Myocardial infarction (MI) is the most acute and severe presentation of ischemic heart disease. Approximately 620,000 people have a new coronary attack each year in the United States, and 15 % of those do not survive the event [1, 2]. Besides, survivors of MI have a higher chance of illness and death from cardiac or noncardiac causes compared with the general population [1‐3]. Patients with MI had a 79 % increased risk of incident infection compared with those without an MI history, and the most frequent infection was pneumonia [3]. Additionally, MI patients had a significantly higher rate of all-cause mortality during the course of pneumonia than that of patients without a history of MI [4]. Therefore, strategies for preventing the development of adverse cardiovascular events and incident pneumonia among patients with MI are crucial.

Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme of the cholesterol biosynthesis pathway [5], and are commonly used in the primary and secondary prevention of atherosclerotic cardiovascular diseases [6]. Previous researches have also demonstrated that statin pretreatment improves the clinical outcomes of MI [7, 8]. Recently, epidemiological studies have shown that statins have pleiotropic effects, resulting in a reduced risk of incident pneumonia in the general population as well as patients with diabetes [9‐12]. However, whether statin use is associated with a reduced risk of pneumonia in MI patients who are at high cardiovascular risk and susceptible to pneumonia remains unclear.

The aim of this study was to investigate the association between statin use and pneumonia hospitalization among patients with a history of MI. We conducted a nested case–control study by using data from the National Health Insurance Research Database (NHIRD) of Taiwan. Subgroup analysis was performed to identify the aforementioned association among patients with different characteristics and those who were unexposed to statin pretreatment.

Of the 24,975 patients with a history of MI, we identified 2686 case patients who were hospitalized for pneumonia and 10,726 control patients who were not hospitalized for pneumonia (Fig. 1). Compared with the control patients, the case patients had higher CHADS₂ scores (CHADS₂ scores ≥ 1: case 36.6 %; control 17.7 %), and higher rates of previous or coexisting DM, HTN, CHF, stroke, asthma, COPD, CKD, CLD and dementia. In addition, the case patients were more likely to use antineoplastic drugs, proton pump inhibitors (PPIs), steroids, angiotensin converting enzyme inhibitor and angiotensin receptor blockade (ACEI/ARBs), immunosuppressants, immunostimulants and nitrates compared with the control patients (Table 1).

The percentage of any use of statins among the case and control patients was 68.9 and 71.6 %, respectively. Statin use was associated with a 15 % reduced risk of incident pneumonia requiring hospitalization after we controlled for all risk factors (aOR 0.85, 95 % CI 0.77–0.95, P = 0.004) (Table 2). Additionally, the timing of statin use for the case patients significantly differed from that for the control patients (Table 2). The odds of current users for the case patients were lower than that for the control patients (aOR 0.75, 95 % CI 0.67–0.85, P < 0.001). We also observed that the DDD₉₀ was associated with a dose-dependent manner that the benefits of statin to prevent the occurrence of pneumonia were determined when the DDD₉₀ was ≥ 0.5. However, the protective effect of a DDD₉₀ of 0.5–1.0 (aOR 0.75, 95 % CI 0.66–0.84, P < 0.001) was closed to that of a DDD₉₀ ≥ 1.0 (aOR 0.74, 95 % CI 0.63–0.87, P = 0.002) (Table 2).

Of the patients who were unexposed to statin pretreatment at the time of being diagnosed with MI, we identified 1313 case patients who were hospitalized for pneumonia and 6321 control patients who were not hospitalized for pneumonia. The percentage of any use of statins among the case and control patients was 60.4 and 66.3 %, respectively. Among patients unexposed to pretreatment, statin users had a 24 % decreased risk of pneumonia hospitalization (aOR 0.76, 95 % CI 0.64–0.90, P = 0.001). The results of current users and dosage manner were consistent with the findings of the primary analysis, but the association was stronger (Table 3).

We performed a stratified analysis and redefined “statin users” if patients had a statin of DDD₉₀ ≥ 0.5. Our results showed a negative association between statin exposure and the risk of pneumonia requiring hospitalization in the patients who were female, were aged ≥ 65 years, had lower CHADS₂ scores (0 or 1), or had no history of DM, HTN, CHF, asthma or COPD (Fig. 2).

The major statins used within a 90-day period prior to the index date were atorvastatin, fluvastatin and simvastatin (Table 4). For all patients with MI, fluvastatin and simvastatin had similar associations with the risk of pneumonia requiring hospitalization compared to atorvastatin (fluvastatin: aOR 1.14, 95 % CI 0.85–1.52, P = 0.390; simvastatin: aOR 1.19, 95 % CI 0.87–1.64, P = 0.283). For patients unexposed to statin pretreatment, the results were consistent with the findings of overall MI patients.

In this nested case-control study, we observed that statin use in MI patients was associated with a 15-25 % reduced risk of pneumonia requiring hospitalization. We also observed that the benefits of statins were particularly marked for current users who used statins within 90 days and for those who used statins of ≥ 0.5 DDD₉₀. In addition, the favorable effect was shown in the patients who were female, were aged ≥ 65 years, and had no history of cardiovascular and respiratory diseases. Atorvastatin, fluvastatin and simvastatin were the most common prescribed statins and had similar effects on reducing the risk of pneumonia requiring hospitalization.

The effect of statin use on reducing the occurrence of pneumonia has been shown in the general population [10, 11]. In this present study, we additionally found that statin use might also have a favorable effect on decreasing pneumonia hospitalization in MI patients who were more susceptible to pneumonia and had more comorbidities compared to general population. However, this favorable effect was not significant when the analysis was limited to MI patients with a higher CHADS₂ score (CHADS₂ score ≥ 2). Some unmeasured differences in baseline characteristics might still exist in statin users and nonusers, resulting in overestimating the benefits of statins on pneumonia hospitalization. For example, patients who adhered to statin therapy might have other related preventive behaviors (eg, exercising, avoiding tobacco and accessing medical help). Thus, rigorous and randomized controlled clinical trials are required to minimize the potential confounding bias and confirm the preventive effect of statin use on pneumonia hospitalization.

Our analyses showed some discrepancies about the recency of the benefits of statins compared with the previous studies. Nielsen demonstrated that statin use within 125 days before index pneumonia had a protective effect [10]. In another case-control study [11], Vinogradova demonstrated that the benefit was observed only in patients who used statin within 28 days before pneumonia. In the present study, we observed the protective effect on MI patients lasted for 90 days. The possible mechanisms underlying these discrepancies might be related to the differences of study designs, prescription rates of statin, commonly prescribed statins and patient characteristics between studies. Although discrepancies existed, the observations from our and previous research revealed that statin use might be associated with prevention of pneumonia in different patient groups.

Regarding prevention of adverse cardiovascular events, it remains controversial whether statin therapy before an MI event is beneficial. Some studies have reported that chronic statin pretreatment resulted in a small infarct area, more preserved ventricular function [7], and low hospital mortality [8] when patients developed acute MIs. However, Feurnau et al. recently showed that chronic statin pretreatment was not associated with minimal myocardial damage during MI events [20]. The differences of baseline risk profiles between patients exposed to statin pretreatment and those unexposed to pretreatment might have affected the effects of statin therapy [7, 8, 20]. Based on our results, statin use has superior benefits for patients unexposed to statin pretreatment than for all patients with MI. The major reason might be that MI patients exposed to statin pretreatment might have a significantly greater risk profile (e.g. hyperlimpidia) than patients unexposed to pretreatment [7, 8, 20]. Other potential reasons such as exact type, dose, duration and compliance of statin pretreatment might have also contributed to the heterogeneity [20]. These findings provide implications for further research on the pleiotropic effects of statins.

In our stratified analysis, statin users who were female or had fewer comorbidities had a significantly low risk of pneumonia. Our observations are similar to those of van de Garde, who reported that statin use was associated with a reduced risk of pneumonia in patients with diabetes who were female and had no previous pulmonary diseases [12]. Both findings suggested that the clinical presentation of pleiotropic effects of statins might be influenced by the individual’s risk profiles of patients. The specific conditions that might affect the effects of statins on the occurrence of pneumonia provide crucial information on how a randomized controlled trial should be designed to clarify the role of statins as an adjunctive treatment for the prevention of pneumonia in patients with MI.

In addition to time-dependent effect of statin use, our results showed a dose-dependent relationship of the benefits of statins that were similar to those reported by Wang et al., who demonstrated that statins prescribed at a medium or high DDD led to a 40–67 % reduction in the risk of COPD exacerbation, including concurrent pneumonia [21]. Additionally, two randomized controlled trials showed that statins exerted an anti-inflammatory effect in a dose-dependent manner [22, 23]. These findings raise a concern of optimal dosage of statins regarding their anti-inflammatory and pleiotropic effects. The exact mechanisms behind the effect of statin use on reducing the occurrence of pneumonia have not been completely elucidated. Statins have been shown to exert variable antimicrobial activity against various bacterial strains [24] and control the bacilli burden by enhancing host-induced autophagy and phagosomal maturation during pathogen invasion [25]. In addition, statins promote the clearance of microparticles from lung tissues to regional lymph nodes, attenuate recruitment and activation of alveolar macrophages, thereby reducing local proinflammatory cytokine production in the lungs [26]. The results from these aforementioned studies might provide possible mechanisms for the protective benefits of statin therapy. It still remains unclear whether different lipid-lowering abilities of statins can be correlated to their different anti-inflammatory abilities. In the present study, we observed that atorvastatin, fluvastatin and simvastatin had similar effects on reducing the risk of pneumonia among MI patients. Our findings were consistent with those of Vinogradova, who demonstrated that atorvastatin and simvastatin had similar associations with the risk of pneumonia in the general population [11]. These observations might provide implications for further clinical trials to compare the effects of different statins on the risk of pneumonia.

We observed that the percentage of any use of statins after MI in present study was only 60–70 %. Another study which was also conducted from an administrative database in the United States showed that 46.9 % of patients with high risk of cardiovascular disease were no longer taking a statin at a mean time of 3 months after drug initiation [27]. Adherence rates of statins in most observational studies have been low, with approximately 50 % at 6 months and 25 % at 1 year [28]. Even in clinical studies, adherence with statins is suboptimal, with 5-year discontinuation rate of 33 and 18 % in primary and secondary prevention trials, respectively [29, 30]. The most common reasons contributing to discontinuation and non-adherence are statin-related muscle side effects [31]. To increase the adherence rate and benefits of statins, especially in patients with MI and high risk of cardiovascular disease, statins should be prescribed after thoroughly evaluating the patient’s comorbidities, types and dosage of statins, and concomitant medications [31]. In this study, we considered the risk of COPD and found that COPD was associated with an increased risk of pneumonia requiring hospitalization (crude OR = 3.43, 95 % CI = 2.82–4.18, P < 0.001). The adherence rate of inhaled therapy in patients with COPD has been reported about 41.357 % and underuse of medications was common [32‐34]. We did not analyze the adherence of medications for COPD because the numbers of MI patients with coexisting COPD were relatively small. Further clinical research is needed to investigate whether concomitant adherence to statins use and COPD treatment in MI patients with COPD could be an effective treatment in reducing the incidence of pneumonia requiring hospitalization.

Statin use among patients with MI might be associated with a decreased risk of hospitalization for pneumonia in time- and dose-dependent manners, particularly for patients who were unexposed to statin pretreatment or had fewer comorbidities. Our results suggest that statin use might be used in an adjunctive therapy in preventing pneumonia hospitalization for patients with MI under thorough evaluation of individual comorbidities, previous statin use and optimal dosage.