By Dr. Geoffrey Modest
There was a recent large case-control study confirming several other studies showing a significant risk of heart failure with the use of NSAIDs (see doi.org/10.1136/bmj.i4857).
Details:
- Five large population health care databases from Europe, with 92,163 hospital admissions for heart failure, matched with 8,246,403 controls.
- Mean age 77, 45% men, patients who developed heart failure were more likely to have history of cardiovascular disease (acute MI in 3.3 vs 1%, atrial fibrillation in 5.0 vs 1.3%, valvular heart disease in 2.6 vs 0.9%, hyperlipidemia in 20.4 vs 14.1%, diabetes in 19.4 vs 8.8%; and be on more meds (ACE/ARB in 42.1 vs 24.6%, b-blockers in 24.4 vs 15.2%, diuretics in 53.2 vs 18.6%)
Results:
- Current use of any NSAID in the preceding 14 days (vs past use greater than 183 days in the past) was associated with a 19% increase of hospital admission for heart failure with OR 1.19 (1.17 to 1.22)
- In terms of specific NSAIDs, odds ratios of first admissions for heart failure:
- ketorolac: OR 1.94 (1.71 – 2.19)
- indomethacin: OR 1.52 (1.31 – 1.77)
- diclofenac: OR 1.21 (1.16 – 1.26)
- ibuprofen: OR 1.15 (1.08 – 1.21)
- naproxen: OR 1.19 (1.08 – 1.31)
- nabumetone: OR 1.07 (0.81 – 1.43), nonsignificant
- celecoxib: OR 0.95 (0.89 – 1.02), nonsignificant
- Almost all of these associations were more profound in those with prior history of heart failure admissions (most extreme was for ketorolac, which developed an OR of 5.09; though the association with naproxen and diclofenac became nonsignificant in those with prior history)
- There were pretty evident dose-response curves, with the higher doses of NSAIDs associated with more heart failure for many of the NSAIDs. This was measured using Daily Dose Equivalents (DDD), which is the “average maintenance dose”, not specifically defined for each NSAID, but they found the following, with medium dose being 0.9-1.2 DDD, high 1.3-1.9, and very high (>=2): [note: there were only 2 databases which provided this info, and the numbers of people in some of the categories was small]
- Diclofenac went from insignificant increase in heart failure at low to medium dose, then to OR 1.1 for high and 2.2 for very high
- Indomethacin increased with increasing dose (p<0.001) for the trend, with OR 1.7 for medium and high dose, jumping to 2.5 for very high, but too wide a confidence interval to make it significant
- Naproxen OR 1.3 for high and 1.4 for very high
- Not a clear trend (the very high DDD had OR 1.9, but very wide confidence intervals)
- Celecoxib: no trend
Commentary:
- This study basically confirms that NSAIDs are associated with heart failure, and that some are better than others (though I should add that those who developed heart failure were sicker and had more co-morbidities that would make heart failure more likely, even though there were attempts to mathematically control for that). Of note, this study and some others have found that celecoxib (as opposed to pretty much any of the other COX-2 inhibitors) seems to be better [and other studies have found that it does not seem to provoke MIs as does rofecoxib/Vioxx]
- Most of the above associations applied to men and women, though were stronger in men
- The dose response curve found with several of the meds (higher dose with more heart failure) serves to reinforce the likely causality of the association
- The likely mechanisms are related to inhibition of prostaglandin synthesis, which leads to increased peripheral resistance (and blood pressure, another important adverse effect), decreased renal perfusion/GFR (and renal dysfunction, yet another), and decreased sodium excretion/sodium retention
- As many of you know, I am very concerned about long-term use of NSAIDs and PPIs, in part because they are used so frequently (and are available OTC, which also creates the impression that they must be safe) and because of their litany of significant adverse events (for some of my previous blogs on NSAIDs, see links below). And, of course, the reason they are used so much is because they are really effective. Which makes our tasks harder: how to convince patients to use less toxic meds
- By downgrading NSAIDs, preferably to nonpharmacologic therapies such as PT or yoga; or through local injections, often given once or infrequently, which do spare systemic side effects in general
- And downgrading PPIs to H2-blockers or calcium antacids along with sometimes helpful dietary changes
See https://stg-blogs.bmj.com/bmjebmspotlight/2015/07/29/primary-care-corner-with-geoffrey-modest-md-nsaid-warning-by-fda/ for FDA warning about NSAIDs and increased risk of heart attack or stroke
See https://stg-blogs.bmj.com/bmjebmspotlight/2015/06/01/primary-care-corner-with-geoffrey-modest-md-h-pylori-and-nsaids-increased-gi-bleeding/ for blog on the role of H pylori in increasing the risk of GI bleeds in those on NSAIDs
See https://stg-blogs.bmj.com/bmjebmspotlight/2014/05/02/primary-care-corner-with-geoffrey-modest-md-nsaid-and-atrial-fibrillation/ for increased risk of afib with NSAIDs
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