cohort and 27 case-control)3.0 (1.9–4.7)
Gabriel et al, 1991 (10)GI AEs16 studies (7 cohort and 9 case-control)2.7 (2.5–3.0)
Hernandez-Diaz et al, 2000 (11)UGIB§18 studies (3 cohort and 15 case-control)3.8 (3.6–4.1)
GI risks of COX-2–selective NSAIDs

The GI risk associated with NSAID use is best assessed by studies of clinically relevant endpoints, such as perforations, ulcers, and GI bleeds (PUBs). Two large, multicenter studies (the Vioxx Gastrointestinal Outcomes Research [VIGOR] trial and the Celecoxib Long-term Arthritis Safety Study [CLASS]) (29, 30) were designed specifically to compare the upper GI toxicity of COX-2–selective and nonselective NSAIDs using clinically relevant endpoints. Additionally, 2 pooled analyses have examined similar outcomes (31, 32). In 3 of these studies, the incidence of clinically meaningful upper GI bleeding was lower among the COX-2–selective agents than comparator NSAIDs for the primary study endpoints (29, 31, 32). In the CLASS trial, a reduction in upper GI ulcer complications (primary endpoint) was not statistically significant at 6 months (30) or at 1 year (33), but when combined with symptomatic gastroduodenal ulcers (secondary endpoint), a significant difference between celecoxib and pooled NSAIDs (diclofenac and ibuprofen) was reported at both time points (30, 33). Results of these studies are summarized in Table 3.

Table 3. RCTs and pooled analyses of COX-2–selective NSAIDs and clinically relevant GI endpoints*
Author, year (ref.)SubjectsGI endpointAnnualized incidence of GI events (per 100 patient-years)
COX-2 agentActive comparator drug
  • *

    RCT = randomized controlled trial; COX-2 = cyclooxygenase 2; NSAIDs = nonsteroidal antiinflammatory drugs; GI = gastrointestinal; RA = rheumatoid arthritis; b.i.d. = 2 times per day; OA = osteoarthritis; t.i.d. = 3 times per day; NDA = new drug application; PUBs = perforations, ulcers, or GI bleeds.

  • Indicates gastroduodenal perforations or obstructions, upper GI bleeding, or symptomatic gastroduodenal ulcers.

  • P = 0.001 versus rofecoxib.

  • §

    Indicates gastric or duodenal perforation, gastric outlet obstruction, or upper GI bleeding (primary analysis); endoscopic/radiographic evidence of a gastric or duodenal ulcer combined with upper GI ulcer complications (secondary analysis).

  • Silverstein et al (30) and NDA 20-998 (33) report data from the same study. NDA 20-998 reports 52-week outcomes in addition to the 6-month outcomes reported by Silverstein et al (30).

  • #

    P = NS versus celecoxib (primary analysis); P = 0.02 versus celecoxib (secondary analysis).

  • **

    P = 0.092 versus celecoxib.

  • ††

    P = 0.45 versus celecoxib.

  • ‡‡

    P = 0.04 versus celecoxib.

  • §§

    Pooled data from 8 double-blind, randomized phase 2b/3 rofecoxib trials.

  • ¶¶

    P value not reported (relative risk = 0.5; 95% confidence interval 0.3–1.00).

  • ##

    Pooled analysis of 14 multicenter RCTs.

  • ***

    Indicates bleeding, perforation, or gastric outlet obstruction.

  • †††

    P = 0.002 versus celecoxib.

Randomized controlled trials    
 Bombardier et al, 2000 (29)8,076 RA patientsConfirmed upper GI eventsRofecoxib (50 mg/day)Naproxen (500 mg b.i.d.)
  2.14.5
 Silverstein et al, 2000 (30)7,968 RA and OA patientsUpper GI ulcer complications (primary)Celecoxib (400 mg b.i.d)Ibuprofen (800 mg t.i.d.)
 Symptomatic gastroduodenal ulcer (secondary)§ Diclofenac (75 mg b.i.d)
  0.8 (primary)1.5 (primary)
   2.1 (secondary)3.5 (secondary)#
 NDA 20–998 Lu, Reviewer (33)7,968 RA and OA patientsUpper GI ulcer complications (primary),Celecoxib (400 mg b.i.d)Ibuprofen (800 mg t.i.d.)
  Diclofenac (75 mg b.i.d.)
   26-week crude rate: 0.28% (primary)26-week crude rate: 0.50% (primary)**
  Symptomatic gastroduodenal ulcer (secondary)§52-week crude rate: 0.43% (primary)52-week crude rate: 0.53% (primary)††
  1.05% (secondary)1.56% (secondary)‡‡
Pooled analyses    
 Langman et al, 1999 (31)5,435 OA patients§§PUBsRofecoxib (12.5–50 mg/day)Ibuprofen (800 mg t.i.d.)
   Diclofenac (50 mg t.i.d.)
    Nabumetone (1,500 mg/day)
   1.32.6¶¶
 Goldstein et al, 2000 (32)11,008 RA and OA patients##UGI ulcer complications***Celecoxib (25–400 mg b.i.d)Naproxen (500 mg b.i.d.)
   Diclofenac (50 or 75 mg b.i.d.)
    Ibuprofen (800 mg t.i.d.)
   0.21.7†††

Neither the VIGOR trial nor the CLASS study contained a placebo control. However, Arthritis, Rheumatism and Aging Medical Information System epidemiologic data have estimated the annual hospitalization rate for GI complications in osteoarthritis and rheumatoid arthritis patients not taking NSAIDs as 0.29% and 0.19%, respectively (34). Additionally, retrospective cohort data of >100,000 Tennessee Medicaid recipients reported rates of hospitalization for upper GI hemorrhage of 0.42 per 100 person-years for current NSAID nonusers (35). Moreover, the standardized incidence rate of hospitalization for upper GI bleeding has been defined from a Danish population-based cohort as 0.2 per 100 patient-years for those aged ≥75 years without NSAID exposure (36).

In addition to comparing the incidence of clinically relevant endpoints among COX-2–selective users to that of nonselective NSAID users (as shown in Table 3) and to historical placebo controls, pooled analyses by Langman et al (31) and Goldstein et al (32) included a placebo comparator (data not shown). Langman et al (31) compared the incidence of upper GI tract PUBs in patients receiving rofecoxib, ibuprofen, or placebo by pooling data from 4 double-blind, randomized, phase 2b/3 rofecoxib trials with placebo controls. The annualized incidence rates (per 100 patient-years) over 4 months of therapy were 2.7 for placebo and 2.5 for rofecoxib (P not significant). Goldstein et al pooled 10 multicenter, randomized controlled trials (RCTs) of celecoxib-treated patients with a placebo comparator (32). In this analysis, the annualized incidence (per 100 patient years) of upper GI ulcer complications (GI bleeding, perforation, and gastric outlet obstruction) in celecoxib-treated patients was 0.2 compared with an incidence rate of 0 in placebo-treated patients (P not significant).

Other studies comparing COX-2–selective NSAIDs to nonselective NSAIDs and placebo have used endoscopically detected ulcerations (37–39) and commonly reported clinical and research-related GI adverse events (nonulcer dyspepsia and study discontinuation rates) (31, 40–43) as surrogate endpoints of GI toxicity. These studies report nonsignificant trends toward more endoscopic ulcerations, nonulcer dyspepsia, and study discontinuation rates in COX-2–selective NSAID users compared with placebo. However, the relationship between endoscopic ulcers and clinically significant GI adverse events is not well established (34).

In summary, investigations of COX-2–selective NSAIDs collectively suggest GI safety advantages over nonselective NSAIDs. However, based on secondary analyses of existing data, analysis of pooled RCT data, comparison with historical controls, data from endoscopic studies, and patient withdrawal rates, there appears to be a small GI risk for COX-2 users in comparison with nonusers.

GI risks of low-dose aspirin

We identified 3 metaanalyses and 3 case-control studies that assessed the GI toxicities of low-dose aspirin. All but 1 of these studies demonstrated an increased risk of gastrointestinal bleeding with low-dose aspirin use (relative risk ranging from 1.5 to 3.2). These studies are summarized in Table 4.

Table 4. Meta-analyses and observational studies of low-dose aspirin use and gastrointestinal outcomes*
Author, year (ref.)Study designnDosageEndpointGI risk OR or RR (95% CI)
  • *

    GI = gastrointestinal; OR = odds ratio; RR = relative risk; 95% CI = 95% confidence interval.

Derry and Loke, 2000 (78)Meta-analysis49,927 (8 studies pooled)50–162.5 mgGI bleeding1.6 (1.4–1.8)
Stalnikowicz-Darvasi, 1995 (79)Meta-analysis29,513 (9 studies pooled)75–325 mgGI bleeding1.5 (1.3–1.8)
Roderick et al, 1993 (80)Meta-analysis(7–15 studies pooled)≥300 mg versusAll GI bleedingNonsignificant difference for all endpoints
 ≤300 mgUpper GI symptoms
    Withdrawal due to side effects 
Weil et al, 1995 (81)Case-control3,23675–300 mgHospitalization with peptic ulcer bleeding3.2 (2.3–4.4)
de Abajo et al, 2001 (82)Case-control13,605≤300 mgUpper GI bleed/perforation2.0 (1.7–2.3)
Lanas et al, 2000 (83)Case-control3,353≤300 mgGI bleeding2.4 (1.8–3.3)

The CLASS study conducted a subgroup analysis evaluating the interaction of low-dose aspirin with celecoxib and nonselective NSAIDs on the incidence of upper GI ulcer complications and symptomatic gastroduodenal ulcers (30). In this study, low-dose aspirin use was found to negate the potential GI safety benefits of celecoxib use.

Renal risks of nonselective NSAIDs

At least 8 case-control studies have reported an increased risk of both acute and chronic renal dysfunction with use of nonselective NSAIDs. Risk and NSAID exposure definitions range substantially across populations studied. These are summarized in Table 5.

Table 5. Case-control studies of nonselective NSAIDs, analgesics, and acute and chronic renal toxicity*
Author, year (ref.)Number of subjectsExposure definitionRenal risk OR (95% CI)
CasesControls
  • *

    NSAIDs = nonsteroidal antiinflammatory drugs; OR = odds ratio; 95% CI = 95% confidence interval; ARF = acute renal failure; ESRD = end stage renal disease.

  • Hospitalized patients with a discharge diagnosis indicating newly diagnosed chronic renal dysfunction.

  • Including aspirin, pyrazolones, phenacetin, or any combination of the 3.

  • §

    Includes phenacetin, acetaminophen, aspirin, metamizole, phenazones, or others (not defined).

  • Includes aspirin, acetaminophen, or phenacetin (either alone or in combination with other drugs).

Acute effects    
 Griffin et al, 2000 (6)1,799 Tennessee Medicaid enrollees hospitalized with community acquired ARF9,899 randomly selected population controlsNonaspirin NSAID prescription overlapping index date1.6 (1.3–1.9)
 Perez Gutthann et al, 1996 (7)28 Canadian health plan members hospitalized for ARF1,997 health plan members with ≥1 NSAID prescriptionNSAID prescription within 30 days before index date4.1 (1.5–10.8)
 Evans et al, 1995 (84)207 Scottish patients hospitalized with a diagnostic code for ARF1,238 community and 411 hospital age- and sex-matched controls≥1 oral NSAID prescription within 90 days prior to index date2.2 (1.5–3.3) versus community controls 1.8 (1.2–2.9) versus hospital controls
Chronic effects    
 Perneger et al, 1994 (8)716 ESRD patients identified form the US Mid-Atlantic Renal Coalition361 randomly selected community controls≥5,000 NSAID pills in lifetime8.8 (1.1–71.8)
 Sandler et al, 1991 (9)554 US patients hospitalized with chronic renal disease516 randomly selected community controls360 days of consecutive NSAID use2.1 (1.1–4.1)
 Morlans et al, 1990 (85)340 Spanish ESRD patients on a hemodialysis program673 hospital controls≥30 days of nonnarcotic analgesics taken every other day before the first renal disease symptoms2.9 (1.8–4.7)
 Pommer et al, 1989 (86)517 German ESRD patients under going renal replacement therapy517 sex-, age-, and nationality-matched hospital controls≥15 analgesic doses per month for ≥1 year§2.4 (1.8–3.4) for any analgesic use
    2.7 (1.9–3.7) for combination analgesics
 Murray et al, 1983 (87)527 US ESRD patients on hemodialysis1,047 sex-, age-, and race-matched hospital controls≥30 days of analgesic use1.1 (0.8–1.5) for overall analgesic exposure

In contrast, a large prospective cohort over a 14-year study period, the Physicians' Health Study (n = 11,032), found no associations between self-reported use of acetaminophen, aspirin, or other NSAIDs and elevated serum creatinine (≥1.5 mg/dl) or reduced creatinine clearance (≤55 ml/minute) (44). The results of this large cohort study are further substantiated by 2 additional cohort studies that did not identify any association between NSAID use and long-term renal adverse events (45, 46).

Renal risks of COX-2–selective NSAIDs

We identified 3 RCTs (47–49) that were designed to primarily assess the effect of COX-2–selective NSAIDs on physiologic measures of renal function. Each of these studies, examining both celecoxib and rofecoxib, demonstrated reductions in various parameters of renal function for the COX-2–selective NSAIDs assessed (Table 6).

Table 6. Randomized controlled trials of COX-2–selective NSAIDs and renal function*
Author, year (ref.)DrugStudy durationnRenal function measure
  • *

    COX-2 = Cyclooxygenase 2; NSAIDs = nonsteroidal antiinflammatory drugs; [DOWNWARDS ARROW] = decreased; t.i.d. = 3 times per day; b.i.d. = 2 times per day.

  • P < 0.05 for all measures.

  • Versus placebo.

  • §

    Versus baseline.

Swan et al, 2000 (47)Rofecoxib (250 mg)Single dose15[DOWNWARDS ARROW] Glomerular filtration rate
    [DOWNWARDS ARROW] Creatinine clearance
    [DOWNWARDS ARROW] Urinary sodium excretion
    [DOWNWARDS ARROW] Urinary potassium excretion
 Rofecoxib (12.5 mg/day)2 weeks60[DOWNWARDS ARROW] Glomerular filtration rate
 Rofecoxib (25 mg/day)  [DOWNWARDS ARROW] Glomerular filtration rate
Catella-Lawson et al, 1999 (49)Rofecoxib (50 mg t.i.d.)2 weeks36[DOWNWARDS ARROW] Urinary sodium excretion§
 Celecoxib (200 mg b.i.d.)  [DOWNWARDS ARROW] Urinary sodium excretion
Rossat et al, 1999 (48)Celecoxib (400 mg b.i.d.)7 days40[DOWNWARDS ARROW] Glomerular filtration rate§
    [DOWNWARDS ARROW] Effective renal plasma flow§

Despite the lack of a placebo comparator, both the CLASS and VIGOR trials provide ancillary data on renal-associated adverse events of celecoxib and rofecoxib compared with nonselective NSAIDs. CLASS patients taking comparator NSAIDs experienced more hypertension (n = 90, 2.3%) and increased serum creatinine levels (n = 48, 1.2%) compared with those using celecoxib (P ≤ 0.05 versus celecoxib for both outcomes) (30). The withdrawal rate due to renal-associated adverse events did not differ significantly between groups. The VIGOR trial reported a nonsignificant difference in the incidence of renal-associated adverse events between rofecoxib- (1.2%) and naproxen- (0.9%) treated patients (29). The discontinuation rate due to these adverse events was 0.2% in both groups. However, data on discontinuations due to hypertension-related adverse events presented to the Food and Drug Administration Arthritis Advisory Committee on February 8, 2001 (www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_01_merck.pdf) identified a significantly greater incidence in patients taking rofecoxib (0.7%) than in those taking nonselective NSAIDs (0.1%) (P < 0.001).

Other RCTs with secondary renal outcomes (39, 41, 43, 50) found no significant differences in the frequency of renal-associated adverse events (changes in blood pressure, incidence of hypertension, peripheral edema, or increases in serum creatinine levels) among patients receiving COX-2–selective NSAIDs, traditional NSAIDs, or placebo. Direct comparisons of blood pressure, sodium retention, and renal function were not conducted in these smaller studies.

In summary, predominately observational study data using surrogate endpoints, and to a lesser extent RCT results, demonstrate increased risk of renal toxicity with nonselective and COX-2–selective NSAIDs.

Hepatic risks of acetaminophen

This indicator was created and validated by the expert panel. Although routinely recommended as a first-line analgesic due to its safety profile (14, 51), acetaminophen has been associated with hepatotoxicity in patients receiving very high doses (typically ≥10 gm/day) (52, 53) or having risk factors, such as chronic alcoholism (52, 54–57), fasting (58, 59), or existing renal or cardiovascular disease (60).

NSAID choice and GI prophylaxis in patients at higher GI risk

For the purpose of QIs 4–7, based on the many non-NSAID risk factors (summarized below), heightened risk for GI bleeding was defined as age ≥75 years, history of peptic ulcer disease, history of GI bleeding, or glucocorticoid use. Coumadin as a risk factor for GI bleeding is addressed separately in QI 8.

QI 4: IF a patient is treated with a nonselective NSAID, AND the patient has risk factors for GI bleeding, THEN the patient should be treated concomitantly with either misoprostol or a proton pump inhibitor (PPI), BECAUSE these agents can reduce the risk of GI bleeding.

QI 5: IF a patient is treated with a COX-2–selective NSAID AND the patient takes low-dose aspirin daily AND the patient has risk factors for GI bleeding, THEN the patient should be treated concomitantly with either misoprostol or a PPI, BECAUSE these agents can reduce the risk of GI bleeding.

QI 6: IF a patient is treated with low-dose aspirin daily AND the patient has 2 or more risk factors for GI bleeding, THEN the patient should be treated concomitantly with either misoprostol or a PPI, BECAUSE these agents can reduce the risk of GI bleeding.

QI 7: IF a patient who is NOT treated with low-dose aspirin has risk factors for GI bleeding and is prescribed an NSAID, THEN the patient should receive EITHER a nonselective NSAID plus a gastroprotective agent (PPI or misoprostol) OR a COX-2–selective NSAID BECAUSE these agents can reduce the risk of GI bleeding.

QI 8: IF a patient who takes coumadin is prescribed an NSAID, THEN the NSAID should be either COX-2–selective or a nonacetylated salicylate BECAUSE these agents can reduce the risk of GI bleeding.

GI toxicity risk factors for NSAID users

A variety of factors may predispose NSAID users to GI adverse events. Advanced age, history of GI adverse events, and concomitant therapy with either anticoagulants or glucocorticoids have been linked to an increased GI risk. Studies that have defined the risk of various factors for GI adverse events are described in Table 7. Although this literature search did not identify any formal investigations of potential risk factors of GI events in COX-2–selective NSAID users, secondary descriptive analyses of RCTs have identified similar risk factors to that of nonselective agents (32).

Table 7. Meta-analyses, clinical trials, and observational studies of nonselective NSAIDs and risk factors for gastrointestinal adverse events*
Author, year (ref.)Study designGI endpointsSampleRisk factorGI risk OR or RR (95% CI)
  • *

    NSAIDs = Nonsteroidal antiinflammatory drugs; GI = gastrointestinal; OR = odds ratio; RR = relative risk; 95% CI = 95% confidence interval; AEs = adverse events; RA = rheumatoid arthritis.

Gabriel et al, 1991 (10)Meta-analysisBleeds, perforations, or other GI events resulting in hospitalization or death8 studies pooledAge ≥ 605.5 (4.6–6.6)
   Not reportedConcomitant corticosteroid use1.8 (1.2–2.8)
  Subsequent or unspecified GI event10 studies pooledHistory of GI AEs4.8 (4.1–5.6)
Hernandez-Diaz and Rodriguez, 2000 (11)Meta-analysisBleeds, perforations, or other GI events resulting in hospitalization or visit to a specialist7 studies pooledAge > 80 years9.2 (7.6–11.1)
   12 studies pooledHistory of ulcer5.9 (5.2–6.7)
Silverstein et al, 1995 (12)Randomized, placebo-controlled trialPerforations, gastric outlet obstructions, or bleeds8,843 RA patientsAge ≥ 75 years2.5 (1.5–4.1)
    History of peptic ulcer2.3 (1.3–4.1)
    History of GI bleeding2.6 (1.3–5.0)
Singh et al, 1996 (13)Prospective cohortRisk of hospitalization or death due to NSAID-induced GI events1,921 RA patientsAdvancing age1.0 (1.0–1.1)
    Previous NSAID GI side effect1.6 (1.0–2.4)
    Prednisone use1.8 (1.2–2.7)
Shorr et al, 1993 (73)Retrospective cohortHospitalization for hemorrhagic peptic ulcers2,203 person-years of oral anticoagulant (Medicaid enrollees)Anticoagulant use12.7 (6.3–25.7)
Garcia Rodriguez and Jick, 1994 (72)Case-controlUpper GI bleeds or perforations1,457 cases, 10,000 controlsAnticoagulant use6.4 (2.8–14.6)
Piper et al, 1991 (88)Case controlHospitalization for gastric or duodenal ulcer1,415 cases, 7,063 controls (Medicaid enrollees)Concomitant corticosteroid use4.4 (2.0–9.7)
Hernandez-Diaz and Rodriguez, 2001 (89)Case-controlUpper GI complications2,105 cases, 11,500 controlsConcomitant oral steroid use8.9 (5.0–15.8)
GI prophylaxis for nonselective NSAID users

The protective effects of misoprostol and histamine-2 (H2) receptor antagonists on the incidence of endoscopically determined gastric and duodenal ulcers and clinically relevant GI adverse events have been examined in both a metaanalysis and the Misoprostol Ulcer Complication Study Outcomes Safety Assessment (MUCOSA) study (12, 61). These studies have reported a significant protective effect of misoprostol cotherapy compared with placebo in patients taking nonselective NSAIDs on the incidence of both gastric and duodenal ulcers; these studies have also reported a protective effect of H2-receptor antagonists in the prevention of duodenal ulcers alone (Table 8).

Table 8. Meta-analysis and clinical trial of misoprostol and histamine-receptor antagonists and the incidence of gastric and duodenal ulcers among patients treated with nonselective NSAIDs*
Author, year (ref.)Study designnOutcomeRisk reduction with cytoprotective agent OR (95% CI)
MisoprostolH2 receptor antagonist
  • *

    NSAIDs = nonsteroidal antiinflammatory drugs; OR = odds ratio; 95% CI = 95% confidence interval; RA = rheumatoid arthritis; OA = osteoarthritis; RCT = randomized, placebo-controlled trial.

  • All comparisons versus placebo.

  • Endoscopically determined ulcers.

  • §

    UGI AE = upper gastrointestinal adverse event (perforation, gastric outlet obstruction, or GI bleeding).

Koch et al, 1996 (61)Meta-analysis (24 studies pooled)4,325 RA and OA patients; 680 healthy subjectsGastric ulcers0.29 (0.20–0.42)0.86 (0.55–1.34)
   Duodenal ulcers0.28 (0.16–0.48)0.38 (0.19–0.75)
Silverstein et al, 1995 (12)RCT8,843 RA patientsUGI AE§0.6 (0.36–0.98)

The aforementioned metaanalysis and MUCOSA trial both focused solely upon primary prevention of NSAID-related gastric and duodenal ulceration through cotherapy with GI prophylactic agents. The Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment (62) and the Omeprazole Versus Misoprostol for NSAID-Induced Ulcer Management (OMNIUM) (63) studies examined the healing effects of misoprostol, PPIs, and H2-receptor antagonists on secondary prevention of endoscopically confirmed ulcers and erosions in patients receiving NSAID therapy. Both studies enrolled patients who required continuous NSAID therapy and had either endoscopic ulcers or >10 gastric or duodenal erosions at baseline. In each trail, those patients achieving “treatment success” (absence of endoscopically determined ulcers and the presence of <5 erosions in the stomach or duodenum) were rerandomized to a treatment arm and monitored for the maintenance of gastric and duodenal integrity over an additional 6 months of continued cotherapy. Of note, the OMNIUM trial utilized a placebo control during this maintenance phase. As noted in Table 9, greater than two-thirds of all patients achieved treatment success, irrespective of treatment arm. The patients randomized to omeprazole treatment had the highest rate of healing. Of those in the maintenance phase, at least half of all patients remained ulcer-free across each treatment arm.

Table 9. Randomized clinical trials of omeprazole, ranitidine, and misoprostol and prevalent and recurring gastric and duodenal ulcers*
Author, year (ref.)PopulationCytoprotective agentGI outcome Success rate, %Gastric ulcer healing rate, %Duodenal ulcer healing rate, %Remission at 6 months
  • *

    GI = gastrointestinal; b.i.d. = twice daily; q.i.d. = 4 times daily.

  • Success rate = absence of ulcers and <5 erosions in stomach or duodenum.

  • Remission = absence of a relapse of lesions, dyspeptic symptoms, and adverse events leading to the discontinuation of treatment.

  • §

    P < 0.001 for comparisons with ranitidine.

  • P = 0.03 for comparison with ranitidine.

  • #

    P = 0.004 for comparison with misoprostol.

  • **

    P < 0.001 for comparison with misoprostol.

  • ††

    P = 0.001 for comparison with misoprostol.

  • ‡‡

    Placebo in maintenance phase only.

  • §§

    P < 0.001 for comparison with omeprazole and misoprostol.

Yoemans et al, 1998 (62)541 patients with ulcers or ≥10 erosions in stomach or duodenumOmeprazole (20 mg/day)80§84§9272
  Omeprazole (40 mg/day)7987§88
  Ranitidine (150 mg b.i.d.)63648159
Hawkey et al, 1998 (63)935 patients with ulcers or ≥10 erosions in stomach or duodenumOmeprazole (20 mg/day)7687#93**61†† — — 48
  Omeprazole (40 mg/day)7580§73**
  Misoprostol (200 mg q.i.d.)717377
  Misoprostol (200 mg b.i.d.)48
  Placebo‡‡27§§
GI toxicity and prophylaxis of COX-2–selective NSAIDs with low-dose aspirin use

Our literature review did not identify any studies that evaluated with the prophylactic use of cytoprotective agents in NSAID users taking concomitant low-dose aspirin. However, no significant difference was observed in the frequency of upper GI complications between the celecoxib and nonselective NSAID groups among 581 patients who were taking concomitant low-dose aspirin in the CLASS study. Thus, the interaction of celecoxib with low-dose aspirin may negate the potential GI safety benefits of celecoxib. There is no comparable data from large RCTs with other COX-2–selective NSAIDs. Of note, aspirin cotherapy has become increasingly prevalent due to concerns of an increased risk of myocardial infarction seen in patients randomized to rofecoxib compared with those receiving naproxen in the VIGOR study (naproxen relative risk = 0.2, 95% confidence interval 0.1–0.7) (29).

GI prophylaxis for aspirin

The literature regarding concomitant misoprostol or PPI therapy in individuals taking aspirin (including doses <325 mg daily) has been primarily restricted a number of small, placebo-controlled trials (64–71). These studies confirmed a reduction in endoscopically measured gastroduodenal ulcers and erosions in patients receiving one of these cytoprotective agents.

Coumadin and NSAID use

This indicator was created and validated by the expert panel. The concomitant use of anticoagulants (such as coumadin) and nonselective NSAIDs has been associated with an increased risk of clinically relevant upper GI adverse events in both cohort and case-control studies (72, 73). These studies are summarized in Table 7. Although validated by the panel process, our literature search did not identify any studies evaluating a decreased risk of GI bleeding when either a COX-2–selective or nonacetylated salicylate is substituted for a nonselective NSAID.

Side effect monitoring practices for NSAIDs

The final 2 QIs deal with side effect monitoring.

QI 9: IF a patient is treated with daily NSAIDs (selective or nonselective) and has risk factors for GI bleeding, THEN a complete blood count should be performed at baseline and during the first year after initiating therapy BECAUSE monitoring NSAID therapy can reduce the incidence and severity of associated adverse events.

QI 10: IF a patient is treated with daily NSAIDs (selective or nonselective) and has risk factors for developing renal insufficiency, THEN a serum creatinine should be assessed at baseline and at least once in the first year following the initiation of therapy BECAUSE monitoring NSAID therapy can reduce the incidence and severity of associated adverse events.

For the purpose of QI 9, GI risk factors include age ≥75 years, peptic ulcer disease, GI bleeding, current coumadin use, or glucocorticoid use. For QI 10, renal insufficiency risk factors include age ≥75 years, diabetes mellitus, hypertension, angiotensin-converting enzyme inhibitor or diuretic use.

Our literature search did not identify any experimental or observational evidence on the efficacy of drug monitoring to improve outcomes for analgesic users. Despite the absence of empirical data, a number of prior expert groups have recommended monitoring for GI and renal adverse events in patients taking NSAIDs, particularly those at increased risk (14–18). A summary of these recommendations and alternate approaches for NSAID-treated patients is included in Table 10.

Table 10. Consensus statements on NSAID and analgesic safety and monitoring recommendation*
Consensus groups (ref.)Informing patients about riskAlternate approaches in NSAID-treated patients at high GI riskSide effect monitoring practices
  • *

    NSAID = Nonsteroidal antiinflammatory drug; GI = gastrointestinal; CBC = complete blood count; COX-2 = cyclooxygenase 2; PPI = proton pump inhibitor; ACE = angiotensin-converting enzyme.

  • No evidence of cost-effectiveness of NSAID plus GI prophylaxis in osteoarthritis patients.

American College of Rheumatology (17–20)Cautious use of acetaminophen in patients with existing liver disease and avoidance in patients with history of chronic alcohol abuse.Low-dose prednisone Nonacetylated salicylate COX-2–selective NSAID Nonselective NSAID with misoprostol or PPIGI: CBC at baseline and yearly Renal: Creatinine at baseline; serial measurement of creatinine may be required (weekly for at least 3 weeks in patients receiving concomitant ACE inhibitors or diuretics)
Canadian Consensus Conferences (15, 16)Discuss safety with patients requiring NSAIDs (including COX-2).COX-2–selective NSAID Nonselective NSAID with misoprostol or PPIRenal: Baseline creatinine clearance and electrolyte concentrations
National Kidney Foundation (14)Over-the-counter label warning of renal risksRenal: Monitor renal function in patients with preexisting volume disease or volume depletion
North of England Evidence Based Guideline Development Project (21)Discuss risk and side effects of NSAIDs with patients before treatmentParacetamol Low-dose ibuprofen Co-codamol Lower NSAID dose
US Preventative Services Task Force (22)Discuss GI risk of aspirin in those taking for coronary heart prophylaxis
International COX-2 Study Group (23)COX-2–selective or nonselective NSAID with misoprostol or PPI in users taking low-dose aspirinRenal: At-risk patients (preexisting cardiac, renal, or hepatic disease) should be monitored (including COX-2)
American College of Gastroenterology (24)Nonselective NSAID with misoprostol or PPI

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Although analgesics are among the most commonly used classes of therapeutics in the United States, their popularity and efficacy are offset by the risks of drug-related adverse events. There is a large body of evidence associating nonselective, and to a lesser extent low-dose aspirin and COX-2–selective NSAIDs, with GI risks. Evidence also implicates NSAIDs and acetaminophen with renal and hepatic adverse events, respectively. Based on a review of the evidence we have performed and by subsequent expert consensus, 10 indicators are presented that were judged to be valid measures of the quality of care for analgesic use in the treatment of musculoskeletal disorders. These indicators were divided into 3 categories: 1) informing patients about the risks of analgesic use, 2) NSAID choice and GI prophylaxis in patients at higher risk of GI side effect, and 3) side effect monitoring.

Knowledge of involved risks may help patients and providers make better decisions leading to improved identification of adverse effects (74–76). However, ∼75% of regular NSAID users are not informed about potential drug-related GI complications (34). This finding suggests issues with patient informed consent, but also highlights a patient population at greater risk of drug-related complications because harbingers of potential complications may not be recognized.

Through numerous metaanalyses and observational studies, important patient characteristics associated with increased risk of NSAID adverse events have been identified (10–13). The toxicity burden may be lessened in high-risk groups by prudent use of GI prophylaxis and/or COX-2–selective NSAIDs. Laboratory monitoring for GI bleeding and renal damage has the potential for early identification of significant side effects and could therefore improve patient outcomes (77). This is particularly relevant for NSAID-induced GI complication because the minority of users experience early warning symptoms (13).

It should be noted that the indicators selected by our process are not comprehensive and do not necessarily represent recommendations for optimal care, but instead they should be construed as minimally acceptable standards. For example, guidelines from the American College of Rheumatology recommend that renal monitoring is needed weekly for the first few weeks in patients coprescribed NSAIDs with angiotensin converting inhibitors or diuretics (18), yet the panel validated a much less stringent quality indicator for this situation.

In summary, we propose 10 validated processes of care indicators. These indicators developed by literature review and finalized by an expert panel process can serve as a basis to compare the quality of analgesic use provided by different health care providers and health care delivery systems.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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