Edwin L. Alderman

Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators.

BACKGROUND Coronary-artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are alternative methods of revascularization in patients with coronary artery disease. We tested the hypothesis that in selected patients with multivessel disease suitable for treatment with either procedure, an initial strategy of PTCA does not result in a poorer five-year clinical outcome than CABG. METHODS Patients with multivessel disease were randomly assigned to an initial treatment strategy of CABG (n = 914) or PTCA (n = 915) and were followed for an average of 5.4 years. Analysis of outcome events was performed according to the intention to treat. RESULTS The respective in-hospital event rates for CABG and PTCA were 1.3 percent and 1.1 percent for mortality, 4.6 percent and 2.1 percent for Q-wave myocardial infarction (P < 0.01), and 0.8 percent and 0.2 percent for stroke. The five-year survival rate was 89.3 percent for those assigned to CABG and 86.3 percent for those assigned to PTCA (P = 0.19; 95 percent confidence interval of the difference in survival, -0.2 percent to 6.0 percent). The respective five-year survival rates free from Q-wave myocardial infarction were 80.4 percent and 78.7 percent. By five years after study entry, 8 percent of the patients assigned to CABG had undergone additional revascularization procedures, as compared with 54 percent of those assigned to PTCA; 69 percent of those assigned to PTCA did not subsequently undergo CABG. Among diabetic patients who were being treated with insulin or oral hypoglycemic agents at base line, a subgroup not specified by the protocol, five-year survival was 80.6 percent for the CABG group as compared with 65.5 percent for the PTCA group (P = 0.003). CONCLUSIONS As compared with CABG, an initial strategy of PTCA did not significantly compromise five-year survival in patients with multivessel disease, although subsequent revascularization was required more often with this strategy. For treated diabetics, five-year survival was significantly better after CABG than after PTCA.

Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP).

BACKGROUND Recent clinical trials have shown that modification of plasma lipoprotein concentrations can favorably alter progression of coronary atherosclerosis, but no data exist on the effects of a comprehensive program of risk reduction involving both changes in lifestyle and medications. This study tested the hypothesis that intensive multiple risk factor reduction over 4 years would significantly reduce the rate of progression of atherosclerosis in the coronary arteries of men and women compared with subjects randomly assigned to the usual care of their physician. METHODS AND RESULTS Three hundred men (n = 259) and women (n = 41) (mean age, 56 +/- 7.4 years) with angiographically defined coronary atherosclerosis were randomly assigned to usual care (n = 155) or multifactor risk reduction (n = 145). Patients assigned to risk reduction were provided individualized programs involving a low-fat and -cholesterol diet, exercise, weight loss, smoking cessation, and medications to favorably alter lipoprotein profiles. Computer-assisted quantitative coronary arteriography was performed at baseline and after 4 years. The main angiographic outcome was the rate of change in the minimal diameter of diseased segments. All subjects underwent medical and risk factor evaluations at baseline and yearly for 4 years, and reasons for all hospitalizations and deaths were documented. Of the 300 subjects randomized, 274 (91.3%) completed a follow-up arteriogram, and 246 (82%) had comparative measurements of segments with visible disease at baseline and follow-up. Intensive risk reduction resulted in highly significant improvements in various risk factors, including low-density lipoprotein cholesterol and apolipoprotein B (both, 22%), high-density lipoprotein cholesterol (+12%), plasma triglycerides (-20%), body weight (-4%), exercise capacity (+20%), and intake of dietary fat (-24%) and cholesterol (-40%) compared with relatively small changes in the usual-care group. No change was observed in lipoprotein(a) in either group. The risk-reduction group showed a rate of narrowing of diseased coronary artery segments that was 47% less than that for subjects in the usual-care group (change in minimal diameter, -0.024 +/- 0.066 mm/y versus -0.045 +/- 0.073 mm/y; P < .02, two-tailed). Three deaths occurred in each group. There were 25 hospitalizations in the risk-reduction group initiated by clinical cardiac events compared with 44 in the usual-care group (rate ratio, 0.61; P = .05; 95% confidence interval, 0.4 to 0.9). CONCLUSIONS Intensive multifactor risk reduction conducted over 4 years favorably altered the rate of luminal narrowing in coronary arteries of men and women with coronary artery disease and decreased hospitalizations for clinical cardiac events.

Effect of Intrathoracic Pressure on Left Ventricular Performance

Left ventricular dysfunction is common in respiratory-distress syndrome, asthma and obstructive lung disease. To understand the contribution of intrathoracic pressure to this problem, we studied the effects of Valsalva and Müller maneuvers on left ventricular function in eight patients. Implantation of intramyocardial markers permitted beat-by-beat measurement of the velocity of fiber shortening (VCF) and left ventricular volume. During the Müller maneuver, VCF and ejection fraction decreased despite an increase in left ventricular volume and a decline in arterial pressure. In addition, when arterial pressure was corrected for changes in intrapleural pressure during either maneuver it correlated better with left ventricular end-systolic volumes than did uncorrected arterial pressures. These findings suggest that negative intrathoracic pressure affects left ventricular function by increasing left ventricular transmural pressures and thus afterload. We conclude that large intrathoracic-pressure changes, such as those that occur in acute pulmonary disease, can influence cardiac performance.

A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients : Mycophenolate Mofetil Investigators

BACKGROUND After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation. METHODS In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients). RESULTS Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025). CONCLUSIONS Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

Ten-year follow-up of survival and myocardial infarction in the randomized Coronary Artery Surgery Study.

The Coronary Artery Surgery Study (CASS) randomized 780 patients to an initial strategy of coronary surgery or medical therapy. Of medically randomized patients, 6% had surgery within 6 months and a total of 40% had surgery by 10 years. At 10 years, there was no difference in cumulative survival (medical, 79% vs. surgical, 82%; NS) and no difference in percentage free of death and nonfatal myocardial infarction (medical, 69% vs. surgical, 66%; NS). Patients with an ejection fraction of less than 0.50 exhibited a better survival with initial surgery treatment (medical, 61% vs. surgical, 79%; p = 0.01). Conversely, patients with an ejection fraction greater than or equal to 0.50 exhibited a higher proportion free of death and myocardial infarction with initial medical therapy (medical, 75% vs. surgical, 68%; p = 0.04) although long-term survival remained unaffected (medical, 84% vs. surgical, 83%; p = 0.75). There were no significant differences either in survival and freedom from nonfatal myocardial infarction, whether stratified on presence of heart failure, age, hypertension, or number of vessels diseased. Thus, 10-year follow-up results confirm earlier reports from CASS that patients with left ventricular dysfunction exhibit long-term benefit from an initial strategy of surgical treatment. Patients with mild stable angina and normal left ventricular function randomized to initial medical treatment (with an option for later surgery if symptoms progress) have survival equivalent to those patients randomized to initial surgery.

Intracoronary ultrasound in cardiac transplant recipients. In vivo evidence of "angiographically silent" intimal thickening.

BackgroundAccelerated coronary atherosclerosis is a major factor limiting allograft longevity in cardiac transplant recipients. Histopathology studies have demonstrated the insensitivity of coronary angiography for detecting early atheromatous disease in this patient population. Intracoronary ultrasound is a new imaging techniquse that provides characterization of vessel wall morphology. The purpose of this study was to compare in vivo intracoronary ultrasound with angiography in cardiac transplant recipients. Methods and ResultsThe left anterior descending coronary artery was studied with intracoronary ultrasound in 80 cardiac transplant recipients at the time of routine screening coronary angiography 2 weeks to 13 years after transplantation. A mean and index of intimal thickening were obtained at four coronary sites. Intimal proliferation was classified as minimal, mild, moderate, or severe according to thickness and degree of vessel circumference involved. Twenty patients were studied within 1 month of transplantation and had no angiographic evidence of coronary disease. An intimal layer was visualized by ultrasound in only 13 of these 20 presumably normal hearts. The 60 patients studied 1 year or more after transplantation all had at least minimal intimal thickening. Twenty-one patients (35%) showed minimal or mild, 17 (28%) moderate, and 21 (35%) severe thickening. Forty-two of these 60 patients had angiographically normal coronary arteries, 21 (50%) of whom had either moderate or severe thickening. All 18 patients with angiographic evidence of coronary disease had moderate or severe intimal thickening, but there was no statistically significant difference in intimal thickness or index when compared with the patients with moderate or severe proliferation and normal angiograms (thickness, 0.53±0.35 mm versus 0.64±0.30 mm, p = NS; index, 0.28±0.10 versus 0.34±0.10, p = NS). ConclusionsThe majority of patients 1 or more years after cardiac transplantation have ultrasound evidence of intimal thickening not apparent by angiography. Intracoronary ultrasound offers early detection and quantitation of transplant coronary disease and provides characterization of vessel wall morphology, which may prove to be a prognostic marker of disease.

Five-year angiographic follow-up of factors associated with progression of coronary artery disease in the Coronary Artery Surgery Study (CASS)☆

OBJECTIVES The Coronary Artery Surgery Study (CASS) required participants to undergo follow-up angiography at 5 years to identify clinical and angiographic features associated with progression of coronary artery disease. BACKGROUND The CASS randomized 780 patients at 11 participating clinical centers between an initial strategy of medical therapy versus bypass surgery. Five clinical sites accomplished follow-up angiography in > 50% of their randomized subjects within a 42- to 66-month period after the entry arteriogram (n = 314). METHODS Qualified clinical site angiographers, using side by side film review, evaluated an average of 13 segments/patient on both arteriograms for initial stenosis severity, morphologic features, lesion location and occurrence of disease progression or occlusion. Progression was defined as further definite narrowing by > or = 15% and occlusion as lesion progression to > or = 98%. Lesions were subcategorized as to whether they were univariate and had or had not been treated with bypass surgery. Multivariate logistic regression analyses were performed. RESULTS For nonbypassed segments, right coronary artery and left anterior descending artery proximal and midlocations were associated with disease progression. For stenosis-containing segments, the initial severity, a non-left anterior descending artery location and increased treadmill duration predicted progression. Segment occlusion was associated with initial lesion severity, right coronary artery location and subsequent interval myocardial infarction. There were few predictors of progression or occlusion in bypassed arteries, other than initial lesion severity. CONCLUSIONS Univariate and multivariate associations with lesion progression and occlusion included diabetes, lesion location, elevated cholesterol level, interval infarction and lesion morphology. These angiographic results, collected in a prospective trial, are consistent with known risk factors.

A Preliminary Study of Diltiazem in the Prevention of Coronary Artery Disease in Heart-Transplant Recipients

BACKGROUND Accelerated coronary artery disease is a major cause of late morbidity and mortality among heart-transplant recipients. Because calcium-channel blockers can suppress diet-induced atherosclerosis in laboratory animals, we assessed the efficacy of diltiazem in preventing coronary artery disease in transplanted hearts. METHODS Consecutive eligible cardiac-transplant recipients were randomly assigned to receive diltiazem (n = 52) or no calcium-channel blocker (n = 54). Coronary angiograms obtained early after cardiac transplantation and annually thereafter were used for the visual assessment of the extent of coronary artery disease. The average diameters of identical coronary artery segments were measured on the angiograms obtained at base line and at the first and second follow-up examinations. RESULTS In the 57 patients who had all three angiograms, the average coronary artery diameter (+/- SD) 0.27 decreased in the group that received no calcium-channel blocker from 2.41 +/- 0.27 mm at base line to 2.19 +/- 0.28 mm at one year, and to 2.22 +/- 0.26 mm at two years (P < 0.001 for both years). The average diameter in the diltiazem group changed little from the base-line value of 2.32 +/- 0.22 mm (2.32 +/- 0.27 mm at one year and 2.36 +/- 0.22 mm at two years). The average change in the diameter of the segment differed significantly between the two treatment groups (P < 0.001), and the estimated effect of treatment changed only negligibly after adjustment for other relevant clinical variables. New angiographic evidence of coronary artery disease developed in 14 patients not given calcium-channel blockers, as compared with 5 diltiazem-treated patients (P = 0.082). Coronary stenoses greater than 50 percent of the luminal diameter developed in seven patients not given calcium-channel blockers, as compared with two patients given diltiazem; death due to coronary artery disease or retransplantation occurred in five patients in the group that did not receive calcium-channel blockers and none of those who received diltiazem. CONCLUSIONS Our preliminary results suggest that diltiazem can prevent the usual reduction in the diameter of the coronary artery in cardiac-transplant recipients, but further follow-up will be required to determine whether diltiazem can decrease the long-term incidence of symptomatic coronary artery disease.

Prognostic value of angiographic indices of coronary artery disease from the Coronary Artery Surgery Study (CASS).

The Coronary Artery Surgery Study, CASS, enrolled 24,959 patients between August 1975 and June 1979 who were studied angiographically for suspected coronary artery disease. This paper compares the prognostic value for survival without early elective surgery of eight different indices of the extent of coronary artery disease: the number of diseased vessels, two indices using the number of proximal arterial segments diseased, two empirically generated indices from the CASS data, and the published indices of Friesinger, Gensini, and the National Heart and Chest Hospital, London. All had considerable prognostic information. Typically 80% of the prognostic information in one index was also contained in another. Our analysis shows that good prediction from angiographic data results from a combination of left ventricular function and arteriographic extent of disease. Prognosis may reasonably be obtained from three simple indices: the number of vessels diseased, the number of proximal arterial segments diseased, and a left ventricular wall motion score. These three indices account for an estimated 84% of the prognostic information available. 6-yr survival varies between 93 and 16% depending upon the values of these three indices.

Measurement of midwall myocardial dynamics in intact man by radiography of surgically implanted markers.

Tiny radiopaque helices (0.85 × 1.5 mm) of pure tantalum wire were implanted by means of a simple insertor instrument into the left ventricular myocardium in 24 patients at the time of cardiac surgery. The markers were positioned in such a way as to outline the profile of the left ventricle when viewed in a 30° right anterior oblique projection. Biplane studies showed that all markers could be placed very nearly in a plane using the surface anatomy of the heart as a guide to implantation. Implantation of markers required approximately two minutes. No intraoperative or postoperative complications ascribable to the markers have occurred. They remain firmly in place and allow acquisition of a noninvasive ventriculogram at any time after surgery. The dynamic geometry of the left ventricle was determined by analysis of cineradiograms of these markers. Utilization of a single-plane (right anterior oblique) cineradiogram to obtain measurements of major transverse ventricular diameters, mean circumferential shortening, and circumferential shortening velocity results in underestimation of lengths by 1.4%, overestimation of shortening by 1.2% of end-diastolic length, and overestimation of velocity by 0.05 circ/sec, when compared with values obtained simultaneously from biplane cineradiograms.