Low-dose warfarin and low-dose aspirin in the primary prevention of ischemic heart disease

Low-Dose Warfarin and Low-Dose Aspirin in the Primary Prevention of Ischemic Heart Disease

Thomas W. Meade, DM

The thrombotic component in ischemic heart disease (IHD) is now universally recognized. It is therefore logical to consider modifying both fibrin formation and platelet function in primary (as well as secondary) prevention. The scientific case for evaluating lower-dose warfarin in primary prevention rests on the implications of the secondary prevention trials, increasing evidence of an association between the level of factor VII coagulant activity, VII,, and the incidence of IHD, and the results of short-term lower-dose trials for the prevention of venous thrombosis and thromboembolism. The general case for considering aspirin in primary prevention is well known, but the potential vakre of low- dose aspirin in men at high risk needs to be established. Currently available evidence suggests that the combination of lower doses of both warfarin and aspirin in primary prevention may be effective and safe. The objective of the factorial Thrombosis Prevention Trial is to demonstrate a reduction in the incidence of IHD in men at high risk attributable to low-dose warfarin or low-dose aspirin, or both, with 1 group receiving both active treatments. The feasibility of this trial has been demonstrated. An International Normalized Ratio of about 1.5, achieved with an average daily dose of 4.6 mg warfarin, has resulted in no increase in the number of men ever reporting minor bleeding episodes, although rectal bleeding occurs more frequently in those men who do report this symptom.

(Am J Cardiol 1990;65:7C-11C)

From Northwick Park Hospital, Harrow, England. Address for reprints: Thomas W. Meade, DM, MRC Epidemiolo-

gy and Medical Care Unit, Northwick Park Hospital, Harrow HA1 3UJ, England.

A lthough disputed until comparatively recently, a thrombotic component in ischemic heart disease (IHD) is now almost universally recognized.

Pathologic and clinical evidence has demonstrated the thrombotic contribution not only to myocardial infarction (MI), but also to unstable angina pectoris and sudden coronary death.

An obvious point-although infrequently acknowl- edged-is the varying composition of thrombi at different sites. Venous thrombi are largely composed of fibrin and red cells. Coronary artery thrombi may vary from pre- dominantly platelet bodies in the vessel wall to mainly fibrin accumulations in the lumen It is possible that platelets are chiefly responsible for the thrombotic component of unstable angina. The obvious value of oral anticoagulants in preventing venous thrombosis, and the possibility (although by no means the certainty) that aspirin is particularly valuable in patients with unstable angina are perhaps clinical reflections of these pathologic distinctions. Especially in MI and sudden coronary death, where both platelet aggregates and fibrin deposition may be involved, it seems logical to consider modifying both in attempts at primary prevention. However, it is also worth bearing in mind the influence of the coagulation system on platelets. Thrombin (Fig. 1) is a potent platelet-aggre- gating agent as well as being responsible for the conver- sion of fibrinogen to fibrin. Furthermore, thrombin-induced aggregation is not inhibited by aspirin, and it may therefore be a pathologically significant mechanism even in patients taking aspirin prophylactically. If so, there is added reason for trying to limit the potential for thrombin production in people at high risk.

Finally, thrombosis may contribute to the onset of clinically manifest IHD not only as an acute complication of atheroma and plaque rupture, but also as a result of the chronic process of atherogenesis.

WARFARIN Until very recently, the proposition that even in lower

doses warfarin might be used in the primary prevention of IHD would have been dismissed out of hand. However, the scientific case for this approach is strong, and it rests on evidence from several different sources (Table I).

First, oral anticoagulants reduce mortality after MI by about 20%.‘92 However, many deaths soon after infarction are electrical in origin, and are therefore not amena- ble to prevention by antithrombotic agents. Confining attention to events that are almost entirely thrombotic in origin-such as recurrent MI and thromboembolism- shows that oral anticoagulants reduce episode rates by about 50%.3+4 In short, they are extremely effective in these circumstances.

THE AMERICAN JOURNAL OF CARDIOLOGY FEBRUARY 2.1990 7C

A SYMPOWJM: THROMBOSlS AND ANTlTHROMBOllC lIlERAPY4RECYION FOR THE ‘SDS

INTRINSIC EXTRINSIC 1

Fibrinogen d Fibrin

v-1 1:

Thrombin

flGURE 1. A slmmaryoffbeeoa[phtioncascade.

TABLE I Lower Dose Warfarin in the Primary Prevention of

VII, and risk of ischemic heart disease

IHD within 5 years of examination SRE 1.62 1.84 1.43

Factor VII Fibrinogen L M H

Cholesterol

FIGURE 2. Nmlbsrs of events of bcbsmb bed dbeass (MD) (fafd and nonfafal) wifhin 5 years of examinafion by bw (L), mld&~(M)andligb(H)tbirdsof -offacforvIIac-

cbdededafenbyfofbeNorlbwicb lvgmdon edfeds (SRE)

SbOWfbS&blfSkOfallcventfor~SbUllbrd&Vbtbll inweaw e.g., a 1 -&vietion imrease in facfor VII ac- fivifyinawmesfheriskofnevenfwithin5yearsby62%. (Repmdud wifh pemhsh from Lmcef?)

Furthermore, it is likely that in some of the secondary prevention trials the intensity of anticoagulation was a good deal less than intended. If so, this provides the first indication that lower intensities than those usually aimed for may be effective.

With regard to primary prevention, the recently reported preliminary findings from the trial in doctors in the United StatesI showed a significant reduction due to aspirin in the incidence of IHD. There was no obvious effect in the trial in British doctors,*O although the results were not incompatible with those of the American trial. Both trials raised the possibility of increased risk of cere- bral hemorrhage due to aspirin. Neither trial used aspirin doses that would be considered “low” according to cur- rent thinking. The dose in the American trial was 325 mg on alternate days, and in the British trial it was 500 mg/ day for most participants.

Second, there is growing evidence that the level of factor VII coagulant activity, VII,, is associated with the risk of IHD. Factor VII is the procoagulant clotting factor whose activity is most rapidly and extensively reduced by warfarin.

Both trial populations were at low risk of IHD. The question of whether low doses of aspirin in men at high risk might be effective against IHD without an increase in the risk of bleeding therefore remains open.

Figure 2 summarizes the results of the prospective COMBINED PROPHYLAXIS Northwick Park Heart Study.5 Besides the expected rela- Would warfarin and aspirin together reduce the inci- tion between cholesterol and IHD incidence, increasing dence of IHD more than either agent on its own, and levels of both VII, and fibrinogen were associated with without inducing unacceptable bleeding? increased risk. Figure 3 summarizes the findings of the International

These relations have now been confirmed in the preliminary findings of another prospective study.6 A growing number of cross-sectional studies also show a relation between the VII, level and IHD or the risk of IHD.‘-‘O Besides suggesting that VII, may be involved in the pathogenesis of IHD, these findings also raise the possibility of reducing risk by lowering the VII, level. The general epidemiologic characteristics of VII,, including the effects of dietary fat intake, are all consistent with the hypothesis that high VII, levels do contribute to the onset of IHD.”

Third, the VII, level probably influences the rate of thrombin production. lag* Added to these experimental results is the value of factor VII concentrates in treating factor VIII-resistant hemophiliacs, l 3 an approach that is presumably successful because of enhanced extrinsic pathway activity on thrombin production.

Finally, 4 randomized controlled trials have now demonstrated that lower intensities of oral anticoagulation are equally effective in preventing perioperative venous thrombosis after surgeryt4-I6 or thromboembolism after tissue heart-valve replacement,t’ but, as expected, with less bleeding than with conventional intensities.

For a variety of reasons, therefore, it is reasonable to ask whether, in carefully selected men at high risk of IHD, a relatively modest degree of oral anticoagulation with warfarin would reduce the incidence of IHD without increasing the risk of serious bleeding.

ASPIRIN The case for aspirin in the primary prevention of IHD

is much more familiar and less controversial-although still open.

The prolonged effect of aspirin on the secondary phase of platelet aggregation is well known. There is no doubt about the value of aspirin in those who have al- ready had clinical vascular disease, whether MI, transient ischemic attacks or unstable angina pectoris.18

8c THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

FlGuRE3.-vcucularmorLctyh daysOto3S.(Rephtedwithpemhion from Lancet.5)

500

c” ti; s 400

3 z f 300

6

g 200

F E 1 i 100

3

0

Placebo infusion and tablets 56614300 (13.2%)

461/4295 (10.7%) Aspirin Streptokinase 446/4300 (10.4%)

Streptokinase and aspirin 34314292 (6.0%)

0 7 14 21 28 35 Days from randomization

1

Study of Infarct Survival (ISIS-2) trial of streptokinase and aspirin (160 mg/day) immediately after suspected ML2i Used separately, both streptokinase and aspirin reduced cardiovascular mortality over the 35day period by about 20%. When they were used together, the reduction was over 40%. These results support the case for primary prevention by simultaneously modifying platelet function and fibrin formation (by oral anticoagulation rather than streptokinase).

In ISIS-2, anticoagulation (heparin or oral agents, or both) was planned for over 11,000 of the participants, and in most cases these plans were implemented. Among these patients the incidence of major bleeding episodes was no higher in those who took aspirin during the trial than in those who did not (personal communication from ISIS-2 investigators). This suggests that the concurrent use of anticoagulants and aspirin may not be as hazard- ous as is often assumed.

A special study undertaken during the planning of the Thrombosis Prevention Trial (TPT, see later) showed that anticoagulation of the intensity aimed for in TPT (International Normalized Ratio [INR] of about 1.5) with 75 mg aspirin did not increase the rate of gastric bleeding above the very low level attributable to this dose of aspirin.22

Finally, the pooled experience of 3 trials of patients undergoing valve replacement23-25 indicates a high degree of effectiveness from concurrent use of warfarin and aspirin in conventional doses in preventing thromboembolism. Any risk of bleeding was confined mainly to the gastrointestinal tract.

In summary, therefore, the combined use of warfarin and aspirin may be particularly effective and will not necessarily lead to unacceptable levels of bleeding. This is

particularly significant if we keep in mind that in a trial such as TPT the greatest risk facing participants is major events of IHD, about 50% of which are fatal.

THROMBOSIS PREVENTION TRIAL The objective of this factorial tria126 is to demonstrate

a 30% reduction in the incidence of IHD in men at high risk, attributable to low-dose warfarin or low-dose aspirin, or both. One group will receive active warfarin and active aspirin. The aim of the warfarin component is to reduce VII, from a high-risk level of about 120% to about 70%, the VII, level characteristic of patients with little or no IHD. Full anticoagulation reduces VII, to about 30%.

The TPT is being carried out through the British Medical Research Council’s General Practice Research Framework. This framework was originally established for the mild hypertension trial of the Medical Research Council Working Party27; it has now been enlarged for other studies that can most appropriately be performed through general practice.

The first step for each practice is a search of all the notes of men aged 45 to 69 years, to permit exclusion of all those whose participation would be contraindicated- e.g., because of a recent history of peptic ulceration or because of alcohol abuse.

Those who remain eligible are then invited to a screening examination at which smoking status and family history are elicited, body mass index and blood pressure are determined, and cholesterol, fibrinogen and VII, levels are measured. Each of these risk variables is then weight- ed according to its association with IHD in the North- wick Park Heart Study. Those men in the top 20% of the risk-score distribution are invited to take part in the treat-

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18

15 2 .p 12

4 9

B

p 6

3

0 L 1 1.5 ‘2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 6.5 9 9.5 10

FtGURE 4. DiMbuth ot stabk+ wdarin doses. (Reprinkd Wlthpennbdonfrom EUfH&WtJ.26)

140 I

s ::.I---ylg-j 604 . . . . . . 1

0 3 6 9 12 15 18 21 24 27 30

Months at stable dose TPT stable dose distribution

I

FIGURE 5. VI& (pmen&ge of StadW7l)dmdore.TP.T =-Revention T&l. (Reprinted with pwmbhn from EurkartJ.~

1.5

::::

2 I.21 - Placebo

: J! 1.1 1 - - Active

0.8. . . . . . 0 3 6 9 12 15 18 21 24 27

Months at stable dose

TPT stable dose distribution.

FIGURE 6. I- Rommlized Ratio (INR) at stable doee. TPT = l’bmbod Preventh Trial. (Reprinted with pemisshfromEurHeartJ.~

TABLE II Numbers of Men Ever Reporting Symptoms

Any Dose Stable Dose

Active Placebo Active Placebo

Nose bleed 21 21 12 15 Red/pink urine 2 5 0 3 Rectal bleeding 17 11 11 8 Bruising 17 10 11 5 Total no. of men 215 226 148 158

Some men report more than 1 symptom.

TABLE Ill Numbers of Episodes of Reported Symptoms

Nose bleed Red/pink urine Rectal bleeding* Bruising Total no. of

questionnaires

Any Dose Stable Dose

Active Placebo Active Placebo

38 46 23 28 2 5 0 3

41 (p = 0.04) 24 29 (p = 0.03) 16

18 14 12 5 2,180 2,187 1,143 1,288

* One man receiving active treatment accounted for 10 of the 41 epasodes at any dose and 7 of the 29 episodes at stable dose. The slghtly larger number of questionnaires at stable dose from men receiving placebo treatment IS the expected interim consequence of the procedure for matching patients re

ceiving active and placebo treatment.

ment phase. Just over 70% of those invited for screening attend, and about the same proportion of those eligible for treatment enter the trial.

Treatment is double-blind; monitoring of the pro- thrombin time (expressed as INR) and dose regulation are performed from the coordinating center. Anticoagu- lation is induced with a starting dose of 2.5 mg of warfarin (or placebo) daily, increasing by 0.5 or 1.0 mg/day at monthly intervals until the appropriate stable dose for each man has been achieved. The average dose is 4.6 mg/day, but the doses range widely, as expected, from 1.5 to 10.0 mg/day (see Fig. 4). Figures 5 and 6 show that there has been no difficulty in achieving the VII, objective of about 70%, corresponding to an INR of about 1.5.

Thus far (Table II), there is no difference in the numbers of men ever reporting nose bleeds, possible hematu- ria, rectal bleeding, or bruising at stable dose. The frequency (Table III) of rectal bleeding (but not any of the other 3 symptoms) is greater in those receiving active treatment. In other words, whereas treatment does not increase the number of men who ever report rectal bleeding, it does increase the frequency of bleeding in those who do report it.

The aspirin component of the trial has just been intro- duced as a 75-mg controlled-release preparation whose main effect is presystemic, maximizing the inhibition of thromboxane while minimizing the effect on prostacylin.

It is hoped that the 6,000 men required for the trial will have been recruited by the end of 1990 or early 199 1.

1OC THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

Each man’s participation will be for a minimum of 5 years.

CONCLUSION In circumstances in which it is difficult or impossible

to achieve the primary prevention of IHD through life- style modifications, pharmacologic methods have to be considered. Given the difficulty of achieving regression of atheroma, the most effective approach may be through prevention of thrombosis. There is increasing interest in the possibility that this may be achieved by the concurrent modification of fibrin formation and platelet function, using low doses of warfarin and aspirin that do not result in an unacceptable level of bleeding.

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Low-dose warfarin and low-dose aspirin in the primary prevention of ischemic heart disease