Methods

This was a prospective, multicenter, hospital-based, case-control study with the aim of quantifying the risk for each type of ACS associated with traditional NSAIDs as a group and with diclofenac, ibuprofen, and naproxen individually, as well as ascertaining a potential dose and duration response in risk. Investigators from a set of Spanish hospitals integrated in the Red de Investigación Cardiovascular (RECAVA) del Instituto de Salud Carlos III research network or the Working Group on Ischemic Heart Disease of the Spanish Society of Cardiology were requested to enroll a minimum of 100 consecutive patients with ACS and corresponding controls during the recruitment period. Patients were defined as individuals admitted to 1 of the participant centers for clinical events diagnosed as ACS at discharge. Inclusion criteria were a definite diagnosis of ACS, age 40 to 85 years, and capability and willingness to personally answer the questionnaire. Controls were recruited from individuals visiting the patients (relatives or not) of similar age (±5 years) who fulfilled the same eligibility criteria as patients. Patients were not enrolled if (1) reliable information could not be obtained because of their clinical conditions or social circumstances, (2) they refused to participate, or (3) they had diagnoses of malignant neoplasms in the year before the interview.

ACS were defined as clinical events characterized by episodes of chest pain or other symptoms consistent with myocardial ischemia that also met the following criteria: (1) required emergent hospitalization (<24 hours after symptom onset); (2) received 1 of the following definitive diagnoses: ACS, unstable angina, or acute myocardial infarction; (3) presented with ≥1 of the following signs of myocardial ischemia: increase and decrease of any myocardial necrosis marker or dynamic changes in electrocardiographic repolarization; and (4) was not triggered by extreme pathophysiologic conditions, such as tachycardia >120 beats/min, severe hypotension or hypertension (systolic blood pressure <80 or >200 mm Hg), or severe anemia (hemoglobin <9 g/dl). ACS were classified as unstable angina when no elevation of myocardial necrosis markers occurred and as myocardial infarction when there were elevations of myocardial necrosis markers within the first 24 hours of admission. These were subsequently classified into ST-segment elevation myocardial infarction, when presenting electrocardiography showed persistent (lasting ≥30 minutes and not resolved after nitroglycerin administration) ST-segment elevation ≥0.1 mV in ≥2 contiguous leads, or left bundle branch block, and non-ST-segment elevation myocardial infarction when presenting electrocardiography did not show ST-segment elevation or left bundle branch block.

After obtaining written informed consent, patients were interviewed by a trained staff member (physician, nurse, or medical student) unaware of the study’s main hypothesis using a structured questionnaire that included information on sociodemographic features, co-morbidities, symptoms and signs that led to hospitalization, information related to the ACS episode, and drugs of interest consumed in the past year. Co-morbidity reported by interviewees had to be confirmed by medical staff members. These included the traditional risk factors, previous cardiovascular disease (ischemic heart disease [IHD] angina, myocardial infarction, or percutaneous or surgical coronary revascularization), heart failure, peripheral arterial disease or intermittent claudication, and cerebrovascular disease (stroke or transient ischemic attack), and osteoarticular disease (osteoarthritis, rheumatoid arthritis, or other inflammatory arthritis).

Patients and their respective controls were interviewed by the same individual to avoid differential information bias. A patient was considered a current user when intake occurred <7 days before index date (date of ACS episode onset for patients and date of interview for controls). The date of onset was defined as the day on which the first symptom suggestive of ACS occurred (patients). Past users were individuals who had their most recent use 8 to 365 days before the index date. Nonusers were individuals who did not take the drugs during the year before the index date. Current users were subdivided into single and multiple users. Single users were those who used only 1 specific NSAID in the month before the index date, and multiple users were those who used either 2 NSAIDs concomitantly or ≥2 NSAIDs at different times during the month before the index date. We categorized current single users into low- to medium-dose or high-dose users. Specific cut-off values for high NSAID dose were as follows: aceclofenac 100 mg, celecoxib 200 mg, diclofenac 100 mg, ibuprofen 1,200 mg, indomethacin 75 mg, ketoprofen 150 mg, ketorolac 10 mg, meloxicam 7.5 mg, naproxen 750 mg, and piroxicam 10 mg. Doses less than or equal to the cut-off values were grouped under low to medium doses, and doses greater than the cut-off value were grouped under high doses. We divided current single users into 2 categories according to the duration of the treatment. Treatments <1 month were classified as of short-term duration, and treatments >30 days were classified as of mid- to long-term duration. To help patients and controls recall the name of the drugs, interviews were always performed with the support of a booklet that included pictures of all anti-inflammatory and cardiovascular drugs available on the Spanish market at that time.

The sample size was calculated according to a previous study performed in Spain, which showed that 9% of controls were using NSAIDs the week previous to an interview. Similarly, the percentages of use for ibuprofen, diclofenac, and naproxen were estimated at 3%, 2.5%, and 1%, respectively. The percentage of use of any of the 3 main NSAIDs was estimated in 2% of the control population. For an α value of 0.05 and a β value of 0.80, and assuming that NSAIDs could increase the risk for ACS by a factor of 1.5, sample sizes of 3,000 patients and 3,000 controls were estimated to be necessary for the study. The odds ratios (ORs) and 95% confidence intervals (CIs) of all types of ACS as well as for each specific ACS type associated with using NSAIDs and other factors were estimated using conditional logistic regression (Stata/IC version 10.0; StataCorp LP, College Station, Texas). All estimates were adjusted by gender, traditional risk factors, body mass index, previous IHD, and the use of statins, antiplatelet drugs, and antihypertensive drugs. The effects of daily dose and duration were investigated in current single users. Unconditional logistic regression was performed in stratified analyses (previous IHD) or subtype ACS analyses because of reduced power of the conditional model and no virtual changes in the estimates compared to the conditional model. In addition to the variables used in the conditional regression models, age was entered in the unconditional regression models.

Results

From February to November 2007, 5,908 study subjects were interviewed at 32 Spanish hospitals (see online Appendix ). Patients and controls were well matched for age (mean age 65.2 ± 12.4 years in patients, 64.4 ± 12.2 years in controls), but there was a significantly higher proportion of women in the control group (50% vs 26%, p <0.001). The proportion of risk factors was consistently higher in patients than in controls (current smoking, 30% vs 19%, p <0.0001; diabetes, 30% vs 13%, p <0.001; hypertension, 60% vs 42%, p <0.001; dyslipidemia, 50% vs 31%, p <0.001; and body mass index ≥30 kg/m ² , 25% vs 21%, p <0.001), as was the prevalence of previous cardiovascular disease (IHD, 36% vs 10%, p <0.001; myocardial infarction, 21% vs 5%, p <0.001; angina, 26% vs 6%, p <0.001; percutaneous coronary revascularization, 19% vs 4%, p <0.001; cerebrovascular disease, 6% vs 4.4%, p = 0.038; peripheral arterial disease, 10% vs 5.3%, p <0.001; heart failure, 6.2% vs 3.5%, p <0.001; and aortic aneurysm, 1.0% vs 0.4%, p = 0.011). Gout (5.3% vs 3.3%, p = 0.003) but not rheumatoid arthritis (2.3% vs 3.2%, p = 0.22) was also more prevalent in patients.

There was a significantly higher proportion of current NSAID use in women compared to men (21% vs 11%, p <0.001). After adjustment for gender, traditional risk factors, and previous cardiovascular history, the OR of overall ACS associated with current use of NSAIDs was 1.16 (95% CI 0.95 to 1.42). There was no increased risk for ACS associated with occasional NSAID use, consumption <30 days, or use of low to medium daily doses ( Table 1 ). We found the use of high doses of NSAIDs to be associated with a significant increase in the risk for ACS (OR 1.64, 95% CI 1.06 to 2.53). When individual NSAIDs were considered, differences in ACS risks between the most frequently used agents were found. No increased risk was found with ibuprofen (OR 0.88, 95% CI 0.68 to 1.14) and naproxen (OR 1.30, 95% CI 0.60 to 2.82), while estimates for diclofenac (OR 1.56, 95% CI 0.99 to 2.45) and aceclofenac (OR 3.50, 95% CI 1.45 to 8.47) were compatible with an increased risk. Celecoxib was the only coxib with some use in our population (10 exposed patients and 5 controls) and had an OR of 4.96 (95% CI 1.09 to 22.47).

When we analyzed the effect according to the type of ACS, we found that most of the observed ACS risk with NSAIDs was due to an increased risk for non-ST-segment elevation ACS, whereas no association was found with ST-segment elevation myocardial infarction ( Table 2 ). Additionally, patients free of IHD presented no increased risk for ACS when using NSAIDs, while a history of IHD greatly predisposed users of NSAIDs to increased ACS risk, again mostly concentrated in an increase in non-ST-segment elevation ACS ( Table 3 ).

Table 2

Odds ratios and 95% confidence intervals of different acute coronary syndromes according to recency, duration, and daily dose of nonsteroidal anti-inflammatory drug exposure compared to nonuse

	Controls (n = 2,954)	Unstable Angina			Non-ST-segment Elevation Myocardial Infarction			ST-Segment Elevation Myocardial Infarction
		Patients (n = 819)	Adjusted OR	95% CI	Patients (n = 1,006)	Adjusted OR	95% CI	Patients (n = 1,120)	Adjusted OR ⁎	95% CI
Recency
Nonuse	1,831	542	1	—	650	1	—	719	1	—
Current use	464	115	1.22	0.93–1.60	155	1.23	0.97–1.56	149	1.00	0.80–1.26
Duration
Nonuse	1,831	542	1	—	650	1	—	719	1	—
Use ≤30 days	65	8	0.66	0.29–1.52	24	1.32	0.77–2.27	23	1.02	0.60–1.75
Use >30 days	333	100	1.43	1.06–1.92	108	1.21	0.92–1.58	96	0.92	0.70–1.20
Daily dose
Nonuse	1,831	542	1	—	650	1	—	719	1	—
Low to medium dose	347	84	1.17	0.86–1.60	103	1.09	0.83–1.44	101	0.89	0.68–1.16
High dose	72	24	1.64	0.93–2.88	29	1.51	0.91–2.50	25	1.23	0.74–2.06

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Comparison of Usefulness of N-Terminal Pro-Brain Natriuretic Peptide as an Independent Predictor of Cardiac Function Among Admission Cardiac Serum Biomarkers in Patients With Anterior Wall Versus Nonanterior Wall ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
2. Incidence of Subclinical Atherosclerosis as a Marker of Cardiovascular Risk in Retired Professional Football Players
3. Characteristics and Predictors of Obstructive Sleep Apnea in Patients With Systemic Hypertension
4. As With Space Flight, a Magnesium Deficit May Be Responsible for Both Peripheral Vascular Dysfunction and Kidney Disease

Stay updated, free articles. Join our Telegram channel

Join