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Peterson K, McDonagh M, Thakurta S, et al. Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs): Final Update 4 Report [Internet]. Portland (OR): Oregon Health & Science University; 2010 Nov.

Cover of Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs): Final Update 4 Report [Internet].

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Compared with placebo, nonsteroidal antiinflammatory drugs (commonly called NSAIDs) reduce pain significantly in patients with arthritis,2 low back pain,3 and soft tissue pain. However, NSAIDs have important adverse effects, including gastrointestinal bleeding,4 peptic ulcer disease, hypertension,5 edema, and renal disease. More recently, some NSAIDs have also been associated with an increased risk of myocardial infarction.

NSAIDs reduce pain and inflammation by blocking cyclo-oxygenases (COX), enzymes that are needed to produce prostaglandins. Most NSAIDs block 2 different cyclo-oxygenases, COX-1 and COX-2. COX-2, found in joints and muscle, contributes to pain and inflammation.

NSAIDs cause bleeding because they also block the COX-1 enzyme, which protects the lining of the stomach from acid. In the United States, complications from NSAIDs are estimated to cause about 6 deaths per 100 000, a higher death rate than that for cervical cancer or malignant melanoma.6 A risk analysis7 based on a retrospective case-control survey of emergency admissions for upper gastrointestinal disease in 2 United Kingdom general hospitals provided useful estimates of the frequency of serious gastrointestinal complications from NSAIDs.8 In people taking NSAIDs, the 1-year risk of serious gastrointestinal bleeding ranges from 1 in 2100 in adults under age 45 to 1 in 110 for adults over age 75, and the risk of death ranges from 1 in 12353 to 1 in 647 (Table 1).

Table 1. One-year Risk of Gastrointestinal Bleeding Due to NSAID.

Table 1

One-year Risk of Gastrointestinal Bleeding Due to NSAID.

NSAIDs differ in their selectivity for COX-2; that is, how much they affect COX-2 relative to COX-1. An NSAID that blocks COX-2 but not COX-1 might reduce pain and inflammation in joints but leave the stomach lining alone.10 Appendix A summarizes the NSAIDs and their selectivity based on assay studies (done in the laboratory instead of in living patients). The table gives an idea of how widely NSAIDs vary in their selectivity, but should be interpreted with caution. Different assay methods give different results, and no assay method can predict what will happen when the drug is given to patients. Clinical studies, rather than these assay studies, are the best way to determine whether patients actually benefit from using more selective NSAIDs.

As a result of concerns over the long-term use of rofecoxib and increased risk of serious cardiovascular events (particularly myocardial infarction), the manufacturer voluntarily withdrew rofecoxib from the market in September 2004.11 Subsequently, the US Food and Drug Administration Arthritis and Drug Safety and Risk Management Advisory Committees reviewed all available data on selective COX-2 inhibitors. This led to a request by the US Food and Drug Administration to the manufacturer for the voluntary withdrawal of valdecoxib from the market in April 2005 and a re-labeling of celecoxib to include a more specific warning of the risks of serious cardiovascular adverse events associated with its use. See Table 2 below for the list of interventions included in the report. Black box warnings for drugs included in this report are listed in Appendix B.

Table 2. Included NSAIDs.

Table 2

Included NSAIDs.

We are aware of the April 2010 approval of the fixed-dose combination product Vimovo®, which contains naproxen delayed release and esomeprazole. However, the Drug Effectiveness Review Project participating organizations determined that fixed-dose combination products are outside the scope of the review at this time (Update 4).

Purpose and Limitations of Systematic Reviews

Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. They focus on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with careful formulation of research questions. The goal is to select questions that are important to patients and clinicians then to examine how well the scientific literature answers those questions. Terms commonly used in systematic reviews, such as statistical terms, are provided in Appendix C and are defined as they apply to reports produced by the Drug Effectiveness Review Project.

Systematic reviews emphasize the patient’s perspective in the choice of outcome measures used to answer research questions. Studies that measure health outcomes (events or conditions that the patient can feel, such as fractures, functional status, and quality of life) are preferred over studies of intermediate outcomes (such as change in bone density). Reviews also emphasize measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions depends on the number of events in each group, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant between groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than absolute risk reduction. Another useful measure is the number needed to treat (or harm). The number needed to treat is the number of patients who would need be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat.

Systematic reviews weigh the quality of the evidence, allowing a greater contribution from studies that meet high methodological standards and, thereby, reducing the likelihood of biased results. In general, for questions about the relative benefit of a drug, the results of well-executed randomized controlled trials are considered better evidence than results of cohort, case-control, and cross-sectional studies. In turn, these studies provide better evidence than uncontrolled trials and case series. For questions about tolerability and harms, observational study designs may provide important information that is not available from controlled trials. Within the hierarchy of observational studies, well-conducted cohort designs are preferred for assessing a common outcome. Case-control studies are preferred only when the outcome measure is rare and the study is well conducted.

Systematic reviews pay particular attention to whether results of efficacy studies can be generalized to broader applications. Efficacy studies provide the best information about how a drug performs in a controlled setting. These studies attempt to tightly control potential confounding factors and bias; however, for this reason the results of efficacy studies may not be applicable to many, and sometimes to most, patients seen in everyday practice. Most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, adherence to treatment, or severity of illness. For many drug classes, including the antipsychotics, unstable or severely impaired patients are often excluded from trials. In addition, efficacy studies frequently exclude patients who have comorbid disease, meaning disease other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that are impractical in typical practice settings. These studies often restrict options that are of value in actual practice, such as combination therapies and switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.

Systematic reviews highlight studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, more often assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from the highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, frequency or duration of hospitalizations, social function, and the ability to work. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures, such as scores based on psychometric scales.

Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling a study as either an efficacy or an effectiveness study, although convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice or to a particular patient.

Studies anywhere on the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how large the quantity, may have limited applicability to practice. Clinicians can judge the relevance of study results to their practice and should note where there are gaps in the available scientific information.

Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment.

In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. By themselves, they do not say what to do. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice.

Scope and Key Questions

The goal of this report is to compare the effectiveness and adverse event profiles of cyclo-oxygenase (COX) inhibitors and nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of chronic pain from osteoarthritis, rheumatoid arthritis, soft tissue pain, back pain, and ankylosing spondylitis. The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, outcomes of interest, and, based on these, eligibility criteria for studies. A draft of these questions and inclusion and exclusion criteria were posted on the Drug Effectiveness Review Project website for public comment. The draft was reviewed and revised by representatives of the organizations participating in the Drug Effectiveness Review Project. Revision took into consideration input from the public and the organizations’ desire for the key questions to reflect populations, drugs, and outcome measures of interest to clinicians and patients. These organizations approved the following key questions to guide the review for this report:

  1. Are there differences in effectiveness between NSAIDs, with or without antiulcermedication, when used in adults with chronic pain from osteoarthritis, rheumatoidarthritis, soft-tissue pain, back pain, or ankylosing spondylitis?
    1. How do oral drugs compare to one another?
    2. How do topical drugs compare to one another?
    3. How do oral drugs compare to topical drugs?
  2. Are there clinically important differences in short-term harms (< 6 months) between NSAIDs, with or without antiulcer medication, when used in adults with chronic pain from osteoarthritis, rheumatoid arthritis, soft-tissue pain, back pain, or ankylosing spondylitis?
    1. How do oral drugs compare to one another?
    2. How do topical drugs compare to one another?
    3. How do oral drugs compare to topical drugs?
  3. Are there clinically important differences in long-term harms (≥ 6 months) between NSAIDs, with or without antiulcer medication, when used chronically in adults with chronic pain from osteoarthritis, rheumatoid arthritis, soft-tissue pain, back pain, or ankylosing spondylitis?
    1. How do oral drugs compare to one another?
    2. How do topical drugs compare to one another?
    3. How do oral drugs compare to topical drugs?
  4. Are there subgroups of patients based on demographics, other medications (e.g., aspirin), socio-economic conditions, co-morbidities (e.g., gastrointestinal disease) for which one medication is more effective or associated with fewer harms?
Copyright © 2010, Oregon Health & Science University.
Bookshelf ID: NBK53947
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