Aspirin in the Cardiovascular System
BleedingTimeand Platelet Function Aspirin wasin clinical use for about half a century, when the first reports about disturbed hemostasis were published. In 1945, Singer, an ETN specialist, reported late bleedings after tonsillectomies . He attributed this to his prescription of aspirin for analgesic purposes. Withdrawal of aspirin or its replacement by metamizol (dipyrone) resulted in disappearance of bleeding. A relationship between aspirin intake and bleeding was also considered for tooth extractions and epistaxis [39,40]. Beaumont and Willie  reported that aspirin prolonged bleeding time in patients with cardiac diseases. Quick and Clesceri  suggested that this effect of high-dose (6 g) aspirin might be caused by the reduction of a stable procoagulatory factor in plasma, probably prothrombin. In 1967, Quick demonstrated that a prolonged bleeding time was specific for aspirin and was not seen after salicylate was administered . Similar results were obtained by the group of Mustard . These authors confirmed the results of Quick and extended them also to several animal species. In addition, they showed that the antiplatelet effect of aspirin depends on the kind of platelet stimulus. Specifically, aspirin did not inhibit ADP-induced primary platelet aggregation, a finding that was largely ignored later in many platelet function assays in vitro (Section 2.3.1). During 1967-1968, Weiss and colleagues, Zucker and Peterson, and O'Brien published the first more systematic studies on the action of aspirin on platelet function in healthy men [45-48]. O'Brien found a significant inhibition ofplatelet function at the "subclinical" dose of 150 mg and strongly recommended a clinical trial on the compound in patients at elevated thrombotic risk.
Mechanisms of Antiplatelet Action of Aspirin The elucidation of the mechanism of action of aspirin as an antiplatelet drug starts with a study by Bryan Smith and Al Willis , both working at the time in the laboratory of John Vane. These authors were the first to show that inhibition of platelet function by aspirin was associated with the inhibition of prostaglandin biosynthesis and concluded that this explains the antiplatelet effects of the compound. At this time, thromboxane was still unknown. A few years later, Roth and Majerus  showed that aspirin causes irreversible acetylation and inhibition of platelet cyclooxygenase. The group of Garret FitzGerald  confirmed this finding as well as serine 529 (530) in the COX substrate channel as acetylation site for the cloned enzyme from human platelets. These studies provided the rationale for the use of aspirin as an antiplatelet drug in the secondary and primary prevention of atherothrom-botic vessel occlusion, specifically myocardial infarction and ischemic stroke (Sections 4.1.1 and 4.1.2). Preeclampsia is another indication for prophylactic aspirin administration after the description of a positive effect of aspirin in high-risk patients by Crandon and Isherwood  and its confirmation in a randomized trial by Beaufils and colleagues 6 years later  (Section 4.1.5).
Aspirin and Prevention of Myocardial Infarction and Stroke In1949, PaulC. Gibson reported for the first time the successful use of aspirin for prevention of anginal pain and coronary thrombosis . This report was based on a questionnaire sent by him to 20 doctors: fifteen of them had already successfully used the compound for this condition and all of them considered aspirin as "valuable" or "very valuable," specifically with respect to its analgesic properties. Gibson explained these beneficial effects by a combination of anticoagulatory and analgesic properties of the compound. The recommended doses were 1300 mg (20 grain) or 650 mg (10 grain) aspirin.
The first larger and more systematic investigation ofthe significance ofantithrombotic effects of aspirin for the prevention of myocardial infarctions was published in 1950 by Lawrence Craven  (Figure 1.6), a suburban general practitioner from Glendale (California) .
His finding reads in the original contribution as follows:
".. .duringthepasttwoyears,Ihaveadvisedallofmy male patients between the ages of 40 and 65 to take from 10-30 grains [650-1950 mg] of acetylsalicylic acid daily as a possible preventive of coronary thrombosis. More than 400 have done so, and of these none has suffered a coronary thrombosis. From past experience, I should have expected at least a few thrombotic episodes among this group. There would appear to be enough evidence of the antithrombotic action of acetylsalicylic acid to warrant further study under more carefully controlled conditions "
In the following years, Craven increased the number of his patients to about 8000 - still without having seen any myocardial infarction - and recommended the agent also for prevention of stroke [56, 57]. Unfortunately, he died in 1957, 1 year after publication ofhis last study, at the age of 74 from a heart attack - despite regularly using aspirin .
Craven's study was a stroke of luck in several aspects: first, he treated exclusively males at an age of increased risk for myocardial infarction who, according to the current knowledge, benefit most from aspirin prophylaxis. He used a dose of aspirin that was high, but in comparison to anti-inflammatory doses at the time for treatment of chronic inflammatory diseases, was rather low. Thus, not too many side effects were to be expected, which was good for the compliance ofhis patients. Finally, he had no problems with statistics because there were no infarctions in the patient group.
Unfortunately, these data did not find the necessary attention during the following 20 years -possibly due to the low impact factor of the journals where they were published and the fact that Craven himself died of heart attack despite regularly taking aspirin. Until the 1970s of the last century, the significance of thrombosis against spasm for the genesis of myocardial infarction was also in question. Until 1988, more than 15 000 patients were studied in seven placebo-
controlled trials for the secondary prevention of myocardial infarction at the cost ofmany millions of dollars. None of these studies was significant on its own, possibly because, from today's viewpoint, of poor study design, the highly variable aspirin doses (300-1500 mg/day), the apparently absent systematic control of patient compliance, and a highly variable time point when aspirin treatment was started, in one study (AMIS) up to 5 years (!) after the acute event .
These data finished the discussion on the possible use of aspirin for the prevention of myocardial infarctions. In addition, infrequent though severe side effects such as GI or cerebral bleeding and a suggested though never established relationship with Reye's syndrome (Section 3.3.3) have tainted its reputation and resulted in its removal from the list of essential drugs by the WHO in 1988. Ironically, at about the same time, that is, 1988/1989, the first prospective randomized placebo-controlled trial - the US American Physicians' Health Study (Section 4.1.1) - and the subsequent meta-analyses by the Antiplatelet Trialists' Collaboration were published and showed a significant reduction of the incidence of myocardial infarction or other atherothrombotic events in both healthy volunteers and patients at elevated cardiovascular risk . The ISIS-2 study of1989 convincingly demonstrated for the first time a significant reduction in infarct mortality by aspirin and resulted in the first official guideline recommendation of aspirin use in these patients . The prevention of atherothrombotic vessel occlusions by aspirin in patients at increased vascular risk is now a therapeutic standard. The medical decision to use aspirin in the individual patient is determined by the individual benefit/risk ratio. This issue is particularly relevant in the primary prevention in patients with a low risk profile (Section 4.1.1).
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