Cilostazol is a new phosphodiesterase inhibitor that suppresses platelet aggregation and also acts as a direct arterial vasodilator. This prospective, randomized, placebo-controlled, parallel-group clinical trial evaluated the efficacy of cilostazol for treatment of stable, moderately severe intermittent claudication.

METHODS AND RESULTS:

Study inclusion criteria included age > or =40 years, clinical claudication distance (ICD) on treadmill (12.5% incline, 3.2 km/h) between 30 and 200 m, and confirmation of diagnosis of chronic lower-extremity arterial occlusive disease. After stabilization and single-blind placebo lead-in, 81 subjects (62 male, 19 female) from 3 centers were randomized unequally (2:1) to 12 weeks of treatment with cilostazol 100 mg PO BID or placebo. Primary outcome measures included ICD and maximum distance walked (absolute claudication distance , or ACD). Secondary outcome measures included ankle pressures, subjective assessments of benefit by patients and physicians, and safety. Treatment and control groups were similar with respect to age, severity of symptoms, ankle pressures, and smoking status. Statistical analyses used intention-to-treat analyses for each of 77 subjects who had > or = 1 treadmill test after initiation of therapy. Comparisons between groups were based on logarithms of ratios of ICD and ACD changes from baseline using ANOVA test at last treatment visit. The estimated treatment effect showed a 35% increase in ICD
(P<0.01) and a 41% increase in ACD (P<0.01). There was no significant change in resting or postexercise ankle/brachial indexes. Patients' and physicians' subjective assessments corroborated the measured improvements in walking performance observed in the cilostazol-treated group.

CONCLUSIONS:

Cilostazol improved walking distances, significantly increasing ICD and ACD. The data suggest cilostazol is safe and well tolerated for the treatment of intermittent claudication.

COMMENT:

In terms of side effects, gastrointestinal complaints were noted in 44% of cilostazol-treated patients (vs 15% of placebo group) most common side effects included diarrhea, loose stools, flatulence, and nausea. Importantly, these symptoms were typically mild and often self-limited. Headaches occurred in 20% of cilostazol-treated patients and 15% of placebo-treated patients.

Small sample size is the limitation of the study. The duration of the study was rather short ( 12 week study) and longer study period ( > 6- 12 months) is suggested to see the additional benefit such as improvement of ICD and ACD compared to placebo group.

However although no patients found that cilostazol worsened their walking, half reported no change in performance. This may suggest that there may be a subgroup of patients with claudication who derive a clinical benefit. Clinical features that might predict who would be expected to respond to therapy with cilostazol have yet to be identified.

Among all of the risk factors which have been linked to coronary artery disease (CAD), hypercholesterolemia appears to be preeminent. Populations whose plasma cholesterol levels are inherently low can withstand exposure to high levels of tobacco consumption and arterial hypertension without developing significant coronary disease. Conversely, in Western industrialised countries, where hypercholesterolemia is endemic, coincidence of the other two risk factors is linked to more extensive aortic atherosclerosis and to a multiplicative increase in coronary morbidity and mortality. The lipid hypothesis, formulated more than 20 years ago, proposed that reduction of plasma (or more specifically low density lipoprotein (LDL)) cholesterol would lead to a fall in coronary disease. This review assesses the current status
of that hypothesis.


Review:

WOSCOPS: primary prevention of coronary heart disease in middle aged, hypercholesterolemic men

The West of Scotland Coronary Prevention Study recruited 6595, 45–64 year old men who had never had a myocardial infarction but were at risk because their average total cholesterol despite dietary advice was 7.0 mmol/l (270 mg/dl) and their LDL cholesterol, 4–6 mmol/l (155–232 mg/dl). 5% of the participants had evidence of angina as determined by a positive Rose questionnaire, but none had been hospitalised for investigation of this problem within the last twelve months, nor did they demonstrate any major ECG abnormalities like the presence of Q waves, significant ST-T wave changes or left bundle branch block. The participants were randomised to receive pravastatin 40 mg nocte or placebo and followed up in the community at 3 monthly intervals for an average of 4.9 years. Smoking and dietary advice were provided throughout the study. The primary endpoint in the trial was combined definite nonfatal myocardial infarction and coronary heart disease death. Other (secondary) endpoints included definite nonfatal myocardial infarction, coronary heart disease death, all cardiovascular deaths, the need for revascularisation procedures, death from noncardiovascular causes and all cause mortality.

AFCAPS/TexCAPS: primary prevention of coronary heart disease in men and women with `average' plasma cholesterol levels

Like WOSCOPS, AFCAPS was a randomised, double blind placebo controlled trial designed to test the benefit of cholesterol reduction in the primary prevention of CHD. There were, however, minor but important design differences between the two trials. For example, AFCAPS employed a cholesterol lowering diet strategy combined with lovastatin whose dose was titrated upward if necessary in order to achieve an LDL cholesterol target of 2.84 mmol/l (110 mg/dl). In addition, women were admitted into the project and accounted for 15% of the total recruits. Average baseline total, LDL cholesterol and HDL cholesterol values were 5.71±0.54 mmol/l (221 mg/dl), 3.89±0.43 mmol/l (150±17 mg/dl) and 0.94±0.14 mmol/l (36±5 mg/dl) (for men) or 1.03±0.14 mmol/l (40±5mg/dl) ( for women) all lower than in the WOSCOPS cohort. The primary endpoint in AFCAPS was also expanded from the narrower constraints of the WOSCOPS definition to include, in addition, the development of unstable angina pectoris and sudden cardiac death. Secondary endpoints focused on cardiovascular episodes and included fatal and nonfatal myocardial infarction, unstable angina pectoris, cardiovascular events, coronary events, cardiovascular death and coronary heart disease deaths. The precise definitions of the last four phenomena are still awaited. Finally, safety issues were dealt with in the tertiary endpoints of incident and fatal cancers, non-cardiovascular death and death from any cause.

WOSCOPS and AFCAPS: How do they compare?

There are remarkable similarities and interesting points of difference between WOSCOPS and AFCAPS. encapsulates the design features of both studies. WOSCOPS, which pioneered primary CHD prevention with statins, specifically targetted high risk males from a population in which coronary heart disease was prevalent and resistance to cholesterol lowering among clinicians was the norm. Conversely, AFCAPS focused on lower risk Air Force men and women (15% of the total cohort) or civilians from the vicinity without clinical evidence of atherosclerotic disease and with substantially lower baseline lipid levels, simply because there is a much greater enthusiasm among American physicians for intervention against hypercholesterolemia, even in individuals who are otherwise healthy. This arrangement presumably was responsible for the decision to admit older participants (up to 75 years) into the AFCAPS trial with a view to increasing the number of endpoints expected throughout its course. Both studies recruited virtually identical numbers of subjects and followed them for an average of 4.9 years, the decision being taken to terminate AFCAPS prematurely for reasons based on issues other than safety. One unique feature of AFCAPS was the decision to aim for an on-treatment plasma LDL cholesterol value of 2.84 mmol/l (110 mg/dl). This necessitated upward titration of the dose of administered lovastatin form 20 to 40 mg/day in those individuals who failed to achieve the desired LDL cholesterol at the basal drug dose. Approximately 50% of the actively treated participants were prescribed the higher dosage, so that on average, the mean prescribed lovastatin dose was 30 mg/day.

It is clear that lovastatin and pravastatin therapy each help to reduce the risk of first myocardial infarction. Interpretation of the results of both studies in the their broadest sense would lead to the conclusion that since clinical experience with the two statins suggests that side effects are not a major issue all patients eligible for recruitment to the trials would benefit from intervention and consequently merit treatment. However, implementation of such a liberal strategy is clearly economically impractical. Instead, it is more rational to identify and intervene only in those individuals whose risk of an event exceeds an accepted specified value. In 1994, a joint Task Force from the European Atherosclerosis Society, the European Society of Cardiology and the European Society for Hypertension ruled that a 20% risk of a vascular event over the next 10 years (or, broadly, a 2% risk per annum) warranted consideration for intervention, fully aware that such an arbitrary decision required enough flexibility in its interpretation to meet the circumstances of populations with differing financial and healthcare constraints. With that caveat in mind, how can one target patients for treatment on the basis of their prospective risk of an event? Consideration of the frequency and distribution of cardiovascular events in the placebo groups of WOSCOPS and AFCAPS permit such a selection to be made. Individuals with a 10% risk of an ischemic event over the five years of the trial warrant active intervention. In
WOSCOPS only one quarter of the placebo group had a risk of definite CHD death or nonfatal myocardial infarction which exceeded this 10% treatment threshold, and undoubtedly the percentage of the AFCAPS population who would be targetted is even less. Detailed examination of the top risk quartile in WOSCOPS showed that it encapsulated 45% of
the coronary events in the study. In other words, application of the European Joint Guidelines to WOSCOPS or AFCAPS will successfully identify 45% (or fewer) of the incipient infarcts in this mild to moderate risk group and disregard the majority of all first myocardial infarct victims. The simplest way to locate the highest risk patients is on the basis of his or her non lipid risk factor profile, cogent argument that cholesterol screening of asymptomatic individuals
should be limited to middle aged or older individuals at high short term risk of a coronary event, with treatment restricted to this group and to those who present with atherosclerotic disease. Compared with a strategy of untargetted screening and treatment, this approach would ensure the maximum absolute benefit and cost effectiveness of therapy. However, adoption of this strategy would result in the majority of events being missed, even although it is clear that the two statins induced the same relative reduction in coronary risk across the entire spectrum of the WOSCOPS and AFCAPS cohorts. So, the number of people needed to be treated to prevent one major coronary event is considerable in the low-risk WOSCOPS subjects and even greater in AFCAPS. Treatment targetted to higher risk individuals in WOSCOPS improves this situation and makes more economic sense. Consequently, these two trials make a strong case for the kind of aggressive lifestyle intervention proposed by the Task Force of the European Societies of Cardiology, Atherosclerosis and Hypertension and the National Cholesterol Education Program Adult Treatment Panel before any consideration is given to drug therapy. The relative merits of targetted versus generalised approaches to cholesterol screening and treatment are the subject of current debate which hopefully will lead to enlightened guidance for the average clinician. Both WOSCOPS and AFCAPS were initiated prior to publication of the NCEP or joint European Task Force guidelines. According to the latter, as noted above, only one quarter of the WOSCOPS participants had a high enough absolute risk at baseline to warrant statin intervention, but, reflecting the more liberal approach to therapy in the USA, three quarters of the group lay within the NCEP drug treatment watershed. Inevitably, economic constraints will continue to wield an ever growing
influence on clinical decision making, but for these 25% high risk individuals in Europe and 77% in the USA, pravastatin therapy can be recommended on the firm evidence base of WOSCOPS as a safe and effective means of reducing the risk of major coronary events, if lifestyle intervention fails to achieve the expected benefits. A detailed risk-benefit analysis
of the AFCAPS patients, currently underway, will allow clinicians to judge how best to target lovastatin therapy at lower risk subjects in order to help avoid a first myocardial infarction.

There is heated ongoing debate over the value of aggressive total and LDL cholesterol reduction in the prevention of coronary heart disease. The protagonists assert that increasing benefit will accrue from greater lipid lowering, implying that there is a linear association between plasma cholesterol values and coronary risk. But, the Multiple Risk Factor
Intervention Trial , the largest observational study of its kind, and other similar large scale prospective projects make it clear that populations experience a curvilinear rise in coronary events with increasing plasma cholesterol. By inference, then, cholesterol lowering strategies would most effectively reduce events in individuals with more severe hypercholesterolemia and would become attenuated in their capacity to do so as individual plasma cholesterol values
fell. In other words, a patient will receive greater absolute cardioprotection from the first, say, 25% cholesterol reduction than from efforts to lower cholesterol by 25% more. Comparison of AFCAPS with WOSCOPS exemplifies this point. Both studies produced approximately a one third relative reduction in risk of a cardiovascular event but this benefit translated into an avoidance of 74 fatal and nonfatal myocardial infarctions in WOSCOPS versus 57 avoided aggregate cases of unstable angina, fatal and nonfatal infarcts and sudden cardiac deaths in AFCAPS, despite the more aggressive drive to achieve a lower target on-treatment LDL cholesterol value. Of course, the average absolute risk of an event in AFCAPS was about 30% lower than in WOSCOPS and so the absolute gain from intervention was, not
unexpectedly, less.

This principle of diminishing returns was tested in the WOSCOPS population using the following approach . First, the percentage reduction of LDL cholesterol from baseline was calculated for each individual in the pravastatin treated group. To provide the most accurate measure of plasma lipid concentration during follow-up, on-treatment lipid values were calculated as the mean of all lipid measurements made after randomisation until the patient had an event or reached the end of the study. If a lipid value was missing at a visit but study medication had been issued at the previous visit (3 months earlier), the most recent measurement that had been preceded by a medication issue was carried forward. If before the visit no such on-treatment measurement existed then the baseline value was imputed. Baseline value was also imputed if no medication had been issued at the previous visit and the present lipid level was missing. Not unexpectedly, the response of the pravastatin-treated individuals varied substantially. Some experienced virtually no change in their plasma LDL cholesterol while in others it fell by 50% or more. The cohort was therefore divided into quintiles of achieved LDL reduction and the diminution in risk of a coronary event calculated for each quintile. The men in quintile 1, who showed no LDL cholesterol fall, experienced the same rate of coronary events as the placebo treated WOSCOPS cohort. Quintiles 2 through 5, which had mean percentage LDL reductions of 12, 24, 31 and 39% exhibited 28, 47, 31 and 43% fewer coronary events respectively. In other words, an LDL reduction of 25% in WOSCOPS (as seen in Quintile 3) yielded as much benefit as was seen in Quintile 5, where the achieved LDL cholesterol was almost 40% lower than the baseline value.

Conclusion:

A second analysis compared the event rates of subjects in the placebo group and in the pravastatin treated group who had the same LDL cholesterol for the duration of the study. The majority of individuals on placebo had LDL cholesterol levels of about 4.4 mmol/l (170 mg/dl) and the majority of individuals on pravastatin had values below 3.0 mmol (116
mg/dl) but there existed an overlap where the two groups were similar. The 446 individuals on the placebo group with an average LDL cholesterol of 4.2 mmol/l (162 mg/dl) had a risk of a coronary event over the duration of the study of 5.6%. The 466 pravastatin users, with a similar LDL cholesterol of 4.1 mmol (159 mg/dl) had a significantly lower risk of 3.88%.
In other words, receiving pravastatin resulted in 47% less risk of a coronary event than receiving placebo, despite the subjects having the same LDL level. Other factors must exist to account for this benefit. Statins may confer benefit beyond LDL cholesterol reduction like, for example, reducing blood viscosity, stabilising plaques, suppressing inflammatory responses, decreasing the probability for lipoprotein oxidation, and so on. Post hoc analyses of this kind
are, of course, fraught with difficulties and must be viewed with caution, but these trends in the WOSCOPS data were consistent with the general outcome of the trial and with the early benefit seen in response to treatment. It will be instructive to determine whether a similar analysis of the other statin endpoint trials and of AFCAPS in particular reveals the same benefit.

The second-generation oral anticancer agent UFT, a combination of uracil and tegafur (TGF), results in a higher fluorouracil (5-FU) concentration in the tumor tissues than is achieved by TGF or comparable doses of intravenous 5-fluorouracil. UFT has been extensively studied in Japan and has been in use in the Orient for many years, particularly for
patients with gastric carcinoma. UFT has recently entered extensive investigations in North America and Europe.

METHODS:
Relevant studies that have chronicled the establishment of UFT, its mechanism of action, preclinical toxicology, human pharmacokinetics, phase I studies, and activity against gastric carcinoma are described in detail. RESULTS: The uracil in UFT slows degradation of 5-FU by dihydropyrimidine dehydrogenase (DPD), which results in sustained concentrations of 5-FU in blood and tumor tissues. UFT is well tolerated, but such toxic effects as nausea, vomiting, and diarrhea are dose- and schedule-dependent. In phase I pharmacokinetic studies, UFT given orally on a 28-day schedule resulted in blood concentrations comparable to those following low-dose continuous intravenous infusion of 5-FU. In patients with gastric
carcinoma, UFT alone has a response rate of approximately 20%. In the adjuvant setting, UFT plus mitomycin appears superior to TGF plus mitomycin. In Japan, UFT is part of the standard adjuvant chemotherapy for gastric carcinoma.

CONCLUSION:
UFT is one of the first second-generation oral 5-FU prodrugs under investigation in North America and Europe. The literature suggests UFT is well tolerated and has cellular pharmacokinetic superiority over the first-generation 5-FU prodrug TGF. UFT has a more favorable toxicity profile than intravenous 5-FU. The issues of efficacy, patient convenience, and quality of life need to be studied in controlled randomized trials.