We found that the risk of new AMI hospitalization was increased with the current use of oral ns-NSAIDs overall. The risk was higher with parenteral ns-NSAIDs overall. The associations between AMI risk and individual oral ns-NSAID were mild to moderate, and not significantly increased for celecoxib with adjusted analysis. We did not find any specific NSAID with significantly protective effect to prevent new AMI hospitalization.
Parenteral NSAIDs and ketorolac
The new AMI hospitalization risk in users of parenteral ns-NSAIDs overall was significantly higher than that observed in oral ns-NSAIDs users. This higher risk of parenteral ns-NSAIDs remained for subgroups categorized by status of hypertension diagnosis and use of low-dose-aspirin, and was consistent across sensitivity analyses.
We found the use of ketorolac, in both oral and parenteral forms, was associated with the highest risk for new AMI hospitalization among all the NSAIDs. In 2006, 766,948 patients (about 3.3% of total population) received parenteral ketorolac, and more than one million DDDs (1 DDD = 30 mg) of injectable ketorolac were reimbursed by NHI (additional file 1 table S4). It was the most popular parenteral NSAID prescribed. Arora et al.  point out that although "physicians [might hold the] belief that parenteral administration of ketorolac are more effective than oral administration of ibuprofen", their review shows this belief to be false. Kimmel et al.  reported a reduced MI risk for parenteral ketorolac in comparison with use of parenteral opioids in a matched hospitalized cohort. Their study reported 18 MI events out of 10,219 courses of ketorolac treatment and 45 MI events out of 10,145 opioid treatment courses, by using propensity score adjusted analysis. Their inpatient setting was different from that of the present study, however. And it would be difficult to discern from the study whether this result was due to a lower risk of MI in the ketorolac group, or a higher risk in opioids group if compared to no use of either one. The subjects in our study received their NSAIDs in outpatient clinics, and we compared risks of AMI associated with use and non-use of various NSAIDs. These reasons may explain the different in study results.
Given the off-patent status of ketorolac and many generic products are currently available, thus it would be difficult to initiate well-controlled randomized trials with sufficient subject number to examine the safety of parenteral ketorolac in a outpatient clinic population. Consequently, large scale observational studies may be the only feasible information source. In our study, there were 364 new AMI patients exposed to parenteral ketorolac before their hospitalization. This may be the largest exposed AMI-patient series of this kind so far.
There were other safety concerns related to ketorolac , such as acute renal failure  and stroke . Due to reports of anaphylactic shock leaded to patient death with use of ketoroloac, the Department of Health of Taiwan government has ruled that a new warning must be added to the package insert of all ketorolac-containing products from 2008 onwards. Because of these safety concern, and because other NSAIDs are available, in Taiwan parenteral ketorolac is now used only with patients for whom oral intake is contraindicated, and should be used for no more than five days [Department of Health, regulatory document (in Chinese)] . Nevertheless, AMI risk related to the use of ketorolac in a general population has not been mentioned until now.
Whit  conducted a meta-analysis of 39 RCTs of celecoxib which were compared to a placebo or other ns-NSAIDs for cardiovascular risk. They found no significant difference in non-fatal AMI risk for celecoxib compared to other ns-NSAIDs. Our study reports similar findings. We found that the strength of adjusted association between current use of celecoxib and the risk of new AMI hospitalization was a moderate aOR of 1.36. It was comparable to the aORs with other oral ns-NSAIDs in the present study, and also within the range of non-fatal AMI relative risk of 1.24 to 1.56 for celecoxib compared to placebo in White's analysis. However, the total number of patients in the celecoxib group with MI was limited to 79 for all the 39 trials included in the meta-analysis . This limitation may have affected the results. In our study, by using the 210 identified celecoxib users with new AMI hospitalization, the crude OR was 1.47 and statistically significant, but this reduced to a non-significant 1.36 with adjusted analysis. Similar significant crude and non-significant adjusted associations were seen in the other large scale population based observational studies [24, 32, 36–38, 59], as well as non-significant results [19, 22, 26, 30, 35, 38, 39]. On the other hand, significantly increased AMI risk with current use of celecoxib were also observed in studies from the United Kingdom , the Netherlands , and in patients with previous MI from Canada . A further study reported significantly reduced AMI risk . The meta-analysis of 13 observational studies by McGettigan reported neutral cardiovascular risk with celecoxib . Significantly increased risk for composite cardiovascular events with celecoxib compared to a placebo has been reported in the "Adenoma Prevention with Celecoxib" trial, which found 18 patients with non-fatal MI incidence in the celecoxib group . The meta-analysis of 121 RCTs by Kearney reported a significantly increased summary risk of MI for five COX-2 selective inhibitors as a group compared to the placebo (rate ratio = 1.86, p < 0.01). The analysis including 41 trials for celecoxib, and no significant heterogeneity (p = 0.9) between the effects of individual drugs studied was found . The pooled analysis of individual subjects from six RCTs by Solomon found increased risk for composite cardiovascular risk with celecoxib . Chen looked at five celecoxib versus placebo trials for MI events, and found no significant association. Though in a summary of another nine trials, they report that the risk was higher for celecoxib compared to other NSAIDs . The controversy surrounding the relationship between use of celecoxib and cardiovascular risk seems to be based on evidence cumulated to date. The result of the large scale trial, "Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen" (PRECISION, ClinicalTrials.gov Identifier: NCT00346216), expected in 2013, may shed further light on this issue.
Several previous studies reported moderately increased AMI risk with statistical significant for current (< 30 days) or recent (< 3 months) use of ns-NSAIDs or NSAIDs overall [20, 23, 31–33, 36–38, 43, 44, 47]. Some other study results did not show statistical significant [22, 24, 25, 30, 34, 35, 40, 42, 43, 46]. Aside from two case-control studies based on telephone interviews with patients concerning their use of NSAIDs [27, 29], no other studies have reported significantly protective effects against AMI with ns-NSAIDs use in general. Though the difference in patient characteristics, clinical settings, study design, types and use of NSAIDs studied might have impact on the association between ns-NSAIDs use and AMI risk, current evidence collectively shows a tendency towards increased AMI risk for current or recent ns-NSAIDs users by studies using either cohort or case-control design. By using a case-crossover design in present study we found a 42% relative increase of AMI risk, which was consistent with the range of most adjusted relative associations, from 5% reduction to 77% increase of risk in previous studies. The four studies reported different results were as follows: two found a significant 39% and 47% relative reduction of risk based on telephone interviews ; one reported a non-significant 14% relative decrease of risk ; and one reported a significant 161% relative increase of risk by using a hospital control group .
Among the individual ns-NSAIDs, for current us of naproxen: three previous studies reported significant reduction of AMI risk [19, 22, 41]; two studies reported significantly increased AMI risk [37, 38]; and a number of studies showed no statistically significant associations [19, 20, 24–26, 31, 34–36, 39–41, 43, 46, 47]. Salpeter conducted a meta-analysis of 13 RCTs of ns-NSAIDs, 8 of which were for naproxen, and found no significant effect on cardiovascular events or death with a pooled OR (95%CI) of 1.3 (0.8, 2.1) . In the present study, the aOR (95%CI) of naproxen was 1.26 (0.88, 1.81) - a similar level of association as the meta-analysis result. The effect of naproxen on the risk of AMI could be considered as neutral-to-marginal increase.
Except for naproxen, no significant reduction of AMI risk has been reported for current or recent use of other individual ns-NSAID in previous studies. This was also the case in our study. We did not observe a significant protective effect of any individual NSAID in preventing AMI hospitalization in any subgroup of patients. Nevertheless, significantly increased AMI risk with use of diclofenac has been repeatedly reported in previous studies [18, 20, 28, 31, 34, 37, 41, 43, 47] and most of the non-significant results showed a trend of elevated AMI risk with diclofenac [19, 22, 62]. A meta-analysis of 10 observational studies for diclofenac on cardiovascular risk conducted by McGettigan, showed an increased pooled summary relative risk of 1.40 (1.19, 1.65) . The aOR (95%CI) of diclofenac in our study was a significant 1.29 (1.13, 1.47). Though the strength of association was not as strong as the meta-analysis result, it was in the same direct and with a similar level of association. Diclofenac could therefore be said to slightly increase the risk of AMI. Diclofenac was the most widely prescribed NSAIDs in Taiwan. Of more than 7 million patients, account for one third of total population had received at least one prescription in 2006 (additional file 1 table S4). Our results suggest that use of diclofenac should be managed with caution from public health point of view.
Consistent with four previous studies which found a significantly increased AMI risk with current use of ibuprofen [18, 25, 37, 47], we found a significant aOR of 1.45 for ibuprofen in the present study. The level of association was within the range of 9% reduction to 56% elevation reported in previous studies [18–20, 22, 25, 26, 31, 34, 37, 38, 42, 43, 47, 62]. Ibuprofen is frequently prescribed in Taiwan and other countries [63–65]. Attention should be paid to the relative safety and benefit of such extensive use.
Flurbiprofen was another oral ns-NSAID associated with significantly elevated AMI risk in the present study. Few studies had previously evaluated this drug specifically. One study reported a non-significant 2.26 times increase of first-time AMI risk with flurbiprofen in a population based case-control study, but with only 22 users of this drug .
One more oral ns-NSAID significantly associated with AMI risk in the present study was sulindac, with aOR (95%CI) of 1.44 (1.02, 2.03). In the case-control study by Mangoni, users of sulindac and oxicams were pooled together and no association with AMI was found . However, the effects of sulindac, piroxicam, and meloxicam in the present study were not very close. The risks of AMI associated with piroxicam or meloxicam in the present study were not significant. If all three drugs had been considered as one group, the results would have been non-significant. Previous studies also reported non-significant associations for piroxicam, and meloxicam [20, 31, 35, 40, 43, 46]. More information is required to elucidate the cardiovascular risk of above four drugs.
Interactions between use of NSAIDs and use of low dose aspirin or hypertension diagnosis
We did not find significant interaction effects between the use of NSAIDs and low-dose aspirin on AMI risk. Both significant and non-significant interaction results had been reported in previous studies [5, 27, 31, 48]. Limited number of patients used low-dose aspirin, and the possible over-the-counter use of low-dose aspirin could lead to statistical imprecision and reduce our ability to test for the interactions in the present study. More evidence is required in order to evaluate the effect of NSAIDs on cardiovascular risk in patients taking low-dose aspirin regularly.
The interaction between NSAIDs use and hypertension in patients was also a concern . A fairly high AMI risk with oral ketorolac was observed in patients with hypertension diagnosis, the aOR (95%CI) was 7.64 (1.74, 33.47), and the test for interaction of NSAID by hypertension was significant (p = 0.03). The AMI risk with oral ns-NSAIDs overall was also higher in patients with hypertension than those without hypertension in the present study. Though not all the results were statistically significant, the effects on risk of AMI tended to be higher in hypertensive patients than those without hypertension for most of the individual ns-NSAIDs in the present study. Consider hypertension a strong indicator of cardiovascular risk, patients with higher cardiovascular risk may be more susceptible to the AMI risk with use of ns-NSAIDs. This trend consistent with previous case-control study by Brophy  and the pooled subjects analysis of six RCTs by Solomon . It seems that the higher cardiovascular risk effect of NSAIDs for patients with higher background cardiovascular risk may not be limited to clelcoxib. Caution should be taken when prescribing NSAIDs to patients with higher background cardiovascular risk.
Study population and study design
The database used in this study covered the entire population of Taiwan. This not only provided large patient pool but also enabled follow up of each patient, thus minimizing the problem of case ascertainment. Owing to the large population pool, subjects recruited within a year were sufficient for most of the drugs studied, and more individual drugs could be analysed in one study. By limiting the recruitment period to one year, we were able to limit the potential influence of environmental changes, such as introduction of new drugs, change in medical practice, and epidemic trends of AMI in the community. The NHI reimburses a comprehensive list of prescription drugs, thus reducing the possibility and proportion of patients taking over-the-counter NSAIDs.
An important issue for most non-randomized studies using cohort or nested case-control design to analyse AMI risk with use of NSAIDs is the challenge of selection of appropriate comparison subjects. The unmeasured risk factors of outcomes may differ between subjects in the comparison groups, leading to a confounded result. The case-crossover design of the present study utilized a within-subject comparison, removing the potentially confounding by between-subjects difference , has also been applied to study the risk of NSAIDs in other studies [17, 18, 67]. Some risk factors, like body weight, smoking status, alcohol consumption, family history of cardiac vascular disease, were not captured in the database. These factors do not change substantially in the short term for a single patient, however, and thus a within-subject comparison balances their impact on the outcome. Though the case-crossover design is an efficient design, it may be sensitive to the time widow selected for the analysis. The sensitivity analyses of the present study revealed robust results for the main findings. The 30-day before new AMI hospitalization period selected in this study was similar to that used in previous cohort or case-control studies for current or recent use of NSAIDs [17, 18, 21, 22, 30–32, 46]. Though the outcome of AMI events used in this study was based on the claimed diagnosis, medical charts were regularly audited by clinical experts when claims were submitted as part of routine NHI reimbursement process. Hospitalization was used to increase the specificity of outcome measurement. This outcome definition might lead to the inclusion of sever subjects only and underestimate the effect. By using the prescription records of a claim database, we were unable to measure the level of compliance of patients taking the medication prescribed, which could lead to non-differential misclassification and may bias association toward null. This should not be a concern for parenteral use of NSAIDs, however, as patients received their injections in clinics under prescribing doctor's direct supervision. As a result, the difference between effects of oral and parenteral NSAIDs seen in the present study may be exaggerated.