Andrzej S. Kosinski

Beneficial Effects of Cholesterol-Lowering Therapy on the Coronary Endothelium in Patients with Coronary Artery Disease

BACKGROUND Impaired endothelium-mediated relaxation contributes to vasospasm and myocardial ischemia in patients with coronary artery disease. We hypothesized that cholesterol-lowering therapy with the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin could improve endothelium-mediated responses in patients with coronary atherosclerosis. METHODS In a randomized, double-blind, placebo-controlled trial, we studied coronary endothelial responses in 23 patients randomly assigned to either lovastatin (40 mg twice daily; 11 patients) or placebo (12 patients) plus a lipid-lowering diet (American Heart Association Step 1 diet). Patients were studied 12 days after randomization and again at 5 1/2 months. These patients had total cholesterol levels ranging from 160 to 300 mg per deciliter (4.1 to 7.8 mmol per liter) and were undergoing coronary angioplasty. At the initial and follow-up studies, patients received serial intracoronary infusions (in a coronary artery not undergoing angioplasty) of acetylcholine to assess endothelium-mediated vasodilatation. The responses of the coronary vessels were analyzed with quantitative angiography. RESULTS The patients in the placebo and lovastatin groups had similar responses to acetylcholine at a mean of 12 days of therapy (expressed as the percentage of change in diameter in response to acetylcholine doses of 10(-9) M, 10(-8) M, 10(-7) M, and 10(-6) M). In the placebo group, the respective mean (+/- SE) changes were 1 +/- 2, 0 +/- 2, -2 +/- 4, and -19 +/- 4 percent; in the lovastatin group, they were -2 +/- 2, -4 +/- 4, -12 +/- 5, and -16 +/- 7 percent (P = 0.32). (Coronary-artery constriction is reflected by negative numbers). The responses to acetylcholine in the placebo group after a mean of 5.5 months of therapy were -3 +/- 3, -1 +/- 2, -8 +/- 4, and -18 +/- 5 percent, respectively; there was significant improvement in the lovastatin group, which had responses of 3 +/- 3, 3 +/- 3, 0 +/- 2, and 0 +/- 3 percent (P = 0.004). CONCLUSIONS Cholesterol lowering with lovastatin significantly improved endothelium-mediated responses in the coronary arteries of patients with atherosclerosis. Such improvement in the local regulation of coronary arterial tone could potentially relieve ischemic symptoms and signal the stabilization of the atherosclerotic plaque.

Outcomes of Anatomical versus Functional Testing for Coronary Artery Disease

BACKGROUND Many patients have symptoms suggestive of coronary artery disease (CAD) and are often evaluated with the use of diagnostic testing, although there are limited data from randomized trials to guide care. METHODS We randomly assigned 10,003 symptomatic patients to a strategy of initial anatomical testing with the use of coronary computed tomographic angiography (CTA) or to functional testing (exercise electrocardiography, nuclear stress testing, or stress echocardiography). The composite primary end point was death, myocardial infarction, hospitalization for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterization that did not show obstructive CAD and radiation exposure. RESULTS The mean age of the patients was 60.8±8.3 years, 52.7% were women, and 87.7% had chest pain or dyspnea on exertion. The mean pretest likelihood of obstructive CAD was 53.3±21.4%. Over a median follow-up period of 25 months, a primary end-point event occurred in 164 of 4996 patients in the CTA group (3.3%) and in 151 of 5007 (3.0%) in the functional-testing group (adjusted hazard ratio, 1.04; 95% confidence interval, 0.83 to 1.29; P=0.75). CTA was associated with fewer catheterizations showing no obstructive CAD than was functional testing (3.4% vs. 4.3%, P=0.02), although more patients in the CTA group underwent catheterization within 90 days after randomization (12.2% vs. 8.1%). The median cumulative radiation exposure per patient was lower in the CTA group than in the functional-testing group (10.0 mSv vs. 11.3 mSv), but 32.6% of the patients in the functional-testing group had no exposure, so the overall exposure was higher in the CTA group (mean, 12.0 mSv vs. 10.1 mSv; P<0.001). CONCLUSIONS In symptomatic patients with suspected CAD who required noninvasive testing, a strategy of initial CTA, as compared with functional testing, did not improve clinical outcomes over a median follow-up of 2 years. (Funded by the National Heart, Lung, and Blood Institute; PROMISE ClinicalTrials.gov number, NCT01174550.).

Eight-year mortality in the Emory Angioplasty versus Surgery Trial (EAST)

OBJECTIVES To evaluate the long-term outcome of patients randomized to coronary bypass surgery or coronary angioplasty. BACKGROUND The Emory Angioplasty versus Surgery Trial (EAST) is a single center randomized comparison of a strategy of initial coronary angioplasty (n = 198) or coronary bypass surgery (n = 194) for patients with multivessel coronary artery disease. The primary end point (death, myocardial infarction or a large ischemic defect at 3 years) was not different, and repeat revascularization was significantly greater in the angioplasty group. Subsequently, the National Heart, Lung and Blood Institute supported a five-year extension of the trial. METHODS After the three year anniversary visit, annual questionnaires, telephone contact and examination of medical records were accomplished until death or the eight year anniversary in 100% of the patients surviving at 3 years. RESULTS Survival at 8 years is 79.3% in the angioplasty group and 82.7% in the surgical group (p = 0.40). Patients with proximal left anterior descending stenosis and those with diabetes tended to have better late survival with surgical intervention although not reaching statistical significance. After the first 3 years, repeat interventions remained relatively equal for both treatment groups. CONCLUSIONS Long-term survival is not significantly different between angioplasty and surgery, and late (three to eight year) revascularization procedures were infrequent. Patients without treated diabetes had similar survival in both groups.

Lack of Effect of Lovastatin on Restenosis after Coronary Angioplasty

BACKGROUND Experimental and clinical observations suggest that lowering serum lipid levels may reduce the risk of restenosis after coronary angioplasty. We report the results of a prospective, randomized, double-blind trial evaluating whether lowering lipid levels with lovastatin can prevent or delay restenosis after angioplasty. METHODS Seven to 10 days before angioplasty, we randomly assigned eligible patients to receive lovastatin (40 mg orally twice daily) or placebo. Patients who underwent successful, complication-free, first-time angioplasty of a native vessel (the index lesion) continued to receive therapy for six months, when a second coronary angiogram was obtained. The primary end point was the extent of restenosis of the index lesion, as assessed by quantitative coronary arteriography. Of 404 patients randomly assigned to study groups, 384 underwent angioplasty; 354 of the procedures were successful, and 321 patients underwent angiographic restudy at six months. RESULTS At base line, the patients in the lovastatin group (n = 203) and the placebo group (n = 201) were similar with respect to demographic clinical, angiographic, and laboratory characteristics. At base line the mean (+/- SD) degree of stenosis, expressed as a percentage of the diameter of the vessel, was 64 +/- 11 percent in the lovastatin group, as compared with 63 +/- 11 percent in the placebo group (P = 0.22). Despite a 42 percent reduction in the serum level of low-density lipoprotein cholesterol in the lovastatin group, after six months of treatment the amount of stenosis seen in the second angiogram was 46 +/- 20 percent in the placebo group, as compared with 44 +/- 21 percent in the lovastatin group (P = 0.50). Similarly, there were no significant differences in minimal luminal diameter or other measures of restenosis. A trend was noted toward more myocardial infarctions in the lovastatin group, as a result of acute vessel closure or restenosis at the site of angioplasty, but there were no other important differences between the two groups in the frequency of fatal or nonfatal events at six months. CONCLUSIONS Treatment with high-dose lovastatin initiated before coronary angioplasty does not prevent or delay the process of restenosis in the first six months after the procedure.

Outcome of Coronary Bypass Surgery Versus Coronary Angioplasty in Diabetic Patients With Multivessel Coronary Artery Disease

OBJECTIVES This study sought to compare the outcome of percutaneous transluminal coronary angioplasty (PTCA) (n = 834) and coronary artery bypass graft surgery (CABG) (n = 1805) in diabetic patients with multivessel coronary disease from an observational database. BACKGROUND There is concern about selection of revascularization in diabetic patients with multivessel coronary artery disease. METHODS Data were collected prospectively and entered into a computerized database. Follow-up was by letter or telephone or additional events resulting in readmission. RESULTS After CABG there were more in-hospital deaths (0.36% vs. 4.99%, p < 0.0001) and a trend toward more Q wave myocardial infarctions than after PTCA. Five- and 10-year survival rates were 78% and 45% after PTCA and 76% and 48% after CABG, respectively (p = 0.47). At 5 and 10 years, insulin-requiring patients had lower survival rates of 72% and 31% after PTCA and 70% and 48% after CABG, respectively (p = 0.54). Multivariate correlates of long-term mortality were older age, low left ventricular ejection fraction, heart failure and hypertension. In the total group, insulin requirement was a correlate of long-term mortality. For the total group, choice of therapy had a multivariate hazard ratio close to 1. In the insulin-requiring subgroup, the multivariate hazard ratio was 1.35 (95% confidence interval 1.01 to 1.79) for PTCA versus CABG. Corrected for baseline differences, 5- and 10-year survival rates were 68% and 36% after PTCA and 75% and 47% after CABG, respectively, in the insulin-requiring subgroup. Nonfatal events were more common after PTCA, especially additional revascularization. CONCLUSIONS This study reveals a high incidence of events in diabetic patients and raises further questions about angioplasty in insulin-requiring diabetic patients with multivessel disease.

Can restenosis after coronary angioplasty be predicted from clinical variables

OBJECTIVES The purpose of this study was to determine whether variables shown to correlate with restenosis in one group (learning group) could be shown to predict recurrent stenosis in a second group (validation group). BACKGROUND Restenosis remains a critical limitation after percutaneous transluminal coronary angioplasty. Although several clinical variables have been shown to correlate with restenosis, there are few data concerning attempts to predict recurrent stenosis. METHODS The source of data was the clinical data base at Emory University. Patients who had had previous coronary surgery and patients who underwent coronary angioplasty in the setting of acute myocardial infarction were excluded. A total of 4,006 patients with angiographic restudy after successful angioplasty were identified. They were classified into a learning group of 2,500 patients and a validation group of 1,506 patients. The correlates of restenosis in the learning group were determined by stepwise logistic regression, and a model was developed to predict the probability of restenosis and was tested in the validation group. By using various cut points for the predicted probability of restenosis, a receiver operating characteristic curve was created. Goodness of fit of the model was evaluated by comparing average predicted probabilities with average observed probabilities within subgroups on the basis of risk level determined by linear regression analysis. RESULTS In the learning group 1,145 patients had restenosis and 1,355 did not. Correlates of restenosis were severe angina, severe diameter stenosis before angioplasty, left anterior descending coronary artery dilation, diabetes, greater diameter stenosis after angioplasty, hypertension, absence of an intimal tear, eccentric morphology and older patient age. The model derived from the learning group was used to predict restenosis in the validation group. By varying the cut point for the predicted probability of restenosis above which restenosis is diagnosed and below which it is not, a receiver operating characteristic curve was created. The curve was close to the line of identity, reflecting a poor predictive ability. However, the model was shown to fit well with the predicted probability of restenosis correlating well with the observed probability (r = 0.98, p = 0.0001). CONCLUSIONS Clinical variables provide limited ability to predict definitively whether a particular patient will have restenosis. However, the current model may be used to predict the probability of restenosis, with some uncertainty, at least in well characterized patients who have already had angioplasty.

The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) Trial

Background: Transcranial Doppler ultrasound (TCD) and magnetic resonance angiography (MRA) can identify intracranial atherosclerosis but have not been rigorously validated against the gold standard, catheter angiography. The WASID trial (Warfarin Aspirin Symptomatic Intracranial Disease) required performance of angiography to verify the presence of intracranial stenosis, allowing for prospective evaluation of TCD and MRA. The aims of Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial were to define abnormalities on TCD/MRA to see how well they identify 50 to 99% intracranial stenosis of large proximal arteries on catheter angiography. Study Design: SONIA standardized the performance and interpretation of TCD, MRA, and angiography. Study-wide cutpoints defining positive TCD/MRA were used. Hard copy TCD/MRA were centrally read, blind to the results of angiography. Results: SONIA enrolled 407 patients at 46 sites in the United States. For prospectively tested noninvasive test cutpoints, positive predictive values (PPVs) and negative predictive values (NPVs) were TCD, PPV 36% (95% CI: 27 to 46); NPV, 86% (95% CI: 81 to 89); MRA, PPV 59% (95% CI: 54 to 65); NPV, 91% (95% CI: 89 to 93). For cutpoints modified to maximize PPV, they were TCD, PPV 50% (95% CI: 36 to 64), NPV 85% (95% CI: 81 to 88); MRA PPV 66% (95% CI: 58 to 73), NPV 87% (95% CI: 85 to 89). For each test, a characteristic performance curve showing how the predictive values vary with a changing test cutpoint was obtained. Conclusions: Both transcranial Doppler ultrasound and magnetic resonance angiography noninvasively identify 50 to 99% intracranial large vessel stenoses with substantial negative predictive value. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis trial methods allow transcranial Doppler ultrasound and magnetic resonance angiography to reliably exclude the presence of intracranial stenosis. Abnormal findings on transcranial Doppler ultrasound or magnetic resonance angiography require a confirmatory test such as angiography to reliably identify stenosis.

A Comparison of the Charlson Comorbidity Index Derived from Medical Record Data and Administrative Billing Data

The objective of this article is to compare the Charlson comorbidity index derived from medical record data (Chart Index) with the same index derived from billing data (ICD-9 Index) to determine how well each predicted inpatient and 30-day mortality, length of stay, and complications among Medicare beneficiaries hospitalized for carotid endarterectomy. Economic and time constraints have increased the need for risk adjusters derived from administrative data, yet few studies have compared these measures with those derived from chart review. Using logistic regression, the Chart Index was found to be a significant predictor of inpatient mortality, 30-day mortality, length of stay, and complications, after controlling for age, gender, and neurologic and medical risk factors (P values = 0.004, 0.056, 0.0001, and 0.042, respectively). The ICD-9 Index approached significance as a predictor of the outcomes (P values = 0.092, 0.100, 0.093, and 0.080, respectively). The Chart Index was shown to be superior to the ICD-9 Index within this patient sample.

A Comparison of the Costs of and Quality of Life After Coronary Angioplasty or Coronary Surgery for Multivessel Coronary Artery Disease Results From the Emory Angioplasty Versus Surgery Trial (EAST)

BACKGROUND The Emory Angioplasty Versus Surgery Trial (EAST) is a randomized trial that compares, by intention to treat, the clinical outcome and costs of percutaneous transluminal coronary angioplasty (PTCA) and coronary surgery for multivessel coronary artery disease. METHODS AND RESULTS The primary end point was a composite of death, Q-wave myocardial infarction, and a large reversible thallium defect at 3 years. Multiple measures of quality of life also were made. Charges were assessed from the hospital UB-82 bills; professional charges were assessed from the Emory Clinic. Hospital charges were reduced to cost through step-down accounting methods. All costs and charges were deflated to 1987 dollars. Costs were assessed for the initial hospitalization and the cumulative costs of the initial hospitalization and additional revascularization procedures for up to 3 years. There was no difference in mortality or the primary end point. Mean initial hospital charges were

Percutaneous transluminal coronary angioplasty in women compared with men

12,654 for the PTCA group and