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The cardiovascular safety of nonsteroidal anti-inflammatory drugs: putting the evidence in perspective.

INTRODUCTION

Pain and inflammation are common complaints experienced by all humans at some time during their lifetime. Among the wide variety of available analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for relief of acute and chronic pain. Data from the 2010 National Health Interview Survey suggest that approximately 43 million adults in the United States took aspirin at least 3 times per week for more than 3 months, while more than 29 million adults used an NSAID regularly. (1) Traditional NSAIDs (tNSAIDs), such as aspirin, ibuprofen, naproxen, and diclofenac, represent an effective, long-lasting option that may offer advantages over cyclooxygenase-2 (COX-2) selective NSAIDs, such as celecoxib. The use of NSAIDs is not without controversy, however.

The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, published in 2000, was the first to raise concerns that NSAIDs (specifically, the COX-2 selective inhibitor rofecoxib) might be associated with a higher risk for cardiovascular (CV) events. (2) As discussed below, subsequent trials and meta-analyses have demonstrated a higher CV risk with use of not only COX-2 inhibitors (coxibs) but also certain tNSAIDs. These investigations have contributed to actions by the US Food and Drug Administration (FDA), most recently in July 2015, requiring strengthening of CV risk warnings on labels for all prescription and over-the-counter NSAIDs, despite evidence suggesting that differences in CV risk may exist among the NSAIDs.

To address unanswered questions regarding CV risk of coxibs vs tNSAIDs, the FDA mandated a comparison of celecoxib with 2 tNSAIDs, ibuprofen and naproxen. (3) As a result, the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial was launched in 2006. PRECISION was a noninferiority trial to assess CV outcomes with long-term use, with secondary end points such as gastrointestinal (GI), renal, and other outcomes. The results of the PRECISION trial, published in November 2016, are difficult to interpret because of the study's limitations and may have contributed to confusion regarding the CV safety of NSAIDs. Before further discussing the PRECISION trial and its implications for primary care providers, it is important to put the PRECISION trial in perspective by highlighting the pharmacologic differences among the NSAIDs and their implications for CV safety and considering a historical review of key CV safety trials involving NSAIDs.

CLINICAL PHARMACOLOGY OF NSAIDs

NSAIDs reduce pain and inflammation through inhibition of the cyclooxygenase enzyme, resulting in downstream inhibition of the production of thromboxane [A.sub.2] (Tx[A.sub.2]), prostacyclin, and other prostanoids. (4) The analgesic and anti-inflammatory effects of NSAIDs largely result from inhibition of the COX-2-iso-form at sites of inflammation, while gastrointestinal and other adverse events stem from inhibition of COX-1 isoforms, which are constitutive, present in most organs, and primarily serve a homeostatic function. For example, in the stomach, COX-1 mediates a cytoprotective effect, helping maintain mucosal integrity by increasing mucosal blood flow and increasing GI mucus and bicarbonate secretion. (4,5) Inhibition of COX-1 is the mechanism primarily responsible for the gastric and duodenal ulceration and bleeding long associated with tNSAID use.

In vascular endothelium, COX-2 is involved in the production of prostacyclin (PGI2), which antagonizes platelet activation and produces vasodilation, whereas in platelets, COX-1 is responsible for the production of Tx[A.sub.2], which causes platelet activation and vasoconstriction. It is thought that the selective inhibition of COX-2 by coxibs results in a relative reduction in endothelial PGI2 synthesis, leaving platelet production of Tx[A.sub.2], intact. As a result, it has been theorized that coxibs shift the balance of prostaglandin production to Tx[A.sub.2], at the platelet-vascular endothelial interface, thereby favoring thrombogenic stimulation and arterial vasoconstriction and a greater risk for an atherothrombotic cardiovascular event. (6)

Although COX-2 selectivity is a likely contributor to the higher CV risk seen with NSAID use, it is not the only factor, given that a higher CV risk has been seen with both coxibs as well as tNSAIDs. Other important variables implicated in NSAID risk include dosage, half-life, impact on blood pressure, and interaction with aspirin. (7)

ASPIRIN INTERACTION

In contrast to inhibition of arachidonic acid observed with other NSAIDs, aspirin causes an irreversible inactivation of COX-1 and COX-2. Inhibition of COX-1 is responsible for the antiplatelet effects of aspirin and its cardioprotective effect. (4) The coadministration of some tNSAIDs, eg, ibuprofen and naproxen (but not COX-2 selective inhibitors), with low-dose aspirin (LD-ASA) causes transient and modest inhibition of COX-1 and has been shown to interfere with the antiplatelet effect of aspirin. (7,8) The effect of naproxen on the antiplatelet effect of LD-ASA may be lower than with ibuprofen. (9) Concerns that such an interaction might reduce the cardioprotective effect of LD-ASA resulted in an advisory from the FDA in 2007 recommending ibuprofen be taken at least 30 minutes after aspirin to avoid any potential interaction. (10)" Taking naproxen 2 hours after aspirin appears to lessen the interference. (11) Furthermore, there is evidence that suggests that high-dose naproxen at a prescription dose of 500 mg twice daily may actually produce its own aspirin-like antipltelet effect. (12)

The variable effect of NSAIDs to interfere with the ability of aspirin to inhibit platelet activation may be due to differences in their ability to form hydrogen bonds with specific amino acids within the COX-1 hydrophobic channel. (13) The possibility of differences among NSAIDs with respect to an interaction with aspirin is of clinical importance as many patients who use NSAIDs for anti-inflammatory and analgesic effects often use LD-ASA to prevent CV events. This becomes a particularly important consideration in older adults with osteoarthritic pain, who are likely to be at increased CV risk. (14)

CARDIOVASCULAR SAFETY

The CV safety of NSAIDs has been assessed in hundreds of clinical trials over the past almost 2 decades. Details regarding several key clinical trials are provided in the table. (2,15-22) These trials show that NSAIDs variably alter the rate of thromboembolic events and suggest that NSAIDs with a greater affinity for COX-2, particularly at higher doses, are associated with a higher CV risk.

KEY PROSPECTIVE CLINICAL TRIALS

The VIGOR trial was the first trial to suggest a higher incidence of adverse CV outcomes with COX-2 selective inhibitors compared with tNSAIDs. (2) After a median follow-up of 9 months, the incidence of myocardial infarction (MI) was found to be 4-fold higher with rofecoxib than naproxen (0.4% vs 0.1%, respectively). (2) A post hoc analysis was also concerning, showing that the relative risk for developing a confirmed, adjudicated thrombotic CV event with rofecoxib compared with naproxen was 2.38 (95% confidence interval [CI], 1.39-4.00). (15)

The Adenoma Prevention with Celecoxib (APC) trial compared 2 doses of celecoxib (200 mg or 400 mg twice daily) with placebo for the prevention of colorectal adenomas. (16) After approximately 3 years of follow-up, the study was terminated early because of a dose-related increase in a composite of CV events with celecoxib.

The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial determined the effect of rofecoxib vs placebo on the risk for recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. (17) The rate of a confirmed thrombotic event was significantly higher with rofecoxib, becoming apparent after 18 months of treatment. The results primarily reflect a greater number of MIs and ischemic cerebrovascular events in the rofecoxib group. The results of the APPROVe trial contributed to the withdrawal of rofecoxib from the market in 2004.

The therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) assessed the CV outcomes in high-risk patients with osteoarthritis. TARGET comprised 2 parallel substudies comparing the COX-2 selective inhibitor lumiracoxib (not available in the United States) 400 mg daily with either ibuprofen 800 mg three times daily or naproxen 500 mg twice daily. (18) In aspirin users, ibuprofen was associated with a significantly higher rate of CV events at 1 year compared with lumiracoxib, whereas naproxen was not. In nonaspirin users, naproxen was associated with significantly fewer CV events compared with lumiracoxib, whereas ibuprofen was not. In addition, ibuprofen was associated with a higher rate of congestive heart failure. Shortcomings of this trial included the post hoc design; not being appropriately powered for CV safely, resulting in imprecision due to the small number of events in the subgroups; the use of aspirin in some but not all patients for unspecified reasons; lack of data collection on aspirin use during the study; and a lack of a placebo arm, making it difficult to evaluate absolute CV risk.

The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) evaluated naproxen 220 mg twice daily and celecoxib 200 mg twice daily with placebo for the primary prevention of Alzheimer's dementia. (19) After the results of the APC trial were released, the ADAPT study was terminated, with a median of approximately 15 months of treatment. ADAPT findings suggested the cardiovascular and cerebrovascular risks with celecoxib were similar to placebo. The CV risk was significantly greater with naproxen compared with placebo, due to a higher incidence of heart failure and transient ischemic attack. Besides early termination, the study had several limitations, including that it was not designed to detect differences in CV or cerebrovascular risk and was not appropriately powered for CV safety, resulting in imprecision due to the small number of events; the patient population had unknown CV risk at baseline, complicating extrapolation to the general population; and there was no a priori procedure for adjudication of CV or cerebrovascular events.

Lastly, the Standard care versus Celecoxib Outcome Trial (SCOT) was a prospective, open, blinded end point trial that compared the CV and GI safety of celecoxib with a variety of tNSAIDs (eg, diclofenac, ibuprofen, naproxen, meloxicam) in patients ages >60 years with osteoarthritis (OA) or rheumatoid arthritis (RA) but free of CV disease. (20) Over a median of 3 years, fewer patients than expected developed an on-treatment CV event with a rate similar for celecoxib and tNSAIDs. (21) Although the trial was conducted in the United Kingdom, Denmark, and the Netherlands, full data regarding mean NSAID daily doses were available only in Scotland: celecoxib 169.8 mg (standard deviation [SD], 80.6), diclofenac 79.4 mg (SD, 38.3), ibuprofen 675.9 mg (SD, 345.9), and naproxen 581.9 mg (SD, 263.4). Significantly more patients withdrew from celecoxib than tNSAIDS, with the dominant reason being lack of efficacy. The rate of NSAID-associated GI complications was low (attributed by the authors to the coadministration of concomitant anti-ulcer agents as well as the relatively low doses of the NSAIDs used; as expected, the rate was higher with tNSAIDs than with celecoxib.

DANISH REGISTRY STUDY

A nationwide registry of Danish patients ages [greater than or equal to] 30 years admitted with first-time MI was analyzed to assess NSAID use and CV risk. Overall, NSAID treatment was significantly associated with an increased risk for death/recurrent MI commencing within 7 days of treatment initiation (hazard ratio [HR], 1.45; 95% CI, 1.29-1.62). (22) The risks persisted over more than 5 years of follow-up, with an increased risk for death (HR, 1.60; 95% CI, 1.49-1.71) and coronary death or nonfatal recurrent MI (HR, 1.41; 95% CI, 1.29-1 .S6). (23) The risk for coronary death or nonfatal recurrent MI was greater with rofecoxib (HR, 2.19; 95% CI, 1.27-3.77) than with celecoxib (HR, 1.17; 95% CI, 0.63-2.17). Among the most commonly used tNSAIDs, the risk was greatest with diclofenac (HR, 1.58; 95% CI, 1.31-1.91) and lowest with naproxen (HR, 1.15; 95% CI, 0.71-1.85).

The bleeding rates were also significantly greater in patients treated with NSAID therapy. The risk for a CV event or bleeding was independent of concomitant antithrombotic treatment. (24) These results suggest that NSAIDs should be used cautiously, if at all, in patients with a history of MI.

META-ANALYSES

Meta-analyses have been conducted to assess the CV risk of NSAIDs. The McGettigan-Henry meta-analysis examined population-based controlled observational studies of individual NSAIDs used at typical doses in community settings. (25) Trelle et al conducted a network meta-analysis of 31 large-scale, randomized controlled trials comparing any NSAID with another NSAID or placebo. (26) The Coxib and Traditional NSAID Trialists' (CNT) Collaboration identified 639 randomized trials of an NSAID vs placebo or 1 NSAID regimen vs another for analysis. It included 297 trials that compared a COX-2 selective NSAID vs placebo or a COX-2 selective NSAID vstNSAID. (27)

The 3 meta-analyses yielded generally similar results, suggesting that all NSAIDs are associated with an increased CV risk, with naproxen conferring the lowest risk. The CNT analysis showed the estimated relative risk for major CV events among the tNSAIDs vs placebo was highest with diclofenac (HR, 1.41; 95% CI, 1.12-1.78) and ibuprofen (HR, 1.44; 95% CI, 0.89-2.33) and lowest with naproxen (HR, 0.93; 95% CI, 0.69-1.27). (27) Although the CNT analysis demonstrated a similar risk for major CV events with rofecoxib and celecoxib, the McGettigan-Henry analysis showed a higher risk with rofecoxib (HR, 1.45; 95% CI, 1.33-1.59) vs celecoxib (HR, 1.17; 95% CI, 1.08-1.27). (25,27) All 3 meta-analyses provided support to the premise that the CV risk associated with celecoxib was dose-dependent, with the CNT and the McGettigan-Henry analyses suggesting no increased risk with doses of 200 mg daily. In addition to looking at CV risk, the CNT analysis also examined upper GI complications (ie, upper GI bleeding and/or perforation, or peptic ulcer) and showed the risk to be nearly twice as high for ibuprofen and naproxen compared with diclofenac or a coxib. (27)

US FOOD AND DRUG ADMINISTRATION ACTIONS

Following publication of the CNT meta-analysis, the FDA convened 2 advisory panels to review this and other related information. (28) Results of this meeting, as well as its own analysis, led the FDA to issue a drug safety communication in July 2015 that required prescription NSAID labels to communicate the following:

* The risk for heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID.

* The risk appears greater at higher doses.

* It was previously thought that all NSAIDs may have a similar risk. Newer information makes it less clear that the risk for heart attack or stroke is similar for all NSAIDs; however, this newer information is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.

* NSAIDs can increase the risk for heart attack or stroke in patients with or without heart disease or risk factors for heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drugs and the doses studied.

* In general, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors because they have a higher risk at baseline.

* Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared with patients who were not treated with NSAIDs after their first heart attack.

* There is an increased risk for heart failure with NSAID use.

PRECISION TRIAL

This CV safety trial mandated by the FDA in 2014 was initiated in 2006 following a 2004 FDA review. The PRECISION trial enrolled patients who required NSAID therapy for OA or RA and were deemed at high CV risk for CV disease based on having established CV disease or risk factors for CV disease (approximately 35% of patients had a history of diabetes, 78% a history of hypertension, and 62% a history of dyslipidemia). Patients were randomized to celecoxib 100 to 200 mg twice daily, ibuprofen 600 to 800 mg three times daily, or naproxen 375 to 500 mg twice daily. (3) The primary endpoint was non-inferiority on the composite of CV death (including hemorrhagic death), nonfatal MI, or nonfatal stroke. A total of 24,081 patients were randomized with a mean treatment duration of 20.3 months and a mean follow-up period of 34.1 months. During the trial, 68.8% of patients stopped taking the treatment drug and 27.4% discontinued follow-up.

Celecoxib was found to be noninferior to ibuprofen and naproxen with regard to CV safety, with the primary endpoint occurring in 2.3% of celecoxib patients compared with 2.7% and 2.5% of ibuprofen and naproxen patients, respectively. (3) Hazard ratios for celecoxib were 0.85 (95% CI, 0.70-1.04) vs ibuprofen and 0.93 (95% CI, 0.76-1.13) vs naproxen (P<.001 for both). In contrast, pairwise comparisons for each of the components of the primary endpoint showed no significant differences between celecoxib and ibuprofen as well as celecoxib and naproxen. As expected, based on their mechanistic differences, the risk for GI events was significantly lower with celecoxib than with ibuprofen (P=.002) or naproxen (P=.01). The risk for renal events was significantly lower with celecoxib compared with ibuprofen (P=.004) but not compared with naproxen (P=.19).

The design and results of PRECISION have been questioned and its findings should be interpreted with caution. (29) In addition to high rates of patients discontinuing the study drug as well as discontinuing follow-up, the rate of primary outcome events occurring during the study period was considerably lower than expected and appeared more indicative of a study group at relatively low risk for CV events. Because of this lower rate and problems with subject recruitment, the statistical power for noninferiority, which was originally planned to be 90%, was relaxed to 80%, thereby lessening the reliability of any judgment of noninferiority. Moreover, based on prior studies, the CV risk associated with celecoxib use appears dose-related. In the PRECISION trial, the mean daily celecoxib dose of 209 mg may be considered low dose (30) and lower than that associated with increased CV risk. For comparison, the mean daily doses of ibuprofen and naproxen were 2045 mg and 852 mg, respectively. Lastly, since interference with the antiplatelet activity of LD-ASA and potential negation of its cardioprotective effect is not a class effect (ie, both naproxen and ibuprofen have been shown to interfere with the antiplatelet activity of aspirin, whereas celecoxib has not), the failure to control for use of LD-ASA use introduces a potential source of bias favoring celecoxib and calls into question any conclusions in this regard.

SUMMARY

At the present time, the totality of evidence suggests that all NSAIDs are associated with an increased risk for adverse CV events. Several factors are involved, including COX-2 selectivity, dosage, half-life, impact on blood pressure, and interaction with aspirin. Although the evidentiary standard needed by the FDA to rank order NSAID compounds with regard to CV risk has not been met, the balance of evidence continues to favor naproxen as the safest NSAID from a CV perspective. A caveat is that naproxen may also pose a higher risk for an upper GI bleed than other tNSAIDs. Although data from the SCOT trial and the PRECISION trial support the improved CV safety of low-dose celecoxib (200 mg daily) seen in earlier studies, the shortcomings of these 2 trials serve only to raise doubt regarding any conclusions about the comparative safety of the NSAID agents studied and leaves unanswered the question of differential CV risk.

Although widely used and clinically valuable, NSAID use is not without risk. When considering the use of an NSAID, careful consideration of risk factors associated with NSAID toxicity should be given, including the patient's age and the risk for developing renal, GI, and CV complications. NSAIDs should be used only with due caution in patients with known CV disease and are best avoided in patients following an MI. Until definitive evidence becomes available, it remains prudent to follow the basic rule of prescribing the lowest effective dose of an NSAID for the shortest duration possible.

REFERENCES

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(2.) Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000; 343(21):1520-1528, 2p following 1528.

(3.) Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular Safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016; 375(26):2519-2529.

(4.) Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Paitl Res. 2015; 8:105-118.

(5.) Whittle B). COX-1 and COX-2 products in the gut: therapeutic impact of COX-2 inhibitors. Cut. 2000; 47(3):320-325.

(6.) Yu Y, Ricciotti E, Scalia R, et al. Vascular COX-2 modulates blood pressure and thrombosis in mice. Sci Transl Med. 2012; 4(132):132ra54.

(7.) Farkouh ME, Greenberg BR An evidence-based review of the cardiovascular risks of nonsteroidal anti-inflammatory drugs. Am J Cardiol. 2009; 103(9): 1227-1237.

(8.) Schmidt M, Lamberts M, Olseil AM, et al. Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology. Eur Heart J. 2016; 37(13):1015-1023.

(9.) Farkouh ME, Kirshner H, Harrington RA, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet. 2004; 364(9435):675-684.

(10.) Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007; 115(12):1634-1642.

(11.) Anzellotti P, Capone ML, Jeyam A, et al. Low-dose naproxen interferes with the antiplatelet effects of aspirin in healthy subjects: recommendations to minimize the functional consequences. Arthritis Rheum. 2011; 63(3):850-859.

(12.) Patrono C, Baigent C. Nonsteroidal anti-inflammatory drugs and the heart. Circulation. 2014; 129(8):907-916.

(13.) Saxena A, Balaramnavar VM, Hohlfeld T, et al. Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets. Eur J Pharmacol. 2013:721(1-3): 215-224.

(14.) Mamdani M, Juurlink DN, Lee DS, et al. Cyclo-oxygenase-2 inhibitors versus nonselective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet. 2004:363(9423): 1751-1756.

(15.) Mukherjee D, Nissen SE, Topol EI. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001; 286(8):954-959.

(16.) Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005; 352(11): 1071-1080.

(17.) Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. NEngl I Med. 2005; 352(11):1092-1102.

(18.) Farkouh ME, Greenberg JD, Jeger RY et al. Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Ann Rheum Dis. 2007; 66(6):764-770.

(19.) ADAPT Research Group. Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT). PLoS Clin Trials. 2006; 1(7):e33.

(20.) MacDonald TM, Mackenzie IS, Wei L, et al. Methodology of a large prospective, randomised, open, blinded endpoint streamlined safety study of celecoxib versus traditional non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis: protocol of the standard care versus celecoxib outcome trial (SCOT). BMJ Open. 2013; 3(1).

(21.) MacDonald TM, Hawkey CJ, Ford I, et al. Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT). Eur Heart J. 2016. doi: https://doi.org/10.1093/eurheartj/ehw387.

(22.) Schjeming Olsen AM, Fosbol EL, Lindhardsen J, et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011; 123(20):2226-2235.

(23.) Olsen AM, Fosbol EL, Lindhardsen J, et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation. 2012; 126(16):1955-1963.

(24.) Schjeming Olsen AM, Gislason GH, McGettigan P, et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA. 2015; 313(8):805-814.

(25.) McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011; 8(9):e1001098.

(26.) Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 201 l; 342:c7086.

(27.) Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of nonsteroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013; 382(9894):769-779.

(28.) US Food and Drug Administration. FDA briefing document: Joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee. February 10-11, 2014. http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetmgMaterials/Drugs/ArthritisAdvisoryCommittee/UCM383180.pdf. Published 2014. Accessed February 2,2017.

(29.) FitzGerald GA. ImPRECISION: Limitations to interpretation of a large randomized clinical trial. Circulation. 2016; 135(2):113-115.

(30.) Felson DT. Safety of nonsteroidal antiinflammatory drugs. N Engl J Med. 2016:375 (26):2595-2596.

Martin Quan, MD, Professor of Clinical Family Medicine, David Geffen School of Medicine at UCLA, Vice Chair for Academic Affairs, UCLA Department of Family Medicine, Los Angeles, CA

DISCLOSURES

Dr. Quan discloses that he has no real or apparent conflicts of interest to report.

SUPPORT

This article is sponsored and developed by Primary Care Education Consortium.
TABLE Evidence concerning the cardiovascular risks associated with
COX-2 inhibitors

Trial; year(s)
conducted        Design; patients

VIGOR,           R, DB, MC
1999 (2,15)      Patients with RA
                 (N=8076)

APC,             R, DB, MC
1999-2002 (16)   Patients at risk for
                 colorectal adenoma
                 (N=2035)

APPROVe, 2000-   R, DB, MC
2001 (17)        Patients with
                 colorectal adenoma
                 (N=2586)

TARGET,          R, DB, MC
2001-2002 (18)   Patients with OA ages
                 [greater than or equal to]
                 50 y
                 (N=18,325)

ADAPT,           R, DB, MC
2001-2004 (19)   Patients ages
                 [greater than or equal to]
                 70 y with family history
                 of AD (N=2528)
                 Design; patients

Danish           Retrospective
Registry,        review of national
1997-2006 (22)   registry
                 Patients ages
                 [greater than or equal to]
                 y with first-time
                 MI (N=83,675)

SCOT,            PROBE, MC
2008-2013        Patients ages
(20,21)          [greater than or equal to]
                 60 y with OA
                 or RA (N=7297)

Trial; year(s)
conducted        Treatment

VIGOR,           Rofecoxib 50 mg/d
1999 (2,15)      vs
                 Naproxen 500 mg bid
                 (median follow-up 9 mos)

APC,             Celecoxib 200 mg bid
1999-2002 (16)   vs
                 Celecoxib 400 mg bid vs
                 Placebo
                 (2.8-3.1 y follow-up)

APPROVe, 2000-   Rofecoxib 25 mg/d
2001 (17)        vs
                 Placebo X 3 y

TARGET,          Lumiracoxib 400 mg/d
2001-2002 (18)   vs
                 Ibuprofen 800 mg tid
                 X 52 wks

                 Lumiracoxib 400 mg/d
                 vs
                 Naproxen 500 mg bid
                 X 52 wks

ADAPT,           Celecoxib 200 mg bid
2001-2004 (19)   vs
                 Naproxen 220 mg bid
                 vs
                 Placebo
                 X 3 y
                 Treatment

Danish           Any NSAID
Registry,
1997-2006 (22)

SCOT,            Celecoxib
2008-2013        [less than or equal to]
(20,21)          200 mg bid
                 vs
                 tNSAID (f)
                 (median follow-up 3 y)

Trial; year(s)
conducted        Results (a)

VIGOR,           GI events (per 100 PY): 2.1 vs 4.5 (HR, 0.5;
1999 (2,15)      95% CI, 0.3-0.6)
                 Ml: 0.4% vs 0.1%
                 MACE (b): HR, 2.38; 95% CI, 1.39-4.00

APC,             MACE (c): HR vs PBO: HR, 2.3; 95% CI, 0.9-
1999-2002 (16)   5.5: HR, 3.4; 95% CI, 1.4-7.8

APPROVe, 2000-   Thrombotic event (d) (per 100 PY): 1.50 vs
2001 (17)        0.78 (HR, 1.92; 95% CI, 1.19-3.11)
                 Cardiac events (per 100 PY): 1.01 vs 0.36
                 (HR, 2.80; 95% CI, 1.44-5.45)
                 Cerebrovascular events (per 100 PY): 0.49 vs 0.21
                 (HR, 2.32; 95% CI, 0.89-6.74)

TARGET,          High-risk using aspirin (75-100 mg/d):
2001-2002 (18)   MACE (e): 0.25% vs 2.14% (HR, 9.08; 95%
                 CI, 1.13-72.8)
                 High-risk not using aspirin:
                 MACE (e): 0.80% vs 0.92%
                 (HR, 0.91; 95% CI, 0.15-5.47)
                 High-risk using aspirin (75-100 mg/d):
                 MACE (e): 1.48% vs 1.58% (HR, 1.07; 95%
                 CI, 0.40-2.84)
                 High-risk not using aspirin:
                 MACE (e)0: 1.57% vs 0% (HR, N/A)

ADAPT,           MACE (f): 5.54% vs 8.25% vs 5.68% [HR
2001-2004 (19)   vs PBO: HR.1.10; 95% CI, 0.67-1.79; HR,
                 1.63; 95% CI, 1.04-2.55]

Danish           Risk for death or recurrent Ml
Registry,        (>90 days treatment)
1997-2006 (22)   All NSAIDs: HR, 1.55; 95% CI, 1.46-1.64
                 Rofecoxib: HR, 1.72; 95% CI, 1.45-2.04
                 Celecoxib: HR, 1.65; 95% CI, 1.42-1.92
                 Ibuprofen: HR, 1.53; 95% CI, 1.40-1.69
                 Diclofenac: HR, 1.92; 95% CI, 1.66-2.22
                 Naproxen: HR, 1.50; 95% CI, 0.10-2.05
                 Other NSAIDs: HR, 1.44; 95% CI, 1.28-1.62

SCOT,            MACE (per 100 PY) (h): 1.14 vs 1.10 (HR,
2008-2013        1.04; 95% CI, 0.81-1.33)
(20,21)          Hospitalization or death for upper GI ulcer
                 (per 100 PY): 0.09 vs 0.04 (HR, 2.08; 95%
                 CI, 0.65-7.74)

Trial; year(s)
conducted        Limitations

VIGOR,           Withdrawal
1999 (2,15)      from treatment:
                 29.3% vs 28.5%;
                 not placebo-controlled

APC,
1999-2002 (16)

APPROVe, 2000-   Withdrawal from
2001 (17)        treatment: 31.9%
                 vs 24.6%

TARGET,          Post hoc analysis; not
2001-2002 (18)   placebo-controlled;
                 few events; withdrawal
                 from treatment: 43%

ADAPT,
2001-2004 (19)

Danish           Observational
Registry,        design;
1997-2006 (22)   informational bias

SCOT,            Withdrawal from
2008-2013        treatment: 48.2%
(20,21)          VS 31.5%

Abbreviations: AD, Alzheimer's disease; ADAPT, Alzheimer's Disease
Anti-inflammatory Prevention Trial; APC, Adenoma Prevention with
Celecoxib; APPROVe, Adeno-matous Polyp Prevention on Vioxx; bid,
twice daily; CHF, congestive heart failure; CV, cardiovascular; d,
day; DB, double-blind; GI, gastrointestinal; HR, hazard ratio; MACE,
major adverse cardiovascular events; MC, multicenter; Ml, myocardial
infarction; N-A, not applicable; N, number; NSAIDs, nonsteroidal
anti-inflammatory drugs; OA, osteoarthritis; PBO, placebo; PROBE,
prospective, randomized, open-label, blinded endpoint evaluation; PY,
person-years; R, randomized; RA, rheumatoid arthritis; SCOT, Standard
care versus Celecoxib Outcome Trial; TARGET, Therapeutic Arthritis
Research and Gastrointestinal Event Trial; tid, 3 times daily;
tNSAID, traditional, ie, non-COX-2 selective NSAID; VIGOR, Vioxx
Gastrointestinal Outcomes Research; wks, weeks; y, year(s).

(a) 95% confidence interval.

(b) Composite of Ml, unstable angina, cardiac thrombus, resuscitated
cardiac arrest, sudden or unexplained death, ischemic stroke,
transient ischemic attack

(c) Composite of CV death, Ml, stroke, heart failure.

(d) Composite of fatal and nonfatal Ml, unstable angina, sudden
cardiac death, fatal and nonfatal ischemic stroke, transient ischemic
attack, peripheral arterial thrombosis, peripheral venous thrombosis,
pulmonary embolism.

(e) Composite of CV death, nonfatal Ml, stroke.

(f) Composite of CV death, Ml, stroke, congestive heart failure,
transient ischemic attack.

(g) lbuprofen, aceclofenac, acemetacin, dexibuprofen, dexketoprofen,
diclofenac sodium, diflunisal, etodolac, fenbufen, fenoprofen,
flurbiprofen, ibuprofen, indometacin, ketoprofen, mefenamic acid,
meloxicam, nabumetone, naproxen, piroxicam, sulindac, tenoxicam,
tiaprofenic acid, diclofenac/misoprostol.

(h) Composite of hospitalization for nonfatal Ml or other biomarker
for positive acute coronary syndrome, nonfatal stroke, or CV death.
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Author:Quan, Martin
Publication:Journal of Family Practice
Article Type:Report
Date:Apr 1, 2017
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