Anti-atherosclerotic properties of nifedipine. Benefit of early intervention to prevent cardiovascular complications.

Early stages of the atherosclerotic plaque are considered to be responsible for about 2/3 of all acute coronary syndromes. Therefore, suppression of this initial stage of plaque formation constitutes a major target to reduce the incidence of the disease itself as well as its complications. Ca antagonists, like Nifedipine, interfere with Ca++ ions crucially involved in atherogenesis. Consequently, interval angiographic trials with Nifedipine in patients afflicted with coronary artery disease assessed a significant reduction of coronary lesions. Clinical outcome trials will establish the prognostic importance of the anti-atherosclerotic properties of Nifedipine.

Influence of the selection of angiographic projections on the results of coronary angiographic follow-up trials. International Nifedipine Trial on Antiatherosclerotic Therapy Investigators.

In recent years follow-up trials on coronary artery disease with angiographic end points analyzed quantitatively have gained increasing relevance and popularity. There is no consensus, however, on the method of calculation of progression or regression from multiple angiographic projections. Therefore the influence of the selection of angiographic projections on the outcomes of such trials was investigated with the data of the International Nifedipine Trial on Antiatherosclerotic Therapy. In 348 patients with coronary artery disease, repeated coronary angiograms were compared in multiple identical angiographic projections. Changes in angiographic parameters were averaged over the 1063 stenoses analyzed. Five methods of evaluation of multiple projections in the individual stenoses were applied, resulting in different extents of overall progression, or even regression of coronary artery disease (p < 0.01). It is concluded that in quantitative coronary angiographic follow-up trials changes should be averaged over all angiographic projections available for a stenosis to avoid overestimation of progression or regression.

Evolution of coronary stenoses is related to baseline severity--a prospective quantitative angiographic analysis in patients with moderate coronary disease. INTACT Investigators. International Nifedipine Trial on Antiatherosclerotic Therapy.

A correlation of the angiographic evolution of coronary stenoses (stenosis diameter > or = 20%) with morphological stenosis parameters at baseline could help to identify the risk of progressive stenoses. Therefore, the data of the prospective INTACT study (International Nifedipine Trial on Antiatherosclerotic Therapy) were reviewed. In 348 patients with moderate coronary artery disease, standardized coronary angiograms were taken 3 years apart and were quantitatively analysed. Changes in the minimal diameter of the 1063 preexisting coronary stenoses compared between both angiograms were set in relation to a number of conventional stenosis parameters at baseline. Regression analysis demonstrated a significant correlation of the changes in minimal diameter with baseline % diameter stenosis (r = 0.30; P < 0.001), minimal diameter (r = -0.28; P < 0.001) and reference diameter of stenoses (r = -0.14; P < 0.001). The changes were not correlated with stenosis length and plaque area. The baseline parameters of 22 preexisting stenoses progressing to occlusions differed from those remaining patent only with regard to the % diameter stenosis (43 +/- 9% vs 39 +/- 11%; P < 0.05). Additional progression of coronary disease became manifest through development of 228 stenoses and 19 occlusions at arterial sites free from definitive stenoses in the baseline angiograms. Thus, progression of atherosclerosis predominantly occurred in mild preexisting coronary stenoses and developed at previously angiographically normal sites. Since the conventional angiographic parameters analysed in this study failed to identify individual arterial sites with an increased risk for progression, definition of new angiographic parameters or application of new techniques seem mandatory to this end.

Hypertension treatment and prevention of new atherosclerotic plaque formation.

The effect of hypertension on the arterial vascular wall is characterised primarily by morphological changes to the endothelium and hypertrophy of smooth muscle cells within the arterial media. Endothelial dysfunction is manifest through increased permeability to high molecular weight compounds as well as mitogenic and vasoactive substances. At the same time, denudation of the vascular endothelium promotes platelet aggregation and subsequent release of platelet-derived growth factor (PDGF). In conjunction with endothelium- and monocyte-derived growth factors, this mitogen stimulates subintimal smooth muscle cell proliferation and migration and arterial wall thickening, resulting in a haemodynamically important increase in vascular resistance, particularly at the precapillary level. In addition, focal endothelial dysfunction allows entry of lipids into the vascular wall, thereby promoting formation of a lipid-rich fatty streak, the primary 'early' atherosclerotic lesion. Most of these changes, including endothelial injury, subintimal lipid-binding, cellular proliferation and migration, platelet aggregation and PDGF release are common to both hypertensive and early atherosclerotic processes and involve the participation of calcium ions as 'second messengers'. Thus, antihypertensive treatment with calcium antagonists may not only lead to a protective decrease in wall shear stress through a reduction in blood pressure, but may also inhibit those cellular processes within the vascular wall that are responsible for initiating atherosclerosis. Indeed, experimental as well as human studies have demonstrated a beneficial suppressant effect of calcium antagonists on the early stages of atherosclerosis.

Myocardial infarction. Secondary prevention with nifedipine.

The rationale for the use of nifedipine in patients with acute myocardial infarction (MI) is based on the various cardiovascular actions of the compound: reduction of myocardial oxygen consumption by attenuation of cardiac and vascular smooth muscle tension; augmentation of oxygen and substrate supply after increased coronary blood flow with dilatation of epicardial coronary arteries (particularly in coronary obstructions) and dilatation of coronary resistance and collateral vessels; myocardial 'protection', i.e. reduction of myocardial damage via a complex intracellular mechanism, the primary outcome of which is the maintenance of an energy level sufficient to preserve the ionic homeostasis of the myocyte. The effect of nifedipine on reinfarction and mortality rates was evaluated in 6 well designed studies involving 8670 patients with evolving or established acute MI. Compared with placebo, short term therapy (for up to 6 months) with nifedipine 30 to 120 mg/day initiated, in some patients, as early as 3 hours after the onset of symptoms did not reduce either reinfarction rate or mortality. In one study (SPRINT I) [Israeli Sprint Study Group 1988], where a regimen of nifedipine 30 mg/day was only started 7 to 21 days after infarction, the exceptionally low mortality rate (5.7%) over 10 months in the placebo group precluded the demonstration of a beneficial effect of nifedipine. These results collectively suggest that nifedipine does not prevent the 'secondary' coronary events of plaque rupture and thrombus formation associated with MI and sudden cardiac death. However, the suppression of early lesions by nifedipine (as demonstrated in the INTACT study [Lichtlen et al. 1990]) might reduce 'primary' progression and improve the long term survival after MI.

Features of the angiographic evaluation of the INTACT study. International Nifedipine Trial on Antiatherosclerotic Therapy.

INTACT (International Nifedipine Trial on Antiatherosclerotic Therapy) is a prospective, placebo-controlled, randomized, double-blind, multicenter trial analyzing the influence of 80 mg nifedipine/day on the angiographic progression of early stage coronary atherosclerosis. Coronary angiograms were taken in identical projections before and after a treatment period of 3 years. Quantitative analysis of the angiograms was performed with the computer-assisted contour detection system CAAS. For definition purposes, the coronary artery system was subdivided into 25 different segments, including all anatomic variants. Measurement parameters of segments were mean and minimal diameter, and of stenoses minimal diameter, percentage diameter reduction (at least 20%), length, and plaque area. The variable extent of the changes of these parameters in the different projections analyzed per patient in the two study angiograms was considered by separate computation of the maximal, mean, and minimal changes over these projections; the comparison of the parameter changes between the two treatment groups was performed separately according to these three modes. For all parameters, this comparison was performed on the basis of the individual 25 segments, as well as after aggregation of individual segments to arteries (RCA, LAD, and LCX), to groups of large and small segments, and to the entire coronary artery system. Assessment of changes of the coronary (patho)morphology by quantitative analysis of coronary angiograms is associated with a number of methodical limitations, which may lead to a certain variability of the results. However, due to the double-blind feature of INTACT, this variability should be comparable in the two groups of this study, allowing for a conclusive comparison.

Retardation of angiographic progression of coronary artery disease by nifedipine. Results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT). INTACT Group Investigators.

425 patients showing mild coronary artery disease (CAD) on arteriography were enrolled in a multicentre trial and randomised to treatment with nifedipine (80 mg/day) or placebo. The two groups were well matched for age, sex, and risk factors. 348 patients (82%) underwent repeat arteriography 3 years later; 282 (134 nifedipine, 148 placebo) had received treatment throughout, but treatment had been stopped in 39 nifedipine-treated and 27 placebo-treated patients after average periods of 354 and 467 days. Computer-assisted measurements of arteriograms from all restudied patients (175 placebo, 173 nifedipine) showed no significant differences in the number or severity of lesions on initial arteriograms, or in the progression or regression of existing lesions over 3 years. In contrast, the number of new lesions per patient was significantly lower in the nifedipine group than in the placebo group (0.59 vs 0.82 lesions per patient, a 28% reduction). Thus in patients with mild CAD nifedipine substantially suppresses disease progression as shown by the appearance of new lesions detectable by quantitative coronary arteriography.

International nifedipine trial on anti-atherosclerotic therapy (INTACT)--methodologic implications and results of a coronary angiographic follow-up study using computer-assisted film analysis.

Animal experiments demonstrated a significant suppressive effect of various calcium channel blockers on the formation of atherosclerotic lesions. Therefore, a prospective, placebo-controlled, randomized, double blind multicenter study was performed to investigate the inhibitory influence of the calcium channel blocker nifedipine (80 mg/day) on the progression of coronary artery disease in man. Study endpoints were changes of coronary morphology documented by coronary angiography with particular respect to the formation of new coronary stenoses. In 348 out of 425 patients included in the study, coronary angiograms were repeated after three years. The angiograms were standardized by induction of a maximal coronary vasodilation with high doses of nitrates and by using absolutely identical angiographic projections. Quantitative analysis of coronary cineangiograms was performed with the computer-assisted contour detection system CAAS. Parameters were mean and minimal diameter of all segments and minimal stenosis diameter, percent diameter stenosis, length and plaque area of all stenoses. Continuous intake of study medication was registered in 282 patients, 134 on nifedipine and 148 patients on placebo. In these patients, a total of 3808 coronary segments with 893 stenoses (greater than or equal to 20% diameter reduction in at least one angiographic projection) were compared on the baseline and follow-up cineangiograms. The changes in all angiographic parameters analyzed averaged over all patients by considering all angiographic projections analyzed, indicated significant progression of the disease (p less than 0.006). The average changes in all parameters were even about three times more profound, when in the individual patients only the respective projections indicating the maximal changes were considered for the calculation (p less than 0.001). However, with neither of these two analysis modes, the differences in progression between the treatment groups were statistically significant. In the follow-up angiograms, a total of 196 new coronary lesions (185 stenoses, 11 occlusions) were found at previously normal arterial sites. In patients on nifedipine, an average of only 0.58 new lesions per patient were detected versus 0.80 lesions per patient on placebo (-27%; p = 0.031). INTACT is the first prospective angiographic trial on the progression of coronary artery disease using computer-assisted quantitative coronary angiography in such a high number of patients. All parameters analyzed indicated significant progression of coronary artery sclerosis. Nifedipine had no influence on the progression of preexisting coronary stenoses, but inhibited significantly the formation of new angiographically recognizable lesions. Further prospective coronary angiographic trials with calcium channel blockers using a comparably exact method are needed to confirm the results of this study.

Coronary dilation with nitrocompounds and calcium antagonists.

The vasodilatory effects of nitrocompounds and calcium antagonists on epicardial coronary arteries represent substantial antianginal mechanisms in the presence of coronary vasospasm or eccentric coronary stenoses. With high doses of nitrocompounds, angiographically normal coronary segments can be dilated by an average of approx. 30%, some coronary stenoses even by up to 100%, usually without severe reduction of blood pressure. With calcium antagonists, a similar extent of dilation of normal coronary arteries and eccentric stenoses can be obtained. Our own group demonstrated an average dilation of normal coronary arteries of about 20% after intravenous administration of dihydropyridine calcium antagonists; however, the average systolic blood pressure dropped below 100 mmHg after these compounds. Hence, although in isolated human coronary arteries high concentrations of calcium antagonists were shown to induce a considerably greater vasodilation than nitrocompounds, the early drop in blood pressure prohibits a higher dosage of calcium antagonists in vivo. In the presence of coronary artery disease, particularly when associated with coronary vasospasm, a combination of the two groups of compounds might be recommendable, since an addition of the effects of coronary vasomotor tone is likely. Furthermore, the antianginal effects of a reduction of preload and afterload are complementary.

[Computer-assisted geometric measuring technic in coronary angiography interval studies: results of initial angiograms of the International Nifedipine Trial of Anti-atherosclerotic Therapy (INTACT) study]. / Computergestützte geometrische Messtechnik in koronarangiographischen Intervallstudien: Ergebnisse bei Erstangiogrammen der INTACT-Studie.

In 396 of 423 (93.6%) patients with mild to moderate coronary artery disease participating in a coronary angiographic follow-up trial, diameters of the epicardial coronary arteries were measured with an automatic contour detection system (CAAS). The underlying INTACT study (International Nifedipine Trial on Antiatherosclerotic Therapy), a prospective, placebo-controlled, randomized, double-blind multicenter trial, investigates the influence of the calcium antagonist nifedipine (80 mg/day) on the progression of coronary atherosclerosis over a three-year interval. The study is based on coronary angiograms repeated in identical projections after premedication with 10 mg isosorbide dinitrate sublingually. For quantitative analysis the coronary artery system was, in consideration of all anatomical variations, subdivided into 25 segments. In the first angiograms of the 396 patients evaluated up to April 1, 1988, altogether 5,425 different coronary segments could be analyzed over their entire length in one or more angiographic projections--on the average 13.7 +/- 2.8 segments per patient. Analysis parameters were the mean diameters of the entire segments and of the individual subsegments (about 5 mm in length). The 10 major proximal segments could be evaluated in 76-94% of patients respectively in more than two different angiographic projections on the average; in 0-13% of patients the respective segments were occluded. In 1-4% of patients the evaluation of these segments was prevented by poor film quality and in 1-16% of patients prevented by anatomical abnormalities (e.g., segment too short or too small). 184 segments were found occluded (RCA 42%, LAD 30%, CX 28%) and 909 mostly low-grade to moderate stenoses (RCA 34%, CX 32%, LAD 30%, left main 4%) were analyzed with a special algorithm. The following obstruction parameters were derived: minimal diameter, percentage severity, length, and plaque area. The present data demonstrate that in an angiographical multicenter follow-up study such as INTACT a nearly complete quantitative morphometric analysis of the visualized coronary artery system can indeed be obtained in virtually all angiograms when a computer-assisted contour detection system is applied.

Clinical application of quantitative coronary angiography using the CAAS system: preliminary results of the INTACT study (International Nifedipine Trial on Antiatherosclerotic Therapy).

It is the objective of the INTACT-study to test in man, whether a significant retardation of the progression of coronary artery disease is attainable with the Ca-antagonist nifedipine; this may be possible on the basis of numerous animal experiments. INTACT is a prospective, randomized, double blind, placebo controlled investigation in 423 patients with preferably early stages of coronary sclerosis in whom a progression of the disease seems likely. A proper coronary angiogram led to inclusion of the patients in the study (October 1983-June 1985). Over the following 3-years-period patients received either nifedipine 80 mg/day or placebo. The study is concluded by a control coronary angiogram with angiographic projections which are identical to those of the first coronary angiography. The extent of coronary sclerosis is objectivated by computer-assisted quantitative measurement of the entire coronary arterial system with the CAAS-system (Rotterdam). For definition purposes the coronary artery system subdivided into 25 segments. Parameters for progression assessment will be mean segment diameter, minimal obstruction diameter, percentage severity of obstruction, length of obstruction and plaque area. So far 4826 coronary segments have been analyzed from the first angiograms of 383 patients. Per patient an average of 12.6 different segments could be evaluated in at least one angiographic projection. The major coronary segments could be measured in 72-93% of the patients in one or more angiographic projections (at the average about 2 different projections). Five hundred and forty-six coronary obstructions were analyzed; 131 of these were total occlusions. Only 9% of the length of the vessel contours detected by the computer algorithm required manual correction by the operators, suggesting a high reliability of the system. It can be concluded that quantitative measurement of the complete coronary artery system can indeed be obtained in a large angiographical multicenter study such as INTACT.

International nifedipine trial on antiatherosclerotic therapy (INTACT).

A number of animal studies revealed an inhibition or retardation of the progression of atherosclerosis by calcium-antagonists. Encouraged by these studies, a multicenter trial on the progression of coronary artery disease (CAD) in man was initiated testing the antisclerotic effect of nifedipine against placebo in 426 patients with mild to moderate coronary disease over 3 years. All patients underwent coronary angiography before entering the trial and will be restudied after 3 years; changes of the coronary artery lumen size are quantitatively assessed by a computer-assisted system (CAAS). INTACT (International Trial on Antiatherosclerotic Coronary Therapy) is therefore the first randomized prospective study on the progression of CAD based on a quantitated anigraphic control of the coronary system. This report presents the design of this still-ongoing study as well as inclusion and exclusion criteria. The quantitative evaluation of the coronary angiograms and the mode of compliance test are described in detail. A number of baseline data as well as the preliminary results of the quantitative evaluation of the first coronary angiograms are presented. Beside the results on the effect of the calcium-antagonist nifedipine on the progression of CAD, INTACT might also supply information on the antiatherosclerotic potency of other drugs administered additionally (beta-blockers and nitrates) and of HDL-cholesterol.