Current Status of Isosorbide-5-Mononitrate Therapy in Chronic Stable Angina Pectoris

A review was made of all known published data on the use of isosorbide-5-mononitrate (5-ISMN) in chronic stable angina pectoris, and efficacy in terms of exercise testing (bicycle or treadmill) was assessed. Adequate documentation for effectiveness for 12 h with steady-state treatment (2 weeks) of 5-ISMN in immediate-release tablets is available only with a dosage of 20 mg twice daily, taken 7 h apart. For other dosage regimens, efficacy has been documented for 2 or at most 4 h duration after dose intake. Immediate-release tablets of 40 mg are effective only for 2 h in steady-state treatment. These data suggest that tolerance develops to some immediate-release tablet regimens. A satisfactory explanation for this is still lacking. The possibility that a rapid plasma level rise is conducive to tolerance development needs to be tested. Extended-release tablets in strengths from 30 to 100 mg are effective for 12 h after the first dose. In steady-state treatment of 3--6 weeks' duration, 12-h efficacy has been shown only for one brand of extended-release 5-ISMN (Imdur((R))) in doses ranging from 60 to 240 mg taken once daily in the morning. Currently, the best explanation to the maintained efficacy with long-term extended-release 5-ISMN is that the plasma level profile allows for a sufficiently low organic nitrate level for a sufficiently long uninterrupted fraction of the dosage interval, occurring during the night when tablet intake is once daily in the morning. Twice daily dosage every 12 h of extended-release 5-ISMN tablets causes tolerance development. Tolerability is similar for both types of tablets, and overall it is excellent. Headache is a common symptom at initiation of treatment but wanes quickly. No rebound effect in the nitrate-low period has been noted with either regimen. Few well-controlled studies have addressed quality of life efficacy, that is, the influence of symptoms and signs of daily life. Many trials of those reviewed were of suboptimal design, and conclusions were often overstated.