1495
have preferentially inhibited a putative co-factor effect of CMV which has been reported to accelerate the rate of progression of human immunodeficiency virus (HIV) infection.3In either case, one has to ask why foscamet could control these CMV effects better than ganciclovir. Is it possible that some patients had received ganciclovir previously for CMV disease other than retinitis and so were more likely to have resistant strains?4 Finally, foscamet may have had a direct effect on HIV itself through inhibition of reverse
immunodeficiency syndrome. Arch Pathol Lab Med 1988; 112: 540-44. A, Lee CA, Cook DG, et al. Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection. Lancet 1989; ii: 63-65. 4. Erice A, Chou S, Biron KK, Stanat SC, Balfour HH, Jordan MC. Progressive disease due to ganciclovir-resistant cytomegalovirus in immunocompromised patients. N Engl J Med 1989; 320: 289-93. 5. Majumdar C, Abbotts J, Broder S, Wilson SH. Studies on the mechanism of human immunodeficiency virus reverse transcriptase. J Biol Chem 1988; 263: 15657-65. 6. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl Med 1987; 317: 185-91. J 3. Webster
transcriptase.5
There are also reasons why the observed survival benefit of foscamet could be spurious. Zidovudine significantly delays death in AIDS patients,6yet this drug would be less well tolerated in those allocated to receive ganciclovir because both drugs are myelotoxic. Furthermore, patients in the trial who were intolerant of zidovudine could be given dideoxycytidine or dideoxyinosine, drugs whose efficacy has not been proven in controlled trials and whose efficacy by comparison with zidovudine is unknown. Clearly, rigorous statistical analyses of these confounding variables will be needed to ensure that the better survival was not attributable to unequal antiretroviral therapy in the two groups. However, even if this was shown to be the explanation for the results, the conclusion that foscamet is better than ganciclovir in clinical practice could still be correct if doses of antiretrovirals were indeed reduced because of
ganciclovir toxicity. This study shows, once again, how controlled trials in AIDS patients can identify therapeutic advantages more rapidly than can anecdotal clinical experience; the results also show that unexpected benefits (eg, survival) may emerge. The reported survival benefit has been described only in patients with CMV retinitis, so the trial results have no relevance for AIDS patients without this complication. Furthermore, neither foscamet nor ganciclovir is the ideal drug for CMV retinitis since both agents have side-effects and have to be given by intravenous infusion. Other drugs with anti-CMV activity are clearly needed; meanwhile, results of trials of oral ganciclovir are awaited. What about the ethics of stopping the trial prematurely and issuing an alert to physicians many months before they can hope to see the detailed analyses presented in a peer-reviewed journal? We believe that the correct balance has been struck here between the science and art of medicine. The scientific data will be published in due course and will be examined in great detail to determine whether the initial conclusions of the investigators can be supported. Until then, the researchers have given their colleagues a medical opinion about the best means of treating a serious infection which, like all medical opinions, does not come with a guarantee. 1. Foscavir’s survival benefit in CMV retinitis. SCRIP Oct 30, 1991: 22. 2. Klatt EC, Shibata D. Cytomegalovirus infection in the acquired
Should trials carry
a
health
warning?
Wilt thou forgive that sinne which I did shunne A yeare, or two: but wallowed in, a score?- JOHN DONNE
Preventive cardiology has rightly been seen as the ultimate answer to coronary artery disease. Nevertheless, it is important that attempts at riskfactor reduction are subjected to the rigours of clinical trials. The first convincing demonstration of this principle came from the World Health Organisation clofibrate trial.12In this study, the success of the lipid-lowering agent in decreasing plasma cholesterol and reducing cardiac events and cardiac mortality in a high-cholesterol group was counterbalanced by an increase in all-cause mortality. This unexpected outcome has given rise to much speculation but as yet
wholly convincing explanation. Superficially, the report by Strandberg and colleagues in Helsinki3 of an increase in long-term mortality in the intervention group after a five-year multifactorial primary prevention trial in middle-aged no
suggests a rerun of the clofibrate controversy. The immediate temptation is to pour it into the already large pool of existing intervention trial data, which overall shows benefit from selective risklowering strategies.4,5 Yet on closer inspection the differences between Strandberg’s results and those of the clofibrate trial and other multifactorial interventions6 are much more striking than the similarities. In the Finnish study, participants were randomised either to an intensive risk-factor-lowering strategy-including control of hypercholesterolaemia (principally with probucol or clofibrate), blood pressure reduction (propranolol and/or diuretics), and regular counselling--or to a control group. The controls received "usual health care". Although there was a substantial reduction in the estimated coronary artery disease risk score, at the end of the five-year trial period there was no significant difference in cardiovascular or all-cause mortality between the groups.’ However, after the trial ended the cumulative mortality curves of the intervention and control groups began to diverge, and at ten-year follow-up there was a marginally significant increase in total mortality and a highly significant increase in cardiovascular deaths and deaths associated with violence or accident in the intervention group. Simultaneously, the trialists noted that there was a men
1496
the mean of the risk-factor differences between the two groups, so at five years there was no longer any significant difference between the groups in terms of the use of drugs or coronary risk factors. The most obvious, and most boring, interpretation of these results is that, by some quirk of selection, the intervention group had a higher cardiovascular disease risk, which was held in check by risk-factor reduction during the trial period, but which became manifest after the end of the trial. It is difficult to confirm or refute this view from the baseline pre-trial data, although some potential risk indicators such as alcohol consumption did seem to be higher in the intervention group. To blame the drugs given during the trial period for a mortality difference that only became apparent some ten years after the trial ended seems unfair. There is no suggestion in this study that any of the excess mortality was due to malignant disease, which might have had a lengthy induction
rapid regression
to
period. A factor that seems to have been neglected is the long-term effect on patient psychology and lifestyle of being subjected to an intense period of drug treatment and counselling, which is then terminated. Enthusiasts for corrective training and "short sharp shocks" might hope that lifestyle modification so induced would be long lasting. Clinical experience suggests otherwise, and recent reports, especially from general practice, have emphasised the need for long-term reinforcement if behavioural changes of any kind are to be made to stick. 8,9 It is not inconceivable that in susceptible patients the rebound from a strict and perhaps unpalatable regimen might lead to excessive complacency, or worse to an actual deterioration in disease-avoiding behaviour. Although it is tempting to find supporting evidence in the increased incidence of "violent deaths", the Helsinki researchers wisely caution that many of these deaths were accidental and could have involved an unrecognised cardiac component. Nevertheless, a recent review of primary prevention trialsl° also suggested that cardiac benefits may be offset by deaths from accidents, suicide, and violence. We can return to Donne to sum up the complexities: When thou hast done, thou hast For,I have more.
not
done,
1. Committee of Principal Investigators. A cooperative trial in the primary presentation of ischaemic heart disease using clofibrate. Br Heart J 1978; 40: 1069-118. 2. Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet 1984; n: 600-04. 3. Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarna SJ, Miettinen TA. Long term mortality after 5 year multifactorial primary prevention of cardiovascular diseases in middle aged men. JAMA 1991; 226: 1255-29. 4. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Lancet 1990; 335: 827-38. 5. Report of the Expert Panel on Population Strategies for Blood Cholesterol Reduction: a statement from the national cholesterol education program, National Institutes of Health. Circulation 1991; 83: 2154-232.
6. The Multiple Risk Factor Intervention Trial Research Group. Mortality rate after 10·5 years for participants in the Multiple Risk Factor Intervention Trial: findings related to a priori hypotheses of the trial. JAMA 1990; 263: 1795-801 7. Miettinen TA, Huttunen JK, Naukkarinen V, et al. Multifactorial primary prevention of cardiovascular diseases in middle aged men. JAMA 1985; 254: 2097-102. 8. Imperial Cancer Research Fund OXCHECK Study group. Prevalence of risk factors for heart disease in OXCHECK trial: implications for screening in primary care. Br Med J 1991; 302: 1057-60. 9. Hart JT, Thomas C, Gibbons B, et al. Twenty five years of case finding and audit in a socially deprived community. Br Med J 1991; 302: 1509-13. 10. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol and mortality: a quantitative review of primary prevention trials. Br Med J 1990; 301: 309-14.
Understanding diabetic neuropathy Debate about the aetiology of diabetic neuropathy has largely focused on metabolic and vascular factors. Although metabolic imbalances were once thought to be caused by the neuropathy, diabetic neuropathy is now generally believed to be a consequence of long-term hyperglycaemia.1 Suggestions that genetic factors such as acetylator status might help to predict which patients are at risk of neuropathy2 have not been confirmed.3 However, the occurrence of this complication in both main types of diabetes as well as in secondary cases, the strong association with previous metabolic control,3,4 and the association between neuropathy and diabetes duration all point to a common aetiological mechanism involving hyperglycaemia. That progression of polyneuropathy may be halted after many years of hyperglycaemia if blood glucose concentrations are restored to normal by successful pancreatic transplantations lends further support to the metabolic hypothesis. of One of the metabolic consequences is increased polyol pathway hyperglycaemia activity.1,6 Despite strong evidence implicating increased flux through the polyol pathway in the peripheral nerves of both man and laboratory animals, the putative link between nerve dysfunction, polyol pathway activity, and nerve myoinositol levels is less clear.6 Further doubt on the role of myoinositol in the pathogenesis of neuropathy is cast by experimental evidence that the reduction in nerve conduction velocity associated with exaggerated polyol pathway flux is not related to myoinositol concentrations or Na + K-ATPase activity,’ and that treatment with an aldose reductase inhibitor has no effect on oubainsensitive ATPase activity.8 Despite these negative findings there is evidence that aldose reductase inhibitors, which block the rate-limiting enzyme in the polyol pathway, are beneficial even in patients with long-established neuropathy.9 Moreover, nerve function deteriorated following withdrawal of therapy from patients treated for 4 years with such an inhibitor. to Alterations in endogenous concentrations of nerve growth factor (NGF) may be another consequence of hyperglycaemia that is relevant to the aetiology of neuropathy. NGF is essential for the growth and
have preferentially inhibited a putative co-factor effect of CMV which has been reported to accelerate the rate of progression of human immunodeficiency virus (HIV) infection.3In either case, one has to ask why foscamet could control these CMV effects better than ganciclovir. Is it possible that some patients had received ganciclovir previously for CMV disease other than retinitis and so were more likely to have resistant strains?4 Finally, foscamet may have had a direct effect on HIV itself through inhibition of reverse
immunodeficiency syndrome. Arch Pathol Lab Med 1988; 112: 540-44. A, Lee CA, Cook DG, et al. Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection. Lancet 1989; ii: 63-65. 4. Erice A, Chou S, Biron KK, Stanat SC, Balfour HH, Jordan MC. Progressive disease due to ganciclovir-resistant cytomegalovirus in immunocompromised patients. N Engl J Med 1989; 320: 289-93. 5. Majumdar C, Abbotts J, Broder S, Wilson SH. Studies on the mechanism of human immunodeficiency virus reverse transcriptase. J Biol Chem 1988; 263: 15657-65. 6. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl Med 1987; 317: 185-91. J 3. Webster
transcriptase.5
There are also reasons why the observed survival benefit of foscamet could be spurious. Zidovudine significantly delays death in AIDS patients,6yet this drug would be less well tolerated in those allocated to receive ganciclovir because both drugs are myelotoxic. Furthermore, patients in the trial who were intolerant of zidovudine could be given dideoxycytidine or dideoxyinosine, drugs whose efficacy has not been proven in controlled trials and whose efficacy by comparison with zidovudine is unknown. Clearly, rigorous statistical analyses of these confounding variables will be needed to ensure that the better survival was not attributable to unequal antiretroviral therapy in the two groups. However, even if this was shown to be the explanation for the results, the conclusion that foscamet is better than ganciclovir in clinical practice could still be correct if doses of antiretrovirals were indeed reduced because of
ganciclovir toxicity. This study shows, once again, how controlled trials in AIDS patients can identify therapeutic advantages more rapidly than can anecdotal clinical experience; the results also show that unexpected benefits (eg, survival) may emerge. The reported survival benefit has been described only in patients with CMV retinitis, so the trial results have no relevance for AIDS patients without this complication. Furthermore, neither foscamet nor ganciclovir is the ideal drug for CMV retinitis since both agents have side-effects and have to be given by intravenous infusion. Other drugs with anti-CMV activity are clearly needed; meanwhile, results of trials of oral ganciclovir are awaited. What about the ethics of stopping the trial prematurely and issuing an alert to physicians many months before they can hope to see the detailed analyses presented in a peer-reviewed journal? We believe that the correct balance has been struck here between the science and art of medicine. The scientific data will be published in due course and will be examined in great detail to determine whether the initial conclusions of the investigators can be supported. Until then, the researchers have given their colleagues a medical opinion about the best means of treating a serious infection which, like all medical opinions, does not come with a guarantee. 1. Foscavir’s survival benefit in CMV retinitis. SCRIP Oct 30, 1991: 22. 2. Klatt EC, Shibata D. Cytomegalovirus infection in the acquired
Should trials carry
a
health
warning?
Wilt thou forgive that sinne which I did shunne A yeare, or two: but wallowed in, a score?- JOHN DONNE
Preventive cardiology has rightly been seen as the ultimate answer to coronary artery disease. Nevertheless, it is important that attempts at riskfactor reduction are subjected to the rigours of clinical trials. The first convincing demonstration of this principle came from the World Health Organisation clofibrate trial.12In this study, the success of the lipid-lowering agent in decreasing plasma cholesterol and reducing cardiac events and cardiac mortality in a high-cholesterol group was counterbalanced by an increase in all-cause mortality. This unexpected outcome has given rise to much speculation but as yet
wholly convincing explanation. Superficially, the report by Strandberg and colleagues in Helsinki3 of an increase in long-term mortality in the intervention group after a five-year multifactorial primary prevention trial in middle-aged no
suggests a rerun of the clofibrate controversy. The immediate temptation is to pour it into the already large pool of existing intervention trial data, which overall shows benefit from selective risklowering strategies.4,5 Yet on closer inspection the differences between Strandberg’s results and those of the clofibrate trial and other multifactorial interventions6 are much more striking than the similarities. In the Finnish study, participants were randomised either to an intensive risk-factor-lowering strategy-including control of hypercholesterolaemia (principally with probucol or clofibrate), blood pressure reduction (propranolol and/or diuretics), and regular counselling--or to a control group. The controls received "usual health care". Although there was a substantial reduction in the estimated coronary artery disease risk score, at the end of the five-year trial period there was no significant difference in cardiovascular or all-cause mortality between the groups.’ However, after the trial ended the cumulative mortality curves of the intervention and control groups began to diverge, and at ten-year follow-up there was a marginally significant increase in total mortality and a highly significant increase in cardiovascular deaths and deaths associated with violence or accident in the intervention group. Simultaneously, the trialists noted that there was a men
1496
the mean of the risk-factor differences between the two groups, so at five years there was no longer any significant difference between the groups in terms of the use of drugs or coronary risk factors. The most obvious, and most boring, interpretation of these results is that, by some quirk of selection, the intervention group had a higher cardiovascular disease risk, which was held in check by risk-factor reduction during the trial period, but which became manifest after the end of the trial. It is difficult to confirm or refute this view from the baseline pre-trial data, although some potential risk indicators such as alcohol consumption did seem to be higher in the intervention group. To blame the drugs given during the trial period for a mortality difference that only became apparent some ten years after the trial ended seems unfair. There is no suggestion in this study that any of the excess mortality was due to malignant disease, which might have had a lengthy induction
rapid regression
to
period. A factor that seems to have been neglected is the long-term effect on patient psychology and lifestyle of being subjected to an intense period of drug treatment and counselling, which is then terminated. Enthusiasts for corrective training and "short sharp shocks" might hope that lifestyle modification so induced would be long lasting. Clinical experience suggests otherwise, and recent reports, especially from general practice, have emphasised the need for long-term reinforcement if behavioural changes of any kind are to be made to stick. 8,9 It is not inconceivable that in susceptible patients the rebound from a strict and perhaps unpalatable regimen might lead to excessive complacency, or worse to an actual deterioration in disease-avoiding behaviour. Although it is tempting to find supporting evidence in the increased incidence of "violent deaths", the Helsinki researchers wisely caution that many of these deaths were accidental and could have involved an unrecognised cardiac component. Nevertheless, a recent review of primary prevention trialsl° also suggested that cardiac benefits may be offset by deaths from accidents, suicide, and violence. We can return to Donne to sum up the complexities: When thou hast done, thou hast For,I have more.
not
done,
1. Committee of Principal Investigators. A cooperative trial in the primary presentation of ischaemic heart disease using clofibrate. Br Heart J 1978; 40: 1069-118. 2. Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet 1984; n: 600-04. 3. Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarna SJ, Miettinen TA. Long term mortality after 5 year multifactorial primary prevention of cardiovascular diseases in middle aged men. JAMA 1991; 226: 1255-29. 4. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Lancet 1990; 335: 827-38. 5. Report of the Expert Panel on Population Strategies for Blood Cholesterol Reduction: a statement from the national cholesterol education program, National Institutes of Health. Circulation 1991; 83: 2154-232.
6. The Multiple Risk Factor Intervention Trial Research Group. Mortality rate after 10·5 years for participants in the Multiple Risk Factor Intervention Trial: findings related to a priori hypotheses of the trial. JAMA 1990; 263: 1795-801 7. Miettinen TA, Huttunen JK, Naukkarinen V, et al. Multifactorial primary prevention of cardiovascular diseases in middle aged men. JAMA 1985; 254: 2097-102. 8. Imperial Cancer Research Fund OXCHECK Study group. Prevalence of risk factors for heart disease in OXCHECK trial: implications for screening in primary care. Br Med J 1991; 302: 1057-60. 9. Hart JT, Thomas C, Gibbons B, et al. Twenty five years of case finding and audit in a socially deprived community. Br Med J 1991; 302: 1509-13. 10. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol and mortality: a quantitative review of primary prevention trials. Br Med J 1990; 301: 309-14.
Understanding diabetic neuropathy Debate about the aetiology of diabetic neuropathy has largely focused on metabolic and vascular factors. Although metabolic imbalances were once thought to be caused by the neuropathy, diabetic neuropathy is now generally believed to be a consequence of long-term hyperglycaemia.1 Suggestions that genetic factors such as acetylator status might help to predict which patients are at risk of neuropathy2 have not been confirmed.3 However, the occurrence of this complication in both main types of diabetes as well as in secondary cases, the strong association with previous metabolic control,3,4 and the association between neuropathy and diabetes duration all point to a common aetiological mechanism involving hyperglycaemia. That progression of polyneuropathy may be halted after many years of hyperglycaemia if blood glucose concentrations are restored to normal by successful pancreatic transplantations lends further support to the metabolic hypothesis. of One of the metabolic consequences is increased polyol pathway hyperglycaemia activity.1,6 Despite strong evidence implicating increased flux through the polyol pathway in the peripheral nerves of both man and laboratory animals, the putative link between nerve dysfunction, polyol pathway activity, and nerve myoinositol levels is less clear.6 Further doubt on the role of myoinositol in the pathogenesis of neuropathy is cast by experimental evidence that the reduction in nerve conduction velocity associated with exaggerated polyol pathway flux is not related to myoinositol concentrations or Na + K-ATPase activity,’ and that treatment with an aldose reductase inhibitor has no effect on oubainsensitive ATPase activity.8 Despite these negative findings there is evidence that aldose reductase inhibitors, which block the rate-limiting enzyme in the polyol pathway, are beneficial even in patients with long-established neuropathy.9 Moreover, nerve function deteriorated following withdrawal of therapy from patients treated for 4 years with such an inhibitor. to Alterations in endogenous concentrations of nerve growth factor (NGF) may be another consequence of hyperglycaemia that is relevant to the aetiology of neuropathy. NGF is essential for the growth and
