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Clinical Trials
Soejima et al., J Clin Trials 2014, 4:2
http://dx.doi.org/10.4172/2167-0870.1000162
Protocol
Open Access
The Changes of Biomarkers by Telmisartan and their Significance in
Cardiovascular Outcomes: Design of a Trial of Telmisartan Prevention of
Cardiovascular Diseases (ATTEMPT-CVD)
Hirofumi Soejima1,2, Hisao Ogawa1*, Osamu Yasud1,3, Shokei Kim-Mitsuyam1,4, Kunihiko Matsui5 , Koichi Nod5,6, Megumi Yamamuro1, Eiichiro Yamamoto1,
Keiichiro Kataok1,4, Hideaki Jinnouchi7 and Taiji Sekigami8
1Department
2Health
of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Care Center, Kumamoto University, Kumamoto, Japan
3Department
of Cardiovascular Clinical and Translational Research, Japan
4Department
of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
5Department
of General Internal Medicine, Yamaguchi University, Ube, Japan
6Department
of Cardiovascular Medicine, Saga University, Saga, Japan
7Diabetes
Care Center, Jinnouchi Clinic, Kumamoto, Japan
8Department
of Metabolism and Endocrine, Kumamoto Social Insurance General Hospital, Yatsushiro, Japan
*Corresponding
author: Ogawa H, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto City,
Japan, Tel: 81-96-373-5175; Fax: 81-96-362-3256; E-mail: [email protected]
Copyright: © 2014 Soejima H, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received date: Feb 06, 2014; Accepted date: March 13, 2014; Published date: March 17, 2014
Abstract
Objective: Angiotensin II receptor blocker (ARB) has become first-line agent for the treatment of hypertensive
patients because they are associated with an excellent effect for blood pressure control and a lower rate of
occurrence of adverse reactions. To our knowledge, there is no report of the large-scale study that measures
biomarkers in 1000 or more patients for long follow-up period. To compare the effects of ARB therapy and that of
standard therapy except ARB on the changes of biomarker levels and the incidence of cardiovascular events, a trial
of telmisartan prevention of cardiovascular diseases (ATTEMPT-CVD) was planned. Urinary albumin creatinine
rates, plasma brain natriuretic peptide, serum high sensitivity c-reactive protein, urinary 8-hydroxy-deoxy-guanosine,
serum adiponectin, and high-molecular weight adiponectin were selected as biomarkers. These biomarkers are
known to be predictive factors for cardiovascular event, renal dysfunction, or atherosclerosis.
Methods: ATTEMPT-CVD is a multicenter, prospective, randomized open-label, controlled trial with blinded endpoint assessment. High-risk patients with heart, peripheral, renal, or cerebrovascular disease or diabetes are being
recruited and followed for 3 years. The randomization is performed as stratified randomization after age, gender,
past history of disease and usage of angiotensin converting enzyme inhibitor are adjusted for. The biomarker
assessment is performed at the start of the study (at registration), after 6, 12, 24 and 36 months from the start of the
study. Furthermore, survey of general laboratory tests, cardiovascular events, adverse events, and drug compliance
is also performed at the same point of biomarker assessment and after 3 months from the start of the study.
Conclusions: The ATTEMPT-CVD is the first large clinical trial focusing of the efficacy of ARB therapy on the
relationship between prevention of cardiovascular event and the changes of biomarkers. This study will provide a
novel insight into the significance of biomarkers considering the therapy on high-risk hypertensive patients.
Keywords: Angiotensin II receptor blocker; Biomarker;
Cardiovascular event; Hypertension; Urinary albumin creatinine rates;
Brain natriuretic peptide; High sensitivity c-reactive protein; Urinary
8-hydroxy-deoxy-guanosine; Adiponectin; Estimated glomerular
filtration rate
Introduction
Angiotensin Converting Enzyme (ACE) inhibitors reduce rates of
heart failure, myocardial infarction, stroke, and death among patients
with heart failure [1], left ventricular dysfunction [2-4], previous
vascular disease alone [5-7], or high-risk diabetes [8]. ACE inhibitors
reduce bradykinin degradation, which enhances vasodilatation, but
increase the rates of angioedema and cough. The effect of Angiotensin
J Clin Trials
ISSN:2167-0870 JCTR, an open access journal
II Receptor Blocker [ARB] on BP is the same as those of other
antihypertensive agents, including Ca antagonists, ACE inhibitors, and
others [9,10]. ARBs have become first-line agents for the treatment of
hypertensive patients because they are associated with a lower rate of
occurrence of adverse reactions than ACEIs and Ca antagonists. The
ongoing telmisartan alone and in combination with ramipril global
end-point trial (ONTARGET) demonstrated no inferiority of
termisartan to ACE inhibitor ramipril with regard to death from
cardiovascular causes, myocardial infarction, stroke, or hospitalization
for heart failure in high-risk patients who had cardiovascular disease
or diabetes mellitus but did not have heart failure [11].
Urinary albumin and blood Brain Natriuretic Pepetide (BNP) are
biomarkers that are expected to improve by ARB administration
Volume 4 • Issue 2 • 100016
Citation:
Soejima H, Ogawa H, Yasud O, Kim-Mitsuyam S, Matsui K, et al. (2014) The Changes of Biomarkers by Telmisartan and their
Significance in Cardiovascular Outcomes: Design of a Trial of Telmisartan Prevention of Cardiovascular Diseases (ATTEMPT-CVD). J
Clin Trials 4: 162. doi:10.4172/2167-0870.1000162
Page 2 of 8
[12-14]. There is also a report that urinary albumin and BNP were not
improved by ARB [15]. Increased Urinary Albumin Creatinine Rates
(UACR) have been linked to the development of diabetic nephropathy
and macrovascular disease in patients with type 1 and type 2 diabetes
[16,17]. In the Heart Outcome Prevention Evaluation (HOPE) substudy, microalbuminuria increased the risk of cardiovascular events,
absolute lethal and hospitalization due to congestive heart failure and
regardless of the presence or absence of diabetes, microalbuminuria
increased cardiovascular events [18].
Elevated plasma natriuretic peptide levels has also been reported to
predict the risk of death and cardiovascular events after adjustment for
traditional risk factors [19,20].　Although there are many studies that
observed the relationship between the cardiovascular events and
biomarker levels on enrolment, there is no report of the large-scale
study that measures biomarker in 1000 or more patients in the time
course.
In the present study, we will compare the effects of ARB therapy
and that of standard therapy except ARB on the changes of biomarker
levels. The effect of the two treatments on the incidence of
cardiovascular events will be also compared. Moreover, the
relationship between the incidence of cardiovascular events and the
changes of biomarkers will be exploratorily reviewed.
and occurring acute disorders in the target organ such as brain, heart,
kidney, and great vessels.
Diabetic factor
Type 2 Diabetes
Renal factors
Serum creatinine level for men should be 1.2 mg/dl to <2.0
mg/dl and for women 1.0 mg/dl to <2.0 mg/dl
Protein urea: qualitative value ≥+1
Protein urea: quantitative value: proteinurea corrected for
urinary creatinine of ≥ 0.3g/g.creatinine in spot urine
Chronic kidney disease stage 3 or higher
Cardiac factors
Angina pectoris
Heart failure (NYHA Classification I or II)
Left ventricular hypertrophy (thickness of the posterior wall of
left ventricle ≥12 mm on echocardiography before obtaining
the informed consent or Sv1 + Rv5 ≥35 mm on
electrocardiography.)
Transient or persistent atrial fibrillation
Cerebral factors
Past history of cerebral infarction, cerebral hemorrhage,
subarachnoid hemorrhage and transient cerebral ischemic
attack at least 6 months prior to obtaining the informed
consent
Peripheral
artery factors
Past history of lower extremities bypass surgery or
angioplasty at least 6 months prior to obtaining the informed
consent
Methods
A trial of telmisartan prevention of cardiovascular diseases
(ATTEMPT-CVD) is a multicenter, prospective, randomized openlabel, controlled trial with blinded end-point assessment. Patient
enrollment started July 2009 and was completed in April 2011; each
patient is followed up for three years. Patients are followed up at 168
institutions throughout Japan.
Study population
The inclusion criteria are outpatients, 40 ≤ age < 80 years old,
patients whose two latest casual blood pressure levels measured in the
sitting position are ≥ 140 mmHg (systolic blood pressure) or ≥
90 mmHg (diastolic blood pressure) or patients still need to lower
their blood pressure even in patients with systolic blood pressure<140
mmHg and diastolic blood pressure<90 mmHg, ability to provide
informed consent, and patients having at least one risk among the
cardiovascular risks shown in Table 1. Blood pressure is measured at
least twice at intervals of 1 to 2 minutes and if these two values largely
differ, it is measured one more time; patients’ blood pressure levels are
judged based on the mean value of the two closest blood pressure
measurements. The exclusion criteria is type 1 diabetes, severe renal
disorder (serum creatinine level ≥ 2.0 mg/dL), heart failure (NYHA
Classification III or IV), myocardial infarction, percutaneous
revascularization and bypass grafting of coronary artery/lower
extremity vessel, cerebral infarction, cerebral hemorrhage,
subarachnoid hemorrhage and transient cerebral ischemic attack
within 6 months before the observation period, malignant
hypertension, secondary hypertension, pregnant women, clinically
problematic allergic disease or past history of hypersensitivity to the
drugs used, past history of significant adverse drug reactions,
extremely poor biliary secretion or serious hepatic disorder, patients
who require treatment for a malignant tumor, and other patients who
are judged by the physician to be unsuitable for the study. Malignant
hypertension is defined as the state of abnormally high blood pressure
Past history of myocardial infarction at least 6 months prior to
obtaining the informed consent
Ankle-brachial index of <0.9 or with intermittent claudication
Table 1: Cardiovascular risks
Study protocol
The study protocol is in agreement with the guidelines of the ethics
committees at our institutions and the study complies with the
Declaration of Helsinki. The institutional review board at each
participating hospital approved this trial, and written informed
consent was obtained from each patient.
Registration and allocation
If possible, the physician is requested to stop ARB for two weeks or
more before registration when the physicians in charge at the study
sites register the patient who has taken ARB. After patients are judged
to be eligible as a subject during the observation period, the physicians
in charge at the study sites send the case registration form to the
independent allocation center for the patient's enrollment. The
independent allocation center receives the patients’ information by fax
from the physicians. The patients are allocated to either the ARB
group or the non-ARB (standard treatment except ARB) group. The
randomization is performed as stratified randomization after age ≥ 65
or age<65, men or women, past history of cardiovascular events, past
history of diabetes mellitus, and usage of ACE inhibitor are adjusted
(Table 2).
Gender: Male or Female
Age: <65 years old or ≥ 65 years old
Past history of cardiovascular diseases: Yes or No
J Clin Trials
ISSN:2167-0870 JCTR, an open access journal
Volume 4 • Issue 2 • 100016
Citation:
Soejima H, Ogawa H, Yasud O, Kim-Mitsuyam S, Matsui K, et al. (2014) The Changes of Biomarkers by Telmisartan and their
Significance in Cardiovascular Outcomes: Design of a Trial of Telmisartan Prevention of Cardiovascular Diseases (ATTEMPT-CVD). J
Clin Trials 4: 162. doi:10.4172/2167-0870.1000162
Page 3 of 8
Complication of diabetes: Yes or No
Survey at the start of the study (at registration)
Concomitant use of ACE-I: Yes or No
Inquiry
ACE-I=angiotensin converting enzyme inhibitor
Gender, date of birth, time when the patient is diagnosed with
hypertension, complications (past or present history of cardiovascular
diseases, presence or absence of diabetes, other complications), drugs
used (antihypertensive agents, medicine for diabetes, hypolipidemic
agents, antithrombogenic agents), history of alcohol consumption and
smoking history are inquired.
Table 2: Allocation factors
The independent allocation center faxes back to the physicians in
charge at the study sites after the allocation and notified the physicians
the treatment group to which the patient is allocate within 30 minutes
from the fax receiving.
Study drugs
Telmisartan is used for the patients allocated for the ARB group. On
the other hand, standard treatment except ARB is performed for the
patients allocated for the Non-ARB group.
Start of the study
After completion of registration and allocation, administration of
telmisartan at the indicated low (20 mg) or middle (40 mg) dose is
started in the ARB group. Or, additional antihypertensive drug except
ABR is started in the Non-ARB group. The dose level is selected
depending on the patient's condition. The dose level of telmisartan is
increased to the middle or the highest dose (80 mg) (daily dose) for
patients who do not achieve the target blood pressure. In this regard,
however, the dose increase is eventually left to the discretion of the
physician because the patient's condition needs to be considered. The
rough standard is as described in Figure 1.
Physical findings
Height, body weight, abdominal circumference, blood pressure and
the pulse rate are measured.
Laboratory tests
Blood cell count, general blood biochemistry (AST, ALT, LDH,
creatinine, estimated glomerular filtration rate (eGFR), urea nitrogen,
uric acid, Na, K, Cl, total cholesterol, LDL cholesterol, HDL
cholesterol, total protein, albumin, triglycerides, blood glucose,
HbA1c), urine test (sugar, protein (quantitative, qualitative),
creatinine, occult blood, special test (UACR, plasma BNP, serum high
sensitivity c-reactive protein (hsCRP), urinary 8-hydroxy-deoxyguanosine (8-OHdG), serum adiponectin, high-molecular weight
adiponectin), standard 12-lead ECG, and chest X-ray are examined.
Survey 3 months after the start of the study
Drug compliance, concomitant drugs and concurrent therapies,
blood pressure and pulse rate, subjective symptoms and objective
findings, occurrence of cardiovascular events, occurrence of adverse
events, and discontinuation/dropout are surveyed.
Survey at 6, 12, 24 and 36 months after the start of the study
Drug compliance, concomitant drugs and concurrent therapies,
blood pressure and pulse rate, and abdominal circumference (only at
36 months after the start of the study), subjective symptoms and
objective findings, general laboratory tests, annually standard 12-lead
ECG, annually chest X-ray examination (time is not specified.),
occurrence of cardiovascular events, occurrence of adverse events, and
discontinuation/dropout are surveyed.
Patients are followed up at each hospital visit or by telephone if
necessary. Follow-up visits are scheduled every 2 weeks for patients
seen in a clinic setting and every 4 weeks for patients seen in a hospital
setting. Data for patients who are lost to follow-up are included at the
day of last follow-up.
Figure 1: Study design of A Trial of Telmisartan Prevention of
Cardiovascular Diseases (ATTEMPT-CVD)
Survey
The physicians examine the survey items at the start of the study (at
registration), after 3, 6, 12, 24 and 36 months from the start of the
study, at a discontinuation/dropout, at the occurrence of any
cardiovascular event, and at the occurrence of any adverse event.
Thereafter, the physicians in charge at the study sites describe the
results of the survey in the required forms and send them to the
independent data center.
J Clin Trials
ISSN:2167-0870 JCTR, an open access journal
Discontinuation and dropout
In case the physicians in charge judge that continuation of the
study is difficult due to discontinuation of administration of the study
drug, patients' withdrawal of informed consent, or impossible followup etc., the physicians in charge discontinue the study and send a
discontinuation/dropout report to the independent data center. In case
a patient does not visit the institution for 3 months or longer, the
patient's condition is confirmed by phone or mail, etc.
Cardiovascular events and adverse events
The cardiovascular events consist of cerebral events, coronary
events, cardiac events, aortic/peripheral arterial events, complication
Volume 4 • Issue 2 • 100016
Citation:
Soejima H, Ogawa H, Yasud O, Kim-Mitsuyam S, Matsui K, et al. (2014) The Changes of Biomarkers by Telmisartan and their
Significance in Cardiovascular Outcomes: Design of a Trial of Telmisartan Prevention of Cardiovascular Diseases (ATTEMPT-CVD). J
Clin Trials 4: 162. doi:10.4172/2167-0870.1000162
Page 4 of 8
of diabetes, and aggravation of renal function. The detail of each
cardiovascular event is shown in the Table 3. Adverse events refer to
all unfavorable signs, symptoms or diseases occurring during the study
period regardless of the causal relationship with the study drug. All
cardiovascular events are adjudicated by the independent Events
Monitoring Committee that is unaware of the group assignments. All
adverse events are also adjudicated by the independent Data and
Safety Monitoring Committee. The Data and Safety Monitoring
Committee monitors the safety and efficacy of the study during the
study period.
Name of events
Applicable events
Cerebral events
Stroke (cerebral infarction, cerebral hemorrhage,
subarachnoid hemorrhage, unknown type of stroke),
transient ischemic attack
Coronary events
Myocardial infarction, angina pectoris, asymptomatic
myocardial ischemia
Cardiac events
Myocardial infarction, angina pectoris, asymptomatic
myocardial ischemia, heart failure
Aortic/peripheral arterial Aortic aneurysm, aortic dissection, arteriosclerotic
events
disease (aorta, carotid artery, renal artery,
mesenteric artery, peripheral artery, etc.)
Complications
diabetes
Aggravation
function
of Diabetic
nephropathy*,
diabetic neuropathy*
of
diabetic
retinopathy*,
renal Doubling of serum creatinine level, ESRD (initiation
of dialysis, renal transplantation)
*Newly occurred (or) aggravated ESRD=End Stage Renal Disease
Table 3: Detail of cardiovascular events
be 450 cases. This result indicates that the difference in plasma BNP
level would be larger by about 3.8pg/mL in the telmisartan group than
in the ramipril group after 3 months of treatment. As described above,
in case the level of significance was set at 0.05, the power at 0.80 and
the standard deviation in both groups at 20, 435 cases would be
required for each group (two-sample t-test).
As for UACR, a comparison with the ARB valsartan showed that
UACR decreased by 32.7% from 28.1 mg/g to 18.9 mg/g in the
telmisartan group [23]. While in the group administered the ACE
inhibitor ramipril, UACR decreased by 4.2% from 14.4mg/mol to
13.8mg/mol after 3 months of treatment [24]. When the results
described above are applied to the already described repeated
measurement model and the comparison involves 500 cases per group
with the level of significance set at 0.05, the number of observations is
3 and the correlation coefficient between the respective observation
time points is 0.7, the power exceeds 0.9. Therefore, the rationale for
setting the sample size for plasma BNP can also serve for UACR.
Statistical Analyses
As efficacy analysis population, a Full Analysis Set (FAS) and a Per
Protocol Set (PPS) were defined. The primary efficacy analysis
population will be FAS, an analysis identical to that carried out in FAS
will be carried out in PPS and consistency of the results will be
reviewed. The FAS shall be composed of the remaining patients after
the patients who are not done blood sampling for biomarkers are
excluded from the allocated patients. The PPS shall be composed of
the remaining patients after the patients shown in the Table 4 are
excluded from the FAS.
Ineligible patients
Endpoints
Patients who withdraw their consent
Primary endpoint is longitudinal data of UACR and plasma BNP in
each treatment group (the change from baseline and their percent
change). Secondary endpoint was longitudinal data of urinary 8OHdG, serum adiponectin, high-molecular weight adiponectin, serum
hsCRP, eGFR in each treatment group (the change from baseline).
Moreover, secondary endpoints are difference in biomarkers (beforeand-after comparison and inter-group comparison at each
measurement time point and at the final measurement time point),
time until occurrence of an event, and relationship between incidence
of cardiovascular events and the 7 biomarkers.
Patients for whom the initial blood sample is collected later than 2 weeks from
the start of administration of the study drug
Sample Size Calculation
The primary endpoint of this research is the change in UACR and
plasma BNP from baseline values, and in statistical analysis, intergroup comparison by closed testing procedure is planned for the
respective markers. The sample size necessary to assess the effect of the
test drug on UACR and plasma BNP was calculated. As a result, the
sample size necessary for the research was confirmed to follow the
sample size necessary for verification in plasma BNP.
Based on a comparison between ramipril and telmisartan, plasma
BNP level decreased from baseline by 2.6pg/mL in the ramipril group
and by 7.0 pg/mL in the telmisartan group after 3 months of treatment
[21]. When these values are applied to a repeated measurement model
with a level of significance of 0.05, power of 0.80, the 3 observation
points and a correlation coefficient between respective observation
points of 0.7 [22], the necessary sample size of each group turns out to
J Clin Trials
ISSN:2167-0870 JCTR, an open access journal
Patients who start taking the study drug later than 3 months from the initial blood
collection at the start of the study or patients who do not start taking the study
drug
Patients who discontinue taking the ARB within 1 week before the start of the
study
Patients who are administered any prohibited drug for 1 month or longer
Patients who take <80% of the study drug
Patients who do not take the study drug is 1 month or longer
Table 4: Exclusion criteria for per protocol set
Safety analysis population shall be composed of the subjects who
receive at least one dose of the study drug and whose safety
information is obtained. In this regard, however, the subjects who
withdraw their consent will be excluded.
The summary statistics shown in this document refer to the sample
size, mean value, standard deviation, and minimum value, median and
maximum value. Clopper-Pearson method will be used to calculate the
confidence interval of proportion. In contingency table analysis,
Fisher's exact test will be used for 2 × 2 table (two by two table) and χ2
test will be used for other items. Yates’ correction will not be
implemented. The software to be used in this statistical analysis will be
Volume 4 • Issue 2 • 100016
Citation:
Soejima H, Ogawa H, Yasud O, Kim-Mitsuyam S, Matsui K, et al. (2014) The Changes of Biomarkers by Telmisartan and their
Significance in Cardiovascular Outcomes: Design of a Trial of Telmisartan Prevention of Cardiovascular Diseases (ATTEMPT-CVD). J
Clin Trials 4: 162. doi:10.4172/2167-0870.1000162
Page 5 of 8
Windows SAS Version 9.2 or subsequent versions. P-values of less
than 0.05 were considered statistically significant.
Primary endpoints
Based on the change from baseline of the biomarkers (UACR,
plasma BNP) and their percent change, the profile will be compared
between the treatment groups and reviewed by repeated-measure
analysis of variance with measurement time points as repetition.
Primary endpoints will be analyzed by the closed testing procedure in
the order of UACR, plasma BNP, and their percent change in
consideration of multiplicity.
Secondary endpoints
Relationship between the treatment groups and longitudinal
data of biomarkers (the change from baseline)
Based on the change from baseline of the biomarkers (urinary 8OHdG, serum adiponectin, high-molecular weight adiponectin, serum
hsCRP, eGFR), the profile will be compared between the treatment
groups and reviewed by repeated-measure analysis of variance with
measurement time points as repetition.
Change of biomarkers at each measurement time point and
at the final measurement time point
Summary statistics will be calculated for observed values at each
measurement time point and change from baseline to each
measurement time point and to the final measurement time point by
group.
Comparison will be implemented for values at each measurement
time point and at the final measurement time point will be compared
with those at baseline by paired t-test. Change at each measurement
time point and at the final measurement time point will be compared
between the two groups by analysis of covariance with the baseline
value as covariate. As these reviews will be exploratorily, multiplicity
will not be adjusted. Concerning UACR and eGFR, the correlation
coefficient will be obtained for the observed value at baseline and
change from baseline at each measurement time point.
Time until occurrence of an event
For the following cardiovascular composite events (A) to (D),
Kaplan-Meier curves will be prepared and time until occurrence of an
event (median) and its 95% confidence interval will be obtained.
Groups will be compared using log-rank test with the treatment group
as a factor. Using Cox proportional hazard model, the hazard ratio of
the ARB group to the Non-ARB group and its 95% confidence interval
will be calculated.
(A) Occurrence of fatal and nonfatal composite cardiovascular
events (cerebral events, cardiac events, aortic/peripheral arterial
events, complications of diabetes, aggravation of renal function)
shown in Table 3.
(B) Death from events other than cardiovascular events (noncardiovascular death)
(C) Occurrence of composite cardiovascular events and noncardiovascular death
Concerning subgroups, the same analysis will be carried out in
subgroups of gender, age (<65 years old, ≥ 65 years old), past history of
cardiovascular diseases, complication of diabetes, concomitant use or
not of ACE-I, eGFR (<60, ≥60 mL/min/1.73 m2), UACR (<30 mg/gCr,
≥30 mg/gCr), and BMI (<25 kg/m2, ≥25 kg/m2).
Relationship between occurrence of cardiovascular events
and various biomarkers
As for the relationship between the biomarkers (UACR and plasma
BNP, urinary 8-OHdG, serum adiponectin, high-molecular weight
adiponectin, serum hsCRP) and occurrence of cardiovascular events,
the following will be exploratorily analyzed.
Relationship between biomarker values and occurrence of
cardiovascular events
For presence or absence of occurrence of cardiovascular events,
logistic regression analysis will be carried out for the conventional risk
factors shown in Table 5. Variables will be selected by step-down
procedure.
Items
Handling
Gender
Male/Female
Age (at of the time informed consent <65 years old / ≥65 years old
was obtained)
Body mass index
<25 kg/m2 / ≥25 kg/cm2
Smoking history
Smoker/Ex-Smoker/Non-smokeer
Diabetes
Yes/No
Hyperlipidemia
Yes/No
eGFR
<60 mL/min/1.73 m2/ ≥60 mL/min/
1.73 m2
Past
history
diseases
of
cardiovascular Yes/No
Table 5: Conventional risk factors
Any baseline value of a biomarker, value of a biomarker at the final
measurement time point (the latest observed value before occurrence
of an event, observed value at the final measurement time point in
patients who do not develop an event) and change in biomarker
(change from the baseline value to the value at the final measurement
time point) will be added to the conventional risk factors and the same
review will be implemented.
Calculation of C-statistics and net reclassification index
For observed values of the biomarkers (UACR and plasma BNP,
urinary 8-OHdG, serum adiponectin, high-molecular weight
adiponectin, serum hsCRP, eGFR), usefulness as a prediction model of
risk factors for occurrence of cardiovascular events will be evaluated.
Prediction of occurrence of events by conventional risk factors
(Framingham Heart Study: coronary heart disease, 2-year risk) and
prediction model in combination with the biomarkers will be
compared and evaluated using C-statistics [25] and net reclassification
index (NRI) [26].
(D) Occurrence of cardiac events and vascular events (cerebral
events, cardiac events, aortic/peripheral arterial events)
J Clin Trials
ISSN:2167-0870 JCTR, an open access journal
Volume 4 • Issue 2 • 100016
Citation:
Soejima H, Ogawa H, Yasud O, Kim-Mitsuyam S, Matsui K, et al. (2014) The Changes of Biomarkers by Telmisartan and their
Significance in Cardiovascular Outcomes: Design of a Trial of Telmisartan Prevention of Cardiovascular Diseases (ATTEMPT-CVD). J
Clin Trials 4: 162. doi:10.4172/2167-0870.1000162
Page 6 of 8
Trial progress and baseline characteristics of the patients
As shown in Figure 2, the study screened 1267 patients from July
2009 to April 2012. Twenty-two patients met exclusion criteria. We
randomly assigned 1245 patients, however, 17 patients were not done
blood sampling for biomarker measurement. Finally, the study was
started as follow: 615 patients in the ARB group and 613 patients in
the Non-ARB group. Tables 6 and 7 summarized the characteristics of
the patients at baseline. There was no significant deference in the
baseline characteristics between the ARB and Non-ARB groups as
shown in the Table 6.
Angiotensin
converting 72 (5.9)
enzyme inhibitor combined
use, (%)
Estimated
glomerular
filtration rate, mL/min/1.73 m2
*72.7
± 19.7
35 (5.7)
37 (6.0)
#72.4
&73.1
± 19.6
± 19.8
ARB= angiotensin II receptor blocker, * No. of patients=1222, **No. of patients=
1221, #No. of patients=612, ##No. of patients=611, & No. of patients=610
Table 6: Baseline characteristics of the two patient groups
Furthermore, there was no significant deference in the history of
cardiovascular risks between the ARB and Non-ARB groups as shown
in the Table 7.
Total
ARB Group
Non-ARB
Group
Type 2 Diabetes
819 (66.7)
411 (66.8)
408 (66.6)
Renal factors
78 (6.4)
43 (7.0)
35 (5.7)
- Elevated creatinine level
139 (11.3)
64 (10.4)
75 (12.2)
- Protein urea
74 (6.0)
40 (6.5)
34 (5.5)
Cardiac factors
54 (4.4)
29 (4.7)
25 (4.1)
- Myocardial infarction
114 (9.3)
55 (8.9)
59 (9.6)
- Angina pectoris
43 (3.5)
23 (3.7)
20 (3.3)
- Heart failure
172 (14.0)
91 (14.8)
81 (13.2)
- Left ventricular hypertrophy
87 (7.1)
42 (6.8)
45 (7.3)
Cerebral factors
98 (8.0)
51 (8.3)
47 (7.7)
- Cerebral infarction
13 (1.1)
6 (1.0)
7 (1.1)
- Cerebral hemorrhage
8 (0.7)
4 (0.7)
4 (0.7)
- Subarachnoid hemorrhage
48 (3.9)
23 (3.7)
25 (4.1)
- CKD stage 3 or more
Figure 2: Participation in A Trial of Telmisartan Prevention of
Cardiovascular Diseases (ATTEMPT-CVD)
Total
ARB Group
Non-ARB
Group
No (%) or No (%) or
mean ± SD
No
(%)
mean ± SD
mean ± SD
or
- Transient or persistent atrial
fibrillation
- Transient ischemic attack
No. of patients
1228
615
613
Peripheral artery factors
3 (0.2)
2 (0.3)
1 (0.2)
Men, (%)
715 (58.2)
359 (58.4)
356 (58.1)
- lower extremities bypass
4 (0.3)
3 (0.5)
1 (0.2)
Age, years
66 ± 9
66 ± 9
66 ± 10
surgery or angioplasty
Body mass index, kg/m2
**25
##25
&25
- Ankle-brachial index of <0.9
or
with
intermittent
claudication
±4
±4
±4
Systolic
mmHg
blood
pressure, 150 ± 16
151 ± 16
150 ± 15
Diastolic
mmHg
blood
pressure, 84 ± 12
85 ± 12
84 ± 12
CKD =chronic kidney disease, ARB=angiotensin II receptor blocker
Table 7: Cardiovascular risks of the two patient groups
Discussion
Pulse rate, beats/min
72 ± 11
72 ± 11
73 ± 11
Current smoker, (%)
*216
(17.7)
#107
(17.5)
&109
(17.9)
Past smoker, (%)
*263
(21.5)
#133
(21.7)
&130
(21.3)
Every day alcohol use, (%)
*308
(25.2)
#157
(25.7)
&151
(24.8)
Sometimes alcohol use, (%)
*313
(25.6)
#156
(25.5)
&157
(25.7)
Dyslipidemia, (%)
*704
(57.6)
#352
(57.5)
&352
(57.7)
J Clin Trials
ISSN:2167-0870 JCTR, an open access journal
To our knowledge, there is no report of the large-scale study that
measures biomarkers in 1000 or more patients in the time course for 3
years like the ATTEMPT-CVD. There are many studied that elucidate
the relationship between biomarkers and cardiovascular events. We
are very interested in not only the levels of biomarkers at enrolment
but also the changes of biomarker levels in patients suffering from
cardiovascular events during the study period. We focus on the
changes of plasma BNP and UACR levels in the present study because
the efficacies that ARB improves those biomarker levels and the
incidence of cardiovascular events are generally known. It is good
Volume 4 • Issue 2 • 100016
Citation:
Soejima H, Ogawa H, Yasud O, Kim-Mitsuyam S, Matsui K, et al. (2014) The Changes of Biomarkers by Telmisartan and their
Significance in Cardiovascular Outcomes: Design of a Trial of Telmisartan Prevention of Cardiovascular Diseases (ATTEMPT-CVD). J
Clin Trials 4: 162. doi:10.4172/2167-0870.1000162
Page 7 of 8
opportunity for us to confirm whether the two markers sensitively
change as predictive factors.
In the present study, we chose telmisartan as an ARB, because it was
proven in the ONTARGET that termisartan had equivalent effects
comparing to that of ACE inhibitor ramipril. Furthermore, of the
components of the primary composite outcome, telmisartan reduced
the incidence of myocardial infarctions compared to placebo group in
the telmisartan randomised assessment study in ACE intolerant
subjects with cardiovascular disease (TRANCEND) [27], although the
power of ARB that reduces myocardial infarction is thought to be
weak.
We selected urinary 8-OHdG, eGFR, serum adiponectin, highmolecular weight (HMW) adiponectin, serum hsCRP other than
UACR BNP as biomarkers. 8-OHdG is an excellent marker of
oxidative DNA damage, which increases in diabetes [28]. Recently, it
was also shown that urinary 8-OHdG had a positive correlation with
UACR in type 2 diabetics [29]. The association between 8-OHdG and
UACR could be clear in the present study. Furthermore, eGFR is
independently associated with heightened risk for death and
hospitalization for heart failure in patients with chronic heart failure
[30] and all-cause mortality in patients undergoing cardiac
catheterization [31]. Adiponectin, the most abundant circulating
adipokine, is paradoxically decreased in obesity, with the HMW
adiponectin considered to be the biologically active moiety [32,33].
HMW adiponectin levels are associated with greater insulin sensitivity,
antioxidative and anti-inflammatory effects [34,35], and consistently
lower risk of future type 2 diabetes mellitus in prospective analyses
[36,37]. In 2002, on the basis of data from 27,939 initially healthy
women followed up over a decade, plasma levels of high sensitivity creactive protein (hsCRP) <1 mg/l, 1 to 3 mg/l, and >3 mg/l were
established as representing lower, average, or higher relative vascular
risk when added to traditional risk factors [38]. In an effort to improve
vascular risk detection, many physicians screen for hsCRP, an
inflammatory biomarker associated with a markedly increased risk of
myocardial infarction, stroke, peripheral arterial disease, and sudden
cardiac death [39]. These attractive and interesting markers are also
investigated in the present study.
In conclusion, the ATTEMPT-CVD is a multicenter, prospective,
randomized open-blinded end-point design study, and is the first
study to assess the efficacy of ARB therapy to the changes of
biomarkers in patients with high-risk hypertension through the time
course, in terms of cardiovascular morbidity and mortality. Hence, the
results of this study are expected to provide a novel insight into the
significance of biomarkers considering the therapy on high-risk
hypertensive patients.
Acknowledgement
Dr Kim-Mitsuyama reported receiving grant support and lecture’s
fees from Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi
Sankyo, Kyowa Hakko Kirin, Novartis, Sionogi, Takeda.
Dr Node reported receiving grant support and lecture’s fees from
Astellas, Boehringer Ingelheim, Daiichi Sankyo, Kowa, Merck,
Mitsubishi Tanabe, Novartis, Pfizer, Takeda
Dr Yasuda reported receiving grant support from Bayer, Boehringer
Ingelheim, Mitsubishi Tanabe, Shionogi.
No other conflicts were reported.
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This study is supported by the Japan Foundation for Aging and
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Conflict of Interest
Dr Ogawa reported receiving grant support and lecture’s fees from
AstraZeneca, Astellas, Bayer, Boehringer lngelheim, Chugai, Daiichi
Sankyo, Dainippon Sumitomo Pharma, Eisai, Kowa, Kyowa Hakko
Kirin, Mitsubishi Tanabe, MSD, Novartis, Otsuka, Pfizer, Sanofi,
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