Are NSAIDs and selective cyclo-oxygenase 2 inhibitors associated with increased risk of myocardial infarction?

Scott et al. conducted a systematic review to evaluate the risk of myocardial infarction (MI) associated with cyclo-oxygenase-2 (COX2) inhibitors and traditional NSAIDs. The review found a small increased risk of MI associated with COX2 inhibitors, particularly rofecoxib. Although a fixed-effects model of 14 case-control studies suggested a slightly increased risk of MI with NSAID use, a random-effects model of the same data and analysis of 6 cohort studies found no such link. An increased risk of MI was found in four RCTs of NSAID use in colonic adenoma. In an analysis of 14 RCTs that compared COX2 inhibitors with traditional NSAIDs in patients with arthritis, the odds ratio for MI with COX2 inhibitors was 1.6 (95% CI 1.1-2.4), although most of this risk was accounted for by rofecoxib. COX2 inhibitors were, however, associated with a reduced risk of serious gastrointestinal events. An analysis of previous systematic reviews showed increased risks of MI associated with rofecoxib and celecoxib.     

Simultaneous assessment of short-term gastrointestinal benefits and cardiovascular risks of selective cyclooxygenase 2 inhibitors and nonselective nonsteroidal antiinflammatory drugs: an instrumental variable analysis

OBJECTIVE: To simultaneously assess the short-term reduction in risk of gastrointestinal (GI) complications and increase in risk of acute myocardial infarction (MI) by celecoxib compared with rofecoxib and several nonselective nonsteroidal antiinflammatory drugs (NSAIDs) using instrumental variable analysis. METHODS: A population of 49,711 Medicare beneficiaries ages 65 years and older who initiated nonselective NSAID or selective cyclooxygenase 2 inhibitor therapy between January 1, 1999, and December 31, 2002, was identified. The increase in risk of GI complications and MI within 180 days after initiation of NSAID (rofecoxib, diclofenac, ibuprofen, and naproxen compared with celecoxib) therapy was assessed using instrumental variable analysis. RESULTS: Compared with nonselective NSAIDs, celecoxib reduced the risk of GI complications by 1.4 per 100 users but increased the risk of MI by 0.3 per 100 users. Rofecoxib decreased GI complications by 1.1 per 100 users and increased the risk of MI by 0.3 per 100 users. Using celecoxib as the reference exposure showed an increase in the MI risk for rofecoxib (risk difference [RD] 1.40, 95% confidence interval [95% CI] -0.20, 3.01) and diclofenac (RD 6.07, 95% CI -0.02, 12.15). The RD for naproxen as well as its upper 95% CI was the lowest of all NSAIDs (RD -0.30, 95% CI -2.74, 2.14) and there was no significant difference in GI complication rates among all NSAIDs. CONCLUSION: In this instrumental variable analysis, diclofenac and rofecoxib had the least favorable benefit-risk balance among NSAIDs in older adults.     

Simultaneous assessment of short‐term gastrointestinal benefits and cardiovascular risks of selective cyclooxygenase 2 inhibitors and nonselective nonsteroidal antiinflammatory drugs: An instrumental variable analysis

Objective

To simultaneously assess the short‐term reduction in risk of gastrointestinal (GI) complications and increase in risk of acute myocardial infarction (MI) by celecoxib compared with rofecoxib and several nonselective nonsteroidal antiinflammatory drugs (NSAIDs) using instrumental variable analysis.

Methods

A population of 49,711 Medicare beneficiaries ages 65 years and older who initiated nonselective NSAID or selective cyclooxygenase 2 inhibitor therapy between January 1, 1999, and December 31, 2002, was identified. The increase in risk of GI complications and MI within 180 days after initiation of NSAID (rofecoxib, diclofenac, ibuprofen, and naproxen compared with celecoxib) therapy was assessed using instrumental variable analysis.

Results

Compared with nonselective NSAIDs, celecoxib reduced the risk of GI complications by 1.4 per 100 users but increased the risk of MI by 0.3 per 100 users. Rofecoxib decreased GI complications by 1.1 per 100 users and increased the risk of MI by 0.3 per 100 users. Using celecoxib as the reference exposure showed an increase in the MI risk for rofecoxib (risk difference [RD] 1.40, 95% confidence interval [95% CI] −0.20, 3.01) and diclofenac (RD 6.07, 95% CI −0.02, 12.15). The RD for naproxen as well as its upper 95% CI was the lowest of all NSAIDs (RD −0.30, 95% CI −2.74, 2.14) and there was no significant difference in GI complication rates among all NSAIDs.

Conclusion

In this instrumental variable analysis, diclofenac and rofecoxib had the least favorable benefit–risk balance among NSAIDs in older adults.

     

Subgroup analyses to determine cardiovascular risk associated with nonsteroidal antiinflammatory drugs and coxibs in specific patient groups

OBJECTIVE: To explore the extent to which clinical characteristics influence the association between cyclooxygenase 2 inhibitors (coxibs) and/or nonselective nonsteroidal antiinflammatory drugs (NSAIDs) and increased cardiovascular disease (CVD) risk in specific patient subgroups. There is substantial concern regarding the potential cardiovascular adverse effects of selective coxibs and nonselective NSAIDs, but many patients with arthritis experience important clinical benefits from these agents. METHODS: The study population consisted of Medicare beneficiaries also eligible for a drug benefits program for older adults during the years 1999-2004. We calculated the relative risk (RR) for CVD events (myocardial infarction [MI], stroke, congestive heart failure, and cardiovascular death) among users of coxibs or nonselective NSAIDs in the prior 6 months compared with nonusers. We assessed biologic interaction between these medication exposures and important patient characteristics. RESULTS: In the primary cohort, we identified 76,082 new users of coxibs, 53,014 new users of nonselective NSAIDs, and 46,558 nonusers. Compared with nonusers, the adjusted RR of CVD events for new users of each agent increased for rofecoxib (RR 1.22, 95% confidence interval [95% CI] 1.14, 1.30) and decreased for naproxen (RR 0.79, 95% CI 0.67, 0.93). Several patient characteristics were found to increase the risk of CVD events among users of some agents in both the primary and secondary cohorts, including age >/=80 years, hypertension, prior MI, prior CVD, rheumatoid arthritis, chronic renal disease, and chronic obstructive pulmonary disease. Rofecoxib and ibuprofen appeared to confer an increased risk in multiple patient subgroups. CONCLUSION: Many nonselective NSAIDs and coxibs are not associated with an increased risk of CVD events. However, several patient characteristics identify important subgroups that may be at an increased risk when using specific agents.     

Systematic review and meta-analysis: anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis

Objective

Control of rheumatoid arthritis (RA) may reduce the risk of cardiovascular events. We sought to systematically assess the association between anti–tumor necrosis factor α (anti‐TNFα) therapy in RA and cardiovascular event rates.

Methods

Observational cohorts and randomized controlled trials (RCTs) reporting on cardiovascular events (all events, myocardial infarction [MI], congestive heart failure, and cerebrovascular accident [CVA]) in RA patients treated with anti‐TNFα therapy compared to traditional disease‐modifying antirheumatic drugs were identified from a search of PubMed (1950 to November 2009), EMBase (1980 to November 2009), and conference abstracts. Relative risks (RRs) or hazard ratios and 95% confidence intervals (95% CIs) were extracted. If the incidence was reported, additional data were extracted to calculate an incidence density ratio and its variance.

Results

The systematic review and meta‐analysis include 16 and 11 publications, respectively. In cohort studies, anti‐TNFα therapy was associated with a reduced risk for all cardiovascular events (pooled adjusted RR 0.46; 95% CI 0.28, 0.77), MI (pooled adjusted RR 0.81; 95% CI 0.68, 0.96), and CVA (pooled adjusted RR 0.69; 95% CI 0.53, 0.89). Meta‐analysis of RCTs also produced a point estimate indicating lower risk of cardiovascular events, but this was not statistically significant (pooled RR 0.85; 95% CI 0.28, 2.59).

Conclusion

Anti‐TNFα therapy is associated with a reduced risk of all cardiovascular events, MI, and CVA in observational cohorts. There was heterogeneity among cohort studies and possible publication bias. The point estimate of the effect from RCTs is underpowered with wide 95% CIs, and cardiovascular events were secondary outcomes, but RCTs also demonstrated a trend toward decreased risk.     

Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure

BACKGROUND: Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed and are associated with blood pressure (BP) elevation. The development of selective cyclooxygenase-2 inhibitors (coxibs) raises the issue of the magnitude of BP response compared with nonselective NSAIDs. We therefore performed a meta-analysis comparing the effects of coxibs with placebo, nonselective NSAIDs, and each other on BP elevation and hypertension. METHODS: Nineteen randomized controlled trials involving coxibs were published before May 2004, with a total of 45 451 participants in which BP data were available. The Cohen method statistically combined weighted mean difference (WMD). The Der Simonian and Laird method pooled results concerning the relative risk (RR) of developing hypertension and the RR of clinically important BP elevations. RESULTS: Among the trials analyzed, coxibs caused a WMD point estimate increase in systolic and diastolic BP compared with placebo (3.85/1.06 mm Hg) and nonselective NSAIDs (2.83/1.34 mm Hg). Cyclooxygenase-2 inhibitors were associated with a nonsignificantly higher RR of causing hypertension compared with placebo (RR, 1.61; 95% confidence interval [CI], 0.91-2.84; P = .10) and nonselective NSAIDs (RR, 1.25; 95% CI, 0.87-1.78; P = .23). Rofecoxib induced a WMD point estimate increase in systolic BP (2.83 mm Hg) and a nonsignificantly higher risk of developing clinically important systolic BP elevation (RR, 1.50; 95% CI, 1.00-2.26; P = .05) compared with celecoxib. CONCLUSIONS: Cyclooxygenase-2 inhibitors were associated with a point-estimate BP elevation compared with placebo and nonselective NSAIDs. There was a nonsignificantly higher incidence of developing hypertension compared with nonselective NSAIDs, as was observed with rofecoxib compared with celecoxib. These BP elevations may be clinically significant in relation to increased cardiovascular risk.     

胆囊切除与结直肠腺瘤相关性的Meta分析

目的有胆囊切除史的患者已被认为是我国结直肠癌早期筛查的高危人群,但国内外对胆囊切除与结直肠腺瘤(结直肠癌癌前病变)的相关性研究较少。采用Meta分析方法对国内外已发表的有关胆囊切除与结直肠腺瘤关系的研究进行综合评价。方法对符合纳入标准的13篇文献按研究方法不同分为队列研究组(6篇)和病例对照研究组(7篇),均使用Review manager 5.2软件进行Meta分析,计算前者的相对危险度(RR)和后者的比值比(OR),以及二者的95%可信区间(CI)。结果队列研究组和病例对照研究组分别纳入总样本量5940例和158 995例,Meta分析综合RR=1.32,95%CI:1.07~1.61;OR=1.17,95%CI:1.08~1.26。结论胆囊切除导致结直肠腺瘤发生的危险性增加。     

A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas

BACKGROUND & AIMS: In human and animal studies, nonsteroidal anti-inflammatory drugs have been associated with a reduced risk of colorectal neoplasia. Although the underlying mechanisms are unknown, inhibition of cyclooxygenase (COX), particularly COX-2, is thought to play a role. We conducted a randomized, placebo-controlled, double-blind trial to assess whether use of the selective COX-2 inhibitor rofecoxib would reduce the risk of colorectal adenomas. METHODS: We randomized 2587 subjects with a recent history of histologically confirmed adenomas to receive daily placebo or 25 mg rofecoxib. Randomization was stratified by baseline use of cardioprotective aspirin. Colonoscopic follow-up evaluation was planned for 1 and 3 years after randomization. The primary end point was all adenomas diagnosed during 3 years' treatment. In a modified intent-to-treat analysis, we computed the relative risk of any adenoma after randomization, using Mantel-Haenszel statistics stratified by low-dose aspirin use at baseline. RESULTS: Adenoma recurrence was less frequent for rofecoxib subjects than for those randomized to placebo (41% vs 55%; P < .0001; relative risk [RR], 0.76; 95% confidence interval [CI], 0.69-0.83). Rofecoxib also conferred a reduction in risk of advanced adenomas (P < .01). The chemopreventive effect was more pronounced in the first year (RR, 0.65; 95% CI, 0.57-0.73) than in the subsequent 2 years (RR, 0.81; 95% CI, 0.71-0.93). As reported previously, rofecoxib was associated with increased risks of significant upper gastrointestinal events and serious thrombotic cardiovascular events. CONCLUSIONS: In this randomized trial, rofecoxib significantly reduced the risk of colorectal adenomas, but also had serious toxicity.     

Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding

Objective

Traditional nonsteroidal antiinflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX‐1) and COX‐2 in vitro.

Methods

We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX‐1 and COX‐2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation.

Results

The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82–5.31) for traditional NSAIDs and 1.88 (95% CI 0.96–3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17–3.33]), rofecoxib (2.12 [95% CI 1.59–2.84]), aceclofenac (1.44 [95% CI 0.65–3.2]), and celecoxib (1.42 [95% CI 0.85–2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87–36.04]) and piroxicam (9.94 [95% CI 5.99–16.50). Estimated RRs were 5.63 (95% CI 3.83–8.28) for naproxen, 5.57 (95% CI 3.94–7.87) for ketoprofen, 5.40 (95% CI 4.16–7.00) for indomethacin, 4.15 (95% CI 2.59–6.64) for meloxicam, and 3.98 (95% CI 3.36–4.72) for diclofenac. The degree of inhibition of whole blood COX‐1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r² = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half‐life and with a slow‐release formulation were associated with a greater risk than NSAIDs with a short half‐life.

Conclusion

The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half‐life or slow‐release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation.

     

Risk of congestive heart failure with nonsteroidal antiinflammatory drugs and selective Cyclooxygenase 2 inhibitors: a class effect?

OBJECTIVE: Nonsteroidal antiinflammatory drugs (NSAIDs) as a class have been shown to increase the risk of congestive heart failure (CHF) compared with celecoxib. The magnitude of the risk for individual NSAIDs is not known. METHODS: Using administrative databases, we performed a nested case-control study in a population-based cohort of patients ages >or=66 years admitted for CHF between January 1998 and March 2003. Cases were patients readmitted for CHF after cohort entry (index date). Four controls were matched to each case on date of cohort entry and time between cohort entry and index date. Exposure was the current use of an NSAID or a coxib in the 7 days prior to CHF readmission. Using conditional logistic regression, we calculated the odds of readmission for CHF in patients exposed to naproxen, diclofenac, ibuprofen, indomethacin, or rofecoxib compared with celecoxib, after adjusting for possible confounding variables. RESULTS: We identified 8,512 cases and 34,048 controls. The baseline characteristics between the groups were similar in general. The odds of being readmitted for CHF were higher in patients currently exposed to indomethacin (odds ratio [OR] 2.04, 95% confidence interval [95% CI] 1.16-3.58) or rofecoxib (OR 1.58, 95% CI 1.19-2.11) compared with celecoxib. There was no difference between naproxen, diclofenac, and ibuprofen compared with celecoxib, although the numbers of exposed cases and controls were small. CONCLUSION: In elderly patients with known CHF, indomethacin and rofecoxib are associated with a greater risk of recurrent CHF compared with celecoxib. Alternatives should be considered for patients with CHF who require antiinflammatory drugs.     

Cardiac rehabilitation after myocardial infarction in the community.

OBJECTIVES: The aim of this study was to examine participation in cardiac rehabilitation after myocardial infarction (MI) by age and gender and the association of participation with survival. BACKGROUND: Lesser participation in cardiac rehabilitation has been reported for women and the elderly. METHODS: All incident MIs in Olmsted County were validated. Baseline characteristics and outcomes were ascertained from the medical record. Logistic regression examined the association between participation, age, and gender. Propensity scores were used to examine the association between participation and outcome. RESULTS: Among 1,821 persons with incident MI (58% men, 46% age >70 years), 55% participated in cardiac rehabilitation. Participants were more likely to be men, younger, and have fewer comorbidities (p < 0.01 for all comparisons). After adjustment, women were 55% less likely to participate than men (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.34 to 0.60), and persons 70 years or older were 77% less likely to participate than persons younger than 60 (OR 0.23, 95% CI 0.16 to 0.33). Participants had a lower risk of death and recurrent MI at three years (p < 0.001 and p = 0.049, respectively). The survival benefit associated with participation was stronger in more recent years (relative risk [RR] for 1998 vs. 1982 0.28, 95% CI 0.18 to 0.43; RR for 1990 vs. 1982 0.41, 95% CI 0.33 to 0.52). CONCLUSIONS: Approximately half of the patients participated in cardiac rehabilitation after MI. Participation did not increase over time. Women and elderly persons were less likely to participate, independently of other characteristics. Participation in rehabilitation was independently associated with decreased mortality and recurrent MI, and its protective effect was stronger in more recent years.     

Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations

BACKGROUND: The risks and benefits of coxibs, non-steroidal anti-inflammatory drugs (NSAIDs), and aspirin treatment are under intense debate. OBJECTIVE: To determine the risk of peptic ulcer upper gastrointestinal bleeding (UGIB) associated with the use of coxibs, traditional NSAIDs, aspirin or combinations of these drugs in clinical practice. METHODS: A hospital-based, case-control study in the general community of patients from the National Health System in Spain. The study included 2777 consecutive patients with endoscopy-proved major UGIB because of the peptic lesions and 5532 controls matched by age, hospital and month of admission. Adjusted relative risk (adj RR) of UGIB determined by conditional logistic regression analysis is provided. RESULTS: Use of non-aspirin-NSAIDs increased the risk of UGIB (adj RR 5.3; 95% confidence interval (CI) 4.5 to 6.2). Among non-aspirin-NSAIDs, aceclofenac (adj RR 3.1; 95% CI 2.3 to 4.2) had the lowest RR, whereas ketorolac (adj RR 14.4; 95% CI 5.2 to 39.9) had the highest. Rofecoxib treatment increased the risk of UGIB (adj RR 2.1; 95% CI 1.1 to 4.0), whereas celecoxib, paracetamol or concomitant use of a proton pump inhibitor with an NSAID presented no increased risk. Non-aspirin antiplatelet treatment (clopidogrel/ticlopidine) had a similar risk of UGIB (adj RR 2.8; 95% CI 1.9 to 4.2) to cardioprotective aspirin at a dose of 100 mg/day (adj RR 2.7; 95% CI 2.0 to 3.6) or anticoagulants (adj RR 2.8; 95% CI 2.1 to 3.7). An apparent interaction was found between low-dose aspirin and use of non-aspirin-NSAIDs, coxibs or thienopyridines, which increased further the risk of UGIB in a similar way. CONCLUSIONS: Coxib use presents a lower RR of UGIB than non-selective NSAIDs. However, when combined with low-dose aspirin, the differences between non-selective NSAIDs and coxibs tend to disappear. Treatment with either non-aspirin antiplatelet or cardioprotective aspirin has a similar risk of UGIB.     

Acute myocardial infarction complicated by heart block in the elderly: prevalence and outcomes

BACKGROUND: Although second- and third-degree heart block (HB) are common conduction disorders associated with acute myocardial infarction (MI), patient characteristics and HBs association with outcomes, particularly among the elderly, remain poorly defined. METHODS: We evaluated 106,780 Medicare beneficiaries aged 65 years and older treated for acute MI between January 1994 and February 1996 for development of HB. HB and non-HB patients were compared by univariate analysis, and the influence of HB on outcomes was evaluated by unadjusted and multiple logistic regression. RESULTS: HB was documented in 5048 (4.7%) patients; 1646 presented with HB and 3402 developed HB during hospitalization. HB was more common among patients with inferior infarctions than anterior infarctions (7.3% vs 3.0%, P =.001), particularly the cohort of patients with inferior MI treated with reperfusion therapy (8.3%). HB patients had higher rates of in-hospital mortality (29.6% vs. 17.5% vs. non-HB patients, P =.001). After adjustment for demographic and clinical factors, HB remained an independent predictor of in-hospital mortality (relative risk [RR] 1.41, 95% confidence interval [CI] 1. 34-1.48), but HB had no prognostic significance at 1 year among hospital survivors (RR 0.94, 95% CI 0.88-1.01). Mortality risks varied on the basis of MI location. Both anterior MI (RR 1.46, 95% CI 1.30-1.63) and inferior MI (RR 1.52, 95% CI 1.39-1.66) patients with HB had increased risks of in-hospital mortality. There was a trend toward increased mortality among patients with anterior MI (RR 1.15, 95% CI 0.99-1.32) at 1 year, whereas those with inferior MI were at lower risk (RR 0.83, 95% CI 0.75-0.98). CONCLUSIONS: HB is a common complication of acute MI in elderly patients, particularly among patients with inferior MIs who received reperfusion therapy. HB is independently associated with short-term but not long-term mortality.