A Randomized, Single-Center Double-Blinded Trial on the Effects of Diltiazem Sustained-Release Capsules in Patients with Coronary Slow Flow Phenomenon at 6-Month Follow-Up
Single-Center Double-Blinded Trial on the Effects of Diltiazem Sustained-Release Capsules in
Patients with Coronary Slow Flow Phenomenon at 6-Month Follow-Up. PLoS ONE 7(6): e38851. doi:10.1371/journal.pone.0038851
A Randomized, Single-Center Double-Blinded Trial on the Effects of Diltiazem Sustained-Release Capsules in Patients with Coronary Slow Flow Phenomenon at 6- Month Follow-Up
Lun Li 0
Ye Gu 0
Tao Liu 0
Yupeng Bai 0
Lingbo Hou 0
Zhong Cheng 0
Liqun Hu 0
Bo Gao 0
Pierfrancesco Agostoni, University Medical Center Utrecht, Netherlands
0 Department of Cardiology, Wuhan Puai Hospital, Huazhong University Of Science and Technology , Wuhan , China
Objective: The aim of this study is to observe the chronic effects of diltiazem release capsules on patients with coronary slow flow (CSF) phenomenon. Methods: From 2004 to 2009, 80 consecutive patients with chest pain and normal coronary arteries evidenced by coronary angiography and CSF were included in this randomized, double-blind, placebo-controlled trial. CSF patterns were evaluated by the corrected TIMI frame count. Patients were randomly assigned at 1:1 ratio to diltiazem sustained-release capsules treatment group (Dil, 90 mg twice daily) or placebo control group. Holter, liver and kidney function, treadmill exercise test, coronary angiography and left ventricular angiography were measured at baseline and after 6 months. The incidence of cardiovascular events (re-admission or progress in coronary heart disease, myocardial infarction, malignant arrhythmia or cardiac death) was evaluated during the 6 months follow up. Results: Thirty-nine patients in control and 40 patients in Dil group completed the 6 months follow-up. There was no medication induced drug withdraw during follow up. Left ventricular ejection fraction was similar between the 2 groups at baseline and during follow up. Heart rate was significantly lower in Dil group than in control group and there was no symptomatic bradycardia and II and III degree atrioventricular conduction block in both groups. Significant improvement was observed in the onset of chest pain, treadmill exercise test and coronary blood flow in Dil group while these parameters remained unchanged in control group at the end of 6 months follow up. The incidence of cardiovascular events was similar between the two groups. Conclusion: Diltiazem slow-release capsules improved coronary blood flow and alleviated angina in patients with CSF. Trial Registration: Chinese Clinical Trial Registry ChiCTR-TCC-11001864 PLoS ONE | www.plosone.org
Funding: The funding was provided by Puai Hospital, Huazhong University of Science and Technology. The funders had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
In 1972, Tambe  first reported coronary slow flow (CSF)
phenomenon defining chest pain patients without significant
coronary artery lesion but with slowed down coronary blood flow
during coronary angiography examination. Mangieri  et al.
reported that incidence of CSF was around 7% in patients with
suspected coronary heart disease. CSF can lead to myocardial
ischemia, acute coronary syndrome and acute myocardial
infarction . It was suggested that coronary microcirculation
obstacle might be the main reason for CSF phenomenon [4,5,6].
Previous studies have shown that calcium antagonists could relief
microvascular spasm [7,8] and intravascular application of
diltiazem could to attenuate coronary artery spasm in patients
with microvascular angina [9,10]. Effects of chronic oral calcium
antagonists on CSF patients remain largely unknown now. This
study aimed to observe the chronic effects of oral diltiazem
sustained-release capsules in patients with CSF phenomenon.
Data of chest pain frequency, 24-hour Holter, treadmill exercise
test, coronary angiography and left ventricular angiography at
baseline and at the end of 6 months follow up were compared
between CSF patients receiving oral diltiazem sustained-release
capsules or placebo. Major adverse cardiac events
(re-hospitalization; acute coronary syndrome, malignant arrhythmia or
cardiac death) during follow-up were also recorded and liver and
kidney functions were monitored during the study period.
The protocol for this trial and supporting CONSORT checklist
are available as supporting information; see Checklist S1 and
Eighty patients with chest pain and diagnosed as CSF using the
corrected (corrected TIMI frame count, CTFC) method  from
2004 to 2009 in our department were included. Exclusion criteria:
1) A history of myocardial infarction or coronary angioplasty; 2)
Cardiomyopathy, valvular disease, hypertensive heart disease,
congenital heart disease; 3) Coronary artery dilatation, stenosis
(stenosis .40%); 4) Systolic blood pressure ,90 mmHg; 5) The
resting heart rate ,60 times/min, sick sinus syndrome, second or
third degree atrioventricular conduction block; 6) NYHA
functional class $ III; 7) Liver or renal dysfunction (serum aspartate
transaminase or alanine transaminase ALT increased by 2-fold,
creatinine $2 mg/dL); 8) Study drug allergy.
CSF patients were randomly assigned to diltiazem
sustainedrelease capsules treatment group (Dil, 90 mg twice daily, n = 40) or
placebo control group (n = 40) at 1:1 ratio. Drug and placebo were
made and numbered 180 randomly by Office of Good Clinical
Practice of Puai hospital and were identically packaged in capsule
form. The code was broken only after the study was completed
and investigators remained blind throughout the study, and
analysis was conducted by a statistician who had no patient
contact. The compliance was determined by pill counts. Pill counts
were attempted on all prescribed medications that were to be
taken regularly in discrete dosages. Percent adherence was
calculated using the following equation: (number of tablets
taken/number of tablets that should have been taken) 6 100.
Both groups stopped using anti-angina drugs (nitrates,
betaadrenoblockers, nifedipine) two weeks before study begin; angina
attack could be treated with sublingual isosorbide dinitrate at any
time. Patients were followed up for 6 months. Chest pain
frequency, 24-hour Holter, treadmill exercise test, coronary
Body Mass Index (kg/m2)
Ejection fraction (%)
Chest pain (times/week)
LAD, Left anterior descending; LCX, Left circumflex artery; RCA, right coronary
artery; ETPR, exercise test positive rate; CSFBV, coronary slow flow blood vessel;
CTFC, corrected TIMI frame count; ACEI, Angiotensin converting enzyme
inhibitor; ARB, Angiotensin-II receptor typy-1 blocker. Unpaired Students t test
or Mann-Whitney-Test was used to compare differences in means or mean
ranks of variables between control group and Dil group.
angiography and left ventricular angiography were examined at
baseline and at the end of 6 months follow up. Major adverse
cardiac events (re-hospitalization; acute coronary syndrome,
malignant arrhythmia or cardiac death) during follow-up were
recorded. Liver and kidney functions were also monitored during
the study period. The study was approved by the hospital ethics
committee[Appendix S1], written consent[Appendix S2] was
obtained from each participating patient.
Evaluation of Coronary Flow Velocity
Coronary flow velocity was determined by CTFC method.
Briefly, PHILIPS CV12 digital subtraction angiography was used
for multi-position selective coronary angiography by Judkins
method, total frame rate was of 25 frames/s. Left anterior
descending coronary artery (LAD) was acquiesced by right
anterior oblique 30u value plus foot position 30u, number of
frames from the opening of the left anterior descending artery to
the apical bifurcation was measured. Right coronary artery (RCA)
was acquiesced by left anterior oblique 45u, number of frames
from the opening of RCA to left ventricle branch after the first
collateral branch bifurcation was measured; Left circumflex artery
(LCX) was acquiesced by right anterior oblique 30u plus foot
position 30u, number of frames from the opening of left circumflex
Heart rate (beats/min)
Ejection fraction (%)
Alanine transaminase (U/L)
p,0.05 vs. baseline. Unpaired Students t test or Mann-Whitney-Test was used
to compare differences in means or mean ranks of variables between control
group and Dil group. Paired Students t test or Wilcoxon signed-rank test was
used to compare the means or mean ranks of the two related samples (baseline
vs. Follow up) as indicated. The Bonferroni correction was applied and adjust
pvalues (p value x 2) were obtained.
artery to the distal obtuse marginal branch was measured.
According to the Gibson method , the number of frames of
LAD was divided by 1.55. TIMI-FC ,40 was defined as normal
flow (normal coronary flow, NCF), $40 as slow flow (slow
coronary flow, SCF).
Treadmill Exercise Test
Exercise test was performed at the same time in the morning by
the same physician. All patients underwent submaximal exercise
treadmill test (ETT) according to the standard Bruce protocol
. The protocol continued until one of several endpoints was
reached. These included if the patient achieved the target HR
[85% of their age-predicted maximal HR = (220 2 age) 685%)].
The exercise was terminated in following conditions: developed
severe chest pain, fatigue, leg discomfort or dyspnea; developed
frequent premature ventricular beats, systolic blood pressure (SBP)
.250 mmHg or .10 mmHg SBP drop compared to pretest SBP;
or developed any other reasons necessitating termination of
exercise. The criteria for positive were: ECG showed ST
segments of adjacent leads descended horizontally or
downslopingly for at least 0.1 mV, and last for more than 2 min, with or
without concomitant typical angina symptoms. The criteria for
negative were: objective load achieved without ST-T changes.
Calculation of the sample size was determined by using
standard methods for binomial data. The effective rate (marked
reduction) of CFS at the last day of treatment was the determining
factor for sample size calculation. Assuming the estimated effective
rate in the control group and Dil group is 20% and 55%,
respectively, 35 patients per each group are necessary to detect the
statistically significant difference between 2 groups using a 2-sided
test at 90% power and a = 0.05.
Control group Dil group
(n = 39) (n = 40)
49.4611.0 (p,0.001) 41.2612.9*
(p = 0.002) (p,0.001)
10 (25%)(p = 0.024)
Table 3. The effects of the treatment.
Chest pain (episodes/week)
p,0.05 vs. baseline; *p,0.05 vs. control. CSF, coronary slow flow; CTFC,
corrected TIMI frame count; ETPR, exercise test positive rate. Unpaired Students
t test or Mann-Whitney-Test was used to compare differences in means or mean
ranks of variables between control group and Dil group. Paired Students t test
or Wilcoxon signed-rank test was used to compare the means or mean ranks of
the two related samples (baseline vs. Follow up) as indicated. The Bonferroni
correction was applied and adjust p-values (p value x 2) were obtained.
Continuous data are expressed as mean 6 standard deviation.
Categorical or dichotomous variables were expressed as
percentages. Normality of distribution of all continuous variables was
explored by examining skewness, kurtosis, and QQ aplots.
Unpaired Students t test or Mann-Whitney-Test was used to
compare differences in means or mean ranks of variables between
control group and Dil group. Paired Students t test or Wilcoxon
signed-rank test was used to compare the means or mean ranks of
the two related samples (baseline vs. Follow up) as indicated.
Fishers exact test (rate comparison) was performed to compare
proportions. The Bonferroni correction was applied when
comparing baseline and follow up measures in the control or Dil
groups and comparing measures at the baseline and at follow up
between control and Dil groups and adjust p-values (p value x 2)
were obtained. P value of less than 0.05 was considered to be
statistically significant. Statistical analyses were performed using
SPSS 14.0 software (SPSS Inc., Chicago, IL, USA).
A total of 122 patients were screened and 42 patients were
excluded due to not meeting inclusion criteria, declined to
participate etc. [Figure 1] and the remaining 80 patients were
included for the study. All patients (n = 40) in Dil group and 39
patients in control group completed the study and 1 patient in
control group was lost to follow up. Baseline clinical and
angiographic characteristics were comparable between the two
groups (Table 1). The drug compliance was 94.7% in placebo
group and 93.8% in Dil group (p.0.05).
Left ventricular ejection fraction, serum creatinine and alanine
transaminase remained unchanged during follow up in all patients
while average 24 hours heart rate was significantly lower in Dil
group than in control group during follow up (Table 2), there was
no symptomatic bradycardia, II and III degree AVB at baseline
and during follow up. There was no drug withdrawal due to
serious side effects. As shown in table 3, coronary flow during
follow up returned to normal in 32 out of 50 vessels in Dil group
and in only 10 out of 47 vessels in control group (p,0.001). CTFC
was improved between baseline and at the end of follow up in both
groups and the improvement was more significant in Dil group
than in control group. Chest pain frequency (episodes/week) was
similar between control and Dil group at baseline and remained
unchanged in control group at the end of follow up while it was
significantly reduced in Dil group at the end of follow up.
Similarly, exercise test positive rate (ETPR) during treadmill
exercise test was similar between control and Dil group at baseline
and was significantly reduced in Dil group but not in control group
after 6 months treatment. There was no deaths, myocardial
infarction or need for revascularization procedures. Five patients
in control group and 2 patients in Dil group were rehospitalized
due to chest pain (Table 4, p.0.05).
Coronary slow flow phenomenon refers to normal coronary
arteries with delayed distal perfusion during coronary angiography
[13,14]. The main reason for slow flow phenomenon is considered
to microvascular dysfunction [15,16]. Rim et al . found that
coronary slow flow resistance in CFP patients increased
significantly compared with the control group. Cell edema, capillary
damage and reduced capillary lumen were evidenced in
myocarRehospitalization for chest pain
Progress in coronary heart disease
Myocardial infarction, malignant arrhythmia or cardiac death
Fishers exact test (rate comparison) was performed to compare proportions between control group and Dil group.
dial biopsy of CSF patients by Mangieri et al . and they
speculated that these pathological changes might allow a remote
increase in vascular resistance resulting in reduced blood flow slow
in these patients. Besides the morphological changes,
microvascular spasm might also play an important role in the pathogenesis of
CSF . Clinical and basic studies have shown calcium
antagonists could attenuate microvascular spasm [7,8,20]. In line
with above findings, our results showed that diltiazem treatment
was safe and oral administration of diltiazem sustained-release
capsules can improve coronary blood flow and exercise test
tolerance, relieve chest pain in patients with CSFP. The most
possible mechanism is considered to be the effect on attenuating
vascular smooth muscle spasm related to calcium channel
blockers. To our knowledge, this is the first clinical report
demonstrating the beneficial chronic effects of oral diltiazem
release capsules on patients with CSF.
All patients in Dil group completed follow-up, there was no
significant difference between the 2 groups at the baseline and the
end of follow up on LVEF, serum creatinine and alanine
transaminase. There was also no symptomatic bradycardia or
second degree and above AVB during follow up. These data
suggest that oral administration of diltiazem on patients with CSF
Larger multi-centre studies are warranted to verify the effects of
Diltiazem Hydrochloride Sustained-release Capsules in CSF
patients obtained from this cohort with small patient number.
CSF may be a manifestation of microvascular dysfunction. This
study found that oral administration of diltiazem sustained-release
capsules could improve coronary blood flow and exercise test
tolerance, and relieve the chest pain symptoms in patients with the
Approval about clinical trial for drugs.
Informed consent form.
Conceived and designed the experiments: YG LL. Performed the
experiments: LL ZC L. Hu BG. Analyzed the data: YB. Wrote the paper:
LL YG TL L. Hou.
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