Aspirin for Acute Myocardial Infarction Patients

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Organization of the Study

IV ASPIRIN FOR ACUTE MYOCARDIAL INFARCTION PATIENTS

IV ASPIRIN FOR ACUTE MYOCARDIAL INFARCTION PATIENTS

Aspirin (ASA) has been known to influence the bleeding time of individuals who take aspirin and it this is presumably due to the inhibition of prostaglandis biosynthesis and the resultant platelet secretion time. All observations in man indicate that long-term ingestion of aspirin is associated with impaired platelet function and prolongation of the bleeding time. Patients with inadequate platelet inhibition by aspirin, which is commonly referred to as aspirin resistance, may have an increased risk of suffering cardiovascular events. Because of this, identification of these patients with aspirin resistance by measuring platelet function is of great interest. This work reports a study that used the VerifyNow Assay to formulate IV aspirin for administration to patients with Acute Myocardial Infarction.

IV ASPIRIN FOR ACUTE MYOCARDIAL INFARCTION PATIENTS

CHAPTER ONE

INTRODUCTION

Aspirin (ASA) has been known to influence the bleeding time of individuals who take aspirin and it this is presumably due to the inhibition of prostaglandis biosynthesis and the resultant platelet secretion time. All observations in man indicate that long-term ingestion of aspirin is associated with impaired platelet function and prolongation of the bleeding time. Patients with inadequate platelet inhibition by aspirin, which is commonly referred to as aspirin resistance, may have an increased risk of suffering cardiovascular events. Because of this, identification of these patients with aspirin resistance by measuring platelet function is of great interest.

As the platelets adhere, they undergo secretion and recruitment of other platelets to build a platelet plug. This is termed 'platelet aggregation' and 'platelet secretion'. Low platelet response to aspirin has been consistently reported to be associated with a high incidence of vascular events. The ability of platelets to aggregate in response to an agonist is determined in clinicopathological studies by using the principle of light transmission.

In vitro platelet aggregation studies the Born method has traditionally been used and is the method of choice in assessing platelet function. This method has been used to assess aspirin sensitivity in several studies. Another method that has been used extensively is measurement of the urinary TXA2 metabolite 11-dehyro-TXss using both radioimmunoassay (RIA) and enzyme immunoassay (EIA). A revision of EIA is commercially available under the marketed name of 'Aspirin Works' (Creative Chemical Concepts Inc.).

Two automated point-of-care (POC) Platelet function assays have also been studied: the Platelet Function Analyzer 100 (PFA-100) (Dade Behring Inc.) and the verify Now Aspirin Assay (Accumetrics Inc.). Platelet aggregation is also determine dosing an optical platelet aggregometer (OPA) such as the PAP4 (Bio Data Corp) and Model 700 whole blood optical Lumi Aggregometer (Chronolog Inc.) This method relies on the concept that the platelet aggregations in a uniform solution of platelet-rich plasma (PRP) decreases the turbidity of the solution as the platelets cross-link and clump together. The amount of platelet aggregation is directly related to the amount of light that is allowed to be transmitted through the solution. Results area expressed in units of percentage of light transmission on a scale of 0-100%.

Like the PFA-100 the VerifyNow is a whole blood (WB) point-of-care device that conveniently measures platelet aggregation using different easy-to-load cartridges for different applications. Unlike the PFA-100 the VerifyNow is designed only to detect platelet dysfunctions or the result of exposure to antiplatelet agents such as aspirin, clopidogrel and glycoprotection II-IIIa receptor antagonists (eg absiximab). Platelet aggregation detection is based on the agglutination of platelets on fibringogen-coated beads detected by an optical turbidity method.

Anticoagulant therapy was routine management of patients with myocardial infarction in the 1950s however, this management "fell into disrepute because of the fear of bleeding complications and doubt about its effectiveness." (Stein, 1998, p.639) Stein states that the primary objectives of anticoagulant treatment in patients with myocardial infarction are: (1) to improve survival; (2) to prevent recurrent infarction, mural thrombosis and systemic embolism; and (3) to prevent the complication of venous thromboembolism. (p.639)

The use of "long-term anticoagulant therapy for improving survival and preventing recurrent infarction has been controversial." (Stein, p.639) Stein reports that the risk of complications from bleeding associated with long-term anticoagulant therapy in patients with prosthetic heart valves has been reported to range form 1% to 40%. Major bleeding ranged from 0% to 7% and fatal bleeding from 0% to 4.1%. (Stein, 1998, p. 640) When aspirin is added to warfarin the risk of bleeding increases yet, when aspirin in low doses are used (100 mg/day) the increase is due to bleeding episodes of a minor nature without major bleeding increases.

BACKGROUND OF THE STUDY

It is stated in one report that approximately eighty to one-hundred percent of an oral dose of aspirin is absorbed from the GI tract but that the actual bioavailability of the drug as unhydrolyzed aspirin is "lower since aspirin is partially hydrolyzed to salicylate in the GI mucosa during absorption and on first pass through the liver." (Medscape, 2009) There are only very few studies on the bioavailability of unhydrolyzed aspirin. One study reports administration of aspirin through an IV and as an oral aqueous solution. The study shows that the "...solution was completely absorbed but only about 70% reached the systemic circulation as unhydrolyzed aspirin." (Medscape, 2009) In yet another study in which aspirin was administered through an IV and orally as capsules it is reported that approximately 50% of the oral dose reached the systemic circulation as unhydrolyzed aspirin.

The report states specifically that "there is some evidence that the bioavailability of unhydrolyzed aspirin from slowly absorbed dosage forms (e.g., enteric-coated tablets) may be substantially decreased. Food does not appear to decrease the bioavailability of unhydrolyzed aspirin or salicylate; however, absorption is delayed and peak serum aspirin or salicylate concentration may be decreased. There is some evidence that absorption of salicylate following oral administration may be substantially impaired or is highly variable during the febrile phase of Kawasaki disease." (Medscape, 2009)

The majority of studies that have been reported to the present date have stated the bioavailability of aspirin "in terms of salicylate. Effervescent or noneffervescent oral aqueous solutions of aspirin appear to be completely absorbed. Oral buffered aspirin tablets, uncoated plain aspirin tablets, and methylcellulose film-coated (non-enteric) plain aspirin tablets are approximately 80 -- 100% absorbed. Erratic and incomplete absorption of some enteric-coated aspirin tablets (particularly those with shellac coatings) has been reported, but recent studies indicate that the extent of absorption of currently available enteric-coated aspirin tablets is similar to that of buffered, uncoated plain, and film-coated plain aspirin tablets." (Medscape, 2009)

It is stated that there is a lack of well-designed studies however, that the "...extent of absorption of extended-release aspirin tablets appears to be similar to that of uncoated plain aspirin tablets. There are apparently no published studies on the bioavailability of aspirin capsules. Following rectal administration as a suppository, aspirin is slowly and variably absorbed; the extent of absorption increases with increasing rectal retention time. In general, 20 -- 60% of the dose is absorbed if the suppository is retained for 2 -- 4 hours and 70 -- 100% is absorbed if the suppository is retained for at least 10 hours." (Medscape, 2009)

The work of Jawaia (2006) entitled "Under Use of Aspirin in Acute Coronary Syndrome" states "From simple pain relief to clot buster, it is an amazing success story of Aspirin the miracle drug of 21st century which continues to surprise the healthcare professionals with its ever increasing indications." (p.1) Aspirin first appeared on the market in 1899 and is stated by Jawaia to have "entered the world with a whisper...but has now emerged as a pharmaceutical superstar." (p.1) Estimates state that more than 25,000 scientific papers on Aspirin have been published and that the average is two scientific papers on Aspirin are published every two hours. Aspirin has been referred to according to Jaiwa as "a poor man's statin." (Jaiwa, 2006, p.1)

More than a trillion aspirin tablets have been consumed since Aspirin was first introduced. Jaiwa states of Aspirin that "Its analgesic and antipyretic properties were well-known but the pioneering work regarding its use in cardiovascular diseases was done by a Scottish physician Peter Elwood." (2006, p.1) Soluble aspirin is stated to have been formally introduced in 1948 at London Medical Exhibition. Many studies have now confirmed the safety and efficacy of Aspirin in both "primary and secondary prevention of heart attacks" as well as in "stroke, deep vein thrombosis, bowl, lung, breast cancer, cataract, migraine, infertility, Alzheimer's disease and herpes." (Jawai, 2006, p.1)

The list is now increasing with the every passing day as more and more indications are being identified by the investigators. It is by far the most extensively studied and researched drug. Jawai reports that a study conducted in 2002 in Pakistan states findings that "only 10.5% of patients experiencing chest pain took aspirin on their own at home while 23.4% of them were prescribed Aspirin by their local GPs. Local hospitals administered aspirin…