Objective: To assess the effects of non-steroid antirheumatic drugs (NSARDs) on the occurrence of major adverse cardiac events (MACEs) in cardiac patients.

Methods: This is a retrospective observational study. Statistical analysis was performed by self-con­trolled case-series design. All patients had cardiac diseases. Patients who did not use NSARDs were compared to patients who used these drugs. Laboratory and hemodynamic data were compared at baseline and at the end of the observation (occurrence of either a MACE or, 1 year after begin). MACEs were recorded and related to the use of NSARDs.

Results: MACEs were significantly related to the use of ibuprofen plus paracetamol. Diclofenac, lor­noxicam, mefenamin, naproxen, acemetacin, celecoxib and rofecoxib also reduced renal function and increased LDL-C but we did not find an increased risk of MACEs. However, the chance of detecting MACEs is reduced by the fact that these NSARDs were used less frequently than ibuprofen.

The use of NSARDs was associated with decreased renal function and increased blood pressure and LDL-C. NSARDs favored the occurrence of MACEs mainly by reducing renal function.

A confounding condition ought to be considered, because patients taking NSARDs have a reduced physical activity, which is a risk for the occurrence of cardiovascular complications.

Conclusion: Our results confirm previous reports that have shown that the use of NSARDs is associ­ated with an increased risk of MACEs. The regression model analysis shows that MACES are related to the use of ibuprofen plus paracetamol and that this adverse event is statistically related to a de­creased renal function.

Keywords: Non-steroid antirheumatic drugs, Adverse cardiovascular events, Renal function

BACKGROUND

Non-steroid antirheumatic drugs (NSARDs) are frequently used for the treatment of many conditions and many of these drugs can be bought over the counter. NSARDs differ in chemical structure, phar­macodynamics and pharmacokinetics. These agents block different isoenzymes of cyclooxygenase (COX).The inhibition of COX-1 brings about a decrease of prostaglandins at inflammatory sites. The inhibition of COX-2 is associated with alleviation of pain, partly due to reducing levels of prostaglan­dins in the central nervous system. COX-3 inhibitors interfere with hypothalamic endothelial cells and block COX synthesizing prostaglandins near sensory receptors of sub-diaphragmatic vagal afferents.

It is established that treatment with NSARDs is a potential risk for a decline in renal function and the occurrence of major cardiovascular adverse events (MACEs) [1-3].

The different propensity of NSARDs in inducing MACEs is likely to be explained by dissimilar effects on prostacyclin and thromboxane A₂ synthesis, endothelial function, nitric oxide production, blood pressure, volume retention and other renal effects [1]. Furthermore, dissimilar pharmacokinetics may contribute to the toxicity profile because the individual half-lives of NSARDs are likely to interfere with different cardiovascular complications.

Systematic reviews have highlighted apparent differences in cardiovascular risk between COX-1 and COX-2 inhibitors. Yet, data on the impact of COX-2 inhibitors on the occurrence of MACEs are con­flicting. Indeed, previous studies [6] claimed that the use of COX-2 inhibitors is associated with an increased risk of MACEs. In contrast, a recent meta-analysis [2] found no clear relation between COX-2 inhibitors and MACEs. Furthermore, it is unlikely that an increased cardiovascular risk is a class effect of COX-2 inhibitors, because COX-2 inhibitors may exert different effects on the COX system [1-5]. Indeed, the frequency of MACEs is increased by rofecoxib but is seems to be decreased by celecoxib [4]. A possible explanation for the contrasting effect of these two COX-2 inhibitors might be related to their different pharmacokinetics, the half-life of rofecoxib being long and that of celecoxib short.

Cardiac patients frequently use NSARDs, mostly because of rheumatic pathologies. On the basis of uncertain data on the propensity of NSARDs in inducing MACEs we analyzed the effect of the use of NSARDs in our cardiac patients.

STUDY DESIGN

This is a retrospective observational study. We analyzed data from January 1998 till January 2017.

Population and Definitions

'Traditional' cardiovascular risk factors were: age, sex, smoking status, blood pressure, glomerular filtration rate (GFR), glucose, low-density lipoprotein cholesterol (LDL-C), body weight and family hi­story for cardiovascular diseases. Patients who never smoked or stopped since >3 years were consi­dered non-smokers. Physical activity was assessed recording the daily walking steps. Rheumatic pa­thologies, pulmonary diseases, cancer, thyroid dysfunction, cerebral stroke, psychic disorders, liver pathologies, hemoglobin disorders and psoriasis may influence the occurrence of cardiovascular events and were recorded. Hepatic dysfunction was defined by >3 fold normal values for ASAT / ALAT.

MACEs were defined as all-cause events or re hospitalization or death for a cardiovascular related illness (myocardial infarction, congestive heart failure, cerebral stroke).

The patients were divided into two groups: a) control group (COGR), 254 patients (63%) who did not or less than twice per month used NSARDs, and b) observational group (OBGR), 152 patients (37%) who used NSARDs on a regular basis.

STATISTICAL ANALYSIS

Analysis was performed with Statgraphics Centurion software. All statistical tests were two-tailed, and P values of <0.05 were considered to indicate statistical significance. The statistical analysis was ba­sed on the self-controlled case-series design [8]. Baseline data were compared to those of the obser­vation period, i.e., the interval from before the use of NSARDs and either the occurrence of MACEs or after 1 year. The observation time was truncated in this manner to minimize time varying confounding, since the self-controlled case-series design does not control for time varying confounding. We in­cluded in our analysis patients who had at least one MACE during the observation period.

RESULTS

Demographics (Table 1)

Sex: 100 COGR patients (39%) were male and 154 (61%) female. 62 OBGR patients (41%) were male and 90 (59 %) female. The female/male ratio is similar in both groups. Age was similar in both groups (60 to 63 years).

Weight: in both groups males were significantly (p <00001) heavier than females. The male/female weight difference was similar in both groups.

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