Volume 2, Number
11: November 1999
A new pharmacological treatment for intermittent
claudication: results of a randomized, multicenter trial.
Impact of cilostazol on clinical and angiographic outcome after primary stenting for acute
myocardial infarction
European multicenter study on propionyl-L-carnitine in intermittent claudication
A new pharmacological treatment for intermittent
claudication: results of a randomized, multicenter trial.
Reference: Arch Intern Med 1999;159(17):2041-50.
BACKGROUND: Effective medication is limited for the relief of intermittent claudication, a common
manifestation of arterial occlusive disease. Cilostazol is a potent inhibitor of platelet aggregation with
vasodilation effects. OBJECTIVE: To evaluate the safety and efficacy of cilostazol for the treatment of
intermittent claudication. METHODS: Thirty-seven outpatient vascular medicine clinics at regional tertiary and
university hospitals in the United States participated in this multicenter, randomized, double-blind,
placebo-controlled, parallel trial. Of the 663 screened volunteer patients with leg discomfort, a total of 516 men
and women 40 years or older with a diagnosis of moderately severe chronic, stable, symptomatic intermittent
claudication were randomized to receive cilostazol, 100 mg, cilostazol, 50 mg, or placebo twice a day orally for
24 weeks. Outcome measures included pain-free and maximal walking distances via treadmill testing,
patient-based quality-of-life measures, global assessments by patient and physician, and cardiovascular
morbidity and all-cause mortality survival analysis.
RESULTS: The clinical and statistical superiority of active
treatment over placebo was evident as early as week 4, with continued improvement at all subsequent time
points. After 24 weeks, patients who received cilostazol, 100 mg, twice a day had a 51% geometric mean
improvement in maximal walking distance (P<.001 vs placebo); those who received cilostazol, 50 mg, twice a
day had a 38% geometric mean improvement in maximal walking distance (P<.001 vs placebo). These
percentages translate into an arithmetic mean increase in distance walked, from 129.7 m at baseline to 258.8
m at week 24 for the cilostazol, 100 mg, group, and from 131.5 to 198.8 m for the cilostazol, 50 mg, group.
Geometric mean change for pain-free walking distance increased by 59% (P<.001) and 48% (P<.001),
respectively, in the cilostazol, 100 mg, and cilostazol, 50 mg, groups. These results were corroborated by the
results of subjective quality-of-life assessments, functional status, and global evaluations. Headache, abnormal
stool samples or diarrhea, dizziness, and palpitations were the most commonly reported potentially
drug-related adverse events and were self-limited. A total of 75 patients (14.5%) withdrew because of any
adverse event, which was equally distributed between all 3 treatment groups. Similarly, there were no
differences between groups in the incidence of combined cardiovascular morbidity or all-cause mortality.
CONCLUSION: Compared with placebo, long-term use of cilostazol, 100 mg or 50 mg, twice a day significantly improves walking distances in patients with intermittent claudication.
The
effect of alpha-tocopherol and beta-carotene supplementation on symptoms and
progression of intermittent claudication in a controlled trial
Reference: Atherosclerosis 1999;147(1):193-197.
Abstract
We evaluated the effect of
long-term supplementation with vitamin E (alpha-tocopherol) and beta-carotene on
occurrence of claudication symptoms and risk for peripheral vascular surgery
among men with intermittent claudication. Subjects, 50–69-year old male
smokers, were participants in the Alpha-Tocopherol, Beta-Carotene Cancer
Prevention Study, who reported intermittent claudication through a structured
questionnaire (Rose) at study entry (n=1484). They were randomly assigned
to receive either 50 mg/day of alpha-tocopherol, or 20 mg/day of beta-carotene,
or both, or placebo, in a 2×2 design. During follow-up, claudication was
evaluated by repeating use of the questionnaire once a year. Information on
peripheral vascular surgery came from the National Hospital Discharge Register.
We observed no effect of alpha-tocopherol and beta-carotene supplementation on
claudication during a mean follow-up of 3.7 years. A slightly increased risk
(odds ratio (OR) 1.60, 95% confidence interval (CI) 1.05–2.44) for vascular
surgery was observed among beta-carotene supplemented men compared to those who
did not receive beta-carotene. Alpha-tocopherol supplementation had no effect.
In conclusion, long-term supplementation with alpha-tocopherol and beta-carotene
showed no beneficial effect on symptoms and progression of intermittent
claudication.
Discussion
This randomized, double-blind, placebo-controlled study showed no effect of
alpha-tocopherol and beta-carotene supplementation on claudication symptoms as
evaluated by the Rose questionnaire. Our findings contradict observations
indicating beneficial effects of alpha-tocopherol on intermittent claudication.
However, prior evidence is only suggestive, and the few controlled, double-blind
studies have given inconsistent results. Major limitations of those studies were
small number of patients and supplementation lasting only some months; thus for
the time being, no recommendation on vitamin E supplementation has been given.
Our dose of alpha-tocopherol was about one-tenth that used in those studies, but
was administered over a much longer period. Furthermore, our result is
consistent with our earlier finding of no primary preventive effect of alpha-tocopherol
or of beta-carotene supplementation on intermittent claudication.
We evaluated, additionally, the effect of alpha-tocopherol and beta-carotene
supplementation on risk for peripheral vascular surgery. A significantly more
elevated risk appeared among those receiving beta-carotene than among those who
did not, but the mechanism remains unknown. Beta-carotene has a tendency to be
incorporated into the atherosclerotic plaque , but no data indicate how
beta-carotene or its metabolites might function there. Increased risk for
surgery was found only among those reporting at baseline mild symptoms of
claudication. If mild symptoms indicate smooth, 'active' atherosclerotic plaques
rather than calcified ones, beta-carotene might be preferentially incorporated
into the former, making the atheroma plaque more prone to rupture, leading to
acute thrombosis requiring emergency surgery.
Smoking is a major risk factor for intermittent claudication; cessation of
smoking relieves its symptoms, and we indeed observed a slight, non-significant
reduction in risk for occurrence of symptoms among those smokers who ceased.
However, cessation did not modify the effect of alpha-tocopherol and
beta-carotene on claudication.
Our definition of intermittent claudication was based solely on the Rose
questionnaire, which is designed for large field surveys. The sensitivity and
specificity of the questionnaire are reported to be 60–92%, and 91–100%,
respectively. We are unaware of the number of false-positive and false-negative
cases, but based on the Edinburgh Artery Study, the number of false positives
can be assumed to be some 30% . Our study lacked objective measurement of
symptoms such as treadmill exercise testing, but in a large trial with nearly 30
000 participants it was not feasible to perform such tests. The questionnaire
did allow us to detect changes in symptoms from severe to mild, in addition to
resolution of symptoms. In contrast, the other endpoint—peripheral vascular
surgery—was based on register data. In an evaluation performed in Finland,
codes for surgery from the Hospital Discharge Register matched hospital records
in 85% of cases. In our opinion, the register data thus can be considered valid
for purposes of analysis.
The number of dropouts was moderately high, as all subjects had symptoms of
atherosclerotic disease at the beginning of this study. However, the drop-out
rate was similar in all intervention groups and occurrence of claudication had
no effect on drop-out risk.
In conclusion, we observed no benefit from alpha-tocopherol or beta-carotene
supplementation in regard to occurrence of intermittent claudication, as
evaluated by a questionnaire among male smokers, whereas beta-carotene
supplementation slightly increased risk for peripheral vascular surgery. There
is thus no reason to recommend supplementation with either substance.
Impact of cilostazol on clinical and angiographic outcome after primary stenting for acute
myocardial infarction
Reference: Am J Cardiology 1999;84(9):1074-1076.
Primary stenting is a recent major breakthrough in the treatment of acute myocardial infarction (AMI) that has been
shown to improve clinical outcome compared with conventional primary balloon angioplasty.
Antiplatelet therapy with aspirin plus ticlopidine are widely used to reduce risk of thrombotic occlusion of the
stent. However, angiographic restenosis was still allowed in 15% to 20% of patients enrolled in early trials
and ticlopidine is not associated with significant reduction in angiographic restenosis or need for repeat interventions.
Thus, drugs more effective than ticlopidine in reducing restenosis are needed. Cilostazol, or
6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3, 4-dihydro-2 (1H)-quinolinone, is a novel and potent inhibitor of
phosphodiesterase in platelets and vascular smooth muscle cells. This agent has an antiplatelet effect
similar to ticlopidine and is effective in preventing subacute stent thrombosis. Moreover, cilostazol appears to have
an inhibitory effect on intimal proliferation, and may reduce the occurrence of restenosis after directional coronary
atherectomy or elective stent implantation. The objective of this study was to compare 6-month clinical and
angiographic outcomes in patients randomized to receive either cilostazol or a brief course of ticlopidine after
primary stenting for AMI.
Primary stenting was defined as intentional implantation of a coronary stent in the culprit lesion of AMI. Successful
primary stenting was defined angiographically as visually estimated residual stenosis 5% associated with grade 3
flow according to the criteria of the Thrombolysis In Myocardial Infarction (TIMI) trial. 12 Major cardiac events
were defined as cardiac death, reinfarction, or need for emergent revascularization procedure to the stent occlusion.
Vascular complications were defined as occurrence of bleeding or hematoma at the puncture site requiring
transfusion or vascular repair.
Between September 1995 and May 1997, 54 patients who presented within 12 hours of an AMI with total occlusion
(TIMI grade 0 or 1 flow) of the infarct-related artery underwent primary stenting using a Palmaz-Schatz stent. AMI
was defined as ischemic chest pain lasting >30 minutes, accompanied by ST-segment elevation 0.1 mV in 2
contiguous electrocardiographic leads. Patients with cardiogenic shock were included. Primary stenting was
attempted if the infarct-related artery did not show evidence of severe calcification on fluoroscopy or excessive
angulation proximal to the lesion likely to increase the risk of stent dislodgment, and if the arterial diameter was 2.5
mm. We excluded a total of 3 patients from the study because of a culprit lesion located in a saphenous vein graft (n
= 1), or true ostial lesions of the left anterior descending (n = 1) or left circumflex (n = 1) artery. 2 Therefore, 51
patients who underwent primary stenting were enrolled. Written informed consent was obtained before study
enrollment.
After the patients received 3 chewable 81-mg baby aspirin tablets and an intravenous bolus infusion of 150 U/kg of
heparin, primary stenting was performed via a femoral approach. After predilation at a pressure of 10 atm for 30
seconds, an articulated 15-mm Palmaz-Schatz stent (Johnson and Johnson Interventional Systems, Warren, New
Jersey) was either mounted manually on a low-profile balloon catheter or implanted using a delivery system. The
balloon size was chosen carefully with respect to the diameter of the adjacent nondiseased coronary artery
(balloon-to-artery ratio, 1:1 to 1:1.2). Stenting throughout the length of the lesion was considered essential. After the
stent was deployed, high-pressure poststenting dilation (15 to 18 atm) was performed. To reduce the residual stenosis
to <5%, additional poststenting dilation using either higher inflation pressures (up to 20 atm) or a larger balloon was
required in some cases. Continuous intravenous infusion of 150 U/kg/day of heparin was continued for 72 hours. As
antiplatelet treatment, all patients received aspirin (81 mg 3 times a day for 6 months); in addition, patients were
randomized by means of sealed envelopes to receive cilostazol (100 mg twice a day for 6 months) or control
medication. The control medication, given to prevent subacute stent thrombosis, was ticlopidine 100 mg twice a day
for 1 month.
Clinical and angiographic outcomes at 6 months were analyzed. All randomized patients were encouraged to
undergo follow-up coronary arteriography 6 months after the procedure (or earlier in the event of recurrent
symptoms or clinical evidence of ischemia). Quantitative angiographic parameters (minimal lumen diameter,
reference diameter, and percent stenosis) were measured by using a digital edge-detection algorithm (Cardio 500;
Kontron Electronik, Eching, Germany). The measurements were obtained during diastole using the single matched
images demonstrating the greatest degree of stenosis. Restenosis was defined as diameter stenosis >50% at the
6-month follow-up angiography. Acute gain was defined as poststenting minimal lumen diameter, because the culprit
lesion had shown total occlusion before predilation. Late loss was calculated as the difference between the acute gain
and the minimal lumen diameter measured at follow-up angiography. Loss index was calculated as the ratio of late
loss to acute gain.
Detailed case report forms were completed for all patients, and the information was entered into a computer
database. Data are expressed as mean ± SD. Comparisons between the study groups were made using the
Mann-Whitney U test for continuous variables and chi-square test for categorical variables. A p value <0.05 was
considered statistically significant.
Of the 51 patients in whom primary stenting was attempted, a successful result was obtained in 50 (98%). In the
failed procedure, a stent mounted on a low-profile balloon could not be crossed through the target lesion. This patient
was treated with conventional balloon angioplasty. The 50 patients with successful primary stenting were randomized
to the cilostazol (n = 25) or the control group (n = 25). Particulars for the 50 patients and procedures, summarized in
Tables I and II , included no significant differences between the 2 groups.
Clinical and angiographic follow-up outcomes at 6 months are summarized in Table III. There were 4 major cardiac
events; during the first month, 4 patients (2 in the cilostazol group and 2 in the control group), all with cardiogenic
shock on admission, died of refractory cardiogenic shock with no clinical or electrocardiographic evidence of stent
occlusion. No adverse effects of antiplatelet agents such as neutropenia, liver dysfunction, or bleeding were observed
during the follow-up period. Two asymptomatic patients in the control group declined follow-up coronary
angiography. Therefore, angiographic outcomes at 6 months were assessed in 44 patients (cilostazol group [n = 23]
and control group [n = 21]). The rate of restenosis was lower in the cilostazol group than in the control group.
Although the quantitative angiographic parameters immediately after the procedure did not differ between groups,
late loss and loss index were significantly less in the cilostazol group than in the control group (Table III). All target
lesion revascularization procedures in 4 control group patients were repeat balloon angioplasties. Although 2 control
patients had no angina 4 months after the procedure, they had ST-segment depression during stress
electrocardiography, and underwent early follow-up coronary arteriography and target lesion revascularization.
With regard to the angina status, only 2 control group patients, who developed restenosis at 6-month follow-up
angiography, had mild effort angina and required target lesion revascularization.
This study demonstrated that administration of cilostazol after primary stenting with the Palmaz-Schatz stent was
associated with decreased angiographic late loss and loss index, resulting in better overall clinical and angiographic
outcomes.
Significant residual stenosis after primary balloon angioplasty in patients with AMI, in concert with intimal
hyperplasia, unopposed vessel recoil, and late remodeling, results in angiographic restenosis in >40% of
infarct-associated arteries within 6 months.Although the process of neointimal formation is not
fully understood, adherent platelets and the resulting mural thrombus may be important in promoting the migration
and proliferation of smooth muscle cells. However, most clinical trials designed to assess the effects of
antithrombotic agents on restenosis have been disappointing.
Because stenting produces much greater initial gain, it is associated with lower restenosis rate than balloonangioplasty, but stenting induces more late loss of luminal diameters. Because this late effect is caused predominantlyby neointimal formation,
antiproliferative therapies may have greater importance than after balloon angioplasty,
when both early elastic recoil and late arterial remodeling contribute to luminal narrowing.
Cilostazol is a novel inhibitor of type III phosphodiesterase in both platelets and vascular smooth muscle cells that
increases intracellular levels of cyclic adenosine monophosphate. The antiplatelet effects of cilostazol are
10 to 30 times more potent than those of aspirin in inhibiting aggregation induced by adenosine
diphosphate, collagen, epinephrine, or arachidonic acid. 7 Notably, cilostazol also inhibits proliferation of rat vascular smooth
muscle cells in tissue culture. This effect also may be mediated by increased intracellular levels of cyclic adenosine
monophosphate. Recent molecular biologic studies indicate that cilostazol increases expression of the p53 gene,
which inhibits the proliferation cycle of vascular smooth muscle cells and suppresses expression of heparin-binding
epidermal growth factor–like growth factor. This drug also opposes endothelial cell death by increasing
local concentrations of hepatocyte growth factor. In a controlled study in dogs, oral administration of cilostazol
prevented intimal hyperplasia after placement of Gianturco Z stents. Accordingly, cilostazol appears to show
potential for reducing restenosis after coronary interventions, such as directional coronary atherectomy
or elective stent implantation. These trials depict a significantly smaller late loss and/or loss index in patients treated
with cilostazol than in those treated with aspirin or ticlopidine, as did the present study. However, the
present study involved relatively few patients for randomization, and the interpretation of the data should be rather
cautiously done.
Cilostazol, an antiplatelet drug that also may inhibit smooth muscle proliferation, was given together with aspirin after
primary stenting to treat patients with AMI. In a randomized controlled trials of 50 patients, clinical and angiographic
outcome at 6 months was significantly improved by cilostazol.
European multicenter study on propionyl-L-carnitine in intermittent claudication
Reference: J Am College Cardiology 1999;34(5):1618-1624.
Abstract
OBJECTIVES
This study was performed to identify a target population of claudicants for propionyl-L-carnitine treatment.
BACKGROUND
Previous studies suggest that the efficacy of propionyl-L-carnitine in intermittent claudication is greater in patients
with severe functional impairment than in those with mild walking disability.
METHODS
After run-in, 485 claudicant patients were randomized to placebo or propionyl-L-carnitine (1 g bid, po) and then
stratified on the basis of maximal walking distance (cutoff point 250 m) and maximal walking distance variability
(cutoff point 25%). Treatment lasted 12 months. Walking capacity was assessed by treadmill and quality of life by a
questionnaire exploring various aspects of daily life.
RESULTS
In the target population, that is, patients who at baseline walked 250 m and showed a maximal walking distance
variability 25%, per-protocol analysis showed that the effect of propinyl-L-carnitine was significantly greater than
that with placebo for both maximal walking distance and initial claudication distance (ICD). In the intention-to-treat
population, maximal walking distance increased by 62 ± 14% on propionyl-L-carnitine and by 46 ± 9% (p < 0.05)
on placebo, while no difference between treatments was observed for ICD. The beneficial effect of
propionyl-L-carnitine was confirmed when data of the target population were pooled with those of patients who at
baseline walked 250 m and showed a >25% maximal walking distance <50% variability. Actually, maximal walking
distance increased by 98 ± 16% in the propionyl-L-carnitine group and by only 54 ± 10% in the placebo group (p <
0.01). The corresponding values for ICD were 99 ± 21% and 51 ± 8% (p < 0.05). For patients with baseline
maximal walking distance >250 m, no difference between treatments was observed.
CONCLUSIONS
Claudicants with maximal walking distance 250 m benefited from the use of
propionyl-L-carnitine, with improvement in walking distance and quality of life. However, patients with mild functional impairment (i.e., walking
distance >250 m) showed no response to propionyl-L-carnitine.
