# NSAIDs use, kidney outcomes and the effect of empagliflozin: an analysis from EMPEROR-Preserved

João Pedro Ferreira, Faiez Zannad, Francisco Vasques-Nóvoa, Pedro Marques, Gerasimos Filippatos, Stuart J Pocock, Javed Butler, Milton Packer, Stefan D Anker

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João Pedro Ferreira, Faiez Zannad, Francisco Vasques-Nóvoa, Pedro Marques, Gerasimos Filippatos, et al.. NSAIDs use, kidney outcomes and the effect of empagliflozin: an analysis from EMPEROR-Preserved. Journal of Cardiac Failure, 2025, 10.1016/j.cardfail.2025.03.019. hal-05042242

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**NSAIDs use, kidney outcomes and the effect of empagliflozin: an analysis from
EMPEROR-Preserved**

**Short title: NSAIDs use in HFpEF and empagliflozin effect**

João Pedro Ferreira<fnref n="1" />,<fnref n="2" />,<fnref n="3" />; Faiez Zannad<fnref n="3" />; Francisco Vasques-Nóvoa<fnref n="1" />,<fnref n="4" />; Pedro

Marques<fnref n="1" />,<fnref n="4" />; Gerasimos Filippatos<fnref n="5" />; Stuart J. Pocock<fnref n="6" />; Javed Butler<fnref n="7" />; Milton

Packer<fnref n="8" />,<fnref n="9" />; Stefan D. Anker<fnref n="10" />,<fnref n="11" />

Affiliations:

Contact to:

Prof. João Pedro Ferreira

Faculty of Medicine of the University of Porto, Portugal

Alameda Prof. Hernâni Monteiro, 4200-319 Porto

Phone: +351225513600

Mail: [jpferreira@med.up.pt](mailto:jpferreira@med.up.pt)

Twitter handle: @unicYNcardiovasc

<footnote n="1">¹ UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Portugal.</footnote>

<footnote n="2">² Heart Failure Clinic, Internal Medicine Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal.</footnote>

<footnote n="3">³ Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, and INSERM U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.</footnote>

<footnote n="4">⁴ Internal Medicine Department, Centro Hospitalar Universitário de São João, Porto, Portugal.</footnote>

<footnote n="5">⁵ National and Kapodistrian University of Athens School of Medicine, Athens, Greece.</footnote>

<footnote n="6">⁶ London School of Hygiene and Tropical Medicine, London, UK.</footnote>

<footnote n="7">⁷ Baylor Scott and White Research Institute, Dallas, TX, USA & University of Mississippi, Jackson, MS, USA.</footnote>

<footnote n="8">⁸ Baylor Heart and Vascular Institute, Dallas, TX, USA.</footnote>

<footnote n="9">⁹ Imperial College, London, UK.</footnote>

<footnote n="10">¹⁰ Department of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany.</footnote>

<footnote n="11">¹¹ Institute of Heart Diseases, Wrocław Medical University, Wrocław, Poland.</footnote>
**Introduction**

Empagliflozin improved heart failure (HF) outcomes in patients with heart failure and mildly reduced or preserved ejection fraction (HFmr/pEF) enrolled in the EMPEROR-Preserved trial (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction; NCT03057951).¹ Despite the pronounced reduction of HF events, empagliflozin failed to reduce the progression of kidney disease in HFmr/pEF, contrasting with the findings seen among patients with heart failure and reduced ejection fraction (HFrEF).²

Patients with HFmr/pEF are usually treated with multiple medications, including non-steroidal anti-inflammatory drugs (NSAIDs), which have been associated with adverse HF outcomes. ³⁻⁵ The influence of NSAID use on the kidney effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors have not been studied in HFmr/pEF.

We hypothesize that the use of NSAIDs was frequent in HFmr/pEF and associated with an increased risk of kidney events which might have influenced empagliflozin's effect on kidney outcomes in EMPEROR-Preserved.

**Methods**

**Study design and patient population**

The design and primary results of the EMPEROR-Preserved trial have been published previously.¹,² The protocol was approved by the Ethical Committee of each participating site and all patients gave written informed consent. The median follow-up was 26 months.

**Randomization**

A total of 5988 patients were randomized in a double-blind manner (1:1 ratio) to receive placebo or empagliflozin 10 mg/daily. NSAID use at randomization was reported by the investigators in the Case Report Form.

**Endpoints**

The primary endpoint was a composite of cardiovascular death and hospitalization for HF. For this analysis a kidney composite outcome of sustained ≥40% eGFR decline from baseline, dialysis, transplantation, or ESRD was considered an event of special interest, along with the outcomes of doubling in serum creatinine and an
eGFR drop of 50% or greater from baseline. In addition, HF hospitalization, cardiovascular mortality, a composite of myocardial infarction, stroke, or cardiovascular death (MACE) and all-cause mortality were analyzed.

## Statistical analysis

Baseline characteristics were compared between NSAIDs users and non-users at baseline. The association between NSAID use and clinical outcomes was studied by means of Cox models, both crude and adjusted for the prespecified variables of age, sex, region, diabetes status, eGFR and LVEF.¹ The effect of empagliflozin (vs placebo) was studied using a treatment-by-NSAID interaction term in the Cox model. P values and 95% confidence intervals presented in this report have not been adjusted for multiplicity. All analyses were performed using Stata®, version 18. All analyses were performed within the Vivli® (https://vivli.org/) platform: ID 00010411. The trial sponsor was not involved in this analysis.

## Results

### Baseline characteristics by NSAIDs use

At baseline 2735 (45.7%) patients were using NSAIDs. Compared to non-users, NSAID users were younger, more frequently men, more frequently from Latin and North America and less frequently from Europe, more likely to have type 2 diabetes (T2D), hypertension, and ischemic HF, and less likely to have been hospitalized for HF in the past and to have atrial fibrillation flutter (AFib). Table 1.

In EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure with Reduced Ejection Fraction; NCT03057977) only 1% of patients were using NSAIDs at baseline.

### Outcome associations by NSAID use

NSAID use was not associated with the primary outcome of cardiovascular death or HF hospitalization: HR 0.96, 95%CI 0.84-1.09, P =0.54. Using NSAIDs was associated with a higher risk of atherosclerotic MACE: crude HR 1.20, 95%CI 1.03-1.40, P =0.020; an association that lost statistical significance after adjustment. NSAID use was independently associated with a higher risk of kidney outcomes including the prespecified kidney composite outcome and doubling in serum
creatinine from baseline: adjusted HR 1.33, 95%CI 1.02-1.76, P =0.039 and adjusted HR 1.41, 95%CI 1.06-1.88, P =0.020, respectively. Table 2.

## Treatment effect according to NSAID use

The use of NSAIDs did not modify the benefit of empagliflozin to reduce the rates of the primary outcome of cardiovascular death or HF hospitalization: NSAID users HR 0.78, 95%CI 0.65-0.95 and NSAID non-users HR 0.80, 95%CI 0.67-0.95; interactionP =0.88.

Despite underpowered for interaction analyses, the direction and magnitude of the effect of empagliflozin on kidney events might have been influenced by the background use of NSAIDs, whereby empagliflozin allocation was directionally associated with a lower rate of the prespecified kidney outcome among NSAID non-users (HR 0.81, 95%CI 0.54-1.21) and a higher rate of the prespecified kidney outcome among NSAID users (HR 1.10, 95%CI 0.77-1.56); interactionP =0.27.

Figure 1.

## Discussion

This analysis showed that NSAID use was frequent among patients with HFmr/pEF. NSAID users were younger and more frequently men than NSAID non-users. Regional variation in NSAID prescription patterns was observed, with a more frequent use in Latin and North America. NSAID use was not associated with increased rates of HF hospitalization or cardiovascular death, but it was associated with worsening kidney function events including the prespecified kidney outcome of sustained ≥40% eGFR decline from baseline, dialysis, transplantation, or ESRD. Despite being similarly effective among NSAID users and non-users regarding HF outcomes, the direction and magnitude of the effect of empagliflozin on kidney outcomes might have been influenced by NSAID use; still, the small number of events within subgroups undermines the power of such analyses.

These hypothesis-generating findings are potentially important from a clinical perspective, because they provide further evidence for the avoidance of NSAID in HFmr/pEF and suggest that NSAID use may have contributed to an increased risk of kidney events, which might have contributed to the lack of kidney benefit of empagliflozin in this population. Therefore, NSAID use may potentially explain some
of the differences observed between HFrEF and HFmr/pEF regarding the effect of empagliflozin on the prespecified kidney outcome, whereby empagliflozin reduced kidney events in HFrEF but not in HFmr/pEF.

Compared with HFrEF, patients with HFpEF are older and have more comorbidities which may contribute to polypharmacy including the use of NSAIDs.³ Beyond this, HFrEF patients are more likely to be followed by HF specialists who may be more aware of the harmful effects of NSAIDs. Still, NSAIDs are often sold over-the-counter in convenience stores without expert advice.

NSAIDs inhibit cyclooxygenase (COX), thus decreasing the synthesis of thromboxanes and prostaglandins from arachidonic acid. It has been proposed that excessive cardiovascular and kidney risk with use of NSAIDs is due primarily to the suppression of prostacyclin synthesis, which may worsen endothelial function, reduce nitric oxide production, and promote vasoconstriction.⁶ In patients with advanced HF, the NSAID indomethacin decreased cardiac index, increased pulmonary capillary wedge pressure and systemic vascular resistance.⁷ Although the use of NSAIDs has been associated with poor HF outcomes,⁴,⁸ in the present study the association was stronger for kidney outcomes. To the best of our knowledge, this is the first study to suggest a potential attenuation of benefit in kidney outcomes with a concomitant use of NSAIDs and SGLT2 inhibitors in HF.

This study has some limitations. It is a post-hoc analysis of a randomized trial and some of these findings may be prone to chance. Additionally, a lack of power for subgroups analysis, may have affected the capacity to detect statistically significant interactions. NSAIDs use was classified at baseline as a yes/no variable, and we do not have further details. Lastly, we do not know whether these were daily NSAID or “as needed” intakes.

## Conclusions

NSAID use was frequent in EMPEROR-Preserved, and it was associated with an increased risk of adverse kidney outcomes. NSAID use might have influenced empagliflozin's effect on kidney outcomes, a finding that warrants further investigation.
References

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2. Packer M, Butler J, Zannad F, Pocock SJ, Filippatos G, Ferreira JP, Brueckmann M, Jamal W, Zeller C, Wanner C, et al. Empagliflozin and Major Renal Outcomes in Heart Failure. *N Engl J Med*. 2021. doi: 10.1056/NEJMc2112411

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5. Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory drugs: effects on kidney function. *J Clin Pharmacol*. 1991;31:588-598. doi: 10.1002/j.1552-4604.1991.tb03743.x

6. Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk. *Circulation*. 2005;112:759-770. doi: 10.1161/circulationaha.105.568451

7. Dzau VJ, Packer M, Lilly LS, Swartz SL, Hollenberg NK, Williams GH. Prostaglandins in severe congestive heart failure. Relation to activation of the renin-angiotensin system and hyponatremia. *N Engl J Med*. 1984;310:347-352. doi: 10.1056/nejm198402093100603

8. Hudson M, Richard H, Pilote L. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study. *Bmj*. 2005;330:1370. doi: 10.1136/bmj.330.7504.1370
<table><caption>Table 1. Baseline characteristics by NSAID use</caption><thead><tr><td>Characteristic</td><td>No</td><td>Yes</td><td>P-value</td></tr></thead><tbody><tr><td>N.</td><td>3253</td><td>2735</td><td>-</td></tr><tr><td>Age, years</td><td>72.8 (9.6)</td><td>71.0 (9.4)</td><td>&lt;0.001</td></tr><tr><td>Women</td><td>1546 (47.5%)</td><td>1130 (41.3%)</td><td>&lt;0.001</td></tr><tr><td>Race</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>White</td><td>2588 (79.6%)</td><td>1954 (71.4%)</td><td></td></tr><tr><td>Asian</td><td>423 (13.0%)</td><td>401 (14.7%)</td><td></td></tr><tr><td>Black</td><td>107 (3.3%)</td><td>151 (5.5%)</td><td></td></tr><tr><td>Indian</td><td>73 (2.2%)</td><td>121 (4.4%)</td><td></td></tr><tr><td>Other</td><td>62 (1.9%)</td><td>108 (3.9%)</td><td></td></tr><tr><td>Region</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>Asia</td><td>364 (11.2%)</td><td>322 (11.8%)</td><td></td></tr><tr><td>East Europe</td><td>1166 (35.8%)</td><td>720 (26.3%)</td><td></td></tr><tr><td>Latin America</td><td>636 (19.6%)</td><td>879 (32.1%)</td><td></td></tr><tr><td>North America</td><td>338 (10.4%)</td><td>381 (13.9%)</td><td></td></tr><tr><td>Other</td><td>201 (6.2%)</td><td>178 (6.5%)</td><td></td></tr><tr><td>West Europe</td><td>548 (16.8%)</td><td>255 (9.3%)</td><td></td></tr><tr><td>Smoking status</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>Currently smokes</td><td>207 (6.4%)</td><td>229 (8.4%)</td><td></td></tr><tr><td>Former smoker</td><td>1206 (37.1%)</td><td>1197 (43.8%)</td><td></td></tr><tr><td>Never smoked</td><td>1837 (56.5%)</td><td>1308 (47.8%)</td><td></td></tr><tr><td>Type 2 diabetes</td><td>1399 (43.0%)</td><td>1514 (55.4%)</td><td>&lt;0.001</td></tr><tr><td>Hypertension</td><td>2881 (88.6%)</td><td>2543 (93.0%)</td><td>&lt;0.001</td></tr><tr><td>Prior HFH</td><td>806 (24.8%)</td><td>563 (20.6%)</td><td>&lt;0.001</td></tr><tr><td>AFib/Flutter</td><td>2430 (74.7%)</td><td>705 (25.9%)</td><td>&lt;0.001</td></tr><tr><td>COPD</td><td>423 (13.0%)</td><td>372 (13.6%)</td><td>0.50</td></tr><tr><td>Ischemic HF</td><td>731 (22.5%)</td><td>1386 (50.7%)</td><td>&lt;0.001</td></tr><tr><td>SBP, mmHg</td><td>131.2 (15.5)</td><td>132.6 (15.8)</td><td>&lt;0.001</td></tr><tr><td>DBP, mmHg</td><td>76.3 (10.6)</td><td>75.0 (10.4)</td><td>&lt;0.001</td></tr><tr><td>Heart rate, bpm</td><td>71.9 (12.3)</td><td>68.6 (11.0)</td><td>&lt;0.001</td></tr><tr><td>BMI, Kg/m²</td><td>29.9 (6.0)</td><td>29.7 (5.8)</td><td>0.11</td></tr><tr><td>NYHA</td><td></td><td></td><td>0.011</td></tr><tr><td>I/II</td><td>2617 (80.4%)</td><td>2270 (83.0%)</td><td></td></tr><tr><td>III/IV</td><td>636 (19.6%)</td><td>465 (17.0%)</td><td></td></tr><tr><td>Peripheral edema</td><td>938 (28.8%)</td><td>809 (29.6%)</td><td>0.53</td></tr><tr><td>Rales</td><td>205 (6.3%)</td><td>248 (9.1%)</td><td>&lt;0.001</td></tr><tr><td>LVEF, %</td><td>55.0 (48.0, 60.0)</td><td>52.0 (45.0, 60.0)</td><td>&lt;0.001</td></tr><tr><td>Haemoglobin, g/dL</td><td>13.4 (1.6)</td><td>13.2 (1.6)</td><td>&lt;0.001</td></tr><tr><td>eGFR*, ml/min</td><td>58.7 (45.5, 74.0)</td><td>61.0 (45.5, 76.5)</td><td>0.013</td></tr><tr><td>eGFR &lt;60 ml/min</td><td>1674 (51.5%)</td><td>1310 (48.0%)</td><td>0.007</td></tr><tr><td>UCAR*, mg/g</td><td>20.3 (8.0, 68.1)</td><td>21.2 (7.1, 76.9)</td><td>0.22</td></tr><tr><td>NT-proBNP*, pg/mL</td><td>1199 (659, 2009)</td><td>727 (414, 1389)</td><td>&lt;0.001</td></tr><tr><td>KCCQ-OSS*, points</td><td>71.9 (54.7, 85.9)</td><td>72.9 (53.9, 87.0)</td><td>0.25</td></tr><tr><td>ACEi/ARB</td><td>2430 (74.7%)</td><td>2275 (83.2%)</td><td>&lt;0.001</td></tr><tr><td>ARNi</td><td>79 (2.4%)</td><td>55 (2.0%)</td><td>0.28</td></tr><tr><td>Loop diuretic</td><td>2344 (72.1%)</td><td>1710 (62.5%)</td><td>&lt;0.001</td></tr><tr><td>MRA</td><td>1298 (39.9%)</td><td>946 (34.6%)</td><td>&lt;0.001</td></tr></tbody></table>
<table><tr><td>Beta-blocker</td><td>2776 (85.3%)</td><td>2391 (87.4%)</td><td>0.019</td></tr></table>

Legend: NSAID, non-steroidal anti-inflammatory drug; HFH, heart failure hospitalization; COPD, chronic obstructive pulmonary disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio; KCCQ-OSS, Kansas City Cardiomyopathy Questionnaire-Overall Symptom Score; ACEi/ARB, angiotensin converting enzyme inhibitor/angiotensin receptor blocker; ARNi, angiotensin receptor neprilysin inhibitor; MRA, mineralocorticoid receptor antagonist; *Median (percentile<sub>25-75</sub>).
<table><caption>Table 2. Associations between the use of NSAIDs and study outcomes</caption><thead><tr><th>Outcome<br>n (%)</th><th>No NSAID<br>N =3253</th><th>NSAID<br>N =2735</th><th>Crude HR (95%CI)<br>P-value</th><th>Adj. HR (95%CI)<br>P-value</th></tr></thead><tbody><tr><td>CVD or HFH</td><td>510 (15.7)</td><td>416 (15.2)</td><td>0.96 (0.84-1.09)<br>P =0.54</td><td>0.89 (0.77-1.01)<br>P =0.078</td></tr><tr><td>HFH</td><td>349 (10.7)</td><td>262 (9.6)</td><td>0.88 (0.75-1.04)<br>P =0.13</td><td>0.83 (0.70-0.98)<br>P =0.027</td></tr><tr><td>ACH</td><td>1394 (42.9)</td><td>1217 (44.5)</td><td>1.04 (0.97-1.13)<br>P =0.27</td><td>1.06 (0.98-1.14)<br>P =0.18</td></tr><tr><td>MACE</td><td>324 (10.0)</td><td>326 (11.9)</td><td>1.20 (1.03-1.40)<br>P =0.020</td><td>1.12 (0.96-1.31)<br>P =0.16</td></tr><tr><td>CVD</td><td>234 (7.2)</td><td>229 (8.4)</td><td>1.15 (0.96-1.38)<br>P =0.13</td><td>1.08 (0.90-1.31)<br>P =0.41</td></tr><tr><td>ACM</td><td>450 (13.8)</td><td>399 (14.6)</td><td>1.04 (0.91-1.19)<br>P =0.56</td><td>0.98 (0.86-1.13)<br>P =0.85</td></tr><tr><td>Kidney EP</td><td>95 (2.9)</td><td>125 (4.6)</td><td>1.55 (1.19-2.03)<br>P =0.001</td><td>1.33 (1.02-1.76)<br>P =0.039</td></tr><tr><td>Doubl. creat.</td><td>84 (2.6)</td><td>118 (4.3)</td><td>1.64 (1.24-2.16)<br>P =0.001</td><td>1.41 (1.06-1.88)<br>P =0.020</td></tr><tr><td>eGFR 50% drop</td><td>76 (2.3)</td><td>89 (3.3)</td><td>1.36 (1.00-1.85)<br>P =0.049</td><td>1.19 (0.87-1.64)<br>P =0.27</td></tr></tbody></table>

Legend: NSAID, non-steroidal anti-inflammatory drug; CVD, cardiovascular death; HFH, heart failure hospitalization; ACH, all-cause hospitalization; MACE, major adverse cardiovascular events composite of myocardial infarction, stroke or cardiovascular death; ACM, all-cause mortality; Kidney EP, composite endpoint of sustained eGFR decrease of 40% or more from baseline, dialysis, transplantation, or end-stage renal disease; Doubl. creat., doubling in serum creatinine from baseline; eGFR 50% drop, eGFR drop of 50% or greater from baseline; Adj., model adjusted for the prespecified variables of age, sex, region, diabetes status, eGFR, and LVEF.
<figure><img src="image_2.png" /><figcaption>Figure 1. Composite kidney endpoint by treatment allocation and NSAID use</figcaption></figure>

Legend: NSAID, non-steroidal anti-inflammatory drug; Pbo, placebo; Empa, empagliflozin; HR, hazard ratio.

Caption: Cumulative incidence of the composite kidney endpoint of 40% or greater sustained eGFR decrease from baseline, dialysis, transplantation, or end-stage-renal disease. Log-rank test P-value =0.009. Despite underpowered for interaction analyses, the direction and magnitude of the effect of empagliflozin on kidney events seemed influenced by NSAID use: prespecified kidney composite outcome NSAID users HR 1.10, 95%CI 0.77-1.56 and NSAID non-users HR 0.81, 95%CI 0.54-1.21; interactionP =0.27.