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Arterial Disease: Nutritional Rescue

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Acetylsalicylic acid (ASA or Aspirin) is the wonder drug of the century. Taken in a small dose daily, ASA can prevent heart attacks and strokes. The use of platelet inhibitory drugs, such as aspirin, has resulted in a significant reduction of thrombotic complications in primary and secondary prevention of heart attacks.

Course Work Abstracts

Inflammation, Aspirin, and the Risk of Cardiovascular Disease in Apparently Healthy Men

NEJM April 3, 1997 -- Volume 336, Number 14

Paul M. Ridker, Mary Cushman, Meir J. Stampfer, Russell P. Tracy, Charles H. Hennekens

Abstract

Background. Inflammation may be important in the pathogenesis of atherothrombosis. We studied whether inflammation increases the risk of a first thrombotic event and whether treatment with aspirin decreases the risk.

Methods. We measured plasma C-reactive protein, a marker for systemic inflammation, in 543 apparently healthy men participating in the Physicians' Health Study in whom myocardial infarction, stroke, or venous thrombosis subsequently developed, and in 543 study participants who did not report vascular disease during a follow-up period exceeding eight years. Subjects were randomly assigned to receive aspirin or placebo at the beginning of the trial.

Results. Base-line plasma C-reactive protein concentrations were higher among men who went on to have myocardial infarction (1.51 vs. 1.13 mg per liter, P<0.001) or ischemic stroke (1.38 vs. 1.13 mg per liter, P = 0.02), but not venous thrombosis (1.26 vs. 1.13 mg per liter, P = 0.34), than among men without vascular events. The men in the quartile with the highest C-reactive protein values had three times the risk of myocardial infarction (relative risk, 2.9; P<0.001) and two times the risk of ischemic stroke (relative risk, 1.9; P = 0.02) of the men in the lowest quartile. Risks were stable over long periods, were not modified by smoking, and were independent of other lipid-related and non-lipid-related risk factors. The use of aspirin was associated with significant reductions in the risk of myocardial infarction (55.7 percent reduction, P = 0.02) among men in the highest quartile but with only small, nonsignificant reductions among those in the lowest quartile (13.9 percent, P = 0.77).

Conclusions. The base-line plasma concentration of C-reactive protein predicts the risk of future myocardial infarction and stroke. Moreover, the reduction associated with the use of aspirin in the risk of a first myocardial infarction appears to be directly related to the level of C-reactive protein, raising the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease. (N Engl J Med 1997;336:973-9.)

What effect does controlling platelets have on atherosclerosis?

Author

Numano F; Kishi Y; Ashikaga T; Hata A; Makita T; Watanabe R

Address

Department of Internal Medicine, Tokyo Medical and Dental University, Japan.

Source

Ann N Y Acad Sci, 748:1995 Jan 17, 383-92; discussion 392-3

Abstract

Platelets play important roles for hemostasis with activated platelets adhering to the injured vessel wall to initiate platelet aggregation. At the same time, our study revealed the cytotoxic effect on endothelial cells characterized by an increase of intracellular Ca++ and a decrease of EDRF production, which may cause plasmal infiltration including blood cells and lipids. Our clinical survey using a small dose of aspirin as an antiplatelet therapy clearly demonstrated its suppressive effect on platelet aggregation and its favorable effect on fibrinolysis. These data suggest that the therapeutic effect of aspirin in vascular disease could be applied to the prevention of thrombus formation and the protection of endothelial cells from the cytotoxic effect of activated platelets.

 

Pharmacokinetic optimisation of the treatment of embolic disorders.

Author

Lutomski DM; Bottorff M; Sangha K

Address

Department of Pharmacy Services, University of Cincinnati Medical Center, Ohio, USA.

Source

Clin Pharmacokinet, 28: 1, 1995 Jan, 67-92

Abstract

Management of thromboembolic disease involves administration of anticoagulants, thrombolytics or antiplatelet agents to lyse or prevent thrombus extension. Despite widespread use and decades of experience with some of these agents, much is unknown about the effects of dose and plasma concentration on patient response.

 

Unfractionated heparin (UFH) improves outcome in many thromboembolic disorders when administered to a target activated partial thromboplastin time (aPTT) or plasma heparin concentration. UFH exhibits dose-dependency both with absorption from subcutaneous sites and elimination. Doses based on bodyweight or estimated blood volume attain therapeutic aPTTs faster than fixed or standard doses. Low molecular weight heparins (LMWHs) were developed to increase the anti-factor Xa:anti-factor IIa activities. Several different LMWHs are as effective as UFH in treating deep venous thrombosis. Evidence fails to support a relationship between anti-factor Xa activity and either thrombosis evolution or bleeding. No comparisons have been made between bodyweight-based and anti-factor Xa activity-based doses.

 

The dose of orally administered warfarin is adjusted to achieve a target International Normalised Ratio (INR). Maintenance doses are estimated on the basis of the patient's INR during the first 3 days of therapy: the dose required to achieve an optimal INR decreases with age > 50 years.

 

The thrombolytic agents are administered in standard doses to achieve rapid thrombolysis with minimal alteration in systemic haemostasis. Accelerated intravenous alteplase may result in the highest rate of coronary artery reperfusion. Nevertheless, standard doses of streptokinase, anisoylated plasminogen streptokinase complex and alteplase result in similar 1-month mortality rates. The minimal advantage seen with alteplase is offset by higher rates of stroke. Future trials will focus on administration strategies achieving rapid thrombolysis, while minimising the risk of serious bleeding. With the antiplatelet agents, unpredictability in the pharmacokinetic parameters of different products has confounded interpretation of published reports.

 

Optimal aspirin (acetylsalicylic acid) administration would include administration of an initial dose of 160 to 325mg after an acute vascular event, followed by maintenance dosages of approximately 75 mg/day for prophylaxis or treatment.

 

Ticlopidine does not exhibit a relationship between either plasma concentration or dose and adverse effects, while pharmacodynamic effects may be dose-, but not plasma concentration-, dependent. The correlation between the concentration of dipyridamole and some of its antiplatelet effects may be the strongest amongst all the antiplatelet agents. However, unfortunately all clinical trials used standard doses and the current consensus is that dipyridamole alone is not an effective antiplatelet agent.

Effects of thromboxane A2 synthase inhibitors (CV-4151 and ozagrel), aspirin, and ticlopidine on the thrombosis caused by endothelial cell injury.

Author

Terashita Z; Imura Y; Kawamura M; Kato K; Nishikawa K

Address

Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.

Source

Thromb Res, 77: 5, 1995 Mar 1, 411-21

Abstract

The antiplatelet and antithrombotic effects of CV-4151 (isbogrel), a potent selective thromboxane A2 (TXA2) synthase inhibitor, were compared with those of ozagrel (OKY-046), aspirin, and ticlopidine in rats.

 

Two hours after oral administration, CV-4151, ozagrel and aspirin inhibited blood TXA2 generation with ID50 values of 0.04, 0.3 and 6.4 mg/kg, respectively. These values were similar to the oral ID50 values of CV-4151 (0.06 mg/kg), ozagrel (0.92 mg/kg) and aspirin (7.0 mg/kg) for arachidonic acid (AA)-induced platelet aggregation ex vivo.

 

Two hours after p.o. administration, CV-4151 and ozagrel inhibited femoral vein platelet-rich thrombosis caused by endothelial injury with ID50 values of 2.46 and 13.7 mg/kg, respectively. However, aspirin (100 mg/kg, p.o.) only slightly inhibited the thrombosis. Ticlopidine (300 mg/kg, p.o.) slightly but significantly inhibited AA-induced and ADP-induced platelet aggregation, however, it potently inhibited the thrombosis. CV-4151 and ozagrel given by i.v. injection showed therapeutic effects on the thrombosis with ED50 values of 0.026 and 0.066 mg/kg, respectively. These values were similar to the i.v. ED50 values of CV-4151 (0.0056 mg/kg) and ozagrel (0.042 mg/kg) for blood TXA2 generation. However, aspirin (30 mg/kg, i.v.) only moderately reduced the thrombosis. CV-4151 (> 0.3 mg/kg, p.o.), ozagrel (> 3 mg/kg, p.o.) and ticlopidine (300 mg/kg, p.o.) all significantly prolonged tail bleeding time. Aspirin (100 mg/kg, p.o.) tended to prolong the bleeding time. The antiplatelet and antithrombotic effects of CV-4151 are more potent than those of ozagrel, aspirin and ticlopidine in rats. CV-4151 may therefore be a useful drug for the treatment of thrombotic diseases.

 

Acute myocardial infarction. Then and now.

Author

Simmons J; Willens HJ; Kessler KM

Address

Department of Medicine, University of Miami School of Medicine, Fla., USA.

Source

Chest, 107: 6, 1995 Jun, 1732-43

Abstract

Dramatic changes in the management of acute myocardial infarction (AMI) have occurred in the past decade. While previous management strategies were primarily supportive, current strategies focus on achieving and maintaining patency of the infarct-related artery restoring blood flow to jeopardized myocytes, preserving left ventricular function, and preventing recurrences and complications in addition to promoting healing. Restoration of blood flow can be achieved pharmacologically with thrombolytic agents or mechanically with percutaneous transluminal coronary angioplasty (PTCA).Early use of antiplatelet agents and anticoagulants helps maintain patency of the infarct-related arteries and prevents thromboembolic complications.Administration of beta-blockers and angiotensin enzyme inhibitors are more specific means of conserving myocardium and preserving ventricular function.  Additionally, several strategies for preventing arrhythmias such as prophylactic lidocaine use and routine long-term suppression of premature ventricular contractions with antiarrhythmic drugs are no longer routinely advocated. 

 

Basically, in the era prior to the eighth decade of this century, the primary direction of the therapeutic strategy for AMI was to reduce the oxygen demands in the infarcted myocardium; whereas in the subsequent years, the emphasis shifts to improvement in oxygen delivery, via thrombolysis, PTCA, and coronary artery bypass graft surgery. These interventional changes, when added to greater sophistication in the use of drugs to reduce oxygen demands, resulted in significant lowering of myocardial mortality.

 

Pharmacologic therapy of angina pectoris.

Author

Zavecz JH; Bueno

Address

Dept of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport 71130-3932, USA.

Source

J La State Med Soc, 147: 5, 1995 May, 208-10, 213-6

Abstract

The primary drugs utilized in the treatment of angina pectoris include organic nitrates, beta-adrenoceptor antagonists, Ca2+ antagonists, and the antithrombotic agents aspirin and heparin. Not all of these drugs are useful in every form of angina, and treatment is symptomatic rather than curative.

 

In stable effort angina, beta-blockers, Ca2+ antagonists, and organic nitrates provide relief from angina pain and improve exercise tolerance primarily through their ability to decrease oxygen demand.

 

The antiplatelet action of aspirin may decrease the incidence of myocardial infarction in these patients.

 

Ca2+ channel blockers and organic nitrates are the drugs of choice for variant angina. These vasodilators restore blood flow by relieving the coronary vasospasm that triggers the ischemic episode. In unstable angina, aspirin and heparin reduce the risk of myocardial infarction, and aspirin increases survival. Heparin and nitrates alleviate angina pain, and under some circumstances beta-blockers and Ca2+ antagonists have a role in the relief of pain.

 

The mechanism of action of aspirin--is there anything beyond cyclo-oxygenase?

Author

Ghooi RB; Thatte SM; Joshi PS

Address

Medical Division, Unichem Laboratories Limited, Bombay, India.

Source

Med Hypotheses, 44: 2, 1995 Feb, 77-80

Abstract

Aspirin, today, is an established drug in the regime for the prevention of myocardial infarction, especially in high-risk groups. This use of aspirin has given it a new lease of life in its tenth decade of clinical use. Aspirin is probably the oldest synthetic drug in the Pharmacopoeias today; thus one would have imagined that understanding about the drug would have reached a zenith and if not, that at least there should be certainty about its mechanism of action.

 

Most workers agree that aspirin inhibits the cyclo-oxygenase enzyme in the platelets leading to reduced formation of prostaglandin G2, the precursor of thromboxanes. This explanation does not appear to be complete, since the role of the platelet activating factor (PAF) seems to have been ignored. The precursor for PAF is the lysophospholipid that is almost always formed when membrane phospholipid breakdown takes place. Any effective antiplatelet drug would have to inhibit the formation and/or the action of PAF, if it were to prevent platelet aggregation. Alternatively, the pathophysiological role attributed to PAF is highly exaggerated and needs to be reassessed.

 

Epidemiological feasibility of cardiovascular primary prevention in general practice: a trial of vitamin E and aspirin. Collaborative group of the Primary Prevention Project.

• Author
• Anonymous
• Source
• J Cardiovasc Risk, 2: 2, 1995 Apr, 137-42
• Abstract
• BACKGROUND: Antioxidant and antiplatelet drugs might help prevent the progression of atherosclerosis or its thrombotic consequences as adjuncts to specific treatment of cardiovascular risk factors. METHODS: Primary health care may be the ideal setting for screening people at risk, for monitoring the evolution of risk factors and for minimizing their clinical consequences. We therefore estimated the fraction of the general population who would be suitable candidates for preventive strategies because of the presence of at least one known cardiovascular risk factor. We used an ad-hoc protocol in a random sample of people aged 50-75 years who consulted their general practitioner for any reason over a predefined 2-week period.
•  
• RESULTS: Complete information was available for 2522 participants (94.3% of 2674 patients screened by 91 general practitioners), 44.8% male and 55.2% female, with a mean +/- SD age of 62.2 +/- 6.7 years. Of these, 1977 (78.4%) had at least one of the recognized cardiovascular risk factors (arterial hypertension, hypercholesterolaemia, obesity, a family history of myocardial infarction, diabetes mellitus). Half of the study population had two or more risk factors, and one-third had a single one. On the assumption that vitamin E and aspirin are an attractive basis for a clinical trial of primary prevention strategies, we evaluated the fraction of the population at risk who would be suitable for recruitment. Exclusion criteria reduced this fraction to 50.2% (992 out of 1977) of eligible patients. General exclusion criteria were present in 501 (25.3%), indications for aspirin in 428 (21.6%) and contraindications to aspirin in 526 patients (26.6%). Because no contraindications to vitamin E are known, three-quarters of the exclusion criteria used applied to aspirin treatment only; this implies that a larger fraction of the population at risk would be suitable for testing the efficacy of vitamin E or other preventive strategies. CONCLUSION: The large proportion of candidates for cardiovascular prevention within the general population (992 out of 2522, 39.3%) and the reliability of the general practitioners' participation in the study supported the feasibility of clinical tests of preventive strategies in primary health care.

Antithrombotic and thrombolytic therapy in patients undergoing coronary artery interventions: a review.

Author Schwartz L; Seidelin PH

Address Toronto General Hospital, Ontario, Canada.

Source Prog Cardiovasc Dis, 38: 1, 1995 Jul-Aug, 67-86

Abstract  The controlled arterial injury that occurs with balloon angioplasty and other coronary interventions is characterized by evanescent endothelial denudation and vascular disruption. As a consequence, platelet activation occurs at the treated site, and there is a risk of thrombotic occlusion. This risk is heightened by several factors including unstable clinical presentation, lesion complexity, deep injury, and dissection.

Aspirin has been shown to unquestionably reduce, although not eliminate, acute complications and is now part of the routine periprocedural regimen. Heparinization with more intense anticoagulation than is conventionally used is also standard treatment and is initiated before vessel instrumentation. Adjunctive thrombolysis is rarely necessary unless refractory thrombus precedes or complicates the procedure. However, thrombolysis may have a role in the treatment of saphenous vein graft obstructive lesions in which guide wire- or catheter-induced distal thromboembolization may cause infarction in spite of successful graft recanalization. In contrast to their success in the periprocedural phase of coronary interventions, anticoagulants and a wide variety of platelet active agents have been ineffective in reducing the 30% to 40% incidence of restenosis. Only 7E3, which targets the final common pathway of platelet aggregation by irreversibly blocking the IIb/IIIa receptor, has been shown to decrease the 6-month clinical event rate after balloon angioplasty, possibly by a surface pacification mechanism. This suggests that newer more potent antiplatelet and anticoagulant agents may also find a role in the long-term management of these patients.

Novel antithrombotic drugs in development.

Author

Verstraete M; Zoldhelyi P

Address

Center for Molecular and Vascular Biology, University of Leuven, Belgium.

Source

Drugs, 49: 6, 1995 Jun, 856-84

Abstract

Platelet activation plays a critical role in thromboembolic disorders, and aspirin remains a keystone in preventive strategies. This remarkable efficacy is rather unexpected, as aspirin selectively inhibits platelet aggregation mediated through activation of the arachidonic-thromboxane pathway, but not platelet aggregation induced by adenosine diphosphate (ADP), collagen and low levels of thrombin. This apparent paradox has stimulated investigations on the effect of aspirin on eicosanoid-independent effects of aspirin on cellular signalling. It has also fostered the search for antiplatelet drugs inhibiting platelet aggregation at other levels than the acetylation of platelet cyclo-oxygenase, such as thromboxane synthase inhibitors and thromboxane receptor antagonists.

 

The final step of all platelet agonists is the functional expression of glycoprotein (GP) IIb/IIIa on the platelet surface, which ligates fibrinogen to link platelets together as part of the aggregation process. Agents that interact between GPIIb/IIIa and fibrinogen have been developed, which block GPIIb/IIIa, such as monoclonal antibodies to GPIIb/IIIa, and natural and synthetic peptides (disintegrins) containing the Arg-Gly-Asp (RGD) recognition sequence in fibrinogen and other adhesion macromolecules. Also, some non-peptide RGD mimetics have been developed which are orally active prodrugs. Stable analogues of prostacyclin, some of which are orally active, are also available. Thrombin has a pivotal role in both platelet activation and fibrin generation. In addition to natural and recombinant human antithrombin III, direct antithrombin III-independent thrombin inhibitors have been developed as recombinant hirudin, hirulog, argatroban, boroarginine derivatives and single stranded DNA oligonucleotides (aptanes). Direct thrombin inhibitors do not affect thrombin generation and may leave some 'escaping' thrombin molecules unaffected. Inhibition of factor Xa can prevent thrombin generation and disrupt the thrombin feedback loop that amplifies thrombin production.

 

Two-pronged antiplatelet therapy with aspirin and ticlopidine without systemic anticoagulation: an alternative therapeutic strategy after bailout stent implantation.

Author

Van Belle E; McFadden EP; Lablanche JM; Bauters C; Hamon M; Bertrand ME

Address

Division of Cardiology B, H?ital Cardiologique, Lille, France.

Source

Coron Artery Dis, 6: 4, 1995 Apr, 341-5

Abstract

BACKGROUND: Intracoronary stent implantation for failed angioplasty is associated with a relatively high incidence of coronary and peripheral complications. On the basis of previous clinical and experimental data, we investigated a protocol of intensive antiplatelet therapy, with aspirin (200 mg) and ticlopidine (500 mg), without oral anticoagulation, and with only periprocedural heparin, after stent implantation. METHODS: Between November 1993 and May 1994, 650 patients underwent balloon angioplasty in our institution. Stent implantation was attempted in 45 patients because of acute (58%) or threatened acute (22%) closure, or because the result of the primary angioplasty was inadequate (9%). RESULTS: Stents were successfully implanted in 42 (93%) patients. Two patients were not enrolled in the protocol (referring physician preference in one, metallic heart valve prosthesis in the other). In the remaining 40 patients, two sustained Q-wave infarctions and three sustained non Q-wave infarctions, which were already established at the time of stent implantation. No further clinical events occurred during hospitalization. During follow-up (mean 3.2 months) none of the patients died and none developed unstable angina or myocardial infarction. Ticlopidine-related rash occurred in two patients who were consequently put on warfarin therapy instead. CONCLUSIONS: Antiplatelet therapy with ticlopidine and aspirin, without systemic anticoagulation, appears to be a promising alternative to the classical approach with heparin and warfarin therapy, which requires intensive biological monitoring. This approach considerably simplifies patient management, and it could reduce the need for prolonged hospitalization.

 

The Thrombostat system. A useful method to test antiplatelet drugs and diets.

Author

Kratzer MA; Negrescu EV; Hirai A; Yeo YK; Franke P; Siess W

Address

Institut f? Prophylaxe and Epidemiologie der Kreislaufkrankheiten b.d. Universit? M?chen, Germany.

Source

Semin Thromb Hemost, 21 Suppl 2:1995, 25-31

Abstract

The use of platelet inhibitory drugs, like aspirin, has resulted in a significant reduction of thrombotic complications in primary and secondary prevention of heart attacks. To find more effective substances or better drug combinations, inhibition of primary hemostasis in vitro (Thrombostat system) was investigated, with different drugs and fish diet, using small samples (1 ml) of anticoagulated (Na- citrate 3.8%, 1/9) human blood. RESULTS: 1. In the presence of 1 mM aspirin, which had no effect on bleeding volume, only 0.6 nM iloprost were necessary to show a 50% inhibition, in contrast to 2.5 nM without aspirin. 2. At aspirin concentrations of 1 mM, 50% inhibition of primary hemostasis could be achieved with 20 microM SIN-1, or with 7 microM SIN-1 together with iloprost (500 pM). The same effect was seen only with very high doses of SIN-1 (1000 microM) alone. 3. For 50% inhibition of primary hemostasis in vitro, RGDS concentrations were reduced from 250 microM to 160 microM when blood was pretreated with 1 mM aspirin and to 75 microM when 500 pM iloprost were added additionally. 4. Japanese fishermen (eating 270 g fish/day) demonstrated significantly longer in-vivo bleeding times and in-vitro bleeding volumes (6.49 min/224 microliters), respectively, as compared to Japanese farmers (90 g fish/day, 4.85 min/137 microliters). 5. In Japanese subjects in-vivo bleeding times correlated with in-vitro bleeding volumes (0.69). The Thrombostat system proved to be a sensitive method to detect synergistic effects of various antiplatelet drugs in vitro and of a platelet inhibitory diet ex vivo.

 

Acute cerebral infarction. Optimal management in older patients.

Author

Langhorne P; Stott DJ

Address

Academic Section of Geriatric Medicine, Royal Infirmary, Glasgow, Scotland.

Source

Drugs Aging, 6: 6, 1995 Jun, 445-55

Abstract

The optimal management of acute cerebral infarction requires consideration of the diagnosis, aetiology, identification of problems, general and specific aspects of care, and prevention of further vascular events. Stroke is a clinical diagnosis but cranial computed tomography (CT) scanning is invaluable to exclude the possibility of cerebral haemorrhage or where the diagnosis is uncertain. Good general care under a specialist multidisciplinary team can reduce mortality and the need for institutional care. Despite promising results from experimental studies, no routine drug therapies have yet shown clinical benefit in acute stroke. Several large trials are currently evaluating anticoagulant, antiplatelet, thrombolytic and neuroprotective agents. Many other proposed therapies have been subject to limited evaluation. Aspirin has a proven role in the prevention of further vascular events after a stroke or transient ischaemic attack. Warfarin, and to a lesser extent aspirin, can prevent recurrent events in patients with nonrheumatic atrial fibrillation. Concerns remain about the safety of warfarin in routine geriatric medical practice. The risk of recurrent stroke in patients with a symptomatic severe carotid artery stenosis is greatly reduced by endarterectomy.

 

Contemporary management of atrial fibrillation.

Author

Ukani ZA; Ezekowitz MD

Address

Department of Medicine, Norwalk Hospital, Connecticut.

Source

Med Clin North Am, 79: 5, 1995 Sep, 1135-52

Abstract

The incidence of atrial fibrillation approximately doubled for every 10-year increment in age in the Framingham Heart Study cohort; thus physicians will be faced with an increasing patient population with atrial fibrillation. Hypertension is observed to be the most common associated risk factor in both sexes. The management of patients with atrial fibrillation is evolving as a result of a number of published studies. Calcium channel blockers and beta-blockers are emerging as the preferred choices for rate control rather than digoxin. Low-dose anticoagulation therapy has shown beneficial effects not only in primary prevention, but also for secondary prevention of thromboembolism. Thus, patients who cannot be successfully cardioverted should be anticoagulated if there are no contraindications (Table 3) and if they do not fall into the low-risk group--defined as patients under the age of 65 without risk factors (hypertension, diabetes, previous stroke). Patients not eligible for anticoagulation should be on aspirin therapy. Patients with lone atrial fibrillation are not at higher risk for thromboembolism than the general population; therefore, they can be managed without anticoagulation or antiplatelet therapy. Antiarrhythmic treatment should be approached cautiously; amiodarone in low doses is the most effective and safe treatment, but this remains controversial.

 

Antiplatelet drugs. A comparative review.

Author

Schr? K

Address

Institut f? Pharmakologie, Heinrich-Heine-Universit? D?seldorf, Germany.

Source

Drugs, 50: 1, 1995 Jul, 7-28

Abstract

Antiplatelet therapy has become a useful means of preventing acute thromboembolic artery occlusions in cardiovascular diseases. The rationale for this is an enhanced activity of circulating platelets and release of platelet-derived vasoactive mediators, probably due to endothelial dysfunction. This review discusses the current status of 4 major classes of antiplatelet compounds: (i) aspirin and related drugs active via cyclo-oxygenase product formation; (ii) thienopyridines (ticlopidine and clopidogrel); (iii) direct thrombin inhibitors (e.g. hirudin); and (iv) GPIIb/IIIa receptor antagonists [e.g. abciximab (c7E3 Fab)]. It is concluded that aspirin is the drug of choice for long term oral treatment, specifically for secondary prevention of myocardial infarction, and is also a suitable basic but not maximally efficient drug in percutaneous transluminal coronary angioplasty (PTCA) and platelet activation during clot lysis. Ticlopidine has a similar indication and may be superior to aspirin in prevention of ischaemic stroke and peripheral arterial occlusion. Direct thrombin inhibitors and glycoprotein GPIIb/IIIa receptor antagonists need further investigation in clinical trials. To date, these compounds have a higher bleeding risk and currently they are available only for short term parenteral application. They are superior to aspirin in acute platelet-dependent ischaemic syndromes, such as unstable angina, and in connection with therapeutic PTCA because of their high potency in preventing platelet-dependent reocclusion. Future developments include more selective thromboxane inhibitors, i.e. combined-mode agents; nonpeptide clot-specific thrombin inhibitors with longer lasting action and nonpeptide fibrinogen receptor antagonists.

 

Advances in antithrombotic drug therapy for coronary artery disease.

Author

Rihal CS; Flather M; Hirsh J; Yusuf S

Address

McMaster University, Hamilton, Ontario, Canada.

Source

Eur Heart J, 16 Suppl D:1995 Jul, 10-21

Abstract

Compounds which inhibit the coagulation cascade and antagonize platelet function are fundamental to the successful treatment of acute coronary syndromes. In a high proportion of patients with acute myocardial infarction, unstable angina, or sudden cardiac death, the acute ischaemic event is precipitated by intracoronary thrombus. Occlusive or non-occlusive thrombi have been found in the majority of cases, either in vivo or at autopsy. Aspirin and unfractionated heparin have been the cornerstones of antithrombotic therapy in such patients for the past decade, but while their benefits have been convincingly demonstrated, there are significant pharmacokinetic, pharmacodynamic, and clinical limitations. These limitations have provided the impetus for the development of newer antithrombotic agents with several theoretical advantages over aspirin and heparin. This paper has four aims. First it reviews the pathogenesis of intracoronary thrombi in acute coronary artery syndromes. Second, it outlines the limitations of current antithrombotic therapies. Third, it explores the potential advantages of new antithrombin and antiplatelet compounds, which may be understood and classified by their mechanism of action (Table 1); how the theoretical advantages may translate into clinical practice will be examined. Fourth, the initial clinical experience with these new agents will be reviewed briefly.

 

Current and future perspectives on antithrombotic therapy of acute myocardial infarction.

Author

Hennekens CH; O'Donnell CJ; Ridker PM

Address

Brigham and Women's Hospital, Department of Medicine, Boston 02215-1204, USA.

Source

Eur Heart J, 16 Suppl D:1995 Jul, 2-9

Abstract

Randomised trials of coronary artery patency and mortality support the routine use of antithrombotic therapy in all patients with suspected acute myocardial infarction. At present, it is unclear whether antiplatelet therapy with aspirin alone will suffice or the addition of anticoagulation with either heparin or the newer specific thrombin inhibitor, hirudin, will confer a net benefit. The ongoing randomised trials, such as GUSTO-2 and TIMI-9, will provide relevant information on the use of aspirin plus heparin or aspirin plus hirudin in patients treated with thrombolytic therapy. The First American Study of Infarct Survival (ASIS-1) will provide data which are relevant to the large population of patients who, in the United States, do not receive thrombolytic therapy. When these data become available it will be possible for clinicians to make rational individual decisions and policy-makers to formulate guidelines concerning optimal antithrombotic therapy in myocardial infarction.

 

Interaction of antiplatelet drugs in vitro: aspirin, iloprost, and the nitric oxide donors SIN-1 and sodium nitroprusside.

Author

Negrescu EV; Gr?berg B; Kratzer MA; Lorenz R; Siess W

Address

Institut f? Prophylaxe und Epidemiologie, Kreislaufkrankheiten b. d. Universit? M?chen, Munich, Germany.

Source

Cardiovasc Drugs Ther, 9: 4, 1995 Aug, 619-29

Abstract

The interaction of three antiplatelet drugs was studied in vitro: aspirin, an inhibitor of the cyclooxygenase pathway of platelet activation; iloprost, a stable analog of prostacyclin that increases platelet cAMP; and the nitrix oxide donors SIN-1 and sodium nitroprusside (SNP), which both raise platelet cGMP. Platelet adhesion and aggregation evoked by collagen/ADP were measured in anticoagulated blood under physiological flow conditions using the new Thrombostat. Aggregation was also measured in platelet-rich plasma (PRP) upon stimulation by a low (2.5 micrograms/ml) and high (20 micrograms/ml) dose of collagen, ADP, or thrombin-receptor activating peptide (TRAP). We found a synergism between iloprost and aspirin in inhibiting platelet adhesion/aggregation in flowing blood and aggregation of PRP stimulated by collagen. The mean inhibitory concentrations (IC50) of iloprost in the presence of aspirin were much lower (0.7 nM and 0.5 nM in flowing blood and low-dose collagen-stimulated PRP, respectively) than in the absence of aspirin (3 and 3.6 nM, respectively). Synergism between SIN-1 and aspirin was observed in inhibiting platelet activation in flowing blood but was much less pronounced in inhibiting collagen-induced aggregation of PRP. SIN-1/SNP and iloprost synergistically inhibited the aggregation of PRP induced by collagen as well as platelet adhesion/aggregation in blood. We found that two protein substrates of cAMP- and cGMP-dependent protein kinases, rap1B and a 50 kD protein, were associated with the functional synergism between SIN-1 and iloprost and were synergistically phosphorylated by platelet treatment with both iloprost and SIN-1. Platelet inhibition by SIN-1, iloprost, and aspirin was synergistic when measured in blood. In contrast, only additive effects of SIN-1 and iloprost were observed when platelet aggregation was measured in aspirin-treated PRP stimulated by ADP, TRAP, or collagen. Our study defines the basis for a more effective antiplatelet therapy using a combination of cGMP- and cAMP-elevating and cyclooxygenase-inhibiting drugs. The results also emphasize the importance of using various methods for the evaluation of antiplatelet drugs.