Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02291796 |
| Other study ID # |
R-2010-3604-17 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
November 7, 2014 |
| Last updated |
November 11, 2014 |
| Start date |
January 2011 |
| Est. completion date |
December 2013 |
Study information
| Verified date |
November 2014 |
| Source |
Instituto Mexicano del Seguro Social |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Mexico: Coordinación de Investigación en Salud |
| Study type |
Interventional
|
Clinical Trial Summary
Introduction: Plasma fibrinogen levels have been identified as an important risk factor for
cardiovascular diseases and could have a prognostic value. Bezafibrate decreases fibrinogen
levels and also the incidence of major cardiovascular events in primary prevention, but its
effects in acute coronary syndrome is unknown.
Hypothesis: Bezafibrate effect over statin therapy reduces fibrinogen concentrations,
inflammatory response and clinical events, in patients with ST segment elevation ACS and
hyperfibrinogenemia.
Methods: In a randomized clinical trial, controlled with conventional therapy. Patients with
ST elevation acute myocardial infarction (STEAMI) and with fibrinogen concentration >500
mg/dl at 72 h of evolution, were randomly assigned to bezafibrate 400 mg/day (group I n=50)
or just conventional therapy (group II n=50). Serum fibrinogen, c reactive protein and
cytokines were measured. Clinical end points were recurrence of angina or infarction, left
ventricular failure, cardiovascular mortality and combined end points during
hospitalization.
Description:
Patients >18 years of age who were admitted to the Cardiovascular Intensive Care Unit of the
Cardiology Hospital, National Medical Center, Century XXI (Mexico City) and diagnosed with
ST segment elevation Acute Coronary Syndrome (ACS) and hyperfibrinogenemia within 72 h of
symptom onset were included. Acute myocardial infarction (AMI) was diagnosed when high
myocardial necrosis markers were found such as CPK total >150% basal value or troponin I ≥1
ng/ml plus one of the following: ischemic precordial pain >30 min with/without dyspnea,
diaphoresis, nausea, vomiting, or ST segment elevation >1 mm in two or more contiguous leads
or left bundle branch block, new or presumed new. Hyperfibrinogenemia was diagnosed after
fibrinogen concentrations reached >500 mg/dl at 72 h of evolution. All patients signed an
informed consent form to participate in the study.
Patients with known bezafibrate allergy, previous fibrate treatments, patients with
cardiogenic shock, hepatic failure, renal failure, history of neoplastic disease, chronic
inflammatory disease or active infectious process, anti-inflammatory or immunosuppressive
therapies, fibrinolysis with streptokinase and patients with triglyceride concentrations
>150 mg/dl were excluded.
Patients were classified into two groups: group I, patients who received a 400-mg
bezafibrate dose every 24 h plus conventional anti-ischemic therapy; and group II, patients
who only received conventional anti-ischemic therapy. Patients were assigned to each group
using random numbers tables. Conventional adjunctive anti-ischemic therapy included dual
antiplatelet therapy, antithrombotic, beta blockers, statins, angiotensin converting enzyme
inhibitors, and others according to each case. Twelve-lead ECG was carried out daily and
under recurrent ischemic event. Laboratory tests were also carried out including cardiac
enzymes, lipid profile and CRP.
Our goal was to determine if bezafibrate therapy combined with conventional anti-ischemic
therapy reduces fibrinogen levels. Primary endpoints were recurrent ischemic event such as
reinfarction or post-infarction angina and left ventricular failure. Secondary endpoints
were death, need for revascularization and combined clinical endpoints that will be
presented after randomization and before patient discharge.
Blood samples were taken in all patients by venipuncture in an upper extremity (Vena
basilica, cephalic or any tax): 4.5 ml of blood, collected into a 0.5 ml tube vacutainer
with sodium citrate buffer (9: 1) 0129 M 3.8% (blue top), which is used to determine the
coagulation time and fibrinogen; and another 7 ml, which will be collected in vacutainer
tubes dry (red cap). The samples will be centrifuged at 2000 rpm for 10 min and the serum
obtained will be divided into aliquots of 200 ul to keep at -70 ° C for subsequent
biochemical determinations. This procedure will be performed on admission to the
Cardiovascular Intensive Care Unit and on days 5, 7 and 30 of its randomizationAll patients
after hospital discharge, will be cited by telephone at 30 days after randomization, for
taking blood samples, as well as for clinical evaluation.Fibrinogen Determination All venous
blood samples (4.5 ml) will be taken from an upper limb (basilic vein, cephalic vein or any
of their tributaries) and collected in a Vacutainer (Becton Dickinson, Franklin Lakes, NJ)
tube with 0.5 ml sodium nitrate buffer (9:1) 0.129 M 3.8% (blue top). This procedure was
repeated at discharge or after 7 days when the patient was subjected to a long hospital
stay. PT-Fibrinogen HS Plus kit (Beckman Coulter, Brea, CA) was used. This contains
high-sensitivity calcium thromboplastin to determine prothrombin time and fibrinogen and to
evaluate extrinsic pathway of coagulation in citrated human plasma using an auto-analyzer
ACL-800 (Cobas, Roche Diagnostics, Indianapolis, IN) where fibrinogen levels are determined
through turbidimetry. Test measure correlation was r = 0.95. Units reported for fibrinogen
are mg/dl and the standard control is 273 mg/dl with a linearity of 700 mg/dl.
c) Clinical evaluation For clinical follow-up evaluation after randomization, the presence
of recurrent cardiovascular events and is regarded as secondary endpoints: events of
recurrent ischemia either the presence of angina, reinfarction, or silent ischemia, need for
procedures Emergency myocardial revascularization left ventricular failure, shock and death,
stating the time from randomization to the presentation of the event, electrocardiographic
or biochemical changes that occur time. Both during their hospital stay, as at discharge,
data were obtained either directly by history, physical examination and laboratory, and the
clinical record, taking into account the assessment of the treating physician and recorded
in the data collection sheet.
Cytokines assay Concentration of cytokines (IL-8, IL-1β, IL-6, IL-10, TNF e IL-12) were
measured by ELISA system (Biosource), with two different monoclonal antibodies against
different epitopes of interleukins, biotinylated detector antibodies, conjugated
Streptavidin-HRP (SAV) buffer, chromogen substrate and stop solution. Once the plasma
samples and the supernatants were unfroze, all the standard and samples were diluted with
the standard dilutor assay buffer. A100μl of the standard, samples, supernatants and
controls were added to a coated microtiter plate by duplicate test and incubated by an hour.
The biotinylated detector antibodies were diluted in buffer and added 50μl to 100 μl to each
well, excepted the empty chromogen, then incubated for 1 hour at 37°C. Plates were the
washed; a 100 μl of SAV diluted with buffer, was added to each well and incubated for other
45 min. Microtiter plate was washed again. Tetramethylbenzidine substrate was added (100 μl
each well), incubated for 15min more in darkness at room temperature. Finally 50 to 100 μl
of stop solution was used. Plates were read 30 min after, at 490 nm in an automated
microplate reader.
Statistical Analysis Continuous variables were described according to distribution (mean ±
standard deviation, median and percentiles). Demographic characteristics of the population
were expressed in frequency percentage. Student t-distribution was used for bivariate
analysis of continuous variables and group comparison for those parameters with normal
distribution and Mann-Whitney U test for those with non-normal distribution. Wilcoxon test
was used to analyze the fibrinogen concentration difference within each group. Dichotomous
variables were tested using X2 and Fisher's exact test depending on expected values.
Relative risk (RR) and 95% confidence intervals (CI) were calculated. Multivariate analysis
adjusted for potential confounders will be performed. Calculation of the number needed to
treat and the analysis with intention to treat will be done. Relative risks and confidence
interval of 95% will be calculated. The value p, equal or less to 0.05, will be consider
significant. SPSS v.20.0 software will be used for data analysis
Ethical considerations The study will be evaluated by the Research Committee and Local
Research Ethics in Health UMAE Cardiology Hospital National Medical Center Siglo XXI, for
approval. The study conforms to the standards set by the Declaration of Helsinki, the rules
of the General Health Law in research in our country and the Good Clinical Practice of the
International Conference on Harmonization.
The study considered more than minimal risk and its main objective is to evaluate the
additive effect of bezafibrate to conventional anti-ischemic drug therapy in patients with
acute coronary syndrome with ST segment elevation.
Bezafibrate is a drug that is in the institutional basic list, is used to provide treatment
for patients with dyslipidemia, particularly in patients with hypertriglyceridemia. During
the study, there were not changes or interventions against the standard treatment prescribed
by the treating physician, which has proven benefits according to the Clinical Practice
Guidelines for the treatment of patients with acute coronary syndrome with ST segment
elevation.
In accordance with the provisions of the Belmont Report, can be carried out in conjunction
with the usual therapeutic practices used in these patients, since it is designed to assess
the safety and efficacy of a therapy, however it will be subject to formal investigation in
order to determine its safety and effectiveness for protection of those involved.
Adverse events reported in general are rare, transient and mild to moderate intensity. The
adverse reactions reported most frequently are loss of appetite (about 1.8%); with less
frequency (1 case in 1,000 patients who take the bezafibrate) abdominal pain, nausea
diarrhea, distension of the stomach, erectile dysfunction, feeling dizzy, gastrointestinal
problems, hair loss, headaches, abnormal laboratory test results, anaphylactic reactions,
hypersensitivity reactions, itching, kidney problems, muscle problems including muscle
weakness, cramps, pain or tenderness, photosensitivity skin reaction, skin rash or rashes,
urticaria. Other uncommon side effects (more than 1 in 10,000 people who take bezafibrate)
are neuropathy of the extremities, pancreatitis, paraesthesiae. dizziness,. There are
reported very rare, fewer than 1 in 10,000 patients receiving bezafibrate, of blood
problems, erythema multiforme, gallstones, lung problems, rhabdomyolysis, Stevens-Johnson
syndrome, toxic epidermal necrolysis, unexplained or easy bruising of the skin or mucous
membranes.
During the study, patients in addition to conventional studies of 12-lead electrocardiogram
at rest, echocardiography, X-rays and laboratory tests, need the venous blood samples for
serial measurements of fibrinogen, C-reactive protein and serum proinflammatory cytokines,
at 5, 7 and 30 days after randomization.
Patients who meet the selection criteria will be included. No patients were included in
critical condition or hemodynamic decompensation. All patients were requested to sign for
informed consent after explaining potential risks and benefits of treatment. They were
explained in detail, what it will be patient participation in the study, assessment
processes and monitoring to be performed, as well as the actions to be carried out in case
of any adverse events. The invitation to participate and signed consent application will be
requested by a different doctor than the treating physician. It will make the clarification
to the patient that their participation in the study is completely voluntary and if so
manifest, may withdraw from the study at any time If the patient has an adverse drug event
may be addressed immediately in the emergency department of the Hospital UMAE Cardiology.
The corresponding report of any side effects will to be performed to the committee of
pharmaco-vigilance (hospital committee), the VENCER system (Institutional system for reports
of any adverse event, side effect and pharmacology interaction) ant to the COFEPRIS (that is
the national Committee). The side effects are part of the study analysis for the evaluation
of drug safety. The patient shall record in a log any side or adverse event occurring during
the treatment time and given a telephone number to contact the physician 24 hours a day
during the six months being treated with bezafibrate, and time duration of the study. The
patient may also contact the physician if any questions regarding the study.
The patient data will be handled confidentially and no personal information that could
identify them will be used, in case of distribution and publication of results. Every
patient is assigned a serial number according to the time of study entry to identify him in
subsequent evaluations.
Because the drug used is part of the basic list of the IMSS, there is no conflicts of
interest among researchers.
