Ignite Creation Date:
2024-05-06 @ 3:38 PM
Last Modification Date:
2024-10-26 @ 1:53 PM
Study NCT ID:
NCT04701242
Status:
RECRUITING
Last Update Posted:
2021-07-28
First Post:
2021-01-06
Brief Title:
Ezetimibe Utilization Early After Acute Myocardial Infarction EzAMI Trial
Sponsor:
Cairo University
Organization:
Cairo University
Study Overview
Official Title:
Ezetimibe Utilization Early After Acute Myocardial Infarction EzAMI Trial
Status:
RECRUITING
Status Verified Date:
2024-08
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
EzAMI
Brief Summary:
Rationale
Patients with acute coronary syndromes are at an increased risk for recurrent adverse coronary events particularly during the early period following their initial presentation Early in-hospital initiation of high-intensity statins reduces the risk of recurrent events and is therefore recommended by the best current practice guidelines12 However the delayed onset of action of statin therapy and given the frequent failure of patients to achieve the recommended LDL-C targets using statins alone as per the current practice guidelines recommendations might be placing large number of patients at increased risk during such a vulnerable period early after an ACS3 More rapid and effective reduction of LDL-C levels using combination therapy from the outset may therefore be beneficial in these patients This hypothesis has been tested with combining Evolocumab and a statin in the recent EVOPACS study in which this combination after ACS has shown to be safe and more effective in achieving LDL-C targets at 6 weeks compared to statin monotherapy4 However Evolocumab a PCSK9i is an expensive drug which is not affordable by many healthcare systems in low- and middle-income countries Ezetemibe on the other hand is a safe and a cheap drug that can prove to be extremely cost-effective if a meaningful and timely reduction in LDL-C levels can be achieved when combined with a statin early after an ACS
Study population Patients presenting with acute myocardial infarction with baseline LDL-C levels not likely to achieve recommended targets on statin monotherapy This is assumed to be with LDL-C level 125 mgdl for those not on lipid lowering therapy or with LDL-C 100 mgdl on moderate intensity statin therapy at the time of presentation
Study design Prospective randomized controlled single-blinded trial A sample size of 500 patients 250 in each arm was calculated to provide a power of 09 and an adjusted type 1 error as 005
Primary outcomes
Percentage of patients achieving target LDL-C levels 70 mgdl at 6 weeks interval Efficacy endpoint
Freedom from alanine transaminase elevation ALT more than 3 folds upper reference limit URL or statin associated muscle symptoms associated with CK elevation more than 4 folds URL Safety endpoint Secondary outcomes
Percentage of patients achieving 50 reduction of LDL-C and to levels below 70mgdl at 6 weeks interval
Percentage of LDL-C reduction at 6 weeks interval
Reduction of high-sensitive C-reactive protein hs-CRP from baseline to 6 weeks interval
Correlating statins efficacy to reduce LDL-C and likelihood to cause statins related adverse effects to genetic alleles of ABC ATP Binding Cassette types A1 G5 and G8 and of CYP450 isoenzymes
MACE free survival at 1 year CV death non fatal-MI hospitalization for ACS urgent unplanned revascularization and stroke
Patients with acute coronary syndromes are at an increased risk for recurrent adverse coronary events particularly during the early period following their initial presentation Early in-hospital initiation of high-intensity statins reduces the risk of recurrent events and is therefore recommended by the best current practice guidelines12 However the delayed onset of action of statin therapy and given the frequent failure of patients to achieve the recommended LDL-C targets using statins alone as per the current practice guidelines recommendations might be placing large number of patients at increased risk during such a vulnerable period early after an ACS3 More rapid and effective reduction of LDL-C levels using combination therapy from the outset may therefore be beneficial in these patients This hypothesis has been tested with combining Evolocumab and a statin in the recent EVOPACS study in which this combination after ACS has shown to be safe and more effective in achieving LDL-C targets at 6 weeks compared to statin monotherapy4 However Evolocumab a PCSK9i is an expensive drug which is not affordable by many healthcare systems in low- and middle-income countries Ezetemibe on the other hand is a safe and a cheap drug that can prove to be extremely cost-effective if a meaningful and timely reduction in LDL-C levels can be achieved when combined with a statin early after an ACS
Study population Patients presenting with acute myocardial infarction with baseline LDL-C levels not likely to achieve recommended targets on statin monotherapy This is assumed to be with LDL-C level 125 mgdl for those not on lipid lowering therapy or with LDL-C 100 mgdl on moderate intensity statin therapy at the time of presentation
Study design Prospective randomized controlled single-blinded trial A sample size of 500 patients 250 in each arm was calculated to provide a power of 09 and an adjusted type 1 error as 005
Primary outcomes
Percentage of patients achieving target LDL-C levels 70 mgdl at 6 weeks interval Efficacy endpoint
Freedom from alanine transaminase elevation ALT more than 3 folds upper reference limit URL or statin associated muscle symptoms associated with CK elevation more than 4 folds URL Safety endpoint Secondary outcomes
Percentage of patients achieving 50 reduction of LDL-C and to levels below 70mgdl at 6 weeks interval
Percentage of LDL-C reduction at 6 weeks interval
Reduction of high-sensitive C-reactive protein hs-CRP from baseline to 6 weeks interval
Correlating statins efficacy to reduce LDL-C and likelihood to cause statins related adverse effects to genetic alleles of ABC ATP Binding Cassette types A1 G5 and G8 and of CYP450 isoenzymes
MACE free survival at 1 year CV death non fatal-MI hospitalization for ACS urgent unplanned revascularization and stroke
Detailed Description:
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 events1-4 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 settings56 We learnt from the Cholesterol Treatment Trialist CTT collaboration through studying 170000 cases from 26 trials that the magnitude of LDL-C reduction is translated into a proportionate reduction of adverse events7 It was found that every 1 mmolL 388 mgdl 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 deaths7 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 mgdl or 55 mgdl for ACC or ESC guidelines respectively12 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-ups12 High intensity statins as monotherapy are expected according to ESC and ACC guidelines12 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 reductions89 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 19 million patients with ASCVD only 319 of those on statin monotherapy could achieve LDL-C 70 mgdl10 Similar results were reported in the NHANES EUROASPIRE and GOULD registries81112 There is large body of evidence that the early period after an ASCVD event is the most vulnerable period for recurrent events71314 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 years7 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 1515 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 alone12 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 weeks9 At 8 weeks interval LDL-C was reduced by 354 in the atorvastatin group compared to 771 in Evolocumab atorvastatin from 342094 mmolL to 206063 and from 361100 mmolL to 079046 respectively Worth mentioning that by the 8 weeks follow up time achieving LDL-C 70 mgdl 18 mmolL occurred only in 376 in the statin monotherapy compared to 957 in the combination arm9 Despite the high potency of PCSK9 inhibitors in LDL-C reduction the ACC describes them as overpriced and not cost-effective in the contemporary prices2 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 levels1617 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 ezetimibe2 In the IMPROVE-IT IMProved Reduction of Outcomes Vytorin Efficacy International Trial adding Ezetimibe to Simvastatin 40 mg reduced MACE by 64 compared to Simvastatin 40 mg alone in patients with ACS and LDL-C 125 mgdl17 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 discouraged12 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 rusovastatin216 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
The researchers do not have any connections to industry did not and will not receive funds or support from any sponsors
III Study population Patients presenting by acute myocardial infarction both STEMI and NSTEMI are included Diagnosis will depend on clinical presentation twelve-lead ECG cardiac biomarkers and echocardiography when diagnosis is doubtful as recommended by the 4th universal definition of myocardial infarction18 IV Eligibility Criteria Patients presenting by AMI who are likely not to achieve LDL-C targets on statin monotherapy
1 Inclusion criteria
Age more than 18 years Both genders are eligible
Acute myocardial infarction STEMI or NSTEMI within 48 hours from the onset of symptoms
Baseline LDL-C above 125 mgdl for those who were not on consistent lipid lowering therapy or above 100 mgdl for those who were compliant 90 days on moderate intensity statin therapy
2 Exclusion criteria
Refusal to participate in the study
Proved intolerance to statins on previous use
Having conditions or taking medications that would not allow concomitant safe statins use such as patients receiving Cyclosporine - Gemfibrozil -Pazopanib - Tipranavir - Itraconazole - Ketoconazole
Those who are already compliant on high intensity statins
Those who are already on statins plus non-statin agent ezetimibe-PCSK9i-BAS
Known familial dyslipidemia or having TG500 mgdl or LDL-C190 mgdl which are highly suggestive of familial or secondary causes
Pregnant or contemplating pregnancy in the following 12 months relevant for females in the child-bearing period V Study Procedures
1 Randomization Within 48 hours of the onset of symptoms a computer-generated sequence will be used for randomization into 11 fashion to allocate eligible patients into either statin monotherapy will receive atorvastatin 80 mg or statins-ezetimibe combination will receive atorvastatin 80 mg ezetimibe 10 mg
2 Study Protocol A baseline lipid profile will be checked within 48 hours from the AMI onset A fasting lipid profile will be ordered if the triglycerides were 400 mgdl in the non-fasting results Eligible patients will be recruited after explaining the study protocol and acquiring a written informed consent A venous blood sample for genetic analysis will be provided to perform cutting edge next generation sequencing to investigate for genetic alleles of ATP Binding Cassette ABC types A1 G5 G8 and CYP450 and correlate isoform variants with statins responsiveness and efficacy to achieve LDL-C targets Genetic sequencing will be performed using high throughput sequencers
Management of the AMI will be according to the most recent guidelines recommendations including both the interventional and the medical aspects The statin monotherapy arm will receive atorvastatin 80 mg once daily as their lipid lowering therapy compared to the combination therapy arm who will receive atorvastatin 80 mg plus ezetimibe 10 mg once daily To ensure blinding and compliance participants will be provided free of charge with 2 differently colored packings for lipid control through the 12 months of the study In the statins alone arm both will contain atorvastatin 40mg tablets while for the combination arm one of them will contain atorvastatinezetimibe 4010mg and the other will be atorvastatin 40mg tablets Patients will be instructed to have 1 tablet from each packing at night
Apart from LDL-C management life-style interventions and all other guidelines directed medical therapy GDMT will be equally implemented in both arms The study team as part of the general practice in AHC will be consolidating advices for compliance to life-style interventions and all other GDMT but will not be providing them
Hs-CRP ALT CK and lipid profile will be tested at baseline and at 6 weeks of the study Repeating these or ordering any other laboratory workup will be allowed at any other time deemed clinically indicated Patients on the statin monotherapy arm not achieving target LDL-C levels on the 6-weeks follow-up will be prescribed ezetimibe in addition to their regimen as per current best practice guidelines but will remain labelled as initial monotherapy group
Participants will have a clinical follow-up visit at 6 weeks 6 months then at 1 year However they will be instructed to contact the research team at any relevant clinical complaint or emergency Magdi Yacoub foundation is completely responsible for the management of any clinical complication or adverse events resulting from or related to the study agent After the study ends 1 year participants will be offered the regular follow-up appointments according to AHC institutional policy
VI Study outcomes
1 Primary outcome
Percent of patients who achieve required LDL-C targets according to the ACC guidelines 70 mgdl at 6 weeks interval Efficacy endpoint
Freedom from Alanine Transaminase elevation ALT more than 3 folds upper reference limit OR muscle pains associated with CK elevation more than 4 folds upper reference limit Safety endpoint
2 Secondary outcomes
Percent of patients achieving 50 reduction from baseline and to a level 70 mgdl of LDL-C to 6 weeks interval
Percent of LDL-C reduction from baseline to 6 weeks interval
Reduction of high-sensitive C-reactive protein hs-CRP from baseline to 6 weeks interval
Correlating efficacy of statins to reduce LDL-C andor cause statins related adverse effects to genetic alleles of ABC types A1 G5 and G8 and CYP450 which are believed to impact statins pharmacokinetics and pharmacodynamics
MACE free survival at 1 year cardiovascular death non fatal-MI hospitalization for ACS urgent unplanned revascularization and cerebrovascular stroke
Statistical Analysis I Sample size Sample size was calculated using MedCalc Statistical Software version 1904 MedCalc Software Ostend Belgium httpswwwmedcalcorg 2019 adjusting margin for type 1 error as 005 and utilizing a study power of 90 The expected proportion of patients on statin monotherapy achieving LDL-C targets was adjusted to 50 it was 376 in the control arm of EVOPACS 9 and we expected that this proportion to be 70 in the combination group Accordingly a minimum sample of 268 patients randomized in 11 fashion was suggested The research group planned to have a sample of 500 patients on 2 groups of 250 each
II Statistical analysis Statistical package for social science SPSS software version 22 for Microsoft Windows SPSS Inc Chicago IL USA will be used for data analysis Categorical data will be presented as frequency and percentages n and correlations among them will be analysed by chi square test Continuous data will be checked for normality using Shapiro-Wilk test and will be presented as mean standard deviation or median interquartile range as appropriate Continuous data will be analysed using one-way analysis of variance ANOVA Repeated measures will be analysed using analysis of variance ANOVA for repeated measures with post-hoc pairwise comparisons using the Tukey and Bonferroni tests A probability p value less than 005 will be considered statistically significant
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 events1-4 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 settings56 We learnt from the Cholesterol Treatment Trialist CTT collaboration through studying 170000 cases from 26 trials that the magnitude of LDL-C reduction is translated into a proportionate reduction of adverse events7 It was found that every 1 mmolL 388 mgdl 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 deaths7 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 mgdl or 55 mgdl for ACC or ESC guidelines respectively12 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-ups12 High intensity statins as monotherapy are expected according to ESC and ACC guidelines12 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 reductions89 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 19 million patients with ASCVD only 319 of those on statin monotherapy could achieve LDL-C 70 mgdl10 Similar results were reported in the NHANES EUROASPIRE and GOULD registries81112 There is large body of evidence that the early period after an ASCVD event is the most vulnerable period for recurrent events71314 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 years7 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 1515 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 alone12 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 weeks9 At 8 weeks interval LDL-C was reduced by 354 in the atorvastatin group compared to 771 in Evolocumab atorvastatin from 342094 mmolL to 206063 and from 361100 mmolL to 079046 respectively Worth mentioning that by the 8 weeks follow up time achieving LDL-C 70 mgdl 18 mmolL occurred only in 376 in the statin monotherapy compared to 957 in the combination arm9 Despite the high potency of PCSK9 inhibitors in LDL-C reduction the ACC describes them as overpriced and not cost-effective in the contemporary prices2 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 levels1617 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 ezetimibe2 In the IMPROVE-IT IMProved Reduction of Outcomes Vytorin Efficacy International Trial adding Ezetimibe to Simvastatin 40 mg reduced MACE by 64 compared to Simvastatin 40 mg alone in patients with ACS and LDL-C 125 mgdl17 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 discouraged12 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 rusovastatin216 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
The researchers do not have any connections to industry did not and will not receive funds or support from any sponsors
III Study population Patients presenting by acute myocardial infarction both STEMI and NSTEMI are included Diagnosis will depend on clinical presentation twelve-lead ECG cardiac biomarkers and echocardiography when diagnosis is doubtful as recommended by the 4th universal definition of myocardial infarction18 IV Eligibility Criteria Patients presenting by AMI who are likely not to achieve LDL-C targets on statin monotherapy
1 Inclusion criteria
Age more than 18 years Both genders are eligible
Acute myocardial infarction STEMI or NSTEMI within 48 hours from the onset of symptoms
Baseline LDL-C above 125 mgdl for those who were not on consistent lipid lowering therapy or above 100 mgdl for those who were compliant 90 days on moderate intensity statin therapy
2 Exclusion criteria
Refusal to participate in the study
Proved intolerance to statins on previous use
Having conditions or taking medications that would not allow concomitant safe statins use such as patients receiving Cyclosporine - Gemfibrozil -Pazopanib - Tipranavir - Itraconazole - Ketoconazole
Those who are already compliant on high intensity statins
Those who are already on statins plus non-statin agent ezetimibe-PCSK9i-BAS
Known familial dyslipidemia or having TG500 mgdl or LDL-C190 mgdl which are highly suggestive of familial or secondary causes
Pregnant or contemplating pregnancy in the following 12 months relevant for females in the child-bearing period V Study Procedures
1 Randomization Within 48 hours of the onset of symptoms a computer-generated sequence will be used for randomization into 11 fashion to allocate eligible patients into either statin monotherapy will receive atorvastatin 80 mg or statins-ezetimibe combination will receive atorvastatin 80 mg ezetimibe 10 mg
2 Study Protocol A baseline lipid profile will be checked within 48 hours from the AMI onset A fasting lipid profile will be ordered if the triglycerides were 400 mgdl in the non-fasting results Eligible patients will be recruited after explaining the study protocol and acquiring a written informed consent A venous blood sample for genetic analysis will be provided to perform cutting edge next generation sequencing to investigate for genetic alleles of ATP Binding Cassette ABC types A1 G5 G8 and CYP450 and correlate isoform variants with statins responsiveness and efficacy to achieve LDL-C targets Genetic sequencing will be performed using high throughput sequencers
Management of the AMI will be according to the most recent guidelines recommendations including both the interventional and the medical aspects The statin monotherapy arm will receive atorvastatin 80 mg once daily as their lipid lowering therapy compared to the combination therapy arm who will receive atorvastatin 80 mg plus ezetimibe 10 mg once daily To ensure blinding and compliance participants will be provided free of charge with 2 differently colored packings for lipid control through the 12 months of the study In the statins alone arm both will contain atorvastatin 40mg tablets while for the combination arm one of them will contain atorvastatinezetimibe 4010mg and the other will be atorvastatin 40mg tablets Patients will be instructed to have 1 tablet from each packing at night
Apart from LDL-C management life-style interventions and all other guidelines directed medical therapy GDMT will be equally implemented in both arms The study team as part of the general practice in AHC will be consolidating advices for compliance to life-style interventions and all other GDMT but will not be providing them
Hs-CRP ALT CK and lipid profile will be tested at baseline and at 6 weeks of the study Repeating these or ordering any other laboratory workup will be allowed at any other time deemed clinically indicated Patients on the statin monotherapy arm not achieving target LDL-C levels on the 6-weeks follow-up will be prescribed ezetimibe in addition to their regimen as per current best practice guidelines but will remain labelled as initial monotherapy group
Participants will have a clinical follow-up visit at 6 weeks 6 months then at 1 year However they will be instructed to contact the research team at any relevant clinical complaint or emergency Magdi Yacoub foundation is completely responsible for the management of any clinical complication or adverse events resulting from or related to the study agent After the study ends 1 year participants will be offered the regular follow-up appointments according to AHC institutional policy
VI Study outcomes
1 Primary outcome
Percent of patients who achieve required LDL-C targets according to the ACC guidelines 70 mgdl at 6 weeks interval Efficacy endpoint
Freedom from Alanine Transaminase elevation ALT more than 3 folds upper reference limit OR muscle pains associated with CK elevation more than 4 folds upper reference limit Safety endpoint
2 Secondary outcomes
Percent of patients achieving 50 reduction from baseline and to a level 70 mgdl of LDL-C to 6 weeks interval
Percent of LDL-C reduction from baseline to 6 weeks interval
Reduction of high-sensitive C-reactive protein hs-CRP from baseline to 6 weeks interval
Correlating efficacy of statins to reduce LDL-C andor cause statins related adverse effects to genetic alleles of ABC types A1 G5 and G8 and CYP450 which are believed to impact statins pharmacokinetics and pharmacodynamics
MACE free survival at 1 year cardiovascular death non fatal-MI hospitalization for ACS urgent unplanned revascularization and cerebrovascular stroke
Statistical Analysis I Sample size Sample size was calculated using MedCalc Statistical Software version 1904 MedCalc Software Ostend Belgium httpswwwmedcalcorg 2019 adjusting margin for type 1 error as 005 and utilizing a study power of 90 The expected proportion of patients on statin monotherapy achieving LDL-C targets was adjusted to 50 it was 376 in the control arm of EVOPACS 9 and we expected that this proportion to be 70 in the combination group Accordingly a minimum sample of 268 patients randomized in 11 fashion was suggested The research group planned to have a sample of 500 patients on 2 groups of 250 each
II Statistical analysis Statistical package for social science SPSS software version 22 for Microsoft Windows SPSS Inc Chicago IL USA will be used for data analysis Categorical data will be presented as frequency and percentages n and correlations among them will be analysed by chi square test Continuous data will be checked for normality using Shapiro-Wilk test and will be presented as mean standard deviation or median interquartile range as appropriate Continuous data will be analysed using one-way analysis of variance ANOVA Repeated measures will be analysed using analysis of variance ANOVA for repeated measures with post-hoc pairwise comparisons using the Tukey and Bonferroni tests A probability p value less than 005 will be considered statistically significant
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None