Aspirin for diabetic retinopathy

The earliest clinically recognisable lesions in diabetic retinopathy are capillary occlusions, which can be shown on fluorescein angiograms, a standard investigation in patients with retinopathy. The response to capillary blockage is dilation of neighbouring ones, leading to breakdown of the blood-retina barrier and leakage. Later large vessels become affected, and the result is retinal ischaemia, which is responsible for the secretion of vasoactive cytokines, leading to formation of the sight threatening proliferative lesions.

Since capillary occlusion is a pivotal lesion, causes and cures for it have been sought for a long time. Aggregation of platelets is increased in diabetes, and this has been proposed as the underlying abnormality.¹ An early paper by Pope et al showed platelet thrombi in retinal capillaries of diabetic patients.² Furthermore, observational evidence showed that patients treated with acetyl salicylic acid had less retinopathy than expected in a general diabetic population.³ More recently in a detailed postmortem study on nine eyes Boeri et al found large thrombi more often in retinas from diabetic patients than in control retinas and double the number of vascular segments immunostaining for platelet glycoprotein IIIa.⁴ They suggested as a result of their findings that aspirin be considered as an intervention in early diabetic retinopathy. This work was supported by the finding of Kern and Engerman, who in diabetic dogs found that treatment with aspirin reduced the number of acellular capillaries and retinal haemorrhages after five years of diabetes.⁵

Important advances have occurred in the understanding of diabetic retinopathy in the past 10 years. Platelets by themselves are no longer thought to be of prime importance in blocking retinal capillaries; rather, changes in the endothelial cells and white cells are responsible for capillary occlusion, as shown in the review of their own extensive work by Schroder et al.⁶ Adamis's group noted the underlying inflammatory component of early diabetic retinopathy, and in a series of elegant experiments in the diabetic rat model showed that high dose aspirin (2 mg/kg/day) reduced leucocyte adhesion in diabetic retinal capillaries, arterioles, and venules.⁷ Aspirin also reduced expression of integrins on the surface of leucocytes and the adhesion molecules, ICAM-1, in the capillary wall. Further effects included reduction of nitric oxide synthetase (eNOS) levels and reduced production of the vasoactive cytokine, tumour necrosis factor α, found to be raised in diabetic retinopathy. Thus there seems to be ample reason for using of aspirin in diabetic retinopathy.

Only two large studies of aspirin for retinopathy have been reported. The joint French-UK aspirin and dipyridamole trial was a randomised controlled study of 475 patients followed for five years. Patients with early retinopathy were included (at least five microaneurysms on fluorescein angiograms or areas of nonperfusion in the macular area).⁸ The dosage of aspirin used was 330 mg, three times daily, given alone or in combination with dipyrimadole (75 mg three times daily). After five years fewer new microaneurysms formed in patients taking aspirin (the reduction was 1-2 new microaneurysms per patient per year). The findings were statistically significant but were not thought to be clinically important, and it was thought that there was only slight beneficial effect and no contraindication to the use of aspirin in patients with diabetes and retinopathy. In contrast the large early treatment of diabetic retinopathy study (ETDRS) found that aspirin at a daily dose of 650 mg had no effect in 3711 patients allocated randomly to active treatment or placebo.⁹ In this study retinopathy was more severe than in the French-UK study. ETDRS also found no effect of aspirin on either the development of cataracts or problems during extraction of cataracts.

Evidence that aspirin causes increased risk of haemorrhage in patients with diabetes and proliferative retinopathy is lacking. Patients treated with aspirin do not have their drug stopped during cataract extraction, and recent work indicates that it does not have to be discontinued even during vitreo-retinal surgery. (Williamson, personal communication, 2003)

Should we give aspirin to patients with diabetes for the treatment of retinopathy? In a recent detailed review of all important previous work (but before the publication of the work of Adamis's group), Berghoff et al thought that there were no real indications and no contraindications to the use of aspirin in diabetic retinopathy.¹⁰ In view of recent basic investigations this view may have to be reconsidered, and high dose aspirin may become one of the possible additions to preventive treatment in diabetic retinopathy.