Platelet tests and antiplatelet drugs in coronary artery disease

This study was designed to clarify discrepancies in the literature concerning platelet survival time and beta-thromboglobulin (beta TG) levels in patients with coronary artery disease (CAD) and the effect of platelet-suppressant drugs on these tests. Platelet survival time and plasma beta TG levels were determined in 48 patients with angiographically documented CAD. The effect of sulfinpyrazone or aspirin/dipyridamole on these measurements was investigated in a double-blind, crossover trial that included a placebo phase. In patients with CAD, the mean plasma beta TG concentration was significantly elevated, but the mean platelet survival time was not significantly different from that in controls. Treatment with sulfinpyrazone or aspirin/dipyridamole did not produce changes in platelet survival time or plasma beta TG concentration that were significantly different from the values during the placebo phase. This study demonstrates that compared with the spontaneous variation in platelet survival time or beta TG concentration, there was no measureable effect of sulfinpyrazone or aspirin/dipyridamole on the results of the tests.     

Antithrombotic therapy for deep arterial injury by angioplasty. Efficacy of common platelet inhibition compared with thrombin inhibition in pigs.

BACKGROUND. Platelet-thrombus formation is a complication of arterial wall deep injury by balloon angioplasty that may lead to acute arterial occlusion and may contribute to restenosis. METHODS AND RESULTS. Because common platelet-inhibitor drugs with a heparin bolus (100 units/kg) may be effective in inhibiting platelet-thrombus formation after arterial angioplasty, these were compared with a bolus of heparin alone (control), the specific thrombin inhibitor hirudin (1.0 mg/kg), and saline (hirudin control) in normal pigs after angioplasty of the common carotid arteries. In the presence of deep arterial wall injury (injury exposing the media), indium-111-labeled platelet deposition (x 10(6)/cm2) was 68.8 +/- 12.3 and 48.1 +/- 16.9 in the control animals. This was significantly reduced by pretreatment with low-dose aspirin (1 mg/kg/day), by high-dose aspirin (20 mg/kg/day) plus dipyridamole, and especially by thrombin inhibition with hirudin. Treatment regimens with aspirin alone (20 mg/kg/day), dipyridamole alone, or sulfinpyrazone were ineffective. Likewise, the incidence of mural thrombosis was 75% and 80% in deeply injured arteries of controls and was significantly reduced to 46% with aspirin plus dipyridamole, 25% with low-dose aspirin, and 0% with hirudin. The incidence of mural thrombosis was unchanged with high-dose aspirin (69%), dipyridamole (90%), or sulfinpyrazone (92%). This mural thrombosis could not be identified by angiography. In the presence of mild injury (deendothelialization), platelet deposition was low (less than 10 x 10(6)/cm2, a single layer) and was not changed by any therapy, including hirudin. CONCLUSIONS. These therapies do not affect platelet adhesion to deeply or mildly injured artery. These data suggest a greater role for thrombin inhibition than with thromboxane or cyclooxygenase inhibition in the pathogenesis of platelet-rich mural thrombosis after deep injury during angioplasty. Antithrombotic therapy for arterial thrombosis by thrombin inhibition appears promising.     

Role of platelet inhibitor therapy in myocardial infarction

Summary Atherosclerotic plaque disruption is the predominant pathogenetic mechanism underlying the acute coronary syndromes. Plaque rupture leads to the exposure of collagen and vessel media, resulting in platelet and clotting activation, and occlusive thrombus formation. While drugs that interfere with platelet activation and function have been available for years, more powerful agents with novel mechanisms of action are being developed. Of the available platelet inhibitor drugs, only aspirin, sulfinpyrazone, and dipyridamole have undergone extensive clinical testing in patients with cardiovascular disease. More recently ticlopidine, a new and potent platelet inhibitor, has been successfully tested in patients with coronary and vascular disease.In acute myocardial infaction, aspirin significantly reduces cardiovascular mortality and reinfarction. Furthermore, the combination of aspirin and a thrombolytic agent produces maximal benefit. A role for heparin in the prevention of early mortality and reinfaction is emerging. This drug is effective for the prevention of left ventricular thrombosis in patients with anterior myocardial infarction.In the secondary prevention of reinfarction and cardiovascular mortality, available data support the use of a platelet inhibitor. Trials have shown that aspirin is as effective alone as in combination with dipyridamole, and is probably more effective than sulfinpyrazone. Long-term anticoagulant therapy also appears to be beneficial, but is associated with a high cost, need for extensive monitoring, and potential for hemorrhagic side effects.The role of aspirin in primary prevention is controversial. It may be indicated for patients at high risk for coronary disease in whom the benefit of therapy may outweigh the potential risk of cerebral bleeding.Coronary atherosclerotic plaque rupture, associated with thrombus formation, is fundamental to the development of acute myocardial infarction. Based on this concept, the role of antithrombotic therapy for the prevention or treatment of ischemic events in patients with coronary artery disease has stimulated enormous interest among clinicians and basic investigators. In this review we will examine: a) the pathogenesis of coronary thrombosis, b) the pharmacology of plateletinhibitor agents, and c) their role in the management of patients with acute myocardial infarction and in primary and secondary prevention of cardiovascular disease.Platelets interact with both the coagulation and fibrinolytic systems in the pathogenesis of thrombosis. While the purpose of this review is to discuss the role of platelets and platelet inhibitors in coronary disease, the use of anticoagulant or thrombolytic agents will be analyzed briefly when pertinent.     

Indium-111 platelet imaging for detection of platelet deposition in abdominal aneurysms and prosthetic arterial grafts

Thirty-four platelet imaging studies were performed in 23 patients to determine whether platelet deposition could be detected in patients with vascular aneurysms (18 patients) or in patients in whom Dacron prosthetic grafts had been placed (5 patients). In patients in whom abnormal platelet deposition was detected, the effect of administration of platelet-active drugs on platelet deposition was examined.Of the 18 patients with an aneurysm, 12 had positive studies on initial imaging and 2 had equivocally positive images. Of five patients with Dacron arterial grafts in place, four had diffuse platelet deposition in the grafts; the fifth patient had platelet deposition only in a pseudoaneurysm. Eight patients with an abdominal aneurysm and positive or equivocally positive baseline images were restudied during platelet-active drug therapy either with aspirin plus dipyridamole (seven patients) or with sulfinpyrazone (four patients). No patient studied during treatment with aspirin plus dipyridamole had detectably decreased platelet deposition compared with baseline determinations. In contrast, two of four patients studied while receiving sulfinpyrazone showed decreased platelet deposition. Thus, platelet imaging may be of value for studying platelet physiology in vivo and for assessing platelet-active drugs and the thrombogeniclty of prosthetic graft materials in human beings.     

Human equivalent doses of platelet inhibitors and experimental atherosclerosis

The effects of aspirin, dipyridamole and sulfinpyrazone on the development of atherosclerotic lesions in the aorta were studied in cholesterol-fed rabbits. Aspirin and sulfinpyrazone prevented the development of atherosclerosis, whereas dipyridamole-treated animals developed advanced atherosclerotic lesions. As all the three drugs inhibit platelet function, some non-platelet effects are probably responsible for the differences in results. It is felt that dipyridamole should be avoided in hypercholesterolemic individuals.     

Effects of platelet inhibitors on the platelet aggregation induced by plasma from patients with thrombotic thrombocytopenic purpura

Antiplatelet drugs have been used in the treatment of thrombotic thrombocytopenic purpura (TTP) but there in vivo efficacy remains controversial. It has been shown that, in vitro, the plasmas obtained from patients with TTP induced the aggregation of washed platelets from normal donors as well as patients in remission. The effects of platelet inhibitors on the TTP plasma-induced platelet aggregation were examined. It was found that aspirin, indomethacin, ibuprofen, sulfinpyrazone, 5, 8, 11, 14-eisacotetraynoic acid, prostaglandin E1, prostaglandin I2, dBcAMP, apyrase, creatine phosphate/creatine phosphokinase, antimycin, 2-deoxy-D-glucose, dipyridamole, clofibrate, dextran 40, dextran 70, dibucaine, xylocaine, methylmaleimide, and ethylenediamine tetraacetic acid had little or no effect at all. These data lead us to conclude that at least in certain cases, antiplatelet drugs probably play a limited role in the treatment of patients with TTP.     

The effects of antithrombotic drugs in patients with left ventricular thrombi: assessment with indium-111 platelet imaging and two-dimensional echocardiography

Patients with left ventricular thrombi not caused by recent myocardial infarction were prospectively studied by indium-111 platelet imaging and two-dimensional echocardiography to determine the reproducibility of these techniques and the short-term effects of sulfinpyrazone (200 mg four times daily), aspirin (325 mg three times daily) plus dipyridamole (75 mg three times daily), and full-dose warfarin. At baseline, all patients underwent indium-111 platelet imaging and echocardiography, and the results were positive for thrombus. In six patients on no antithrombotic drug therapy, repeat platelet scans and echocardiographic studies at 6.0 +/- 3.3 weeks remained positive and were unchanged. In seven patients studied on sulfinpyrazone, three platelet scans became negative, two became equivocal, and two were unchanged; the presence and size of thrombus was constant by echocardiography in all seven patients. Of the six patients studied on aspirin plus dipyridamole, one platelet scan became negative, those of three became equivocal, and two were unchanged; all echocardiographic findings remained positive, but one patient had decreased thrombus size. Among four warfarin-treated patients, three had resolution of platelet deposition and one was unchanged; by echocardiography, thrombus resolved in one patient, was decreased in size in one, and was unchanged in two. We conclude that, in the absence of antithrombotic drug therapy, platelet imaging and echocardiographic findings are stable in patients with left ventricular thrombi not caused by recent myocardial infarction. Sulfinpyrazone, aspirin plus dipyridamole, and warfarin all interrupt platelet deposition in some patients with chronic left ventricular thrombi.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protection against epinephrine-induced myocardial necrosis by drugs that inhibit platelet aggregation

To investigate the possibility that the myocardial necrosis seen after epinephrine infusion is related to the platelet aggregating effects of epinephrine, 10 dogs pretreated with aspirin, 10 dogs pretreated with dipyridamole and 10 dogs not pretreated were infused with epinephrine, 4 μg/kg per min; their hearts were studied histologically after sacrifice 1 week later. All of the control animals had necrosis, 6 with 3+, 2 with 2+, and 2 with 1+ necrosis. Seven of the 10 dogs pretreated with aspirin and 7 of the 10 pretreated with dipyridamole had no evidence of myocardial necrosis. Three dogs pretreated with aspirin had 1+ necrosis; 3 pretreated with dipyridamole had 2+, 1+ and trace degrees of necrosis, respectively. This demonstration of a protective effect of antiplatelet aggregating agents suggests that intravascular platelet aggregation plays a role in catecholamine-induced myocardial necrosis. Clinical acute myocardial infarction seen after prolonged stress (during which catecholamine secretion is increased) may be related to similar intravascular platelet thrombosis induced by catecholamines occluding a coronary artery previously narrowed by atherosclerosis.     

Platelet inhibition in the management of thrombosis

The role of platelets in the initation of arterial thrombosis is clear. In venous thrombosis as well, platelets may in some circumstances play a significant role. For these reasons, and because of the complications and limitations of anticoagulant therapy, antithrombotic trials have been launched with several agents which inhibit platelet function. Regarding postoperative deep vein thrombosis, neither aspirin nor dipyridamole alone appears effective, although the combination offers promise. Results with dextrans are conflicting. In recurrent idiopathic deep vein thrombosis, sulfinpyrazone may be beneficial. On the arterial side, transient cerebral ischemic attacks may be favorably affected by either aspirin or sulfinpyrazone. Prevention of thromboembolism associated with prosthetic heart valves appears possible with combination warfarin-dipyridamole therapy, and the beneficial effect of sulfinpyrazone on shortened platelet survival in this group suggests that this agent may also be effective. Sulfinpyrazone may also be beneficial in preventing thrombosis in arteriovenous canulas. The issue which has attracted the greatest attention and about which no clear answer exists at present is whether antiplatelet agents can modify the course of acute myocardial infarction. Several trials with aspirin are currently underway, and it would be premature to recommend its use in this condition until the results of these trials are available, probably in 1975.     

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.     

Effect of dipyridamole alone and in combination with aspirin on whole blood platelet aggregation, PGI2 generation, and red cell deformability ex vivo in man

STUDY OBJECTIVE--The aim was to investigate the effects of dipyridamole, aspirin, and a combination of dipyridamole plus aspirin on platelet aggregation in whole blood, PGI2 generation, and red cell deformability ex vivo. SUBJECTS--were 16 male volunteers, aged 22-39 years, mean age, 26.6 years. DESIGN--This was a randomised, double blind, placebo controlled trial. The volunteer received each of the following treatments 10 days apart: dipyridamole 200 mg; aspirin 300 mg; dipyridamole 200 mg plus aspirin 300 mg; matched placebos. MEASUREMENTS AND MAIN RESULTS--Blood was taken for platelet function tests, PGI2 metabolite assay, and red cell deformability before and 2 h after the trial dose was taken. Platelet aggregation was quantified by measuring the fall in single platelet count after stimulation with 2 micrograms.ml-1 collagen or 50 nM platelet activating factor (PAF), or by rollermixing aliquots of blood to initiate spontaneous aggregation. The platelet function tests were completed at 37 degrees C within 10 min of venepuncture. The stable metabolite of PGI2, 6-keto PGF1 alpha, was measured in serum. There was inhibition of spontaneous platelet aggregation by dipyridamole (p less than 0.004), aspirin (p less than 0.005), and the combination of dipyridamole plus aspirin (p less than 0.0001) as compared with placebo. PAF induced platelet aggregation was inhibited by dipyridamole (p less than 0.002) and the combination of dipyridamole plus aspirin (p less than 0.0001) but aspirin alone had no inhibitory effect. Collagen induced platelet aggregation was inhibited by all three treatments: dipyridamole (p less than 0.06), aspirin (p less than 0.0001), and the combination of dipyridamole plus aspirin (p less than 0.0001). PGI2 generation was markedly inhibited by aspirin (p less than 0.0001) and the combination doses (p less than 0.0001) but was unaffected by dipyridamole alone. Of the three active treatments, only dipyridamole alone significantly (p less than 0.001) increased red cell deformability; there was a modest decrease in red cell deformability with aspirin. CONCLUSIONS--The results with PAF support the view that dipyridamole inhibits platelet activation by more than one mechanism; the effect on collagen induced and spontaneous platelet aggregation suggests that the effect of the combination doses is additive and that on red cell deformability the synergy is negative.     

The Effect of Pyrimidine Compounds on the Potentiation of Adenosine Inhibition of Aggregation, on Adenosine Phosphorylation and Phosphodiesterase Activity of Blood Platelets

S ummary . Three pyrimidine compounds (dipyridamole, RA233 and VK 744) produced variable degrees of direct inhibition as well as potentiation of adenosineinduced inhibition of ADP aggregation of blood platelets. RA233 and VK744 were more potent direct inhibitors of platelet aggregation, whereas RA233 was a more powerful potentiator of adenosine–induced inhibition. A relation between the effect of these compounds on platelet aggregation and on adenosine phosphorylation and phosphodiesterase activity of platelets was looked for in an attempt to elucidate possible modes of action.
RA233 and dipyridamole were powerful inhibitors of [¹⁴C]adenosine phosphorylation by platelets and VK744 had no effect. There was no correlation with inhibition of platelet aggregation. Adenosine-induced inhibition of platelet aggregation in the presence of dipyridamole could be maintained for at least 10 min after the rapid clearance of the adenosine with exogenous deaminase. The presence of the pyrimidine so modified the inhibition response that there was no correlation between the concentration of adenosine in the system and the degree or rate of recovery from the inhibition.
Dipyridamole, VK744 and RA233 produced 45%, 45% and 55% inhibition of phosphodiesterase activity as measured by the rate of breakdown of [³H]cyclic AMP to AMP in platelet lysates. There was possible correlation between the effect of the three pyrimidine compounds on platelet phosphodiesterase activity and their potentiatory action on adenosine-induced inhibition of platelet aggregation. These findings suggested that adenosine might induce inhibition of platelet aggregation through the adenyl cyclase, cyclic AMP, phosphodiesterase system.     

Relationship of plasma anti-heparin activity and platelet survival time in coronary disease

Platelet-endothelial interaction probably plays a role in the development of atherosclerotic vascular disease and its complications. Platelet survival time has been found to be shortened and plasma anti-heparin activity has been shown to be increased in patients with coronary atherosclerosis. Platelet survival (autologous labelling with ⁵¹Chromium) and plasma anti-heparin activity (heparin-thrombin clotting time of platelet poor plasma) were measured in 75 men with coronary artery disease. Platelet survival was shortened (< 3.3 days) in 60 men (80%) and averaged 2.6 ± 0.06 days (AVE $\text{t}\text{1}\text{2}\text{± SEM}$; normal $\text{t}\text{1}\text{2}$ 3.7 ± 0.03 days; N = 28; P < 0.001). Anti-heparin activity was abnormal (< 0.96) in 26 men (35%) and averaged 1.04 ± 0.02 (ratio patient to blank; seconds/seconds; normal ratio 1.10 ± 0.01; N = 25; P < 0.01). Platelet survival time correlated with anti-heparin activity (r = 0.68). Sulfinpyrazone (800 mg. daily) and indomethacin (100 mg. per day) increased platelet survival and decreased heparin neutralizing activity. Dipyridamole (100 mg. orally per day) in combination with aspirin (1,200 mg. per day) increased platelet survival and decreased anti-heparin activity, but aspirin alone had a comparatively weak effect on these tests. Results suggest that plasma heparin neutralizing activity correlates with platelet survival time in men with coronary artery disease. Sulfinpyrazone, indomethacin, and dipyridamole in combination with aspirin alter platelet survival and heparin neutralizing activity, but aspirin alone has a comparatively weaker effect.     

Reduction of thrombosis in canine coronary bypass vein grafts with dipyridamole and aspirin

The potential benefit of platelet inhibitor drugs in reducing early thrombosis of coronary arterial vein bypass grafts was assessed in dogs. There were 26 control dogs and 24 dogs treated with dipyridamole, 55 mg/day plus aspirin, 325 mg/day. The dogs in both groups were killed at 2 hours and 1, 2, 3, 7 and 14 days after operation. The grafts were perfused with flxative in vivo, harvested and examined with light microscopy. Severe alterations of the graft wall were observed in the dogs in both groups. The grafts in the control group had a high incidence rate of thrombosis, which occurred early after the operation; those in the treated group had a significantly reduced incidence of thrombosis (p = 0.025). Our study indicates that a combined regimen of dipyridamole and aspirin is effective in reducing early graft thrombosis in dogs.     

Reduction of intimal thickening in canine coronary bypass vein grafts with dipyridamole and aspirin

The potential benefit of platelet inhibitor drugs on coronary arterial bypass vein grafts was assessed in dogs with magnification-corrected angiographic luminal measurements and quantitative histologic evaluation of the vein grafts. There were 11 control animals and 11 animals treated with dipyridamole, 55 mg/day, plus aspirin, 325 mg/day. Eighteen animals with patent grafts were studied when electively killed 2, 4 or 6 months after grafting. At 14 days, there was greater angiographic narrowing in the most distal 1 cm of vein grafts in control than in treated dogs (P < 0.01). This same angiographic narrowing persisted in control dogs until they were killed (P < 0.03). Computer-assisted measurements of the entire area of intimal thickening were done on vein graft cross sections taken 1 cm from the distal anastomosis. The circumference of the vein grafts at the intimal-media junction was measured from the same section and the potential maximal luminal area calculated. The calculated luminal narrowing due to intimal thickening was greater in control than in treated dogs (P < 0.03). These data correlate well with the demonstrated angiographic narrowing. The findings indicate that the degree of early intimal thickening that persists 2 to 6 months postoperatively in canine coronary bypass vein grafts may be reduced by the platelet inhibitor combination of dipyridamole plus aspirin.     

Effects of dipyridamole and low-dose aspirin therapy on platelet adhesion to vascular subendothelium

The effect on platelet function of low-dose aspirin (ASA) and dipyridamole alone or in combination was evaluated after repeated dosing in 5 healthy volunteers. The subjects were treated according to a randomized, single-blind, crossover design with 150 mg of dipyridamole, 25 mg of ASA, the 2 drugs together or placebo twice a day for 3 days. Platelet adhesion was evaluated using an experimental model of adhesion to rat aorta subendothelium under controlled hemodynamic conditions in the presence of red blood cells. Dipyridamole significantly reduced platelet adhesion both alone and in combination with ASA. ASA by itself did not significantly modify platelet adhesion, but completely blocked serum thromboxane production and platelet aggregation by arachidonic acid. Thus, low-dose ASA and dipyridamole may have a complementary action, modifying at the same time 2 platelet functions, adhesion and aggregation, both relevant in the pathogenesis of thrombosis.     

Cessation of platelet-mediated cyclic canine coronary occlusion after thrombolysis by combining nitric oxide inhalation with phosphodiesterase-5 inhibition

OBJECTIVES: We sought to evaluate the ability of type 5 phosphodiesterase (PDE5) inhibitors to augment the antithrombotic effects of inhaled nitric oxide (NO) in a canine model of platelet-mediated coronary thrombosis after thrombolysis. BACKGROUND: Type 5 phosphodiesterase inhibitors potentiate the ability of NO to inhibit platelet aggregation in vitro by preventing platelet cyclic guanosine monophosphate catabolism. We previously reported that breathing low concentrations of NO gas attenuated, but did not prevent, cyclic flow reductions (CFRs) in a canine model of coronary thrombosis after thrombolysis. METHODS: Cyclic flow reductions were induced after creation of a left anterior descending coronary artery stenosis, endothelial injury, thrombus formation and thrombolysis. Dogs were either untreated or treated with inhaled NO (20 ppm by volume), intravenous zaprinast, intravenous dipyridamole or the combination of inhaled NO with either PDE5 inhibitor (n = 4 per group). RESULTS: Cyclic flow reductions ceased, and complete coronary patency was achieved in all dogs after they breathed NO combined with zaprinast (by 12.0+/-4.7 min [mean +/- SEM]) or dipyridamole (by 9.8+/-4.7 min). The frequency of CFRs was unaffected by NO, dipyridamole or zaprinast alone. Systemic arterial blood pressure and bleeding time were unchanged with any treatment. Ex vivo thrombin-induced platelet aggregation in dogs breathing NO and receiving dipyridamole was reduced by 75+/-7% (p < 0.05). CONCLUSIONS: The PDE5 inhibitors potentiated the antithrombotic properties of inhaled NO in a canine model of platelet-mediated coronary artery thrombosis after thrombolysis, without prolonging the bleeding time or causing systemic hypotension.     

Platelet suppressant therapy in patients with prosthetic cardiac valves. Relationship of clinical effectiveness to alteration of platelet survival time.

Platelet survival time (SURV) has correlated with thromboembolism in patients with prosthetic cardiac valves. Sulfinpyrazone increases SURV. SURV (autologous labeling with 51Chromium) was measured in 126 patients who had aortic or mitral valve replacement. These patients were followed prospectively. Ninety-four with shortened SURV received sulfinpyrazone; 32 with normal SURV were not treated with platelet suppressants. Eighty-seven patients were anticoagulated with warfarin--67 with shortened SURV and 20 with normal SURV. Eleven patients have had thromboembolism, and all had shortened SURV (2.4 +/- 0.08 days; average half-time +/- SEM; normal 3.7 +/- 0.03 days; n = 26) none had an increase of SURV with sulfinpyrazone (2.3 +/- 0.09 days). Of 83 patients with shortened SURV who did not have embolism, sulfinpyrazone increased SURV in 59 (71%) 2.6 +/- 0.05 to 2.9 +/- 0.06 days). Of 35 patients with shortened SURV who failed to increase SURV with sulfinpyrazone, 11 (31%) had embolism; none of 59 (0%) with an increase of SURV with sulfinpyrazone had thromboembolism. These results suggest that patients with thromboembolism after prosthetic cardiac valve replacement have shortened SURV and that patients treated with slufinpyrazone who have thromboembolism do not have an increased SURV.     

Inhibitors of "spontaneous" platelet aggregation in whole blood

In vitro 'spontaneous' platelet aggregation has been studied in whole blood. The spectrum of activity of materials known to influence platelet aggregation in platelet-rich plasma proved different in whole blood. Thus dipyridamole and one of its analogues SH1242 had a striking effect in whole blood whilst aspirin, chlorpromazine and K3920 had little or no effect. The combination of aspirin and dipyridamole as currently employed in clinical practice had no greater inhibitory effect than dipyridamole alone. The possible clinical relevance of these findings is discussed.     

Aspirin or dipyridamole individually prevent lipid accumulation in primate vein bypass grafts

Although platelet inhibition with both aspirin and dipyridamole is widely prescribed for patients with coronary artery bypass grafts, data are lacking to prove that combined drug therapy has greater efficacy in preserving graft integrity than either drug given independently. Thus, the ability of combined vs single drug therapy to reduce cholesterol and apolipoprotein-B accumulation were compared in autologous cephalic veins grafted into femoral arteries of 23 stump-tailed macaque monkeys. Ten monkeys were studied in 2 phases. They were treated with aspirin (80 mg/day) during 1 phase and with dipyridamole (50 mg/day) during the other phase. Five monkeys received aspirin plus dipyridamole in combination and 8 received no medication and served as controls. When grafts were removed 3 months after insertion cholesterol and apolipoprotein-B concentrations in grafts were similar for groups treated with aspirin, with dipyridamole, and with the drugs combined, and in each of the treated groups these concentrations were significantly reduced compared with grafts from untreated control monkeys. Cholesterol and apolipoprotein-B concentrations in grafts from the treated groups were similar to concentrations in normal ungrafted veins, whereas cholesterol and apolipoprotein-B levels in grafts from control monkeys were significantly greater than those in ungrafted veins (250% and 925% of normal, respectively). Our findings reaffirm the ameliorative effect of anti-platelet drugs in reducing the accumulation of lipid in vein bypass grafts and indicate that the efficacy of aspirin or dipyridamole given individually equals that of the combination of these drugs in this subhuman primate model. The relation of the lipid-lowering effect of these agents to their antithrombotic effect is uncertain.