Original Article

Suppression of Thromboxane A₂ but Not of Systemic Prostacyclin by Controlled-Release Aspirin

Robert J. Clarke, M.D., Gail Mayo, R.N., Patricia Price, B.S., and Garret A. FitzGerald, M.D.

N Engl J Med 1991; 325:1137-1141October 17, 1991

Abstract

Abstract

Background.

The antithrombotic efficacy of aspirin is attributed to its inhibition of the enzyme prostaglandin G/H synthase, which is necessary for the formation of thromboxane A₂ in platelets. Thromboxane A₂ is a potent vasoconstrictor and platelet agonist. However, the formation of prostacyclin by vascular endothelium also requires prostaglandin G/H synthase, and prostacyclin exerts opposite effects on platelet function and vascular tone. We wanted to see whether controlled-release aspirin would affect the formation of thromboxane A₂ but not prostacyclin by reducing the aspirin concentration that reaches the posthepatic circulation.

Full Text of Background. ...

Methods.

A controlled-release formulation containing 75 mg of aspirin, designed to release 10 mg per hour, was developed to inhibit prostaglandin G/H synthase in platelets in the prehepatic circulation. The effects of the controlled-release preparation on plasma levels of aspirin and salicylate, serum levels of thromboxane B₂, and urinary dinor metabolites of prostacyclin and thromboxane B₂ (measured by gas chromatography—mass spectrometry) were compared with the effects of conventional immediate-release aspirin in normal volunteers. The release of prostacyclin was stimulated by intravenous bradykinin.

Full Text of Methods. ...

Results.

Steady-state inhibition of serum thromboxane B₂ required two to four days and appeared slower with 75 mg of controlled-release aspirin than with the same amount of immediate-release aspirin. Maximal inhibition was achieved rapidly by adding a single loading dose of 162.5 mg of immediate-release aspirin to the regimen. Over a 28-day period, suppression of thromboxane A₂ with this regimen was comparable to that with immediate-release aspirin taken either as 162.5 mg daily or as 325 mg on alternate days, despite the minimal systemic bioavailability of controlled-release aspirin. Bleeding time was prolonged to a similar degree with each of the three regimens. The five- to six-fold increase in the prostacyclin metabolite induced by bradykinin was depressed by pretreatment for four days with 75 mg of immediaterelease aspirin, but not by 75 mg of controlled-release aspirin.

Full Text of Results. ...

Conclusions.

Maximal inhibition of platelet thromboxane A₂ production was sustained during long-term dosing with controlled-release aspirin, whereas basal prostacyclin biosynthesis fell only slightly and systemic synthesis of prostacyclin stimulated by bradykinin was preserved. Controlled-release aspirin may facilitate determination of the clinical importance of preserving prostacyclin during platelet inhibition in humans. (N Engi J Med 1991;325: 1137–41.)

Full Text of Conclusions. ...

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Media in This Article

Figure 1Mean (±SD) Systemic Plasma Aspirin Levels on Day 27 before Dosing and for One Hour Afterward.

Figure 2Mean (±SD) Thromboxane B₂ Inhibition in the Groups Assigned to Three Aspirin Regimens.

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Article

ASPIRIN has been shown to reduce the incidence of death significantly in patients presenting with unstable coronary vascular disease.1 2 3 The clinical benefit of aspirin is thought to derive from inhibition of thromboxane A₂ production.4 Thromboxane A₂ is formed from arachidonic acid in platelets by the sequential action of the enzymes prostaglandin G/H synthase and thromboxane synthase; it is a potent vasoconstrictor and platelet agonist.5 Aspirin acetylates Ser529 in prostaglandin G/H synthase and inhibits the enzyme irreversibly.6 , 7 It has been speculated that aspirin's antithrombotic efficacy may be limited by the coincidental inhibition of prostacyclin, a major product of vascular endothelium whose formation also requires prostaglandin G/H synthase.8 Prostacyclin exerts effects on platelet function and vascular tone opposite to those of thromboxane A₂.9

Two strategies have been proposed to enhance the biochemical selectivity of aspirin for THROMBOXANE A₂: a reduced dose and alternate-day dosing.10 , 11 However, the long-term administration of low doses of conventionally formulated aspirin depresses both basal12 and stimulated13 biosynthesis of prostacyclin. A third approach to the modification of aspirin delivery involves taking advantage of its pharmacokinetic properties. Aspirin is subject to extensive first-pass metabolism in the liver to salicylate,14 a weak, reversible inhibitor of prostaglandin G/H synthase.15

Modification of the rate of drug delivery so that it fell below the hepatic threshold for the extraction of aspirin might theoretically permit the cumulative inhibition of platelet prostaglandin G/H synthase in the prehepatic circulation while reducing the exposure of the systemic vascular endothelium to aspirin.16 We studied a controlled-release preparation of aspirin designed to meet this requirement — that is, to inhibit the formation of thromboxane A₂ in platelets while sparing the capacity of a systemic stimulus to evoke prostacyclin biosynthesis in humans.

Methods

We studied male volunteers 18 to 45 years of age (mean [±SEM], 29±1 years) who had a normal physical examination, prothrombin time, partial-thromboplastin time, complete blood count, platelet count, and screening panel (SMA-12) and who abstained from all drugs for at least two weeks before the study and throughout its duration. Informed consent was obtained from all the subjects after the study protocol was approved by the hospital's ethics committee.

To determine the number of daily doses required to attain maximal steady-state inhibition of platelet thromboxane A₂,10 , 17 , 18 10 volunteers were randomly assigned in a double-blind, crossover design to receive 75 mg of either immediate-release or controlled-release aspirin daily for five days. A third group of 15 volunteers was given 162.5 mg of immediate-release aspirin as an initial dose, followed by 75 mg of controlled-release aspirin daily for the next four days. After a washout period of two weeks, they took the other aspirin formulation daily for five days. Forty-five male volunteers were then randomly assigned to one of three groups receiving treatments in a double-blind fashion, as follows: 75 mg of controlled-release aspirin daily for 28 days, with a single dose of 162.5 mg of immediate-release aspirin taken 12 hours before the first dose (the controlled-release group); 162.5 mg of immediate-release aspirin daily for 28 days, with a single aspirin placebo taken 12 hours after the first dose (the 162.5-mg group); and 325 mg of immediaterelease aspirin on alternate days for 28 days, starting on day 1, with matching placebo taken on the days when the active preparation was not administered and a single placebo tablet taken 12 hours after the first dose of aspirin on day 1 (the 325-mg alternate-day group).

Finally, in a separate experiment, the same volunteers were randomly assigned to receive one of the following five treatments for four days: (1) 75 mg per day of immediate-release aspirin, (2) 162.5 mg per day of immediate-release aspirin, (3) 325 mg per day of immediate-release aspirin every other day, with matching placebo on the alternate days, (4) 75 mg of controlled-release aspirin per day, or (5) aspirin placebo daily. After hydration with 1 liter of saline over a 2-hour period, prostacyclin release was stimulated by infusing intravenous bradykinin, a stimulant to endothelial prostacyclin release,19 through an arm vein, with the volunteers supine, as described elsewhere,20 1 hour after aspirin administration; bradykinin was given at doses of 100, 200, 400, and 800 μg per kilogram of body weight per minute sequentially, with each dose lasting 15 minutes.

Urinary eicosanoid metabolites21 , 22; serum levels of thromboxane B₂,23 aspirin, and salicylate24; and bleeding times25 were measured as described elsewhere. Aspirin (Glenbrook Pharmaceuticals, New York) was a controlled-release 75-mg matrix formulation, designed to release 10 mg per hour.26 Nonparametric methods of statistical analysis were used.27 Results are given as means ±SD.

Results

Two daily doses of immediate-release aspirin (75 mg) were required to attain complete inhibition of the capacity of platelets to generate thromboxane A₂, as reflected by serum concentrations of thromboxane B₂ (Table 1Table 1Cumulative Inhibition of Serum Thromboxane B₂ Production by Three Regimens of Low-Dose Aspirin.). With the controlled-release preparation, the time to maximal effect tended to be longer than with the immediate-release preparation at the same dosage. However, when the volunteers were given 162.5 mg of immediate-release aspirin as a loading dose 12 hours before they began the controlled-release regimen on day 1, maximal inhibition of the serum concentration of thromboxane B2 was attained rapidly.

The profiles of plasma aspirin concentration over time during the first hour after dosing are shown in Figure 1.Figure 1Mean (±SD) Systemic Plasma Aspirin Levels on Day 27 before Dosing and for One Hour Afterward. The systemic plasma aspirin concentration (10.7± 1.65 nmol per milliliter) measured 30 minutes after dosing with 325 mg of immediate-release aspirin on alternate days was reduced to 6.81 ±1.28 nmol per milliliter after a dose of 162.5 mg of immediate-release aspirin and to 0.29±0.03 nmol per milliliter (P<0.001) after a 75-mg dose of controlled-release aspirin. The corresponding peak plasma salicylate levels measured were 21.67±2.95, 15.42±1.63, and 2.25±0.39 nmol per milliliter, respectively.

During long-term dosing, the volunteers assigned to all regimens had rapid and sustained inhibition of serum thromboxane B2, in the range of 97 to 99 percent (Fig. 2Figure 2Mean (±SD) Thromboxane B₂ Inhibition in the Groups Assigned to Three Aspirin Regimens.). The degree of suppression did not differ among the three groups during the dosing period. As expected,4 , 10 , 18 , 28 the time to recovery corresponded to platelet turnover time. On day 30, 48 hours after the last dose, the recovery of serum levels of thromboxane B₂ was more pronounced in the group taking the controlled-release preparation (19±4 percent) than in either of the groups taking the immediate-release preparation (11±2 percent in the 162.5-mg group, and 14±2 percent in the 325-mg alternate-day group). Although this may reflect protection of cyclooxygenase in megakaryocytes from aspirin in the first group,18 , 29 30 31 these differences failed to attain statistical significance. The recovery of thromboxane B₂ production appeared identical in the groups by day 35, and pretreatment levels had been attained by day 42.

All three groups had similar effects on the template bleeding time on day 27 of the treatment period (Fig. 3Figure 3Comparative Effects of the Three Aspirin Regimens on the Prolongation of Bleeding Time.). The mean bleeding time was significantly prolonged in all three groups: from 228±23 to 385±30 seconds (P<0.05) in the controlled-release group, from 267±19 to 408±33 seconds (P<0.01) in the 162.5-mg group, and from 242± 16 to 514±40 seconds (P<0.01) in the 325-mg alternate-day group. The differences between the groups were not significant. Similar prolongations of bleeding times were seen on day 5.

The effects of the three regimens on the excretion of thromboxane A₂ and prostacyclin metabolites on days 27 and 28 are shown in Figure 4.Figure 4Mean (±SD) Effects of the Three Aspirin Regimens on Prostacyclin and Thromboxane Biosynthesis in the Final Two Days of the Dosing Period. Excretion of 2,3-dinor-thromboxane B₂ was depressed significantly from base-line values by day 27 with the 75-mg controlled-release regimen (93±13 vs. 28±5 pmol per nanomole of creatinine; P<0.01), with the 162.5-mg immediate-release regimen (100±25 vs. 14±3 pmol per nanomole of creatinine; P<0.001), and with the 325-mg alternate-day regimen (92±9 vs. 10±3 pmol per nanomole of creatinine; P<0.001). A similar depression was evident in both daily-dosing groups on day 28, whereas there was some degree of recovery (to 14±2 pmol per nanomole of creatinine) in the 325-mg group. When the data were expressed as a percentage of the base-line values, excretion of thromboxane metabolites was significantly lower on the last day of dosing (day 27) in the 325-mg group than on the corresponding day in the other treatment groups (Fig. 4).

Prostacyclin biosynthesis on day 27, as reflected by the excretion of 2,3-dinor-6-keto-prostaglandin F_1α, was depressed from base line (17±3 vs. 38±4 pmol per nanomole of creatinine, respectively; P<0.001) in the 325-mg group. This corresponded to 43 ±6 percent of the pretreatment levels. Surprisingly, 24 hours after the last dose of aspirin, recovery remained depressed at 57±8 percent of pretreatment levels, or 21 ±3 pmol per nanomole of creatinine (P<0.01). Excretion of prostacyclin metabolites fell from 34±3 to 23±3 pmol per nanomole of creatinine (P<0.05) in the controlled-release group by day 27, which represented a fall in metabolite excretion to 84± 13 percent of baseline values (Fig. 4).

At the highest dose of infused bradykinin, some volunteers experienced facial flushing, lacrimation, dryness of the mouth, nasal congestion, and palpitations.15 , 20 The mean heart rate rose from 60±2 beats per minute before the infusion to 81 ±2 beats per minute (P<0.002) when the infusion reached its highest rate. Heart rate did not change significantly at the lower rates of infusion, and blood pressure was unaltered throughout the study. In the volunteers assigned to take aspirin placebo for four days, bradykinin increased excretion of prostacyclin metabolites by 567±193 percent of base-line values (P<0.01). Pretreatment with 75 mg of controlled-release aspirin for four days failed to suppress this response (640 ±139 percent of base line). By contrast, all the immediate–release regimens, including the 75-mg daily regimen, suppressed this index of stimulated systemic prostacyclin biosynthesis (P<0.001) (Fig. 5Figure 5Mean (±SD) Effects of Various Aspirin Doses for Four Days on Bradykinin-lnduced Biosynthesis of Prostacyclin.).

Discussion

Given the potent antiplatelet and vasodilator activities of prostacyclin in vitro9 and its formation during platelet activation in vivo,32 , 33 the preservation of this eicosanoid might enhance the effectiveness of aspirin as an antithrombotic drug. This may have particular importance in patients with heart failure or renal dysfunction in whom renal blood flow becomes dependent on vasodilator prostaglandins.34 , 35

A controlled-release preparation of aspirin was designed to meet the pharmacokinetic requirements for the presystemic inhibition of thromboxane A₂.16 , 26 , 36 A 75-mg dose of aspirin in either the controlled-release or the immediate-release formulation cumulatively inhibited the formation of thromboxane A₂ in platelets. There was a tendency for the time to maximal effect to be delayed with the controlled-release preparation. A similar delay has been noted with an enteric-coated, low-dose preparation.18 When the 75-mg daily dose of the controlled-release preparation was combined with a loading dose of 162.5 mg of immediate-release aspirin, maximal inhibition of platelet thromboxane A₂ was achieved and was sustained over a four-week dosing period. This effect is comparable to that of conventional dosing regimens that are clinically effective.3 The prolongation of the bleeding time, an index of interactions between platelets and the vessel wall, was also similar to that observed with conventional regimens.

This approach contrasts with two strategies that have been used previously to achieve biomedical selectivity for thromboxane A₂ with aspirin. Low doses of conventionally formulated aspirin depress both basal and stimulated prostacyclin biosynthesis.12 , 13 Their biochemical selectivity is at best relative, not absolute.37 , 38 Dosing with aspirin on alternate days is based on the premise that endothelial cells, unlike platelets, retain the capacity to generate new enzyme despite the irreversible inhibition of prostaglandin G/H synthase. Recovery of basal and stimulated indexes of prostacyclin biosynthesis occurs rapidly in volunteers after single doses of aspirin.15 , 20 , 39 A surprising finding in the present study was that this assumption was not borne out with a prolonged, alternate-day dosing regimen. Long-term daily administration of the controlled-release preparation also tended to reduce basal urinary excretion of prostacyclin metabolites, although less so than was observed with either of the higher-dose, immediate-release regimens. To discriminate between an unlikely effect of systemic salicylate15 and the aspirin-induced inhibition of prostacyclin in the gut, the systemic vasculature, or both,40 we assessed the effect of aspirin on the increment in the excretion of prostacyclin metabolites that was evoked by the systemic infusion of bradykinin. This increment was not significantly altered by pretreatment with the 75-mg controlled-release preparation, but it was significantly depressed by the same total dosage in the conventional formulation.

In conclusion, the controlled-release preparation of aspirin may permit a controlled evaluation of the clinical importance of preserving systemic prostacyclin biosynthesis during platelet inhibition by aspirin, a point that is still at issue. In addition, given the potential importance of inhibiting maternal platelet thromboxane A₂ with aspirin in preeclampsia,41 a condition characterized by impaired prostacyclin biosynthesis,42 avoiding a depression in fetal platelet thromboxane A₂ 43 by reducing the systemic bioavailability of low-dose aspirin in the mother may prove to be clinically desirable.

Supported by a grant (HL 30400) from the National Institutes of Health and by a grant from Glenbrook Pharmaceuticals. Dr. Clarke is the recipient of a Fogarty International Fellowship (TWO 4262) from the National Institutes of Health. Dr. FitzGerald shares in a pending patent application in reference to the controlled-release preparation of aspirin described in this paper.

We are indebted to W.N. Charman, S.A. Charman, and A.K. Pedersen for helpful suggestions that have contributed to this work.

Source Information

From the Division of Clinical Pharmacology, Rm. 538, Medical Research Bldg., Vanderbilt University, Nashville, TN 37232, where requests for reprints should be addressed to Dr. FitzGerald.

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