Fish oils and low-molecular-weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty. The EMPAR Study.

BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) is complicated by restenosis within 6 months in > 40% of patients. Theoretical, animal experimental, and human epidemiological and clinical trial findings have suggested that fish oils (n-3) might reduce restenosis. Low-molecular-weight heparin (LMWH) has reduced cellular proliferation and restenosis in several experimental systems. METHODS AND RESULTS: We randomized 814 patients to fish oils (5.4 g n-3 fatty acids) or placebo a median of 6 days before PTCA and continued for 18 weeks. At the time of sheath removal, 653 patients with at least one successfully dilated lesion were randomized to LMWH (30 mg SC BID) or control for 6 weeks in a 2 x 2 factorial design. Follow-up with quantitative coronary angiography (QCA; target, 18 weeks) was interpretable on 96% of these patients. Restenosis rates per patient were for n-3, 46.5%; placebo, 44.7%; LMWH, 45.8%; and control, 45.4%. Restenosis rates per lesion were for n-3, 39.7%; placebo, 38.7%; LMWH, 38%; and control, 40.4%. At follow-up QCA, mean minimal lumen diameters were (mm) for n-3, 1.12; placebo, 1.10; LMWH, 1.12; and control, 1.10. Fifteen percent of patients permanently discontinued n-3/placebo before study completion, and 21% of patients discontinued LMWH early. There were no significant differences in the occurrences of ischemic events. Bleeding was more common with LMWH, usually was mild, and led to early discontinuation of study medication in only 0.9% of patients. Gastrointestinal side effects were more common in patients receiving n-3 than placebo. CONCLUSIONS: There is no evidence for a clinically important reduction of PTCA restenosis in this trial by either n-3 or LMWH. Evaluation of the results for n-3 in the context of previously published data on the reduction of PTCA restenosis indicates that n-3 is not efficacious and that further trials are unwarranted.

Myocardial uptake and washout kinetics of T1-201 with the VEX (vasodilator plus exercise) test: contribution of stress mode components and coronary stenosis severity.

OBJECTIVE: To assess the vasodilator plus exercise (VEX) test as an adjunct to myocardial perfusion imaging with respect to the accuracy of kinetics of thallium-201 (Tl-201) and other indicators of ischemia. SETTING: A nuclear medicine laboratory in which patients referred for myocardial scintigraphy are triaged to undergo the stress component with symptom-limited bicycle exercise, dipyridamole or VEX as appropriate. DESIGN: Cases having correlating scintigraphy and angiography (n = 425) were selected retrospectively. Immediate poststress and redistribution images were quantified using a circumferential profile analysis with interpolative background subtraction. For each of nine sectors on the left anterior oblique image, multivariate analyses were performed, comparing the relative uptake and net washout of Tl-201 to the exercise workload attained, use of dipyridamole, time to redistribution, gender, and the angiographic presence and severity of stenoses at five key sites. Washout values standardized according to gender, exercise level and time to redistribution, were compared with relative uptake profiles and ST depression using receiver operating curves. RESULTS: For each sector, a significant contribution to Tl-201 washout was made by the exercise level (P < 0.001) and by at least one site of stenosis (P < 0.0001), but not by use of dipyridamole (P > 0.5); female gender was associated with increased washout (P < 0.01) except for the three lateral sectors. For each stress modality, standardized washout performed better than ST depression but not as well as relative uptake profiles in detecting coronary artery disease. CONCLUSIONS: For combined pharmacological-exercise stress, quantitative uptake profiles may assist in confirming subjective scan interpretation; washout profiles, even when standardized for gender and stress level, are suboptimal for confirming defect reversibility.

The usefulness of stress tests performed in the nuclear medicine department: mathematical methods to assess efficacy at various angiographic endpoints.

Stress myocardial perfusion scintigraphy (SMPS) may be used to amplify or supplant information available from stress electrocardiography (ECG) in directing the clinical management of patients, including the need for coronary angiography. The apparent usefulness of SMPS may depend on referral bias, the stress mode employed and the criterion for disease. We compared markers of ischaemia on quantitative planar SMPS with 201 Tl in 503 referred patients; stress was tailored to the individual patient to include exercise (n = 154), dipyridamole (n = 118) or a combination of the two (n = 231). Four angiographic criteria of increasing severity (A-D) were targeted. The fraction of the population receiving diagnostic benefit was calculated for reversible defects (RD) or lung uptake (LU) in comparison to concurrent ST depression; abnormal baseline tracings and fixed 201Tl defects were regarded as indeterminate. Decision tree induction, a computer-learning algorithm and logistic regression were also used to assess the contribution of 13 scintigraphic and other input variables. In comparison to ST depression, RD showed incremental value in 167 (33%) patients with criterion A, decreasing to 5% with criterion D; LU showed its greatest benefit (21%) with criterion D. Both scintigraphic markers were more useful with dipyrida-mole-based tests than with exercise alone. Decision trees induced at each criterion for disease showed the predominant contribution of scintigraphic results in comparison to clinical and ECG data. In conclusion, in a referred population with a frequent requirement for pharmacological stress, the clinical utility of scintigraphy can be determined by comparison of markers of ischaemia; the results will depend, however on the angiographic criterion for disease.

Contralateral disease progression after carotid endarterectomy.

BACKGROUND: We report the natural history of the carotid artery contralateral to the ipsilateral endarterectomized carotid artery. METHODS: The incidence of new symptoms and disease progression of the patient contralateral side after unilateral carotid endarterectomy (CE) was studied by clinical follow-up and serial duplex scanning in 127 patients. RESULTS: During a mean follow-up of 44 months, new hemispheric events occurred in nine (7%) and significant progression was recorded in 27 (21%) patients. In 97 patients with initial stenosis of less than 50% (group I), contralateral progression to greater than 50% was noted in 22% and new symptoms (one transient ischemic attack and one cerebrovascular accident) in 2% of patients; three patients underwent CE. In 30 patients with initial stenosis between 50% and 99% (group II), new symptoms (all transient ischemic attacks) occurred in seven (23%) (group II vs group I; p < 0.003) and nine underwent CE (group II vs group I; p < 0.001). Progression in 26 patients with 50% to 79% stenosis within group II to greater than 80% was noted in 19% of patients (difference not significant compared with group I). CONCLUSIONS: Overall, new symptoms occurred in 7% and significant contralateral disease progression in 21% of patients; subsequent CE was performed in 9.4% of patients. Initial presence of greater than 50% contralateral stenosis is a predictor of future hemispheric symptoms, which are likely to be transient ischemic attacks. New symptoms did not necessarily correlate with disease progression. Because disease progression was observed in patients with varying degrees of initial contralateral stenosis, serial clinical and duplex scanning in all patients undergoing unilateral CE is recommended.

Pulmonary thallium-201 uptake following dipyridamole-exercise combination compared with single modality stress testing.

Angiographic and clinical determinants of pulmonary uptake of thallium-201 were assessed in a laboratory setting where supine bicycle exercise is used for stress testing in the absence of limiting pharmacologic or physical factors, and where symptom-limited exercise is added to intravenous dipyridamole infusion in other cases. Angiographic correlation was available in 400 patients, including 130 tested with exercise, 94 in whom only handgrip or abbreviated bicycle exercise could be used after dipyridamole, and 176 in whom intravenous dipyridamole was combined with a significant level of exercise. For each test mode, lung/myocardial ratios on the immediate image were highly correlated (p less than or equal to 0.001) with a score based on the number of critical coronary artery stenoses, with grading by contrast ventriculography, and with the number of stenosed (greater than or equal to 50%) arteries; relationships (p less than 0.05) to history of myocardial infarction and to gender were also present. Multiple regression analysis showed the critical stenosis score and ventricular dysfunction to be the only significant determinants. When dipyridamole based tests were compared with exercise, curves of receiver-operating characteristics showed a tendency to better diagnostic performance. When dipyridamole is incorporated in stress testing, the value of increased lung uptake as an ancillary diagnostic sign is similar to that established for exercise.

Dipyridamole combined with symptom-limited exercise for myocardial perfusion scintigraphy: image characteristics and clinical role.

Although dipyridamole can be used with myocardial scintigraphy to demonstrate reversible perfusion defects, combining exercise with the pharmacologic tool could improve image quality and information yield. The incidence of perfusion defects and the quality of thallium 201 images were reviewed in a series of 820 patients who had been assigned to a specific stress-test mode. Supine bicycle exercise alone was used (group I) where no pharmacologic or physical factors (e.g., beta-blockers, arthritis) limited performance; otherwise, intravenous dipyridamole was followed by symptom-limited exercise (group II). Angiographic correlation was available in 57 patients in group I, and in 158 in group II; of these, 109 performed significant exercise (greater than or equal to 3 min at increasing workloads) following dipyridamole (group IIA), whereas in 49 (group IIB) the exercise phase following dipyridamole was truncated. All test-mode groups were similar with respect to the incidence of ST segment depression during testing, patient throughput, and the sensitivity of perfusion defects. Chest pain and reversible defects were induced more frequently in group II than in group I. In group IIA, splanchnic background activity was lower (P less than 0.001) than in group IIB, and the false-positive rate tended to be lower. Thus, combining exercise with dipyridamole in patients with non-cardiac limitations to exercise enabled the achievement of optimal results for perfusion scintigraphy.

Nuclear magnetic resonance and radionuclide angiographic assessment of acute myocardial infarction in a randomized trial of intravenous streptokinase.

Sixty-six patients presenting with their first evolving transmural acute myocardial infarction (AMI) were randomized to receive either streptokinase (n = 41) or placebo therapies (n = 25) within 6 hours of the onset of chest pain. These patients then underwent supine rest, exercise and after-nitroglycerin radionuclide angiography 3 weeks after AMI. Nuclear magnetic resonance (NMR) imaging was performed at 3 weeks as a more direct estimate of AMI size. Although peak creatine kinase values were comparably elevated between groups (2,367 +/- 1,486 IU/liter for streptokinase vs 2,637 +/- 1,305 IU/liter for placebo), there was a significant reduction in NMR-measured AMI size in the streptokinase group (3 +/- 2% of left ventricular volume vs 10 +/- 4% in the placebo group, p less than 0.05). This occurred despite comparable resting (54 +/- 11 vs 47 +/- 10% and exercise (53 +/- 12 vs 49 +/- 11%) global ejection fractions. However, following nitroglycerin, there was an improvement in global ejection fraction in the streptokinase-treated group that was not observed with placebo (61 +/- 13 vs 48 +/- 10%, p less than 0.05). A similar pattern was also observed with regional functional analysis. Thus, streptokinase therapy leads to a significant reduction in NMR-measured AMI size and to a greater degree of reversible left ventricular dysfunction.

Nephrotoxicity of high- and low-osmolality contrast media.

Nephrotoxicity of radio-opaque contrast media (CM) is generally believed to involve toxic injury of proximal tubular cells. Measurement of urinary tubular enzyme excretion has been advocated as a sensitive marker of such toxic injury. It has been claimed that the new low-osmolality or nonionic CM reduce the incidence of nephrotoxicity but this remains uncertain. We studied 23 patients with normal renal function undergoing coronary angiography; patients were randomized into three groups receiving either diatrizoate (1,800 mmol/kg H2O), ioxaglate (600 mmol/kg H2O) or iohexol (850 mmol/kg H2O). Urinary excretion of a panel of enzymes increased significantly in all groups by 20 h (p less than 0.05 to less than 0.005). Alanine aminopeptidase excretion at 20 h was greater after the administration of high osmolality ionic CM than with the others but all three CM produced a similar pattern of enzyme excretion. No significant change in glomerular filtration rate was found in any group so the significance of the enzymuria remains uncertain.

Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial.

We performed a randomized, double-blind, placebo-controlled trial in 555 patients with unstable angina who were hospitalized in coronary care units. Patients received one of four possible treatment regimens: aspirin (325 mg four times daily), sulfinpyrazone (200 mg four times daily), both, or neither. They were entered into the trial within eight days of hospitalization and were treated and followed for up to two years (mean, 18 months). The incidence of cardiac death and nonfatal myocardial infarction, considered together, was 8.6 per cent in the groups given aspirin and 17.0 per cent in the other groups, representing a risk reduction with aspirin of 51 per cent (P = 0.008). The corresponding figures for either cardiac death alone or death from any cause were 3.0 per cent in the groups given aspirin and 11.7 per cent in the other groups, representing a risk reduction of 71 per cent (P = 0.004). Analysis by intention to treat yielded smaller risk reductions with aspirin of 30 per cent (P = 0.072), 56 per cent (P = 0.009), and 43 per cent (P = 0.035) for the outcomes of cardiac death or nonfatal acute myocardial infarction, cardiac death alone, and all deaths, respectively. There was no observed benefit of sulfinpyrazone for any outcome event, and there was no evidence of an interaction between sulfinpyrazone and aspirin. Considered together with the results of a previous clinical trial, these findings provide strong evidence for a beneficial effect of aspirin in patients with unstable angina.

Biases in the measurement of arterial pressure.

We compared cuff to simultaneous direct intra-arterial pressure in 26 seriously ill patients, in order to: test the accuracy of oscillometric and auscultatory estimates of direct systolic pressure; test muffling and disappearance of sound as indices of direct diastolic pressure; gain insight into the timing of the different phases of Korotkoff sounds; and assess the local and general effects of cuff inflation on blood pressure. We found that conventional estimation of systolic blood pressure by auscultation of the first Korotkoff sound (K1) underestimates direct systolic pressure by an average of 16 to 17 mm Hg. Oscillometric pressure measurement provides a significantly better estimate than K1 but still underestimates by 7 to 8 mm Hg. These systolic cuff measurements are biased downward from direct values because of local cuff effect and cuff error. Diastolic cuff measurements deviate from direct values primarily because of a local cuff effect which produces an upward bias of 5 mm Hg at the point of sound muffling (K4), and 3 mm Hg at the point where sounds disappear (K5). We recommend oscillometric measurement of systolic pressure and K5 measurement of diastolic pressure as the best indirect estimates of blood pressure in critically ill patients.