Organic nitrates have been used in the treatment of both acute and chronic heart diseases for many years. The most important component of the antiischaemic activity of nitrates is believed to be preload reduction owing to their venous dilator effect (1). It has also been suggested that nitrates may decrease myocardial oxygen demand by reducing afterload (2). Arterial effects on coronary and systemic conductance vessels have also proven to play an important part in relieving myocardial ischaemia (3-5). However, the inability to achieve optimal effects on conductance vessels without affecting resistance vessels, thereby inducing hypotension, may limit the clinical use of these compounds (6,7). Furthermore, the onset of tolerance to nitrates during long-term administration leads to a progressive loss of clinical benefit (6,8-10). Other vasodilator compounds have therefore been sought with the aim of identifying potential drugs that selectively dilate the major coronary arteries, without the development of tolerance.
ITF-296 is a new organic nitrate ester (11) that, in conscious dogs, has been shown selectively to dilate large coronary arteries, with much reduced peripheral haemodynamic effects compared with glyceryl trinitrate (12,13). Maximal dilatation of large coronary vessels is achieved before systemic blood pressure and heart rate are affected. Animal models have, thus far, shown no evidence of the development of tolerance (13), and studies in healthy male volunteers have confirmed very good overall safety and tolerability of ITF-296 (14). The haemodynamic effects occur within 5-10 min after the start of intravenous infusion and last for ∼1 h after termination. These effects include a reduction in systolic and diastolic blood pressure and stroke volume, but no change in heart rate. In contrast, isosorbide dinitrate has been shown to increase heart rate and exert greater neurohumoral counterregulatory effects (15). Furthermore, ITF-296 appears to be better tolerated than isosorbide dinitrate.
The objective of this study was to assess, for the first time, the safety, tolerability, haemodynamic effect, and antiischaemic efficacy of escalating doses of intravenously administered ITF-296 in male patients with chronic stable angina.
This was a single centre, double-blind, parallel-group, dose-escalating study in design. Twenty-four male patients with chronic stable angina were equally divided into three groups to evaluate three different dose levels of ITF-296; at each dose level, the ratio of active dose to placebo was 6:2, and treatments were randomised. Ethical approval was obtained from the hospital ethics committee, and each patient gave written informed consent before participation. Antianginal therapy was withdrawn ≥1 week before enrollment into the study. At the screening visit, patients underwent a history, physical examination, blood sampling for routine haematologic and biochemical tests, urinalysis, and exercise electrocardiography in conjunction with echocardiography. Specific inclusion criteria were (a) nonobese men aged 40-75 years in sinus rhythm, (b) chronic stable effort-induced angina for ≥3 months, (c) ischaemia threshold <9 min during supine bicycle exercise, and (d) exercise-induced wall-motion abnormality identified by echocardiography. Those with myocardial infarction within 3 months, heart failure, uncontrolled hypertension, rhythm disturbance, renal impairment, or insulin-dependent diabetes mellitus were excluded.
Patients who exercised for <9 min, with demonstrable new wall-motion abnormality at peak exercise, underwent a reproducibility exercise test 1 week later. Those with a <15% difference in exercise duration between these baseline tests were requested to return 3-7 days later for intravenous infusion of study treatment over a period of 30 min. At this visit, blood pressure, heart rate, and echocardiography were performed 5-10 min and 25-30 min into the infusion. Patients were questioned about adverse events at the times that resting blood pressure were recorded. Five minutes after termination of the infusion, a final exercise test was performed to assess the effects of study treatment on exercise variables. Patients returned 24 h later for safety assessments including physical examination, haematologic and biochemical blood tests, urinalysis, and recording of any interim adverse events.
Patients were allocated to a treatment group according to a randomisation schedule. Treatments were given by intravenous infusion. Patients received a single dose of ITF-296 (0.3, 1.0, or 3.0 μg/kg/min) or placebo, infused for 30 min. There were eight patients per dose level (six active and two placebo). The dose level was increased only when all eight patients had been treated at the previous, lower dose level and only if that dose level had been well tolerated by the group. The ampoules for both active and placebo medications (stored at 4°C until dosing) were identical to maintain anonymity of treatment. The contents included either 10 mg of ITF-296 in 1 ml of solvent (propylene glycol/ethanol, 2:1) or placebo, containing solvent alone. The contents of eah ampoule were diluted with sterile 0.9%N saline, and dilutions were made in such a way that similar volumes were infused over the entire dose range studied. The infusion was administered with an automatic syringe pump.
Exercise was performed by using bicycle ergometry with the patient lying semisupine at 30° to the horizontal. Exercise was started at a workload of 50 W and increased by 25 W every 3 min. Twelve-lead electrocardiographic monitoring was performed throughout the test, and blood pressure was measured at each stage of exercise. End points for test termination included intolerable symptoms, significant arrhythmia, systolic blood pressure >220 mm Hg, or diastolic blood pressure >120 mm Hg, and fatigue. Echocardiography was performed at baseline and immediately after exercise in the left lateral decubitus position. The following were recorded: reason for test termination, time to onset of angina, total exercise time, ST-segment changes from baseline measured at 60 ms after the J-point, and echocardiographic wall-motion score index as described later. For those patients in whom angina or 1-mm ST-segment depression did not develop, these values were replaced by total exercise time.
Two-dimensional and Doppler echocardiography were performed by one of two investigators by using an Ultramark 9 system (Advanced Technology Laboratories, Bothell, Washington, U.S.A.) with a 2.5-Mhz transducer in the parasternal long and short axis and apical four- and two-chamber views. Images were stored on VHS videotape. For wall-motion analysis, the left ventricle was divided into 11 segments, such that four segments were ascribed to the anterior and anteroseptal walls, four to the inferior and inferoseptal walls, two to the lateral wall, and one to the apex. Each segment was analysed for systolic wall thickening and graded as normal, 1; mild hypokinesia, 2; severe hypokinesia, 3; akinesia, 4; and dyskinesia, 5. The development of a new or worsening wall-thickening abnormality was considered evidence of ischaemia.
The main variables of interest were normally distributed or conformed to a normal distribution after suitable transformation by standard statistical methods. Comparisons were therefore performed by using a parametric analysis of variance to compare differences between treatments. Continuous variables were described as means ± standard deviation or medians and range. The null hypothesis was usually rejected when p < 0.05. However, that rule was not applied rigidly or without careful consideration of the plausibility of the size and the direction of the differences between treatments, given the small sample size. Calculation of 95% confidence intervals (CIs) was undertaken to help in the interpretation of the data.
There were no significant differences in age, ethnic origin, body-mass index, resting heart rate, or resting blood pressure between the four treatment groups (placebo, 0.3, 1.0, and 3.0 μg/kg/min of ITF-296) consisting of six patients in each group.
Safety and tolerability of ITF-296
Only one subject had an adverse event considered to be related to treatment, that of "heaviness in the head" at the end of the infusion of 3.0 μg/kg/min of ITF-296. There were no changes in haematologic or clinical chemistry variables attributable to treatment.
Effects of ITF-296 at rest
Among the 18 patients who received ITF-296, systolic blood pressure decreased by a mean of 12 mm Hg (13, 12, and 12 mm Hg reductions at 0.3, 1.0, and 3.0 μg/kg/min doses, respectively) compared with a 2 mm Hg increase in the placebo group (95% CI, −23 to −6); this was not associated with symptoms. Whereas the 0.3 and 1.0 μg/kg/min doses of ITT-296 were associated with reductions in heart rate, a slight increase in heart rate was noted with 3.0 μg/kg/min of ITF-296, causing a lesser reduction in rate-pressure product at this dose level. Diastolic blood pressure was not affected by ITF-296.
Effects of ITT-296 on exercise performance
ITT-296 caused consistent increases in total exercise time, time to angina threshold, and time to 1-mm ST-segment depression compared with placebo (Table 1). Dose escalation of ITF-296 was accompanied by enhanced antiischaemic activity of the drug, as shown by the increases in these parameters from baseline to postinfusion exercise tests (Fig. 1). Whereas the effects of the 0.3-μg/kg/min dose on exercise time, time to angina threshold, and time to 1-mm ST-segment depression were similar to those of placebo, the 1.0-μg/kg/min dose of ITF-296 resulted in an increase in these parameters with further but lesser increments in time to angina threshold and 1-mm ST-segment depression with the 3.0-μg/kg/min dose. From postinfusion to peak exercise, wall-motion abnormality increased by a score index of 0.5 with placebo compared with 0.31 with ITF-296 (difference, −0.19; CI, −0.38−0.31).
ITF-296 administration increased systolic blood pressure at peak exercise by 30-40 mm Hg with similar effects in all three active treatment groups. Although this may in part be attributed to the increase in exercise time, ITF-296 intrinsically increased the rate at which systolic blood pressure increased during exercise compared with placebo as shown by the slope of the systolic blood pressure-time curve (Fig. 2). In addition, as depicted in Fig. 3, the slope of the heart rate-time curve during exercise was blunted by all three dose levels. Figure 4 shows the change in rate-pressure product versus change in exercise time; these are values of the postinfusion exercise test minus the means of the two baseline exercise tests. This shows that the 0.3-μg/kg/min dose of ITF-296 has an effect on exercise tolerance similar to that of placebo and tends to increase rate-pressure product. In contrast, the 1.0- and 3.0-μg/kg/min doses prolonged exercise time by >2 min in each case, with no important change in rate-pressure product compared with baseline exercise tests. This effect was particularly evident for the 3.0-μg/kg/min dose of ITF-296.
This study entailed the first administration of ITF-296 to patients with coronary heart disease, after previous studies on healthy male normotensive volunteers. The safety profile of ITF-296 infusions up to maximal doses of 3.0 μg/kg/min, in our group of patients with chronic stable angina, was very good. The adverse event experienced by one patient during the highest dose of ITF-296 probably represents the headache commonly experienced by patients taking organic nitrates and was presumably due to dilatation of extracranial blood vessels. ITF-296 infusion was otherwise remarkably well tolerated.
With respect to exercise haemodynamics, ITF-296 showed a trend toward an increase in the slope of the systolic blood pressure-to-time curve and a reduction in the slope for the heart rate-to-time curve during exercise, at all three dose levels compared with placebo. Although these differences failed to reach statistical significance (partly because of the small number of subjects in each treatment group with wide CIs), these findings might suggest that ITF-296 intrinsically increased the systolic blood pressure response but reduced the heart rate response to any given level of exercise and that the lack of any difference in peak heart rate between placebo and the active treatments was due to the longer period of exercise after the active treatments.
Although a dose effect was not observed with these observations, ITF-296 exhibited a trend toward a doserelated blunting of the rate-pressure product during exercise. Rate-pressure product may be considered a surrogate measure of myocardial oxygen consumption, and this attenuation of myocardial oxygen consumption by increasing doses of ITF-296 was paralleled by dose-related increases in total exercise time, time to angina threshold, and time to 1-mm ST-segment depression. The 0.3 μg/kg/min dose showed exercise performance similar to placebo and a relative increase in rate-pressure product. The 1.0- and 3.0-μg/kg/min doses prolonged exercise time by >2 min in each case, being of the same order as those of organic nitrates in clinical use. These increases in exercise time were associated with no important change in rate-pressure product compared with that at peak exercise during the baseline exercise tests. At least some of the improved exercise tolerance may be due to beneficial effects of ITF-296 on preload, heart rate, and afterload. The effects on afterload might include changes in arterial compliance as well as in the resistance vessels.
Systolic wall-motion abnormality is one of the earliest manifestations of myocardial ischaemia, occurring before the development of electrocardiographic changes or onset of symptoms (16). The augmentation of exercise performance by ITF-296 was matched by a dose-related reduction in wall-motion abnormality at peak exercise. The differences in wall-motion abnormality between active and placebo treatments are small but consistent with the data for total exercise time and time to angina threshold. The effect of ITF-296 on wall-motion abnormality may have been better assessed, and the differences compared with placebo possibly more obvious if echocardiography had been performed at identical baseline and postinfusion exercise workloads.
As this was the first study to assess the effects of ITF-296 in patients with manifest coronary heart disease, a small patient population was considered prudent. The use of only six subjects per treatment means that the study had very limited power to distinguish differences between treatments. Even though many observations failed to reach statistical significance, the trends were consistently pharmacologically plausible and indicate that ITF-296 shows potential antiischaemic efficacy in patients with chronic stable angina. Larger studies are now required further to assess the dose-response relation of variable doses of ITF-296 in a randomized manner.
Acknowledgment: We thank Dr. Steven Warrington for his help in compiling the manuscript.
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