Bleeding during acetylsalicylic acid and

anticoagulant therapy in patients with reduced

platelet reactivity after aortic valve

replacement

Jon Dale, M.D. Eric Myhre, M.D. Dieter Loew, M.D. Oslo, Norway

The antithrombotic effects of drugs that modify platelet functions have been evaluated in several clinical trials.‘-‘” Such agents may be particularly useful in conditions related to arterial thrombo- sis, because platelets play a dominant role in the formation of the thrombi.” Platelet adhesion, release, and aggregation are important steps in the thrombotic process.ll Several drugs inhibit the platelet release reaction and thereby the subsequent irreversible aggregation.” Most im- portant are acetylsalicylic acid (ASA), indometh- acin, sulfinpyrazone, and butazolidin, while dipy- ridamole may reduce platelet aggregation through other mechanisms.13 ASA is most exten- sively used, and the results from several studies indicate a preventive effect on arterial thrombus formation.‘~ 2. ’

Anticoagulant in adequate doses effectively prevents venous thromboembolism because plas- ma coagulation is the predominant mechanism in this type of thrombosis. Low-dose heparin admin- istration has recently been introduced as an alternative treatment in this condition.” Antico- agulant drugs are also widely used in the preven- tion of arterial thrombosis, particularly after prosthetic valve implantation,15. Ifi and are em- ployed by several centers in coronary heart dis- ease. The effect is limited, however, and further

From Medical Department B and Institute for Thrombosis Research, Riishospitalet, University Hospital, Oslo, Norway.

Received for publication March 1, 1979.

Accepted for publication June 12, 1979.

Reprint requests: Dr. J. Dale, Medical Department B, Rikshospitalet, Oslo 1, Norway.

research is needed to find a therapy that effective- ly inhibits arterial thrombus formation. The com- bination of drugs that modify platelet function and anticoagulants may prove useful, since it attacks more than one step in the thrombotic process9 A combination of anticoagulants with dipyridamole,” and later with ASA,“, lo gave an antithrombotic effect superior to anticoagulants alone in patients with prosthetic heart valves. Others have combined two drugs that affect platelet function.17

All agents that inhibit thrombus formation are potential inducers of bleeding, since the mecha- nisms responsible for stopping hemorrhage are the same that form thrombi when stimulated pathologically.” Combined antithrombotic thera- py might be particularly dangerous, since it affects more than one part of the hemostatic mechanism. Therefore, the tendency of bleeding that a therapy may induce should always be evaluated along with its antithrombotic effects.

Patients with prosthetic heart valves are par- ticularly useful for studies on prevention of arte- rial thromboembolism, because such complica- tions are frequent and quite well defined.‘“, l6 In such patients, however, the platelet adhesiveness is reduced,18 the bleeding time is prolonged, and platelet survival is’ shortened,1s-2* most probably because of trauma inflicted by the prosthetic valves.‘*. ?? This reduced platelet reactivity might in itself predispose to bleeding.

Patients with aortic ball valve prostheses have participated in a randomized clinical trial and have received either anticoagulants alone or com-

746 June, 1980, Vol. 99, No. 6 0002-8703/80/060746 + 07$00.70/O 0 1980 The C. V. Mosby Co.

Bleeding during anticoagulant therapy

bined with ASA.” In the present study the bleed- ing complications are analyzed in relation to platelet function, intensity of anticoagulant treatment, and administration of ASA.

Materials and methods

Patient material. Included in the study were 148 patients who had received a Starr-Edwards aortic ball valve more than two years previously, and who were willing to participate.” Two types of the valve had been used, series 1200 with silicone rubber ball and metal cage, and series 2300 with hollow Stellite ball and cloth-covered cage. Twenty-one patients had been excluded, either because they were older than 70 years, had suf- fered gastrointestinal or other types of bleeding previously, or because other heart operations were planned. They had all taken anticoagulants since the operation.

Antithrombotic study. The patients received either one gm. of microencapsulated ASA (Colfar- it, Bayer AG, Wupperthal, West Germany) daily, or placebo according to randomization, the study being double-blind. The patients were strictly informed not to take any other preparations containing ASA, a list with all forbidden prepara- tions being given to them. All patients received anticoagulant therapy, the intensity of which was controlled by Thrombotest (TT),23 aiming at levels of 10% of normal activity.

We had decided that ASA or placebo should be discontinued after all acute complications except those related to thromboembolism or cardiocircu- latory performance. This was done in order to avoid possible undesired effects of the combined therapy.

The patients were examined after one and finally after two years. A clinical examination was done, x-ray of the heart and lungs was performed, and an ECG and several routine blood tests were taken. Three stool specimens from each patient were examined for occult blood by the benzidine method, and plasma salicylate levels were determined. The few patients that were unable to meet were controlled by local physi- cians or hospitals, and questionnaires were sent to the doctors of all patients in order to obtain complete information.

The diagnostic criteria used for thromboem- bolic complications and a more detailed descrip- tion of the management of the study have been published earlier.9

Table I. Bleeding complications in patients receiv- ing ASA and anticoagulants, and in patients on anticoagulants alone

Intracranial 2 1 3 2 Gastrointesti- 11 2

nal Other 2 1

Total 15 1 6 2

Platelet functions. Platelet counts, platelet retention in glass bead columns, and bleeding time were determined in 16 patients with bleeding complications, either before the study startedI or after discontinuation of ASA or placebo when the patients had recovered completely from the effects of blood loss. The results were compared with those from unselected patients without bleeding complications.18 All patients received anticoagulants when tested.

Platelets were counted in a hemocytometer using a modification of Nygaard’s method.z’ Platelet adhesiveness was estimated from reten- tion in glass bead columns according to the modified method of Hellem.‘j The bleeding time was measured from two incisions by a modifica- tion of Ivy’s method.‘6 The length of the cuts was approximately one cm., and the depth adjusted so that a drop of a matchhead’s size emerged in 30 seconds.

Results

The combined therapy was given to 75 patients, while 73 received placebo and anticoagulants.

Bleeding complications were more frequent in patients on ASA and anticoagulants than in those on anticoagulants alone (Table I), the incidence being 13.9 and 4.7 episodes per 100 patients per year, respectively. The difference is statistically significant (p < 0.02). The difference is entirely due to the significantly higher inci- dence of gastrointestinal hemorrhage (p = 0.01) in the former group of patients. Intracranial bleeding, which was the most serious complica- tion, was not more frequent in patients who received ASA in addition to anticoagulants. It

American Heart Journal 747

Dale, Myhre, and Loew

Table I I. Bleeding complications classified accord- ing to the effect on whole blood hemoglobin (hb.) concentration (intracranial hemorrhage is not included)

Lowest hb. concentration

Lower than 8 g./dl. 5 2 8 to 11 g./dl. 6 Higher than 11 g./dl. 2 1

Table HI. TT values before bleeding episodes in the two groups of patients with aortic ball valve prostheses

TT, % ofnormal 11

Lower than 5 4 2 6 to 10 9 4 11 to 15 1 16 to 20 1

Table IV. Relation between the intensity of anti- coagulant therapy and the severity of bleeding (intracranial hemorrhage is not included)

TT before bleeding

No. of patients with hb. concentration:

>I1 g./dl. 8-11 g./dl. (8 g./dl.

Lower than 5% 4 6% to 10% 2 5 3 11% to 15% 1 16% to 20% 1

caused one death in patients on combined thera- py and two in the placebo group.

The patient taking ASA had, for some weeks, clinical signs of sepsis before she died from intra- cranial hemorrhage, and autopsy revealed that the bleeding had occurred in a septic locus. In a second patient on combined therapy, and subdu- ral hematoma developed less than one week after the start of the study, but this 56-year-old woman recovered completely after operation.

Only two of the bleeding episodes in the group receiving combined therapy occurred after TT values higher than 10% (Table III). The TT values of all patients throughout the observation period were reflected by those found at the annual controls. In comparison, only 33% of all values in patients on combined therapy and 28% in those on anticoagulants alone were 10% or lower. The differences between the proportions of low TT values before bleeding and at annual controls were highly significant in both groups of patients (p < 0.01). The episodes of intracranial bleeding all occurred at TT values of 9% or lower. Thus, intense anticoagulant therapy was asso- ciated with an increased risk of bleeding, particu- larly when ASA was given.

In the placebo group a 53-year-old man died The severity of the bleeding episodes was after two days in deep coma. At autopsy a related to the intensity of the anticoagulant subdural hematoma as well as an embolus in the therapy before hemorrhage (Table IV). The middle cerebral artery was found. There was, results indicate that the blood loss at low TT

Table V. Time relationship between the start of the study and the onset of bleeding

Less than 1 week 3 1 week to 1 month 4 2 to 6 months 2 2 7 to 12 months 4 2 13 to 18 months 1 19 to 24 months 2 1

however, no connection between bleeding and embolus, and no history of trauma could be revealed. It was regarded most likely that the bleeding had occurred first and was of the greatest significance. Two other men on anticoag- ulants alone suffered from intracranial hemor- rhage; one died, the other survived after surgical evacuation, but with considerable functional dis- turbances. The blood pressure was normal in all patients with intracranial bleeding.

The severity of the other types of bleeding episodes was estimated from the lowest hemoglo- bin concentration after the hemorrhage (Table II). In five patients on combined therapy and two on anticoagulants alone, Hb fell below 8 g./dl. and blood transfusions were required. The blood loss was gastrointestinal in these seven patients and all of them recovered completely.

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Bleeding during anticoagulant therapy

Table VI. Comparison of platelet functions in patients with and without bleeding episodes, with level of significance

Platelet pl per Adhesiveness, % Bleeding time, min.

No.

19 16 16

Patients with’ Patients without

bleeding: bleeding:

Mean S.E.M. No. Mean S.E.M. P

176,400 13.900 133 191,300 5.000 N.S.

24.3 2.3 67 35.4 2.5 p < 0.05 6.9 0.5 24 6.7 0.4 N.S.

values, regardless of ASA ingestion, tended to be particularly abundant. Thus, Hb fell below 8 g./dl. during all episodes in patients with TT at 5% or lower, and two of the five episodes of intracranial bleeding occurred at such low TT values.

The time from the start of the study until the onset of bleeding was recorded (Table V). Nearly half of the episodes developed during the first month of ASA ingestion, and only two patients on combined therapy bled during the second year of the study. In the placebo group, however, the six episodes were scattered throughout the obser- vation period as could be expected, since the patients had received anticoagulants constantly since the operation.

Platelet counts were moderately, but insignifi- cantly, lower in the patients’who developed bleed- ing episodes than in the others, and the bleeding time did not differ significantly between the groups (Table VI). Platelet retention in glass bead columns, which is considerably reduced in patients with prosthetic ball valves,‘* was signifi- cantly lower (p < 0.05) in patients with bleeding episodes than in those without.

Bleeding complications are not rare in patients who receive anticoagulants after valve replace- ment, and intracranial hemorrhage, which is par- ticularly serious, did not occur more frequently in our study than in others.27-33 A comparable anti- thrombotic effect was demonstrated in a simulta- neously performed study on valve patients as in our trial,l” while the incidence of bleeding was similar in these two groups and slightly lower than in our patients given combined therapy. The daily dose of ASA was 0.5 gm., and the anticoagu- lation aimed at TT values of 8 to 15%, but the intensity was not further documented. The com- bination of dipyridamole and anticoagulants offered a good antithrombotic effect in a previous trial in ball valve patients, but lethal intracranial bleeding occurred in two of 79 patients in one year, while gastrointestinal hemorrhage did not occur.3

Occult blood loss was detected in 12 of the 47 patients who remained on combined therapy until the end of the study, and in three of the 53 patients of the placebo group,

Discussion

The study revealed a higher incidence of bleed- ing episodes in the ball valve patients who received ASA in addition to anticoagulants, than in those given equally intensive anticoagulant therapy alone. The rate of complications was, however, acceptable in view of the effective pro- tection achieved against arterial thromboembol- ism with the combined treatment.g Moreover, the higher incidence was entirely attributable to gas- trointestinal bleeding, from which all recovered.

The thrombotic and hemostatic mechanism, and the interactions between platelets and anti- coagulation, are complex.” Thus, platelet phos- pholipoproteins exposed by the platelet release reaction accelerate the intrinsic coagulation sys- tem with the formation of thrombin, which is a potent inducer of just the platelet release reac- tion. ASA and anticoagulants affect thrombosis and thereby hemostasis on different levels. ASA inhibits irreversible platelet aggregation by inhib- iting the enzyme. cycle-oxygenase, preventing the production of labile endo-peroxides which are strong inducers of the release reaction.34 Antico- agulants lead to a diminished production of some coagulation factors and thereby to reduced thrombin formation after activation of coagula- tion. One could therefore expect an additive or even synergistic effect on arterial thrombosis and hemostasis by these drugs. The reduced adhesive- ness of the platelets, a reactivity involved in primary hemostasis, might further potentiate the inhibitory effect on thrombosis and hemostasis.

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Dale, Myhre, and Loew

Consequently, a particularly high incidence of bleeding complications could be feared in patients given combined therapy, since hemostasis would be affected in three different ways.

The prevention of arterial thromboembolism must be weighed against the increased risk of bleeding, and our study represents a step in the search for a therapy that may offer a satisfactory protection against arterial thrombosis at an acceptable risk of bleeding. Whether this can be achieved by intensive anticoagulant therapy or by large doses of ASA, or by a combination of the two in more conventional doses, can only be determined in clinical trials.

The influence of each of the two drugs of the reduced platelet reactivity may to some extent be analyzed from our results. Thus, the dose of ASA given undoubtedly increased the bleeding tenden- cy, but apparently only from the gastrointestinal tract. Such bleeding is also well known to occur after ASA ingestion even in patients without anticoagulants and with a presumably normal platelet function.35. 36 This indicates that local irritation of the mucosa, either from the normal gastric contents or from ASA liberated in spite of the microencapsulation, is important in addition to the general effect on hemostasis. Bleeding may be more easily precipitated in some patients than in others because their platelets might be partic- ularly sensitive to the effects of ASA.“’

The role of anticoagulants for the occurrence of bleeding complications also seems obvious. Thus, bleeding correlated with the intensity of the therapy as judged from the TT levels before the episodes. And equally important, the severity of bleeding was related to the intensity of the treat- ment. Intensive anticoagulation was therefore without doubt responsible for several serious bleeding episodes. In a study on the effects of intensive anticoagulant therapy in coronary heart disease, a condition with near normal plate- let function, bleeding episodes occurred almost as frequently as in our patients using combined therapy.“8 The majority of TT values were below lo%, with a mean of 855, as compared to 11% in our trial. In studies with less intensive anticoagu- lation, bleeding is less frequent.3Y Standardization of reagents for control of anticoagulant therapy is difficult, and different thromboplastins give dif- ferent results.“” The coagulation activity in per- cent of normal as measured with Thrombotest and Simplastin A roughly parallel each other,

while most other methods give considerably high- er values.1o Our results demonstrate the intensity of anticoagulant therapy is also important for the bleeding tendency when given in combination with ASA.

The role of the reduced platelet function is more difficult to evaluate. However, the correla- tion between the number of adhesive platelets and the bleeding time,‘” as well as the particularly marked prolongation when ASA is given to patients with a low platelet adhesiveness,“’ sug- gest that the reduced platelet reactivity was of importance. The low number of adhesive platelets in patients who developed bleeding as compared to the others indicate that reduced platelet adhe- siveness predisposed to hemorrhage. The consid- erably reduced platelet adhesiveness is not fur- ther diminished by ASA ingestion, which demon- strates that the trauma by the valve and ASA influence different platelet functions.q’

Bleeding tended to occur shortly after the start of ASA administration, which may have two possible explanations: the bleeding may be ini- tiated as soon as the TT level drops according to unavoidable physiological variations, or some patients may be particularly susceptible to the effect of ASA. A combination of the two mecha- nisms is probably the most likely cause of early gastrointestinal bleeding at low TT values. The results indicate that the combined therapy can be continued more safely if it is tolerated for the first two months.

In conclusion, the greater tendency towards gastrointestinal bleeding was acceptable in rela- tion to the antithrombotic effect achieved with the combined therapy. The correlation between the intensity of anticoagulation and the incidence of bleeding raises a question which is the issue of a present investigation: Will a slightly less inten- sive anticoagulant therapy in combination with ASA offer an equally effective protection against arterial thromboembolism, and will the bleeding tendency thereby be reduced?

Summary

Bleeding complications were evaluated in 148 patients with single Starr-Edwards aortic ball valve prostheses in a study designed to prevent arterial thromboembolism. They received either one gm. of ASA daily or placebo in combination with anticoagulants, and were observed for two years. Only two embolic episodes occurred in

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patients on combined therapy, as compared to 12 episodes in the placebo group.

Fifteen bleeding complications developed in patients receiving ASA, seven during the first month. Two patients suffered intracranial hemor- rhage and one died, the others recovered com- pletely. Six episodes occurred in patients on anti- coagulants alone; three intracranial complica- tions caused two deaths. The higher incidence of bleeding induced by the combined therapy was entirely due to gastrointestinal hemorrhage, indi- cating that irritation of mucosa was important in addition to the ASA-induced inhibition of hemo- stasis.

The intensity of anticoagulation correlated sig- nificantly with the occurrence of bleeding, and severe blood loss developed only after intensive therapy. This raises the question whether a slightly less intensive anticoagulation in eombi- nation with ASA will maintain a satisfactory antithrombotic effect at a lowered risk of bleed- ing.

Platelet adhesiveness, which is partly responsi- ble for primary hemostasis, was reduced in the ball valve patients, and more in those who bled than in the others.

It is concluded that the higher incidence of gastrointestinal bleeding in patients who received ASA and anticoagulants than in those on anti- coagulants alone was acceptable when compared to the antithrombotic effect achieved with the combined treatment.

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