LAMIS is a substudy of Korea Acute Myocardial Infarction Registry (KAMIR). The KAMIR is a Korean prospective multicenter online registry designed to reflect the “real-world” practice in Asian patients presenting with AMI with support from the Korean Circulation Society since November 2005 [20]. Online registry of AMI (at www.kamir.or.kr) has been performed at 55 university or community hospitals that are high-volume centers with facilities for primary percutaneous coronary intervention (PCI) and onsite cardiac surgery. The LAMIS-II investigators were selected from 11 major PCI centers among the 55 KAMIR sites and 1,101 consecutive AMI patients were randomly assigned to receive either 2 mg of pitavastatin or 4 mg of pitavastatin orally daily within 24 hours after PCI between July 2010 and April 2013. The following concomitant medications were limited in the present study to eliminate any possible influence on the efficacy outcomes. (1) Immunosuppressants are prohibited in the present study due to the possibility of rhabdomyolysis as a result of drug interactions between immunosuppressants (e.g., cyclosporine) and statins. If immunosuppressant use is unavoidable, discontinue administration of pitavastatin and continue follow-up. (2) Statins other than pitavastatin are prohibited in the present study due to the possible influence on the evaluation of the efficacy of pitavastatin. (3) The use of lipid- lowering drugs (e.g., bile acid sequestrants or resins), fibric acid derivatives, nicotine acids and derivatives, probucol, etc. were prohibited in the present study because they may influence the evaluation of the efficacy of the study drug. However, additional lipid-lowering drugs can be used only when the investigator decides its use is necessary for the patient. The patients were followed at 30, 90, 180, 270, and 360 days by telephone communication, office visit, or by contacts with primary physicians or referring cardiologists. As part of the protocol, plasma samples were obtained at randomization, 30 and 360 days for the measurements of lipid profiles, fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c). The data were collected electronically at each participating medical centre, transferred to an independent data management organization, and analysed by an independent clinical research organization. The study protocol was approved by the Institutional Review Board of each participating medical centre, and all patients granted their consent to participate in the study.

The present study was designed to compare MACEs between 2 and 4 mg of pitavastatin treatment. Since the aim of the study was to examine the incidence and the odds ratios (ORs) of MACEs between the two dose groups, not to evaluate the statistical differences, sample size was calculated for the estimation of ORs. A meta-analysis of standard and intensive lipid lowering therapies revealed an OR of 0.84. Therefore, sample size was calculated using the OR of 0.84 as the reference with the precision of the ORs as 25%, considering pitavastatin 2 mg as standard lipid lowering therapy and pitavastatin 4 mg as more intensive lipid lowering therapy. At the significance level of 0.05, precision of the ORs of 0.25, and dropout rate of 10%, the minimum number of subjects was calculated as 483 per group.

Primary efficacy endpoint (target lesion revascularization [TLR]-MACE) was the incidence of a first MACE, defined as composite of cardiac death, nonfatal myocardial infarction (MI), TLR, and hospitalization for unstable angina, heart failure, or arrhythmic events at 12-month follow-up. We did not include cardiovascular events at sites outside the stented segment for TLR-MACE. Secondary efficacy endpoint was as follows: (1) target vessel revascularization (TVR)-MACE which was defined as the incidence of composite of all-cause death, nonfatal MI, TVR, and hospitalization for unstable angina, heart failure or arrhythmic events at 12-month follow-up; (2) changes of lipid profiles from baseline to 12-month follow-up; and (3) changes of FPG and HbA1c from baseline to 12-month follow-up. For TVR-MACE, we included both cardiovascular events in stented segments and those at sites outside the stented segment.

We evaluated the incidence of total adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs). AEs for which a causal relationship to pitavastatin could not be ruled out were counted as ADRs. ADRs were reported by the attending physicians. The terminology for ADRs was based on the WHO-ART 092 (WHO Adverse Reaction Terminology).

SAS version 9.2 (SAS Institute Inc., Cary, NC, USA) was used for statistical analysis. The incidence of a first MACE, primary efficacy endpoints, was summarized and the 95% confidence intervals of OR was calculated. Survival curves of a first MACE and whole cardiovascular events was calculated by Kaplan-Meier and apply log rank test to the comparison between each group. The between-group differences in changes (lipid levels, FPG, and HbA1c) from baseline to the 12-month endpoint were assessed by unpaired t test. Paired t tests were used to assess differences between before and after administration of investigational products within groups. All hypotheses were assessed with 5% of significance level on both sides. While intention-to-treat (ITT) population was defined as the population of patients who had at least one dose of any investigational product administered and had at least one post-baseline measured value of HbA1c along with the baseline level, and ITT population was used for efficacy analysis. Patients who were identified as exclusion criteria deviation during the study and who were not evaluated for efficacy were excluded in the ITT population. For safety analysis, all randomized patients who had at least one dose of investigational product and had visited after the dose was included. Last observation carried forward (LOCF) was applied for patients who were withdrawn in the middle of the study and LOCF data was used for the results of 1-year endpoint. All data were expressed as mean ± SD. A p < 0.05 was considered statistically significant.

Fig. 1 shows a flowchart of the patient enrollment and safety and ITT analyses. The 1,101 patients from 11 facilities in Korea consented to participate in the LAMIS-II. After excluding 55 patients (14 patients, enrolled erroneously; 39 patients, not treated with investigational product; two patients, double randomization), the remaining 1,046 patients were included in the safety analysis. After excluding 68 patients (five patients, violation of inclusion criteria; 63 patients, missing of primary efficacy evaluation), the remaining 978 patients were included in the efficacy analysis. The baseline characteristics are summarized in Table 1. There were no significant differences in age, gender, MI type, and the prevalence of hypertension and diabetes mellitus. Hypercholesterolemia was more prevalent in 4 mg group and current smoking was more prevalent in 2 mg group. There were no significant differences in the prior statin therapy and door to PCI time between both groups. There were no significant differences in the discharge medications between both groups. There were no significant differences in the infarct-related artery (although 438 out of 978 patients were investigated for the infarct-related artery) and used stent types between both groups.

The incidence of primary endpoint is summarized in Table 2. At the time of study termination, 45 first TLR-MACE had occurred in 2 mg group, as compared with 44 in 4 mg group (2 mg group vs. 4 mg group: OR, 0.993; p = 0.976). In overall population, cardiac mortality rate was 0.6% (6/978; 0.2% in 2 mg group [1/496] vs. 1.0% in 4 mg group [5/482], p = 0.119). No difference was observed in primary efficacy endpoints in patients with ST segment elevation MI in both 2 and 4 mg groups (OR, 1.027; p = 0.927), and it was also not differently occurred in patients with non-ST segment elevation MI in both 2 and 4 mg groups (OR, 0.947; p = 0.875). In diabetic subgroups, the incidence of primary efficacy endpoints tended to be lower in 4 mg group compared with 2 mg group (OR, 2.211; p = 0.070), and no difference was observed in primary efficacy endpoints between 2 and 4 mg groups in non-diabetic subgroups (OR, 0.725; p = 0.227).

The incidence of secondary endpoint in terms of TVR-MACE is summarized in Table 2. The incidence of TVR-MACE was not different between both groups (OR, 0.969; p = 0.884). In overall population, all-cause mortality rate was 1.1% (11/978; 0.6% in 2 mg group [3/496] vs. 1.7% in 4 mg group [8/482], p = 0.118). No difference was observed in TVR-MACE in patients with ST segment elevation MI in both 2 and 4 mg groups (OR, 0.985; p = 0.957), and it was also not differently occurred in non-ST segment elevation MI in both 2 and 4 mg groups (OR, 0.947; p = 0.871). The incidence of TVR-MACE tended to be lower in 4 mg group compared with 2 mg group in diabetic subgroups (OR, 2.074; p = 0.082), and no difference was observed in TVR-MACE between 2 and 4 mg groups in non-diabetic subgroups (OR, 0.710; p = 0.189).

Total cholesterol and LDL-C reduced effectively by both 2 and 4 mg of pitavastatin treatment from baseline to 12-month follow-up. The degree of reduction of total cholesterol and LDL-C was significantly greater in 4 mg group compared with 2 mg group from baseline to 12-month follow-up (Fig. 2A and 2B). At baseline, LDL-C level was 129.06 ± 35.36 and 128.46 ± 38.87 mg/dL in the pitavastatin 2 mg group and the pitavastatin 4 mg group, respectively. The two groups did not show statistical significance (p = 0.804). At 12 months, LDL-C level was 95.21 ± 27.63 and 86.30 ± 28.12 mg/dL in the pitavastatin 2 mg group and the pitavastatin 4 mg group, respectively. The changes in LDL-C at 12 months from baseline were statistically significant in both groups with –34.23 ± 31.66 mg/dL in the pitavastatin 2 mg group and –42.05 ± 32.73 mg/dL in the pitavastatin 4 mg group (p < 0.001 and p < 0.001, respectively). And the change in LDL-C level was significantly greater in the pitavastatin 4 mg group. There was no significant change of triglyceride in both groups from baseline to 12-month follow-up. HDL-C increased effectively by both 2 and 4 mg of pitavastatin treatment from baseline to 12-month follow-up; however, there was no significant difference in change of HDL-C between both groups from baseline to 12-month follow-up (Fig. 2C). Apolipoprotein A1 increased effectively by both 2 and 4 mg of pitavastatin treatment, and apolipoprotein B reduced effectively by both 2 and 4 mg of pitavastatin treatment from baseline to 12-month follow-up; however, there were no significant differences in changes of apolipoprotein A1 and B between both groups from baseline to 12-month follow-up (Fig. 2D).

FPG level was reduced significantly in both 2 and 4 mg group from baseline to 12-month follow-up (Fig. 3A) and HbA1c was not changed significantly in both 2 and 4 mg group. And there were no significant differences in changes of FPG and HbA1c between both group from baseline to 12-month follow-up (Fig. 3B). We assessed these parameters separately in diabetic and non-diabetic patients. In diabetic patients, the difference of FPG from baseline to follow-up was –30.56 ± 93.67 mg/dL in pitavastain 2 mg group (p = 0.010) and –20.68 ± 70.87 mg/dL in pitavastain 4 mg group (p = 0.044). In non-diabetic patients, the difference of FPG from baseline to follow-up was –20.37 ± 31.09 mg/dL in pitavastatin 2 mg group (p < 0.001) and –19.90 ± 44.65 mg/dL in pitavastain 4 mg group (p < 0.001). In diabetic patients, the difference of HbA1c from baseline to follow-up was –0.04% ± 1.31% in pitavastain 2 mg group (p = 0.829) and –0.30% ± 1.51% in pitavastain 4 mg group (p = 0.192). In non-diabetic patients, the difference of HbA1c from baseline to follow-up was –0.05% ± 0.89% in pitavastain 2 mg group (p = 0.675) and –0.02% ± 0.96% in pitavastain 4 mg group (p = 0.871).

On the basis of Kaplan-Meier estimates, there were no significant differences of occurrence of TLR-MACE, TVR-MACE, cardiac death, and nonfatal MI between both groups (Fig. 4).

Among 1,101 subjects randomized in the study, 1,046 (95.0%) were included in the safety set except for those who were with double randomization, enrolled erroneously or not treated with pitavastatin (n = 527 vs. 519 for pitavastatin 2 mg and pitavastatin 4 mg groups, respectively).

In the present study, 114/527 subjects (21.6%, 166 events) in the pitavastatin 2 mg group and 115/519 (22.2%, 147 events) in the pitavastatin 4 mg group experienced at least one AEs; there was no statistically significant difference in the incidence of the AEs between two groups (p = 0.837). There was also no statistically significant difference in the incidence of the ADRs between the pitavastatin 2 mg group (10/527 [1.9%], 15 reactions) and the pitavastatin 4 mg group (8/519 [1.5%], 8 reactions; p = 0.658).

The SAEs were reported in 76/527 subjects (14.4%, 99 events) in the pitavastatin 2 mg group and 77/519 (14.8%, 90 events) in the pitavastatin 4 mg group; similarly, there was no statistically significant difference in the incidence of the SAEs between two groups (p = 0.849). Among the SAEs, three events were related to the study drug at the discretion of the investigator, including ‘urticaria’ in pitavastatin 2 mg group (subject no. S04-121) and ‘myocardial infarction’ and ‘malignant lymphoma’ in pitavastatin 4 mg group (subject no. S08-059 and S11-022, respectively).

The incidence of ADR by system organ class (SOC) in safety population is summarized in Table 3. When all ADRs were standardized by SOC and preferred term using WHO-ART 092, the most common SOCs were ‘myoendopericardial & valve disorders’ (seven events) followed by ‘musculoskeletal system disorders’ (five events), ‘body as a whole: general disorders’ (three events), and ‘liver and biliary system disorders’ (three events).