Methods

The Efficacy of Early Intensive Rosuvastatin Therapy in Patients with ST-segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention (ROSEMARY) study was a prospective, multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 4 Korean PCI centers: Severance Hospital and Yonsei University at Seoul, Konyang University Hospital at Daejeon, Eulji University Hospital at Daejeon, and Korea University Anam Hospital at Seoul. Patients were randomly assigned to an early high-dose rosuvastatin therapy or conventional low-dose rosuvastatin therapy group by computer-generated blocks. The randomization was stratified according to the enrolling site and location of myocardial infarction (MI; anterior or nonanterior wall MI). In the early high-dose rosuvastatin group, 40-mg rosuvastatin was loaded in the emergency room before primary PCI and was administered daily for a further 7 days after PCI. In the conventional low-dose rosuvastatin group, a placebo was administered before primary PCI and 10-mg rosuvastatin was given daily for 7 days after PCI. After this 7-day period, a daily dose of 10-mg rosuvastatin was maintained in both groups for 3 weeks, and the dose of rosuvastatin was further titrated to reduce low-density lipoprotein cholesterol <70 mg/dl. Serial cardiac MRI was taken in the acute (4 to 7 days) and chronic (3 months) phases. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by institutional review boards of the participating institutions. Informed consent was obtained from all patients before the enrollment. The study protocol is registered at www.clinicaltrials.gov ( NCT01153334 ).

All patients were treated with aspirin (250 mg) and clopidogrel (600 mg) before primary PCI. Intravenous unfractionated heparin was infused with a target activated clotting time >300 seconds during the procedure. Use of thrombus aspiration or glycoprotein IIb/IIIa inhibitors during the procedure was as at the discretion of the physician. All PCIs were performed by a standard intervention technique using biolimus-eluting stents (Nobori, Terumo Corporation, Tokyo, Japan). Patients received a daily dual antiplatelet therapy of clopidogrel (75 mg) and aspirin (100 mg) for at least 12 months.

Inclusion criteria were STEMI with symptom onset <12 hours, ST-segment elevation of >1 mm in at least 2 contiguous leads of an electrocardiogram or new-onset left bundle branch block, and age >18 years. Patients were excluded if any of the following conditions were present: congestive heart failure (New York Heart Association class III or IV) or left ventricular (LV) ejection fraction <35%; previous MI or coronary bypass graft surgery; hypersensitivity reactions to statins, antiplatelet agents, or heparin; familial hypercholesterolemia; skeletal muscle disease; active liver disease; renal failure with serum creatinine >2.0 mg/dl; secondary causes of hyperlipoproteinemia such as uncontrolled hypothyroidism or nephrotic syndrome; noncardiac morbidity with a life expectancy of <1 year; contraindications to cardiac MRI; pregnant or lactating women; or women with childbearing potential.

Data were collected and documented on electronic clinical research forms by dedicated research coordinators. Twelve-lead electrocardiograms were obtained before and 90 minutes after the procedure. Total ST-segment elevation was measured as the sum of ST-segment elevations from leads exploring the infarct area. Complete ST-segment resolution was defined as a decrease of >70% in the ST-segment resolution at 90 minutes after PCI compared with the baseline. One independent observer blinded to study randomization and angiographic findings analyzed all electrocardiograms. All angiographic analyses were analyzed by 2 independent observers in the angiography core laboratory of Severance Cardiovascular Hospital blinded to the randomization and clinical data. The Thrombolysis In Myocardial Infarction (TIMI) flow grade and the myocardial blush were evaluated by a standard method.

MRI was performed using a 1.5-T imaging unit (Gyroscan Intera, Philips Medical Systems, the Netherlands). ECG-gated cine images were acquired in sequential short-axis slices entirely covering both ventricles using a steady-state free precession technique (slice thickness 10 mm, temporal resolution 42 ms). Delayed enhancement images were obtained by acquiring T1-weighted sequences in an inversion-recovery segmented gradient echo 10 to 15 minutes after intravenous contrast injection (gadolinium 0.2 mmol/kg). Sequential, short-axis, 10-mm-thick slices were obtained, and the presence of significant delayed hyperenhancement was assessed in 16 segments per slice corresponding to the coronary location, with the exception of the apical slice and the basal slice 10 mm below the aortic outflow tract. LV ejection fraction and ventricular volumes were determined by planimetry of the myocardial borders on all contiguous short-axis cine images, including papillary muscles. Infarct size was quantified by planimetry of the hyperenhanced areas in each short-axis image. Hypoenhanced areas within infarct regions representing microvascular obstruction were also quantified by planimetry. Infarct size as a percentage of LV myocardium was calculated by the sum of the volume of all hyperenhanced regions on all slices divided by the sum of the LV myocardial cross-sectional volumes. The absolute mass of the infarcted area was calculated according to the following formula: infarct mass (in grams of tissue) = Σ [hyperenhanced area (in square centimeters)] × slice thickness (in centimeters) × myocardial specific density (1.05 g/cm ³ ). The intra- and inter-observer coefficients of variation values were 6% and 7.5%, respectively.

The infarct transmurality for each segment was calculated by dividing the hyperenhanced area by the total area of the affected myocardium in each segment. The mean transmurality was calculated as the average of all segments with hyperenhanced areas. Transmural infarction was defined as the presence of >70% transmurality in the affected myocardial segment. All cardiac MRI data were analyzed using commercially available software (MASS, Medis, Leiden, the Netherlands) by 2 independent experts in a central core laboratory (Severance Cardiovascular Hospital) blinded to randomization and clinical data.

The primary end point was the relative infarct volume by cardiac MRI in the chronic phase (3 months after primary PCI). Secondary end points of the study included relative infarct volume in the acute phase; other MRI parameters such as microvascular obstruction volume, transmurality, LV volumes, and ejection fraction in the acute and the chronic phases; major adverse cardiac events; a composite of all cause death, recurring MI, or target vessel vascularization; and immediate PCI outcome data such as post-PCI TIMI flow and resolution of ST-segment elevation after PCI.

The calculation of the sample size is based on a 2-sample inequality test. Based on the MRI data of Severance Cardiovascular Hospital, the mean infarct size was assumed to be 25% of total LV mass with an SD of about 10%. We assumed that early high-dose rosuvastatin could reduce infarct size by at least 5% compared with the control group. Based on an alpha error of 0.05 and a statistical power of 80%, 63 patients were required for each group. Assuming that a considerable number of enrolled patients might not be eligible for cardiac MRI because of various reasons, we expected the dropout rate to be approximately 40%. Therefore, the required total study sample size was calculated to be at least 180 patients.

Continuous variables with an approximately normal distribution are expressed as mean ± SD. Differences between the 2 treatment groups are compared using Student t test. Continuous variables not distributed normally were compared using the Mann-Whitney U test. Normally distributed continuous variables between baseline and follow-up in each group were compared by a paired t test. The Wilcoxon signed rank test was used for non-normally distributed variables. Categorical variables are reported as frequencies and percentages and were compared using chi-square statistics or Fisher’s exact test, as appropriate. A multivariate linear regression analysis evaluated the relation between clinical or procedural characteristics and the relative infarct size in the chronic phase. Candidate variables chosen included age, hypertension, hypercholesterolemia, previous use of statins, MI location, pre-PCI TIMI flow grade, time from symptom onset to balloon, sum of baseline ST-segment deviation, post-PCI TIMI flow grade, and high-dose rosuvastatin treatment. All variables were normally distributed, except for the time from symptom onset to randomization and the sum of baseline ST-segments, which both required a logarithmic transformation for the analysis. A p value of <0.05 was considered statistically significant. All statistical analyses were conducted using IBM PASW Statistics 20.0 (IBM Corporation, New York, New York).

Results

During the study period from August 2010 to February 2012, a total of 407 patients with STEMI undergoing primary PCI were screened at 4 PCI centers ( Figure 1 ). Among them, 222 patients met exclusionary criteria before PCI. Of the 185 enrolled patients, 92 patients were randomized to an early high-dose rosuvastatin group and 93 patients to a conventional low-dose rosuvastatin group. Fifty-two patients dropped out after randomization because of inadequate inclusions (n = 34: 2 stent thrombosis, 4 previous MI, 3 NSTEMI, 7 vasospastic angina, 1 claustrophobia, and 1 metal implant for the high-dose group; 1 previous MI, 2 NSTEMI, 7 vasospastic angina, 1 chronic renal failure, 1 age >80 years, 1 familial hypercholesterolemia, 1 claustrophobia, and 2 metal implant for the low-dose group), treatment other than primary PCI (n = 4), hemodynamic instability (n = 6), consent withdrawal (n = 6), and mortality before primary PCI (n = 3; Figure 1 ). A total of 62 and 70 patients remained enrolled in the high-dose and low-dose rosuvastatin groups, respectively. A cardiac MRI during the acute phase was obtained in all 132 patients. At 3 months, a second MRI was performed in 121 patients (high-dose rosuvastatin group n = 54, low-dose rosuvastatin group n = 67). MRI could not be obtained in 11 patients at 3 months because of stent thrombosis (n = 2), follow-up loss (n = 1), aggravated renal failure (n = 1), allergic skin reaction to gadolinium (n = 1), claustrophobia (n = 2), or consent withdrawal (n = 4). For the primary end point analysis, MRI images at 3 months from these 121 patients were evaluated.

Study flow. ^∗ Stratified by enrolling site and territory of myocardial infarction. ^† Inadequate inclusions: 2 stent thrombosis, 4 previous MI, 3 NSTEMI, 7 vasospastic angina, 1 claustrophobia, and 1 metal implant for the high-dose group; 1 previous MI, 2 NSTEMI, 7 vasospastic angina, 1 chronic renal failure, 1 age >80 years, 1 familial hypercholesterolemia, 1 claustrophobia, and 2 metal implant for the low-dose group. CABG = coronary artery bypass graft.

Baseline clinical data between the high-dose and the low-dose rosuvastatin group were similar except for hypertension, which was more prevalent in the high-dose group (61.3% vs 37.1%, p = 0.006, Table 1 ). Door-to-balloon time <90 minutes was achieved almost in all patients (99.2%). Baseline angiographic and procedural data were similar between the 2 groups ( Table 2 ). Final TIMI flow grade, myocardial blush grade, and ST-segment resolution at 90 minutes after primary PCI did not differ between the 2 groups.

Relative infarct volumes assessed by MRI in the chronic phase were not significantly different between the 2 groups ( Table 3 ). The relative infarct volume in the acute phase and the changes in the infarct volume from the acute to the chronic phase did not differ between the 2 groups. However, trends toward reduced absolute infarct volume (−9.1 ± 0.3 vs −5.1 ± 12.7 ml, p = 0.071), infarct mass (−9.5 ± 10.8 vs −5.3 ± 13.3 g, p = 0.072), and relative infarct volume (−6.6 ± 7.9% vs −3.8 ± 8.1%, p = 0.068) from acute phase to chronic phase were observed in the high-dose rosuvastatin group compared with the low-dose rosuvastatin group ( Table 4 ). LV volumes, LV ejection fraction, microvascular obstruction volume, transmurality, and frequency of transmural infarct were similar between the 2 groups in both phases. Multivariate linear regression analysis showed no clinical or procedural variables significantly correlated with the extent of the relative infarct volume in the chronic phase ( Table 5 ).

Table 3

Serial MRI data

Variable	Acute Phase		p-Value	Chronic Phase		p-Value
	Rosuvastatin Dose			Rosuvastatin Dose
	High (n = 62)	Low (n = 70)		High (n = 54)	Low (n = 67)
LVEDV (ml)	140.1 ± 26.0	144.6 ± 31.5	0.399	133.0 ± 31.8	137.5 ± 34.7	0.475
LVESV (ml)	64.2 ± 20.3	66.7 ± 25.9	0.564	61.2 ± 27.9	60.9 ± 28.3	0.955
LVEF (%)	54.6 ± 9.2	54.6 ± 11.0	0.989	55.1 ± 12.0	56.8 ± 10.6	0.450
Myocardial mass (g)	121.8 ± 28.8	123.4 ± 34.2	0.781	112.3 ± 26.8	116.7 ± 32.2	0.432
Infarct volume (ml)	28.0 ± 13.6	25.4 ± 17.8	0.385	18.4 ± 12.1	18.6 ± 13.2	0.944
Infarct mass (g)	29.4 ± 14.2	26.7 ± 18.7	0.387	19.3 ± 12.7	19.5 ± 13.9	0.943
Relative infarct volume (%)	23.0 ± 9.5	20.5 ± 11.7	0.208	15.9 ± 8.3	15.8 ± 9.7	0.943
Microvascular obstruction volume (ml)	1.0 ± 2.4	1.0 ± 2.2	0.894	0.01 ± 0.08	0.01 ± 0.08	0.907
Microvascular obstruction mass (g)	1.2 ± 3.0	1.0 ± 2.3	0.715	0.01 ± 0.08	0.01 ± 0.08	0.907
Transmurality (%)	41.5 ± 14.6	39.1 ± 15.4	0.395	35.0 ± 13.1	32.8 ± 14.2	0.408
Number of segment with transmural infarct	1.0 ± 1.2	0.9 ± 1.3	0.572	0.5 ± 0.7	0.5 ± 1.0	0.779

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. Impact of Albuminuria on the Incidence of Periprocedural Myocardial Injury in Patients Undergoing Elective Coronary Stent Implantation
2. Effect of Statin Therapy on Mortality in Patients With Infective Endocarditis
3. Risk of Pneumonia in Adults With Closed Versus Unclosed Atrial Septal Defect (from a Nationwide Cohort Study)
4. Prevalence and Prognostic Significance of Fragmented QRS Complex in Middle-Aged Subjects With and Without Clinical or Electrocardiographic Evidence of Cardiac Disease

Stay updated, free articles. Join our Telegram channel

Join