Analysis of the cilostazol safety database.
Reference: Am J Cardiol. 2001 Jun 28;87(12 Suppl 1):28-33.
Cilostazol, a type III phosphodiesterase inhibitor, was approved in the
United States in 1999 for
the reduction of the symptoms of intermittent claudication. This article
summarizes the safety data
from 8 cilostazol phase 3 controlled clinical trials, involving 2,702 patients:
1,374 receiving
cilostazol, 973 assigned to placebo, and 355 taking pentoxifylline. The
trials ranged from 12 to
24 weeks in duration. There were a total of 475 patient-exposure years
on cilostazol, 357
patient-exposure years on placebo, and 135 patient-exposure years on pentoxifylline.
Headache,
diarrhea, and other gastrointestinal complaints were seen more often in
cilostazol-treated than
placebo-treated patients; pharyngitis and nausea were more common in pentoxifylline-treated
than placebo-treated patients. Headache requiring discontinuation occurred
in 1.3% of patients
taking cilostazol 50 mg bid and 3.7% of those receiving cilostazol 100
mg bid, compared with
0.3% of placebo-treated patients. Discontinuations due to diarrhea, palpitations,
or myocardial
infarction were similar in cilostazol-, placebo-, and pentoxifylline-treated
patients. The rate of
serious cardiovascular events was similar in all 3 treatment groups. Myocardial
infarction
occurred in 1.0% of cilostazol-treated, 0.8% of placebo-treated, and 1.1%
of
pentoxifylline-treated patients. The incidence of stroke was 0.5% in both
cilostazol- and
placebo-treated patients and 1.1% in pentoxifylline-treated patients. Total
cardiovascular
morbidity and all-cause mortality was 6.5% for cilostazol 100 mg bid, 6.3%
for cilostazol 50 mg
bid, and 7.7% for placebo. There were 16 deaths occurring in 0.6%, 0.5%,
and 0.6% of
cilostazol-, placebo-, and pentoxifylline-treated patients, respectively.
The evaluations showed no
trend toward increased cardiovascular morbidity or mortality risk in patients
receiving cilostazol.
In addition, postmarketing surveillance in the United States, representing
70,430 patient-years of
cilostazol exposure, has shown minimal accounts of myocardial infarction,
stroke, or death. The
safety profile of cilostazol in doses of 50 mg bid and 100 mg bid appears
to offer an acceptable
risk-benefit ratio in patients with intermittent claudication.
Comparative effects of cilostazol and other therapies for intermittent
claudication.
Reference: Am J Cardiol 2001;87(12S1):19-27.
Many patients with peripheral arterial disease (PAD) have intermittent
claudication or problems
with ambulation and mobility. Exercise and smoking cessation are primary
therapies for
claudication, but drug treatment may provide additional benefit. The data
supporting use of
pentoxifylline for claudication are weak, and pentoxifylline is not generally
accepted as
efficacious. Cilostazol is a new drug for the treatment of claudication.
It appears to modestly
benefit walking ability and it has other potentially useful effects, including
inhibition of platelet
aggregation and beneficial effects on serum lipids. In a randomized, prospective,
double-blind
trial examining walking ability in patients with PAD with moderate-to-severe
claudication,
cilostazol was superior to both placebo and pentoxifylline.
Intermittent claudication: effective
medical management of a common circulatory problem.
Reference: Am J Cardiol 2001;87(12S1):14-8.
Intermittent claudication (IC), most often characterized by a reproducible,
painful aching or
cramping in muscle groups of the leg caused by walking and relieved by
rest, is a common,
lifestyle-limiting symptom of lower-extremity peripheral arterial occlusive
disease. Because IC is
usually indicative of systemic atherosclerosis, active investigation and
treatment are
recommended. Positive outcomes have been shown with a treatment regimen
including
risk-factor modification, particularly smoking cessation and control of
diabetes, exercise, and
pharmacotherapy. Pentoxifylline has been used since 1984 for the treatment
of IC with indifferent
results. Recently, clinical trials with cilostazol, a drug approved for
use in the United States, have
shown significant effectiveness in IC patients, generally doubling their
maximal walking distance at
24 weeks of treatment. Cilostazol has also been shown to be significantly
more effective than
pentoxifylline in improving pain-free and maximal walking distance. Other
classes of drugs, such
as platelet antiaggregants, are being studied for the treatment of IC,
but little efficacy has been
shown. Arterial revascularization by endovascular or surgical methods is
an additional option but
must be considered on an individual basis depending on severity of symptoms
and disability in
each patient.
Intermittent
claudication: magnitude of the problem, patient evaluation, and therapeutic
strategies.
Reference: Am J Cardiol 2001;87(12S1):3-13.
Intermittent claudication (IC), the symptom of exercise-induced muscle
ischemia of peripheral
arterial disease (PAD), afflicts and limits the activities of a significant
number of patients.
Incidence and prevalence of IC depends on the population studied and the
diagnostic instruments
used. In large studies, prevalence has ranged from 3% to 10%, with a sharp
increase in those
aged >/=70 years. Over the next 20 years, the total number of patients
affected is expected to
increase significantly due to anticipated demographic changes. Analysis
of the natural history of
IC demonstrates that the risk of cardiovascular morbidity and mortality
far exceeds that of severe
limb ischemia or limb loss. In fact, only 2% to 4% of all patients with
IC will require a major
amputation in their lifetime. However, life expectancy is approximately
10 years less than that of
an age-matched cohort. By now, PAD is well recognized as a marker of systemic
atherosclerosis. The cornerstone of patient evaluation is a history and
physical examination,
including a detailed atherosclerotic risk-factor assessment. In the differential
diagnosis of IC,
clinicians should consider etiologies such as arthritis, spinal stenosis,
radiculopathy, venous
claudication, or inflammatory processes. In >80% of all patients, it is
possible to locate the
responsible arterial segment by combining the location and severity of
pain with a pulse
examination. Noninvasive diagnostic studies help determine the level of
disease, may unmask a
hemodynamically significant stenosis, and are useful in follow-up. Arteriography
is reserved for
patients in whom the decision for revascularization has been made. Knowing
the anatomic detail
of a lesion allows the clinician to determine whether and what type of
intervention is feasible.
Standard therapy for all patients should be directed at both peripheral
and systemic
atherosclerosis, beginning with risk-factor modification in the form of
smoking cessation, optimal
diabetes control, and lipid normalization. The benefits of supervised exercise
rehabilitation include
significantly increased walking distance and enhanced quality of life.
Platelet inhibition has been
shown to reduce the risk of ischemic stroke, myocardial infarction, and
vascular death and should
be prescribed for all but those in whom it is medically contraindicated.
Symptom-specific
pharmacotherapy with a broad range of medications has yielded disappointing
results in the past.
However, recent studies have demonstrated that patients receiving the novel
agent cilostazol
experienced increases in walking distance and improvements in quality of
life.
|
Volume
4, Number 8: August 2001
