American Journal of Hematology 12:131-137 (1982)

Nonsteroidal Anti-Inflammatory Drugs in the Treatment of Hemophilic Arthropathy Patricia Thomas, Bonnie Hepburn, Hugh C. Kim, and Panrin Saidi

Division of Rheumatology (P.T, B.H.) and the Division of Hematology (H.C.K., P.S.), Department of Medicine, College of Medicine and Dentistry of New Jersey- Rutgers Medical School, Piscataway

This study was undertaken to investigate the safety and efficacy of nonaspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) in controlling the pain and stiffness of hemophilic ar- thropathy. Data were collected from eight adult hemophilic patients in successive double- blind controlled studies using choline magnesium trisalicylate (CMT) and ibuprofen (IPF). In seven patients, neither drug consistently affected bleeding times, platelet aggregation studies, frequency of joint hemorrhages, or frequency of factor infusions. In one patient, platelet aggregation appeared to he affected by CMT and bleeding time became markedly prolonged after IPF therapy. Three patients taking CMT and four patients taking IPF re- ported greater relief of pain and stiffness with the drugs than with placebos. Our results sug- gest that IPF and CMT can benefit the hemophiliac and that they can be used safely i n most hemophilic patients under closely supervised conditions.

Key words: hemophilic arthropathy. nonsteroidal anti-inflammatory drugs

INTRODUCTION

The combined incidence of hemophilia A and B in the United States is approxi- mately 1 in 10,OOO male births. Nearly half of these hemophiliacs have severe disease, with a factor level less than 1%. Despite the availability of factor infusion therapy, most patients with moderate to severe factor deficiencies have significant arthropathy by the age of 20 [l].

The treatment of hemophilic arthropathy has been complicated by the lack of anti-inflammatory analgesic agents suitable for this population. Drugs such as aspirin and indomethacin, which have provided effective relief for the rheumatoid patient, have been avoided in the hemophilic patient because of their well-documented adverse effects on platelet function or hemostatis [I-61. In recent years, IPF and CMT have be- come available for the treatment of patients with arthritis. Increasing numbers of he-

Received for publication March 2, 1981; accepted November l l , 1981.

Address reprint requests to Bonnie Hephurn, MD, Division of Rheumatology, Department of Medicine, CMDNJ-Rutgers Medical School, Piscataway, NJ 08854.

0361-8609/82/1202-0131$02.50 0 1982 Alan R. Liss, h e .

132 Thomas et al

mophilic patients are now taking the new NSAIDs for their arthritis. Although pre- vious studies have documented an inhibitory effect of IPF on in vitro platelet function [7-91, the clinical significance of this abnormality is unknown and the safety of the NSAIDs in the hemophilic population has not been thoroughly tested.

The present study was undertaken to determine whether CMT and IPF could be used safely to relieve the pain of chronic hemophilic arthropathy.

PATIENTS AND METHODS Protocol

Eight hemophilic men, ages 28 to 67, participated in the study. Six had severe fac- tor VIII deficiency (level less than lVo), one had moderate factor VIII deficiency, and one (patient 2) had moderate factor IX deficiency. Seven were on home-care infusion programs. All subjects had X-ray and clinical evidence of severe hemophilic ar- thropathy and required some analgesia for joint pains. Three subjects were taking a nonsteroidal anti-inflammatory drug (indomethacin or ibuprofen) prior to the study. The remainder used acetaminophen, propoxyphene, or morphine as needed for pain. Patients excluded were those less than 18 years of age or patients with a history of pep- tic ulcer or significant gastrointestinal bleeding.

CMT or matched placebo was randomly allocated to patients at the start of the study. CMT-placebo crossover occurred at 6 weeks. At 12 weeks, administration of CMT or its placebo was discontinued and IPF or matched placebo was randomly allo- cated to the same patients. Crossover occurred 6 weeks later. Evaluations were per- formed on an outpatient basis. All subjects were advised not to take any medication other than acetaminophen or factor replacement as needed for at least 7 days prior to the start of the study. At the initial visit, a complete joint evaluation, bleeding time, platelet count, and platelet aggregation studies were obtained. For the CMT trial, sub- jects were supplied with 200 tablets of 500 mg CMT or its identical placebo and in- structed to take two tablets twice daily. At the end of 1 week, a salicylate level was per- formed and the result was returned to an independent physician. For the IPF study, each subject was supplied with 170 tablets of 400 mg IPF or its placebo and instructed to take one tablet four times daily.

Data collected by the investigators included results of a joint evaluation at Weeks 1 and 6 of each interval, platelet aggregation and bleeding time at Weeks 1 and 6, an- swers to a questionnaire concerning side effects at Weeks 1, 3 and 6, and tablet counts for both study drug and analgesic at 6 weeks. Each subject kept a record of bleeding and infusions during each 6-week interval. Subjective assessment of efficacy was based on answers to the following questions: 1) Was the trial drug helpful in relieving the pain in your joints during an episode of bleeding? 2) Was the trial drug helpful in relieving the pain in your joints between episodes of bleeding? 3) Was the trial drug helpful in relieving joint stiffness?

Bleeding Time Determinations The standardized Ivy bleeding time test [lo] was performed with the aid of a

disposable duplicate template (Simplate 11, General Diagnostics, Morris Plains, NJ). The average of bleeding times from two cuts was used.

NSAIDs in Hemophilic Arthropathy 133

Platelet Aggregation Method Blood was collected in polyethylene tubes containing 3.8% sodium citrate (9

parts blood to 1 part citrate). Platelet-rich plasma (PRP) was obtained by centrifuging citrated blood at 120g for 10 min at room temperature. Platelet-poor plasma (PPP) was prepared from the remaining blood by centrifugation at 1,200g for 20 min at room temperature. PRP was adjusted to final platelet count of 300,000/mm3 with PPP of same specimen. Platelet aggregation was performed on a Bio-Data platelet ag- gregometer (PAP-2, Harbor, PA) by adding 0.05 ml of aggregating agent to 0.45 ml PRP in siliconized cuvettes and incubating at 37°C with constant stirring. The percen- tage of decrease in optical density was recorded as the measure of platelet aggregation. Aggregating agents were adenosine diphosphate, lo+ and (ADP, Sigma Chemical Company, St. Louis, MO); epinephrine, 5 x (Parke-Davis); collagen, 0.1 mg/ml and 1.5 mg/ml; ristocetin, 1.5 mg/ml and 1.2 mg/ml (Abbott). Aggregation was done in duplicate and the mean value was given as the final result. A normal control was run daily.

RESULTS

Two nonsteroidal anti-inflammatory drugs were administered to hemophilic pa- tients at regular therapeputic doses over a period of 6 weeks without increase in clinical- ly significant bleeding or increase in factor infusions (Table I). Of eight patients who participated in the study, seven completed the CMT trial and six completed the IPF trial. Patient 4 (see tables) dropped from the CMT interval at 5 weeks and from the CMT placebo interval at 3 weeks due to lack of efficacy. Each time, he chose to con- tinue use of IPF, his prestudy analgesic. He refused to participate in the IPF portion of the study in order to avoid another placebo interval. Patient 1 dropped from the IPF placebo interval after 3 weeks to resume use of his prestudy analgesic, indomethacin. Patient 8 was dropped from the study by the investigators after a bleeding time greater than 15 min was recorded at week 1 of the IPF interval. Tablet counts and salicylate levels indicated generally good compliance.

T.4BLE 1. Effect of CMT and IPF on Hemarthroses and Factor Consumption

Patient - ~-

Number of hemarthroses in 6 weehs

C M T trial IPF trial ~ ~~ ~~ ~~

(Placebo) (CMT) (Placebo) (1PF)- ~~ ~~ ~~ -~ __ - -

0 1 3 3 2 2 I 2 3 4 1 1 1C.i 1c Db D 2 3 0 2 5 2 5 I 4 I 3 3

1 1 6 D D

Total 27 19 13 12 Mean+SD 3.Yk3.5 2.7k1.8 2.2k1.8 2.2k1.0

Number of Factor infusions in 6 weeks

C M T trial IPF trial (Placebo) (CMT) (Placebo) (IPF)

~~ _ ~ _ _ _ _ _ _ ~ ~ ~

~~~ ~ __ ~ _ _ _ _ ~

3 5 3 3 2 2 1 2 3 4 1 1 IC IC D D I 2 0 2 5 2 4 1 4 4 4 I

I5 11 D D

33 30 13 10 4.7k4.7 4 .3k3 .2 2.251.7 1.7k0.8

'1Ic' = incomplete interval. h D = dropped from study.

134 Thomas et a1

The patients' subjective impressions of relief afforded by the study drugs are listed in Table 11. The small number of patients makes it difficult to perform a mean- ingful statistical analysis. Results suggest, however, that the study drugs were helpful in relieving pain and stiffness between episodes of bleeding in some patients. The drugs provided little relief from pain of acute hemarthroses. Analgesic tablet counts (acet- aminophen, propopxyphene, etc) showed less analgesic consumption in drug intervals than in placebo intervals, but the values were strongly influenced by patients' previous drug habits and were difficult to analyze. Following the study, patient 3 elected to con- tinue regular daily use of CMT and patients 1,2,4, and 5 continued regular use of IPF. Two other patients continued to use a propoxyphene-acetaminophen combination as needed for relief of pain.

Joint examinations changed little during the study period. Changes in range of motion and degree of synovitis seemed related to recent bleeding rather than to altera- tions in medication.

Both drugs were well tolerated. One patient, whose salicylate level was 22 mg/dl, reported tinnitus during the CMT trial. Two patients taking IPF complained of drowsiness, and patient 7 decreased his dose to 1200 mg daily because of this. There was no significant gastrointestinal bleeding or distress.

Bleeding times (Table 111) deviated from the expected (normal) range in four of eight patients, but no patient had a consistently abnormal bleeding time. One abnor- mality occurred in a placebo interval and three abnormalities occurred in the IPF inter- vals. Patients 6 and 8 had platelet counts between 50,000 and 100,000/mm3. Both had prolonged bleeding times. When mean values were compared, there was no statistically significant difference between bleeding times in the drug and placebo intervals.

ADP (Table 111) closely correlated with results of aggregation by collagen, epinephrine, and ristocetin. Overall, platelet aggregation during drug trials was not significantly different from aggregation in placebo trials. However, a striking decrease in aggregation did occur in patient 8 during the CMT trial.

Results of platelet aggregation by 1 x

TABLE 11. Effect of CMT and I P F on Joint Pain and Stiffness"

CMT Trial IPF Trial -~ ~ __________ Pain reliet Pain relief Pain relief Pain relief

Salicylate during acute between acute Relief of during acute between acute Relief of level hemarthroses hemarthroses stiffness hemarthroses hemarthroses stiffness

Patient (mgldl) (P) (CMT) (P) (CMT) (P) (CMT) (P) (IPF) (P) (IPF) (P) ( IPF) ~~ ~~~ ~ ~~ ~-

22 0 0 22 1 0 2s 0 1 18 0 0 N N N 19 0 1 N 0 0 21 0 1

0 0 I 0 0 2 I 0 2 1 0 1 0 0 0 1

0 0 1 0 0 2 0 0 2 1 0 1 0 0 1 1

0 0 0 2 0 2 O N 0 2 0 2 1 0 1 1 1 0 D N 2 1 2 1 2 0 0 0 0 0 0 0 0 0 0 0 0 D

Totals 1 3 4 5 4 5 I 2 2 1 2 6 ~ ~

*Subjective evaluations of pain relief: 0 =none, 1 =some, 2 =very much, N =no data, D = dropped from interval or from study.

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136 Thomas et al

DISCUSSION

The most significant monitors of hemostasis for the hemophiliac are the frequen- cy of bleeding and infusion requirements. While following these parameters during NSAID therapy, we found no increase in frequency or severity of intra-articular bleeding and, therefore, were unable to show any clinical significance of the alterations in platelet function and bleeding time which occurred during the therapy.

Aspirin decreases platelet aggregation by acetylating platelet cyclooxygenase and inhibiting ADP release [4]. It prolongs bleeding times in normal subjects and hemo- philiacs [2,3,6]. In hemophiliacs the prolongation of bleeding time is highly variable and cannot be correlated with in vitro tests of platelet function [2]. Serious bleeding may follow aspirin ingestion by hemophiliacs [3]. CMT, a nonacetyl salicylate, has been given to normal subjects without in vitro or in vivo alteration in platelet aggrega- tion or serotonin release [5]. Administration of CMT to our hemophilic patients re- sulted in abnormal platelet aggregations only in patient 8 who had chronic liver disease, thrombocytopenia, and an aortic aneurysm. In no patient was there any significant prolongation of bleeding time.

Mclntyre has previously given a single 600-mg dose of IPF to hemophiliacs and observed transient alteration in platelet aggregation 2 hr after a drug dose [9]. Our study was designed to look at the steady-state condition after 1 and 6 weeks of treat- ment at 1600 mg daily and did not attempt to standardize the drug dose-platelet aggre- gation interval. Nevertheless, most patients were seen approximately 2 hr after their morning dose, and no alteration in platelet aggregation studies was found. There was no correlation between results of platelet aggregation studies and bleeding times which were variable during the IPF intervals, but usually within the normal range.

The analgesic potential of CMT and IPF has been previously established in large clinical trials [ 11,121. Although the population studied here is too small to establish or compare efficacy of the two drugs, it is noteworthy that five patients chose to remain on one of the study drugs. Some patients who experienced pain relief while taking the drugs noted that they were better able to differentiate pain of chronic arthritis from pain of hemarthrosis. Better pain discrimination during long-term NSAID therapy might enable patients to avoid inappropriate infusions for pain of chronic arthritis.

Throughout the trials, we found that changes in joint swelling were invariably related to recent hemorrhage, Subjective relief of stiffness was not accompanied by an increased range of motion in affected joints. Failure to demonstrate any anti-inflam- matory effect of the drugs objectively may have been related to the short duration of the study, or to the advanced stage of joint disease in these patients. To evaluate the benefit of long-term anti-inflammatory therapy, it would be helpful to study younger hemophiliacs who frequently have chronic synovitis without fixed contractures.

The results of this pilot study suggest that CMT and IPF can be safely adminis- tered to hemophilic patients under closely supervised conditions for periods up to 6 weeks. We feel that platelet aggregation studies and bleeding times should continue to be performed to identify individuals, such as patient 8, who may be unusually sensitive to one of these drugs.

ACKNOWLEDGMENTS

The authors thank Joan Eisele, RN, and Linda Thompson, RN, for nursing and administrative help.

NSAIDs in Hemophilic Arthropathy 137

Choline magnesium trisalicylate (Trilisate) and placebo were supplied by The Purdue Frederick Company and ibuprofen (Motrin) and placebo were supplied by the Upjohn Company.

This work was supported by USPHS Grant (MCB 310001A), New Jersey State Department of Health Grant (79-68-HEM), and NIH Grant (A1 11593), and in part by a fellowship award from the New Jersey Chapter of The Arthritis Foundation.

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