Dose Antiplatelet Agents; The Relationship Among Side Effects, and Antithrombotic Effectiveness

Dose Antiplatelet Agents; The Relationship Among Side Effects, and Antithrombotic Effectiveness Jack Hirsh, M.D., Chairman Valenten Fuster, M.D. E. Salzman, M.D.

Although the platelet active agents that show promise as clinically effective antithrombotic drugs have effects on platelet function that are dose related, there is little information available from controlled clinical trials of the effect of different drug doses on thrombosis in man. Even among the agents whose therapeutic efficacy has been established by prospective controlled clinical trials, there are few data regarding the .effect of different doses on thrombosis, and most of our present working knowledge is derived from studies of parallel phenomena, such as platelet survival, platelet aggregation, and similar processes whose relation to thrombosis is not always clear.

1'1

ASPIRIN

Clinical trials over the past decade have demonstrated that aspirin is an effective antithrombotic agent. The antithrombotic effect of aspirin has been attributed to its inhibition of platelet function. Aspirin irreversibly inhibits the enzyme cyclo-oxygenase, which, in the platelet, is responsible for the conversion of arachidonic acid to thromboxane A2 , and in vascular wall cells is responsible for the conversion of arachidonic acid to PCI•. Thromboxane A2 induces platelet aggregation and vasoconstriction while PCI. inhibits platelet aggregation and induces vasodilation. Thus, aspirin has the potential to be both antithrombotic and thrombogenic. Aspirin is rapidly absorbed in the stomach and upper intestine and has a half-life of absorption of 4-16 minutes. Peak plasma levels occur 15-20 minutes after aspirin ingestion, and the plasma concentration decays with a half-life of 15-20 minutes. Absorption from enteric coated aspirin tablets may be delayed and sometimes incomplete. Despite its rapid clearance from the circulation, the platelet-inhibitory effect of aspirin lasts for the life span of the platelet because it irreversibly inactivates platelet cycle-oxygenase. There is also evidence that aspirin acetylates platelets before they are released into the circulation and while they are still within megakaryocytes. I The mean lifespan of the human platelet is approximately ten days. Therefore, approximately 10% of circulatory platelets are replaced every 24 hours. However, platelets persist approximately 48 hours after a single dose of aspirin, because the newly released platelets have had their prostaglandin synthetic mechanism inactivated while in megakaryocytes. After 48 hours, newly released platelets are not affected by a single dose of aspirin, so that after 5-6 days, approximately 50% of the platelets function normally, and the hemostatic mechanism is no longer compromised. The optimal antithrombotic dose of aspirin is controversial. There are both theoretical and practical reasons to choose the lowest effective dose of aspirin. Low doses of aspirin (325 mg and less) have a selective inhibitory effect on thromboxane As- Low doses of aspirin would also be desirable (if effective) because the side effects of aspirin are dose

45

dependent, and many of the clinical conditions in which aspirin is effective require that the drug be used over a long term or even indefinitely.

Differential Effects of Aspirin on Thromboxane A 2 and PGl 2 Production Investigations have sought to determine whether there is a dose of aspirin that blocks thromboxane A, production without inhibiting PCI. production. Results of early studies performed by Burch et al' indicated that platelet cyclooxygenase is more sensitive to the inhibitory effects of aspirin than the cyclo-oxygenase in vascular wall cells. Studies by other investigators'" reported that PCI. production by vascular wall cells is restored more quickly after aspirin administration than is thromboxane synthesis by platelets, presumably because vascular wall cells can synthesize new cyclo-oxygenase, while platelets cannot. ' ·4 More recently, the relative effects of aspirin on platelet thromboxane A. production and vessel wall PCI 2 production have been studied using human vessel wall fragments in patients treated with aspirin and by measuring the urinary excretion of metabolic products of PC I. and thromboxane A. in patients who have ingested aspirin.'·9 Studies using vascular wall Fragments'? indicate that doses of aspirin 40 mg/day or greater inhibit both vascular wall PCI. production as well as platelet thromboxane A. production but that the effect of aspirin on thromboxane A. is greater. Patrignani et al" measured the metabolic products of PCI. and thromboxane A. in urine and showed that at doses of 0.45 rug/kg/day of aspirin (equivalent to approximately 30 mg of aspirin in a 70-kg person, thromboxane A. production was inhibited by 95% without affecting the basal leveis of the PCI. metabolic product 6-keto-prostaglandin-F ,-a. Fitzgerald et al" reported that doses of aspirin smaller than 100 mg/day totally inhibited urinary excretion of thromboxane metabolites, while the metabolites of PCI. persisted at 25-40% of their baseline value, even at doses of aspirin of2.6 g/day. Both types of studies have shortcomings. Direct measurement of PCI. from vascular wall cells that have been excised at operation may not reflect PCI2 production by intact vessels, while studies of urinary excretion of metabolites of PCI. and thromboxane A. may reflect the synthesis of these metabolic products from tissues other than platelets and vascular wall cells. 10 Despite these shortcomings, it appears that platelet cycle-oxygenase is more sensitive than vascular wall cyclo-oxygenase to aspirin, that the effect of aspirin on platelet cycle-oxygenase lasts longer than its effect on vascular wall cells, but that even low doses of aspirin inhibit PCI2 synthesis in human vessels. Other mechanisms may also account for the apparent selectivity of aspirin's effect on thromboxane synthesis compared with synthesis of prostacyclin. For example, Pedersen and Fitzgerald" have postulated that low doses of aspirin may act on platelets in blood in the portal circulation to which aspirin is exposed immediately after its absorption from the gut, resulting in depression of platelet thromboxane synthesis, while hepatic hydrolysis of the drug prevents the development of an effective systemic blood level and thus avoids an effect on endothelial cell prostacyclin production, except at much higher doses. These concepts have been supported by ACCP-NHLBI National Conference on Anllthrombotic Therapy

reports that a low dose of aspirin prolongs the bleeding time in human subjects but that the effect is less marked or even reversed at higher doses." Contradictory data have appeared, 13,14 however, and there is no agreement on this point. The therapeutic importance of inhibiting PCI. is uncertain. Experimentally, aspirin is only thrombogenic at extremely high doses (200 mg/kg) that far exceed the minimum dose required to inhibit PCI. production, 14,15 suggesting that inhibition of PC I. alone may not be the mechanism for the thrombogenic effect of very high doses of aspirin. Additional studies in rabbits indicate that the thrombogenicity of aspirin may be due in part to the effect of the salicylate moiety of a second, unidentified substance produced by vascular wall cells." Epidemiologic studies of patients with rheumatoid arthritis treated with very large doses of aspirin do not indicate that there is an increase in thrombosis or atherosclerosis,":" suggesting that high doses of aspirin are not thrombogenic in man. Finally, patients with congenital cyclooxygenase deficiency who lack both PCI. and thromboxane A. do not suffer thrombotic episodes but rather have a mild bleeding tendency," It is likely, therefore, that the importance of vascular wall PCI. production to the resistance of endothelial cells to thrombosis has been overemphasized and that aspirin is not thrombogenic in the therapeutic doses used in man.

Relationships between Dose of Aspirin and Side Effects There is good evidence both from randomized trials and from a case control study that regular aspirin ingestion produces side effects that are mainly gastrointestinal. An association between aspirin ingestion and CI bleeding was suggested by the results of a case control study," In this study, a relationship was sought between long-term regular use of aspirin and hospital admissions for major upper CI bleeding and for newly diagnosed peptic ulcer disease. The survey was carried out on 25,000 consecutive medical and surgical admissions to 24 Boston hospitals. Patients were asked whether they had regularly taken medication during the preceding three months and were classifed as being regular aspirin users ifthey took the drug at least once per week during the preceding 12 weeks. They were further subclassified into heavy aspirin users if they had taken aspirin for 4 + days per week and light aspirin users if aspirin had been taken 1-3 days per week. Four' groups were selected for analysis: (1) patients with acute major upper CI bleeding in the absence of known predisposing conditions, (2) patients with major upper CI bleeding in whom a newly diagnosed duodenal ulcer was found, (3) patients admitted to hospital with newly diagnosed and uncomplicated benign gastric ulcer, and (4) patients admitted with newly diagnosed and uncomplicated duodenal ulcers. The controls consisted of patients admitted to hospital for conditions that were unlikely to be associated with either aspirin consumption or

Table I-Side Effects of Aspirin 900 mglDay or Greater Study

Acute Myocardial Infarction

Increase in GI bleeding (NS)

Elwood II (1233) CPDA (1471) Amis (4,524)

Breddin (946) Paris (1216)

Epsim (6908)

Comment

Comparison With Anticoagulants

Increase in GI discomfort Diarrhea Uric acid and acute gout BUN and hematuria Increase in symptoms of ulcer and/or gastritis , melena, nausea, heart burn, constipation, acute gout, BUN and uric acid Increase in hematemesis and melena (NS) Increase in symptoms of peptic ulcer and/or gastritis hematemesis and melena, nausea and vomiting , heart burn, stomach pain and constipation Increase in symptoms of peptic ulcer, gastritis , and heart burn

conditions predisposing to upper CI bleeding or to peptic ulcer. A statistically significant association was found between heavy, regular aspirin use and major bleeding. A similar association was found in patients with newly diagnosed, benign gastric ulcer, but there was no corresponding association with duodenal ulcer. There was no evidence of a significant association with either upper CI bleeding or peptic ulcer disease when less heavy use of aspirin was considered. Several randomized trials comparing aspirin with placebo or oral anticoagulants in coronary artery disease".•7 and cerebrovascular disease'":" demonstrated that long-term aspirin ingestion produces CI side effects. Patients with coronary heart disease have been treated with an aspirin dose of between 100 and 1,500 mg/day (Tables 1 and 2). All six studies in which aspirin was administered in a dose of at least 900 mg/day reported an increase in side effects when aspirin was compared with placebo (in five studies) or with oral anticoagulants in one study. Symptoms of stomach pain, heart burn, nausea, constipation, hematemesis, and melena all occurred more frequently in the aspirin group than in the coritrol group. Symptoms attributable to peptic ulcer disease and gastritis also were reported to be more common in the aspirin group than in the control group in the majority of studies. In two studies there was a statistically significant increase in acute gout and in uric acid and in BUN. Neither of these biochemical abnormalities was clinically significant. There was no evidence of a generalized bleeding tendency in

Table 2-Side Effects of Low Dose Aspirin Study

Indication

Dose

Duration

Side Effects

Elwood Lewis et all983

Acute Mi Unstable Angina

300 mg 324 mg

12 Months 3 Months

Lorenz et al 1984

A-C Bypass

100 mg

4 Months

No difference in withdrawal due to side effects No difference in GI symptoms, fall in Hb withdrawal due to side effects No difference in side effects

CHEST I 89 I 2 I FEBRUARY, 1986 I Supplement

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the aspirin-treated patients, although in one study there was a statistically significant increase in hematuria. Three studies were performed (Table 2) with an aspirin dose of325 mg/day or less, and in none was there evidence of a higher frequency of side effects in the aspirin group than in the placebo group. Aspirin has been evaluated in three placebo-controlled randomized studies in patients with cerebrovascular disease. 28-30 In all three studies aspirin was administered in a dose of approximately I g/day (Table 3). There was an increase in stomach pain and other GI side effects in two of these studies. A study comparing two aspirin doses is currently reaching completion in patients with transient cerebral ischemia in the UK , and the preliminary results indicate that the high dose of aspirin (1,000 mg/day) produces more side effects than the low dose (300 mg/day" The combination of aspirin and warfarin has been associated with a greater frequency of clinicall y important gen eralized bleeding than warfarin therapy alone.3 1.31 Th er e is also evidence that the combination of aspirin and heparin is more hemorrhagic than heparin alone .33 ,34 The published data are consistent with xhe conclusion that the side effects of aspirin are dose related and that when given in a dose that does not exceed 325 mg/day, aspirin is not associated with clinically important side eJfects. Aspirin docs not appear to produce a generalized ble eding abnormalit y unless it is combined with anticoagulant the rapy.

The Effects of Aspirin on Gastric Mucosa

ity cause no measurable blood loss in normal subjects." There is some evidence that the effect of aspirin on the gastric mucosa is through inhibition of synthesis of prostaglandins. The synthesis of prostaglandins by gastric mucosal preparations is blocked by aspirin.40.4 1 The effect of aspirin on gastric mucosa is reduced by treatment with cimetidine.P'" antacids," and by the use of enteric coated aspirin. " :" Buffered preparations of aspirin do not contain enough alkali to neutralize the effects of650 mg of aspirin and do not protect against aspirin-induced gastric mucosal erosion."

Summary ofAspirin Side Effects Aspirin produces its principal side effects by damaging the gastric mucosa. This effect requires the presence of acid and can be avoided or reduced by neutralizing or preventing acid secretion by large doses of either antacid or cimetidine. The topical effect of aspirin is important for induction of gastric mucosal damage and may be avoided by using enteric-coated aspirin . The damaging effect of aspirin on gastric mucosa may be du e to inhibition of synthesis of a protective prostaglandin, but as yet this is unproved.

Side Effe cts of Short-term Aspirin Use in Relationship to .

~ ~ry

Th e effect of aspirin administered preoperatively and postopcratively has been studied in several clinical trials evaluating its antithrombotic effect in general surgical patients and in patients undergoing hip" and knee surgery. 46,47 Aspirin inge stion has not been associated with an increase in ope rative or postoperative bleeding in these patients, and when compared with warfarin, aspirin produces significantly less postoperative bleeding." There is evidence, however, that wh en aspirin is combined with heparin in patients undergoing open heart surgery," it causes an increase in op erative bleeding.

Endoscopic studies have demonstrated that aspirin produces erythema of the gastric mucosa in approximately 80% of patients with rheumatic diseases, gastri c e rosions in approximately 40% , and gastric ulcer in 15%.3S Topically applied aspirin damages gastric mucosa'";" and induces occult GI bleeding. Aspirin administered by IV injection may also produce effects on gastric mucosa,36,38 but that effect is decreased with parenteral administration. 36 Oral administration of diluted solutions of aspirin cause considerably less Relationship between Aspirin Dose and Clinical J!.fficacy bleeding than similar doses in tablet form, and aspirin Most clinical trials demonstrating benefits of aspirin have solutions containing antacids with sufficient buffering capacdealt only with a single, arbitrarily selected dose of the drug. Table 3-Side Effects of Aspirin Trials in Cerebral Ischemia (TIA) Author

No.

Fields et al 1977

170

Barnett et al 1978

585

Duration

Comments

1300 mg/day

37 Months

PLAC 1300 mg/d ay

26 Months

No increase in withdrawal Slight increase (NS) in fecal occult blood 4 patients on ASA had overt GI bleeding Significant increase in : 1. Upper abdominal pain p
Dose

or or

800 mg/day Sulfinpyrazone

or

Bou sser et al 1983

68

604

Both or Placebo 990 mg/day

or

990 mg/day plus Dipyridamole 225 mg/day or PLAC

36 Months

Significant increase Gl bleeding: 1. Upper abdominal pain 2. Peptic ulcer 3. Withdrawals due to side effects

p<0.05 p
ACCP-NHLBI NationalConference on Antithrombotic Therapy

There is no evidence from clinical trials that high doses of aspirin are thrombogenic. Several trials have compared the effect of different doses of aspirin on thrombotic events, but the results have contributed little to the issue of the optimal dose of aspirin. Hynes et al" reported that thrombotic occlusion of the brachial artery complicating cardiac catheterization occurred with equal frequency after giving aspirin at 325 or 650 mg/day. O'Brien et al" were unable to show a difference in the antithrombotic effectiveness of600 mg or 2,400 mg/day in patients undergoing thoracotomy, but they found no benefit at either dosage . McKenna et al" studied patients undergoing knee replacement operations and paradoxically found significant protection against venous thrombosis at adose of3 ,600 mgdaily but no therapeutic benefit at 900 mg daily. However, the conclusions of this study were weakened by the small number of patients involved and by the failure of other studies to demonstrate a similar dose effect . Thus , Harris et al" subsequently studied the effect of 1,200 mg daily compared with 3,600 mg/day in patients undergoing total hip replacement and found no difference in the therapeutic effectiveness of the two doses. In a more recent study," Harris et al found that postoperative thrombosis occurred with equal frequency (approximately 50%) with 1,200 mg or 300 mg/day in total hip replacement. Thus there is no convincing evidence from comparative studies that anyone dose of aspirin is more or less effective than another. Antithrombotic effects of aspirin have been reported with doses that have varied between 100 mg/day to over 1 g/day. Low doses of aspirin (100 mg/day) have been effective in preventing aortocoronary bypass shunt thrombosis" (level I) thrombosis of arterial venous shunts in patients undergoing long-term hemodialysis (160 mg/day) (level 1),53 and in patients with unstable angina (325 mg/day) (level 1).54 Aspirin has also been shown to be effective in reducing complications in patients with transient ischemia in doses of approximately 1-2 g/day (two level I studies)."" " In the Canadian study, this effect was only seen in males, but in the French study benefit was found in males and females . In this latter study, the addition of dipyridamole to aspirin did not improve the effectiveness of aspirin. There is suggestive, but less conclusive, evidence that aspirin is effective in preventing reinfarction and death in patients who have suffered aeut e myocardial infarction in doses of between 300 mg and 1.5 g/ day (five level II studies)":" and in preventing postoperative venous thrombosis in patients following elective hip surgery" and in patients following elective knee surgery. 4','7 Thus , aspirin is an effective antithrombotic agent in doses between 100 rug/day and 1 g/day. There is no evidence that low doses (325 mg/day or less) are either more effective or less effective than high doses (1,000 mg/day). There is evidence, however, that low doses produce fewer side effects. Because the thrombogenic stimulus may not be the same in the different thromboembolic disorders in which aspirin has been evaluated, the successful results obtained with low doses of aspirin in unstable angina, aortocoronary bypass surgery, and in patients with arteriovenous shunts should not be extrapolated to disorders in which only high doses of aspirin have been evaluated. On the other hand , the results of biochemical studies on its mechanism of action, the doserelated side effects of aspirin and the results of ~linical studies

evaluating antithrombotic efficacy all support the use oflow doses of aspirin in the treatment of most thromboembolic disorders in which the drug has been found to be effective. Effectiveness of aspirin in cerebral ischemia has only been demonstrated at doses of approximately 1 g/day. The results of the Oxford study comparing 300 mg with 1,000 mg are awaited with great interest. Although a greater benefit for aspirin has been reported in males in some studies, this has not been a consistent finding . At present, there is no evidence from clinical studies that the addition of dipyridamole to aspirin improves its clinical efficacy. DIPYRIDAMOLE

Dipyridamole is an inhibitor of the enzyme cyclic AMP phosphodiesterase. It has a substantial effect in prolonging platelet survival when that function is abnormally shortened in states of accelerated platelet turnover, such as prosthetic heart valves or severe atherosclerosis. 55 Dipyridamole in combination with warfarin has been reported to be more effective than warfarin alone in preventing systemic embolism in pati ents with prosthetic heart valves in a level I study?" and in one level II study. " In combination with aspirin, the effect of diyridamole on platelet survival is enhanced so that a dose of 100 mg with aspirin has an effect as great as 400 mg daily of dipyridamole given alone, No such information is available regarding the antithrombotic effectiveness of different doses of dipyridamole. It has been reported" that 225 mg/day dipyridamole given in combination with aspirin has no greater effect on suppression of transient cerebral ischemic attacks than does aspirin alone. In a study of dipyridamole in the treatment of stroke, Acheson et aJ56 found no difference in the therapeutic benefits of 400 mg or 800 mg daily. The principal side effect of dipyridamole is gastric distress, which is dose related. Reports by Chesebro et al57,58 showed that dipyridamole, 225 mg/day, plus aspirin, 975 mg/day, improved the patency of coronary bypass grafts both at early and late follow up (level I). In this latter study the aspirin therapy was started on the first postoperative day and dipyridamole before surgery. It should be noted that five prior studies of the effect of aspirin on coronary bypass patency had reported negative results, but these latter studies had all delayed initiation of the drug therapy several days after the operation, apparently a critical point. Hess et a15 7• recently reported the results of a study that evaluated the effect of aspirin alone, 330 mg three times daily, acorn bination of aspirin 330 mg three times daily, and dipyridamole, 75 mg three times daily, or matching placebo on the progression of peripheral arterial occlusive disease. Serial arteriography of the lower limbs was performed on each patient at the beginning of the study and two years later or earlier if there was clinical deterioration . Two hundred forty patients entered the study and the results of serial angiograms were evaluated in 193. A scoring system based on a change in the severity of the stenosis and in the length of the lesion was used to compare the effects of three treatment regimens. Progressive disease was most marked in the placebo group and least marked in the aspirin and dipyridamole group, with intermediate findings in the aspirin group, The differences were statistically significant for aspirin and dipyridamole, but the trend for a reduced CHEST I 69 I 2 I FEBRUARY. 1966 I Supplement

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progression was not statistically significant for aspirin alone . It is difficult to assess the clinical significance of th e scoring syste m used . No data were provid ed on th e result s of clinically impor tant outco mes , such as progression of symptoms or th e need for surgical int er vention. SU LFINPYRAZ O N E

Sulfinp yrazone is an urico sur ic agent intro duced for the treatment of gout th at also has limited an ti-inflamma tory action . At dose s of 400-800 mg/day, it correc ts short en ed platelet surv ival.t''?' and at 600 mg prol ongs th e paten cy of ar teriovenous shunts for hem odialysis." At a dose of80 0 mg daily, sulfinpyrazone was report ed to have a favorable effect on secondary pr evention of myocard ial infarction .62. 63 At th e same dose , there was no significant be nefi t in ce re brovascular diseas e in a larg e multicenter trial. 64 Th e antithrombotic effectivenes s of sulfinp yrazone at other doses has not been critically assessed. Side effects of sulfipyrazone have been limited to epigastric discomfort. P RO STACYC LIN

Th e platelet active age nt prostacyclin has been ad ministered th er apeutically in states of platelet consumption, such as hemodialysis, 55 cardiopulmonary bypass." :" chronic peripheral arterial insufficiency du e to advanced athe roscle rosis," and in pulmonary hypertension ." It s clinical value is limit ed by th e need for IV injection s and by its most troubl esome side effect, hypot ension.

study claiming to demonstrate improved efficacy of the combination of aspirin and dipyridamole over aspirin alon e has been discounted in making this recommendation becau se of doubt over the clinical validity of the end points used.?" 5. It is recommended that dipyridamole in a dose of 225 mg/ day should be added to warfarin in patients with pros thetic heart valves who have developed thromboembolic complications while receiving therapeutic doses of warfarin. This grade A recommendation is based on one level 132• and one level II study. " Reprint requests: D r. Hirsh, Room 3WlO, 1200 Main Stre et, West, McMaster Universit y, Hamilton , Ontario, Canada UN 3Z5

REFERENCES

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SUMMARY AND RECOMMENDATIONS

1. It is recommended that if aspirin is used as an antithrombotic agent, it should be administered in a dose of325 mg daily. The exception is in patients with ischemic cerebrovascular disease in whom the lowest dose evaluated has been approxim ately 1 g/day, This grade A recommendation is based on one level I study in patients with unstable angina," one level I study (using 100 mg/day) in patients undergoing to coronary byp ass surgery," one Level I study in patients undergoing long-term hern odialysis. " two level I studies in patients with cere bral ischemia," :" one level II study in postm yocardial infarction patients," and one level II study in ce rebral Ischemia. " 2. It is recommended that ent eric coated aspirin should be used in patients who develop GI side effects with aspirin. Thi s grade C recommendation is based on clinical impression only. 3. It is re commended that a lower dose of aspirin should be used in patients with ischemic cerebrovascular disease who cannot tolerate 1 g/day. It would be re asonable to give th ese patients 325 mg/day of enteric coated aspirin if th ey cannot tolerate larger dose s. This grade C recommendation is based on clinical impression and on extrapolations from studies in patients with un stable angina. 4. At present there are no conv incing data that indicate that the addition of dipyridamole to aspirin improves its antithrombotic efficacy. Thi s grade B recommendation is based on one level II study in postmyocardial infarction pati ents" and one level II study in ischemic cerebrovascular disease." The one

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