Interpretation of Thrombosis Prevention Trial

Correspondence

Volume 351, Number 9110 18 April 1998

		Interpretation of Thrombosis Prevention Trial

Sir--In the report of the Thrombosis Prevention Trial (Jan 24, p 233)¹ there is no multivariate analysis of the recognised aetiological factors for ischaemic heart disease (IHD), the most important of which is smoking. The differential effects of aspirin and/or warfarin in smokers (41% of the study population) vs non-smokers should have been reported since, apart from being an independent prognostic variable, smoking may interfere with the therapeutic effects of trial drugs by increasing platelet aggregability. Were smokers advised to quit? How many succeeded--and how many were perhaps inhibited from quitting because they thought they were being offered an antidote? Was it made clear to the smokers that the trial drug(s) were neither an antidote to the detrimental effects of smoking nor an alternative to quitting.

The ultimate aim is to reduce deaths from IHD. In his commentary on this trial (Jan 24, p 227) Freek Verheugt ² mentions "a change of lifestyle" but smoking is not a lifestyle, it is a very powerful addiction. The tobacco industry knows that it does not have to worry about quitters. For its survival, it needs to replenish 3 million dead customers every year with new recruits, inevitably children and adolescents.³ With legal barriers ludicrously absent, the industry has established nicotine addiction on such a large scale that it is renamed as "lifestyle"--and then the concept of personal choice is thrown in, effectively rationalising the addiction and removing all blame from the industry.

Being a non-smoker has the highest value-for-effort risk-reducing ability, and taking aspirin will never reduce the IHD risk of a smoker to that of a non-smoker. Smoking increases the risk of IHD five-fold⁴ and this effect is cumulative and irreversible.⁵ If the risk is 100 for a smoker, it would be 80 for a smoker taking aspirin but only 20-30 for a non-smoker. We must remember that the abolition of the tobacco industry will pay the highest dividends for the health of the nation.

Jayant S Vaidya

Department of Surgery, University College London, London W1P 7LD, UK

1 The Medical Research Council's General Research Framework . Thrombosis Prevention Trial : randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 227-28.

2 Verheugt FWA . Aspirin, the poor man's statin? Lancet 1998; 351: 227-28.

3 Josefson D . Tobacco company targeted marketing campaign at teenagers. BMJ 1998; 316: 329 [PubMed].

4 Parish S, Collins R, Peto R, et al . Cigarette smoking, tar yields, and non-fatal myocardial infarction: 14 000 cases and 32 000 controls in the United Kingdom. BMJ 1995; 311: 471-77 [PubMed].

5 Howard G, Wagenknecht LE, Burke GL, et al, for the ARIC Investigators. Cigarette smoking and progression of atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study. JAMA 1998; 279: 119-24 [PubMed].

Sir--The Thrombosis Prevention Trial ¹ provides evidence that primary prevention of ischaemic heart disease (IHD) is possible by treating high-risk men with low-intensity oral anticoagulation with warfarin and low-dose aspirin. However, we have reservations about how the results of this trial can be applied to individuals.

For the primary endpoint, prevention of IHD, treatment with warfarin plus aspirin led to a proportional rate reduction of 34% when compared with placebo Assuming that there were no serious differences between these groups in the distribution of follow-up times, this translates to an annual NNT of 221 (NNT=number of patients who need to be treated for one year to prevent one episode of IHD). The number of side-effects from warfarin plus aspirin also varied, with corresponding annual NNHs (numbers needed to treat for one year to produce a harmful event) of 1019 (major), 174 (intermediate), and 37 (minor), again assuming similar follow-up profiles. For the individual, the acceptability of warfarin/aspirin is critically dependent on the value he or she places on the benefits of preventing an IHD event compared with the risk of side-effects of treatment. The likelihood of being helped is 4·6 times greater if a person is unconcerned about intermediate and minor side-effects and 1·5 times greater if unconcerned about just minor side-effects. Conversely, the likelihood of being harmed is 7·5 times more likely if a person is concerned about any (major, intermediate, or minor) side-effect.

Furthermore, without knowing whether the relative benefits of treatment are constant across strata of cardiovascular risk, it is very difficult to estimate for an individual patient the likely risk/benefit ratio for warfarin/aspirin. As others have demonstrated for cholesterol-lowering drugs, absolute benefit is critically dependent on the baseline risk of individual patients.^2-4 Given that the side-effects of treatment of warfarin/aspirin are substantial, knowledge of baseline risk is critical for informed decision making with individual patients.

*Tom Fahey, Tim J Peters

Division of Primary Care and Department of Social Medicine, University of Bristol, Canynge Hall, Bristol BS8 2PR, UK

1 The Medical Research Council's General Practice Research Framework. Thrombosis Prevention Trial : randomised trial of low-intensity oral anticoagulation with warfarin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233-41.

2 Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study. Lancet 1995; 345: 1274-75 [PubMed].

3 Vandenbroucke JP, Westendorp RGJ. Are the effects of cholesterol lowering drugs always equal? Lancet 1996; 347: 1267-68 [PubMed].

4 Davey Smith G, Song J, Sheldon T. Cholesterol lowering and mortality: the importance of considering initial level of risk. BMJ 1993; 306: 1367-73 [PubMed].

Sir--The Thrombosis Prevention Trial¹ shows that low-intensity oral anticoagulant therapy protects against ischaemic heart disease (IHD), reducing mortality in high-risk men. Low-dose aspirin was also effective, but only against non-fatal events. Thus both treatments had an independent effect in primary prevention and, presumably, protected different types of high-risk men. Primary prevention implies the treatment of very large numbers, even if at high risk, to avoid a small number of events; indeed, in this trial, 1000 men were treated with either warfarin or aspirin to avoid 6 events. Both treatments carry a small but real chance of bleeding. Progress in primary prevention could be achieved through the identification of subgroups who might differentially benefit from either warfarin or aspirin.

Recent work on genetic determinants of the risk of IHD may help here. Indeed, it has been suggested that some genetic variants of coagulation factor VII protect against myocardial infarction.² These variants were associated with lower plasma levels of factor VII in the same range as those obtained pharmacologically with low-dose warfarin in the Thrombosis Prevention Trial . The "protective" alleles were found in almost one-third of the Italian population tested (21% and 36% for each variant); these naturally protected individuals, if carrying other risk factors, could preferentially benefit from treatments different from warfarin. The frequency of such genetic variants in Italians was significantly higher than in northern European populations,^2,3 contributing to the decreasing north-south gradient of myocardial infarction incidence in Europe. Low-intensity oral anticoagulation may be less effective than other therapies (eg, low-dose aspirin) in primary prevention among high-risk individuals from Italy or other southern European populations, who are more likely than British men to have a "naturally" lower potential for clotting.

Genotyping may also help to define the responders to treatment, as with cholesteryl-ester transfer protein gene and statins.⁴ Further studies are needed to identify polymorphic variants in candidate genes for IHD that are related to the risk of the disease and/or the efficacy of antithrombotic therapy. In the planning of future primary prevention trials the inclusion of genotyping might contribute to the treating with greater efficacy of a smaller population. Genotyping large numbers of people is expensive, though technically easy; its results are not subject, as biochemical tests are, to day-to-day variability and environmental modulation. The cost-effectiveness of genotyping could be judged by carefully considering the possibility that future trials could be smaller.

Licia Iacoviello, *Maria Benedetta Donati

Department of Vascular Medicine and Pharmacology, Istituto di Ricerche Farmacologiche Marion Negri, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Italy

1 The Medical Research Council's General Practice Research Framework. Thrombosis Prevention Trial : randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233-41.

2 Iacoviello L, Di Castelnuovo A, De Knijff P, et al . Polymorphism in the coagulation factor VII gene as an inherited protective factor for myocardial infarction. N Engl J Med 1998; 338: 79-85 [PubMed].

3 Bernardi F, Arcieri P, Chiarotti F, et al. Contribution of factor VII genotype to activated FVII levels: differences in genotype frequencies between Northern and Southern European populations. Arterioscl Thromb Vasc Biol 1997; 17: 2548-53 [PubMed].

4 Kuivenhoven JA, Jukema JW, Zwinderman AH, et al . The role of a common variant of cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. N Engl J Med 1998; 338: 86-93 [PubMed].

Sir--Although evidence from the Thrombosis Prevention Trial ¹ supports the proposition that, for high-risk men, primary prevention of coronary thrombosis is better with prescription of warfarin plus aspirin than with either agent alone. However, the claim is not necessarily valid that "simultaneous modification of platelet activity and of fibrin formation may be more effective than modifying either process alone" in the context of secondary prevention in patients of either sex, with a target INR of 2·5-4·8.^2,3Warfarin, in this context,^2,3 currently occupies an unassailable position in the hierarchy of antithrombotic therapies because, unlike aspirin, whose evidence base is metaanalysis,⁴ its justification is founded on well-powered prospective studies, yielding numbers needed to treat to prevent one myocardial infarction ranging from 42 to 45, as opposed to the NNT of 83 emerging from the comparison with aspirin.⁵ The way forward is to explore the risk/benefit profile of INR intensities of the order of 2-3, so that patients with coexisting atrial fibrillation can derive antithrombotic benefits superior to those conferred by aspirin for either indication without incurring risks such as haemorrhagic stroke and gastroduodenopathy inherent in the coprescription of this agent.

OMP Jolobe

Department of Medicine for the Elderly, Tameside General Hospital, Ashton under Lyne OL6 9RW, UK

2 Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990; 323: 147-52 [PubMed].

3 Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet 1994; 343: 499-503 [PubMed].

4 Antiplatelet Trialists Collaboration. Collaborative overview of randomised trials of antiplatelet therapy: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81-106 [PubMed].

5 Miller DB. Secondary prevention for ischemic heart disease: relative numbers needed to treat with different therapies. Arch Intern Med 1997; 157: 2045-52 [PubMed].

Sir--The Thrombosis Prevention Trial group¹ rightly states that the results give limited, if any, encouragement for the general use of aspirin in primary prevention regardless of risk, which is in marked contrast with the accompanying commentary² which suggests that aspirin was effective. 600 (3·81%) patients of 15734 randomised to aspirin have died in primary prevention studies compared with 639 (4·53%) of 14106 randomised to control (not significantly different).² The risk of major bleeding has been doubled by aspirin. Since myocardial infarction is a condition associated with a 30-day mortality of about 50% and since half or more deaths in these studies were cardiovascular the lack of a mortality difference suggests that the effects of aspirin on non-fatal events in primary prevention studies may only be cosmetic.³ Drugs that reduce only non-fatal myocardial infarction may achieve this by masking symptoms or increasing the risk of sudden death, both possibilities with aspirin.

It is difficult to accept the conclusion that "Combined treatment with warfarin and aspirin is more effective in the reduction of IHD than either agent on its own." The combination was the only regimen to show a significant reduction in the primary endpoint compared with placebo but the effects of the combination on the primary endpoint did not appear significantly greater than those of either agent used alone, and for several other outcomes, including all-cause mortality, the results seem worse. Moreover, a substantial increase in major and moderate bleeds, including haemorrhagic stroke, was observed with the combination compared with either agent used alone. These data add to those from several other trials that suggest that monotherapy, with aspirin or warfarin, is superior or at least not inferior to combination therapy. The Thrombosis Prevention Trial suggests that the safest and most effective regimen for reducing mortality may be warfarin alone and that low and moderate intensity anticoagulation now need to be compared. How to monitor treatment in an acceptable and cost-effective manner remains the major barrier to wider use.

*John G F Cleland, Ian Ford

Clinical Research Initiative in Heart Failure, University of Glasgow, Glasgow G12 8QQ, UK

2 Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81-106 [PubMed].

3 Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas A, Pajak A. Myocardial infarction and coronary deaths in the World Health Organisation MONICA project. Circulation 1994; 90: 538-612 [PubMed].

Sir--The report of the Thrombosis Prevention Trial¹ implied that our letter in The Lancet² had asserted that low-intensity anticoagulation had been proved to be of no clinical benefit in the prevention of arterial thrombosis. That is a significant misinterpretation of the issues we raised. While we acknowledged the absence of evidence for a benefit of fixed or adjusted low-dose warfarin in the then published trials, the main point of our letter was to propose an explanation for the apparent failure of the fixed low-dose warfarin regimen, used in the CARS trial to reduce the risk of thrombosis.³ We were not suggesting that the result of the CARS trial was due to the use of low-dose warfarin per se but that it was related to the minor prolongation of the international normalised ratio (1·2) seen in patients in that trial and that this ratio may have been too low.⁴ A corollary of this explanation is that low-dose warfarin with an INR>1·2 could be an effective treatment for the prevention of arterial thrombosis, a proposition which now appears to be supported by the finding in the Thrombosis Prevention Trial that adjustment of the warfarin dose to produce a mean INR of 1·47 was accompanied by a significant reduction in death due to ischaemic heart disease

*Roger E Peverill, Richard W Harper, Joseph J Smolich

Centre for Heart and Chest Research, Monash Medical Centre and Monash University, Clayton, Victoria 3168, Australia

2 Peverill RE, Harper RW, Smolich JJ. CARS trial: warfarin and thrombin generation. Lancet 1998; 350: 1177-78.

3 Coumadin Aspirin Reinfarction Study (CARS) Investigators. Randomized double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 1997; 350: 389-96 [PubMed].

4 Feinberg WM, Cornell ES, Nightingale SD, et al. Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke 1997; 28: 1101-06 [PubMed].

Sir--The Thrombosis Prevention Trial¹ presents the first clearcut evidence for benefit from low-dose aspirin in the primary prevention of cardiovascular disease. However, the potential relevance of the formulation of aspirin used was barely discussed.

The coincident acetylation of platelets and inhibition of vascular prostacyclin is a common feature of clinically-effective doses of conventional, immediate release aspirin. The development of the 75 mg controlled-release preparation used in this trial was based on the discovery that acetylation of platelets in the presystemic circulation offered a potential approach to avoiding inhibition of prostacyclin formation in the systemic vasculature. Taking advantage of the high first-pass metabolism of aspirin to salicylate (a weak and readily reversible inhibitor of cyclooxygenase), we studied a range of doses and rates of aspirin delivery to optimise selective presystemic platelet acetylation.² A controlled release 75 mg preparation was as efficient in inhibiting serum thromboxane B₂ as the same dose of an immediate-release tablet but, unlike the conventional tablet, it did not depress the bradykinin-stimulated increment in excretion of a major urinary prostacyclin metabolite, an index of stimulated systemic prostacyclin biosynthesis.³

Given recent evidence from mice deficient in the receptor of prostacyclin⁴--suggesting that formation of this platelet inhibitory, vasodilator eicosanoid which is increased in human syndromes of platelet activation,⁵ ameliorates the response to prothrombotic stimuli in vivo--it is certainly possible that a controlled-release aspirin differs from conventional formulations with respect to the prevention of morbidity from vascular occlusive syndromes, such as those recorded in the Thrombosis Prevention Trial. Furthermore, the gastrointestinal epithelium would be exposed to much lower local concentrations of aspirin compared with immediate-release formulations. These observations caution against extending the results of this study to conventional formulations of aspirin.

*Garret A FitzGerald, William N Charman

*Department of Pharmacology, Center for Experimental Therapeutics, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA; and Victorian College of Pharmacy, Montash University, Parkville, Victoria, Australia

2 Charman W, Charman SA, et al. Biopharmaceutic characterization of a low dose (75 mg) controlled-release aspirin formulation in man. Br J Clin Pharmacol 1993; 36: 470-73 [PubMed].

3 Clarke RJ, Price P, Mayo G, FitzGerald GA. Preservation of systemic prostacyclin synthesis by controlled release, low dose aspirin: selectivity for thromboxane A₂. N Engl J Med 1991; 325: 1137-41 [PubMed].

4 Murata T, Ushikubi F, Mtsuoka T, et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 1997; 388: 678-82 [PubMed].

5 FitzGerald DJ, Catella F, FitGerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-89 [PubMed].

Authors' reply

Sir--We share Jayant Vaidya's concern about smoking. However, pharmacological intervention in those at increased risk has to be considered for those unable to modify their lifestyles. Smoking did not confound the results because randomisation ensured that its effects were all the same in all four groups. Men were encouraged to stop smoking (and were advised on other prudent living measures) and there was no evidence that the many smokers who wanted to stop relied on trial treatment instead. During the first three years of participation, the proportion of smokers fell from 41% to 33%. In deriving their NNH (treat to harm) figure for major bleeding, Tom Fahey and Tim Peters appear to assume that the non-significant difference between combined warfarin plus aspirin treatment and placebo is real and precise, whereas it is at least subject to a very wide confidence interval because of the, fortunately, small numbers. We pointed out that decisions about treatment involve considerations other than potential benefits. We will be reporting on treatment effects in the subgroups suggested by Vaidya and by Fahey and Peters, with the qualifications necessary for analyses of this sort.

We agree with the emphasis Licia Iacoviello and Maria Benedetta Donati place on improving the definition of risk and thus on reducing the numbers requiring treatment. Meanwhile, if coronary deaths are to be reduced, the high case fatality of first major attacks and the difficulty of predicting which will be fatal inevitably mean that in primary prevention many more people must be treated than would be the case in a setting of secondary prevention.

O M P Jolobe is correct in drawing attention to the clear value of anticoagulant therapy in secondary prevention but the evidence now available from all the clinical settings in which the combination of platelet-active and fibrin-modifying agents has been used leaves little doubt that it is more effective than either approach on its own.

We agree with John Cleland and Ian Ford that further thought should be given to the use of low-intensity anticoagulation with warfarin alone, not only because of its potential value but also because traditional (indeed, almost knee-jerk) objections to warfarin need to be reconsidered in the new context of low-intensity treatment. There were 18 sudden coronary deaths in those allocated to aspirin compared with 11 in the placebo group (main effect). (Corresponding numbers for warfarin were 16 and 22.) In the US Physicians Study there were 22 sudden deaths in the aspirin group and 12 in the placebo group.¹ At the same time, other studies suggest that aspirin may attenuate the presentation of severity of cardiac ischaemia.^2,3

Roger Peverill and his colleagues agree that the anticoagulant regimen we used appears effective. The CARS trial⁴ does add to evidence suggesting that minor prolongation of INR with both "fixed and adjusted low-dose warfarin" does not reduce the risk of thrombosis but, as they also note, the INR of 1·47 we achieved, hitherto also considered low, is more than the 1·2 to which they refer.

We used the controlled-release aspirin on the basis of the thromboxane inhibition/prostacyclin sparing hypothesis that Garret FitzGerald and William Charman describe. The benefit it conferred is similar to that observed with considerably higher doses in the overview of two other primary prevention trials.⁵ The explanation of any advantage in reducing the risk of bleeding is just as likely to be the aspirin dose as its formulation. Perhaps our results raise some doubts as to the validity of the thromboxane/prostacyclin hypothesis, at least in clinical terms.

*T W Meade, P J Brennan

MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, UK

1 Steering Committee of the Physicians Study Research Group. Final report on the aspirin component of the ongoing physicians study. N Engl J Med 1989; 321: 129-35 [PubMed].

2 Garcia-Dorado D, Théroux P, Tornos P, et al. Previous aspirin use may attenuate the severity of the manifestation of acute ischemic syndromes. Circulation 1995; 92: 1743-48 [PubMed].

3 Col NF, Yarzebski J, Gore JM, Alpert JS, Goldberg RJ. Does aspirin consumption affect the presentation of severity of acute myocardial infarction? Arch Intern Med 1995; 155: 1386-89 [PubMed].

4 Coumadin Aspirin Reinfarction Study (CARS) Investigators. Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 1997; 350: 389-96 [PubMed].

5 Hennekens CH, Burning JE, Sandercock P, Collins R, Peto R. Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. Circulation 1989; 80: 749-56 [PubMed].