Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04701242 |
| Other study ID # |
20200902MYFAHC_EzAMI |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 24, 2021 |
| Est. completion date |
April 2024 |
Study information
| Verified date |
July 2021 |
| Source |
Cairo University |
| Contact |
Ahmad Samir, MD |
| Phone |
00201002647275 |
| Email |
ahmad.samir[@]kasralainy.edu.eg |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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 guidelines.(1,2) 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 ACS.(3) 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 monotherapy.(4) 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 mg/dl for those not on lipid lowering therapy; or with LDL-C > 100
mg/dl 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 0.9 and an adjusted type 1
error as 0.05.
Primary outcomes
- Percentage of patients achieving target LDL-C levels (<70 mg/dl) 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 70mg/dl 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).
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
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.
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 infarction.18 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 mg/dl for those who were not on consistent lipid lowering
therapy; or above 100 mg/dl 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 TG>500 mg/dl or LDL-C>190 mg/dl 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 1:1 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
mg/dl 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 atorvastatin/ezetimibe 40/10mg 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 mg/dl) 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
mg/dl 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 and/or 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 19.0.4 (MedCalc Software, Ostend, Belgium; https://www.medcalc.org; 2019)
adjusting margin for type 1 error as 0.05 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 37.6% 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 1:1
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 0.05 will be considered statistically significant.
