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processes in T lymphocytes remain demonstrable for about 5days following a single intravenous dose of thymopentin.14 A3-week treatment period is obviously insufficient to produce amaximum effect in chronic rheumatoid arthritis, but theimportant point about our findings is that clinical
improvement was obtained rapidly and without serious side-effects. Others have also reported an absence of severe side-effects .20-2 ’ The only probably treatment-related adversereaction we found in our study was temporary hypersomnia,also observed in our earlier, open study;27 its mechanism isunknown.The absence of serious side-effects and the rapid onset of
clinical improvement observed in this study speak in favourof TP-5 in the treatment of active rheumatoid arthritis. Even
though its mechanism of action remains poorly known, TP-5may offer a new approach to the therapy of rheumatoidarthritis.
We thank Mrs C. Blasicek and Miss E. Mailleux for their help.
Correspondence should be addressed to M. G. M., Department of Clinicaland Experimental Rheumatology, Institute of Physical Medicine and
Rehabilitation, Hopital de Baviere, 66 Boulevard de la Constitution, B-4020Liege/Belgium.
REFERENCES
1. Goldstein G. Thymin a thymic polypeptide causing the neuromuscular block ofmyasthenia gravis. Ann NY Acad Sci 1971; 183: 230-40.
2. Schlesinger DH, Goldstein G. The amino acid sequence ofthymopoietin II. Cell 1975;5: 361-65.
3. Goldstein G, Schneid MP, Boyse EA, Schlesinger DH, Van Wauve J. A syntheticpentapeptide with biological activity characteristics of the thymic hormonethymopoietin. Science 1979; 204: 1309-10.
4. Basch RS, Goldstein G. Antigenic and functional evidence for the in vitro inductiveactivity of thymopoietin on thymocyte precursors. Ann NY Acad Sci 1975; 249:290-97.
5. Scheid MP, Goldstein G, Boyse E. The generation and regulation of lymphocytepopulation. J Exp Med 1978; 148: 1727-43.
6. Scheid MP, Goldstein G, Boyse EA. Differentiation of T cells in nude mice. Science1975; 190: 1211-13.
7. Lau CY, Freestone JA, Goldstein G. Effect of thymopoietin pentapeptide onautoimmunity I. TP-5 suppression of induced erythrocyte autoantibodies in C3Hmice. J Immunol 1980; 125: 1634-38.
8. Weksler ME, Innes JB, Goldstein G. Immunological studies of aging IV. Thecontribution of thymic involution to the immune deficiencies of aging mice andreversal with thymopoietin 32-36. J Exp Med 1978; 148: 996-1006.
9. Sunshine GH, Basch RS, Goffrey RG, Cohen KW, Goldstein G, Hadden JW.Thymopoietin enhances the allogenic response and cyclic GMP levels of mouseperipheral thymus-derived lymphocytes. J Immunol 1978; 120: 1594-99.
10. Lau CY, Goldstein G. Functional effects of TP-5 on cytotoxic lymphocyte precursorunits (CLP.U) I. Enhancement of splenic CLP-U in vitro and in vivo aftersuboptimal antigenic stimulations. J Immunol 1980; 124: 1861-65.
11. Lau CY, Wang EY, Goldstein G. Effects of thymopoietin pentapeptide onexperimental tumors I. TP-5 relieves immunosuppression in tumor-bearing mice.Cell Immunol 1982; 66: 217-32.
12. Duchateau J, Delespesse G, Bolla K. Phase variation in the modulation of the humanimmune response. Immunol Today 1983; 4: 213-14.
13. Tischio JP, Patrick JR, Weintraub HS, Chasing M, Goldstein G. Short in vitro half-lifeof thymopoietin 32-36 pentapeptide in human plasma. Int J Pept Prot Res 1979; 14:479-84.
14. DiPerri T, Laghi Pasini F, Auteri A. Immunokinetics of a single dose of thymopoietinpentapeptide. J Immunopharmacol 1980; 2: 567-72.
15. Bolla K, Duchateau J, Delespesse G, Servais G. Clinical-pharmacological evidence forthe immunomodulatory property of thymopentin in elderly volunteers. Proceedingsof the 1st World Conference on Inflammation, Antirheumatics, Analgesics,Immunomodulators, Venice, April 16-18, 1984. Geneva: Bioscience Ediprint Inc(in press).
16. Audhya T, Goldstein G. Comparative efficacy of various routes of administration ofthymopentin (TP-5) with considerations of degradative mechanisms. Int J Pept ProtRes 1983; 22: 187-93.
17 Audhya T, Goldstein G. Thymopentin (TP-5) potency in vivo is enhanced by slowinfusion. Int J Pept Prot Res 1983; 22: 568-72.
18. Janossy G, Duke D, Paulter LW, Panayi G, Bofill M, Goldstein G. Rheumatoidarthritis- a disease of T lymphocyte/macrophage immunoregulation. Lancet 1981;ii: 839-42.
19. Veys EM, Hermans P, Schindler J, et al. Evaluation of T cell subsets with monoclonalantibodies in patients with rheumatoid arthritis. J Rheumatol 1982; 9: 25-29.
20 Veys EM, Huskisson EC, Rosenthal M, et al. Clinical responses to therapy withthymopentin (TP-5) in rheumatoid arthritis. Ann Rheum Dis 1982; 41: 441-43.
21. Rosenthal M, Huskisson EC, Veys E, Vischer JL. Thymopentin bei der Behandlungder chronischen Polyarthritis. Verth Dtsch Ges Rheumatol 1981, 7: 400-43.
22 Horwith DA, Glynn MJ, Barada FA, et al. Effects of thymopoietin 32-36 (TP-5) inrheumatoid arthritis: A preliminary report. In: Krakauer RS, Cathcart MK, eds.Immunoregulation and autoimmunity. Amsterdam: Elsevier/North Holland, 1980:231-40.
23. Thrower PA, Doyle DV, Scott J, Huskisson EC. Thymopoietin in rheumatoidarthritis. Rheumatol Rehab 1982; 21: 72-77.
24. Weaver AL, Churchill MA, Jacobs AJ. Treatment of refractory rheumatoid arthritiswith thymopoietin pentapeptide Abstract. Arthritis Rheum 1984; 27 (suppl): B46.
25. Veys EM, Mielants H, Verbruggen G, et al Thymopoietin pentapeptide(thymopentin, TP-5) in the treatment of rheumatoid arthritis A compilation ofseveral short- and long-term clinical studies J Rheumatol 1984, 11: 462-66
26 Sharpe RM. HCG-induced decrease in availability of rat testis receptors. Nature(Lond)1976; 264: 644-46.
27. Franchimont P, Hauwaert C, Bolla K. Controlled open clinical study with ’Immunox’(TP-5) in the treatment of active rheumatoid arthritis. Schaffhausen, Switzerland:Documentation CILAG Ltd. TPH 01579, 1983.
28. Cooperating Clinic Committee of American Rheumatism Association. Arthritis Rheum1976; 8: 302-10.
29. Steinbrocker O, Traeger Ch, Battermann RC. Therapeutic criteria in rheumatoidarthritis. JAMA 1949; 140: 659-62.
30. Ritchie DM, Boyle JA, McInnes JM, et al. Clinical studies with an articular index forthe assessment of joint tenderness in patients with rheumatoid arthritis. Quart J Med1968; 37: 393-406.
31. Huskisson EC. Measurement of pain. Lancet 1974; ii: 1127-31.32. Umbenhauer ER. Is the ability to detect drug effect in rheumatic diseases increased by
measuring more clinical parameters? In: Paulus HE, Ehrlich GE, Lindenlaub E,eds. Controversies in the clinical evaluation of analgesic-anti-inflammatory-antirheumatic drugs. Stuttgart: F. K. Schattaeur, 1981: 193-202.
CONTROLLED TRIAL OF TAMOXIFEN ASSINGLE ADJUVANT AGENT IN MANAGEMENT
OF EARLY BREAST CANCER
Analysis at Six Years by Nolvadex Adjuvant TrialOrganisation*
Summary A randomised controlled trial of tamoxifenas a single adjuvant agent after mastectomy
for early breast cancer, reported on at an average follow-up ofalmost 2 years in 1983, has now been followed up to a maxi-mum of 6 years. 1285 patients aged 75 or less were enteredinto the trial. Premenopausal women with positive axillarynodes and postmenopausal women with both positive andnegative axillary nodes were randomised to receive eithertamoxifen 10 mg twice daily for two years or to the untreatedcontrol group with systemic therapy reserved until the timeof relapse. 46% of the trial population had primary tumourspecimens assayed for oestradiol receptor (ER) content.
There has been a highly significant prolongation of thedisease-free interval in the tamoxifen-treated group followed
by a highly significant reduction in death rate, with 45(34%)fewer deaths observed in the treated group than in the control
group. This benefit appeared to be independent of
menopausal, nodal, or ER status.
Introduction
ON Nov 1, 1977, recruitment of patients into a multicentrerandomised controlled trial of adjuvant tamoxifen in earlybreast cancer, the Nolvadex Adjuvant Trial Organisation(NATO) study, began. The objective was to see if long-termadjuvant tamoxifen, for 2 years, would prolong the disease-free interval or increase survival, and the opportunity wastaken to find out if the oestradiol receptor (ER) status of theprimary tumour would identify those patients most likely tobenefit from adjuvant therapy with this antioestrogen.Preliminary results were published in 19831,2 when the meanfollow-up was 21 months. This paper presents the full
analysis done 6-7 years after recruitment began and when thefollow-up time was 45 months (median).
’
*Members of the steering committee were: Prof M. BAUM (chairman), DrD. M. BRINKLEY, Dr J. A. DOSSETT, Dr K. MCPHERSON, Dr J. S.
PATTERSON, Dr R. D. RUBENS, Mr F. G. SMIDDY, Dr B. A. STOLL, Mr A.WILSON, Mr D. RICHARDS, and Mr S. H. ELLIS.
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Summary of Trial DesignFull details are given elsewhere.’ 1285 patients aged 75 years or
less were entered into the trial. Primary treatment was total
mastectomy with axillary node clearance or sampling. Patients wererandomised to receive 10 mg tamoxifen (’Nolvadex’) twice daily orno further treatment, the duration of trial medication being 2 yearsor until relapse, if this was earlier. Treatment began within 8 weeksof mastectomy and treatment to be used on relapse was left to thediscretion of the clinicians who were informed of the patient’s ERstatus, ifknown, at the time of relapse. Recruitment ended on Feb 6,1981. After exclusions because of ineligibility there remained 566patients randomised to tamoxifen and 568 controls. Data weremissing for 4 patients in the tamoxifen group and 1 control, leaving562 tamoxifen-treated patients and 567 controls. (The numbers inthe 1983 report were 559 and 567, the difference being due to latearrival of follow-up data in 3 and 2 cases, respectively.)Only 524 (46%) tumour specimens were assayed for ER content,
by modifications of the dextran-coated charcoal method, mainly atlaboratories in Glasgow, Manchester, Cardiff (Tenovus Institute),and London (ICRF). Details of this aspect of the study have beenreported elsewhere. 3,4
Statistical analysis was on the basis of "intention to treat",-theendpoints being first recurrence of breast cancer, including contra-lateral disease and death.The follow-up data used in this analysis were those available at the
trial census date of Dec 31, 1983.
Results
The treatment groups were well-balanced for type of
operation, for age, and for nodal, menopausal, and ERstatus. t A significant benefit was seen in the tamoxifen-treated group both for events (first recurrence or deathwithout recurrence) and survival. At a median follow-up of 45months, 152 events have occurred in the tamoxifen group and220 in the controls (table 1), giving a significant (p<O . 000 l,log-rank analysis) reduction in treatment failure rate in thetamoxifen group of 41% (95% confidence limits 27-53%).These data are displayed in fig 1 as a life table.
Stratification into postmenopausal node negative and nodepositive and premenopausal node positive (table I) shows a
TABLE I-ANALYSIS OF ALL EVENTS: (A) OVERALL AND (B) BYMENOPAUSAL AND NODAL STATUS
TABLE II-ANALYSIS OF EVENTS BY SITE OF RECURRENCE
beneficial observed to expected ratio in all three tamoxifen-treated groups. Cox analysis shows no interaction betweentreatment effect and menopausal and nodal status. There is,therefore, no statistical evidence of a differential treatmenteffect between the subgroups.Tamoxifen appeared to prevent both local/regional and
distant disease (table II). Among patients for whom the firstevent was recorded as local/regional disease there were 15deaths in the tamoxifen treated group and 37 in the no-
Fig 1-Life table (all events).
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TABLE III-OVERALL ANALYSIS OF SURVIVAL
TABLE IV-ANALYSIS OF SURVIVAL BY ER STATUS AT TWO DIFFERENTCUT-OFF POINTS FOR ALL PATIENTS IRRESPECTIVE OF TREATMENT
X2=6.8 (p=0-09) for 5 fmol/mg cut-off; X2 = 11.9 (p=0-0006) for 30
fmol/mg.
treatment group. Most patients in whom the first eventrecorded was distant metastasis have died.
Menopausal status alone was not a significant prognosticvariable, although similar analysis by nodal status showed apoorer prognosis (p<0’0001, log-rank analysis) for patientswith nodal involvement.
Overall (ie, including deaths subsequent to recurrence)there were 113 deaths in the tamoxifen treated groupcompared with 158 in the controls, a reduction of 34% with9507o confidence limits of 16-49% (X2 test; p= 0-0019). Thedata are summarised in table III and displayed in fig 2. Deathsdue to breast cancer and not due to breast cancer but withbreast cancer present were fewer in the tamoxifen treatment
group than in the control arm. Again stratification intomenopausal and nodal subgroups showed a beneficialobserved to expected ratio in all three tamoxifen-treated
groups. Cox analysis showed no interaction between treat-ment effect and menopausal or nodal status, indicating nosignificant evidence of a differential treatment effect betweenthe subgroups.
TABLE V-PREDICTION OF EFFECT OF TREATMENT ON SURVIVAL
BY ER STATUS
Cox analysis: no significant difference in tamoxifen response between
subgroups.
At a cut-off point of 5 fmol/mg cytosol protein, ER statuswas of prognostic significance in relation to survival (tableIV). However, ER status does not appear to predict the effectof treatment on survival (table v). Increasing the cut-off to 30fmol/mg enhances the prognostic significance of ER statusbut there were still no significant differences in treatmenteffects between ER positive and ER negative subgroups(table v). ER status appeared to be of prognostic significanceat both cut-off points for events but, as for survival, therewere no significant differences in treatment effects betweenER positive and ER negative subgroups.The trial medication was generally well tolerated with only
25 patients (4%) of those randomised to receive tamoxifendiscontinuing it because of unwanted effects; the 11 newwithdrawals are detailed in table VI. Non-therapeutic effectswere reported in a total of 80 patients receiving tamoxifen,but these effects were considered to be probably or definitelyrelated to the drug in only 13 patients in addition to those inwhom medication was discontinued. In 8 of these patients,
Detailed tables available from authors.
Fig 2-Life table (all deaths).
839
TABLE VI-SIDE-EFFECTS RESULTING IN WITHDRAWAL OF
TAMOXIFEN
Total side-effects resulting in withdrawal of tamoxifen: 25 casest
*Treatment with tamoxifen subsequently restarted.For other 14 see table VI in 1983 paper.
the reported effect was hot flushes, a well-recognisedpharmacological effect of this anti-oestrogen. Other reportedeffects included anorexia and nausea, depression, migraine,peripheral neuropathy, and superficial thrombophlebitis,and the incidence of these effects was comparable between theno treatment group and the group receiving tamoxifen.There were no reports of hypercalcaemia, anaemia, or
leucopenia in the tamoxifen treated group.
Discussion
At a follow-up of up to 6 years, adjuvant tamoxifen hasprolonged the disease-free interval and significantlyincreased survival, with 45 (34%) fewer deaths observed inthe treated group than in the control group. This benefit is
independent of menopausal, nodal, or ER status. Cautiousinterpretation of these results is necessary, however, since,with a 3-year recruitment period and a duration of treatmentof up to 2 years, the final patients recruited into the trial havenow been off treatment for only a year. Continued follow-upwill be essential to detect any increase in disease recurrence oraccelerated mortality associated with cessation of therapy, ofwhich there is no evidence at present. In addition, it is
important that this result is corroborated from other studiescomparing groups of patients receiving tamoxifen withuntreated controls. Whether the results reported here wouldbe improved by administering tamoxifen for longer than 2years or until recurrence requires investigation in futuretrials, although animal tumour studies support this
hypothesis.5Because it is considered unethical to withhold adjuvant
chemotherapy in the USA, tamoxifen, if used at all, has beenadded to a combination chemotherapy regimen. This hasproduced results which are difficult to interpret, but may beexplicable on the basis that part of the mechanism of action ofadjuvant chemotherapy is mediated by an endocrine
pathway. Thus in the NSABP protocol the addition oftamoxifen to a regimen containing melphalan and5-fluorouracil resulted in a significant increase in disease freesurvival in postmenopausal women, but apparently no extrabenefit in the premenopausal group.6 If chemotherapyablates the major source of oestrogenic drive to the residualtumour burden via an ovarian effect in premenopausalwomen, the addition of tamoxifen might fail to show anadditional benefit. However, in postmenopausal women,where the use of adjuvant chemotherapy alone has failed toshow anything but minor therapeutic advantage, the
additional advantage of tamoxifen might essentially be thatachieved in the current trial.There are hazards in searching through data for
interactions amongst subgroups based on menopausal, nodal,or biological characteristics. Retrospective subgroupanalyses tend to lose sight of the main question addressed bythe trial. Furthermore, the more subgroups analysed, thegreater the chance of throwing up a statistically "significant"random result. In addition, since subgroups get smaller andsmaller, what could be important true differences might belost as the statistical power decreases and the chances of betaerrors increase. For example, this could be the explanation forthe paradoxical result for the ER content of the primarycancer, since it is counterintuitive that such assays should failto predict those patients most likely to benefit from adjuvanttamoxifen. Another possible explanation for the failure ofERcontent to predict response is that the assay was at fault. 7,8 Wethink this is an unlikely explanation since the laboratorieswere measuring something of biological significance: the ERcontent predicted prolongation of disease-free interval andsurvival amongst the ER-positive group. Furthermore thesplit amongst patients whose tumour ER status was greater orless than 30 fmol/mg cytosol protein was about 50:50, asmight be expected from the results of major single centrelaboratory assays. If there had been a significant loss ofreceptor content during the harvesting and transport ofspecimens to the laboratory, one might have expected a muchlarger percentage of patients whose tumours contained lessthan 30 fmol/mg.Again, it is essential that this surprising lack of correlation
between ER and response to tamoxifen be corroborated bytrials of similar design,’ and it is of interest that results
showing beneficial effects of tamoxifen in the adjuvantsituation have been reported for either ER positive patientsonly6,9 or ER positive and negative patients.l0,11 Perhapstamoxifen exerts its action via alternative biological pathwayswithin the cancer cell.12-14
In conclusion, this trial shows a significant increase indisease-free interval and a significant increase in survival inpatients with early breast cancer treated with tamoxifen.These beneficial effects are associated with minimal toxicityduring the treatment period. This is the first trial
demonstrating a significant survival benefit with tamoxifenand we hope for confirmation of this important effect in othertrials of similar design currently in progress.Once again the NATO Steering Committee thanks all the surgeons,
oncologists, pathologists, and biochemists and the external clinical auditorswhose efforts made this study possible. A full list appears in the 1983 paper.This study was supported by Imperial Chemical Industries plc. The Cancer
Research Campaign supported the ER work.
Correspondence to Prof M. Baum, Department of Surgery, King’s CollegeHospital, London SE5 8RX.
REFERENCES
1. Baum M, et al. Controlled trial of tamoxifen as adjuvant agent in management of earlybreast cancer. Lancet 1983; i: 257-61.
2. Baum M, et al. Improved survival amongst patients treated with adjuvant tamoxifenafter mastectomy for early breast cancer. Lancet 1983; ii: 450.
3. King RJB, Barnes DM, Hawkins RA, Leake RE, Maynard PV, Roberts MM.Measurement of oestradiol receptors by five institutions on common tissue samples.Br J Cancer 1978; 38: 428-30.
4. Cowan S, Leake RE. British interlaboratory quality assessment of steroid receptorassays. In: Leclecq G, Toma S, Paridaens R, Heuson JC, eds. Recent results incancer research: Vol XCI. Heidelberg: Springer, 1984: 98-103.
5. Jordan VC, Allen KE, Dix CJ. Pharmacology of tamoxifen in laboratory animals.Cancer Treat Rep 1980; 64: 745-59.
6. Fisher B, et al. Influence of tumor estrogen and progesterone receptor levels on the
response to tamoxifen and chemotherapy in primary breast cancer. J Clin Oncol1983; 1: 227-41.
840
7 Rose C, Thorpe SM, Andersen KW, et al. Beneficial effect of adjuvant tamoxifentherapy in primary breast cancer patients with high oestrogen receptor values.Lancet 1985; i: 16-19.
8. Stewart H, Prescott R. Adjuvant tamoxifen therapy and receptor levels. Lancet 1985; i:573.
9. Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy,endocrine therapy and mastectomy alone in postmenopausal patients with operablebreast cancer and axillary node metastases. Lancet 1984; i: 1256.
10. Palshof T. Adjuvant endocrine therapy of primary operable breast cancer: a clinicaltrial of antioestrogen, oestrogen and placebo to pre- and postmenopausal patients.Presented at 3rd EORTC Breast Cancer Working Conference (Amsterdam, April,1983)
11 Wallgren A, Glas U, Theve NO, Shoag L, Marasjo G. Adjuvant tamoxifen in operablebreast cancer in Stockholm. Presented at 13th International Congress of
Chemotherapy (Vienna, 1983).12. Patterson J, Furr B, Wakeling A, Battersby L. The biology and physiology ofNolvadex
(tamoxifen) in the treatment of breast cancer. Breast Cancer Res Treat 1982; 2:363-74.
13. Taylor CM, Blanchard B, Zava DT. Estrogen receptor-mediated and cytotoxic effectsof the antiestrogens tamoxifen and 4-hydroxytamoxifen. Cancer Res 1984; 44:1409-14.
14 Editorial. Prospects for the future in the management of carcinoma of the breast: thebiological fall out from clinical trials. Br J Cancer 1984; 49: 117-22.
PREVENTION OF PRE-ECLAMPSIA BY EARLYANTIPLATELET THERAPY
M. BEAUFILSR. DONSIMONI
S. UZAN
J. C. COLAU
Service de Néphrologie, Service de Gynécologie-Obstétrique, andService central de Biochimie, Hôpital Tenon, Paris, France
Summary 102 patients at high risk of pre-eclampsiaand/or fetal growth retardation were
randomly allocated to treatment with 300 mg dipyridamoleand 150 mg aspirin daily from 3 months’ gestation onwards(group A) or to the control group (group B, no treatment).Group A was twice as likely as group B to have a normalpregnancy. Pre-eclampsia occurred in 6 patients in group Band none in group A. Major complications (fetal death orsevere growth retardation) occurred in 9 patients in group Band none in group A. Platelet count and plasma volume weresignificantly higher in group A than in group B throughoutpregnancy. The treatment did not produce serious adverseeffects. Antiplatelet therapy given early in pregnancy to high-risk patients may thus protect against pre-eclampsia and fetalgrowth retardation.
Introduction
THE most severe forms ofpre-eclampsia are associated withwidespread placental thrombotic lesions, which are probablyresponsible for the effects of the disease on the fetus.Treatment of pre-eclamptic women with heparin has usuallygiven disappointing or, at best, transient results. Placentallesions are already extensive by the time maternal symptomsappear, and this may be why heparin given after the
appearance of symptoms has not been successful. Our studywas undertaken to determine whether early anticoagulanttherapy can prevent the placental lesions and thereby fetalcomplications.
Methods
We selected 102 patients judged to be at particularly high risk forpre-eclampsia and/or fetal growth retardation, mainly on the basis oftheir obstetric history (table I). To avoid selecting patients with"true pre-eclampsia" and minor risk of recurrence, we selectedeither patients who had had several complicated pregnancies, orpatients who also had vascular risk factors (eg, known essentialhypertension >160/95 mm Hg, familial hypertension). Patientswith secondary hypertension or known or suspected renal diseasewere excluded. On average, patients were 28 years old. All but 3 hadhad one or more abnormal pregnancies; many of these had resultedin a major complication-ie, stillbirth or severe fetal growthretardation (baby under the third percentile of weight for gestationalage.’ Only 3 patients were primiparas, selected because they hadvascular risk factors-known hypertension or diastolic blood-
pressure of >120 mm Hg at the first antenatal visit.Patients entered the study during the first trimester of pregnancy.
On entry they were randomly allocated to group A or B. Patients in
TABLE I-AGE, PARITY, AND OBSTETRIC HISTORY
*Given as number of events, with number of patients in parentheses.
group A received daily 300 mg of dipyridamole and 150 mg ofaspirin from 3 months of gestation until delivery. Group B was thecontrol group. For ethical reasons the study was not double blind.
Patients were examined at least once a month, at both the obstetricand nephrological units of the hospital. Weight, oedema score,blood pressure (measured in the sitting position), proteinuria,serum creatinine and uric acid, and platelet count were recorded atevery antenatal visit. Plasma volume was measured (with the Evansblue method) in the third trimester. All groups underwent the sameclinical, biological, and ultrasound monitoring, and except for
antiplatelet therapy they were managed in the same way.Fetal growth was assessed against the values established by Leroy
and Lefort, who based them on observations made on 25 000 birthsin 21 obstetric clinics in Paris.Numbers of cases were compared by the x test and measurements
by the Student’s t test.
Results
9 patients were excluded from analysis: 2 who were lost tofollow-up (both in group B), and 7 who had a spontaneousabortion before 16 weeks (4 in group A and 3 in group B).Normal pregnancy occurred significantly more often in
group A than in group B (table n), a normal pregnancy beingdefined as one in which the blood-pressure did not reach140/85 mm Hg, no proteinuria appeared, and patientsdelivered a live baby of normal weight after 36 weeks’
gestation. The frequency of uncomplicated hypertension(blood pressure 140/85 mm Hg at least twice) was similar inthe two groups. Pre-eclampsia, defined as severe
hypertension (diastolic blood pressure over 105 mm Hg) withproteinuria over 1’ 5 gm/day in the third trimester, occurredonly in 6 group B patients; the difference was statisticallysignificant.
