COMMENTARY
Which drug for treatment of hypertension? See page 611
There is no longer uncertainty about whether hypertension should be treated, except perhaps in very elderly patients (in whom the question is still being studied)1 or in patients at very low risk of complications.2 The focus of research into antihypertensive therapy is rapidly shifting towards the question of how patients should be treated. This question has been addressed in the Captopril Prevention Project (CAPPP), the results of which are reported in today’s Lancet. The study represents a signal event in the history of large-scale trials of anti-hypertensive therapy. It is the first to report main results from a comparison of the newer agents (angiotensin-converting-enzyme [ACE] inhibitors, calcium-channel blockers, a-adrenergic blockers, angiotensin-II-receptor antagonists) with older first-line drugs (diuretics, b-blockers). The two main issues that clinicians are facing are, first, how low a blood pressure to aim for, and, second, what medical regimen to choose. Several trials, most recently the Hypertension Optimal Treatment (HOT) trial, have attempted to answer the first of these questions.3 Several “positive-control” trials (comparisons against an active agent) are, like CAPPP, addressing the second question.4 These trials are based on the notion that different antihypertensive regimens, despite similar efficacy in lowering blood pressure, have other beneficial or harmful effects that modify their net effect on cardiovascular or allcause morbidity and mortality. Because such effects may be smaller than those of blood-pressure reduction alone, positive-control trials must be conducted with patients at above-average risk for these effects, or with large sample sizes, or both. The requirement of a large sample is one reason why trial organisers recruit patients through primary-care physicians. The CAPPP targeted and enrolled nearly 11 000 patients with at least moderately raised diastolic pressures attending 536 primary-care centres in Sweden and Finland. Patients were randomly assigned captopril, up to 100 mg daily in one or two doses, or diuretic, b-blocker,or both. The researchers do not state how often or why captopril was given once a day; the usual recommendation is two or three daily doses.2 An important point is that at randomisation diastolic blood pressure was about 2 mm Hg higher in the captopril than in the conventionaltherapy group, a difference that should not be expected by chance with such a large sample size, and that may be related to the use of envelopes for randomisation assignments. Figure 2 seems to indicate that this bloodpressure difference was maintained throughout the followup, although the numerical values are not provided. The risk of a major cardiovascular event during an average follow-up of 6·1 years did not differ between treatment 604
groups, after adjustment for baseline differences. The risk of stroke was marginally higher, and that of new diabetes mellitus was marginally lower, in the captopril than in the conventional group. These differences are not entirely surprising; statistical adjustment is unlikely to remove the effect of trial-long blood-pressure differences on stroke, and whether the effect of diuretics and b-blockers on incidence of diabetes is large, or trivial as in the Systolic Hypertension in the Elderly Program,5 clinicians expect such an effect and might have differentially looked for diabetes in this unblinded trial. The investigators report results in two subgroups of particular interest. Results for the primary endpoint for those who were previously untreated did not differ from those for the overall group, but for patients with diabetes, there was a risk reduction of 41% (p=0·019) with captopril. However, without data on blood-pressure control, on actual drug regimens in the subgroup, on whether the subgroups had been defined a priori, or on how many subgroups were examined, these subgroup results are difficult to interpret. Rightly, the investigators do not place emphasis on this finding. The results of the United Kingdom Prospective Diabetes Study (UKPDS 39)6 do not offer external consistency for this finding. That study was part of a larger trial that focused on various approaches to glycaemic control among 5102 patients with newly diagnosed diabetes, aged 25–65 years. The 1148 patients with systolic or diastolic hypertension were randomly assigned conventional or more ambitious goals for blood-pressure reduction (“tight control” meant a blood-pressure goal of <150/<85 mm Hg). Those allocated tight control were further randomised to captopril (n=400) or atenolol (n=358) in an unblinded comparison. Captopril was given twice daily, up to 50 mg per dose, and atenolol once daily, up to 100 mg. Control of blood pressure over an average follow-up of 9 years was similar in these two groups, with both systolic and diastolic blood pressure about 1 mm Hg higher in the captopril group. There was no difference in results for the primary endpoint (“any diabetes-related endpoint”) between the captopril and atenolol groups, whereas there was a highly significant 24% reduction with tight blood-pressure control compared with conventional control. Among patients having tight control, 259 had one or more events, the commonest being myocardial infarction (107), treatment for retinopathy (61), new onset of angina (45), and stroke (36). All except angina were commoner in the captopril group, although these differences were not significant. In view of the hundreds of millions of patients worldwide who receive antihypertensive drugs, and the importance of morbidity and mortality from cardio-
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vascular disease, trials such as CAPPP that attempt to establish whether any class of drugs is superior to traditional ones are immensely important. Such trials can be conducted in primary-care settings with high degrees of methodological rigour, including central randomisation and a double-blind design.7 Nevertheless, there are no perfect trials, and clinicians and patients will be fortunate to have a large body of evidence from randomised trials for informed choice. At present, for most hypertensive patients who require therapy (including patients with type 2 diabetes), drugs other than diuretics or b-blockers should be selected infrequently. Jeffrey Cutler Clinical Applications and Preventive Program, National Heart Lung and Blood Institute, Bethesda, MD 20892, USA 1
Bulpitt C, Fletcher A ,A m e ry A, et al. The hypertension in the very elderly trial (HYVET). Drugs Ageing 1994; 5: 171–83. 2 The sixth report of the joint national committee on prevention, detection,evaluation, and treatment of high blood pressure. Arch Intern Med 1997; 157: 2413–46. 3 Hansson L, Zanchetti A ,C a rruthers S, et al. Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1755–62. 4 World Health Organization-International Society of Hypertension Blood Pressure Lowering Treatment Trialists’Collaboration.Protocol for prospective collaborative overviews of major randomized trials of blood-pressure lowering treatments. J Hypertens 1998; 16: 127–37. 5 Savage P, Pressell S, Curb D, et al, for the SHEP Cooperative Research Group. Influence of long-term,low-dose,diuretic-based, antihypertensive therapy on glucose, lipid,uric acid, and potassium levels in older men and women with isolated systolic hypertension. Arch Intern Med 1998; 158: 741–51. 6 UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317: 713–20. 7 Davis B, Cutler J, Gordon D, et al. Rationale and design for the antihypertensive and lipid lowering treatment of prevent heart attack trial (ALLHAT). Am J Hypertens 1996; 9: 342–60.
Keeping watch over genetically modified crops and foods The concerns about genetically modified (GM) crops and foods derived from them stem from anxieties about potential effects of the breakdown of normal gene barriers. In the UK, these concerns have been intensified in the past 2 weeks by media reports that GM foods harm the immune system and increase the risk of cancer and other diseases,1 and that antibiotic resistance will be transferred from animal food to human pathogens.2 The reports of harm to the immune system and effect on cancer and other diseases have been based on unpublished evidence of work in Aberdeen on GM potatoes into which plant lectin genes were introduced. Some lectins are toxic (and occur naturally in the bean family, which is why some beans must be cooked thoroughly) and affect the immune systems of animals. Until more details are known about the work in Aberdeen, comment is impossible. The breakdown of normal gene barriers has resulted from the application of techniques enabling genes from any organism to be introduced into almost any other organism.3 Plant breeders have been very quick to take advantage of these new techniques to breed for characteristics that are unattainable by traditional agricultural methods. Genes that have been cloned and inserted into plants include plant virus genes, to induce resistance to viruses; genes for a toxin produced by Bacillus thuringiensis (BT), to confer resistance to insects; a fish (Arctic flounder) “antifreeze” gene, to confer frost
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tolerance; and bacterial genes to induce herbicide tolerance by providing alternative pathways for the metabolic step inhibited by the herbicide. To retard ripening of fruit, genes for this process are inserted in reverse orientation. The benefits for plant breeders have been so great that this year over half the soybean crop and a large proportion of maize and cotton in the USA will be genetically modified. In the USA GM grains are not segregated from traditionally bred grains because their modifications (for herbicide tolerance and antibiotic and insect resistance) have been approved for unregulated cultivation and use. Hence, probably all US exports of these grains contain a proportion of GM products. GM crops and foods are subject to regulation.3–6 In the USA, which has the greatest acreage of such crops, environmental risks are judged to be very low. Most of the regulatory activity has been to ensure food safety through assessments of risks by the Food and Drug Administration (FDA), which operates largely on the basis of reviewing evidence that GM foods are Generally Regarded As Safe (GRAS). Producers request GRAS status by demonstrating to the FDA that the gene products in the food are at least as safe as equivalent compounds in unmodified food. A history of the safe consumption of the protein encoded by the gene concerned is an important part of the risk-assessment process. For example, human beings eat flounder, so its antifreeze protein has a safe history and can be assumed to be generally safe. Agriculturalists would prefer a much higher level of frost tolerance than can be conferred by the flounder protein. Such frost tolerance can be obtained by use of insect antifreeze genes, but human beings do not normally eat insects or their proteins, so these would not be regarded as generally safe and would have to undergo full toxicological and allergenicity testing. Another example of issues to be considered in risk assessment based on prior knowledge of safety is that of the BT toxin used to confer resistance of maize to insects. BT toxin has been subjected to exhaustive toxicology tests before approval for surface application on vegetable crops to control insects. Toxicity is so low that BT toxin can be used close to harvesting because its consumption by human beings is judged to be safe. However, when cloned BT toxin genes are inserted into plants, the protein is expressed within the host tissue, and in some GM plants the sequences of toxin gene might be a modification of those of the natural toxin. Risk assessments must take such change into account, rather than be based on the assumption that the toxin in cloned plants is substantially equivalent to that applied externally. Such change is less likely with flounder protein. GM crops are also assessed for their impact on the environment. In the UK, the Advisory Committee on Releases to the Environment (ACRE), which I chair, advises the government on risks of harm to the environment, risks of allergenic responses to pollen and other plant substances, and possible toxicity to human beings or animals who might eat the growing crops. (ACRE is also required to advise on safety of animal feeds until the appropriate advisory committee is established later this year.) ACRE assesses how the genetic modification might change the properties of the existing crop. A particularly important property that could change is the ability of the plant to become a weed. For instance, a crop genetically modified to tolerate drought is likely to be 605