The broad spectrum of unstable angina pectoris and its implications for future controlled trials.
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Angina Pectoris↗
Biomedical subjects
V Fuster
Publications and source records attributed to V Fuster.
Determinants of family size in rural Galicia (Spain).
"The determinants of complete family size and offspring survival were assessed by means of family reconstitution data from 19th and 20th century rural [populations] of Northwest Spain. The reproductive performances of families were submitted to a stepwise regression analysis in which the number of children born alive and those surviving to reproductive age per family were taken as dependent variables, while 13 other variables were defined as independent. Infant mortality appears to explain most fertility variation; an earlier marital age and at first maternity leads to an increased family size. Survival seems to be the result of the apposite interaction of both fertility and mortality in early childhood."
Age Factors↗
Role of platelet activation and fibrin formation in thrombogenesis.
Further progress in the search for more effective but safe antithrombotic agents is coupled to an improved understanding of the factors involved in arterial and venous thrombogenesis. Although arterial thrombosis is initiated by formation of a layer of platelets on modified endothelium or subendothelial constituents and subsequent recruitment of passing-by platelets, this phenomenon is not sufficient to lead to a full thrombus. Further growth of such a platelet mass depends, to a large extent, on the presence of free thrombin. Thrombin is mainly generated by activation of factor XI on the platelet contact with collagen. In addition, thrombin leads to formation of fibrin, which maintains the stability of the arterial platelet thrombus and is the main component of the venous thrombus. The search for agents that inhibit platelet activation and thrombin formation is, therefore, a logical endeavor.
Blood Coagulation↗
Pharmacology of platelet inhibitors.
Although many drugs have inhibitory effects on platelet function, none of them inhibits all of the mechanisms that may be involved in the various forms of thrombosis. Choice of suitable drugs is hampered by lack of full knowledge concerning the reactions that make the major contributions to the formation of arterial thrombi at sites of repeated vessel wall injury or on atherosclerotic lesions. Drugs such as aspirin that inhibit the arachidonate pathway in platelets can only be expected to be effective against thromboembolic events in which the generation of thromboxane A2 plays a major part. If thrombin and fibrin formation are dominant, oral anticoagulant agents or heparin should be beneficial; thus, experimental evidence indicates that with repeated vessel wall injury, the formation of platelet fibrin thrombi on the vessel wall is probably influenced more by inhibitors of thrombin generation than by the subendothelial constituents such as collagen. Agents like prostacyclin that raise platelet cyclic adenosine monophosphate (AMP) levels in platelets by stimulating adenylate cyclase are potent inhibitors of the reaction of platelets to all aggregating and release-inducing stimuli, but these agents are not suitable for long-term administration. The effect of dipyridamole on platelet cyclic AMP levels is weak, and this drug may act through other effects on platelets or on other cells. Indeed, several of the drugs that have been tested in clinical trials may exert their effects through unrecognized mechanisms. Many combinations of drugs have been used to affect platelets or platelets and coagulation. This practice has been based on the theory that because several mechanisms may be involved in thrombus formation, combinations of drugs that inhibit different mechanisms may be beneficial.
Anti-Bacterial Agents↗
Antithrombotic therapy in patients with valvular heart disease and prosthetic heart valves.
Indications and the type of antithrombotic therapy for the prevention of thromboembolism in patients with valvular heart disease, mechanical prosthetic heart valves and bioprosthetic heart valves are discussed. The evidence for these clinical recommendations is described and graded into five levels. The indications for anticoagulation in patients with valvular heart disease are chronic or paroxysmal atrial fibrillation, sinus rhythm with a very large left atrium, severe left ventricular dysfunction or presence of heart failure or a history of previous thromboembolism. Anticoagulant therapy is administered to prolong the prothrombin time to 1.5 to 2.0 times control, using rabbit brain thromboplastin (standardized international normalized ratio = 3.0 to 4.5). Risk factors for thromboembolism in patients with prosthetic heart valves are discussed. Because intracardiac thrombus formation may start during and continues early after operation, restarting heparin therapy 6 hours after operation and continuing it for the duration of the hospitalization is advised. For mechanical prosthetic heart valves, oral anticoagulation as outlined plus dipyridamole is advised indefinitely. Platelet inhibitor therapy alone is insufficient. For bioprosthetic heart valves, heparin is followed by oral anticoagulation as outlined for 3 months after mitral or aortic valve replacement and indefinitely after mitral valve replacement if there is atrial fibrillation or a very large left atrium; aspirin may be recommended indefinitely after aortic valve replacement. Antithrombotic therapy is also considered for four special situations: noncardiac surgery, prosthetic valve endocarditis, anticoagulation after a thromboembolic event, and antithrombotic therapy during pregnancy.
Anticoagulants↗
The pathogenesis and prevention of aortocoronary vein bypass graft occlusion and restenosis after arterial angioplasty: role of vascular injury and platelet thrombus deposition.
Vascular injury during aortocoronary vein bypass graft surgery and arterial angioplasty initiates platelet thrombus deposition and mandates antithrombotic therapy, starting before the procedures to maximize protection against occlusion. This has been shown in studies in animals and in patients undergoing aortocoronary vein bypass graft operation where dipyridamole therapy was started before the operation, heparin was given intraoperatively and combined dipyridamole and aspirin therapy was started 7 hours after operation and markedly reduced vein graft occlusion in patients with grafts at both high and low risk for occlusion without increasing bleeding. Other alternative regimens, particularly preoperative dipyridamole followed postoperatively with aspirin alone, offer a promising future. Therapy should be continued for at least 1 year and perhaps indefinitely. Control of coronary risk factors appears important for long-term therapy to try to retard the atherosclerotic and occlusive process that leads to approximately 50% vein graft attrition by 10 years after operation. The possible role of cod liver oil and internal mammary artery bypass is discussed. Arterial angioplasty appears to cause deep arterial injury that activates both platelets and the coagulation system. These potentiate each other to form macroscopic mural thrombus within 1 hour in more than 90% of arteries that manifested deep arterial injury in pigs. Acute platelet thrombus deposition was retarded but not eliminated by only certain platelet-inhibitor agents. Implications for ongoing trials, current empiric therapy and future therapy are discussed.
Angioplasty, Balloon↗
Role of antithrombotic therapy in unstable angina, myocardial infarction and sudden death.
The role of platelets and the clotting system in the initiation and progression of atherosclerosis has received significant attention. Most importantly, platelets and thrombosis play a pivotal role in the pathogenesis of the acute coronary syndromes of unstable angina, myocardial infarction and sudden death. In each stage of the development of coronary artery disease, from the early symptomatic stage through the growing lesion and finally to the complicated plaque that results in the precipitation of the acute coronary syndromes, platelets and the clotting system serve as a common link among them. Antithrombotic therapy aimed at halting the progression of these syndromes, preventing their occurrence or even reversing them (such as in the early stages of acute myocardial infarction), has provided exciting new modalities to treat these disorders. The use of aspirin in unstable angina in two well designed studies has clearly shown a reduction in fatal as well as nonfatal cardiac events compared with control groups not treated with aspirin. Although demonstration of a benefit of anticoagulant and antiplatelet therapy is difficult owing to a low event rate of thrombotic events (low sensitivity) and other nonthrombotic fatal events (low specificity) after myocardial infarction, pooled results have shown a favorable effect with their use. The usefulness of thrombolytic therapy in the early stages of acute myocardial infarction depends on the timing of initiation of therapy, the severity of the residual stenosis and possible use of agents that protect the ischemic myocardium. Other potential therapies for the acute coronary syndromes are also suggested. Further studies are in progress to establish the clinical benefits of antithrombotic agents in acute coronary syndromes.
Anticoagulants↗
Thrombosis and embolism from cardiac chambers and infected valves.
In a number of cardiac conditions (acute myocardial infarction, chronic left ventricular aneurysm, dilated cardiomyopathy, infective endocarditis and atrial fibrillation in the absence of valvular disease), the risk of embolism gives cause for concern. Although anticoagulation with warfarin (Coumadin)-derivatives has been shown to be effective in some of these situations, there is no evidence regarding the role of antiplatelet agents. The common factor in the thromboembolic potential of acute myocardial infarction, chronic left ventricular aneurysm and dilated cardiomyopathy is mural thrombus. This can be detected by two-dimensional echocardiography and indium-111 platelet scintigraphy. Although of value in elucidating the natural history of mural thrombus, in most cases, management is not substantially aided by these investigations. In patients with extensive myocardial infarction, particularly anterior infarction, moderate intensity anticoagulation started soon after hospital admission reduces the rate of embolism. After 8 to 12 weeks, embolic risk is low so that anticoagulants can usually be discontinued. Patients with chronic left ventricular aneurysm have a low incidence of embolism; anticoagulation is, therefore, inappropriate. Dilated cardiomyopathy is associated with a high risk of embolism; moderate intensity anticoagulation may be advisable in many such cases. Little information is available regarding the incidence of thromboembolism or the role of antithrombotic therapy in the patient with a diffusely dilated left ventricle due to ischemic heart disease. In native valve infective endocarditis, the risk of hemorrhage is high, and the efficacy of conventional anticoagulants unclear; thus, anticoagulation should not be instituted for the cardiac condition as such. However, in prosthetic valve endocarditis, the risk of embolism seems to be very high, and anticoagulant therapy should be continued, but with great care because there is a substantial risk of cerebral hemorrhage. Atrial fibrillation in patients with valvular heart disease is dealt with in a previous review. Patients with nonvalvular atrial fibrillation are at varying risk of embolism, depending on the etiology of the arrhythmia; trials of antithrombotic therapy are needed for the various subsets of patients. In most elderly patients, the etiology is not known, and their stroke risk is high. The risk of embolism in younger patients with idiopathic atrial fibrillation is so low as to make any antithrombotic therapy unnecessary.(ABSTRACT TRUNCATED AT 400 WORDS)
Anticoagulants↗
17th Bethesda conference: Adult cardiology training. Task Force I: Training in clinical cardiology.
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Cardiology↗
Regression in thromboembolic type of primary pulmonary hypertension during 2 1/2 years of antithrombotic therapy.
Primary pulmonary hypertension carries a poor prognosis, with a 5 year survival rate of less than 25%. However, a previous study of more than 100 patients with tissue-proved primary pulmonary hypertension suggested that antithrombotic therapy may have a beneficial effect on survival, especially in patients with the thromboembolic type of primary pulmonary hypertension. This report describes a 54 year old white man with primary pulmonary hypertension of the thromboembolic type (proved by right upper lobe lung biopsy) who, after long-term antithrombotic therapy, showed resolution of symptoms of dyspnea and fatigue, regression of electrocardiographic signs of right ventricular hypertrophy and regression of elevated pulmonary artery pressure. Base-line cardiac catheterization in January 1982 revealed elevated pulmonary artery pressure (104/37 mm Hg) and pulmonary vascular resistance (14.6 units/m2) that did not decrease with 100% oxygen or intravenous hydralazine (12 mg). The patient was treated with warfarin and dipyridamole, 100 mg four times daily. The most recent cardiac catheterization in January 1984 revealed a pulmonary artery pressure of 50/15 mm Hg and a pulmonary vascular resistance of 8.7 units/m2. It is believed that this is the first report of regression of the symptoms and signs of biopsy-proved primary pulmonary hypertension. In view of the lack of a response to vasodilators in 1982, it is suggested that antithrombotic therapy is partially responsible for the improvement of this patient.
Cardiac Catheterization↗
Deep arterial injury during experimental angioplasty: relation to a positive indium-111-labeled platelet scintigram, quantitative platelet deposition and mural thrombosis.
Although it is not clear why coronary occlusion and restenosis occur after successful coronary angioplasty, factors related to the procedure may influence early and late results. The possible adverse effects of a medial tear documented histologically and produced during balloon angioplasty of the common carotid arteries were studied in 30 fully heparinized (100 U/kg body weight) normal pigs. Scanning electron microscopy showed endothelial denudation and extensive platelet deposition in all dilated arterial segments. Visible macroscopic mural thrombus was present within an hour of the procedure in 29 (91%) of the 32 arteries that had a medial tear documented by histologic study; the tear produced an indium-111-labeled platelet deposition of 116.4 +/- 26.5 X 10(6)/cm2 (mean +/- SE) and total thrombotic occlusion in 2 arteries (4%). None of the 24 arteries without a medial tear had a thrombus, and the mean platelet deposition in that group was 7.0 +/- 0.5 X 10(6)/cm2 (p less than 0.0008). In 12 pigs scanned with a gamma camera, visible thrombus was associated with platelet deposition in excess of 20 X 10(6)/cm2 in 12 arteries, 9 of which had a positive indium-111-labeled platelet scintigram. Thus, arterial angioplasty causes deep arterial injury, which appears to be a major cause of mural thrombosis, heavy platelet deposition, a positive indium-111-labeled platelet scintigram and acute arterial occlusion. A positive indium-111-labeled platelet scintigram was always associated with macroscopic thrombus of at least 20 > 10(6) platelets/cm2 and underlying deep arterial injury.
Angioplasty, Balloon↗
Angiographic evolution of coronary artery morphology in unstable angina.
As previously reported in acute presentations of unstable angina, an identifiable characteristic coronary artery lesion has been found in about 70% of cases at coronary arteriography. This takes the form of an eccentrically placed convex stenosis with a narrow neck due to one or more overhanging edges or irregular, scalloped borders, or both. To study the evolution of lesions responsible for unstable angina, coronary artery anatomy and morphology on angiography were evaluated in patients with stable angina progressing to unstable angina. Group I comprised 25 patients with a history of stable angina who were restudied after an acute episode of unstable angina and Group II comprised 21 patients with little or no change in symptoms between catheterizations. Progression of coronary disease occurred in 19 (76%) of 25 patients in Group I compared with 7 (33%) of 21 in Group II (p less than 0.001). Of the 25 lesions with progression in Group I, 17 progressed to less than 100% and 8 to 100% occlusion. Eighteen of these 25 lesions in Group I were previously insignificant (less than 50% occlusion on the first catheterization). In contrast, of the eight lesions with disease progression in Group II, only two were previously insignificant while six showed at least 50% occlusion on the initial study. The eccentric lesion was seen in 71% of all lesions with progression to less than 100% occlusion in Group I, but it was not seen in any Group II vessel with progression.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Platelet-inhibitor drugs before and after coronary artery bypass surgery and coronary angioplasty: the basis of their use, data from animal studies, clinical trial data, and current recommendations.
The pathogenesis of aortocoronary vein-graft occlusion appears to be similar to the development of atherosclerosis, except that it is more accelerated, especially during the first postoperative year. Initiation of platelet-inhibitor therapy before operation is important especially in patients at high risk of bypass graft occlusion because platelet deposition starts during operation and initiates the process of occlusion. The largest and only placebo-controlled trial to start therapy before operation showed that dipyridamole (Persantine) plus aspirin markedly reduced occlusion (compared with placebo) in both high- and low-risk subgroups both early and at a median of 1 year after operation. Arterial balloon angioplasty often causes severe arterial wall injury, which is a potent stimulus for immediate platelet-thrombus deposition and is probably the main contributing factor in the process of restenosis. Animal studies suggest the potential value of antithrombotic therapy starting the day before the angioplasty procedure, but results from placebo-controlled trials in humans are needed before optimal therapy can be established.
Angioplasty, Balloon↗
Role of platelets and platelet inhibitors in aortocoronary artery vein-graft disease.
To study the prevention of occlusion of aortocoronary-artery bypass grafts, we conducted a prospective, randomized, double-blind trial comparing long-term administration of dipyridamole (begun 2 days before operation) plus aspirin (begun 7 hr after operation) with placebo in 407 patients. Results at 1 month and at 1 year showed a reduction in the rate of graft occlusion in patients receiving dipyridamole and aspirin. On the basis of our clinical trial and our experimental studies in dogs and pigs, we describe four consecutive phases of aortocoronary artery bypass vein-graft disease: an early postoperative phase of platelet thrombotic occlusion, which is significantly prevented by platelet inhibitor therapy when started in the perioperative period; in addition, occlusion rates are presently decreasing, perhaps related to better surgical and technical experience; an intermediate phase of platelet-related intimal hyperplasia, within the first postoperative year, which is not prevented with platelet inhibitor therapy; a late phase of occlusion, toward the end of the first postoperative year, in which intimal hyperplasia or complicating platelet thrombi superimposed on the intimal hyperplasia may contribute to occlusion; platelet inhibitor therapy is of significant benefit in the prevention of this thrombotic type of occlusion; a phase of atherosclerotic disease, after the first postoperative year, in which the role of platelets and of platelet inhibitor therapy is under investigation.
Animals↗
Anatomic-physiologic links between acute coronary syndromes.
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Angina, Unstable↗
Dose antiplatelet agents; the relationship among side effects, and antithrombotic effectiveness.
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Aspirin↗
Intracardiac thrombi and systemic embolization.
Recent progress has been made in diagnosing and tracing the natural history of intracardiac thrombi by echocardiography. Left ventricular thrombi occur and cause emboli in three clinical conditions: acute myocardial infarction, left ventricular aneurysm as a sequel to infarction, and idiopathic dilated cardiomyopathy. Echocardiographic studies have shown that one third of patients with acute anterior myocardial infarction have left ventricular thrombi; only a small percentage of these patients have emboli. Administration of anticoagulants decreases the prevalence of left ventricular thrombi and the frequency of embolization in this group. Thrombi that are protruding and mobile are most likely to embolize. Anticoagulation treatment decreases the prevalence of embolization in idiopathic dilated cardiomyopathy and should be instituted regardless of whether atrial or ventricular thrombi are detected by two-dimensional echocardiography. In patients with chronic left ventricular aneurysm, thrombi occur commonly, but emboli, infrequently. Therefore, data are insufficient to suggest that anticoagulation treatment is indicated, even if left ventricular thrombi are detected by two-dimensional echocardiography.
Anticoagulants↗
Indium-111 platelet kinetics in normal human subjects: tropolone versus oxine methods.
The effect of labeling media on the kinetics of[111In]platelets was evaluated by performing a paired crossover study in eight normal human subjects using tropolone and oxine methods. Platelets were labeled in autologous plasma with [111In]tropolone (In-tr) and in ACD-saline with [111In]oxine (In-ox) and reinjected. Starting at 1 hr, ten blood samples were obtained over an 8-day period. The in vivo platelet recovery was higher at 1 hr and throughout the 8 days of study with In-tr and the gamma camera images showed less uptake in liver and spleen than with In-ox. When platelet life-span (PLS) was estimated using all ten samples, only linear regression showed that the platelet life-span was longer with In-tr (10.7 +/- 1.5) than with In-ox (9.5 +/- 0.8). When the PLS was estimated excluding the 1-hr sample point, the life-span of platelets was significantly longer with In-tr than with In-ox based on three out of four models of curve fitting. These results demonstrate that platelets labeled with In-tr in plasma are preserved better in circulation and have equal or longer life-span than platelets labeled with In-ox in ACD-saline.
Adult↗