In severe heart failure, the prostaglandin synthesis inhibition by aspirin counteracts the systemic arterial vasodilation of angiotensin-converting enzyme inhibition with enalapril and substantiates its dependence on the integrity of prostaglandin metabolism. Trends toward reductions of pulmonary artery pressure and slowing of the heart rate were still observed, presumably subsequent to lowered norepinephrine concentrations indicating maintenance of prostaglandin-independent actions of angiotensin-converting enzyme inhibition.

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The objective of this study was to assess the value of a clopidogrel regimen based on a high loading dose initiated before the stent placement procedure. A consecutive series of 864 patients treated with a high-loading-dose clopidogrel regimen (600 mg given 2-4 hr prior to intervention) was compared with 870 patients treated with conventional ticlopidine therapy. Abciximab was given periprocedurally in 62% of the patients. The composite endpoint of death, myocardial infarction, or urgent revascularization was reached by 39 (4.5%) clopidogrel patients and 59 (6.8%) ticlopidine patients. Clopidogrel therapy was associated with a 35% reduction of the risk for early adverse events (odds ratio 0.65; 95% confidence interval, 0.43-0.98). Thus, a high-loading-dose clopidogrel regimen in patients undergoing coronary artery stenting was safe and led to a more favorable clinical outcome than conventional therapy with ticlopidine regardless of concomitant treatment with abciximab.

To address the issues of tolerance development and its circumvention during long-term treatment with nitrates, several controlled studies have been performed. In patients with coronary artery disease, during long-term treatment with isosorbide dinitrate (ISDN) in sustained-release form at dosages of 20 mg t.i.d., 40 mg t.i.d. and 60 mg t.i.d., both the rate of anginal attacks and the ischaemic reaction to exercise were unaffected. After a marked acute anti-ischaemic effect to 40 mg ISDN in nonsustained-release form, during chronic administration of the same dose four times daily, in association with continuously-high nitrate plasma concentrations, similarly, there were no significant effects. On use of nitroglycerin (NTG) transdermal patches delivering 10 mg, 15 mg and 30 mg per 24 hours, respectively, renewed patch application after 24 hours was not met with the same marked response observed after initial application. Clearly attenuated effects could be seen within 8 to 12 hours. These results show that tolerance development is incurred when the incrementation in plasma concentration after a repeated nitrate dose is of relatively limited magnitude with respect to baseline values. The observation of rapid reversibility of nitrate tolerance lead to the concept of interval treatment which on daily use incorporates a sufficiently long period without nitrate administration. On use of a nitrate-free treatment interval employing a regimen of 20 mg ISDN nonsustained-release form twice daily in the morning and at midday, 120 mg ISDN sustained-release form once daily or 50 or 100 mg isosorbide 5-mononitrate once daily, maintained effectiveness has been documented, as it has also been shown for treatment with NTG patches delivering 10 mg per 24 hours on incorporation of a 12-hour patch-free interval. The currently available patch system with discontinuous NTG delivery does not incur a complete loss of action but a considerable attenuation of its effects indicates the need for further refinements. Thus interval treatment guarantees maintenance of nitrate effects, albeit with the limitation that 24-hour therapeutic coverage is not enabled.

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