Stroke Prevention in Women: Role of Aspirin Versus Ticlopidine LINDA A. HERSHEY, M.D., Ph.D., Buffalo, New York

Stroke is the third leading cause of death in North America. Most studies indicate that womenarejustaslikelyasmentohaveaninitial stroke but less likely to have a recurrent stroke. Aspirin and ticlopidine are two antiplatelet drugs that reduce the risk of recurrent stroke by 26 % to 30 % . In some stroke prevention trials, aspirin has been shown to be more effective for men than for wornem In contra& major stroke prevention trials using ticlopidine have demonstrated equal benefit in women and in men. The overall incidence of adverse effects seen with ticlopidine is not significantly different from that observed with aspirin. There are now two effective agents useful in stroke prevention in both men and women.

troke is the most common disabling neurologic diseasein adult life and is the most devastating S result of chronic hypertension and atherosclerosis [l]. Atherothrombotic (ischemic) infarction is the most common type of stroke, accountingfor more casesthan either cerebral embolism, intracerebral hemorrhage,or subarachnoidhemorrhage[2,3].Patients with transient ischemic attacks (TIA) havea 13-fold excessrisk of ischemic stroke within the first year and an overall stroke risk of 6% annually 141. Aspirin is currently the most acceptedtherapy for prevention of acute ischemic stroke following TIA, although somehavequestionedits usefulness in women [5].This reviewwill examineinitial stroke risk and stroke recurrencein women. It will also discussstroke prevention trials using aspirin and a new antiplatelet drug, ticlopidine, focusing on the efficacy of these agentsin women. EPIDEMIOLOGYOF STROKEIN WOMEN Stroke is the third leading cause of death in North America. More than 164,000Americans died from stroke in 1981 [l]. The Framingham Study showedembolic stroke patients to have different fatality ratesaccordingto sex:23%for men and 9% for women [2]. Fatality ratesfor other stroketypes, however,did not differ according to sex. Overall, stroke survival at the end of a 5-yearfollow-up was better for women (60%)than for men (52%). Initial Stroke Risk

From the Departments of Neurology and Pharmacology, Department of Veterans Affairs Medical Center and State University of New York at Buffalo, Buffalo, New York. Requests for reprints should be addressed to Linda Hershey, M.D., Ph.D., Neurology Service (DVAMC). 3495 Bailey Avenue, Buffalo, New York 14215. Manuscript submitted August 23, 1990, and accepted in revised form April 25, 1991.

299

September 1991 The American Journal of Medicine

Hypertension is the most common and most potent precursor to atherothrombotic brain infarction, according to several prospective studies [3,6,7].TIAs, cardiacdisease,cigarettesmoking,diabetes,and ageare alsoimportant risk factors.The association of abdominal adiposity with risk of stroke in older women appearsto be related to the link betweenadiposity and both hypertensionand diabetes [S]. Atrial fibrillation that is unassociatedwith rheumatic, coronary,or hypertensiveheart diseaseappearsto increasethe risk of stroke in somestudies [9], but not in others [7]. The 2-year incidence of atrial fibrillation is higher in men (5.9 per 1,000) than in women (3.8 per 1,000) [9]. Some investigators have found that heavy current alcohol intake is an independentrisk factor for stroke in men [lo], while othersreport that the ap-

Volume 91

STROKE

parent association of alcohol with stroke is the result of the confounding effects of smoking [ll]. Some authors have found men to be twice as likely as women to have an initial stroke [7], while others have reported an equal incidence in both sexes, regardless of stroke type [12]. Two studies have shown women to be more likely than men (59% to 63%) to have a subarachnoid hemorrhage [2,3]. One group reported a female predominance (59%) of embolic strokes [3]. Use of oral contraceptives, in the absence of smoking, hypertension, or migraine, significantly increases the risk of stroke [13] and death from stroke [14]. While hypertension does not seem to potentiate the effect of oral contraceptives, smoking does [13]. Women who smoke and use oral contraceptives have a relative risk of hemorrhagic stroke that is six times that of smokers who do not use the pill. In 23 countries in the world, the decline in stroke mortality during 1970 to 1985 was greater in women than in men [15]. These results are similar to those obtained in the Framingham Cohort during 1968 to 1976 [16]. Women in that study appeared to be more compliant than men in adhering to an antihypertensive drug regimen and in losing excess weight. While control of hypertension seems the most likely explanation for the decline in stroke mortality, a recent study in the United States failed to support this hypothesis [ 171. The greater decline in stroke in women occurred even though women in the Framingham Study were less compliant than men in giving up cigarettes [16]. Stroke Recurrence Recurrent strokes are usually of the same type as the original stroke. In the Framingham Cohort, the cumulative 5-year stroke recurrence rate for brain infarction was twice as great in men as it was in women [2]. Subsequent studies, however, did not find that recurrence rates were influenced by sex. In the Lehigh ValIey Cohort, TIA and heart disease were the strongest predictors of stroke recurrence [18]. In the Stroke Data Bank, hypertension, an abnormal initial computed tomographic scan, and a history of diabetes were important risk factors [19]. Even though there may be a more rapid decline in stroke incidence and mortality for women than for men, both sexes experience an equal degree of functional, cognitive, and affective disability following stroke [20]. Thus, there is a need for safe and effective preventive therapy for stroke that will work as well in women as in men.

PREVENTION

IN WOMEN

/ HERSHEY

treatment and prevention. He summar ized the evidence that aspirin results in a 25% to 30% decrease in the incidence of stroke following TIA. The optimal dose of aspirin now appears to be 325 mg/day, since that dose has been shown to be less gastrotoxic and just as effective in stroke prevention as 1,300 mg/day [21]. This low dose inhibits cyclooxygenase nearly completely, blocking the production of thromboxane Aa in platelets, thereby inhibiting platelet aggregation. The combination of other antiplatelet drugs such as stimpyrazone or dipyridamole with aspirin does not appear to add any further advantage to aspirin in stroke prevention trials [22-251. Male-Female Differences Several studies have reported that benefit from aspirin in stroke prevention is seen primarily in men [21,22,25-271. Other trials have found no sex differences in aspirin’s therapeutic effect [23,24,28]. Table I summarizes results from various aspirin stroke prevention trials in which enrollment and endpoint data were provided according to sex. Epidemiologists have argued that sex differences in aspirin’s clinical effect may be an artifact of the small numbers of women enrolled into many clinical trials. They also have pointed out that studies done prior to the aspirin era have shown women to be less likely than men to have recurrent strokes [2]. An alternative explanation is that there is a real sex difference in the antiplatelet effects of aspirin. In one in vitro study of platelet aggregability, aspirin exerted a greater inhibitory effect on platelet aggregation in normal men than it did in postmenopausal women or orchiectomized men [29]. When testosterone was added to platelets isolated from women or orchiectomixed men, the inhibitory response of aspirin returned to a level seen in normal men. However, the relevance of this finding to differences in the in vivo antiplatelet effects of aspirin in men and women is unclear. A third explanation might be sex differences in the vascular response to platelet aggregation. In one in vivo study of the effect of testosterone on platelet aggregation in mice, enhanced aggregation was observed in mesenteric arterioles of androgen-treated males. However, no effects of androgens were seen in mesenteric vessels of females or in pial arterioles of either sex [30].

ASPIRIN IN STROKEPREVENTIONTRIALS Grotta [5] recently reviewed the available literature on various medical and surgical approaches to stroke September

TICLOPIDINEIN STROKEPREVENTIONTRIALS Ticlopidine is an inhibitor of platelet aggregation and thrombus formation that does not work by inhibition of cyclooxygenase. It enhances the effect of prostacyclin on platelets and inhibits the binding of fibrinogen to adenosine diphosphate-treated platelets. Ticlopidine has been extensively evaluated as an antiplatelet agent for prevention of initial and recurrent stroke and other vascular events [31]. 1991

The American

Journal

of Medicine

Volume

91

289

STROKE PREVENTION IN WOMEN / HERSHEY TABLE I Stroke Prevention Trials Reporting Male/Female Refarence

Responseto Aspirin Prophylaxis

Therapy

[26,271 1221

9”2:

Ei:

AS A P

110:43 101:49

16:5 20:6

27% J in males, NSE in females

ASA f S P+S

200:90

29:17 56:12

48% 4 in males, NSE in females

196:89 42:21 44:17

9:14 20:5

53% 1 in males, NSE in females

145:57

14:7

No difference, males vs females

131:67 143:61

17:4

[251

ASA S

1231

ASA t D AS A P

RauRsofASA

27:a

[241

ASA t D ASA

58~27 58:25

No difference, males vs females

291:151

[281

ASA

169:84

NA

No difference, males vs females

P

145:107

ASA (1,200) ASA (300) P

NA

22% 1 in males, NSE in females

603:203

[211

305:143

600:215 575:239

IA= aspirin; D = dipyridamole; M:F = male:female;NSE = no significant affect; P = placebo; S = suifinpyrazone.

The Ticlopidine Aspirin Stroke Study (TASS) comparedthe effects of 500 mg of ticlopidine per day to 1,300 mg of aspirin per day in 3,069patients with recentTIA or minor stroke [32].After 3 years, there was a 21%reduction in the risk of fatal and nonfatal stroke and a 12%reduction in the risk of death or nonfatal stroke in the ticlopidine group compared with the aspirin group. The risk reductionwith ticlopidine wasjust asap-

Cumulatlve Event Rate (%I

q Aspirin q Ticlopidlne

25

parent for womenas it wasfor men. Of the patients included in TASS, 35% (1,082)were women.They weredistributed equallybetweenticlopidine and aspirin groupsby prospectivestratification.The cumulative eventratesfor womenand men for the primary endpointdeath or nonfatal strokeand for the secondary endpoint fatal or nonfatal stroke are shownin Figures 1 and 2. In women,ticlopidine reducedthe risk of death or nonfatal stroke at 3 yearsby 17% (eventrate of 14.3versus17.2for aspirin)and in men by 10%(eventrateof 18.6versus20.5for aspirin).The risk of fatal or nonfatalstrokeat 3 yearswasreduced

Cumulatlve Event

Rate (%I

20

20

15

q q

1

Aspirfn

Ticlopidlne

10 1 5 0 Dl

’ 1

2

Female

3

1

YEARS

2

3

Male

I-

1

Figure

1. Cumulative

in women

and

men

event rate for death or nonfatal from the Ticlopidine Aspirin Stroke

stroke Study

- ^ igure 2. Cumulative from

~321.

290

Females

September 1991 The American Journal of Medicine

Volume 91

the Ticlopidine

YEAR

2 Males

stroke event rate In women Aspirin Stroke Study [32].

and

men

STROKE

PREVENTION

IN WOMEN

/ HERSHEY

Cumulotlva Event Ret. WI so

Flgure

3. Cumulative event rate for the composite endpoint stroke, myocardial infarction, or vascular death in males and females from the Canadian American Ticlopidine Study [33]. There was no significant difference between women and men (Mantel-Haenszel test).

I

Fomelo

by 27% (7.8 versus 10.8) in women and 19% (11.2 versus13.8)in men.Although therewasa trend for an improved responseto ticlopidine in females,there wasno statistical differencein the responseto ticlopidine betweenmales and females. The Canadian American Ticlopidine Study (CATS) comparedthe effectsof 500mg/day of ticlopidine t.0placeboin 1,053patientswith recentlycompleted atherothromboticstrokes [33]. After 2 years, therewasa 30%reductionin risk of stroke,myocardial infarction, and vasculardeath in the ticlopidine group comparedwith the placebogroup. The incidenceof recurrentstrokeor strokedeathwasreduced by 34%with ticlopidine relative to placebo. Again, ticlopidine wasjust as effective in women as in men. In CATS, 38%(400)of the 1,053patients included in the on-treatment analysiswerewomen. Subgroupanalysisof the risk of stroke, myocardial infarction, or vasculardeath by sexfound no differencein the cumulative event rate betweenmen and

Male

women (Figure 3). The 3-year risk reduction for ticlopidine versusplacebowas 26%(eventrate 26.5 versus35.7)in women and 23%in men (event rate 23.4versus 30.5).There was a trend for a greater risk reduction with ticlopidine in women,especially during the first year of therapy. Adverse Effects

Table II givesthe incidenceof common and serious adverseeffects observedin TASS and CATS [32,33].Patients intolerant of or sensitiveto aspirin andthosewith a history of peptic ulcer diseasewere excluded from TASS prior to randomization. In TASS, the overall incidenceof any adverseeffect in the ticlopidine group (62%) was not significantly different than that recorded in the aspirin group (53%).In CATS, the incidenceof any adverseevent during the study was 54%with ticlopidine and 34% with placebo.The overall incidence of adverseeffects was higher in women than in men, although

TABLE II Adverse EffectsReported with Ticlopidine, Aspirin, and Placebo in TASSand CATS* Number(%I oi Events Placebo Adverse Efkt

&%Et Discontinued Rash Discontinued Any bleeding Neutmpenia

Severe(t450 cells/mm3)

(n = 536)

‘i I::;

Ticlopidine (n = 1,518)

Aspirin (n = 1,527)

1,229 (60) y;

% I::;

p..’

5 (0.9) 43 (8)

2;; p.,)

4 (0.7) 16 (3)

1;; ;;.“41

15 (1) 152 (10)

17 (0.8)

Yi (“.8’

38: I:;

adaptedfrwn 132,331.

September 1991 The Amerlcen

Journal

of Medicine

Volume

91

291

STROKE PREVENTION IN WOMEN / HERSHEY

the difference was not statistically significant; this trend was consistent among treatment groups. In TASS, diarrhea, skin rash, and u&aria were significantly more prevalent among patients receiving ticlopidine than among those receiving aspirin. However, gastrointestinal complaints including gastritis, pain, and hemorrhage were significantly more common among those treated with aspirin (13.1% versus 8.6%). More patients in the aspirin group (45) developed peptic ulcer disease than those in the ticlopidine group (12). Severe, but reversible, neutropenia was the most serious adverse effect of ticlopidine and always occurred within the first 3 months of beginning the drug. Fifty episodea of any neutropenia have been reported with ticlopidine, but only 17 (0.8%) were classified as severe. The risk of neutropenia makes it imperative that ticlopidine-treated patients have repeated complete blood cell counta during the first few months of therapy. Neutropenic patients did not always have symptoms that could serve as a forewarning.

SUMMARY AND CONCLUSIONS Stroke remains an important health care problem. Although the incidence of stroke and stroke mortality is lower in women than in men, the outcome in terms of major disability, decreased quality of life, economic burdens, and impact on family life is just as real for women as for men. Although aspirin has proven efficacy for preventing initial stroke, it may have limited efficacy in preventing recurrent stroke. Moreover, questions remain about the efficacy of aspirin for stroke prevention in women. There is a need for an alternative to aspirin in stroke prevention therapy. Ticlopidine has demonstrated efficacy for both initial and recurrent stroke prevention and has been shown to be more effective than aspirin for patients at high risk for a first stroke. It is just as effective for stroke prevention in women as in men. The overall incidence of adverse effects seen with ticlopidine is not significantly different from that seen with aspirin, although careful hematologic monitoring is required with ticlopidine during the first 3 months of use. Both agents are important tools to use in addition to antihypertensive therapy and smoking cessation in stroke prevention.

ACKNOWLEDGMENT I appreciate the thoughtful comments assistance of Zahra Ghorishi.

of Dr. Oscar Ratnoff and the editorial

REFERENCES 1. Dyken ML, Wolf PA, Barnett HJ. et al. Risk factors in stroke. A statement for physicians by the Subcommittee on Risk Factors and Stroke of the Stroke Council. Stroke 1984; 15: 1105-11.

292

September 1991 The American Journal of Medicine

2. Sacco R. Wolf P, Kannel W. McNamara PM. Survival and recurrence following stroke. The Framingham Study. Stroke 1982; 13: 290-5. 3. Coull BM. Brockschmidt JK, Howard G. et al. Community hospital-based stroke programs in North Carolina, Oregon, and New York. Stroke 1990; 21: 867-73. 4. Dennis MS, Bamford JM. Sandercock PAG. Warlow CP. Prognosis of transient ischemic attacks in the Oxfordshire Community Stroke Project. Stroke 1990; 21: 848-53. 6. Grotta JC. Current medical and surgical therapy for cerebrovascular disease. N Engl J Med 1987; 317: 1505-16. 6. Kannel WB. Wolf PA, Verter J, et a/. Epidemiologic assessment of the role of blood pressure on stroke: The Framingham Study. JAMA 1970; 214: 301-10. 7. Davis PH. Dambrosia JM. Schoenberg BS, eta/. Risk factors for ischemic stroke: a prospective study in Rochester, Minnesota. Ann Neurol 1987; 22: 319-27. 8. Folsom AR, Prineas RJ, Kaye SA. Munger RG. Incidence of hypertension and stroke in relation to body fat distribution and other risk factors in older women. Stroke 1990; 21: 701-6. 9. Wolf PA, Abbott RD. Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly. Arch Intern Med 1987; 147: 1561-4. 10. Gill JS. Zezulka AV. Shipley MJ. Gill SK, Beevers DG. Stroke and alcohol consumption. N Engl J Med 1986; 315: 1041-6. 11. Gorelick PB. Rodin MB, Langenberg P, eta/. Is acute alcohol consumption a risk factor for ischemic stroke? Stroke 1987; 18: 359-64. 12. LaRue L. Alter M, Lai SM. et a/. Acute stroke, hematocrit. and blood pressure. Stroke 1987; 18: 565-9. 13. Collaborative Group for the Study of Stroke in Young Women. Oral contraceptives and stroke in young women. JAMA 1975; 231: 718-22. 14. Layde PM, Beral V. Kay CR. Royal College of General Practitioners’ Oral Contraceptive Study. Lancet 1981; 1: 541-6. 15. Bonita R, Stewart A, Beaglehole R. International trends in stroke mortality: 1970-1985. Stroke 1990; 21: 989-92. 16. Kannel WB, Thorn TJ. Implications of the recent decline in cardiovascular mortality. Cardiovasc Med 1979; 4: 983-97. 17. Klag MJ. Whelton PK. Seidler AJ. Decline in US stroke mortality. Demographic trends and antihypertensive treatment. Stroke 1989; 20: 14-21. 18. Sobd E, Alter M, Davanipour Z. et al. Stroke in the Lehii Valley: combined risk factors for recurrent ischemic stroke. Neurdogy 1989; 39: 669-72. 19. Hier DB, Foulkes MA, Swiontoniowski M. eta/. Stroke recurrence within two years after ischemic infarction. Stroke 1991; 22: 155-61. 20. Santus G. Ranzenigo A, Caregnato R. In&i MR. Social and family integratin of hemielderly patients one year after stroke. Stroke 1990; 21: 1019-22. 21. UK-TIA Study Group. United Kingdom transient ischaemic attack (UKTIA) aspirin trial: interim results. Br Med J 1988; 296: 316-20. 22. Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 1978; 299: 53-9. 23. Bousser MG, Eschwege E, Haguenau M, eta/. “AICLA” controlled trial of aspirin and dipyridamole in the secondary prevention of atherothrombotic cerebral ischemia. Stroke 1983; 14: 5-14. 24. American-Canadian Cooperative Study Group. Persantine aspirin trial in cerebral ischemia. Part II. Endpoint results. Stroke 1985; 16: 406-15. 25. Candalise L. Landi G. Perrone P, Bracdli M, Brambilla G. A randomized trial of aspirin and sutlinpyrazone in patients with TIA. Stroke 1982; 13: 175-9. 26. Fields WS, Lemak NA, Frankowski RF, Hardy RJ. Controlled trial of aspirin in cerebral ischemia. Stroke 1977; 8: 301-15. 27. Fields W. Lemak N, Frankowski R, Hardy RJ. Controlled trial of aspirin in cerebral ischemia. Part II. Surgical results. Stroke 1978; 9: 309-19. 28. Britton M, Helmers C, Samuelsson K. High-dose acetylsalicylic acid after cerebral infarction. A Swedish Cooperative Study. Stroke 1987; 18: 325-34. 29. Spranger M, Aspey B, Harrison M. Sex difference in antithrombotic effect of aspirin. Stroke 1989; 20: 34-7. 30. Rosenblum WI. El-Sabban F. Nelson GH, Allison TB. Effects in mice of testosterone and dihydrotestosterone on platelet aggregation in injured arterioles and ex viva. Thromb Res 1987; 45: 719-28. 31. Saltiel E, Ward A. Ticlopidine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states. Drugs 1987; 34: 222-62. 32. Hass WK. Easton JD. Adams HP, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501-7. 33. Gent M. Blakely JA. Easton JD. et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1: 1215-20.

Volume 91

Stroke prevention in women: role of aspirin versus ticlopidine.

Stroke is the third leading cause of death in North America. Most studies indicate that women are just as likely as men to have an initial stroke but ...
534KB Sizes 0 Downloads 0 Views