Arterial thromboembolic complications in patients with Starr-Edwards aortic ball valve prostheses

Review

Arterial thromboembolic complications in patients with Starr-Edwards aortic ball valve prostheses

Jon Dale, M.D. Oslo, Norway

Arterial thromboembolic complications occur frequently in patients with implanted hearts valves, 1-8 systemic emboli representing a considerable threat in the early and late course of valve replacement,2, 9 since the emboli often lodge in cerebral arteries, l' 7, 8. 1o-13 All patients probably run the same risk of such complications, regard- less of cardiovascular success of the operation.

Anticoagulant t rea tment has been widely used in order to reduce arterial thromboembolism, but full protection has not been achieved. 1, 2, s, 11.14 For the same purpose the older Starr-Edwards aortic ball valves were modified, 15 and a reduced incidence has been found with the cloth-covered valves. 6 More recently, disc valves have been introduced, but although a low rate of thromboembolic episodes has been found in a series of patients with aortic valves of this type, 16 a higher incidence has been reported with mitral disc valves,17, is and arterial thromboembolism still constitutes a serious problem in valve replacement.

The present investigation was performed in order to reveal the incidence of arterial thromboembolic complications in patients with Starr- Edwards aortic ball valves, and to study factors that might influence the incidence. Such evaluation was necessary since the patients entered a clinical trial with acetylsalicylic acid to study its antithrombotic effects. Further, a comparison with results from a similar study in patients with disc valves will be made later.

Material and methods

Single Starr-Edwards aortic ball valves were implanted in 253 patients from January, 1967,

From the Institute for Thrombosis Research, University Hospital. Rikshospitalet. Oslo. Norway.

Received for publication Sept. 11. 1974

Reprint requests to: Jon Dale. M.D.. Institute for Thrombosis Research, University Hospital, Rikshospitalet, Oslo 1. Norway.

until December, 1970. During the first year some valves of other types were also used, but for the rest of the period only Starr-Edwards valves were inserted. Until November, 1968, 80 prostheses of series 1200 with Silastic balls and metal cages were implanted; from then on, 173 valves of series 2300 with hollow stellite balls and cloth- covered cages is were used. T h e operation was performed in 181 men and 72 women, the mean age being 52.2 and the range 20 to 71 years. No patient was regarded to be too ill for operation and 18 of the valve replacements were done as emergency operations because of advanced circu- latory failure.

Valve implantations were only done in this hospital in Norway during those years, which explains the large number of patients included in the study. All operations were performed by the same experienced team of surgeons, and the oper- ating technique and postoperative care remained largely unchanged. Oxygenation was achieved by a Rygg-Kyvsgaard bubble oxygenator, and since 1970 a Kay-Anderson disc-oxygenator has been employed. Light hypothermia, 32 to 34 ~ C., was routinely used, and the left coronary artery was always perfused. The patient was heparinized with 300 I.U. of heparin per kilogram of body weight, and after operation the activity was neutralized by protamine. Oral anticoagulation with Dicumarol or warfarin was started after two to four days unless bleeding persisted.

Follow-up

Most of the patients have been sent to the car- diologic department one or more times after operation, and their hospital records were ex- amined. Reports have been obtained concerning patients who died in other hospitals or at home.

All surviving patients were asked to meet for examination in the autumn of 1972, and all except six were able to come. The examination included

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Table I , Mor ta l i t y a f te r imp lan ta t i on of single S ta r r -Edwards aort ic ball valve pros theses

Valve implantations Early deaths Alive after one month Late deaths Alive at follow-up

Number ofpatien~:

With valvesofseries:

Total 1200 2300

253 80 173 37 10 27

216 70 146 41 18 23

175 52 123

T a b l e II. Pos topera t ive t h romboembo l i c complicat ions in pa t i en t s wi th S t a r r -Edwards aor t ic ball valve prostheses

Type of thromboembolic

complication

No. of compli- No. of No. of cations patients deaths

4 Cerebral emboli (total) 5 A. Serious B. Intermediate C. Mild

Peripheral emboli 1 Myocardial infarction 6 Thrombus on valve, 2

leakage

1 6 6 1

Total 14 12 6

a careful h is tory of t h romboembol i c or bleeding episodes, a physical examinat ion , roentgenolog- ical examina t ion of hea r t and lungs, and blood tests regarding pla te le t function, coagulat ion, fibrinolysis, i n t r avascu la r hemolysis, and anemia . Some of the resul ts will be publ ished separa te ly .

Ant icoagulan t t r e a t m e n t was control led by Th rombo te s t , TM reflecting the activit ies of coagulat ion factors II , VII , and X, a iming a t a the ra - peutic level be tween 5 and 15 per cent.

In addition, a fo rm was sent to the doctors of all pat ients , asking for informat ion. Thus , the da ta presented are collected in three different ways: From hospi ta l records, examina t ion of the pat ients , and informat ion from their doctors. None of the pa t i en t s were lost for follow-up.

Embol ic episodes were listed if the following criteria were fulfilled: (1) Acute onset wi th full deve lopment of s y m p t o m s in the course of 20

minutes, (2) Dis turbance of neurological funct ion in cerebral embolism, or func t iona l d is turbance due to arres ted blood flow to o ther regions, (3) Observat ion of the s y m p t o m s by others t h a n the patient , and (4) Dura t ion of s y m p t o m s for more than 30 minutes. The diagnosis of myocard ia l infarct ion was based on general ly accepted criteria: his tory of acute precordial pain, e lectrocardio- graphic signs, and rise of t empera tu re , leukocyte count or t ransaminases . Al ternat ively , the diagnosis o f ar ter ia l t h romboembo l i sm could be made when a t h rombus was d e m o n s t r a t e d a t au topsy or at operat ion.

Cerebral emboli were divided in three sub- groups according to the severity. "Ser ious" were emboli causing dea th or considerable p e r m a n e n t dis turbance of neurological function, " in te rme- diate" embol i producing more mode ra t e disabil i ty lasting for a t least two weeks, and "mi ld" were episodes wi th slight and t rans ien t symptoms .

Results

The mor t a l i t y ra te a t opera t ion and during the first pos topera t ive m o n t h was 14.6 per cent {Table I), and this r emained cons tan t t h roughou t the period. The pos topera t ive th romboembol ic complicat ions are listed in Tab l e [I. Five cerebral embolic episodes occurred; four led to p e r m a n e n t disability bu t none of t h e m were fatal . Seven myocard ia l infarct ions were diagnosed, all pa- t ients died, and au topsy was per formed in six. Th rombi were found in coronary arteries in five of them, one t h r o m b u s ex tended f rom the ring of the implanted valve into the left coronary ar tery . Coronary atherosclerosis was extensive in one, more m o d e r a t e in two, and min imal in the three other pat ients . A myocard ia l infarc t ion was found in spite of open coronary ar ter ies in a 40-year-old man who died af ter several days of in t rac tab le shock. This case is therefore not recorded as thromboembol ic . Three cerebra l embolic episodes and three myocard ia l infarct ions occurred within the first week.

Thrombos i s format ion migh t also dis turb the function of the valve itself. A 36-year-old man developed leakage of the pros the t ic valve three weeks a f te r the implan ta t ion . At reopera t ion th rombot ic mater ia l , l imit ing the m o v e m e n t of the ball, was removed f rom the cage of the valve. Two weeks la ter the s y m p t o m s reappeared, and a third opera t ion was performed. Newly formed

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Arterial thromboembolic complications in valve prostheses

thrombotic masses interfered with the movement of the ball, and the valve was replaced by another one.

The average observation time for the 216 patients that survived the postoperative period was 36.5 months, as calculated from the begin- ning of the second month (Table III). Thus, a total of 7896 "pat ient-months" were recorded. Late thromboembolic complications were found to be responsible for 7 of the 41 deaths tha t occurred during the follow-up period.

A total of 46 late thromboembolic episodes were recorded in 40 patients, the majority of these suffering from cerebral emboli, causing four deaths (Table IV). Autopsy was done in three patients, emboli were demonstrated in cerebral arteries in two of them, while a cerebral infarction was found in the third. Two other embolic episodes caused severe permanent disability. Five patients suffered a myocardial infarction and three died. Autopsy was performed in two, and thrombi were found in modera- tely atherosclerotic coronary arteries of both. Thus, late arterial thromboembolic complications were observed in 18.5 per cent of the patients during the follow-up period, causing 17 per cent of the deaths. The incidence of the late complications was 7.0 episodes per 100 patients per year.

Autopsy was done in 59 of the 78 patients who died, and a thrombus was found on the ring or cage of the valve in 5 cases, after two early and three late deaths. One of the patients had died two weeks after operation from a myocardial infarction caused by extension of the thrombus as mentioned, and another from a cerebral embolus after six months, both had valves of series 2300. No embolic episodes were revealed in the other three patients, who died from complications unrelated thrombosis, and had valves of the older type.

The incidence of late thromboembolic complications was considerably higher in the patients with valves of model 1200 than in those with the newer valves (Table V), the difference being highly significant (p < 0.01). The mean observation time differed, however, between the two groups. Therefore, the incidences recorded during the first two years after the operations were compared, this difference also being significant (p = 0.01).

Total

Table ]1]. Observation time in patients with Starr-Edwards aortic bail valves. The first postoperative month is not included

Starr-Edwards No. of Mean observation valve series patients time (months)

1200 70 44.7 2300 146 32.7

216 36.5

Table IV. Late thromboembolic complications in patients with Starr-Edwards aortic ball valve prostheses

Thromboembolic complication

No. of complications

No. of patients

No. of deaths

Cerebral emboli 33 28 4 Serious 7 Intermediate 14 Mild 12

Peripheral emboli 7 6 Myocardial infarction 6 6 3

Total 46 40 7

The long observation period in many of the patients made it possible to study thromboembolism in relation to time after operation (Tables V and VI}. Thus, 3,502 "pat ient-months" were observed after more than two years. The episodes recorded were quite equally distributed through- out the observation period. A slight, nonsignifi- cant reduction was found in patients with valves of series 1200 after two years. This contributed to keep the total incidence quite constant, since the number of patients with the less thrombogenic valves of the newer series fell gradually in time, and none of them were followed for more than four years.

An at tempt was made to estimate whether the anticoagulant t reatment was satisfactory at the time of thromboembolic complications. The Thrombotest (TT) values had been determined less than two weeks before 35 of the 46 episodes (Table VII), and 80 per cent of the values lay within the therapeutic range of 5 to 15 per cent activity. This compares favorably with T T levels at the end of the follow-up when 67 per cent of the 169 values were satisfactory. Although the

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Table V. Late thromboembol ic episodes in pa- t ients with S ta r r -Edwards aortic ball valve prostheses. Relat ion to valve type and t ime after operation

Starr-Edwards aortic prostheses

Series Series 2300 1200 Total

No. of thromboembolic episodes 17 29 46 Within two years 10 15 25 After two years 7 14 21

Episodes per 100 patients per year 4.3 11.1 7.0 Within two years 4.0 13.2 6.8 After two years 4.8 9.5 7.2

Table VII. Distr ibution of Thrombotes t (TT) values before 35 of the 46 late thromboembol ic episodes, and at the end of the follow-up period in 169 pat ients with aortic ball valves

TT-value

Distribution of TT-values in per cent

Before At end of episode follow-up

Lower than 5 per cent 0 1.2 6 to 10 per cent 34.3 36.3 11 to 15 per cent 45.7 30.4 16 to 20 per cent 14.3 12.6 21 to 25 per cent 2.9 8.2 Higher than 26 per cent 2.9 11.1

Table VI. Number of late thromboembol ic episodes and calculated incidence for each year af ter valve implanta t ion

I No. of I Episodes per 100 Time after operation episodes patients per year

Within the first year* 13 7.1 One to two years 12 6.6 Two to three years 11 7.7 After three years 10 6.7

*Only episodes observed dur ing the last 11 months of the first yea r are included.

activity of coagulat ion factors could no t be estab- lished at the t ime of th rombus formation, the ant icoagulant therapy was well control led in most of the patients.

Some degree of affection of the mi t ra l valve was found in 25.9 per cent of the pat ients who h a d ' a single aortic valve implanted, and in some of them a mitral commisuro tomy had been performed. Thromboembol i sm did n o t develop more frequently in the pat ients with concomi tan t mitral disease than in the others.

Cont inuous a r rhy thmia , most ly atrial fibrillation, was seen in 29.6 per cent of the patients, bu t was not found to be a predisposing factor for late a r te r ia l thromboembolism.

There was no relation between the incidence of late thromboembol ic complicat ions and the hear t size in pat ients who survived the first postoperative month . Thus, the mean preoperat ive hear t size in pat ients who developed late episodes was 672 ml. per sq. M. as compared to 674 in those who

did not, while the mean values in the two groups at the end of the follow-up period were 573 and 589 ml., respectively. The plasma lacta te dehydrogenase activity (LDH), reflecting the degree of intravascular hemolysis, 2~ was compared in patients with and wi thout late thromboembol ic episodes. The L D H values were insignificantly higher in patients wi thou t late complicat ions in both valve groups.

Discussion

The early incidence of thromboembol ic complications following valve implanta t ion is high,1. 2. 6. s 16. 15 and myocardia l infarct ion is a frequent cause of early death. '- 2. 5. 21.22 Arterial thrombi are mainly composed of platelets and fibrin23, 24 and platelet aggregation and adhesion to subendothelial s t ructures or foreign surface are early steps in t h rombus formation. 25-27 Thus, the foreign mater ia l represented by the valve itself and the turbulence caused by the passage of blood th rough it will favor thrombosis, and thrombi are often found on the cage of the valve 1, 8 .... 21 as demons t ra ted in six of our patients. After a period of th rombocytopen ia following hear t operations, thrombocytos is de- velops with hyperreact ive platelets, 26 which may in par t explain the s t rong tendency to arterial thrombosis. Since in t ravascular hemolysis occurs in a lmost all pat ients with aortic ball valves, ~9 the platelet aggregating substance adenosine diphosphate (ADP) 59 might be liberated in amounts great enough to influence platelet behavior near the valve, even if A D P is rapidly

656 May, 1976, Vol. 91, No. 5


cleared from plasma. 31 As a consequence of these changes, thrombus formation may start imme- diately or shortly after the operation, explaining why valve thrombi are found and emboli occur s. ,0 within the first week.

The high incidence of early myocardial infarction 1, 2 may have several causes. Emboli from the valves may cause infarction, and coronary thrombi may be formed because of interference with the intima at operation or at cannulation, or to disturbance at coronary blood flow during extracorporeal circulation 21 or after the implanta- tion. However, traumatic lesions were found in only one of the patients who died from early infarction.

The incidence of late arterial thromboembolic complications in patients with aortic ball valves receiving anticoagulant t rea tment varies considerably from one investigation to another.'- 3. 4.6.7.8 . . . . . 3 . 1 5 . 2 1 . 3 2 This may part ly be explained by differences in observation time, valve type, diagnostic criteria, registration man- ner, or intensity of anticoagulant t reatment, and most materials have been too small to allow estimation of the incidence. In three studies, the annual rate of complications compared well with the results presented here2, 8. ,1 Most of the late thromboembolic episodes were cerebral, which may reflect the real distribution, but it is more likely that small emboli in other organs are asymptomatic and therefore remain unrecog- nized24

The diagnosis of cerebral embolism was based on strict criteria. A sudden onset was demanded in order to exclude cases of intracerebral hemor- rhage, since studies on general autopsy materials have shown tha t thrombotic or embolic arterial occlusions are the predominant causes of larger ~' and smaller 36 cerebral infarcts. Definite disturbance of neurological function was regarded to be necessary to exclude episodes unrelated to thromboembolism. Nevertheless, a risk of erroneous diagnosis still exists, especially for the milder episodes. On the contrary, the incidence of cerebral embolic episodes may be higher than recorded, since five cases of sudden death, usually believed to be due to ventricular fibrillation or cardiac standstill, were not included. Small cerebral emboli may also remain undetected, and the strict criteria may lead to exclusion of episodes with less typical symptomatology. Late myocardial infarction was regarded as a thromboembolic

complication, although the etiology may be complex. 2~ However, the rate of thrombotic or embolic infarctions might be underestimated, since smaller infarctions with moderate symptoms could be unrecognized.

The ring and cage of the prosthesis of model 2300 was covered with cloth in order to favor endothelialization and thereby reduce thromboembolism.15, 37 A neointima is formed, but not always completely, and thrombotic material may be found instead2, 4 A somewhat lower incidence of arterial thromboembolism with cloth-covered than with uncovered valves has been reported, 6, 7 and the number of embolic episodes has been found to decline after 6 to 12 months 6, 21 when endothelialization should have taken place. In the material presented here the incidence was significantly lower in patients with valves of series 2300 than of series 1200, but the rate was not reduced after one or two years. Since model 2300 has a double cloth-covering of the ring, the orifice-to-ball ratio is smaller than in model 1200,37 and the systolic gradients across the valves are considerably higher2, 37 Consequently, more turbulent flow is probably caused by these valves, and the degree of hemolysis is higher. ~9 In spite of this, the tendency of thromboembolism was reduced, which may be due to endothelialization of the cloth. The cloth-covered prosthesis has been developed further to the "composite seat'" types with a greater orifice-to-ball ratio and better hemodynamic performance, 3 and probably a lowered risk of embolic episodes than with type 2300,6, 14, 33, 38 although thrombi are known to be formed. 14 Composite seat valves have not been used in this hospital, since the disc valves became available.

I t has been claimed that the tendency to arterial thromboembolic complications is reduced after two years J, 11 In the material presented here the observation period is long enough to consider the influence of time upon the occurrence of such complications. The incidence was quite constant from year to year after operation. The longer the observation time, the higher was the percentage o f patients with the older, more thrombogenic valve 1200. This might of course tend to hide a slightly decreasing tendency for thromboembolism. Nevertheless, a striking lowering of the incidence with time did not occur.

Since early studies revealed a reduced incidence of arterial embolic episodes in ball valve patients

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receiving ant icoagulants , 11, 39 such t r ea tmen t has been widely used. Some authors have reported a lower rate of emboli in pat ients with well controlled an t icoagulan t therapy than in those with greater f luctuat ions in the activi ty of coagu- lation factors. 7, 1~ In the present study, the majori ty of T T values lay within the therapeut ic range before the episodes, and the T T levels were quite cons tant in mos t of them, indicating t h a t thrombosis format ion s tar ted in spite of adequate t reatment . Thus, well performed an t icoagulan t therapy does not entirely prevent arterial thromboembolism. This is not surprising, since adhesion and aggregation of platelets are early steps in arteria thrombosis formation, and the platelets remain unaffected by ant icoagulants . Drugs tha t modify platelet funct ions might theoret ical ly have an t i th rombot ic effects, and the pat ients therefore entered a controlled clinical s tudy with acetylsalicylic acid. Sullivan and colleagues 4~ found a significantly reduced incidence of arterial thromboembol ism in pat ients receiving dipyrida- mole.

The lack of correlation between cont inuous ar rhythmia and thromboembol ic episodes is in accordance with the findings of others. 7" 8 .... 34 However, the possible effects of in te rmi t ten t a r rhy thmia canno t be excluded. Concomi tan t mitral valve disease might increase the risk of emboli, but such a relation was not found. The equally low incidence of late thromboembol i sm in patients with a r rhy thmia or mitral disease as in the others could be ascribed to the an t icoagulant treatment.

The rate of late thromboembol ic episodes could be inversely related to the cardiocirculatory success of the valve replacement. However, the mean hear t size did not differ between the patients who developed such complicat ions and the others, indicating tha t a successful operat ion does not lower the risk of thromboembol ism. Substances tha t could induce platelet aggregation and coagulat ion are liberated from red cells during in t ravascular hemolysis21 The degree of hemolysis was, however, unrelated to the incidence of arterial thromboembol ic complications.

Summary

Arterial thromboembol ic complications were studied in 253 pat ients who had a single aortic Starr -Edwards ball valve implanted. During the first postoperative month , six patients died from

myocardial infarction, one was reoperated because of leakage caused by thrombus on the valve, and five others suffered six thromboembolic episodes.

Forty-six late thromboembol ic complications occurred in 40 of the 216 patients who s u r v i v e d the postoperative period. Seven died, four from cerebral emboli and three from myocardia l infarction. The late incidence was 7 episodes per 100 patients per year. Valves of series 1200 carried a significantly higher r i sk of arterial th romboem- bolism than did those of series 2300, and most episodes occurred in pat ients with well controlled ant icoagulant t reatment . The incidence was not influenced by time since operation, cont inuous arrhythmia, concomitan t mitral valve d i s ea se , heart size, or the degree of in t ravascular hemolysis.

I t is concluded tha t arterial thromboembol ic complications represent a major threa t to patients with aortic ball valves even several years after operation and in spite of intense anticoagulant therapy.

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American Heart Journal 659

Documents

Arterial thromboembolic complications in patients with Starr-Edwards aortic ball valve prostheses