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Combined aspirin and sulfinpyrazone in the prevention of recurrent hemodialysis vascular access thrombosis
THROMBOSIS RESEARCH 62; 737-743,199l 0049-3848191 $3.00 + .OOPrinted in the USA. Copyright (c) 1991 Pergamon Press pk. All rights reserved.
COMBINED ASPIRIN AND SULFINPYRAZONE IN THE PREVENTION OF RECURRENT HEMODIALYSIS VASCULAR ACCESS THROMBOSIS
Douglass T. Domoto, Joan E. Bauman, and J. Heinrich Joist Divisions of Nephrology and Hematology, St. Louis University School of Medicine St. Louis, Missouri 63110 U.S.A.
(Received 19.10.1990; accepted in revised form 26.3.1991 by Editor H.C. Kwaan) ABSTRACT We carried out a pilot study in 15 hemodialysis patients with recurrent vascular access thrombosis to examine whether the combination of low dose aspirin (85 mg once daily) and sultinpyrazone (200 mg three times daily) is safe and effective in the prevention of vascular access thrombosis. Hemostatic measurements were performed prior to and after four weeks of starting the drug combination. Baseline values for fibrinopeptide A were elevated in all patients while those for platelet factor 4, fibrinogen, antithrombin III and protein C were generally within normal limits. A major reduction in the frequency of vascular access thrombosis from 0.114 per month to 0.04 per month was noted during combined drug treatment (p < 0.001). Although in vitro platelet aggregation to various stimuli was markedly suppressed and platelet thromboxane B, formation was almost completely inhibited in patients on aspirin/sulfinpyrazone, this was not associated with a significant further prolongation of the bleeding time. A relatively high rate of complications, particularly mild gastrointestinal bleeding, was noted in patients on aspirin/sulfinpyrazone that could not be predicted on the basis of pre-treatment hemostatic test results.
INTRODUCTION Vascular access thrombosis continues to be a serious problem in patients who require chronic maintenance hemodialysis. Several studies have been reported which have examined the use of antiplatelet agents in the prevention of thrombotic occlusion of external arteriovenous shunts. Kaegi et al (1) carried out a double-blind, randomized, placebo-controlled 6-month clinical trial in 52 patients with straight arterio-venous shunts and observed an almost 75% reduction in the incidence of vascular access thrombosis with sulfinpyrazone (200 mg three times daily). Some of the patients in this study were also on warfarin anticoagulant therapy but the extent of reduction by sultlnpyrazone of vascular access thrombosis in these patients was similar to that in patients not on warfarin. Only two patients on sulfinpyrazone experienced a serious side effect (gastrointestinal bleeding) which led to removal from the study of one patient who was also on warfarin. Subsequently, Hatter et al (2) reported a 65% reduction in vascular access thrombosis by low-dose aspirin (160 mg once daily) in a 5-month randomized, doubleKeywords:
Hemodialysis,
shunt thrombosis, aspirin, sulflnpyrazone, 737
hypercoagulability
738
COMBINED ASPIRIN & SULFINPYRAZONE...
Vol. 62, No. 6
blind trial in 44 patients with arterio-venous shunts. Major side effects such as gastrointestinal bleeding were not noted in this study. Additional evidence to support the effectiveness and relative safety of sultinpyrazone as well as aspirin (high-dose, i.e., 500 mg three times daily) in the prevention of vascular access thrombosis has been reported (3,4). Several recent studies have shown that ticlopidine, an antiplatelet agent not available in the United States may also be effective in reducing the incidence of vascular access thrombosis (5,6,7). However, there appears to be no published information as to the effectiveness of low-dose aspirin or sulflnpyrazone in the prevention of vascular access thrombosis with the currently used internal shunts and tistulas which are less thrombogenic than external shunts. In our experience, vascular access thrombosis has continued to occur in patients with the less thrombogenic vascular access, even in those maintained on low-dose aspirin. Thus, the present study was initiated as a pilot study to evaluate the safety and efficacy of a combination of low-dose aspirin and sulflnpyrazone, agents that may inhibit platelet function and thrombus formation by different mechanisms (8), in a selected group of patients who had a history of two or more episodes of vascular access thrombosis. PATIENTS.
MATERIALS AND METHODS
Twenty-six patients who had had two or more vascular access thromboses while on chronic maintenance dialysis were identified from 166 patients at one outpatient dialysis center over a 27-month period. Of this group, 16 patients were enrolled in this study. Of the remainder, 5 patients declined participation, 2 patients were excluded because of multiple thromboses and requirement for central venous access, 1 patient was removed when blood could not be drawn from a peripheral vein for baseline hemostatic measurements, and 2 patients agreed to participate but expired before antithrombotic drugs were started. None of the patients enrolled in the study had a history of gastric or duodenal ulcers or a history of overt gastrointestinal hemorrhage. All patients had a shunt vascular access extending from the radial artery to an antecubital vein, consisting of bovine carotid artery, at the time of entering the study. Five patients had previously had an arteriovenous fistula. Eleven patients had taken at some time in the past or were taking at the time of being entered into the study varying doses of aspirin. All patients gave written informed consent prior to entry into the study. The study protocol was approved by the Institutional Review Board. Sixteen patients underwent initial hemostatic evaluation. Blood was collected immediately before hemodialysis by clean venipuncture using a double syringe technique into syringes containing l/10 volume 3.8% sodium citrate for all tests except complete blood count, including platelet count, (EDTA vacutainer tube) and assays of fibrinopeptide A and platelet factor 4 (special anticoagulant mixtures provided with commercial assay kits), Bleeding time (Simplate II, General Diagnostics, Morris Plains, NJ), platelet count (Coulter S Plus, Coulter Electronics, Hialeah, FL), activated partial thromboplastin time (aPTT) (9) using General Diagnostics Automated aPTT reagent (Organon Teknika Corp., Durham, NC), prothrombin time (PT) (10) using human brain thromboplastin (prepared in the laboratory), and fibrinogen (11) were determined by standard methods. Platelet aggregation in titrated platelet-rich plasma (platelet concentration adjusted to 300,000/~1) in response to different concentrations of adenosine diphosphate (ADP) (1.25,2.5,5.0 PM), epinephrine (1.25,2.5,5.0 PM), acid soluble collagen (0.5, 1.0, 2.5 pg/ml) (all obtained from Sigma Chemical, St. Louis, MO), and sodium arachidonate (10, 12.5, 16.7 mM) (NuCheck, Inc., Elysian, MN) was examined by a turbidimetric technique (12) using a dual channel aggregometer (Payton Scientific, Buffalo, NY). Thromboxane B, crxa;) formation was measured by determining TxB, in platelet-free plasma following incubation of titrated platelet-rich plasma for 5 minutes in the aggregometer at 370C, using a commercial RIA kit (Upjohn Co., Kalamazoo, MI) and 3H-TxB, (New England Nuclear, Boston, MA), as described in detail elsewhere (13). Antithrombin III activity (Ortho Diagnostics, Raritan, NJ) was determined using a commercial kit. Protein C antigen (ASSERA-Plate Protein C, Diagnostica Stago, Asnieres, France), fibrinopeptide A (Fibrinopeptide A, RIA-Quant, Mallinckrodt, St. Louis, MO), and platelet factor 4 (PF4-RIA kit, Abbott Laboratories, North Chicago, IL) were determined using commercial kits. For the initial laboratory evaluation, medications
6 2 2
64 7 12
M Hypertension
M Obstruction
74
59
48
57
56
65
66
74
76
68
64
5
6
7
8
9
10
11
12
13
14
15
8 2 3 4 4 2 2
3
60 13 56 22 22 31 30
16
Diabetes
Hypertension
Hypertension
Diabetes
Pyelonephritis
Acute renal failure postsurgery
M Hypertension
F
F
F
F
F
F
F
Hypertension
M Diabetes
5
128
15
M Systemic lupus
99
8
65
4
Systemic lupus erythematosus
14
4
52
3
F
Hypertension
25
48
2
F
7
30
31
22
GI Bleeding
GI Bleeding
0
0
1
Post-Dialysis Access Bleeding 2
22
2
Noncompliance 9
50
Post-Dialysis Vascular Access Bleeding
GI Bleeding
6
13
0
GI Bleeding
3
15
2
Renal Transplant
2
12
Retroperitoneal Bleeding
GI Bleeding
11
7
0
GI Bleeding
9
12
2
__
12
25 106
Drainage of Hepatic Abscess __
0
4
1
6
__
12
1
12
8
14
On ASAlSULF Pre-ASAISULF Reason for Premature Months # Thrombosis Discontinuation # Access Months # Access Current Current Months Thrombosis of ASA/SULF Dialysis Thrombosis Shunt Shunt
TABLE 1. of Patients, Vascular Access Thromboses and Major Adverse Events During AspirinlSulfinpyraze
M Hypertension
68
1
Etiology Renal Patient Age Sex Failure
Clinical Characteristics
Trial
740
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Vol. 62, No. 6
containing aspirin were withheld for 10 days prior to study and all other medications for 24 hours prior to study. After the initial hemostatic evaluation, patients were placed on 85 mg aspirin once a day and 200 mg sulfinpyrazone (Anturane; kindly provided by CIBA Pharmaceutical Co., Summit, NJ.) three times a day to be continued for a total period of 12 months. One patient was removed from the study after hemostatic evaluation but prior to starting aspirin/sulfinpyrazone because renal function had improved sufftciently for the patient to remain off hemodialysis. After 4 to 8 weeks of combined drug administration, the hemostatic measurements described above were repeated. In addition, the results of monthly routine laboratory tests (hematocrit, blood urea nitrogen and creatinine) were compared pre and post aspirinlsultinpyrazone.
Important clinical characteristics of the 15 patients treated with aspirin/sulfinpyrazone are shown in Table 1. Table 1 also shows the number of vascular access thrombosis events for each patient before and during the aspirin/sulfinpyrazone study. Before the aspirinlsulfinpyrazone trial, the 15 patients had a total of 68 vascular access thrombi over 597 patient months of dialysis for a mean of 0.114 thrombus per month. In contrast, on aspirin/sulfinpyrazone only four thrombi occurred during 99 patient months for a mean of 0.04 thrombus per month corresponding to a 65% reduction in the incidence of vascular access thrombosis (p < 0.001). When the number of access thromboses for the current shunt’were compared before (0.137) and during drug administration (0.038), a similar reduction of access thrombosis was observed (72%; <0.02). Of note is that since completion of the trial, 7 thrombi occurred in 4 patients during a period of 53 patient months at risk, for a mean of 0.132 thrombus per month which is similar to the pre-trial vascular access thrombosis incidence. Baseline plasma levels of fibrinopeptide A were elevated in all patients while levels of fibrinogen, platelet factor 4, antithrombin III, and protein C were generally within normal limits. Only three patients completed the 12 months of combined drug treatment. In 9 patients, aspirinlsulfinpyrazone was discontinued at different times during the study because of bleeding complications (F.able 1). In 4 of the 6 patients with bleeding from the GI-tract, bleeding was considered minor (fall in hematocrit < 3 points within 1 week associated with repeatedly positive stool guaiac tests but no gross evidence of bleeding). One patient developed a recurrent hepatic abscess requiring surgical drainage, one patient received a renal allograft after two months on study, and one patient discontinued taking her medications without consulting her physician between 6 and 9 months of study. Red blood cell (RBC) transfusions were examined for the period of the 27 months prior to the start of the aspirin/sulfinpyrazone trial and compared with those during the trial period. Thirteen of 15 patients received a total of 253 units of packed RBC over 321 patient months for an average of 0.79 unit per patient month in the pre-trial period. Eleven of 15 patients received a total of 76 units of packed RBC during 99 patient months on aspirin/sulfinpyrazone for an average of 0.76 unit per patient month. Thus, RBC transfusions overall did not increase during the trial period. To examine whether and to what extent the reduction by aspirin/ sulfinpyrazone in the incidence of vascular access thrombosis was associated with changes in hemostatic measurements the results of the baseline and follow-up evaluation were compared. This comparison could be carried out in only 11 In 4 patients aspirinlsulfinpyrazone was discontinued within 2 months of starting the patients. medications before follow-up hemostatic evaluation could be carried out. Two of these patients developed upper gastrointestinal bleeding requiring hospitalization and RBC-transfusions, 1 patient was found to have a retroperitoneal hemorrhage associated with pneumonia and sepsis, and 1 patient discontinued taking her medications because of prolonged bleeding from a needle puncture site after hemodialysis. As shown in Table 2, there were no significant differences between baseline and treatment values for any of the measurements.
COMBINED ASPIRIN & SULFINPYRAZONE...
Vol. 62, No. 6
Effects of Combined Treatment Measurements in Eleven Hemodialysis TEST (Normal Range) Bleeding time (3-8 minutes) Platelets (150-400 x lOOO/~l)
TABLE 2. with Aspirin and Sulfinpyrazone on Hemostatic Patients with Recurrent Vascular Access Thrombosis BASELINE 13.0 f
ASPIRIN/SULFINPYRAZONE 8.4
261.5 f 31.2
aP’lT (26.0-36.8 seconds)
30.4 f
PT (13.7-16.1 seconds)
14.5 & 0.4
Fibrinogen
(150-400 mg/dl)
Antithrombin
III activity (80-120%)
Protein C antigen (70-130%) Fibrinopeptide
A (O-2.8 ng/ml)
Platelet Factor 4 (O-10 ng/ml)
741
1.0
367.7 + 32.8 89.8 + 3.3 126.5 + 20.0 25.1 f 16.0 6.0 +
1.1
16.5 & 10.3 245.8 +20.6 29.2 f
1.2
14.2 + 0.4 342.8 +25.5 93.3 f
4.9
152.7 A21.7 6.5 +
1.3
7.6 f
1.5
Hemostatic test values (mean + S.E.M.) before and after a minimum of one month of treatment with aspirin and sulfinpyrazone are shown. No significant differences at the P < 0.05 level were found by one-way analysis of variance for any of the measurements.
When baseline bleeding times and changes in bleeding times (from baseline to aspirin/sulfinpyrazone) were examined separately for those patients who developed abnormal bleeding and compared to those who did not, no significant differences were observed. Platelet aggregation studies were completed in 8 of the 11 patients. Marked suppression of aggregation to different concentrations of ADP (31-55%), epinephrine (72-80%), collagen (88-95%), and arachidonic acid (84-95%) was observed on combined drug treatment as compared to baseline. There was also an almost complete inhibition of arachidonate-induced platelet thromboxane B formation on aspirin/ sulfinpyrazone (0.16 f 0.11 pmoles/lob platelets) as compared to the baseline value (1.3 1 + 0.11). There were no significant differences between average baseline and aspirinlsulflnpyraxone treatment values for hematocrit (24.8 f 2.3 vs. 25.5 f 3.1), BUN (70.1 & 8.4 vs. 71.5 + 14.8) or creatinine (12.9 & 3.2 vs. 13.5 f 3.6). DISCUSSION The findings of the pilot study presented here indicate that combined administration of low-dose aspirin and sulfinpyrazone was associated with a 65% reduction in vascular access thrombosis in a subgroup of chronic hemodialysis patients suffering from recurrent vascular access thrombosis. The question whether this drug combination is more effective than either drug alone cannot be answered by In the Canadian Multicenter Trial in unstable angina (14), the the data obtained in this study. combination of aspirin, at a higher dose than used in the present study (325 mg four times daily), and sulfinpyrazone was not more effective than aspirin alone. It is of particular interest to note that despite evidence of almost complete suppression of platelet thromboxane B formation by aspirin/ sulflnpyrazone (associated with marked inhibition of platelet aggregation in response to ADP, epinephrine, collagen, and arachidonic acid) no significant prolongation of the bleeding time over baseline was observed and there was no significant decrease in plasma of
742
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Vol. 62, No. 6
platelet factor 4, an indicator of in vivo platelet activation (15). These findings seem to indicate that platelets from uremic patients despite their common, well-documented dysfunction (16,17) may not be especially sensitive to agents interfering with platelet thromboxane AZ formation as previously suggested (18). Hence, it seems likely that the high incidence of gastrointestinal bleeding observed during aspirin/sulfinpyrazone administration in the present study was secondary to the combined toxic effects of these agents on the gastric mucosa, rather than due to aggravation of the uremic thrombocytopathy or other possible hemostatic defects associated with uremia. The bleeding complications which led to premature discontinuation (by patient request) of drug treatment in 6 patients were minor and there was no increase in RBC transfusion in the treatment group overall. It is conceivable that many or all of these bleeding complications could have been prevented by appropriate methods of gastrointestinal mucosa protection. Finally, it is of interest to note that all of the patients studied had elevated plasma levels of fibrinopeptide A consistent with chronic, low-grade activation of the coagulation system, possibly at the site of the vascular access. However, a limited hypercoagulability profile did not reveal a deficiency of antithrombin III, as previously reported by some (19) but not by others (20-22), or protein C. Thus, blood alterations or other factors or mechanisms predisposing certain patients on chronic hemodialysis to recurrent vascular access thrombosis remain to be determined. ACKNOWLEDGEMENTS This study was supported by a grant form the Missouri Kidney Program and NIH grant HL 28227. REFERENCES 1.
KAEGI, A., PINEO, G.F., SHIMIZU, A., TRIVEDI, H., HIRSH, J., and GENT, M. Arteriovenous shunt thrombosis: Prevention by sulfinpyrazone. N Engl J Med 290, 304-306, 1974.
2.
HARTER, H.R., BURCH, J.W., MAJERUS, P.W., STANFORD, N., DELMEZ, J.A., ANDERSON, C.B., and WEERTS, C.A. Prevention of thrombosis in patients on hemodialysis by low-dose aspirin. N Ennl J Med 301, 577-579, 1979.
3.
MICHIE, D.D., and WOMBOLT, D.G. Use of sulfinpyrazone to prevent thrombus formation in arteriovenous fistulas and bovine grafts of patients on chronic hemodialysis. Ther Res 22, 196-204, 1977.
4.
ALBERT, F.W. Prevention of early thrombus formation in arteriovenous TransDlant 10, 167C-167D, 1981.
5.
KOBAYASHI, K., MAEDA, K., KOSHIKAWA, S., KAWAGUCHI, Y., SHIMIZU, N., and NAITO, C. Antithrombotic therapy with ticlopidine in chronic renal failure patients on maintenance hemodialysis--a multicenter collaborative double blind study. Thromb Res 20, 255 261, 1980.
6.
FISKERSTRAND, C.E., THOMPSON, I.W., BURNET, M.E., WILLIAMS, P., and ANDERTON, J.L. Double-blind randomized trial of the effect of ticlopidine in arteriovenous fist&s for hemodialysis. Artif Organs 9, 61-63, 1985.
7.
GRONTOFT, K.C., MULEC, H., GUTIERREZ, A., and OLANDER, R. Thromboprophylactic effect of ticlopidine in ateriovenous fistulas for haemodialysis. Stand J Urol Nenhrol 19, 55-57, 1985.
fistulas.
Dial &
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8.
HANSON, S.R., HARKER, L.A., and BJORNSSON, T.D. Effects of platelet-modifying drugs aspirin potentiates the antithrombotic actions of on arterial thromboembolism in baboons: dipyridamole and sultinpyrazone by mechanism(s) independent of platelet cyclooxygenase inhibition. ,I Clin Invest 75, 1591-1599, 1985.
9.
PROCTOR, R.R., and RAPAPORT, S.I. The partial thromboplastintime with Kaolin: A simple screening test for first stage plasma clotting factor deficiencies. Am J Clin Path 36, 212-219.
10.
CLAUSS, A. GerinnungsphysioloischeSchnellmethodezur Haematol 17, 237-246, 1957.
11.
QUICK, A.J., STANLEY-BROWN, M., and BANCROFT, F.W. A study of the coagulation defect in hemophilia and in jaundice. Am J Med Sci 190, 501-511, 1935.
12.
BORN, G.V.R. Aggregation Nature 194, 927-929, 1962.
13.
FITZPATRICK, F.A., GORMAN, R.R., McGUIERE, J.C., KELLY, R.C., WYNALDA, M.A., and SUN, F.F. A radioimmunoassay for thromboxane Bz. Anal Biochem 82, 1-7, 1977.
14.
CAIRNES, J.A., GENT, M., SINGER, J., FINNIE, K.J., FROGGAIT, G.M., HOLDER, D.A., JABLONSKY, G., KOSTUK, W.J., MELENDEZ, L.J., MYERS, M.G., SACKE’IT, D.L., SEALEY, B.J., and TANSER P.H. Aspirin, sulfinpyrazone or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 22, 1369-1375, 1985.
15.
KAPLAN, K.L., and OWEN, J. Plasma levels of &thromboglobulin indices of platelet activation in vivo. Blood 57, 199-202, 1981.
16.
JOIST, J.H., PECHAN, J., and SCHIKOWSKI, U. Untersuchungen zur Natur and Atiologie der ur%rnischen Thrombocytopathie. Verh Dtsch Ges Inn Med 75, 476-479, 1969.
17.
DIMINNO, G., MARTINEZ, J., McKEAN, M-L. Platelet dysfuncton in uremia. defect partially corrected by dialysis. Am J Med 79, 552-559, 1985.
18.
LIVIO, M., BENIGNI, A., VIGANO, G., MECCA, G., and REMUZZI, of aspirin and risk of bleeding in renal failure. Lancet 1, 414-416, 1986.
19.
BERN, M.M., and GREEN, J. Effect of sulfinpyrazone upon antithrombin III and platelet factor 4 in chronic renal failure. Thromb Res 27, 457465, 1982.
20.
PUSINERI, F., BINI, A., MUSSONI, L., REMUZZI, G., and DONATI, M.B. Intermittent heparin treatment does not induce hypercoagulability in haemodialysed patients. J Clin Path 33, 631634, 1980.
21.
BRANDT, P., JESPERSEN, J., and SORENSEN, haemodialysis patients. Nenhron 28, l-3, 1981.
22.
TURNEY, J.H., FEWELL, M., WILLIAMS, L.C., DODD, N., and WESTON, MS. Paradoxical behavior of antithrombin III during hemodialysis and its prevention with prostacyclin. Clin Nenhrol 17, 31-35, 1982.
Bestimmung des Fibrinogens.
of blood platelets by adenosine diphosphate
L.H.
&@
and its reversal.
and platelet factor 4 as
Multifaceted
G. Moderate doses
Antithrombin-III
and platelets in
COMBINED ASPIRIN AND SULFINPYRAZONE IN THE PREVENTION OF RECURRENT HEMODIALYSIS VASCULAR ACCESS THROMBOSIS
Douglass T. Domoto, Joan E. Bauman, and J. Heinrich Joist Divisions of Nephrology and Hematology, St. Louis University School of Medicine St. Louis, Missouri 63110 U.S.A.
(Received 19.10.1990; accepted in revised form 26.3.1991 by Editor H.C. Kwaan) ABSTRACT We carried out a pilot study in 15 hemodialysis patients with recurrent vascular access thrombosis to examine whether the combination of low dose aspirin (85 mg once daily) and sultinpyrazone (200 mg three times daily) is safe and effective in the prevention of vascular access thrombosis. Hemostatic measurements were performed prior to and after four weeks of starting the drug combination. Baseline values for fibrinopeptide A were elevated in all patients while those for platelet factor 4, fibrinogen, antithrombin III and protein C were generally within normal limits. A major reduction in the frequency of vascular access thrombosis from 0.114 per month to 0.04 per month was noted during combined drug treatment (p < 0.001). Although in vitro platelet aggregation to various stimuli was markedly suppressed and platelet thromboxane B, formation was almost completely inhibited in patients on aspirin/sulfinpyrazone, this was not associated with a significant further prolongation of the bleeding time. A relatively high rate of complications, particularly mild gastrointestinal bleeding, was noted in patients on aspirin/sulfinpyrazone that could not be predicted on the basis of pre-treatment hemostatic test results.
INTRODUCTION Vascular access thrombosis continues to be a serious problem in patients who require chronic maintenance hemodialysis. Several studies have been reported which have examined the use of antiplatelet agents in the prevention of thrombotic occlusion of external arteriovenous shunts. Kaegi et al (1) carried out a double-blind, randomized, placebo-controlled 6-month clinical trial in 52 patients with straight arterio-venous shunts and observed an almost 75% reduction in the incidence of vascular access thrombosis with sulfinpyrazone (200 mg three times daily). Some of the patients in this study were also on warfarin anticoagulant therapy but the extent of reduction by sultlnpyrazone of vascular access thrombosis in these patients was similar to that in patients not on warfarin. Only two patients on sulfinpyrazone experienced a serious side effect (gastrointestinal bleeding) which led to removal from the study of one patient who was also on warfarin. Subsequently, Hatter et al (2) reported a 65% reduction in vascular access thrombosis by low-dose aspirin (160 mg once daily) in a 5-month randomized, doubleKeywords:
Hemodialysis,
shunt thrombosis, aspirin, sulflnpyrazone, 737
hypercoagulability
738
COMBINED ASPIRIN & SULFINPYRAZONE...
Vol. 62, No. 6
blind trial in 44 patients with arterio-venous shunts. Major side effects such as gastrointestinal bleeding were not noted in this study. Additional evidence to support the effectiveness and relative safety of sultinpyrazone as well as aspirin (high-dose, i.e., 500 mg three times daily) in the prevention of vascular access thrombosis has been reported (3,4). Several recent studies have shown that ticlopidine, an antiplatelet agent not available in the United States may also be effective in reducing the incidence of vascular access thrombosis (5,6,7). However, there appears to be no published information as to the effectiveness of low-dose aspirin or sulflnpyrazone in the prevention of vascular access thrombosis with the currently used internal shunts and tistulas which are less thrombogenic than external shunts. In our experience, vascular access thrombosis has continued to occur in patients with the less thrombogenic vascular access, even in those maintained on low-dose aspirin. Thus, the present study was initiated as a pilot study to evaluate the safety and efficacy of a combination of low-dose aspirin and sulflnpyrazone, agents that may inhibit platelet function and thrombus formation by different mechanisms (8), in a selected group of patients who had a history of two or more episodes of vascular access thrombosis. PATIENTS.
MATERIALS AND METHODS
Twenty-six patients who had had two or more vascular access thromboses while on chronic maintenance dialysis were identified from 166 patients at one outpatient dialysis center over a 27-month period. Of this group, 16 patients were enrolled in this study. Of the remainder, 5 patients declined participation, 2 patients were excluded because of multiple thromboses and requirement for central venous access, 1 patient was removed when blood could not be drawn from a peripheral vein for baseline hemostatic measurements, and 2 patients agreed to participate but expired before antithrombotic drugs were started. None of the patients enrolled in the study had a history of gastric or duodenal ulcers or a history of overt gastrointestinal hemorrhage. All patients had a shunt vascular access extending from the radial artery to an antecubital vein, consisting of bovine carotid artery, at the time of entering the study. Five patients had previously had an arteriovenous fistula. Eleven patients had taken at some time in the past or were taking at the time of being entered into the study varying doses of aspirin. All patients gave written informed consent prior to entry into the study. The study protocol was approved by the Institutional Review Board. Sixteen patients underwent initial hemostatic evaluation. Blood was collected immediately before hemodialysis by clean venipuncture using a double syringe technique into syringes containing l/10 volume 3.8% sodium citrate for all tests except complete blood count, including platelet count, (EDTA vacutainer tube) and assays of fibrinopeptide A and platelet factor 4 (special anticoagulant mixtures provided with commercial assay kits), Bleeding time (Simplate II, General Diagnostics, Morris Plains, NJ), platelet count (Coulter S Plus, Coulter Electronics, Hialeah, FL), activated partial thromboplastin time (aPTT) (9) using General Diagnostics Automated aPTT reagent (Organon Teknika Corp., Durham, NC), prothrombin time (PT) (10) using human brain thromboplastin (prepared in the laboratory), and fibrinogen (11) were determined by standard methods. Platelet aggregation in titrated platelet-rich plasma (platelet concentration adjusted to 300,000/~1) in response to different concentrations of adenosine diphosphate (ADP) (1.25,2.5,5.0 PM), epinephrine (1.25,2.5,5.0 PM), acid soluble collagen (0.5, 1.0, 2.5 pg/ml) (all obtained from Sigma Chemical, St. Louis, MO), and sodium arachidonate (10, 12.5, 16.7 mM) (NuCheck, Inc., Elysian, MN) was examined by a turbidimetric technique (12) using a dual channel aggregometer (Payton Scientific, Buffalo, NY). Thromboxane B, crxa;) formation was measured by determining TxB, in platelet-free plasma following incubation of titrated platelet-rich plasma for 5 minutes in the aggregometer at 370C, using a commercial RIA kit (Upjohn Co., Kalamazoo, MI) and 3H-TxB, (New England Nuclear, Boston, MA), as described in detail elsewhere (13). Antithrombin III activity (Ortho Diagnostics, Raritan, NJ) was determined using a commercial kit. Protein C antigen (ASSERA-Plate Protein C, Diagnostica Stago, Asnieres, France), fibrinopeptide A (Fibrinopeptide A, RIA-Quant, Mallinckrodt, St. Louis, MO), and platelet factor 4 (PF4-RIA kit, Abbott Laboratories, North Chicago, IL) were determined using commercial kits. For the initial laboratory evaluation, medications
6 2 2
64 7 12
M Hypertension
M Obstruction
74
59
48
57
56
65
66
74
76
68
64
5
6
7
8
9
10
11
12
13
14
15
8 2 3 4 4 2 2
3
60 13 56 22 22 31 30
16
Diabetes
Hypertension
Hypertension
Diabetes
Pyelonephritis
Acute renal failure postsurgery
M Hypertension
F
F
F
F
F
F
F
Hypertension
M Diabetes
5
128
15
M Systemic lupus
99
8
65
4
Systemic lupus erythematosus
14
4
52
3
F
Hypertension
25
48
2
F
7
30
31
22
GI Bleeding
GI Bleeding
0
0
1
Post-Dialysis Access Bleeding 2
22
2
Noncompliance 9
50
Post-Dialysis Vascular Access Bleeding
GI Bleeding
6
13
0
GI Bleeding
3
15
2
Renal Transplant
2
12
Retroperitoneal Bleeding
GI Bleeding
11
7
0
GI Bleeding
9
12
2
__
12
25 106
Drainage of Hepatic Abscess __
0
4
1
6
__
12
1
12
8
14
On ASAlSULF Pre-ASAISULF Reason for Premature Months # Thrombosis Discontinuation # Access Months # Access Current Current Months Thrombosis of ASA/SULF Dialysis Thrombosis Shunt Shunt
TABLE 1. of Patients, Vascular Access Thromboses and Major Adverse Events During AspirinlSulfinpyraze
M Hypertension
68
1
Etiology Renal Patient Age Sex Failure
Clinical Characteristics
Trial
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Vol. 62, No. 6
containing aspirin were withheld for 10 days prior to study and all other medications for 24 hours prior to study. After the initial hemostatic evaluation, patients were placed on 85 mg aspirin once a day and 200 mg sulfinpyrazone (Anturane; kindly provided by CIBA Pharmaceutical Co., Summit, NJ.) three times a day to be continued for a total period of 12 months. One patient was removed from the study after hemostatic evaluation but prior to starting aspirin/sulfinpyrazone because renal function had improved sufftciently for the patient to remain off hemodialysis. After 4 to 8 weeks of combined drug administration, the hemostatic measurements described above were repeated. In addition, the results of monthly routine laboratory tests (hematocrit, blood urea nitrogen and creatinine) were compared pre and post aspirinlsultinpyrazone.
Important clinical characteristics of the 15 patients treated with aspirin/sulfinpyrazone are shown in Table 1. Table 1 also shows the number of vascular access thrombosis events for each patient before and during the aspirin/sulfinpyrazone study. Before the aspirinlsulfinpyrazone trial, the 15 patients had a total of 68 vascular access thrombi over 597 patient months of dialysis for a mean of 0.114 thrombus per month. In contrast, on aspirin/sulfinpyrazone only four thrombi occurred during 99 patient months for a mean of 0.04 thrombus per month corresponding to a 65% reduction in the incidence of vascular access thrombosis (p < 0.001). When the number of access thromboses for the current shunt’were compared before (0.137) and during drug administration (0.038), a similar reduction of access thrombosis was observed (72%; <0.02). Of note is that since completion of the trial, 7 thrombi occurred in 4 patients during a period of 53 patient months at risk, for a mean of 0.132 thrombus per month which is similar to the pre-trial vascular access thrombosis incidence. Baseline plasma levels of fibrinopeptide A were elevated in all patients while levels of fibrinogen, platelet factor 4, antithrombin III, and protein C were generally within normal limits. Only three patients completed the 12 months of combined drug treatment. In 9 patients, aspirinlsulfinpyrazone was discontinued at different times during the study because of bleeding complications (F.able 1). In 4 of the 6 patients with bleeding from the GI-tract, bleeding was considered minor (fall in hematocrit < 3 points within 1 week associated with repeatedly positive stool guaiac tests but no gross evidence of bleeding). One patient developed a recurrent hepatic abscess requiring surgical drainage, one patient received a renal allograft after two months on study, and one patient discontinued taking her medications without consulting her physician between 6 and 9 months of study. Red blood cell (RBC) transfusions were examined for the period of the 27 months prior to the start of the aspirin/sulfinpyrazone trial and compared with those during the trial period. Thirteen of 15 patients received a total of 253 units of packed RBC over 321 patient months for an average of 0.79 unit per patient month in the pre-trial period. Eleven of 15 patients received a total of 76 units of packed RBC during 99 patient months on aspirin/sulfinpyrazone for an average of 0.76 unit per patient month. Thus, RBC transfusions overall did not increase during the trial period. To examine whether and to what extent the reduction by aspirin/ sulfinpyrazone in the incidence of vascular access thrombosis was associated with changes in hemostatic measurements the results of the baseline and follow-up evaluation were compared. This comparison could be carried out in only 11 In 4 patients aspirinlsulfinpyrazone was discontinued within 2 months of starting the patients. medications before follow-up hemostatic evaluation could be carried out. Two of these patients developed upper gastrointestinal bleeding requiring hospitalization and RBC-transfusions, 1 patient was found to have a retroperitoneal hemorrhage associated with pneumonia and sepsis, and 1 patient discontinued taking her medications because of prolonged bleeding from a needle puncture site after hemodialysis. As shown in Table 2, there were no significant differences between baseline and treatment values for any of the measurements.
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Vol. 62, No. 6
Effects of Combined Treatment Measurements in Eleven Hemodialysis TEST (Normal Range) Bleeding time (3-8 minutes) Platelets (150-400 x lOOO/~l)
TABLE 2. with Aspirin and Sulfinpyrazone on Hemostatic Patients with Recurrent Vascular Access Thrombosis BASELINE 13.0 f
ASPIRIN/SULFINPYRAZONE 8.4
261.5 f 31.2
aP’lT (26.0-36.8 seconds)
30.4 f
PT (13.7-16.1 seconds)
14.5 & 0.4
Fibrinogen
(150-400 mg/dl)
Antithrombin
III activity (80-120%)
Protein C antigen (70-130%) Fibrinopeptide
A (O-2.8 ng/ml)
Platelet Factor 4 (O-10 ng/ml)
741
1.0
367.7 + 32.8 89.8 + 3.3 126.5 + 20.0 25.1 f 16.0 6.0 +
1.1
16.5 & 10.3 245.8 +20.6 29.2 f
1.2
14.2 + 0.4 342.8 +25.5 93.3 f
4.9
152.7 A21.7 6.5 +
1.3
7.6 f
1.5
Hemostatic test values (mean + S.E.M.) before and after a minimum of one month of treatment with aspirin and sulfinpyrazone are shown. No significant differences at the P < 0.05 level were found by one-way analysis of variance for any of the measurements.
When baseline bleeding times and changes in bleeding times (from baseline to aspirin/sulfinpyrazone) were examined separately for those patients who developed abnormal bleeding and compared to those who did not, no significant differences were observed. Platelet aggregation studies were completed in 8 of the 11 patients. Marked suppression of aggregation to different concentrations of ADP (31-55%), epinephrine (72-80%), collagen (88-95%), and arachidonic acid (84-95%) was observed on combined drug treatment as compared to baseline. There was also an almost complete inhibition of arachidonate-induced platelet thromboxane B formation on aspirin/ sulfinpyrazone (0.16 f 0.11 pmoles/lob platelets) as compared to the baseline value (1.3 1 + 0.11). There were no significant differences between average baseline and aspirinlsulflnpyraxone treatment values for hematocrit (24.8 f 2.3 vs. 25.5 f 3.1), BUN (70.1 & 8.4 vs. 71.5 + 14.8) or creatinine (12.9 & 3.2 vs. 13.5 f 3.6). DISCUSSION The findings of the pilot study presented here indicate that combined administration of low-dose aspirin and sulfinpyrazone was associated with a 65% reduction in vascular access thrombosis in a subgroup of chronic hemodialysis patients suffering from recurrent vascular access thrombosis. The question whether this drug combination is more effective than either drug alone cannot be answered by In the Canadian Multicenter Trial in unstable angina (14), the the data obtained in this study. combination of aspirin, at a higher dose than used in the present study (325 mg four times daily), and sulfinpyrazone was not more effective than aspirin alone. It is of particular interest to note that despite evidence of almost complete suppression of platelet thromboxane B formation by aspirin/ sulflnpyrazone (associated with marked inhibition of platelet aggregation in response to ADP, epinephrine, collagen, and arachidonic acid) no significant prolongation of the bleeding time over baseline was observed and there was no significant decrease in plasma of
742
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platelet factor 4, an indicator of in vivo platelet activation (15). These findings seem to indicate that platelets from uremic patients despite their common, well-documented dysfunction (16,17) may not be especially sensitive to agents interfering with platelet thromboxane AZ formation as previously suggested (18). Hence, it seems likely that the high incidence of gastrointestinal bleeding observed during aspirin/sulfinpyrazone administration in the present study was secondary to the combined toxic effects of these agents on the gastric mucosa, rather than due to aggravation of the uremic thrombocytopathy or other possible hemostatic defects associated with uremia. The bleeding complications which led to premature discontinuation (by patient request) of drug treatment in 6 patients were minor and there was no increase in RBC transfusion in the treatment group overall. It is conceivable that many or all of these bleeding complications could have been prevented by appropriate methods of gastrointestinal mucosa protection. Finally, it is of interest to note that all of the patients studied had elevated plasma levels of fibrinopeptide A consistent with chronic, low-grade activation of the coagulation system, possibly at the site of the vascular access. However, a limited hypercoagulability profile did not reveal a deficiency of antithrombin III, as previously reported by some (19) but not by others (20-22), or protein C. Thus, blood alterations or other factors or mechanisms predisposing certain patients on chronic hemodialysis to recurrent vascular access thrombosis remain to be determined. ACKNOWLEDGEMENTS This study was supported by a grant form the Missouri Kidney Program and NIH grant HL 28227. REFERENCES 1.
KAEGI, A., PINEO, G.F., SHIMIZU, A., TRIVEDI, H., HIRSH, J., and GENT, M. Arteriovenous shunt thrombosis: Prevention by sulfinpyrazone. N Engl J Med 290, 304-306, 1974.
2.
HARTER, H.R., BURCH, J.W., MAJERUS, P.W., STANFORD, N., DELMEZ, J.A., ANDERSON, C.B., and WEERTS, C.A. Prevention of thrombosis in patients on hemodialysis by low-dose aspirin. N Ennl J Med 301, 577-579, 1979.
3.
MICHIE, D.D., and WOMBOLT, D.G. Use of sulfinpyrazone to prevent thrombus formation in arteriovenous fistulas and bovine grafts of patients on chronic hemodialysis. Ther Res 22, 196-204, 1977.
4.
ALBERT, F.W. Prevention of early thrombus formation in arteriovenous TransDlant 10, 167C-167D, 1981.
5.
KOBAYASHI, K., MAEDA, K., KOSHIKAWA, S., KAWAGUCHI, Y., SHIMIZU, N., and NAITO, C. Antithrombotic therapy with ticlopidine in chronic renal failure patients on maintenance hemodialysis--a multicenter collaborative double blind study. Thromb Res 20, 255 261, 1980.
6.
FISKERSTRAND, C.E., THOMPSON, I.W., BURNET, M.E., WILLIAMS, P., and ANDERTON, J.L. Double-blind randomized trial of the effect of ticlopidine in arteriovenous fist&s for hemodialysis. Artif Organs 9, 61-63, 1985.
7.
GRONTOFT, K.C., MULEC, H., GUTIERREZ, A., and OLANDER, R. Thromboprophylactic effect of ticlopidine in ateriovenous fistulas for haemodialysis. Stand J Urol Nenhrol 19, 55-57, 1985.
fistulas.
Dial &
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743
8.
HANSON, S.R., HARKER, L.A., and BJORNSSON, T.D. Effects of platelet-modifying drugs aspirin potentiates the antithrombotic actions of on arterial thromboembolism in baboons: dipyridamole and sultinpyrazone by mechanism(s) independent of platelet cyclooxygenase inhibition. ,I Clin Invest 75, 1591-1599, 1985.
9.
PROCTOR, R.R., and RAPAPORT, S.I. The partial thromboplastintime with Kaolin: A simple screening test for first stage plasma clotting factor deficiencies. Am J Clin Path 36, 212-219.
10.
CLAUSS, A. GerinnungsphysioloischeSchnellmethodezur Haematol 17, 237-246, 1957.
11.
QUICK, A.J., STANLEY-BROWN, M., and BANCROFT, F.W. A study of the coagulation defect in hemophilia and in jaundice. Am J Med Sci 190, 501-511, 1935.
12.
BORN, G.V.R. Aggregation Nature 194, 927-929, 1962.
13.
FITZPATRICK, F.A., GORMAN, R.R., McGUIERE, J.C., KELLY, R.C., WYNALDA, M.A., and SUN, F.F. A radioimmunoassay for thromboxane Bz. Anal Biochem 82, 1-7, 1977.
14.
CAIRNES, J.A., GENT, M., SINGER, J., FINNIE, K.J., FROGGAIT, G.M., HOLDER, D.A., JABLONSKY, G., KOSTUK, W.J., MELENDEZ, L.J., MYERS, M.G., SACKE’IT, D.L., SEALEY, B.J., and TANSER P.H. Aspirin, sulfinpyrazone or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 22, 1369-1375, 1985.
15.
KAPLAN, K.L., and OWEN, J. Plasma levels of &thromboglobulin indices of platelet activation in vivo. Blood 57, 199-202, 1981.
16.
JOIST, J.H., PECHAN, J., and SCHIKOWSKI, U. Untersuchungen zur Natur and Atiologie der ur%rnischen Thrombocytopathie. Verh Dtsch Ges Inn Med 75, 476-479, 1969.
17.
DIMINNO, G., MARTINEZ, J., McKEAN, M-L. Platelet dysfuncton in uremia. defect partially corrected by dialysis. Am J Med 79, 552-559, 1985.
18.
LIVIO, M., BENIGNI, A., VIGANO, G., MECCA, G., and REMUZZI, of aspirin and risk of bleeding in renal failure. Lancet 1, 414-416, 1986.
19.
BERN, M.M., and GREEN, J. Effect of sulfinpyrazone upon antithrombin III and platelet factor 4 in chronic renal failure. Thromb Res 27, 457465, 1982.
20.
PUSINERI, F., BINI, A., MUSSONI, L., REMUZZI, G., and DONATI, M.B. Intermittent heparin treatment does not induce hypercoagulability in haemodialysed patients. J Clin Path 33, 631634, 1980.
21.
BRANDT, P., JESPERSEN, J., and SORENSEN, haemodialysis patients. Nenhron 28, l-3, 1981.
22.
TURNEY, J.H., FEWELL, M., WILLIAMS, L.C., DODD, N., and WESTON, MS. Paradoxical behavior of antithrombin III during hemodialysis and its prevention with prostacyclin. Clin Nenhrol 17, 31-35, 1982.
Bestimmung des Fibrinogens.
of blood platelets by adenosine diphosphate
L.H.
&@
and its reversal.
and platelet factor 4 as
Multifaceted
G. Moderate doses
Antithrombin-III
and platelets in