Hormone replacement therapy and cardiovascular disease: the case for a randomized controlled trial.

The menopause is associated with an increased risk of developing cardiovascular disease. Oestrogen may influence various metabolic pathways which contribute to the pathogenesis of cardiovascular disease, and observational studies suggest that in postmenopausal women oral oestrogen replacement therapy confers some protection against coronary heart disease and to a lesser extent against stroke. What is not clear is the magnitude of the cardioprotective effect and the overall balance of long-term benefits and hazards. Research is also required to establish the relative effects of oestrogen replacement therapy and combined or opposed hormone replacement therapy (HRT) where progestogen is added to counter the proliferative action of oestrogen on the endometrium. A large randomized controlled trial is the only way to provide accurate estimates of the cardioprotective effect of HRT and of other long-term benefits and hazards. Feasibility studies undertaken through the UK Medical Research Council (MRC) General Practice Research Framework show that such a trial is acceptable to patients and their doctors. Recruitment and withdrawal rates indicate that a trial of sufficient size to show a 25% reduction in cardiovascular disease with 90% power at the 1% level would be feasible. The full trial is costly and it is proposed that the UK collaborates with other countries in a major international trial to complement the Women's Health Initiative trial in the USA. Feasibility studies in Europe are underway, the design and scientific rationale for the trial have been approved by the UK MRC and it is hoped that recruitment to the full-scale trial can begin soon.

The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials.

The proven benefit of aspirin in the secondary prevention of cardiovascular disease and its possible value in primary prevention must be weighted against its potential hazards. This paper is an overview of the gastrointestinal toxicity of aspirin, its most serious complication after intracerebral haemorrhage. Information on toxicity has been drawn only from randomised trials, thus avoiding the potential biases of observational studies. All randomised placebo controlled trials listed in the Anti-platelet Trialists Collaboration where a direct aspirin-placebo comparison was possible were included. Twenty-one trials were included, all but one of secondary prevention. There were over 75,000 person years of aspirin exposure. The pooled odds ratios for categories of gastrointestinal bleeding (e.g. haematemesis, melaena) were between 1.5-2.0; fatal bleeds were very rare. The risk of peptic ulcers was 1.3 and of upper gastrointestinal symptoms 1.7. These risks were lower than those found in observational studies. Attributable disease rates are also presented. For haematemesis for example they varied from 0.2-1.0 per 1000 person years. Toxicity was dose related. Aspirin does have significant gastrointestinal toxicity, although this is rarely fatal. More recent work has demonstrated the efficacy of low doses of aspirin (75 mg daily) but there is limited information yet available on its toxicity.

Extra-cranial bleeding and other symptoms due to low dose aspirin and low intensity oral anticoagulation.

Data from the early stages of the thrombosis prevention trial (TPT) have been used to establish and quantify the risk of extracranial bleeding due to low dose aspirin (75 mg) and low intensity oral anticoagulation with warfarin (international normalised ratio, INR, 1.5) singly or in combination, in men aged between 45 and 69 who are at high risk of ischaemic heart disease (IHD). The design of the trial is factorial, the four treatments being combined low dose aspirin and low intensity anticoagulation (WA), low intensity anticoagulation alone (W), low dose aspirin alone (A) and double placebo treatment (P). The trial is being carried out through the Medical Research Council's General Practice Research Framework, with participating practices throughout the United Kingdom. Results are based on the first 3,667 men entered. The risk of major gastrointestinal bleeding due to active treatment is probably about 1 in 500 man-years of treatment, there currently being no difference between the three active regimes (WA, W, A). Intermediate and minor bleeding episodes occur more frequently with WA than with W or A on their own, the excess being mainly due to minor nose bleeds and bruises. In turn, both W and A on their own cause more such minor episodes than placebo treatment, P. There is no evidence that any of the three active regimens increases the risk of peptic ulceration, nor do they increase reports of indigestion. Aspirin increases reports of constipation and reduces reports of blurred vision. Minor bleeding occurs less frequently in smokers than in non-smokers but is not influenced by age. The antithrombotic regimes used are feasible and acceptable.

Gemfibrozil reduces plasma prothrombin fragment F1 + 2 concentration, a marker of coagulability, in patients with coronary heart disease.

The effects of gemfibrozil on several indices of haemostatic activity were explored in male patients with coronary heart disease (CHD). Sixty-three of 71 patients completed a crossover study in which gemfibrozil 1,200 mg/day and matching placebo were each taken in randomised order for 2 months in a double-blind manner, separated by a 2-month washout period. Serum cholesterol decreased by an average (95% confidence interval) of 12 (9 to 15)% and non-fasting triglyceride concentration by 43 (34 to 51)% during active treatment. Plasma prothrombin fragment F1 + 2 concentration, a marker of the in vivo rate of generation of thrombin, was 25 (12 to 37)% lower on average while on gemfibrozil than during the placebo phase. Factor VII coagulant activity (VIIc) and antigen concentration, and fibrinopeptide A concentration were not influenced by gemfibrozil in the group overall. However, the VIIc response appeared to be dependent upon the untreated cholesterol level. Hypercholesterolaemic men (cholesterol greater than 6.5 mmol/l) experienced a significant reduction in VIIc averaging 6% of standard during active therapy. Other effects of gemfibrozil were a 5 (2 to 9)% increase in plasma fibrinogen by a gravimetric method, an 11 (8 to 13)% increase in platelet count, and a 6 (2 to 10)% reduction in white cell count. The reduced incidence of CHD following gemfibrozil therapy in hyperlipidaemic patients may arise in part through a reduction in procoagulant activity and thus the risk of an occlusive coronary thrombosis.

Hormone replacement therapy in general practice: a survey of doctors in the MRC's general practice research framework.

OBJECTIVES: To survey current prescribing practice for hormone replacement therapy among general practitioners and to elicit their views on the role of hormone replacement therapy in the prevention of osteoporosis and cardiovascular disease; to determine whether they would participate in randomised controlled trials to evaluate the long term beneficial and adverse effects of hormone replacement therapy. DESIGN: Postal questionnaires to general practitioners throughout the United Kingdom. PARTICIPANTS: 1268 general practitioners in the Medical Research Council's general practice research framework. RESULTS: 1081 (85%) doctors in 220 (95%) practices responded. The doctors were currently prescribing hormone replacement therapy to an estimated 9% of their female patients aged 40 to 64, and 55% of doctors were prescribing opposed hormone replacement therapy (oestrogen plus progestogen) to more patients than a year previously. Over half the doctors would consider prescribing hormone replacement therapy for prevention of osteoporosis (670, 62%) and cardiovascular disease (611, 57%) to asymptomatic women. Overall, 79% of the doctors (851) would definitely or probably consider entering women who have had a hysterectomy into a randomised controlled trial comparing unopposed (oestrogen only) hormone replacement therapy with opposed hormone replacement therapy; 49% (524) would enter patients with a uterus into such a trial. Among a subsample, 85% (180/210) would consider entering patients without menopausal symptoms into a trial comparing hormone replacement therapy with no treatment (unopposed in patients who have had a hysterectomy, opposed in those with a uterus). CONCLUSION: There is considerable uncertainty among general practitioners as to the balance of beneficial and harmful effects of hormone replacement therapy in the long term, particularly relating to its use for prevention of osteoporosis and cardiovascular disease. Most of these doctors would be prepared to participate in randomised controlled trials to determine the long term effects of this increasingly widely used treatment.

Variation in the promoter region of the beta fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers.

We investigated the association between fibrinogen levels and a HaeIII restriction fragment length polymorphism located at -453 bp from the start of transcription of the beta fibrinogen gene. 292 healthy men aged 45 to 69 years, recruited from general practices throughout Britain, were studied. None had a history of ischaemic heart disease. 41.1% (120) were smokers and fibrinogen levels were higher in this group. The frequency of the non-cutting allele (designated H2) was 0.19 and was the same in smokers and non-smokers. The H2 allele was associated with elevated levels of fibrinogen in both smokers and non-smokers and the effect of genotype was similar in both groups. After smoking, HaeIII genotype was the strongest predictor of fibrinogen levels and explained 3.1% of the variance in fibrinogen levels. These results confirm earlier studies that variation at the fibrinogen locus contributes to the between-individual differences in plasma fibrinogen level.

Arterial disease risk factors and angiographic evidence of atheroma of the carotid artery.

We conducted a prospective study of serial intravenous digital subtraction angiography to determine the relation of arterial disease risk factors and hemostatic variables with the presence of visible atheroma at the carotid bifurcation. Of the 492 patients with cerebrovascular disease or ischemic heart disease who entered the study, 354 had hematologic studies, including platelet aggregation in 230. Abnormal angiograms were associated with greater age, treated hypertension, current smoking, and lower hemoglobin levels but with higher uric acid, factor VIII, and fibrinogen concentrations. In patients presenting with isolated transient ischemic attacks, abnormal angiograms were also associated with higher levels of cholesterol and triglycerides. To study atheroma progression, the 230 patients with complete data at entry were recalled 2 years later. Repeat angiography in 209 patients showed progression of visible bifurcation disease in 13.4%. There was some evidence that progression was linked to higher age, hypertension, and more severe disease at entry, but further analysis was hampered by the small number of patients showing increased plaque size. The possible role of risk factors and hemostatic variables, especially fibrinogen, is discussed. Factors that did not correlate with progression of angiographically visible disease may also influence clinical end points by other mechanisms, such as thrombogenesis.

Fat consumption and factor VII coagulant activity in middle-aged men. An association between a dietary and thrombogenic coronary risk factor.

Diet was measured by 5-day weighed inventory to search for an association between fat intake in the general population and factor VII coagulant activity (VIIc), a strong predictor of coronary heart disease. Of 275 men aged 40-59 years registered with a medical practice, 203 (74%) participated and 170 (62%) provided a satisfactory record. After allowance for the increase in fat intake with body size, a statistically significant and positive association was found between dietary fat and VIIc (r = 0.18; P less than 0.05). The correlation coefficient was increased to 0.24 when adjusted for the effect of day-to-day variability in individual fat intake, thereby providing an improved estimate of the true strength of association. The mean difference in VIIc of 12% of standard between men in the highest and lowest quarters of the distribution of fat intake was similar to that reported between men experiencing coronary heart disease and those remaining free. The results support previous experimental fat-feeding studies and suggest that a high fat diet has adverse consequences for blood coagulability and coronary thrombosis.

Factor VII coagulant activity is strongly associated with the plasma concentration of large lipoprotein particles in middle-aged men.

A community survey of factor VII coagulant activity (VIIc) and the lipoprotein profile in non-fasting plasma of middle-aged men in NW London was undertaken to search for the determinants of VIIc in the general community. The data demonstrates that associations between VIIc and the plasma concentrations of cholesterol and of triglycerides previously shown in the general population can be explained by the strong and positive associations between VIIc and the large lipoprotein particles, chylomicrons, VLDL and IDL. Consistent with the possibility that the concentration of large lipoproteins determines the in vivo reactivity of factor VII, the association between VIIc and the ratio of lipid in the d greater than 1.019 fraction to the total plasma lipid was also highly significant but negative. The observed correlations between VIIc and lipoproteins smaller than VLDL may be the product of the interrelations that exist between the lipoprotein fractions in plasma. However, the associations between VIIc and the chylomicron lipid concentrations are especially strong when allowance is made for the considerable bias towards zero in the observed correlation, due to large within-person variance in chylomicron concentration.

Randomized controlled trial of low dose warfarin in the primary prevention of ischaemic heart disease in men at high risk: design and pilot study.

We report the pilot stage of a double-blind randomized controlled trial of low dose warfarin in the primary prevention of ischaemic heart disease (IHD) in men at high risk. The first objective was to see if levels of factor VII coagulant activity, VIIc, could be reduced without undue difficulty from a mean level of about 115% to about 70% (the level in patients on conventional warfarin doses being about 30%). This was accomplished with a mean daily dose of 4.6 mg warfarin. The international normalized ratio (INR) corresponding to a VIIc value of 70% was about 1.5. The second objective was to assess the risk of bleeding associated with the intended level of anticoagulation. There was no significant excess in the number of actively treated men ever reporting nose bleeds, possible haematuria, rectal bleeding or bruising, although there may have been an increase in the frequency of rectal bleeding in men who did report this symptom. The third objective was to establish the willingness of patients to take part in a trial of this kind. Of those invited to the initial screening examination, 72% attended. Of those invited to enter the treatment phase of the trial, 71% did so. Compliance with trial treatment was at a very high level. The rate of withdrawal from randomized treatment was within acceptable limits, at about 15% over a three- or four-year period. The scientific case for a full trial is strong and the pilot trial shows that it could be accomplished.