Volume 2, Number 10: October 1999

Comparison of cilostazol versus ticlopidine therapy after stent implantation.

The effect of withdrawal of drugs treating intermittent claudication.

Management of diabetic neuropathy

Long-term effects of fish oil on lipoprotein subfractions and low density lipoprotein size in non-insulin-dependent diabetic patients with hypertriglyceridemia

Comparison of cilostazol versus ticlopidine therapy after stent implantation.

Reference: Am J Cardiol 1999 Sep 1;84(5):511-4.

Abstract:
The aim of this study was to evaluate the efficacy of cilostazol for prevention of stent thrombosis compared with ticlopidine. Cilostazol is a potent antiplatelet agent with less serious side effects. However, few data are available about the effect of cilostazol in preventing stent thrombosis after coronary stent implantation. Four hundred ninety patients selected for elective stent placement were randomized to receive aspirin plus ticlopidine (n = 243) or aspirin plus cilostazol (n = 247) for 1 month. Clinical and laboratory evaluations were performed at regular interval. There were no differences in baseline characteristics between the 2 groups. During the first 30 days after stent implantation, major cardiac events or adverse drug effects were similar between the 2 groups: ticlopidine (2.9%) vs cilostazol (1.6%) group, p = NS; stent thrombosis (0.4% vs 0.8%, p
= NS, respectively), myocardial infarction (0.4% vs 0.8%, p = NS), severe leukopenia (1.2% vs 0%, p = NS), severe thrombocytopenia (0.4% vs 0%, p = NS), and cerebral hemorrhage (0.4% vs 0%, p = NS). Adverse effects led to drug withdrawal in 7 patients in the ticlopidine group (2.9%) and in 5 in the cilostazol group (2.0%). There was no death during the follow-up period. Thus, aspirin plus cilostazol may be an effective antithrombotic regimen with comparable results to aspirin plus ticlopidine after elective coronary stenting. 

Discussion:
This study shows that aspirin plus cilostazol may be a safe and effective poststenting antithrombotic regimen with comparable results to aspirin plus ticlopidine. In addition, cilostazol has a lack of serious side effects, such as leukopenia and liver dysfunction, compared with ticlopidine. These results indicate that aspirin plus cilostazol may be administered as an antithrombotic regimen after elective coronary stenting in various clinical settings.

Coronary stent has become an established treatment for coronary artery disease and increasingly used in interventional cardiology.  Stent thrombosis was a major concern during the early stent experience and was extensively studied in the past few years. Aspirin plus ticlopidine has been a standard poststenting antithrombotic regimen because it reduces the incidence of cardiac events and vascular complications after coronary stent implantation. Currently, stent thrombosis is remarkably reduced with the use of aspirin and ticlopidine coupled with techniques to optimize stent expansion and apposition to the arterial
wall.  Recently, the incidence of stent thrombosis was reported to be <1% in most studies. Ticlopidine is a potent and effective antiplatelet agent, but it has limitations because of serious adverse reactions. In this study, severe neutropenia or thrombocytopenia occurred in 1.6% of patients after hospital discharge. Fortunately, it was reversible in all patients but
required prolonged duration of additional hospitalization for treatment. In addition, it may cause severe hepatic damage and gastrointestinal irritation. For these reasons, careful monitoring of blood cell counts and liver function is required in all patients receiving ticlopidine.

Cilostazol is a potent inhibitor of phosphodiesterase that has an antiplatelet effect similar to ticlopidine.  It is currently used in the treatment of peripheral vascular disease.  In a nonrandomized study, aspirin plus cilostazol was suggested to be a reliable antithrombotic regimen for managing patients after coronary stent implantation.  This study supports the idea that cilostazol may be as effective as ticlopidine in preventing stent thrombosis. Cilostazol is advantageous because there are less serious side
effects. Hematologic complications or liver dysfunction was not observed in patients receiving cilostazol. Furthermore, the study population represents the full spectrum of symptomatic coronary artery disease, including many patients with acute coronary syndromes, technically complex lesions, and long coronary stenting. Therefore, this study indicates that aspirin plus cilostazol may be an effective poststenting antithrombotic regimen after elective coronary stenting in a variety of clinical settings. It was reported that cilostazol has the potential to prevent restenosis after coronary balloon angioplasty.  In addition, recent studies suggest that it may prevent in-stent restenosis after coronary stenting. This study was also designed to evaluate the effects of cilostazol for prevention of in-stent restenosis, and angiographic follow-up data will be available in the future.

A few potential limitations need to be addressed: (1) inadequate statistical power, (2) open-label administration, and (3) low overall event rates. The event rate in the ticlopidine group was smaller than in most unselected series and, therefore, these findings may not be applied to patients at high risk. In addition, antiplatelet agents were administered 2 days before elective coronary stenting. For this reason, our results cannot be directly compared with those of previous studies in which they were begun after coronary stenting.  However, the rapid-onset action of cilostazol  may be of particular advantage in unplanned coronary stenting. Further studies in a larger patient population are required to ascertain these issues.

 The effect of withdrawal of drugs treating intermittent claudication.

Reference: Am J Surg 1999 Aug;178(2):141-6.

BACKGROUND: Pharmacologic treatment for intermittent claudication is a management option. This study
evaluated the effect of withdrawal of drug therapies, cilostazol and pentoxifylline, on the walking ability of
peripheral artery disease patients. METHODS: Single-blind placebo crossover from a randomized,
double-blind trial; 45 claudication patients received either cilostazol 100 mg orally twice daily (n = 16),
pentoxifylline 400 mg orally three times daily (n = 13), or placebo (n = 16) for 24 weeks. After 24 weeks of
double-blind therapy, treatment for all groups was placebo only, and follow-up continued through week 30.
Treatment efficacy was established with treadmill testing. RESULTS: Profile analysis demonstrated a highly
significant loss of treatment benefit after crossover (P = 0.001) for cilostazol-treated patients, but no significant
change after crossover was observed with pentoxifylline. CONCLUSIONS: Drug withdrawal worsened the
walking of claudicants who had benefited from cilostazol therapy. This decline with crossover to placebo
suggests that the initial improvement with cilostazol treatment was due to the drug's action. Withdrawal of
pentoxifylline did not adversely affect walking.

Management of diabetic neuropathy

Reference: Am J Medicine 1999;107(2B): 27-35.

Abstract

The only strategy shown to be consistently beneficial in the treatment of diabetic neuropathy is meticulous control of blood glucose. The largest study of the effects of glycemic control on progression of neuropathy was the Diabetes Control and Complications Trial, which enrolled 1,500 patients. Meticulous control of blood glucose by multiple injections or continuous
subcutaneous infusion both delayed the onset of neuropathy and slowed its progression. A weakness of this and other studies of the effect of glycemic control is that they used surrogate measures of improvement (or slowing of progression) of neurologic function. Most used sensory and motor nerve conduction studies and some used vibration perception thresholds. Whether such measures correlate reliably with neuropathy symptom scores, neurologic examination, quality-of-life measures, neuropathic complications (foot ulcers and amputation), and mortality remains controversial. Also, most studies of tight glycemic control do not address the complications of more intensive therapy, among them severe hypoglycemia. Severe hypoglycemia can precipitate acute painful neuropathy, and it markedly increases axonal degeneration in experimental diabetic neuropathy. Finally, all studies have been confined to patients with mild neuropathy; some patients had no clinical
evidence of neuropathy. Whether benefit can accrue to patients with more advanced neuropathy is not known. The most physiologic means of achieving glycemic control is through pancreas transplantation; this can result in significant improvement in clinical and electrophysiologic measures of motor and sensory function and slightly improve autonomic function. Strategies to reduce the metabolic consequences of hyperglycemia on nerves and to enhance axonal regeneration are needed to supplement careful glycemic control. Aldose reductase inhibitors hold promise for reducing metabolic nerve injury, but further study is needed.

Summary

Meticulous control of hyperglycemia can slow the progression of mild somatic and autonomic neuropathy. There may even be some improvement in surrogate measures of neuropathy. The best means of controlling or improving neuropathy is pancreas
transplantation, but this is an expensive and potentially dangerous procedure that is applicable to only small numbers of patients. Even with pancreas transplantation, the beneficial effects are small and are achieved only after several years of normal glucose metabolism. Furthermore, the benefit is seen mainly in surrogate measures; it has yet to be persuasively demonstrated that this improvement yields benefit in terms of quality of life and reduction in neuropathic complications such as foot ulcers, amputation, and death from autonomic failure.

Even modest gains in glycemic control are beneficial, but the best results are achieved through rigorous control. However, this is very difficult to achieve, even in the most motivated and cooperative patients, and carries significant risks of recurrent hypoglycemia. Strategies to reduce the metabolic consequences of hyperglycemia on nerve function, such as aldose
reductase inhibition and free radical quenching, and to enhance axonal regeneration, perhaps using neurotrophic factors, are needed to supplement careful glycemic control in the management of diabetic polyneuropathy.

Long-term effects of fish oil on lipoprotein subfractions and low density lipoprotein size in non-insulin-dependent diabetic patients with hypertriglyceridemia

Reference: Atherosclerosis 1999 Oct;146(2):361-367.

Abstract

The effects of fish oil on lipoprotein subfractions and low density lipoprotein (LDL) size in non-insulin-dependent diabetes mellitus (NIDDM) patients with hypertriglyceridemia are unknown. To elucidate this, 16 NIDDM hypertriglyceridemic patients (plasma triglyceride 2.25–5.65 mmol/l, plasma cholesterol 7.75 mmol/l) were randomly assigned to a 6-month
period with either moderate amounts of fish oil (n=8) or placebo (n=8) after 4 weeks of wash-out and 3 weeks of run-in. Diet and hypoglycemic treatment were unchanged throughout the experiment. LDL size were evaluated at baseline and after 6 months. Three VLDL and LDL subfractions were measured at the end of the two periods. The total lipid concentration of all very low density lipoprotein (VLDL) subfractions was lower at the end of fish oil treatment compared with placebo (large VLDL 124.3±19.7 mg/dl vs 156.7±45.5 mg/dl; intermediate VLDL 88.5±9.5 mg/dl vs 113.9±23.2 mg/dl; small VLDL 105.9±9.7 mg/dl vs 128.9±40.7 mg/dl) (mean±SEM), although the difference was not statistically significant. Moreover, at the end of the two treatments, the percentage distribution of VLDL subfractions was very similar (large 37.5±3.3% vs 37.6±2.6%, intermediate 27.6±0.9% vs 31.0±2.4%; small 34.9±3.7% vs 31.4±2.1%). Concerning LDL, no significant change in LDL size was observed after the two treatments (255.4±2.2 Å vs 254.2±1.7 Å, fish oil; 253.7±2.0 Å vs 253.3±1.7 Å, placebo). LDL subfraction distribution was also very similar (large 17±3% vs 17±2%; intermediate 62±3% vs 65±3%; small 21±3% vs 18±2%), at the end of the two periods, confirming the lack of effects on LDL size. In conclusion, our study indicates that in NIDDM patients with hypertriglyceridemia, fish oil does not induce any improvement in LDL
distribution and LDL size despite its positive effects on plasma triglycerides.

Discussion

The main findings of our study are as follows: (1) fish oil induces no significant change in either VLDL subfraction distribution or composition; (2) despite the relevant reduction in triglycerides (about 45%), supplementation of fish oil induces no significant change in either distribution of LDL subfractions or LDL size.

Although the literature is full of studies on the effects of fish oil on lipid metabolism , data on VLDL subfraction distribution—especially in diabetic patients—are not available. However, since some of the studies do report a major effect of fish oil on VLDL triglycerides compared with VLDL cholesterol , it has been postulated that fish oil treatment could lead to an increase in smaller VLDL , which may be more atherogenic. Our study, instead, indicates, for the first time, that VLDL subfractions distribution is not affected by fish oil treatment. These results, together with our data on lypolitic activities  and on the significant reduction in plasma free fatty acids induced by fish oil, support the hypothesis that fish oil acts principally by reducing VLDL synthesis , and suggest that this reduction involves the whole particle—not only its triglyceride content.

A preponderance of small, dense LDL particles has been reported to be an independent predictor of CV risk by some, but not all authors , and is present not only in NIDDM patients, but also in subjects characterized by insulin resistance . Moreover, one of the main determinants of smaller LDL particles is represented by the level of plasma triglycerides, inasmuch as the higher the level of plasma triglycerides, the higher the percentage of small LDL and the smaller the size of the predominant LDL particle . Therefore, since one of the most consistent effects of fish oil is a reduction in plasma triglycerides, it is reasonable to expect an increase in LDL size. Our data on LDL subfraction distribution and, more specifically, on LDL size do not support this hypothesis. The data in the literature on this aspect are rather scanty  and no studies have been performed in diabetic patients with hypertriglyceridemia, who are characterized by a predominance of smaller LDL and in whom, therefore, a shift toward larger LDL could be very important from a clinical point of view.

The results of the few studies on this topic are controversial and, moreover, in the one showing a significant increase in LDL size  this increase is far from being striking (from 12.42 to 12.58 nm); although this result could be significant from a statistical point of view, it is unlikely to be clinically relevant.

The lack of any effect of fish oil on LDL size could be interpreted in different ways. First, it may be that the hypotriglyceridemic effect (a 45% reduction) induced by fish oil in our patients is not sufficient to change LDL size. However, against this point is the consideration that a smaller or equal reduction in triglycerides obtained with fibrates was able to
significantly change LDL size by about 20%  More than to the magnitude of the decrease, importance could be given to the levels of plasma triglycerides reached, especially considering that only levels of plasma triglycerides below 1.3 mmol/l are
associated with a very low formation rate of small LDL  In our hypertriglyceridemic diabetic patients, fish oil was indeed able to decrease plasma triglycerides but failed to fully normalize them. Further studies in patients with milder hypertriglyceridemia and in whom fish oil is able to normalize plasma triglyceride levels are needed to clarify this point.

The most plausible explanation for the lack of effects of fish oil on LDL size, compared with other hypotriglyceridemic agents, could be linked to its particular mechanism of action. As a matter of fact, fish oil acts quite exclusively on VLDL synthesis, and does not seem to have major effects on the VLDL catabolic pathways , as confirmed also by our negative
findings on plasma lypolitic activities. Fibrates, instead, act by both reducing VLDL synthesis and increasing their catabolism . It is possible that if a reduction in the VLDL pool is not associated with important changes in the catabolic pathway, especially with regard to HL activities, the complex mechanism involved in the regulation of LDL subfraction distribution will not be sufficiently affected.

Finally, the increase in small LDL is strictly linked to the level of insulin resistance. We have previously shown that fish oil is totally unable to modify the level of insulin resistance in the patients of the present study.. Therefore, the lack of changes in LDL size may also reflect the inability of fish oil to act on insulin resistance, considered by many authors to be the common pathogenetic mechanism of different metabolic abnormalities, including hypertriglyceridemia and high levels of small LDL .

Moreover, our patients present an enrichment in the cholesterol content of LDL and their subfractions, especially the smallest ones, after fish oil treatment. This enrichment is likely to be due to the reduction in VLDL particles with a subsequent decrease in CETP-mediated exchange of cholesterol and triglyceride between VLDL and LDL, as reported to occur in
IDDM patients treated with fish oil. In conclusion, our study shows that in NIDDM patients with hypertriglyceridemia, the positive hypotriglyceridemic effect of fish oil is not associated with any unfavorable effect on VLDL subfraction distribution; neither does it improve LDL distribution pattern, which, instead, would be very useful for these patients, who are characterized by a predominance of small LDL.