Antiplatelet therapy in the prevention of ischemic vascular events: literature review and evidence-based guidelines for drug selection.

BACKGROUND: New antiplatelet drugs are being developed and many clinical trials evaluating the benefits of antiplatelet drugs for the secondary prevention of ischemic events in patients with atherosclerotic vascular disease have been performed. HYPOTHESIS: An updated systematic review and evidence-based guidelines for the appropriate selection of antiplatelet drugs may be beneficial to physicians and healthcare organizations attempting to create or update current clinical practice guidelines or clinical pathways aimed at caring for these patients. METHODS: (1) A systematic review of the recent literature on the relative efficacy and safety of aspirin, ticlopidine, and clopidogrel was undertaken; (2) an evidence-based, expert panel approach using a modified Delphi technique to create explicit guidelines for prescribing antiplatelet therapy was instituted; and (3) the recommendations of an expert panel were summarized. RESULTS: Consensus guidelines were developed for the utilization of aspirin, ticlopidine, or clopidogrel for the prevention of ischemic events in patients with manifestations of atherosclerotic vascular disease (prior myocardial infarction, prior ischemic stroke, or established peripheral arterial disease) who are at increased risk for recurrent ischemic events. Based on efficacy and safety, clopidogrel was recommended as the drug of choice for patients with established peripheral arterial disease; aspirin or clopidogrel should be considered in patients with prior myocardial infarction (with clopidogrel favored for patients who have had a recurrent event while on aspirin or in whom aspirin is contraindicated); aspirin or clopidogrel should be considered as first-line treatment in patients with prior ischemic (nonhemorrhagic) stroke--however, clopidogrel is the favored drug in patients in whom other antiplatelet drugs are either contraindicated or who have had recurrent events while on therapy. CONCLUSIONS: Myocardial infarction, ischemic stroke, and peripheral arterial disease are all clinical manifestations of the same underlying disease process (atherosclerosis), with thrombus formation on the disrupted atherosclerotic plaque (atherothrombosis) being a common precipitating factor of ischemic events in patients suffering from these disorders. An evidence-based approach was used to develop a practice guideline, based on available published evidence, for the appropriate utilization of antiplatelet agents (aspirin, ticlopidine, or clopidogrel). These guidelines may be of use to multidisciplinary teams wishing to create or update clinical guidelines or clinical pathways which address the care of patients with atherosclerotic vascular disease. New antiplatelet agents such as clopidogrel may be more effective and associated with lower risk of selected adverse effects (such as gastrointestinal distress, gastrointestinal hemorrhage, and neutropenia) than those previously used to prevent thrombus formation in the setting of atherosclerotic arterial disease. Combination antiplatelet therapy is being evaluated as an option for those patients who experience recurrent events on a single antiplatelet agent.

Urokinase recanalization of chronically occluded aortocoronary vein grafts.

The problem of aortocoronary vein graft occlusion remains a major clinical challenge. The approach described above offers one method of preserving the life of some occluded vein grafts. Adherence to the protocol, particularly the inclusion and exclusion criteria, is the primary determinant of acute success and lower complications. The following summarizes the experience to date: (1) This procedure is safe and effective when applied to the patients outlined and when the protocol is strictly adhered to. (2) Acute recanalization is improved if TIMI grade 2 or 3 flow is achieved by lysis alone. (3) Acute recanalization is not influenced by (i) age of graft, (ii) duration of occlusion up to 6 months, (iii) size of distal native vessel, (iv) site of stenosis (intragraft versus anastomosis). (4) Six-month patency is greater when (i) TIMI grade 3 flow was achieved by lysis alone, (ii) the site of offending lesion is intragraft versus anastomosis. (5) Six-month patency may be influenced by (i) a size of distal native vessel greater than 2 mm, (ii) graft flow at initial operation greater than 200 ml/min. These studies were performed before the release of the coronary stent. As shown by Tierstein [32], long-term patency can be greatly enhanced by the use of stents. This procedure will presumably permit more patients to become candidates for this new technology and thereby improve the long-term patency and reduce the need for repeat operations.

Recanalization of Chronically Occluded Aortocoronary Saphenous Vein Bypass Grafts With Long-Term, Low Dose Direct Infusion of Urokinase (ROBUST): a serial trial.

OBJECTIVES: This multicenter study sought to evaluate the short-term efficacy and safety of prolonged, low dose, direct urokinase infusion in recanalization of chronically occluded saphenous vein bypass grafts in a large sample of patients, as well as to determine the 6-month patency rates for this procedure. BACKGROUND: Patients with chronically occluded aortocoronary vein grafts and uncontrolled angina pectoris have limited options for therapy. Previous work has shown that chronically occluded vein grafts can be recanalized by thrombolysis. METHODS: A coaxial infusion of urokinase (100,000 U/h) was given directly into occluded vein grafts in 107 patients. Balloon angioplasty was performed after lysis was achieved. Patients were discharged with warfarin and aspirin therapy. Six-month clinical follow-up data were obtained, and repeat angiography was encouraged. RESULTS: Initial patency was achieved in 74 patients (69%). Mean duration of infusion was 25.4 h, and mean urokinase dosage was 3.70 million U. Acute adverse events included acute myocardial infarction in 5 patients (5%), enzyme level elevation in 18 (17%), emergency coronary artery bypass graft surgery in 4 (4%), stroke in 3 (3%) and death in 7 (6.5%). Recanalization was unsuccessful in all seven patients who died. Six-month follow-up angiograms were obtained for 40 patients (54%), 16 of whom maintained a patent graft (40%). Angina was present in 13 patients with successful (22%) and 12 with unsuccessful (71%) recanalization at 6-month follow-up. CONCLUSIONS: Chronically occluded aortocoronary vein grafts can be recanalized in approximately 70% of appropriately selected patients. Complications are similar to those observed with repeat operations. Clinical follow-up shows an improvement in angina. This procedure is intended for patients with only one occluded vein graft. Strict adherence to the protocol will improve patency and reduce complications.

Recanalization of chronically occluded aorto-coronary vein grafts.

The problem of aorto-coronary vein graft occlusion remains a major clinical challenge. The approach described above offers one method of preserving the life of some occluded vein grafts. This study was done before the release of the coronary stent. This procedure will presumably permit patients to become candidates for this new technology and thereby improve the long-term patency.

New recombinant glycosylated prourokinase for treatment of patients with acute myocardial infarction. Prourokinase Study Group.

OBJECTIVES: Three dosage regimens of a new recombinant glycosylated prourokinase (A-74187) were evaluated by measuring coronary artery patency at 90 min in patients with acute myocardial infarction. BACKGROUND: Prourokinase is a thrombolytic drug with unique pharmacologic properties that may be clinically advantageous. METHODS: Aspirin (325 mg), intravenous heparin and prourokinase (60- or 80-mg monotherapy or 60 mg "primed" with a preceding bolus dose of 250,000 IU of recombinant urokinase) were administered to 128 patients. Coronary angiography was performed at 60 min (wherever possible), 90 min (primary end point) and 24 h to determine arterial patency and reocclusion rates. Plasma was collected serially to measure fibrinogen, plasminogen, thrombin antithrombin III and fibrinopeptide A. Clinical events until hospital discharge were recorded. RESULTS: The coronary artery patency rate at 90 min was similar for all three regimens, averaging 73% (95% confidence interval [CI] 64% to 80%); Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow rates averaged 52% (95% CI 42% to 61%). Arterial patency at 60 min was 62% (95% CI 50% to 73%), and reocclusion occurred in 1.4% (95% CI 0.1% to 4.1%). Prourokinase demonstrated relative fibrin specificity at all doses studied. Fibrinopeptide A and thrombin antithrombin III levels were elevated at baseline and declined rapidly during the 1st 12 h. There was no difference in the baseline values of these thrombin markers between patients with patent versus closed arteries at 90 min. There was one death; no strokes occurred. CONCLUSIONS: A-74187 prourokinase is a rapid-acting, effective fibrin-specific thrombolytic agent. Reocclusion was unusual, possibly because of aggressive anticoagulation with intravenous heparin or unique features of the drug. Full definition of the clinical effectiveness of this drug merits examination in future randomized trials evaluating clinical and angiographic effectiveness.

Use of aortic counterpulsation to improve sustained coronary artery patency during acute myocardial infarction. Results of a randomized trial. The Randomized IABP Study Group.

BACKGROUND: Aortic counterpulsation has been observed to reduce the rate of reocclusion of the infarct-related artery after patency has been restored during acute myocardial infarction in observational studies. To evaluate the benefit-to-risk ratio of aortic counterpulsation during the early phase of myocardial infarction, a multicenter randomized clinical trial was performed. METHODS AND RESULTS: Patients who had patency restored during acute cardiac catheterization within the first 24 hours of onset of myocardial infarction were randomly assigned to aortic counterpulsation for 48 hours versus standard care. Intravenous heparin was used similarly in both groups and was continued for a median (25th, 75th percentile) of 5 (2,7) days. A total of 182 patients were enrolled; 96 were assigned to aortic counterpulsation and 86 to standard care. Repeat cardiac catheterization was performed at a median of 5 (4,6) days after randomization in 89% of patients assigned to aortic counterpulsation and in 90% of control patients. Patients randomized to aortic counterpulsation had similar rates of severe bleeding complications (2% versus 1%), number of units of blood transfused (mean, 1.3 +/- 2.6 versus 0.9 +/- 1.8 units), and vascular repair or thrombectomy (5% versus 2%) compared with patients treated in a conventional manner. Patients randomized to aortic counterpulsation had significantly less reocclusion of the infarct-related artery during follow-up compared with control patients (8% versus 21%, P < .03). In addition, there was a significantly lower event rate in patients assigned to aortic counterpulsation in terms of a composite clinical end point (death, stroke, reinfarction, need for emergency revascularization with angioplasty or bypass surgery, or recurrent ischemia): 13% versus 24%, P < .04. CONCLUSIONS: This randomized trial showed that careful use of prophylactic aortic counterpulsation can prevent reocclusion of the infarct-related artery and improve overall clinical outcome in patients undergoing acute cardiac catheterization during myocardial infarction.

Directional atherectomy of aorto-ostial stenoses.

Balloon angioplasty of aorto-ostial right coronary artery (RCA) and aorto-ostial saphenous vein graft (SVG) stenoses has been reported to be associated with a suboptimal acute success rate, a higher incidence of restenosis and an increased risk of emergent coronary artery bypass surgery. In this report, we describe the use of directional coronary atherectomy (DCA) as a treatment alternative in a series of twenty three patients who were documented to have a > 60% stenosis within 3 mm of the origin of the RCA (15 patients) or SVG (8 patients) as measured by on-line quantitative angiography. DCA was successfully performed in 14 of 15 RCA ostial lesions and in all eight SVG lesions. This yielded an acute success rate of 93% and 100% with a mean reduction in percent stenosis from 87% to 9% and from 85% to 8% respectively. Only one patient, presenting with an ostial RCA lesion, was unable to be revascularized using DCA. All successfully treated patients underwent exercise treadmill testing or repeat cardiac catheterization in follow-up. Clinical evidence of restenosis defined as recurrent chest pain or ischemic evidence on exercise treadmill and > 50% angiographic restenosis was demonstrated in three of twenty two patients (14%). Of the nine successfully treated patients who underwent repeat cardiac catheterization, three (33%) had restenosed for an angiographic rate of 25% for RCA and 50% for SVG lesions. In conclusion, DCA of aorto-ostial stenoses is technically feasible and can be performed with good initial results.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of predilatation on coronary angioplasty-induced vessel wall injury.

Fifty-four patients presenting with stenotic lesions in a major coronary artery visually estimated by diagnostic angiography to be greater than 90% but less than 100% were randomized to one of two angioplasty regimens, predilatation (group 1) or no predilatation (group 2). In group 1, the artery was initially dilated with a 2 mm balloon followed by a balloon that was considered by the operator to be the definitive size to fully dilate the target vessel. In group 2, the artery was dilated with a balloon deemed the definitive size to complete the angioplasty procedure. There were no statistical differences between groups with respect to age, sex, history of unstable angina, or prior acute myocardial infarction. There were also no significant differences in the angiographic characteristics of the coronary lesions including artery location, lesion length, concentric or eccentric morphology, tubular versus discrete stenosis, calcium in lesions, or lesions on a bend. Following angioplasty, luminal filling defects were present in 5% of the predilated group and in 9% of the nonpredilated group (p = NS). The incidence of luminal border haziness at the dilatation site did not differ between groups, seven (35%) in group 1 versus eight (24%) in group 2. Angiographic evidence of a linear dissection at the angioplasty site was also similar between groups, one (5%) in group 1 versus five (15%) in group 2. Occlusive complications were witnessed in 10% of the predilated group and 12% of the nonpredilated group (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Recanalization of chronically occluded aortocoronary saphenous vein bypass grafts by extended infusion of urokinase: initial results and short-term clinical follow-up.

Chronic occlusion of saphenous vein aortocoronary bypass grafts is a common problem. Although percutaneous transluminal angioplasty of a saphenous vein with a stenotic lesion is feasible, angioplasty alone of a totally occluded vein graft yields uniformly poor results. Patients with such occlusion are often subjected to repeat aortocoronary bypass surgery. Experience with a new technique that allows angioplasty to be performed in a totally occluded saphenous vein bypass graft is reported. This technique utilizes infusion of prolonged low dose urokinase directly into the proximal portion of the occluded graft. Forty-six consecutive patients with 47 totally occluded grafts were studied. Patients had undergone end to side saphenous vein bypass grafting 1 to 13 (mean 7) years previously. All patients presented with new or worsening angina pectoris with ST-T changes or non-Q wave acute myocardial infarction and all had a totally occluded saphenous vein bypass graft. The new technique entailed the positioning of an angiographic catheter into the stub of the occluded graft and the advancement of an infusion wire into the graft. Patients were returned to the coronary care unit, where urokinase was delivered at a dose of 100,000 to 250,000 U/h. The total dose of urokinase ranged from 0.7 to 9.8 million U over 7.5 to 77 h (mean 31). After therapy, recanalization was seen in 37 (79%) of the 47 grafts. In 20 successfully treated patients, angiography was performed 1 to 24 (mean 11) months after treatment; 13 (65%) of these grafts were patent.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous streptokinase in acute myocardial infarction: experience of community hospitals served by paramedics.

UNLABELLED: We studied 58 consecutive patients, ages 37 to 78, who were given intravenous streptokinase (IV STK) early in the course of acute myocardial infarction (AMI) in three community hospitals served by the same mobile intensive care system. Forty-four patients (76%) received IV STK within 3 hours and 53 patients (92%) received it within 4 hours of onset of chest pain. Half the patients were brought to the hospital by paramedics. The average time from pain to administration of IV STK for paramedic patients was 100 minutes vs 198 minutes for those brought by other modes. Fifty of 58 patients (86%) showed clinical evidence of reperfusion. Forty-six of 54 patients (85%) studied with coronary angiography an average of 6 days post infarction had patent vessels subtending the infarcted region of the myocardium. The average angiographic ejection fraction was 47% for patients with reperfused vessels vs 34% for those with occluded vessels. The in-hospital mortality was 2 of 58 patients (3.4%). There was one late death at 8 months (total 5.2%). Twenty-one patients eventually had coronary bypass surgery and 5 patients had angioplasty. The remaining 29 patients had conventional therapy including 6 months of warfarin sodium. Fifty-four of 55 surviving patients (98%) are in functional class I or II and none have angina at 2 to 18 months of follow-up. Fifty-one of 55 patients are back at work. CONCLUSIONS: (1) IV STK is effective in coronary thrombolysis in a high percentage of AMI patients. (2) IV STK is safely administered in community hospitals.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved three-year disease-free survival in osteogenic sarcoma.

Of 41 consecutive patients with newly diagnosed osteogenic sarcoma admitted to the Children's Orthopedic Hospital and Medical Center in Seattle, Washington, between 1952 and 1977, 19 treated before 1973 did not receive adjunctive chemotherapy (histological group) whereas after 1972 22 have been so treated (chemotherapy group). Chemotherapy consisted primarily of high doses of methotrexate and adriamycin for 16 months after surgical treatment. Patients in the historical group have been observed for a minimum of nine years (six patients) or until death (13 patients). The 13 surviving patients in the chemotherapy group have been followed for a minimum of three years (median five years) and all 12 disease-free patients have been off therapy for between one and a half and five and a half years (median three years). Overall, the chemotherapy group has had a significant increase in both survival (p = 0.03) and disease-free survival (P = 0.02) compared to the historical group. In 35 patients with localised disease at diagnosis, the three-year disease-free survival and the three-year survival rates were 18 per cent and 41 per cent respectively in the historical group, and 67 per cent and 78 per cent (life table estimates) respectively in the chemotherapy group. With adjunctive chemotherapy only one of the seven patients developing pulmonary metastases did so later than nine months after diagnosis. The superior results in the chemotherapy group could not be accounted for by differences in age, sex, presence of metastases at diagnosis, histopathology, location of primary tumour, type of initial or subsequent surgical treatment, or the use of standard or computerised lung tomography. Although the use of historical controls in this study does not exclude other changes as contributing to the observed improvement in outcome, our data support the contention that adjunctive chemotherapy improves both the disease-free survival and the overall survival of patients with osteosarcoma and rarely delays the onset of recurrent or metastatic disease.

A comparison of marrow transplantation with chemotherapy for children with acute lymphoblastic leukemia in second or subsequent remission.

The progress of 24 children with acute lymphoblastic leukemia treated with cyclophosphamide, total-body irradiation, and marrow transplantation during a second or subsequent remission was compared with that of 21 children treated with conventional chemotherapy after they had entered a second remission. Eleven of the transplantation group are alive, including nine in continuing complete remission for 17 to 55 months; only two of the chemotherapy group are alive, one in complete remission after 20 months. Relapse was the major cause of failure in both groups. Acute and chronic graft-versus-host disease in the transplantation group and leukoencephalopathy in both groups were the other major causes of morbidity and mortality. This study demonstrates that marrow transplantation currently offers the best chance of long-term remission and potential cure after a child with acute lymphoblastic leukemia has had a relapse in the marrow.

Development of an education program for parents of children with cancer.

A structured education program for parents of children with cancer has been developed and has undergone pilot testing. Content included both medical and psychosocial materials. The parent education program supplemented the existing educational and emotional support services of a large, childhood cancer treatment center. Written materials, self-instructional exercises, lectures, visual aids, and small group discussions were incorporated into the program. This variety of topics and teaching techniques was appealing to parents and appeared to enhance learning. Parents enthusiastically attended the program pilots, gained and retained the new information, and appeared to benefit emotionally from their participation.

The team approach to the management of pediatric cancer.

The last 20 years have witnessed remarkable improvements in the prognosis of children with many forms of malignant disease. The reasons for these improvements relate not only to the development of better drugs and more effective radiotherapy, but also to the multidisciplinary approach involving surgeon, chemotherapist, radiotherapist and immunotherapist in providing optimum treatment for the child with a particular cancer. In this paper, the changing role of the pediatric oncologist, surgeon and radiotherapist in improving the management of pediatric cancer is discussed.

Chemotactic activity in the coronary sinus after experimental myocardial infarction: effects of pharmacologic interventions on ischemic injury.

Various pharmacologic interventions that suppressed chemotactic factor activity in the coronary sinus after acute ischemia were analyzed for protective effects on myocardium. Ischemic injury was determined by comparing the slopes of the regression lines derived from 24 hour myocardial creatine kinase content versus S-T segment elevation 15 minutes after coronary ligation. Dogs treated 30 minutes after ligation with cobra venom factor, hydrocortisone or Trasylol showed a marked decrease in chemotactic activity in the coronary sinus. These agents also showed a protective effect on ischemic injury when compared to control. Myocardial biopsy specimens from areas of significant ischemia defined by S-T segment elevations in dogs treated with cobra venom factor were essentially devoid of an inflammatory response whereas those from dogs treated with Trasylol or hydrocortisone showed moderate neutrophil infiltration and minimal tissue exudate.

Marrow transplantation in treatment of children with aplastic anaemia or acute leukaemia.

Seventy-six patients, aged 2 to 17 years, were treated with bone marrow transplantation for severe aplastic anaemia or acute leukaemia refractory to conventional therapy. 16 of the 22 patients (73%) who received marrow transplantations for aplastic anaemia are surviving, 12 of these for over one year. In acute leukaemia, using preparation with cyclophosphamide and total body irradiation, 8 of 33 patients (24%) receiving allogeneic and 5 of 8 (63%) receiving syngeneic transplantations are continuing in remission from 3 months to beyond 2 years. The longest continuing remission off therapy is now over 4 1/2 years after preparation with total body irradiation. The major causes of failure remain graft-versus-host disease, infection, graft rejection (aplastic anaemia), and leukaemic relapse.