58 BRITISH MEDICAL JOURNAL 10 JANUARY 1976 I Royal College of Physicians, Fluoride, Teeth and Health. London, Pitman, and pneumonia--diseases known to influence the death rate 1976. 2 The Fluoridation Studies in the United Kingdom and the Results Achieved of coronary disease.5 6 Support for this view comes from the After ElevenYears. London, DHSS, 1969. finding that the decrease in coronary deaths has been mainly Br Med J: first published as 10.1136/bmj.1.6001.58-a on 10 January 1976. Downloaded from 3 Gustafsson, B E, et al, Acta Odontologica Scandinavica, 1954, 11, 232. in the months November to February, the peak months for 4Mansbridge, J N, British Dental_Journal, 1960, 109, 343. 5 McHugh, W D, McEwen, J D, and Hitchin, A D, British Dental3Journal, mortality from respiratory disease. 1964, 117, 246. In Xustralia the decline2 3 in coronary mortality has been 6 Lindhe, J, Axelsson, P, and Tollskog, G, Community Dentistry and Oral Epidemiology, 1975, 3, 150. virtually confined to men. Unfortunately, in England and 7Axelsson, P, and Lindhe, J, Community Dentistry and Oral Epidemiology, Wales coronary mortality overall is still rising, though in men 1975,3, 156. aged under 45 the rates have shown only a slight upward 8 Stephan, R M,Jrournal of the American Dental Association, 1940, 27, 718. 9 Rugg-Gunn, A J, et al, British DentalJrournal, 1975,139, 351. trend7 since 1965. Death rates from influenza and pneumonia 10 Rapaport, I, Bulletin de l'Academie Nationale de Midecine (Paris), have not been falling here in the same way as in the USA, so 1956,140,529. that these British trends in coronary mortality do not conflict 1 Rapaport, I, Bulletin de l'Acadimie Nationale de Midecine (Paris), 1959,143,367. with the suggested explanation for the fall in N America. 12 Rapaport, I, Revue de Stomatologie (Paris), 1953, 46, 207. Among women the smaller decline in coronary deaths in 13 Waldbott, G L, Acta Medica Scandinavica, 1956,156,157. 14 Waldbott, G L, International Archives of Allergy and Applied Immunology, Australia as well as the greater increase in England and Wales 1962,20, suppl 1. as compared with men is consistent with an effect of smok- 15 Waldbott, G L, Acta Medica Scandinavica, 1963,174, suppl 400. ing, which has been increasing recently more in women than 16 Leone, N C, et al, American3Journal of Roentgenology, 1955,74, 874. 17 British Medicaljournal, 1975, 1, 535. in men. Other factors however may also be relevant, such as oral contraception.8 9 Trends in the next few years should clarify some of these uncertainties. Nevertheless, at present the prospects of an appreciable improvement in coronary mortality rates do not seem bright.

A decline in coronary Statistical Bulletin, p 3. New York, Metropolitan Life Insurance Company, 1975. mortality 2 Reader, R, MedicalJoturnal of Australia, 1972, 2, supp no 1, p 3. 3Christie, D, Medical3rournal of Australia, 1974, 1, 390. 4Gordon, T, and Thom, T, Preventive Medicine, 1975, 4, 115. Even given the changes in diagnostic accuracy, death certifica- 5Collins, S D, and Lehmann, J L, Excess Deaths from Influenza and Pneu- mnonia and from Important Chronic Diseases During Epidemic Periods, tion, and classification, there has beeD an alarming rise for 1918-1951. US Department of Health, Education and Welfare, 1953. most of this century in mortality from ischaemic heart disease 6 Anderson, T W, and le Riche, W H, Lancet, 1970, 1, 291. the countries of the world. 7Registrar General's Statistical Review for 1968-73 Part 1. Medical Tables. in developed Perhaps the tide is London, HMSO, 1970-1975. beginning to turn, however, for even a pessimistic observer 8 Mann, J I, et al, British MedicalJouirnal, 1975, 2, 241. would have to allow that a recent decline in coronary mortality 9 Mann, J I, and Inman, W H W, British Medical Journal, 1975, 2, 245. has been reportedl-3 from two countries, the USA and Australia. Advocates of health education have claimed that this change reflects efforts in the last two decades to increase

public awareness of the dangers of tobacco and overeating http://www.bmj.com/ and the merits of physical exercise: but there is no clear The pill and raised blood evidence to justify such claims. Indeed, the first question which must be raised is whether the decline, which is far pressure from dramatic, may be considered real. In the United States mortality from coronary heart disease, Most practitioners, and many women too, know that taking oral after increasing up to the early 1960s, was stable until 1968- contraceptives may lead to a rise in blood pressure. The risk after which all race, sex, and cohort age groups have experien- appears to be higher in women who are heavier or older or ced a small but appreciable decrease.' In 1968 there was an who have a history of hypertension in previous pregnancies or on 25 September 2021 by guest. Protected copyright. important change in the International Clas0ification of Diseases in their families-in other words, those who are more likely affecting coronary heart disease and related causes of death, to become hypertensive anyway. Severe hypertension seems and there is a theoretical possibility that the recent decrease to be rare, but one recent report1 described a patient who is an artefact. Gordon and Thom4 have recently examined developed malignant hypertension and irreversible renal that question, and they concluded that as mortality from failure when given an oral contraceptive. Hypotensive drug other cardiovascular causes has declined even more in the treatment was unsuccessful, and bilateral nephrectomy and same period it is implausible to ascribe all of the decrease later transplantation became necessary in this previously simply to the assignment of coronary deaths to other causes. normotensive 27-year-old woman. Furthermore, they also noted parallel decreases from non- Changes in the cerebral2 and coronary3 circulation are cardiovascular causes of death: in fact the only causes which known to occur in some patients given hormonal contracep- showed an increase were cancer, violence, and hepatic tives. Changes in the renal circulation have recently been cirrhosis. investigated in a remarkably thorough (albeit small) study of Welcome though this fall in coronary mortality is, its lack nine patients.4 All had developed either hypertension or renal of specificity weighs against its being due to improved treat- failure (or both) when given oral contraceptives, and all ment of myocardial infarction. Gordon and Thom believe underwent selective renal angiography and renal biopsy. Five that they have identified at least two relevant factors. Firstly, patients, normotensive before and after contraceptive therapy, there has been a steady decline in mortality from hyperten- but whose mean blood pressure during its administration was sion, an important factor in most cardiovascular diseases- substantially raised (mean 198/123 mm Hg) were shown on though mortality from hypertension was declining before angiography to have definite attenuation of peripheral renal the recent change in coronary mortality. The main reason, vessels with luminal irregularities. In three patients these vas- they suggest, is a decline since 1968 in mortality from influenza cular findings were confirmed on renal biopsy, when all five were BRITISH MEDICAL JOURNAL 10 JANUARY 1976 59 found to have periglomerular thickening and degeneration of relief of pain in inflammatory joint disease? Probably we do. renal tubular cells. Two other patients who were hypertensive Aspirin has long been recognised as the sheet anchor of drug before oral contraceptive administration suffered deterioration therapy, but nearly one-third of patients find full doses Br Med J: first published as 10.1136/bmj.1.6001.58-a on 10 January 1976. Downloaded from ofrenal function which improved on contraceptive withdrawal. unacceptable on account of dyspepsia;' and it also causes acute Both showed evidence of diffuse intravascular coagulation- gastrointestinal haemorrhage in a small proportion of patients, namely, raised blood concentrations of fibrin degradation as does indomethacin-which may also cause chronic peptic products, and intrarenal microthrombi at renal biopsy. These ulceration. Phenylbutazone and oxyphenbutazone induce have been recorded before in patients given combinedoestrogen- bone marrow depression once in every 80 000 prescriptions.2 progestogen pills.5 Two patients resembled the woman Chloroquine and hydroxychloroquine cause irreversible described by Zech and his colleagues,' in that acute oliguric retinal damage in one in every 1-2000 patients on long-term renal failure was apparently precipitated by oral contraceptives treatment.3 In Britain gold has the unenviable reputation of (again with evidence of intravascular coagulation) and there being responsible for more deaths per million prescriptions was no improvement on withdrawing the pill. Both had than any other drug.4 Practitioners still too readily resort previously had apparently normal renal function. It is tempting to corticosteroids, which were responsible in a Glasgow to attribute these changes to the process of hypertension, but, study5 6 for 500 of admissions to hospital and 12% of deaths as the authors point out, the short period of raised pressure in patients with rheumatoid arthritis. Even if it cannot be and the dissimilarity ofthe pathological changes to those found curative there is a very definite need for an effective and in essential hypertension militate against that particular safe anti-inflammatory analgesic drug for rheumatic pain. argument. How good are the new drugs ? One of the advertising claims This grisly collection of contraceptive-induced disease made for iboprufen is that it is "the best tolerated of the reinforces the opinion held by many doctors that administration available anti-rheumatic agents," and experience in Britain ofthese drugs must be as closely controlled as that ofany other supports this claim-though the drug is not quite as effective potentially hazardous therapeutic agent. Moreover, it should as indomethacin.7 8 Other propionic acid derivatives naproxen, also provide thought to those paramedical groups who wish fenoprofen, and ketoprofen have been shown in short-term to remove the prescribing of oral contraceptives into their clinical trials to be effective in relieving pain, but no more own hands. so than aspirin or indomethacin. Benorylate is a condensation As to the management of contraceptive-induced hyper- product of paracetamol and aspirin and is a palatable but tension, as a first step no women with moderately or severely expensive form of aspirin. The fenamates are useful anti- raised blood pressure should be given conventional combined inflammatory agents, but have the disadvantage of producing oestrogen-progestogen oral contraceptives. In those with mild diarrhoea in 10-15°/,% of patients. Other compounds currently hypertension a dogmatic statement of policy is not possible. undergoing clinical trials include azopropazone, tolmectin, Many practitioners will advise other forms of contraception, diftalone, niflumic acid, feprazone, alclofenac, and flurbi- and they will find justification for this attitude in the studies profen. Alclofenac has recently been reported as a possible reported here. It remains to be seen whether the recently cause of vasculitis,9 and Cuthbert'0 has recently reviewed the introduced oral contraceptives with a very low oestrogen side effects of nonsteroidal analgesics reported to the Com- content will prove less likely to precipitate hypertension. In any mittee on Safety of Medicines in the United Kingdom. case, periodic monitoring of blood pressure is mandatory. For There is unlikely to be much to choose between the non- http://www.bmj.com/ the patient already on these agents and whose blood pressure is steroidal anti-inflammatory analgesics in terms of pain relief; found to be raised the counsel of perfection is to review the nor is it likely that using combinations of these drugs, such method of contraception and when possible to find an alterna- as aspirin and indomethacin, will provide any more relief tive means. The practitioner must then weigh the undoubtedly than using them singly.11 A recent study12 has shown that greater chance ofpregnancy when other contraceptive methods about one-third of patients with rheumatoid arthritis treated are used against the dangers of hypertension and the side in hospital receive two or more non-steroidal anti-inflamma-

effects associated with hypotensive therapy. A combination tory agents at the same time; but (in view of the increasing on 25 September 2021 by guest. Protected copyright. of oral contraceptive therapy with antihypertensive therapy is evidence of pharmacokinetic interactions between these particularly unhappy: every effort should be made to avoid drugs) pain should, whenever possible, be controlled with using one drug to treat disease induced by another. single drugs rather than with combinations. We should think again about education in the use of anti- 1 Zech, P, et al, British Medical Journal, 1975, 4, 326. rheumatic drugs (and presumably other classes too). At 2 Collaborative Group Study of Stroke in Young Women, New England this is left too much to the industry.13 J7ournal of Medicine, 1973, 288, 871. present pharmaceutical 3 Coronary Drug Project Research Group, Journal of the American Medical Much of what is done is excellent, especially with the recent Association, 1970, 214, 1303. trend to publish symposia, but it is difficult for the busy doctor 4Boyd, W N, Burden, R P, and Aber, G M, Quarterly Journal of Medicine, 1975, 44, 415. to obtain reliable comparative data between new and existing 5 Brown, C B, et al, Lancst, 1973, 1 1479. drugs. Specialists in pharmacotherapeutics seem to be en- grossed in drug kinetics,'4 the minutiae of drug interactions of dubious clinical relevance,'5 and the use of brand names. They should concern themselves more with educating doctors Antirheumatic drugs: how to use drugs properly.'6 I Lee, P, et al, British MedicalJ7ournal, 1974, 1, 424. 2 Fowler, P D, in Adverse Drug Reactions, Their Prediction, Detection, plenty is not enough and Assessment, eds D J Richards and R K Rondel, p 142. London, Churchill Livingstone, 1972. 3 Von Sallman, L, and Bernstein, H N, Bulletin of Rheumatic Diseases, Musculoskeletal pain is so prevalent that perhaps not sur- 1963 14 327. 4 Girdwood, R H, British MedicalJrournal, 1974, 1, 501. prisingly we are confronted with an ever-rising flood of new 5 Lee, P, et al, Annals ofthe Rheumatic Diseases, 1973, 32, 565. antirheumatic drugs. Yet do we still need new drugs for 6 Brooks, P M, et al, Health Bulletin, 1975, 33, 108.