Intensive Statin Therapy in Patients With AMI
Intensive Statin Therapy in Patients With AMI
Objective: Statins have been shown to have beneficial pleiotropic effects besides being lipid
 lowering. The investigators hypothesized that early and intensive statin treatment was
 associated with improved left ventricular (LV) function and with a stabilization of the
 coronary atherosclerotic plaques in patients with acute myocardial infarction (AMI) Method:
 In a prospective randomized blinded endpoint trial patients with ST segment elevation or non
 ST segment elevation AMI were randomized to either intensive statin-therapy (loading dose
 rosuvastatin 80 mg immediately after randomization followed by 40 mg daily) or usual statin
 therapy (simvastatin 40 mg daily). Patients were followed 12 month and the investigators
 performed echocardiography at randomization, after 30 days and after 12 month. The
 investigators used 2D Speckle Tracking for the assessment of LV-function. Coronary plaque
 assessment was done with Cardiac-CT (MSCT) at baseline and after 12 month.

 Primary outcome for this study was assessment of LV function with global and regional
 myocardial strain. Secondary outcomes can be divided in 4 groups:

 1. Additional echocardiographic measurements such as Ejection Fraction, S´, LV-volume,
 atrial volume, VA-coupling, diastolic function, post systolic strain and strain rate.

 2. Biochemical assessment of inflammation and endothelial function: Hs-CRP, ICAM, VCAM,
 E-selection and Nitrate/Nitrite ratio.

 3. Coronary plaque assessment by MSCT: Plaque volume and plaque stability.

 4. Long term follow-up: Mortality and cardiovascular events
Introduction Coronary heart disease (CHD) remains the leading cause of mortality in the
 western world. In Europe, CHD accounts for one fifth of all deaths annually. Acute myocardial
 infarction (AMI) is caused primarily by plaque rupture and it has been demonstrated that the
 pathogenesis of AMI involves interplay of the endothelium, the inflammatory cells and the
 thrombogenicity of the blood. Following an acute myocardial infarction (AMI), profound
 structural changes can be encountered, resulting in left ventricular (LV) remodeling and
 development of depressed cardiac function.

 Heart failure (HF) is a significant cause of morbidity and mortality worldwide with an
 estimated prevalence of 1% to 2% in the western world and AMI remains the predominant cause.

 Statins were first developed to improve the lipid profile and reduce the development of CVD.
 Several large randomized controlled trials have shown that statin therapy is beneficial in
 both primary and secondary prevention of atherothrombosis. Results from two large, acute
 coronary syndrome trials suggested further clinical benefit of statins in addition to their
 lipid lowering effect. This stemmed from the observation of a cardiovascular event-rate
 reduction in patients with AMI only weeks after initiation of statin treatment. Several
 experimental studies have demonstrated that statins, apart from their LDL lowering effect,
 exert beneficial pleiotropic effects on inflammation, endothelial function, thrombosis,
 plaque stability and ischaemic-reperfusion injury.Other experimental studies in animals have
 reported beneficial effects of statins on LV function after AMI. In clinical settings statins
 have been shown to prevent periprocedural myocardial damage in patients treated with
 percutaneous coronary intervention (PCI) and the ARMYDA-ACS trial demonstrated a protective
 effect of statin loading on the myocardium before PCI in patients with ACS. Only a few
 clinical studies have directly investigated the acute effect of statins on LV function in
 patients with AMI and the results are inconclusive.

 All previous studies have concentrated on patients with STEMI and disregarded those with
 NSTEMI; moreover, no studies have investigated the effect of an early statin loading dose in
 patients with AMI. The investigators hypothesized that early and intensive statin treatment
 was associated with improved left ventricular (LV) function and with a stabilization of the
 coronary atherosclerotic plaques in patients with acute myocardial infarction (AMI) Thus, the
 primary aim of the Intensify trial was to examine the effect of early intensive statin
 treatment on LV function with strain echocardiography in patients with AMI after 30 days.

 Methods Study population This study was a prospective randomized controlled (RCT) trial with
 a blinded endpoint design. The trial was approved by the Regional Scientific Ethics Committee
 for Southern Denmark and the Danish Data Protection Agency. Patients with AMI defined by
 current guidelines were consecutively collected from a single coronary care unit from April
 2010-august 2012. Inclusion criteria were all patients with NSTEMI and STEMI, and the
 exclusion criteria were prior intensive statin treatment, contraindication to intensive
 statin therapy and a time limit above 24 hours from hospital admission.

 Patients were randomized to either intensive statin treatment with rosuvastatin 40 mg or
 usual care with simvastatin 40 mg. The intensive care group was given a loading dose of
 rosuvastatin 80 mg as soon as possible followed by 40 mg daily. The usual care group was
 treated with simvastatin 40 mg daily. Apart from the different statin treatment, all patients
 were treated the same according to current national guidelines.

 Patients were followed for 12 month and examined immediately after randomization, after 1
 month and after 12 month.

 Coronary angiography and Culprit vessel Culprit vessel and infarct location was identified
 from the coronary angiography. In patients with single vessel disease (lumen stenosis < 50%)
 the diseased vessel was identified as culprit. In patients with multi-vessel disease, the
 culprit vessel was identified by a combination of angiographic and electrocardiographic
 criteria. In patients with normal CAG we used electrocardiographic and multi-slice computer
 tomography to identify the culprit lesion. If the culprit lesion could not be found, the
 patient was excluded from the study. The investigators used the AHA scientific statement of
 myocardial segmentation and nomenclature for tomographic imaging from 2002 to define the
 coronary arteries supply area of the myocardium.

 Echocardiography Echocardiography was performed at randomization and after 30 days using the
 GE Vivid 7 ultrasound system (GE Medical System Inc., Horten, Norway) with a standard 3.5 MHz
 ultrasound probe. A standardized protocol was followed at each examination and all
 examinations were performed by one operator. Consecutive heartbeats were recorded at a sweep
 speed of 25 mm/s and digitally stored, blinded to patient identity. Examinations were
 analyzed off-line by one experienced observer using EchoPAC version 1.12.0 (GE, Vingmed). All
 analysis was done with a sweep speed of 67 mm/s and recordings were measured and averaged
 from 3 consecutive heartbeats. Examinations with poor image quality and patients with atrial
 fibrillation were excluded from the analyses. Left ventricular- and atrial volumes were
 estimated using the Simpsons biplane method of discs in the 4- and 2 chamber views and
 ejection fraction was calculated. Mitral inflow pattern was estimated in the apical four
 chamber view and pattern of peak early (E) and peak atrial (A) velocities were measured. E/A
 ratio was calculated by dividing E by A. Mitral annular velocities were estimated in the
 apical 4- and 2 chamber view using pulsed wave tissue Doppler imaging. A pulsed wave Doppler
 sample volume was placed at the level of the mitral annulus first in the lateral wall, then
 in the septum and finally in the anterior- and posterior wall. Using tissue Doppler imaging
 peak early (E´), peak systolic (S´) mitral annular velocities were estimated. E/E´ ratio was
 obtained by dividing E by E´.

 Strain analyses Longitudinal systolic strain was measured by speckle tracking
 echocardiography. This was obtained from 2D gray scale images of the apical 4-chamber,
 2-chamber and long-axis view with optimized focus on the left ventricle and frame rate ≥ 69
 frames/sec. Duration of systole was defined in the 5-chamber apical view by marking aorta
 valve opening and closure from the continuous wave Doppler curve.

 Strain analyses were done in EchoPAC version 1.12.0 (GE, Vingmed) with the Q-analysis
 software. The left ventricular borderline was manually traced in each apical plane and
 tracking of motion was automatically done by the software. Peak systolic strain was
 determined in all 18 segments from the three apical views. Global strain for the left
 ventricle was provided by the software as the average value of the peak systolic longitudinal
 strain of the three apical views. Strain of the infarct zone was calculated as the mean value
 of the segments supplied by the culprit vessel

 Time to intensive statin bolus:

 Patients randomized to the intensive care group were given a loading bolus of rosuvastatin 80
 mg as soon as possible after admission and continued intensive treatment with 40 mg daily.
 Patients randomized to the usual care group were treated after current guidelines with
 simvastatin 40 mg daily and started statin therapy before discharge from the hospital.
 Patients treated intensively were divided in two groups. A very early statin group receiving
 statin treatment before 12 hours after admission and an early statin group receiving statin
 after 12 hours but before 24 hours from admission to the hospital.

 MSCT:

 The investigators performed a contrast enhanced Cardiac CT (MSCT) at randomization and after
 12 month. The investigators used a standardized protocol at every examination and detailed
 method description can be seen elsewhere.

 Biochemistry:

 Blood was drawn at baseline before randomization and after 30 days. The investigators
 measured lipid-profile HBA1C, Creatinin, ALAT and CK.

 Statistical analyses Continuous outcome variables are presented as mean ± standard deviation
 (SD). Changes in outcome variables from baseline to follow-up are presented as Delta (∆)
 values (follow-up values - baseline values) Differences between groups are analyzed with an
 unpaired Students t-test with unequal variance. The investigators used multiple linear
 regressions in order to adjust for potential confounders. The investigators defined the
 confounders to be: Baseline left ventricular output variable, diabetes, hypertension,
 hypercholesterolemia, prior statin treatment, history of ACS, type of infarction, type of
 invasive treatment, culprit vessel, beta-blockers, ACE/ARB-inhibitors and time from symptoms
 to invasive treatment.

 Continuous exposure variables are presented as median and lower and upper quartiles and
 categorical data as frequencies and percentages. Difference in exposure variables were tested
 with Krushal-Wallis test for continuous variables and for categorical variables with
 Fischer's exact test. Statistical tests were two-sided, and a P-value < 0.05 was considered
 to be statistically significant. All statistical analyses were performed using STATA version
 12 (StataCorp LP, Collage Station, TX, USA)
Inclusion Criteria:

 -  All patients with NSTEMI and STEMI

 Exclusion Criteria:

 -  prior intensive statin treatment

 -  contraindication to intensive statin therapy

 -  Time limit above 24 hours from hospital admission.