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We believe that none of these methods is satisfactory. Fall in blood pressure or rise in heart rate by no means guarantees an antianginal effect, and 10 mm Hg or 10 bpm are less than the changes we observed w ith an optimal dose. Furthermore, in our opinion, patients who develop nitrate headache are not only unsuitable for a double-blind study, but they are also unacceptable for a dose titration study that seeks to determine the magnitude and duration of effect of a nitrate preparation administered in a pharmacologically optimal dose. Studies monitoring wedge pressure in congestive heart failure as the parameter for dose titration of nitroglycerin patch have employed doses of 64 sq cm and 120 sq cm to obtain an optimal therapeutic effect. Doses of 60 to 120 sq cm (mean, 104 sq cm) were found effective in reducing ischemic episodes detected by ambulatory electrocardiographic monitoring. We believe that the use of insufficient doses, or acute titrations in patients not taking nitrates long term, are important reasons why many studies have failed to demonstrate significant patch effectiveness or the persistence thereof beyond the acute phase. In our experience with serial observations of response to ISDN during long-term treatment in the titration phase of this study, the large majority of patients developed partial tolerance, and within weeks they responded less well or not at all to a dose that was initially effective.