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European Journal of Heart Failure 2008 10(11):1102-1107; doi:10.1016/j.ejheart.2008.07.013
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© 2008 European Society of Cardiology

Non-steroidal anti-inflammatory drugs and cardiac failure: meta-analyses of observational studies and randomised controlled trials

Paul A Scotta, Gabrielle H. Kingsleyb,c and David L Scottb,d,*

a Department of Cardiology, Southampton University Hospital Southampton, SO16 6YD, UK
b Department of Rheumatology, Kings College London School of Medicine London SE5 9RS, UK
c Department of Rheumatology, University Hospital Lewisham London SE13 6LH, UK
d Department of Rheumatology, Kings College Hospital London SE5 9RS, UK

* Corresponding author. Department of Rheumatology, Kings College London School of Medicine, 10 Cutcombe Road, London SE5 9RS, UK. Tel.: +44 207 848 5215; fax: +44 207 848 5202. E-mail address: david.l.scott{at}kcl.ac.uk (D.L. Scott)


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Role of funding source
 Conflict of interest
 References
 
Aims: To determine the risks of cardiac failure with non-steroidal anti-inflammatory drugs (NSAIDs) and the specific risks with Cox-2 specific NSAIDs (COXIBs).

Methods: We performed meta-analyses examining the risks of developing cardiac failure in observational studies and in randomised controlled trials (RCTs) involving patients with arthritis and non-rheumatic disorders. Electronic databases and published bibliographies were systematically searched (1997–2008).

Results: Five case—control studies (4657 patients, 45,862 controls) showed a non-significant association between NSAIDs and cardiac failure in a random effect model (odds ratio (OR) 1.36; 95% CI 0.99–1.85). Two cohort studies (27,418 patient years, 55,367 control years) showed a significant risk of cardiac failure with NSAIDs (relative risk 1.97; 95% CI 1.73–2.25). Six placebo-controlled trials (naproxen, rofecoxib and celecoxib) in non-rheumatic diseases (15,750 patients) showed more cardiac failure with NSAIDs (Peto OR 2.31; 95% CI 1.34, 4.00). Six RCTs comparing conventional NSAIDs and COXIBs in arthritis (62,653 patients) showed no difference in cardiac failure risk (Peto OR 1.14; 95% CI 0.85–1.53).

Conclusion: Observational studies and RCTs all show that NSAIDs increase the risk of cardiac failure. Overall risks are relatively small and are similar with conventional NSAIDs and COXIBs. Pre-existing cardiac failure increases risk.

Key Words: NSAIDs • OXIBs • Adverse events • Cardiac failure • Meta-analysis

Received February 18, 2008; Revised May 27, 2008; Accepted July 15, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Role of funding source
 Conflict of interest
 References
 
There are concerns about cardiovascular toxicities with non-steroidal anti-inflammatory drugs (NSAIDs), and particularly with Cox-2 specific drugs (COXIBs). Systematic reviews [1-3] have shown that some NSAIDs increase myocardial infarctions. Another potential cardiovascular toxicity is cardiac failure, attributed to their effects on blood pressure and fluid retention [4]. The extent to which NSAIDs increases the risk of cardiac failure, and the possibility of a specific increased risk with COXIBs, has not been examined in detail. We assessed these risks in meta-analyses examining the occurrence of cardiac failure with NSAIDs and COXIBs in observational studies and randomised controlled trials (RCTs) in arthritis and non-rheumatic diseases in which NSAIDs may have therapeutic roles.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Role of funding source
 Conflict of interest
 References
 
2.1. Search strategies
We searched MEDLINE, EMBASE, and CINAHL (January 1997-March 2008) to find primary references and reviews together with published bibliographies and the Cochrane library. We used the following terms: non-steroidal anti-inflammatory drugs, Cox-2 inhibitors, cyclooxygenase-2 inhibitors, rofecoxib, celecoxib, lumiracoxib, valdecoxib, etoricoxib, ibuprofen, diclofenac and naproxen; cardiac failure, congestive cardiac failure and heart failure; colonic adenoma, colonic polyps and colonic neoplasm; Alzheimer's disease, Alzheimer's and Alzheimer's dementia; prostate cancer, carcinoma of the prostate, and prostatic neoplasm; osteoarthritis (OA), rheumatoid arthritis (RA) and arthritis; case-control study, cohort study, observational study and randomised controlled trial. We considered only studies published in English (though no study was excluded because it was not written in English). We excluded studies with insufficient information to assess the presence or frequency of cardiac failure.

2.2. Types of study
We identified three categories of peer-reviewed papers:

  1. Case-control and cohort studies examining cardiac failure with NSAIDs.
  2. RCTs of NSAIDs in patients with colonic adenomas, Alzheimer's disease or a raised prostate specific antigen (PSA).
  3. RCTs comparing COXIBs with traditional NSAIDs or placebo in arthritis.

Our pre-existing knowledge of the literature [3] indicated that there are no trials directly comparing COXIBs with traditional NSAIDs in non-rheumatic disorders.

2.3. Data extraction
PAS and DLS independently assessed studies for eligibility and extracted data on year of publication, population source, design, size, settings, funding and study period. When there were differences between observers they reviewed the papers together to reach joint conclusions.

2.4. Statistics
Results were analysed using Review Manager 4.2.8 (Cochrane Collaboration, Oxford, United Kingdom). We evaluated the relative risk (RR) of cardiac failure in RCTs and cohort studies, and the odds ratios (OR) in case-control studies. The random effects model based on DerSimonian and Laird's method was used to estimate the pooled effect sizes in the observational studies [5]. This gives more equal weighting to studies of different precision in comparison to a simple inverse variance weighted approach, so accommodating between study heterogeneity [6]. The observational studies had differing selection criteria and patient risk profiles, and the true effect of NSAIDs on the occurrence of heart failure is therefore likely to vary between studies, making this model more appropriate. In the RCTs in arthritis and non-rheumatic diseases, where there were few events, we used the Peto odds ratio [7].

For all meta-analyses we performed Cochran's {chi}2 test to assess between study heterogeneity and quantified the I2 statistic [8-10]. We considered a P value less than 0.05 as significant.

2.5. Quality
The quality of RCTs was assessed with the Jadad scoring instrument [11] (Table 1).


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  		Table 1 Studies in meta-analyses

 

   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Role of funding source
 Conflict of interest
 References
 
3.1. Cardiac failure in observational studies
Nine of 159 potentially relevant studies met our inclusion criteria. These comprised five [12-16] case-control studies and two [17,18] cohort studies comparing patients taking NSAIDs with unexposed controls, and two cohort studies comparing patients taking conventional NSAIDs with COXIBs without unexposed controls [19,20] (Table 1). The three types of study were analysed separately.

The case-control studies enrolled 4657 patients taking NSAIDs and 45,862 controls. NSAID use and cardiac failure was related in a random effects model (OR 1.36; 95% CI 0.99, 1.85) (Fig. 1 A). There was evidence of significant statistical heterogeneity between studies ({chi}2 = 43.95; df = 4; P < 0.001; I2 = 90.9%). However this was predominantly due to one study of cardiac failure with a considerably different study population [14]. This study, by Bernatsky et al., which only considered patients with rheumatoid arthritis and excluded patients with pre-existing cardiac failure, showed no evidence of an association between NSAID use and cardiac failure. None of the other four studies, which all showed significant positive associations between NSAIDs and cardiac failure, excluded patients with pre-existing cardiac failure.


Figure 01
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  		Fig. 1 Analysis of five case-control (A) and two cohort studies (B) of cardiac failure in users and non-users of NSAIDs.

 
Comparison of conventional NSAIDs and individual COXIBs in the case-control studies (Table 2) showed significant associations with rofecoxib (OR 1.49; 95% CI 1.10, 2.02) but not celecoxib. There was no significant association with conventional NSAIDs (OR 1.35; 95% CI 0.94, 1.93). There was insufficient data to evaluate individual conventional NSAIDs or other COXIBs. There was significant statistical heterogeneity with conventional NSAIDs (Chi Squared = 38.27; df = 4; P < 0.001; I2 = 89.5%), again predominantly accounted the study by Bernatsky et al. with significantly different methodology [14], and celecoxib (Chi Squared = 6.74; df = 1; P = 0.009; I2 = 85.2%), but not rofecoxib (Chi Squared = 1.81; df = 1; P = 0.18; I2 = 44.7%).


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  		Table 2 Case-control and cohort studies of cardiac failure in users and non-users of NSAIDs

 
The two cohort studies comparing patients taking NSAIDs with unexposed controls [17,18] involved 27,418 years follow-up for patients receiving NSAIDs and 55,367 years follow-up for controls. They showed a significant risk (Fig. 1B) of developing cardiac failure whilst receiving NSAIDs (RR 1.97; 95% CI 1.73, 2.25). There was no evidence of statistical heterogeneity ({chi}2 = 0.95, df = 1, P = 0.33; I2 = 0%). The crude rate of cardiac failure was 16/1000 patient years with NSAIDs and 8/1000 patient years with placebo.

The two cohort studies comparing COXIBs with conventional NSAIDs without untreated controls [19,20] involved 18,591 years of follow-up with 1428 episodes of cardiac failure. Neither rofecoxib (RR 1.19; 95% CI 0.75, 1.90) nor celecoxib (RR 0.98; 95% CI 0.67, 1.46) use significantly increased the risk of cardiac failure compared to other NSAIDs. There was significant statistical heterogeneity between the studies ({chi}2 = 7.15, df = 1, P = 0.008, I2 = 86% with celecoxib and {chi}2 = 10.09, df = 1, P = 0.001, I2 = 90% with rofecoxib). However the studies had important differences in methodology with one study including only patients with a recent diagnosis of cardiac failure [20] and the other excluding such patients [19].

3.2. Cardiac failure in RCTs in non-rheumatic diseases
We identified 703 potential studies; 15 were relevant RCTs but only 6 reported cardiac failure [21-26]. These 6 RCTs enrolled 8542 patients taking NSAIDs and 7208 taking placebo; 40 cases and 13 controls developed cardiac failure. There was no statistical heterogeneity between studies ({chi}2 = 5.37; df = 5; P = 0.37, I2 = 6.9%). More patients receiving NSAIDs developed cardiac failure (Fig. 2) (OR 2.31; 95% CI 1.34, 4.00).


Figure 02
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  		Fig. 2 Analysis of cardiac failure in RCTs comparing NSAIDs with placebo in non-rheumatic diseases.

 
3.3. Cardiac failure in RCTs in arthritis
We identified 1777 potential studies; 243 were relevant RCTs but only 6 of these reported cardiac failure [27-33]. These 6 RCTs enrolled 62,653 patients randomised to receive COXIBs or conventional NSAID; only one involved placebo [29]; 177 patients developed cardiac failure. There was no evidence that COXIBs increased the risk of cardiac failure compared to conventional NSAIDs (OR 1.14; 95% CI 0.85, 1.53), though one study (Fig. 3) showed that etoricoxib had greater risks than diclofenac (OR 1.65; 95% CI 1.11, 2.44) [32]. There was statistical heterogeneity between trials ({chi}2 = 11.96; df = 5; P = 0.04; I2 = 58.2%) which in part may be explained by varying study methodology. The trials differed both in their active and control drugs and the patients they enrolled (some OA, some RA and some both). Furthermore the number of adverse events in 3 of the trials was small [27,29,30] — 6 episodes of cardiac failure in total, with two trials having only 1 each.


Figure 03
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  		Fig. 3 Analysis of cardiac failure in RCTs comparing conventional NSAIDs and COXIBs in arthritis.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Role of funding source
 Conflict of interest
 References
 
Our meta-analyses of case-control studies, cohort studies and RCTs show in all settings that conventional NSAIDs increase the risk of cardiac failure by 30-100%. The absolute risk is small; less than one patient developed cardiac failure attributable to NSAIDs per hundred patient years of treatment. The results for COXIBs are heterogeneous and the data is incomplete. Rofecoxib (in observational studies) and etoricoxib (in one large RCT) may have higher risks than conventional NSAIDs. There is inadequate data to assess individual conventional NSAIDs or other COXIBs.

Several confounding factors limit our findings. Firstly, in observational studies "over the counter" NSAIDs like ibuprofen create difficulties estimating exposure [34]. Secondly, adherence to medication varies across patient groups and clinical contexts [35]. Thirdly, COXIBs were targeted at elderly patients with higher gastro-intestinal risks; they have multiple comorbidities and are prone to cardiac failure. Finally few RCTs published detailed information about cardiac failure. One reason is that it was rarely a pre-specified end-point. In addition most RCTs in arthritis were short term and involved small numbers of patients; patients in these trials would rarely develop cardiac failure, even if its frequency was increased by treatment. It is likely the risks of cardiac failure are under-estimated in RCTs in arthritis.

The studies varied in the patients they enrolled, particularly the presence of pre-existing cardiac failure. Patients with previous cardiac failure were excluded from five RCTs in arthritis [27,29-32], two RCTs in non-arthritic patients [22,25] and one case-control study [14]. By contrast cohort studies entered patients who were elderly [17], taking diuretics [18], hypertensive [19] and had pre-existing cardiac failure [20]. Observational studies variably evaluated inpatient and outpatient occurrences of cardiac failure [19], or first [12] or any admission for cardiac failure [17]. Such variations explain the heterogeneity of results and indicate that estimates of the exact increase in risk attributable to NSAIDs must be treated with caution. In any event there is clear evidence that the risk of cardiac failure in patients receiving NSAIDs is increased in those with pre-existing cardiac failure.

The widespread use of NSAIDs [36], particularly in elderly patients likely to develop cardiac failure [37], makes NSAID-induced cardiac failure an important clinical concern. The risks are comparable to those with left ventricular hypertrophy, diabetes mellitus and valvular heart disease [38,39]. Several studies excluded from our review support the link between NSAIDs and cardiac failure. Firstly, a cohort study of 7277 elderly patients found that NSAIDs increased relapses but not new cardiac failure [40]. Secondly, an ecological study found that for each standard deviation of NSAID use the unadjusted relative risk of hospitalization for heart failure was 1.23 [41]. Thirdly, in 58,432 patients admitted to the hospital with myocardial infarctions there were more deaths in patients taking NSAIDs [42]; many of these deaths may have been attributable to cardiac failure.

These results suggest it is prudent to avoid NSAIDs in patients with or at high risk of developing cardiac failure. This recommendation is supported by a secondary analysis of one large RCT [31], which showed 16 of 7664 (0.2%) patients taking ibuprofen or naproxen with low cardiovascular risk developed cardiac failure compared to 15 of 1463 (1%) with high risk factors [43]. Interestingly in a small interview study of patients with cardiac failure, most were unaware of the risks of NSAIDs, though they would avoid them once educated about the adverse effects these drugs might have on their heart failure [44].

We conclude that all types of study show that NSAIDs increase the risk of cardiac failure, though the absolute risk is relatively small. Different drugs may have varying individual risks but overall conventional NSAIDs and COXIBs confer similar risks. We recommend NSAIDs to be used with caution by patients at high risk of developing cardiac failure, such as patients with diabetes mellitus, renal disease and receiving treatment with anti-hypertensives, as well as patients known to have cardiac failure.


   Role of funding source
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Role of funding source
Conflict of interest
 References
 
This research was supported by the ARC (Grants S0682 and P0572) and NHS R&D Support to University Hospital Lewisham and Kings College Hospital.


   Conflict of interest
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Role of funding source
 Conflict of interest
References
 
PAS and GHK — none.

DLS — support for international/local educational meetings and departmental research grants from companies making anti-inflammatory drugs.

No pharmaceutical company has made contributions to this paper.


   Acknowledgement
 
We thank Fowzia Ibrahim for helpful comments concerning the statistics.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Role of funding source
 Conflict of interest
 References
 

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