Volume 2, Number 8: August 1999

Neuropathic Complications

  Impact of Cilostazol on Restenosis After Percutaneous Coronary Balloon Angioplasty

 Cilostazol or Pentoxifylline for Claudication?

 10 mg aspirin and Gastric toxicity

Neuropathic Complications

Reference: American Diabetes Association 59th Scientific Sessions: June 20, 1999

It has become abundantly clear that diabetic neuropathy is not a single disorder but rather, a complex heterogeneous syndrome with a variety of clinical presentations based upon differences in etiologic mechanisms. Diabetic neuropathies can be divided into the focal and diffuse forms, and the latter may be further divided into small and large fiber neuropathies. This distinction is important since the clinical presentation is so varied and the pathogenesis and approaches to treatment are dictated by the underlying pathogenic mechanism.

The focal forms of neuropathy are, for the most part, entrapment syndromes or mononeuritides that respond to specific forms of treatment aimed at the pathology. These generally do not behave like the diffuse somatic and autonomic neuropathies, are self-limiting, and in certain instances treatments can be directed at specific targets.
For example, nerve entrapments may require splinting, diuretics, or local anesthetic and steroid injection.The situation is quite different in the proximal neuropathies that are often inflammatory conditions, which if recognized will respond to anti-inflammatory or immune therapies. The bain of existence is, however, the distal symmetric polyneuropathies (DSPN).

DSPN is now recognized as being heterogeneous with emphasis on different fibers that convey specific information. There are the large fibers that subserve position, vibration sense, reflexes, and motor activity. People with large fiber damage may become incoordinate, stagger, and have weakness of the small muscles of the hands and feet causing hammer toe deformities and pressure sores on the high points of the knuckles or soles of the feet. The small fibers subserve temperature (both hot and cold), touch, and pain perception as well as autonomic function. Autonomic function embraces the involuntary actions of controlling heart rate, bowel function, bladder, and sexual function. It had been established in animal models of diabetes, that there was a deficiency in nerve growth factor (NGF) and the substances regulated by NGF in the tissues, and that peripheral production by muscles and Schwann cells could be impaired. Based upon phase 1 clinical studies that established the safety of administering NGF by injection into humans, a phase 2 study was conducted in 250 subjects, comprising both male and female, type 1 and type 2 diabetics with approximately 15 years of diabetes and 4.7 years of neuropathy. The study was designed to examine safety and seek trends of efficacy, which would lead to a phase 3 study.The phase 2 study showed that NGF given to humans was safe and caused significant improvement in nerve function as measured by 3 groups of efficacy measures. The first group of efficacy measures included O'Brien's rank sum for nerve impairment score of the lower limbs (NIS-LL), cooling detection threshold (CDT), and heat pain (HP 5.0) (p=0.032); the second group included the first measures as well as the neuropathy symptom profile and Global score (p=0.008); and the third group of measures included neuropathy impairment score-lower limbs (NIS-LL), cold detection threshold (CDT), and HP 5.0 (p<0.005). Unfortunately because of injection site hyperalgesia, physicians were able to discern which patient was in the treatment group 80% of the time and patients became aware of their status 73% of the time. Nonetheless, it was concluded that these results were compatible with the postulated mechanism of action of NGF on small fiber sensory neurons and suggested that it was worthy of initiating a larger phase 3 comparative study using a longer treatment period.

Dr. Vinik presented on behalf of the NGF investigators the results of the phase 3 multicenter, double-blind, placebo-controlled, parallel-group study of the efficacy and safety of rhNGF (0.1ug/kg three times per week) for 12 months. This study involved 1019 subjects with diabetic neuropathy and was carried out in 84 centers in the US. Subjects were 18-75 years of age, had asymptomatic or symptomatic diabetic neuropathy, and were required to have clear electrophysiologic evidence of diabetic neuropathy or abnormal quantitative sensory tests. The primary endpoint was to be a responder analysis using the NIS-LL, with secondary endpoints to include measures of small fiber function. In contrast with the phase 2 study, NGF was shown to be ineffective, failing to meet the target level for effectiveness. Factors that may have contributed to these differences in the study results include: patient demographics; change in the natural history of diabetic neuropathy;  underestimating the degree of bias in the phase 2 study due to unblinding because of the injection site hyperalgesia; inadequate dose; inadequate duration; wrong measures; and possibly loss of the effectiveness of NGF for a variety of reasons.

Many of these factors have been ruled out such as those related to data acquisition; sample size and power; data transfer, merging, and analysis; and the manufacture of the NGFs used in the two different studies. One is left with the exasperating news that the drug is safe to give to humans, that there undoubtedly have been patients who have had a remarkable response, yet the study failed. The questions that remain will require a return to the bench to resolve before the compound or its successor will be reintroduced into the trial arena.

Evidence is accumulating that diabetic neuropathy is heterogeneous and that a major mechanism underlying the damage is restriction of blood flow. There are new and exciting possibilities that this is correctable and therapeutic agents are entering early phase 2 clinical trials.A major trial of one of the most promising growth factors that targets small unmyelinated C fibers induction of nerve regeneration has failed for some mysterious reason. It would be premature to discount this approach but it will be critically important for researchers to return to the bench to resolve the problems before the drug will be seen again in the clinical arena. Some of the effects of autonomic neuropathy on the heart and the predisposition to sudden deaths, arrhythmias, and impaired systolic and diastolic function are beginning to emerge. These ought to have a significant impact on the quality of life and activities of daily living of persons with diabetes.

  Impact of Cilostazol on Restenosis After Percutaneous Coronary Balloon Angioplasty

Reference: Circulation 1999;100:21-26.

Background—Restenosis after percutaneous transluminal coronary (balloon) angioplasty (PTCA) remains
a major drawback of the procedure. We previously reported that cilostazol, a platelet aggregation inhibitor,
inhibited intimal proliferation after directional coronary atherectomy and reduced the restenosis rate in
humans. The present study aimed to determine the effect of cilostazol on restenosis after PTCA.

Methods and Results—Two hundred eleven patients with 273 lesions who underwent successful PTCA
were randomly assigned to the cilostazol (200 mg/d) group or the aspirin (250 mg/d) control group.
Administration of cilostazol was initiated immediately after PTCA and continued for 3 months of follow-up.
Quantitative coronary angiography was performed before PTCA and after PTCA and at follow-up.
Reference diameter, minimal lumen diameter, and percent diameter stenosis (DS) were measured by
quantitative coronary angiography. Angiographic restenosis was defined as DS at follow-up >50%.
Eligible follow-up angiography was performed in 94 patients with 123 lesions in the cilostazol group and in
99 patients with 129 lesions in the control group. The baseline characteristics and results of PTCA showed
no significant difference between the 2 groups. However, minimal lumen diameter at follow-up was
significantly larger (1.65±0.55 vs 1.37±0.58 mm; P<0.0001) and DS was significantly lower (34.1±17.8%
vs 45.6±19.3%; P<0.0001) in the cilostazol group. Restenosis and target lesion revascularization rates
were also significantly lower in the cilostazol group (17.9% vs 39.5%; P<0.001 and 11.4% vs 28.7%;
P<0.001).

Conclusions—Cilostazol significantly reduces restenosis and target lesion revascularization rates after
successful PTCA.

Discussion:

(1) Animal studies have shown that cilostaol controls intimal hyperplasia in denuded carotid arteries of rats and in stented external iliac arteries of dogs.

(2) Several prospective, randomized studies on small populations have indicated that cilostazol has the potential to reduce restenosis after DCA or stent implantation in humans.

(3) The present study clearly suggests that cilostazol reduces the risk of restenosis after balloon angioplasty.

(4) One of the mechanisms by which cilostazol reduces restenosis after PTCA is thought to be inhibition of neointimal proliferation, considered a major mechanism of restenosis after PTCA caused by SMC migration, proliferation, and matrix synthesis. SMC migration and proliferation are induced by growth factors released from activated platelets. Secondly, cilostazol is thought to directly inhibit SMC growth. Thirdly, restenosis reduction may be due to its potent vasodilator effect from the continuous relaxation of vascular smooth muscle.

(5) Only limitation is that the study is not a double-blind trial. A well-designed, large-scale multicenter, double-blind, randomized study is needed to validate the present results.

Cilostazol or Pentoxifylline for Claudication?

Reference: Circulation 1999;99:1939.

Background: Pentoxifylline (PTX) is the only FDA approved drug for treating claudication symptoms in patients with peripheral arterial disease (PAD), but a series of US trials has demonstrated efficacy of a new drug, cliostazol (CLZ). The present study compared these two drugs.

Methods: A 24 week, multicenter, randomized, double-blind, placebo and active controlled parallel group study was conducted to assess the relative efficacy and safety of CLZ 100 mg bid, PTX 400mg tid, and placebo (PLC) for the treatment of claudication secondary to PAD.

Results: Fifty-four centers enrolled 698 patients with stable claudication. Efficacy was evaluated using a constant speed, variable-grade treadmill protocol at baseline and every 4 weeks. Compared to PLZ, CLZ significantly increased Maximum Walking Distance (MWD) and Pain Free Walking Distance (PFD), but PTX did not. There were 6 deaths in the study (CLZ=2, PTX=3, PLC=1). Serious adverse advents were equal in each treatment group (CLZ 11.9%, PTX 13.4%, PLC 13.0%). The most common non-serious adverse events were headache (CLZ 27.8%, PTX 11.2%, PLC 11.7%), abnormal stools (CLZ 14.5%, PTX 5.2%, PLC 2.9%), and palpitations (CLZ 17.2%, PTX 2.2%, PLC 2.9%).

Conclusion: CLZ is an effective and well tolerated alternative for treating symptoms of claudication. PTX did not significantly improve treadmill measured walking distance, compared to PLC.

Mean % Change frpm Baseline * and Mean Walking Distance Change From Baseline ** at Week 24

* ANCOVA of percent change from baseline

** ANOVA of geometric change

*** = not significant vs PLC

# p<0.05 CLZ vs PTZ and p <0.05 CLZ vs PLC

Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans.

Reference: Gastroenterology 1999;117(1):17-25.


BACKGROUND & AIMS: The safety of low-dose daily aspirin therapy in the gastrointestinal tract is uncertain. Our objectives were to evaluate the long-term effects of very low daily aspirin doses in the gastrointestinal tract and effects on platelet-derived serum thromboxane levels in volunteers. METHODS: Subjects were randomized to receive 10 mg (n = 8), 81 mg (n = 11), or 325 mg (n = 10) aspirin daily for 3 months. Before administration of aspirin, all subjects underwent gastroduodenoscopy, and most underwent proctoscopy for assessment of mucosal injury and prostaglandin content. After 1.5 and 3 months, subjects again underwent gastroduodenoscopy and, at 3 months, another proctoscopy.

RESULTS: Each aspirin dose (even 10 mg) significantly reduced gastric mucosal prostaglandin levels, to approximately 40% of the baseline value. All three doses also induced significant gastric injury, and 325 mg caused duodenal injury. Three subjects developed gastric ulcers, 1 while taking 10 mg/day of aspirin. Furthermore, aspirin at 81 mg/day and 325 mg/day (but not 10 mg/day) significantly reduced duodenal mucosal prostaglandin levels to approximately 40% of the baseline value. Only 325 mg of aspirin per day significantly reduced rectal mucosal prostaglandin levels to approximately 60% of the baseline value. Serum thromboxane levels were inhibited 62%, 90%, and 98% with 10, 81, and 325 mg of aspirin.

CONCLUSIONS: The findings explain aspirin's predominant gastric toxicity and question the safety of
even 10 mg of aspirin daily.