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Biomedical subjects

E R Bates

Publications and source records attributed to E R Bates.

At least 55 records · Page 3Linked to original sources
PubMed1997

Clinical trial results with hirudin and bivalirudin for acute coronary artery syndromes.

Thrombin plays a key role in the pathophysiology of acute coronary artery syndromes. The "thrombin hypothesis" states that more complete and consistent thrombin inhibition may improve clinical outcomes in acute ischemic syndromes. The direct thrombin inhibitors hirudin and bivalirudin are potentially superior agents to heparin and have been tested in several clinical trials. More predictable and less variable levels of anticoagulation have been demonstrated. Adverse clinical events have been reduced during active treatment with hirudin or bivalirudin, but increased bleeding, including intracerebral hemorrhage, can occur with excessive anticoagulation. Unfortunately, the short-term benefit has not been sustained during follow-up. The multiplicity of pathways for platelet activation, inadequate treatment duration, or the inability to block thrombin generation may explain the limited efficacy. In contrast, inhibitors of the glycoprotein IIb/IIIa platelet receptor are associated with a more dramatic and durable reduction in clinical events.

Angina, Unstable↗
PubMed1996

Lesion-directed administration of alteplase with intracoronary heparin in patients with unstable angina and coronary thrombus undergoing angioplasty.

Percutaneous coronary revascularization in patients with unstable angina and coronary thrombus carries a high complication rate. A new strategy to reduce thrombus burden before revascularization was tested in a multicenter prospective trial. Patients with unstable angina and coronary thrombus (n = 45) received alteplase through an infusion catheter at the proximal aspect of the target lesion and concomitant intracoronary heparin via a standard guiding catheter. Angiography was performed before and alter lesion-directed therapy and post-intervention. Systemic fibrinogen depletion and thrombin activation were not observed, while fibrinolysis was evident for > or = 4 hr after treatment. Target lesion stenosis did not change significantly after lesion-directed therapy, but thrombus score was reduced, particularly among patients who had large thrombi (mean 2.2 vs. 1.6, P = 0.02). Revascularization was successful in 89% of patients. Median final stenosis was 30% and mean final thrombus score was 0.4. Complications included recurrent ischemia (11%), MI (7%), abrupt closure (7%), severe bleeding (4%), and repeat emergency angioplasty (2%). Patients with overt thrombus appeared to derive the most angiographic benefit from lesion-directed alteplase plus intracoronary heparin. Later revascularization was highly successful. This strategy may be a useful adjunct to percutaneous revascularization for patients with unstable angina and frank intracoronary thrombus.

Adult↗
PubMed1996

Prognostic significance of precordial ST segment depression during inferior myocardial infarction in the thrombolytic era: results in 16,521 patients.

OBJECTIVES: We examined the prognostic significance of precordial ST segment depression among patients with an acute inferior myocardial infarction. BACKGROUND: Although precordial ST segment depression has been associated with a poor prognosis, this correlation has not been adequately quantified, partly because of small sample sizes and methodologic limitations in previous studies. METHODS: We examined the clinical and angiographic outcomes of 16,521 patients with an acute inferior myocardial infarction who underwent thrombolysis in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) study. Patients were classified into those without precordial ST segment depression (n = 6,422 [38.9%]), those with ST segment depression in leads V1 to V3 only (n = 5,850 [35.4%]), those with ST segment depression in leads V4 to V6 only (n = 876 [5.3%]) and those with ST segment depression in both leads V1 to V3 and leads V4 to V6 (n = 3,373 [20.4%]) on initial electrocardiography. Outcome measures included postinfarction complications (second- or third-degree heart block, congestive heart failure or shock) and 30-day and 1-year mortality. RESULTS: Patients with precordial ST segment depression had larger infarctions, more postinfarction complications and a higher mortality rate than those without precordial ST segment depression (4.7% vs. 3.2% at 30 days; 5.0% vs. 3.4% at 1 year; both p < 0.001), regardless of whether ST segment depression was noted in leads V1 to V6 or in leads V4 to V6. The magnitude of precordial ST segment depression (sum of leads V1 to V6) added significant independent prognostic information after adjustment for clinical risk factors; the risk of 30-day mortality increased by 36% for every 0.5 mV of precordial ST segment depression. CONCLUSIONS: Assessment of the magnitude of precordial ST segment depression is useful for acute risk stratification in patients with an inferior myocardial infarction.

Electrocardiography↗
PubMed1995

Rapid hemodynamic improvement after reperfusion during right ventricular infarction.

OBJECTIVES: This study sought to determine the effects of reperfusion on hemodynamic status and hospital course in patients with right ventricular infarction. BACKGROUND: In contrast to the relatively low risk associated with acute inferior myocardial infarction, right ventricular infarction is associated with higher in-hospital morbidity and mortality. However, the potential benefits of reperfusion in patients with right ventricular infarction are unknown. Consequently, this study evaluated the potential benefits of primary angioplasty in patients with right ventricular infarction. METHODS: Of 141 consecutive patients admitted to the hospital for inferior myocardial infarction, 27 were identified as having right ventricular involvement by electrocardiographic and hemodynamic criteria. Seventeen patients achieved patency of the infarct-related right coronary artery by primary coronary angioplasty within 24 h of hospital admission, but 10 patients did not. All patients had invasive hemodynamic monitoring at the time of hospital admission, and subsequent serial hemodynamic status and clinical events were recorded. RESULTS: Patients with successful reperfusion demonstrated improved right atrial pressure, pulmonary capillary wedge pressure and right atrial/pulmonary capillary wedge pressure ratio as early as 8 h after reperfusion, whereas patients without reperfusion had no hemodynamic improvement over 24 h. Right atrial pressure demonstrated the greatest 8-h improvement after successful reperfusion (15.4 +/- 0.8 to 8.4 +/- 0.8 mm Hg [mean +/- SD], p < 0.05) but was unchanged without reperfusion (13.7 +/- 0.9 to 13.9 +/- 0.8 mm Hg, p = NS). Additionally, persistently elevated right atrial pressure was associated with increased mortality. CONCLUSIONS: Reperfusion in the setting of right ventricular infarction leads to rapid hemodynamic improvement and may result in improved survival.

Aged↗
PubMed1995

Directional atherectomy of coronary and saphenous vein graft ostial stenoses.

Directional coronary atherectomy (DCA) has been proposed as an alternative to balloon dilatation for treating coronary ostial stenoses, but the long-term efficacy of this procedure has not been well studied. To determine the procedural success and long-term efficacy of DCA for ostial stenoses, clinical data from 1 large registry database and from 2 single centers were retrospectively reviewed. Patients included in the study underwent DCA of aortocoronary (left main or right coronary artery), non-aortocoronary (left anterior descending or circumflex), or vein graft ostial stenoses. In 158 patients undergoing DCA of 160 lesions (30 left main or right coronary, 73 left anterior descending or circumflex, and 57 vein graft stenoses), overall procedural success, defined as < 50% residual stenosis without death, Q-wave myocardial infarction, or need for urgent bypass graft surgery, was 87%. The major complication rate was 0.6%. There were no deaths or Q-wave infarctions; only 1 patient required urgent bypass surgery. Other complications included non-Q-wave myocardial infarction (9%), arterial dissection (9%), abrupt closure (4%), and distal coronary embolization (4%). Angiographic follow-up was available for 65% of the 138 eligible patients. The overall 6-month angiographic restenosis rate, defined as > 50% diameter stenosis at the site of DCA, was 48% (de novo lesions 40% and restenotic lesions 61%). Restenosis rates for de novo and restenotic lesions were: aortocoronary (33%/50%), native coronary (38%/35%), and vein graft (47%/93%), respectively. We conclude that DCA of ostial stenoses is an effective revascularization strategy associated with a high procedural success rate and a low incidence of major complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Contemporary reperfusion therapy for cardiogenic shock: the GUSTO-I trial experience. The GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.

OBJECTIVES: This study sought to examine the incidence, temporal profile and clinical implications of shock in a large trial of thrombolytic therapy for acute myocardial infarction. BACKGROUND: Despite advances in the treatment of acute ischemic syndromes, cardiogenic shock remains associated with significant morbidity and mortality. METHODS: Patients who presented within 6 h of symptom onset were randomized to four treatment strategies: 1) streptokinase plus subcutaneous heparin; 2) streptokinase plus intravenous heparin; 3) accelerated recombinant tissue-type plasminogen activator (rt-PA) plus intravenous heparin; or 4) streptokinase and rt-PA plus intravenous heparin. The primary end point was 30-day all-cause mortality. RESULTS: Shock occurred in 2,972 patients (7.2%): 315 (11%) had shock on arrival, and 2,657 (89%) developed shock after hospital admission. Reinfarction occurred in 11% of patients who developed shock compared with 3% of patients without shock. The mortality rate was significantly higher in patients who presented with (57%) or developed (55%) shock than in those without shock (3%) (p < 0.001). Shock developed significantly less frequently in patients receiving rt-PA. There were fewer deaths in patients who presented with shock and were treated with streptokinase plus intravenous heparin or who developed shock and were treated with streptokinase plus subcutaneous heparin. Patients who developed shock had a significantly lower 30-day mortality rate if angioplasty was performed. CONCLUSIONS: Because cardiogenic shock occurred most often after admission and with recurrent ischemia and reinfarction, recognizing signs of incipient shock may improve outcome. Fewer patients treated with rt-PA developed shock, yet those developing shock had the same high mortality rate as those presenting with shock, regardless of treatment. Only angioplasty was associated with a significantly lower mortality rate.

Aged↗
PubMed1995

Cardiogenic shock.

Despite advancements in the pharmacologic treatment of acute myocardial infarction and the introduction of mechanical hemodynamic support, in-hospital mortality rates for cardiogenic shock have remained between 70% and 80%. In addition, the proven beneficial effects of thrombolytic therapy in reducing mortality in acute myocardial infarction have not been paralleled by similar results in cardiogenic shock. Emergency revascularization appears to be the only intervention that may modify the prognosis of cardiogenic shock. Because the absence of controlled data, however, final conclusions cannot yet be drawn. Two ongoing randomized clinical trials will try to answer the unsolved issues. In the multicenter international SHOCK trial (Should We Revascularize Occluded Coronaries for Cardiogenic Shock), patients are being randomized to PTCA or conservative treatment, with mortality as the primary end point. A similar end point will be evaluated in the Swiss Multicenter Study of Angioplasty for Shock following Myocardial Infarction (SMASH) trial. It is hoped that these two randomized trials will be able to prove the value of PTCA in cardiogenic shock and identify the subset of patients most likely to benefit from such treatment.

Angioplasty, Balloon, Coronary↗
PubMed1994

A pooled analysis of coronary arterial patency and left ventricular function after intravenous thrombolysis for acute myocardial infarction.

Individual studies of patency rates and left ventricular (LV) function after thrombolysis have generally been limited by small numbers of observations, wide confidence intervals, and limited numbers of time points. To obtain a more reliable estimate of patterns of patency and LV ejection fraction, a systemic overview of angiographic studies was performed after intravenous thrombolytic therapy. A total of 14,124 angiographic observations from 58 studies evaluating patency after no thrombolytic agent, streptokinase, standard dose tissue-type plasminogen activator (t-PA), accelerated dose t-PA, or anistreplase (anisoylated plasminogen streptokinase activator complex [APSAC]) were included. At 60 and 90 minutes, streptokinase had the lowest patency rates of 48% and 51%, respectively, standard dose t-PA and APSAC had similar intermediate rates of approximately 60% and 70%, and accelerated t-PA had the highest patency rates of 74% and 84%. By 2 to 3 hours and longer, the patency rates were similar for the various regimens. Reocclusion rates in studies including 1,172 patients randomized to t-PA versus a nonfibrin-specific agent were higher after t-PA (13.4% vs 8.0%, p = 0.002). Ten studies enrolling 4,088 patients treated with thrombolytic therapy versus control demonstrated a modest improvement in mean LV ejection fraction in the thrombolytic group at each of the times after thrombolytic therapy: hour 4, day 1, day 4, day 7 to 10, and day 10 to 28 after thrombolysis. By 4 days, mean ejection fraction was 53% versus 47% (thrombolytic vs control therapy, p < 0.01); by 10 to 28 days it was 54.1% and 51.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Disease↗
PubMed1994

Emergent percutaneous cardiopulmonary bypass in patients having cardiovascular collapse in the cardiac catheterization laboratory.

Percutaneous cardiopulmonary bypass (PCB) was instituted in 30 initially stable patients who developed either cardiac arrest refractory to resuscitation (n = 7) or cardiogenic shock (mean arterial blood pressure < 50 mm Hg unresponsive to fluid resuscitation or vasopressors) (n = 23) after a catheterization laboratory complication. Events leading to collapse included abrupt closure during percutaneous transluminal coronary angioplasty (PTCA) (n = 22), complications from diagnostic cardiac catheterization (n = 6), left ventricular perforation during mitral valvuloplasty (n = 1), and right ventricular perforation during pericardiocentesis (n = 1). PCB was initiated within 20 minutes of cardiovascular collapse in 83% of patients (arrest: 21 +/- 13 minutes [range 10 to 50]; and shock: 17 +/- 6 minutes [range 10 to 30]). Mean arterial blood pressure increased on PCB from 0 to 56 mm Hg in patients with cardiac arrest and from 37 to 63 mm Hg in those with cardiogenic shock at mean PCB flow rates of 2.5 to 5.0 liters/min. Subsequent therapy on PCB included emergent cardiac surgery (n = 14), PTCA (n = 13) and medical therapy (n = 3). Six patients (20%) survived to hospital discharge (3 with cardiac surgery, 2 with PTCA, and 1 with medical therapy). All 7 patients with refractory cardiac arrest died despite further interventions on PCB, whereas 6 of 23 (26%) with cardiogenic shock survived to hospital discharge. Thus, in response to cardiovascular collapse in the catheterization laboratory, PCB does not salvage patients who do not regain a stable cardiac rhythm. PCB can stabilize patients who develop cardiogenic shock for further interventions which are lifesaving in only a minority of patients.

Aged↗
PubMed1994

Relation between coronary artery stenosis assessed by visual, caliper, and computer methods and exercise capacity in patients with single-vessel coronary artery disease. The Veterans Affairs ACME Investigators.

BACKGROUND: Practitioners often assume a close relation between angiographic coronary artery stenosis and patient functional capacity. To test this unproven hypothesis, we analyzed the relation between coronary artery stenosis measured by different methods and maximal treadmill exercise tolerance in patients with single-vessel disease before and after intervention by percutaneous transluminal coronary angioplasty (PTCA). METHODS AND RESULTS: Coronary angiography and maximal exercise testing off anti-ischemic medication were performed before random assignment of 227 patients with single-vessel coronary artery disease to PTCA or drug therapy. Six months later, angiography and exercise testing were repeated with patients assigned to PTCA off anti-ischemic therapy so that the altered coronary stenosis was the only consistent variable. Patients assigned to drug therapy were exercised on drug therapy. Coronary stenosis was assessed visually by the local investigator and quantitatively by blinded caliper and computer methods in central laboratories. Variabilities of caliper and computer measurements were established in a subset read twice. Visually estimated stenosis > or = 90% at baseline was associated with shorter exercise duration (7.9 versus 9.2 minutes, P < .04). Similar segregation at baseline was not observed with caliper or computer methods. Regardless of the method of measurement used, correlation between changes of lesion severity and exercise duration from baseline to follow-up was poor. Patients were angiographically classified as "better," "unchanged," or "worse" if follow-up stenosis was below, within, or above 2 SD of mean technical variability from baseline (+/- 18.8%, caliper, +/- 14.6%, computer). Exercise duration for PTCA patients improved among those with better lesions (+2.4 minutes, n = 50, P = .001) but also among those with unchanged lesions (+1.9 minutes, n = 41, P < or = .001). Unchanged medically treated patients improved less (+0.5 minutes, n = 86, P = .04). Results were similar when patients were angiographically classified by minimum lumen diameter. CONCLUSIONS: Handheld calipers and quantitative coronary angiography are equivalent techniques for making anatomic measurements. Neither method identified patients having reduced exercise capacity at baseline as well as visual estimation. The relation between changes of coronary stenosis and exercise duration is highly variable, at least in part because of the insensitivity of angiographic methods for detecting small but potentially important changes. Minimal anatomic improvement 6 months after PTCA does not preclude a good functional outcome. Contrary to common belief, angiographic stenosis does not correlate well with functional capacity, even in patients with single-vessel disease.

Angioplasty, Balloon, Coronary↗
PubMed1994

Treatment strategies for acute myocardial infarction complicated by cardiogenic shock in a community hospital.

The risk and benefits of three treatment strategies were examined in 64 consecutive patients with acute myocardial infarction and cardiogenic shock. Thirteen patients received thrombolytic therapy (group 1), 29 patients received intra-aortic balloon pump counterpulsation support (group 2), and 22 patients were treated with combined thrombolytic therapy and intra-aortic balloon pump counterpulsation support (group 3). The groups were similar in regard to age, sex, medical history, hemodynamic data, and extent of coronary artery disease. Survival was improved in patients treated with combined thrombolytic therapy and intra-aortic balloon pump counterpulsation support (group 1, 23 percent; group 2, 28 percent; and group 3, 68 percent; p = 0.0049). Seven percent of the patients who remained at the community hospital survived vs 69 percent who were transferred to a tertiary care center (p < 0.001), and 17 percent survived who were treated medically vs 71 percent who received revascularization (p < 0.001). These findings suggest that patients who present to a community hospital in cardiogenic shock can have their conditions stabilized, and they can then be transferred to a tertiary care hospital for revascularization and have the same outcome as patients who initially present to tertiary care hospitals.

Aged↗
PubMed1994

Prevention of rethrombosis after coronary thrombolysis in a chronic canine model. I. Adjunctive therapy with monoclonal antibody 7E3 F(ab')2 fragment.

We examined the efficacy of the monoclonal antibody (MoAb) 7E3 F(ab')2 fragment, an inhibitor of the platelet glycoprotein (GP)IIb/IIIa receptor, to prevent coronary artery rethrombosis after successful thrombolysis with rt-PA. The circumflex coronary artery of anesthetized dogs was instrumented with a flow probe, an electrode, and a stenosis. After recovery from the surgical procedure, the animals were reanesthetized on post-operative day 9, and vessel wall injury was induced with current applied to the intimal surface of the circumflex coronary artery. The resulting occlusive thrombus was aged for 30 min, and recombinant tissue plasminogen activator (rt-PA) was administered. The animals were allocated to receive either placebo or a single dose of 7E3 [0.8 mg/kg intravenous (i.v.) bolus] as the sole adjunctive agent. Ex vivo platelet function and coronary artery blood flow velocity were recorded on each of 5 consecutive days. Reocclusion and mortality were reduced significantly in animals treated with 7E3 as compared with the placebo-treated group. Significant inhibition of ex vivo platelet aggregation persisted for 48 h after a single injection of 7E3. The MoAb 7E3 F(ab')2 fragment is effective as the sole adjunctive agent with rt-PA for prevention of rethrombosis. The present study is unique in that it examined the efficacy of GPIIb/IIIa inhibition in an experimental model for an extended time, demonstrating the duration of antiplatelet therapy required to prevent rethrombosis after thrombolysis.

Animals↗
PubMed1994

Prevention of rethrombosis after coronary thrombolysis in a chronic canine model. II. Adjunctive therapy with r-hirudin.

We examined the effectiveness of the direct-acting thrombin inhibitor, recombinant hirudin (r-hirudin), for prevention of coronary rethrombosis after thrombolysis with recombinant tissue plasminogen activator (rt-PA) in a canine model of coronary artery thrombosis. The reocclusion rate of 15-30% associated with thrombolytic therapy emphasizes the need for adjunctive therapy to prevent rethrombosis. We studied r-hirudin for its potential to prevent reocclusion in a model of coronary artery thrombosis/thrombolysis. The circumflex coronary arteries of anesthetized dogs were instrumented with a flow probe, an intraluminal electrode, and a ligature stenosis. The dogs were reanesthetized on the ninth postoperative day, and intimal injury was induced with an anodal current. After occlusive thrombus formation, tissue plasminogen activator (rt-PA) was administered. The animals were allocated to receive either placebo, r-hirudin [5 mg/kg intravenously (i.v.) bolus, 2 mg/kg/h i.v., for 3.5 h] or r-hirudin (5 mg/kg i.v., bolus, 1 mg/kg/h i.v., for 12 h). Neither aspirin nor heparin was used. Ex vivo platelet function and coronary artery blood flow velocity were recorded on each of 5 consecutive days. Infarct size and residual thrombus weight were determined at the end of the protocol. r-Hirudin infusion (3.5 and 12 h) provided little benefit over rt-PA alone. Ex vivo platelet aggregation was not affected by r-hirudin. Little improvement in the incidence of reocclusion and mortality in a model of coronary artery thrombosis/thrombolysis resulted from adjunctive treatment with r-hirudin.

Animals↗
PubMed1993

An analysis of the cause of early mortality after administration of thrombolytic therapy. The Thrombolysis Angioplasty in Myocardial Infarction Study Group.

BACKGROUND: The use of thrombolytic therapy in myocardial infarction has been associated with a considerable improvement in survival rate; however, almost 40% of the deaths during hospitalization occur during the first 24 h. Clinical and angiographic characteristics identified through careful comparison of those patients who die early with those who survive may serve as important targets for the development of new strategies for the management of myocardial infarction. METHODS: Medical records and autopsy reports of 810 patients enrolled into four sequential studies evaluating thrombolytic therapy and angioplasty in acute myocardial infarction were reviewed. All patients were enrolled into four similar protocols with administration of thrombolytic therapy (intravenous tissue plasminogen activator in 561 patients, urokinase in 102, and a combination of tissue plasminogen activator and urokinase in 147) and acute cardiac catheterization performed 90 min after starting therapy. RESULTS: The overall in-hospital mortality rate was 6.8% (55 out of 810), with 21 of these deaths (38%) occurring within the first day. The median (25th, 75th percentile) time to death was 3 (0, 12) days. Infarct location was more frequently anterior in patients who died within the first day. Patients who died 24 h after admission to hospital had the lowest patency rate (45%) compared with patients who died within 24 h (59%) and those who survived (71%, P = 0.003). The deaths within the first day were more likely to be a result of cardiogenic shock (48%), ventricular arrhythmias (14%), or cardiac rupture (9%), whereas late deaths were more likely to be a result of recurrent ischemia or reinfarction (32%) and non-cardiac causes (18%). Two patients had an intracranial hemorrhage within the first 24 h which caused immediate death in one and death on the third day of hospitalization in the other. CONCLUSION: Mortality within the first 24 h of thrombolytic therapy administration can be defined by inadequate myocardial reperfusion in patients with cardiac failure, possibly associated reperfusion injury leading to cardiac rupture, and an increased risk of intracranial hemorrhage. These factors may serve as targets for the development of new treatment strategies in acute myocardial infarction that may alter prognosis.

Angioplasty, Balloon, Coronary↗
PubMed1993

Analysis of coronary angioplasty practice in the United States with an insurance-claims data base.

BACKGROUND: Coronary angioplasty is frequently performed in the United States, with more than 300,000 procedures in 1990. Despite the high rate of use of the procedure, there have been few studies addressing practice patterns. METHODS AND RESULTS: From a private insurance claims data base of 5.4 million individuals, a total of 2,101 patients who underwent coronary angioplasty during 1988-1989 were identified. Using their 4,578 hospital admission records and 87,578 outpatient claim records, with an average follow-up of 332 +/- 182 days, we compared patients' outcomes and charges according to whether they had an exercise stress test before the procedure, by sex, by region of the country, and by whether the angioplasty was performed in an institution with a training program. Only 29% of the study cohort had exercise testing before angioplasty; patients in the West (p = 0.001), those undergoing multivessel angioplasty (p = 0.00001), and those whose procedures were performed at sites with training programs (p = 0.04) were more likely to have a screening test, whereas women (p = 0.008) and those with a recent myocardial infarction (p = 0.00001) were less likely to have a screening test. The average length of stay for patients without myocardial infarction as a primary diagnosis was 5.6 days, with a total hospital charge of $15,027. In follow-up, 15.1% had coronary artery bypass surgery and 15% had at least one additional angioplasty procedure; the average follow-up charges were $4,879. Charges varied according to sex, region of the country, and academic status of the angioplasty institution. Certain outcomes showed variation by region of the country and academic status of the angioplasty institution. CONCLUSIONS: The relative lack of an objective definition of myocardial ischemia and the marked variability of use of procedures according to geographic region suggest the need for further implementation of established guidelines.

Age Factors↗