Ezetimibe Utilization Early After Acute Myocardial Infarction. "EzAMI Trial"

Introduction:

After a major event of "atherosclerotic cardiovascular disease" ASCVD, like a stroke or "Acute Myocardial infarction" AMI, best practice clinical guidelines strongly recommend prompt initiation of high-intensity statin therapy for secondary prevention of recurrent events.1-4 Owing to its plaque stabilization effects, pleotropic anti-inflammatory effects, besides its "Low Density Lipoprotein-Cholesterol" LDL-C lowering effects, statins received the highest levels of recommendations in these settings.5,6 We learnt from the Cholesterol Treatment Trialist "CTT" collaboration through studying 170,000 cases from 26 trials, that the magnitude of LDL-C reduction is translated into a proportionate reduction of adverse events.7 It was found that every 1 mmol/L (38.8 mg/dl) reduction in LDL-C is paralleled by a 22% in major vascular events (AMI-death- stroke- any revascularization); 23% in major adverse coronary events; 20% in coronary artery disease deaths; 17% in total stroke and by 10% in total deaths.7 Hence, in secondary prevention of ASCVD, guidelines clearly instructs for aggressive reduction of LDL-C by at least 50% of baseline values and to levels <70 mg/dl or <55 mg/dl for ACC or ESC guidelines respectively.1,2 Nevertheless, both guidelines instructed to initiate statins monotherapy after the index event, and to add other agents (mainly; Ezetimibe or PCSK9i) if targets were found not have been achieved in follow-ups.1,2 High intensity statins as monotherapy are expected according to ESC and ACC guidelines1,2 to reduce LDL-C levels by about 50%, while according to the NICE guidelines4 by 40%. However, most reports from real life experience quite often revealed no more than 35%-to-40% reductions.8,9 Thus, failures to achieve target LDL-C levels is quite prevalent, and obviously is more common with higher baseline LDL-C levels. In the data published from the PINNACLE registry involving 1.9 million patients with ASCVD, only 31.9% of those on statin monotherapy could achieve LDL-C <70 mg/dl.10 Similar results were reported in the NHANES, EUROASPIRE and GOULD registries.8,11,12 There is large body of evidence that the early period after an ASCVD event is the most vulnerable period for recurrent events.7,13,14 The previously mentioned benefits in CTT were observed over 5 years of follow-up, yet, the magnitude of risk reduction in the earliest 12 months was equal to the cumulative reduction in the subsequent 4 years.7 In a sub-analysis from the FOURIER trial, intensifying LDL-C reduction by combining Evolocumab with maximum tolerated statins resulted in larger risk reduction in those with recent (≤12 months) MI compared to those with remote (>12 months) MI; with a RRR for CV death, MI or stroke of 25% vs 15%).15 Plausibly, the absolute benefit of intensified preventive measures is maximized when the absolute risk is more. It can be arguable that initiating combination LDL-C lowering therapies promptly after AMI would be more appropriate than endangering more than two thirds of the patients who would fail to achieve LDL-C targets through such a vulnerable period awaiting to establish the indication in follow-up visits. This is of particular concern in patients with high baseline LDL-C expected not to achieve goals with statins alone.1,2 The EVOPACS study, "Evolocumab for Early Reduction of LDL-Cholesterol Levels in Patients with Acute Coronary Syndromes" tested atorvastatin 40 mg alone compared to combining atorvastatin 40 mg plus PCSK9 Evolocumab 420 mg started during index hospitalization and repeated after 4 weeks.9 At 8 weeks interval, LDL-C was reduced by 35.4% in the atorvastatin group compared to 77.1% in Evolocumab + atorvastatin (from 3.42±0.94 mmol/L to 2.06±0.63 and from 3.61±1.00 mmol/L to 0.79±0.46 respectively). Worth mentioning that by the 8 weeks follow up time, achieving LDL-C < 70 mg/dl (1.8 mmol/L) occurred only in 37.6% in the statin monotherapy compared to 95.7% in the combination arm.9 Despite the high potency of PCSK9 inhibitors in LDL-C reduction, the ACC describes them as overpriced and not cost-effective in the contemporary prices.2 Ezetimibe is a very affordable agent that inhibits exogenous cholesterol absorption by acting on Nieman-pick C1 like1 protein. It is a safe and well tolerated drug that need no dose reduction or adjustment in moderate renal or hepatic dysfunction. Because of acting at different hinge points, Ezetimibe acts additively to statins and leads to further 20% reduction of serum LDL-C levels.16,17 The current ACC 2018 guidelines for cholesterol management gave a class (I) level of evidence (B) that patients with ASCVD judged to be at very high risk and are considered for PCSK9 inhibitors, should be receiving maximally tolerated statins and ezetimibe.2 In the IMPROVE-IT, "IMProved Reduction of Outcomes: Vytorin Efficacy International Trial", adding Ezetimibe to Simvastatin 40 mg reduced MACE by 6.4% compared to Simvastatin 40 mg alone in patients with ACS and LDL-C > 125 mg/dl.17 Though such results are in favor of combining Ezetimibe with statins after ACS, yet Simvastatin at the dose of 40 mg is a moderate intensity statin and up titration to 80 mg is strongly discouraged.1,2 Moreover, Simvastatin is characterized by multiple drug-drug interactions, an issue that increased chances for side effects, intolerance and thus treatment discontinuation compared to the currently more often used atorvastatin and rusovastatin.2,16 Being safe and affordable, upfront combination of high intensity statin plus ezetimibe to AMI patients might be more effective in achieving LDL-C targets and reducing adverse events compared to the current practice of initiating statin monotherapy and deferring intensification weeks-to-months till the time of follow-up.

Aim of the Work Evaluate safety and efficacy of initiating combined ezetimibe plus statin therapy compared to statin monotherapy early after AMI.

Ethical Considerations The study shall be launched after ethical committee approval. Informed consents will be obtained from eligible participants prior enrollment to the study. Patients will be fully oriented about the benefits and potential adverse effects by participation. They will be given a shortcut access (through the study team direct contact) in cases any problems or complaints occurred. Possible side effects of any of the used medications will be thoroughly discussed with the patients for early identification and swift reporting to the research team. Patients will be informed about the schedule of follow up visits and about the study-dictated laboratory workup. Patients' identity and data are completely confidential and will not be disclosed except to treating physicians. All clinical, laboratory data and data from genetic tests will be dealt with complete confidentiality. Data for analysis and laboratory results will be anonymized before they are given to the statistical team, and thus study results will be devoid of any personal data.

Methodology I. Study design A Prospective Randomized Controlled Study. II. Study setting and location The study will be conducted in and fully supported by Aswan Heart Centre, Magdi Yacoub Foundation.