High versus low dose statin therapy in Indian patients with acute ST-segment elevation myocardial infarction undergoing thrombolysis

2.1Study population

It was a prospective double blind single centre study which included patients (18 years-70 years) admitted in coronary care unit from January 2014 to February 2015 with diagnosis of acute ST elevation myocardial infarction (STEMI) undergoing thrombolysis using fibrinolytic therapy after meticulous screening in the emergency department (ED). Patients with previous (within 3 months) or current treatment with statins; known allergy to heparin, aspirin, clopidogrel, active severe bleeding; pregnancy; history of major surgery or trauma; significant gastrointestinal or genitourinary bleeding (<6 weeks); history of cerebrovascular attack; and cardiogenic shock with mechanical ventilation, other contraindication to fibrinolytic therapy, suspected pulmonary thromboembolism, creatinine level of more than 2.0 mg per deciliter, obstructive hepatobiliary disease or other serious hepatic disease, known hypersensitivity to statin, chronic liver or muscle disease, history of treatment with drugs that are strong inhibitors of cytochrome P-450 3A4 within the month before randomization and those undergoing primary PCI were excluded from the study. Diagnosis was confirmed on the basis of ECG, serial CK-MB/troponin T measurements and echocardiography as per universal definition of myocardial infarction. STEMI was defined as a clinical syndrome with characteristic symptoms of myocardial ischemia in association with persistent electrocardiographic (ECG) ST elevation and subsequent release of biomarkers of myocardial necrosis. Diagnostic ST elevation in the absence of left ventricular (LV) hypertrophy or left bundle-branch block (LBBB) was defined as new ST elevation at the J point in at least 2 contiguous leads of ≥2 mm (0.2 mV) in men or ≥1.5 mm (0.15 mV) in women in leads V2–V3 and/or of ≥1 mm (0.1 mV) in other contiguous chest leads or the limb leads. New or presumably new LBBB at presentation, ST depression in ≥2 precordial leads (V1–V4) diagnostic of posterior wall STEMI; multilead ST depression with coexistent ST elevation in lead aVR were also included in STEMI group.6

2.2Study protocol

All the patients received standard treatment for STEMI according to guidelines: thrombolytic therapy, heparin, nitrates, aspirin, clopidogrel, beta blockers, angiotensin converting enzyme inhibitor. Drugs with known or suspected interactions with statin were prohibited within five half-lives prior to inclusion and during the study.

2.3Randomization

They were randomized in 1:1 manner using a table of randomized numbers containing double digits randomization codes (from 11 to 50) generated using computer program. Randomization codes were allotted to the enrolled patients by starting at random point in the table. Patients receiving code from 11 to 30 received low dose 10 mg atorvastatin (group A) and those with code from 31 to 50 received high dose 80 mg atorvastatin (group B). Randomization was performed at entry before starting any treatment. Adverse events were collected during the study period from selection to the end of follow-up at 30 days.

2.4Endpoints

The primary end point was 30-day incidence of MACEs (death from any cause, myocardial infarction, documented Non ST elevation acute coronary syndrome [NSTE-ACS] requiring readmission, ischemia driven revascularization with either percutaneous coronary intervention or coronary-artery bypass grafting, and stroke). Reinfarction within 18 h after initiation of fibrinolytic therapy should be based on recurrence of severe ischemic-type chest discomfort that lasts at least 30 min, usually but not always accompanied by recurrent ST-segment elevation of at least 0.1 mV in at least 2 contiguous ECG leads and re-elevation of CK-MB to more than the upper limit of normal or increased by at least 50% over the previous value and reaching at least >3 times the normal value, in association with ischemic symptoms. After 18 h, reinfarction was defined as new pathological Q waves or re-elevation of CK-MB to >3 times the normal value (24 h to discharge) or >2 times the normal value (after hospital discharge).7 NSTE-ACS was defined as ischemic discomfort at rest for at least 10 min prompting rehospitalization, combined with one of the following: ST-segment or T-wave changes, cardiac-marker elevations that were above the upper limit of normal but did not meet the criteria for myocardial infarction, or a second episode of ischemic chest discomfort lasting more than 10 min and that was distinct from the episode that had prompted hospitalization. Secondary end points included individual components of the primary end point and ST-segment resolution at 90 min after thrombolysis.

2.5Follow-up

A 30 days clinical follow-up was performed for all patients to evaluate MACEs (death from any cause, myocardial infarction, documented NSTE-ACS requiring readmission, ischemia driven revascularization and stroke.)

2.6Statistical analysis

The statistical analysis was performed using IBM SPSS statistics version 20 (Armonk, NY, USA). Continuous variables were expressed as mean ± SD, and categorical variables were presented as absolute number and proportion (%). Comparisons of categorical variables were made using the chi-square test and Fisher exact test, as indicated. Data were analyzed using the 2-tailed test to identify differences between groups and analysis of variance for repeated measures with Bonferroni correction for intragroup data. Nominal data were analyzed by the chi-square test. All efficacy analyses are based on the intention-to-treat principle. Event-free survival analysis was be analyzed by the Kaplan-Meier method with log-rank test group comparison. We considered 95% confidence intervals (CIs) that excluded unity, or, equivalently, p < 0.05, as statistically significant. Calculation of sample size was based on a 2-sample and 2-sided test. We assumed the incidence of MACEs might be similar between patients with STEMI treated with primary PCI or fibrinolytic therapy. Therefore, we calculated a sample size by analogy with the STATIN STEMI (Efficacy of High-Dose Atorvastatin Loading Before Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction) study.8 MACE in the STATIN STEMI study was 5.8% for high-dose (80-mg) atorvastatin arm versus 10.6% for conventional dose (10-mg) arm. Using a 2-sided alpha level of 0.05 and statistical power of 80%, we estimated the need for 511 patients in high-dose atorvastatin arm and 511patients in low dose arm, or a total of 1022 patients.

3.1Baseline characteristics

Baseline demographic and clinical characteristics are displayed in Table 1. Mean age was 57.01 ± 10.65 years and 74.2% of the patients were men. Demographic characteristics did not differ significantly between the 2 groups. Mean left ventricular ejection fraction was 46 ± 8% in all patients and did not differ between the 2 groups. The pain-to-needle time and door-to-needle time were also not different between the 2 groups (4.9 ± 1.77 vs. 4.98 ± 1.88 h, P = 0.483 and 13.6 ± 4.76 min vs. 4.98 ± 1.88 min, P = 0.665, respectively). The proportion of patients taking medications after fibrinolysis was also similar between the 2 groups (Table 1). Peak CK-MB level was 243 ±156 ng/dl in group A vs 253 ± 162 ng/dl in group B (P = 0.314).

3.2Primary end point

For all randomized patients, the Kaplan–Meier event rates of the primary end point at 30 days were 8.79% in the high dose atorvastatin group and 9.32% in the low dose atorvastatin group (p = 0.75) (Fig. 2).No significant difference in major adverse cardiac event (MACE)-free survival at 30 days was observed between the 2 groups (OR = 0.938, 95% CI = 0.612–1.436, P = 0.764).

Fig. 2

Kaplan-Meier 30 days MACE-Free Survival.

Fig. 2

3.3Secondary endpoints

Secondary endpoints are displayed in Table 2 (Fig. 3). With high dose atorvastatin, there was insignificant reduction in rate of reinfarction (0.98% vs 1.75%, OR = 0.555, 95%CI = 0.185–1.666, P = 0.286), revascularization (1.17% vs 1.36%, OR = 0.862, 95% CI = 0.287–2.578, P = 0.791) and death (4.49% vs4.66%, OR = 0.962, 95% CI = 0.536–1.728, P = 0.888). Readmission for NSTE-ACS (OR = 1.299, 95% CI = 0.479–3.514, P = 0.603) and stroke rate (OR = 1.392, 95% CI = 0.555–3.488, P = 0.479) increased in the high dose atrovastatin group, but was not statistically significant. Complete STR (70% STR at 90 min) was also higher in the 80-mg atorvastatin arm (45.90% vs.37.67%; OR = p = 0.008).

Fig. 3

Odds ratio plot of MACE at 30 days follow up.

Fig. 3

3.4Tolerability and safety

At the time of randomization, the mean serum LDL-C concentration was 83.68 ± 17.74 mg/dl in group A vs 83.68 ± 17.74 mg/dl in group B (P = 0.666). Reduction in LDL-C was statistically significant (P = 0.000) at the end of 30 days in atorvastatin 80 mg group (29.16 ± 10.57%) as compared to that of atorvastatin 10 mg (12.51 ± 4.80%) group (Table 3). But this reduction in LDL-C was not related to primary endpoints.

The rates of discontinuation of treatment because of an adverse event or the patient’s preference were 15.43 percent in the high dose atorvastatin group and 4.66 percent in the low dose atorvastatin group at 30 days (P = 0.0001). The percentages of patients who had elevations in alanine aminotransferase levels that were more than three times the upper limit of normal were 0.78 percent in the high dose atorvastatin group and 0.58 percent in the low dose atorvastatin group (P = 0.725). 93 patients (18.06%) in high dose atorvastatin group and 39 patients (7.57%) in low dose atorvastatin group experienced myalgia (p = 0.0001). The study medication was discontinued by the investigators because of a report of moderate to severe muscle symptoms including myalgias, muscle aches, tenderness or stiffness with or without elevations in creatine kinase levels in 11.33 percent of high dose atorvastatin-treated patients, as compared with 3.49 percent of low dose atorvastatin-treated patients (P = 0.0001). There were no cases of rhabdomyolysis in either group.

4.1Study limitations

First, it was a single centre study. A multicentre study is needed to confirm our findings. Second, the follow up period was short, i.e, 30 days. A longer follow up is needed to see the long term outcomes. Third, we did not evaluate C- reactive protein and followed only the clinical parameters. Fourth, only STR was used as the index for myocardial reperfusion. Other indices were not taken into account. Lastly, even though our group of patients experienced higher rates of myalgia in comparison to other studies, we did not perform the genetic study for SLCO1B1 variants.