J. David Talley

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.

Combined Accelerated Tissue-Plasminogen Activator and Platelet Glycoprotein IIb/IIIa Integrin Receptor Blockade With Integrilin in Acute Myocardial Infarction Results of a Randomized, Placebo-Controlled, Dose-Ranging Trial

BACKGROUND Platelet activation and aggregation may be key components of thrombolytic failure to restore and maintain perfusion in acute myocardial infarction. We performed a placebo-controlled, dose-ranging trial of Integrilin, a potent inhibitor of platelet aggregation, with heparin, aspirin, and accelerated alteplase. METHODS AND RESULTS We assigned 132 patients in a 2:1 ratio to receive a bolus and continuous infusion of one of six Integrilin doses or placebo. Another 48 patients were randomized in a 3:1, double-blind fashion to receive the highest Integrilin dose from the first phase or placebo. All patients received accelerated alteplase, aspirin, and intravenous heparin infusion; all but two groups also received an intravenous heparin bolus. The highest Integrilin dose group from the nonrandomized phase and the randomized patients were pooled for analysis and compared with placebo-treated patients. The primary end point was Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 90-minute angiography. Secondary end points were time to ST-segment recovery, an in-hospital composite (death, reinfarction, stroke, revascularization procedures, new heart failure, or pulmonary edema), and bleeding variables. The highest Integrilin dose groups had more complete reperfusion (TIMI grade 3 flow, 66% versus 39% for placebo-treated patients; P = .006) and a shorter median time to ST-segment recovery (65 versus 116 minutes for placebo; P = .05). The groups had similar rates of the composite end point (43% versus 42% for placebo-treated patients) and severe bleeding (4% versus 5%, respectively). CONCLUSIONS The incidence and speed of reperfusion can be enhanced when a potent inhibitor of the glycoprotein IIb/IIIa integrin receptor, such as Integrilin, is combined with accelerated alteplase, aspirin, and intravenous heparin.

Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study☆

Background—The optimal level of platelet inhibition with a glycoprotein (GP) IIb/IIIa antagonist necessary to minimize thrombotic complications in patients undergoing a percutaneous coronary intervention (PCI) is currently unknown. Methods and Results—Five hundred patients undergoing a PCI with the planned use of a GP IIb/IIIa inhibitor had platelet inhibition measured at 10 minutes, 1 hour, 8 hours, and 24 hours after the initiation of therapy with the Ultegra Rapid Platelet Function Assay (Accumetrics). Major adverse cardiac events (MACEs: composite of death, myocardial infarction, and urgent target vessel revascularization) were prospectively monitored, and the incidence correlated with the measured level of platelet function inhibition at all time points. One quarter of all patients did not achieve ≥95% inhibition 10 minutes after the bolus and experienced a significantly higher incidence of MACEs (14.4% versus 6.4%, P =0.006). Patients whose platelet function was <70% inhibited at 8 hours after the start of therapy had a MACE rate of 25% versus 8.1% for those ≥70% inhibited (P =0.009). By multivariate analysis, platelet function inhibition ≥95% at 10 minutes after the start of therapy was associated with a significant decrease in the incidence of a MACE (odds ratio 0.46, 95% CI 0.22 to 0.96, P =0.04). Conclusions—Substantial variability in the level of platelet function inhibition is achieved with GP IIb/IIIa antagonist therapy among patients undergoing PCI. The level of platelet function inhibition as measured by a point-of-care assay is an independent predictor for the risk of MACEs after PCI.

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 and profile of ventricular septal rupture with cardiogenic shock after myocardial infarction: a report from the SHOCK Trial Registry☆

OBJECTIVES We wished to assess the profile and outcomes of patients with ventricular septal rupture (VSR) in the setting of cardiogenic shock (CS) complicating acute myocardial infarction (MI). BACKGROUND Cardiogenic shock is often seen with VSR complicating acute MI. Despite surgical therapy, mortality in such patients is high. METHODS We analyzed 939 patients enrolled in the SHOCK Trial Registry of CS in acute infarction, comparing 55 patients whose shock was associated with VSR with 884 patients who had predominant left ventricular failure. RESULTS Rupture occurred a median 16 h after infarction. Patients with VSR tended to be older (p = 0.053), were more often female (p = 0.002) and less often had previous infarction (p < 0.001), diabetes mellitus (p = 0.015) or smoking history (p = 0.033). They also underwent right-heart catheterization, intra-aortic balloon pumping and bypass surgery significantly more often. Although patients with rupture had less severe coronary disease, their in-hospital mortality was higher (87% vs. 61%, p < 0.001). Surgical repair was performed in 31 patients with rupture (21 had concomitant bypass surgery); 6 (19%) survived. Of the 24 patients managed medically, only 1 survived. CONCLUSIONS There is a high in-hospital mortality rate when CS develops as a result of VSR. Ventricular septal rupture may occur early after infarction, and women and the elderly may be more susceptible. Although the prognosis is poor, surgery remains the best therapeutic option in this setting.

A multicenter, randomized trial of coronary angioplasty versus directional atherectomy for patients with saphenous vein bypass graft lesions

BACKGROUND Directional coronary atherectomy and percutaneous transluminal coronary angioplasty have both been used in symptomatic patients with coronary saphenous vein bypass graft stenoses. The relative merits of plaque excision and removal versus balloon dilatation remain uncertain. We compared outcomes after directional coronary atherectomy or angioplasty in patients with de novo bypass graft stenoses. METHODS AND RESULTS Fifty-four North American and European sites randomized 305 patients with de novo vein graft lesions to atherectomy (n = 149) or angioplasty (n = 156). Quantitative coronary angiography at a core laboratory assessed initial and 6-month results. Initial angiographic success was greater with atherectomy (89.2% versus 79.0%), as was initial luminal gain (1.45 versus 1.12 mm, P < .001). Distal embolization was increased with atherectomy (P = .012), and a trend was shown toward more non-Q-wave myocardial infarction (P = .09). Although the 6-month net minimum luminal diameter gain was 0.68 mm for atherectomy and 0.50 mm for angioplasty, the restenosis rates were similar, 45.6% for atherectomy and 50.5% for angioplasty (P = .491). At 6 months, there was a trend toward decreased repeated target-vessel interventions for atherectomy (P = .092); in addition, 13.2% of patients treated with atherectomy versus 22.4% of the angioplasty patients (P = .041) required repeated percutaneous intervention of the initial target lesion. CONCLUSIONS Atherectomy of de novo vein graft lesions was associated with improved initial angiographic success and luminal diameter but also with increased distal embolization. There was no difference in 6-month restenosis rates, although primary atherectomy patients tended to require fewer target-vessel revascularization procedures.

Economic Assessment of Platelet Glycoprotein IIb/IIIa Inhibition for Prevention of Ischemic Complications of High-Risk Coronary Angioplasty

BACKGROUND In the EPIC trial, c7E3 Fab, an antiplatelet IIb/ IIIa receptor antibody, reduced 30-day ischemic end points after high-risk coronary angioplasty by 35% and 6-month ischemic events by 23% but increased in-hospital bleeding episodes. METHODS AND RESULTS Of the 2099 patients randomized in EPIC, data were collected on 2038 (97%) for prospective hospital cost and major resources. Physician fees were estimated from the Medicare Fee Schedule. Regression analysis was used to examine the economic tradeoff between reduced ischemic events and increased major bleeding during the initial hospitalization. A potential cost savings of

Early ambulation after 5 French diagnostic cardiac catheterization: Results of a multicenter trial☆

622 per patient during the initial hospitalization from reduced acute ischemic events with c7E3 Fab was offset by an equivalent rise (

Peripheral vascular complications in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I)

521) in costs as the result of an increase in bleeding episodes. Baseline medical costs for the bolus and infusion c7E3 Fab arm averaged

Surgical complications from hemostatic puncture closure devices

13,577 (exclusive of drug cost) compared with