Wolfgang Rafflenbeul

Retardation of angiographic progression of coronary artery disease by nifedipine

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.

Increased thrombin levels during thrombolytic therapy in acute myocardial infarction : relevance for the success of therapy

BackgroundIt has been suggested that thrombolysis in a feedback reaction may generate pro-coagulant activities. Methods and ResultsFifty-five patients were treated with urokinase-preactivated pro-urokinase (n = 35) or tissue-type plasminogen activator (n =20) for acute myocardial infarction and underwent coronary angiography at 90 minutes and at 24-36 hours into thrombolysis, and fibrinogen (Ratnoff-Menzie), D-dimer (ELISA) and thrombin-antithrombin III complex levels (ELISA) were measured. Primary patency was achieved in 39 patients (70.9%), 13 of whom (33.3%) suffered early reocclusion. Nonsignificant decreases in fibrinogen levels were observed while D-dimer levels increased +3,008±4,047 gg/l (p<0.01), differences not being significant in respect to the thrombolytic agents or to the clinical course. In contrast, while thrombin-antithrombin III complex levels decreased −4.4 ± 13.0, ug/l in patients with persistent patency, they increased +7.5±13.6 pg/l in case of nonsuccessful thrombolysis (p<0.02) and + 11.9±23.8, g/l in case of early reocclusion (p <0.001). For patients with thrombin-antithrombin III complex levels greater than 6 ng/l 120 minutes into thrombolysis, the unfavorable clinical course was predicted with 96.2% sensitivity and 93.1% specificity. ConclusionGeneration of thrombin, occurring during thrombolysis, is a major determinant for the success of therapy and thrombin-antithrombin III levels may serve as predictors for the short-term prognosis. (Circulation 1991;83:937–944)

Anatomical progression of coronary artery disease in humans as seen by prospective, repeated, quantitated coronary angiography. Relation to clinical events and risk factors. The INTACT Study Group.

BackgroundAt present, there is extensive knowledge on the clinical course of coronary artery disease (CAD), whereas data on the underlying anatomical changes and their relation to clinical events are still limited. Methods and ResultsWe investigated progression and regression of CAD prospectively over 3 years in 230 patients (average age, 53.2 years) with mild to moderate disease by applying quantitated, repeated coronary angiography. Minimal stenotic diameters, segment diameters, and percent stenosis were analyzed by the computer-assisted Coronary Angiography Analysis System (CAAS). Progression was defined either as an increase in percent stenosis of preexisting stenoses by ≥20% including occlusions or as formation of new stenoses ≥20% and new occlusions in previously angiographically “normal” segments. At first angiography, we found 838 stenoses ≥20% (average degree, 39.3%) and 135 occlusions in the four major coronary branches (4.23 lesions per patient). At second angiography, 82 (9.8%) of the preexisting stenoses had progressed, 15 of them up to occlusion (1.8% preocclusion degree averaging 46.6%; 29.7–65.6%). In addition, there were 144 newly formed stenoses (average degree, 39.2%) and 10 new occlusions. Hence, 25 (2.6%) of all stenoses had become occluded. Altogether, 129 patients (56.1%) showed progression: 68 (29.6%) with new lesions only, 27 (11.7%) with preexisting lesions, and 34 (14.8%) with both types. Regression (decrease in degree of stenoses ≥20%) was present in 29 stenoses (3.6%) and 28 patients (12%). The incidence of new myocardial infarctions was low, with three originating from occluding preexisting stenoses and one from new stenoses; hence, only four (16%) of the 25 new occlusions led to myocardial infarctions. Risk factor analysis showed that cigarette smoking correlated significantly with the formation of new lesions (p=0.001), whereas total cholesterol correlated with the further progression of preexisting stenoses (p=0.017) but not with the incidence of new lesions. ConclusionsIn patients with mild to moderate CAD, the angiographic progression is slow (in this study 18.7% of patients and 7% of stenoses per year) but exceeds regression (4.1% of patients and 1.2% of stenoses per year). Progression is predominantly seen in the formation of new coronary stenoses and less in growth of preexisting ones. Most of the stenoses were of a low degree (<50%), clinically not manifest including those going into occlusion and leading to myocardial infarction. Progression was influenced by risk factors, especially cigarette smoking (formation of new lesions) and high cholesterol levels (progression of preexisting stenoses).

Progression of coronary artery disease is dependent on anatomic location and diameter

OBJECTIVES This study represents the first prospective, quantitative analysis of the association of progression of coronary atherosclerosis with anatomic site and diameter. BACKGROUND The progressive course of coronary artery disease has been documented in many angiographic follow-up trials. METHODS The data of 348 patients with coronary artery disease from the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) were reviewed. Standardized coronary angiograms were taken 3 years apart and were analyzed quantitatively. The coronary tree was subdivided into 25 segments. The progression of 1,063 preexisting coronary stenoses and the appearance of 247 newly formed stenoses was assessed in relation to the mean diameter of segments (< 2 mm, 2 to 3 mm, > 3 mm) and to their position in the coronary tree (proximal, mid, distal) and in the three major coronary arteries. RESULTS Decreases in the minimal diameter of preexisting stenoses were largest in segments that were > 3 mm in diameter (mean +/- SD 0.23 +/- 0.5 mm vs. 0.10 +/- 0.4 mm and 0.02 +/- 0.3 mm, p < 0.001), in a proximal position (0.14 +/- 0.5 mm vs. 0.09 +/- 0.4 mm and 0.06 +/- 0.3 mm, p = 0.081) and in the right coronary artery (0.14 +/- 0.4 mm vs. 0.07 +/- 0.4 mm and 0.07 +/- 0.3 mm, p < 0.01). Changes in percent diameter stenosis of preexisting stenoses were lowest in segments that were < 2 mm in diameter and in a distal position (p = NS). The number of new stenoses/segment was lowest in segments that were < 2 mm in diameter (44 of 1,756 vs. 139 of 1,967 and 64 of 1,125, p < 0.001) and in a distal position (77 of 2,370 vs. 84 of 1,193 and 86 of 1,285, p < 0.001) and was highest in segments of the right coronary artery (100 of 1,546 vs. 66 of 1,496 and 72 of 1,492, p = 0.044). CONCLUSIONS Progression of coronary artery disease occurs most frequently in coronary segments that are > 2 mm in diameter, in a proximal or midartery position and in the right coronary artery.

International nifedipine trial on antiatherosclerotic therapy (INTACT).

SummaryA 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.

Features of the angiographic evaluation of the INTACT study

SummaryINTACT (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 doubleblind feature of INTACT, this variability should be comparable in the two groups of this study, allowing for a conclusive comparison.

Influence of the selection of angiographic projections on the results of coronary angiographic follow-up trials

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.

Concept of an antiatherosclerotic efficacy of calcium entry blockers

Animal experiments suggest an inhibitory effect of calcium entry blockers on arterial calcinosis and the formation of atherosclerotic plaques. Experiments with isolated tissues suggest various mechanisms for an antiatherosclerotic effect of calcium entry blockers.INTACT, the International Nifedipine Trial on Antiatherosclerotic Therapy, is the first study investigating, with a prospective, placebo-controlled, randomized, double-blind design, the influence of a calcium entry blocker (nifedipine 80 mg/day) on the progression of coronary atherosclerosis in patients with proven coronary artery disease. Study endpoints were changes of established coronary stenoses (diameter reduction ≥ 20%), as well as the formation of new stenoses as documented by coronary angiography. Standardized coronary angiograms were taken before and after a treatment period of 3 years. The angiograms were quantitatively analyzed with the computer-assisted edge detection system CHAS. Of the 425 patients included in the study, 282 patients (134 on nifedipine and 148 on placebo) revealed no protocol violations. In the inclusion angiograms of these patients, 893 coronary stenoses were detected which were not significantly influenced in their development by nifedipine. However, 196 entirely new coronary lesions, 185 stenoses and 11 occlusions, were found in the follow-up angiograms. There were 78 lesions in 54 patients (40%) on nifedipine (0.58 new lesions/patient) and 118 lesions in 73 patients (49%; n.s.) on placebo (0.8 new lesions/patient; p = 0.031).In two other studies on the inhibiting effect of dihydropyridine calcium entry blockers on the progression of coronary artery disease in man defining angiographic endpoints, the drugs were also shown to reduce the number of newly formed significant coronary lesions. If further trials in man confirm a protective role of calcium entry blockers against the formation of atherosclerotic coronary lesions, a new strategy in the prevention of coronary artery disease has to be considered.

Angiographically undetected plaque in the left main coronary artery

The absence of angiographic findings despite significant coronary artery disease has been previously described. Possible explanations for the limitation of plaque detection by angiography include compensatory vessel enlargement in face of intracoronary plaque formation, the lack of reference segments in diffuse atherosclerosis as well as technical limitations. Intracoronary ultrasound (ICUS) imaging provides the possibility of direct plaque visualization. We studied angiographically normal left main coronary arteries (LMCA) in 72 patients prior to diagnostic angiography or therapeutic interventions using ICUS (30 MHz). ICUS images were continuously recorded and recalled from memory for morphometric analysis. Lumen area, plaque area and the total vessel area were determined by computer software. ICUS imaging revealed atherosclerotic plaque in 55 of the 72 patients with angiographically normal LMCA (76%). The average plaque area stenosis was 22±12% (range 3–44%). Total vessel area showed a significant direct correlation with plaque area, indicating compensation of coronary plaque formation. The average percent change in plaque area (difference between maximal and minimal plaque area within the LMCA) was 11±19%, indicating a diffuse pattern. Measurement of change in lumen area (difference between maximal and minimal lumen area within the LMCA) revealed an average value of 6±7%. Lumen area of the LMCA was 15.9±3.2 mm2 in patients with and 17.2±1.9 mm2 without atherosclerotic plaque (n.s.). Thus, the lack of angiographic changes despite advanced plaque formation in the LMCA could be explained by compensatory vessel enlargement and by diffuse distribution of plaque in the vessel; true lumen narrowings overlooked by angiography seem not to account for the failure of angiography to detect plaque.

The impact of the calcium antagonist nifedipine on the angiographic progression of coronary artery disease: results of the INTACT (international nifedipine trial on antiatherosclerotic therapy)

INTACT is a study on the progression of coronary artery disease based on quantitated coronary angiography, applying the CAAS-system to assess the diameters of segments and stenoses and their changes over time. 348 of 425 patients (82%) underwent 2 angiograms after 3 years (175 on placebo, 173 on nifedipine, 80 mg per day). The analysis followed the intention to treat principle, as 66 patients stopped the trial medication for the last 12-18 months. Progression was defined either as an increase in the degree of stenosis by ≥20% or transition to occlusion, or as development of new stenoses (narrowings ≥20%) or new occlusions in coronary segments or sections previously angiographically normal. New lesions were selected both visually and by computer assessment. After 3 years no differences were found between groups with regard to pro- and regression of existing stenoses; however, there were fewer new lesions on nifedipine (144 on placebo versus 103 on nifedipine, -28%, p = 0.034) and also a trend to fewer patients with new lesions on nifedipine (-17%, n.s.). Hence, the calcium-antagonist significantly reduced the appearance of new stenoses and occlusions. There were interesting insights into the progression of CAD in general. Only 11.3% of existing stenoses showed progression and even fewer (4.3%) regression over 3 years, only few stenoses went into occlusion (2% of existing and 7.7% of new stenoses) (p = 0.000). Altogether, 56% of patients showed progression, 30.5% only in new stenoses, 11.8% only in old ones, and 14.1% in both. Hence, the strongest manifestation of progression of CAD was found in the development of new lesions (44.6% of all patients or 79% of all progressing patients showed new lesions). Conclusions: Repeated coronary angiography on a quantitative basis offers an excellent opportunity to study the progression of coronary artery disease, especially also during preventive interventions. A limitation is the angiographic definition of progression, which has to be based on sound statistical criteria as data from direct comparisons with the abnormal anatomy are not available as of yet.