- Email: [email protected]
Treatment of hypertension in elderly patients
THE LANCET
implications of detailed ultrasound examinations in early pregnancy, and of more time-consuming and costly cytogenetic analyses in the laboratory. Even if the two programmes were equally effective, the financial consequences of first-trimester screening could prove prohibitive. Does nuchal translucency screening generate an unacceptable level of worry among pregnant women? The rate of termination of pregnancy for psychosocial reasons seems to be women strangely high3 among sufficiently well motivated to attend early for nuchal translucency screening. There are several possible explanations but I would wish reassurance that women are not seeking termination merely because of worry about increased nuchal translucency in otherwise normal babies. Also, does the advantage of earlier diagnosis (and, if indicated, earlier termination) outweigh the disadvantages of the transference of a burden of guilt to some woman with chromosomally abnormal pregnancies who would have miscarried before second-trimester screening, but who will now have to make a difficult decision about termination? These vital questions have not yet been answered by observational and uncontrolled data (Soothill and Kyle), however extensive; by the scrutiny of these same data by an independent body (Cuckle); or by majority consensus opinion by a panel of experts based on these very same data (Grudzinskas and Chard) in a report published, incidentally, after my commentary. I am still in no doubt that there are compelling arguments for a randomised trial of first-trimester screening versus second-trimester screening to address clinical, economic, and psychological outcomes. Grudzinskas and Chard imply that a conflict of interest exists in the SURUSS management team. I cannot comment because my involvement in the study is only as a clinician in a participating hospital. Grudzinskas and Chard should address their points to the principal investigators of SURUSS. James P Neilson Department of Obstetrics and Gynaecology, University of Liverpool, L69 3BX, UK 1
2
Alfirevic Z, Gosden C, Neilson JP. Chorion villus sampling vs amniocentesis for prenatal diagnosis. In: Neilson JP, Crowther CA, Hodnett ED, Hofmeyr GJ, Keirse MJNC, eds. Pregnancy and childbirth module of the Cochrane database of systematic reviews (updated March 4, 1997). Oxford: Cochrane Library, issue 4. Update software. Alfirevic Z, Gosden C, Neilson JP. Amniocentesis vs chorion villus sampling. In: Neilson JP, Crowther CA, Hodnett ED,
1632
3
Hofmeyr GJ, Keirse MJNC, eds. Pregnancy and childbirth module of the Cochrane database of systematic reviews (updated March 4, 1997). Oxford: Cochrane Library, issue 4. Update software. Pandya PP, Snijders RJM, Johnson SP, Brizot ML, Nicolaides KH. Screening for fetal trisomies by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation. Br J Obstet Gynaecol 1995; 102: 957–62.
The principal investigators respond SIR—As the principal investigators of the SURUSS (Serum Urine and Ultrasound Screening Study) project we wish to respond to J G Grudzinskas and T Chard. The innuendo in their last paragraph is unjustified. The value of second-trimester screening is established, and we acknowledge the need to evaluate first-trimester screening to see if it is better and more cost effective. We also acknowledge that existing data show that firsttrimester screening based on nuchal translucency measurement and biochemical testing has a reasonable screening performance. Outside the SURUSS project we provide services for both second-trimester and firsttrimester screening. We have not concluded that one is better than the other. There is no doubt that the addition of biochemical markers for nuchal translucency measurement improves the efficacy and safety of first-trimester screening, and to this end we have added biochemical testing to nuchal translucency screening that is done at the Portland Hospital in London. We have not advertised the service, although the Portland Hospital has mailed clinicians who use the hospital to inform them of the benefits of combining biochemical testing with ultrasound measurements. This work does not detract or conflict with our research designed to establish whether first-trimester screening for Down’s syndrome should replace secondtrimester screening on a routine and national basis. With respect to the study group of the Royal College of Obstetricians and Gynaecologists, both the main view presented by Grudzinskas to the working group, and the minority view (also published in the report) leave open the question of whether firsttrimester or second-trimester screening is the approach of choice. Only additional evidence can provide the answer. It is nonsense to claim that obtaining this evidence is ethically and legally indefensible. The SURUSS project has the appropriate design to answer the question, based on a comparison of first-trimester and second-trimester screening results in the same women, so avoiding bias as well as achieving maximum statistical
power. The study is supported by the UK National Health Service research and development programme, and was approved by 18 ethics committees at centres where the study is being conducted. *Nicholas J Wald, Charles H Rodeck *Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St Bartholomew’s and the Royal London School of Medicine and Dentistry, London EC1M 6BQ, UK; and Department of Obstetrics and Gynaecology, University College and Middlesex School of Medicine, University College London Medical School, London
Treatment of hypertension in elderly patients SIR—Several trials in elderly people have shown beneficial effects of diuretics and -adrenoceptor blockers with respect to cardiovascular morbidity and mortality.1,2 By contrast, reports of increases in cardiovascular mortality, neoplastic diseases, and gastrointestinal haemorrhage in retrospective case-control studies have made therapy with calcium-channel blockers seem unfavourable.3,4 In the Systolic Hypertension in Europe (Syst-Eur) trial (Sept 13, p 757),5 active treatment was started with the calcium-channel blocker nitrendipine versus placebo in 4695 patients (of 8926 screened; exclusion criteria included congestive heart failure, a history of stroke or myocardial infarction within 1 year before study, and any severe cardiovascular disease), followed by the possible addition of enalapril, hydrochlorothiazide, or both (median follow-up 2 years, reduction in blood pressure by 23/7 mm Hg with a difference from placebo of 10·1/4·5 mm Hg). The benefits of antihypertensive treatment were similar to those in former trials. The total rate of stroke was reduced by 42%, and fatal and non-fatal cardiac endpoints were reduced by 31% compared with the placebo group. There was no significant difference in cardiovascular mortality (⫺27%) and total mortality (⫺14%), and in the rate of cancer and gastrointestinal bleeding. The Systolic Hypertension in the Elderly Program (SHEP; mean followup 4·5 years; reduction in blood pressure by 12/5 mm Hg)1 trial showed that a thiazide-based treatment (with the possible addition of a adrenoceptor blocker) versus placebo reduced the frequency of stroke by 36%. The occurrence of major cardiovascular events was reduced by 32% and death from all causes by 13%. Similar results were achieved in the Swedish Trial in Old Patients with
Vol 350 • November 29, 1997
THE LANCET
Hypertension (STOP-Hypertension; mean follow-up 25 months; reduction in blood pressure by 19·5/8·1 mm Hg),2 which compared treatment with -adrenoceptor blocker and thiazide versus placebo. The risk of stroke in the active treatment group was reduced by 47% and the risk of all myocardial infarction by 13%. Remarkably, a 43% decrease in overall mortality in the active treatment group was also noted. In view of these studies, especially with respect to blood pressure reduction and follow-up, long-acting calcium-channel blockers seem to confer the same benefits as thiazides and -adrenoceptor blockers to elderly hypertensives, thereby arguing against severe adverse effects of calciumchannel blockade per se. However, for final clarification of the calciumchannel blocker issue, it would have been preferable to study unselected patients with a higher baseline cardiovascular morbidity. Studies in hypertensive patients with a high cardiovascular risk have to prove safety and treatment benefit in this subgroup. *Caroline Nabel, Frank Schweda, Eckard P Kromer, Bernhard K Krämer Klinik und Poliklinik für Innere Medizin II, University of Regensburg, D-93042 Regensburg, Germany 1
2
3
4
5
SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255–64. Dahlöf B, Lindholm LH. Hansson L, Scherstén B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338: 1281–85. Pahor M, Guralnik JM, Ferrucci L, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet 1996; 348: 493–97. Furberg CD, Patsy BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326–31. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757–64.
SIR—The principal results of the Systolic Hypertension in Europe (SystEur) trial1 provide evidence confirming the efficacy of treatment for isolated systolic hypertension established by the Systolic Hypertension in the Elderly Programme (SHEP) in the USA. 2 When the SHEP study was published in 1991 showing a 36% reduction of total stroke (p=0·003), which was similar to that in previous trials of combined
Vol 350 • November 29, 1997
systolic and diastolic hypertension, the organisers of Syst-Eur were faced with an ethical dilemma as to whether they should continue their study. Three of the investigators in an editorial in the Journal of Human Hypertension discussed the features of the SHEP trial that made it necessary and ethical to continue the European study.3 The investigators commented that the reported frequency of intolerable side-effects of treatment in the treatment group of SHEP was a third above that of the control group. Of 29 symptoms listed, 27 were reported more often in the treatment group and two more in the controls. These data appeared in a table in the SHEP report but not in the text. They continued, “obviously, more data are required to obtain an integrated estimate of both the quality and quantity that are being added to life by prescribing antihypertensive treatment to ISH [isolated systolic hypertension] patients”. They noted that the population studied in SHEP was a low-risk group because patients with cardiovascular risks had been excluded, which resulted in a low rate of cardiovascular deaths in the control group. Finally, the investigators believed that because the therapy in SHEP was mainly diuretics it was important to see if the results could be duplicated with calcium-channel blockers and angiotensin-converting enzyme. We have three reservations about the Syst-Eur study. First, the investigators do not mention the critical question of side-effects. Because they used a calcium-channel blocker as a first-line agent, a class of drug with established side-effects, this omission is surprising. This potential problem increases with age and is a common reason for cautious prescribing in elderly patients.4 Second, selection of patients seems to have produced a control group with the same cardiovascular mortality as SHEP and with the same difficulties of generalising the results5 that had been the concern of the Syst-Eur investigators.3 Third, if the intention was to find out if the newer agents had the same beneficial effects as diuretics in this group of patients, surely this would have been better and more acceptably tested by randomising to either a diuretic or a calcium blocker. *John Coope, Malcolm Aylett *Plant Cottage, Beeston Brow, Bollington, Macclesfield, Cheshire SK10 5PR, UK; and Stone Martin, Wooler, Northumberland 1
Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older
2
3
4
5
patients with isolated systolic hypertension. Lancet 1997; 350: 757–64. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255–64. Staessen J Fagard R, Amery A. Isolated systolic hypertension in the elderly: implications of SHEP for clinical practice and for the ongoing trials. J Hum Hypertens 1991; 5: 469–74. Duggan S, Ford GA, Eccles M. Doctors’ attitudes towards the detection and treatment of hypertension in older people. J Hum Hypertens 1997; 11: 271–76. Fayers PM, Hand DJ. Generalisation from phase III clinical trials: survival, quality of life, and health economics. Lancet 1997; 350: 1025–27.
SIR—The Syst-Eur study 1 results accord with those of the Systolic Hypertension in the Elderly Program (SHEP) trial, reported in 1991,2 and those from the Medical Research Council trial of treatment of hypertension in older adults:3 elderly patients with isolated systolic hypertension benefit from antihypertensive therapy. The main reason why the Syst-Eur investigators continued with a placebo group despite the positive SHEP results was centered around the importance of providing data on fatal cerebrovascular events and on overall and cardiovascular mortality. It is now clear, 6 years after the SHEP report, that the new trial (started in fact in 1989) falls short of providing the information aimed at. The final number of primary endpoints (114) is less than half those foreseen in the planning phase. The lack of power of the study had certainly been established earlier, by the same monitoring committee that applied the stopping rules in February, 1997, based on the same end-point used in SHEP— namely, stroke. The very broad 95% CIs around the estimates of mortality (–62/+39 for fatal stroke, –48/+2 for cardiovascular deaths, –33/+9 for total deaths) are only suggestive of a benefit. Continuing placebo-controlled trials against the right of clearly informed patients is nothing new. But, besides the basic concern reiterated in your recent editorial,4 is it possible here to raise another suspicion? The trial has been stopped—and the late decision is welcome for the patients—so that at least a positive, though not innovative, result would be available for at least one of the highly controversial calcium antagonists. In other words: have patients been protected from further placebo exposure by a delayed ethical concern or by more prosaic but highly effective market considerations? Our suspicions may never be allayed, but in
1633
implications of detailed ultrasound examinations in early pregnancy, and of more time-consuming and costly cytogenetic analyses in the laboratory. Even if the two programmes were equally effective, the financial consequences of first-trimester screening could prove prohibitive. Does nuchal translucency screening generate an unacceptable level of worry among pregnant women? The rate of termination of pregnancy for psychosocial reasons seems to be women strangely high3 among sufficiently well motivated to attend early for nuchal translucency screening. There are several possible explanations but I would wish reassurance that women are not seeking termination merely because of worry about increased nuchal translucency in otherwise normal babies. Also, does the advantage of earlier diagnosis (and, if indicated, earlier termination) outweigh the disadvantages of the transference of a burden of guilt to some woman with chromosomally abnormal pregnancies who would have miscarried before second-trimester screening, but who will now have to make a difficult decision about termination? These vital questions have not yet been answered by observational and uncontrolled data (Soothill and Kyle), however extensive; by the scrutiny of these same data by an independent body (Cuckle); or by majority consensus opinion by a panel of experts based on these very same data (Grudzinskas and Chard) in a report published, incidentally, after my commentary. I am still in no doubt that there are compelling arguments for a randomised trial of first-trimester screening versus second-trimester screening to address clinical, economic, and psychological outcomes. Grudzinskas and Chard imply that a conflict of interest exists in the SURUSS management team. I cannot comment because my involvement in the study is only as a clinician in a participating hospital. Grudzinskas and Chard should address their points to the principal investigators of SURUSS. James P Neilson Department of Obstetrics and Gynaecology, University of Liverpool, L69 3BX, UK 1
2
Alfirevic Z, Gosden C, Neilson JP. Chorion villus sampling vs amniocentesis for prenatal diagnosis. In: Neilson JP, Crowther CA, Hodnett ED, Hofmeyr GJ, Keirse MJNC, eds. Pregnancy and childbirth module of the Cochrane database of systematic reviews (updated March 4, 1997). Oxford: Cochrane Library, issue 4. Update software. Alfirevic Z, Gosden C, Neilson JP. Amniocentesis vs chorion villus sampling. In: Neilson JP, Crowther CA, Hodnett ED,
1632
3
Hofmeyr GJ, Keirse MJNC, eds. Pregnancy and childbirth module of the Cochrane database of systematic reviews (updated March 4, 1997). Oxford: Cochrane Library, issue 4. Update software. Pandya PP, Snijders RJM, Johnson SP, Brizot ML, Nicolaides KH. Screening for fetal trisomies by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation. Br J Obstet Gynaecol 1995; 102: 957–62.
The principal investigators respond SIR—As the principal investigators of the SURUSS (Serum Urine and Ultrasound Screening Study) project we wish to respond to J G Grudzinskas and T Chard. The innuendo in their last paragraph is unjustified. The value of second-trimester screening is established, and we acknowledge the need to evaluate first-trimester screening to see if it is better and more cost effective. We also acknowledge that existing data show that firsttrimester screening based on nuchal translucency measurement and biochemical testing has a reasonable screening performance. Outside the SURUSS project we provide services for both second-trimester and firsttrimester screening. We have not concluded that one is better than the other. There is no doubt that the addition of biochemical markers for nuchal translucency measurement improves the efficacy and safety of first-trimester screening, and to this end we have added biochemical testing to nuchal translucency screening that is done at the Portland Hospital in London. We have not advertised the service, although the Portland Hospital has mailed clinicians who use the hospital to inform them of the benefits of combining biochemical testing with ultrasound measurements. This work does not detract or conflict with our research designed to establish whether first-trimester screening for Down’s syndrome should replace secondtrimester screening on a routine and national basis. With respect to the study group of the Royal College of Obstetricians and Gynaecologists, both the main view presented by Grudzinskas to the working group, and the minority view (also published in the report) leave open the question of whether firsttrimester or second-trimester screening is the approach of choice. Only additional evidence can provide the answer. It is nonsense to claim that obtaining this evidence is ethically and legally indefensible. The SURUSS project has the appropriate design to answer the question, based on a comparison of first-trimester and second-trimester screening results in the same women, so avoiding bias as well as achieving maximum statistical
power. The study is supported by the UK National Health Service research and development programme, and was approved by 18 ethics committees at centres where the study is being conducted. *Nicholas J Wald, Charles H Rodeck *Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St Bartholomew’s and the Royal London School of Medicine and Dentistry, London EC1M 6BQ, UK; and Department of Obstetrics and Gynaecology, University College and Middlesex School of Medicine, University College London Medical School, London
Treatment of hypertension in elderly patients SIR—Several trials in elderly people have shown beneficial effects of diuretics and -adrenoceptor blockers with respect to cardiovascular morbidity and mortality.1,2 By contrast, reports of increases in cardiovascular mortality, neoplastic diseases, and gastrointestinal haemorrhage in retrospective case-control studies have made therapy with calcium-channel blockers seem unfavourable.3,4 In the Systolic Hypertension in Europe (Syst-Eur) trial (Sept 13, p 757),5 active treatment was started with the calcium-channel blocker nitrendipine versus placebo in 4695 patients (of 8926 screened; exclusion criteria included congestive heart failure, a history of stroke or myocardial infarction within 1 year before study, and any severe cardiovascular disease), followed by the possible addition of enalapril, hydrochlorothiazide, or both (median follow-up 2 years, reduction in blood pressure by 23/7 mm Hg with a difference from placebo of 10·1/4·5 mm Hg). The benefits of antihypertensive treatment were similar to those in former trials. The total rate of stroke was reduced by 42%, and fatal and non-fatal cardiac endpoints were reduced by 31% compared with the placebo group. There was no significant difference in cardiovascular mortality (⫺27%) and total mortality (⫺14%), and in the rate of cancer and gastrointestinal bleeding. The Systolic Hypertension in the Elderly Program (SHEP; mean followup 4·5 years; reduction in blood pressure by 12/5 mm Hg)1 trial showed that a thiazide-based treatment (with the possible addition of a adrenoceptor blocker) versus placebo reduced the frequency of stroke by 36%. The occurrence of major cardiovascular events was reduced by 32% and death from all causes by 13%. Similar results were achieved in the Swedish Trial in Old Patients with
Vol 350 • November 29, 1997
THE LANCET
Hypertension (STOP-Hypertension; mean follow-up 25 months; reduction in blood pressure by 19·5/8·1 mm Hg),2 which compared treatment with -adrenoceptor blocker and thiazide versus placebo. The risk of stroke in the active treatment group was reduced by 47% and the risk of all myocardial infarction by 13%. Remarkably, a 43% decrease in overall mortality in the active treatment group was also noted. In view of these studies, especially with respect to blood pressure reduction and follow-up, long-acting calcium-channel blockers seem to confer the same benefits as thiazides and -adrenoceptor blockers to elderly hypertensives, thereby arguing against severe adverse effects of calciumchannel blockade per se. However, for final clarification of the calciumchannel blocker issue, it would have been preferable to study unselected patients with a higher baseline cardiovascular morbidity. Studies in hypertensive patients with a high cardiovascular risk have to prove safety and treatment benefit in this subgroup. *Caroline Nabel, Frank Schweda, Eckard P Kromer, Bernhard K Krämer Klinik und Poliklinik für Innere Medizin II, University of Regensburg, D-93042 Regensburg, Germany 1
2
3
4
5
SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255–64. Dahlöf B, Lindholm LH. Hansson L, Scherstén B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338: 1281–85. Pahor M, Guralnik JM, Ferrucci L, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet 1996; 348: 493–97. Furberg CD, Patsy BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326–31. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757–64.
SIR—The principal results of the Systolic Hypertension in Europe (SystEur) trial1 provide evidence confirming the efficacy of treatment for isolated systolic hypertension established by the Systolic Hypertension in the Elderly Programme (SHEP) in the USA. 2 When the SHEP study was published in 1991 showing a 36% reduction of total stroke (p=0·003), which was similar to that in previous trials of combined
Vol 350 • November 29, 1997
systolic and diastolic hypertension, the organisers of Syst-Eur were faced with an ethical dilemma as to whether they should continue their study. Three of the investigators in an editorial in the Journal of Human Hypertension discussed the features of the SHEP trial that made it necessary and ethical to continue the European study.3 The investigators commented that the reported frequency of intolerable side-effects of treatment in the treatment group of SHEP was a third above that of the control group. Of 29 symptoms listed, 27 were reported more often in the treatment group and two more in the controls. These data appeared in a table in the SHEP report but not in the text. They continued, “obviously, more data are required to obtain an integrated estimate of both the quality and quantity that are being added to life by prescribing antihypertensive treatment to ISH [isolated systolic hypertension] patients”. They noted that the population studied in SHEP was a low-risk group because patients with cardiovascular risks had been excluded, which resulted in a low rate of cardiovascular deaths in the control group. Finally, the investigators believed that because the therapy in SHEP was mainly diuretics it was important to see if the results could be duplicated with calcium-channel blockers and angiotensin-converting enzyme. We have three reservations about the Syst-Eur study. First, the investigators do not mention the critical question of side-effects. Because they used a calcium-channel blocker as a first-line agent, a class of drug with established side-effects, this omission is surprising. This potential problem increases with age and is a common reason for cautious prescribing in elderly patients.4 Second, selection of patients seems to have produced a control group with the same cardiovascular mortality as SHEP and with the same difficulties of generalising the results5 that had been the concern of the Syst-Eur investigators.3 Third, if the intention was to find out if the newer agents had the same beneficial effects as diuretics in this group of patients, surely this would have been better and more acceptably tested by randomising to either a diuretic or a calcium blocker. *John Coope, Malcolm Aylett *Plant Cottage, Beeston Brow, Bollington, Macclesfield, Cheshire SK10 5PR, UK; and Stone Martin, Wooler, Northumberland 1
Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older
2
3
4
5
patients with isolated systolic hypertension. Lancet 1997; 350: 757–64. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255–64. Staessen J Fagard R, Amery A. Isolated systolic hypertension in the elderly: implications of SHEP for clinical practice and for the ongoing trials. J Hum Hypertens 1991; 5: 469–74. Duggan S, Ford GA, Eccles M. Doctors’ attitudes towards the detection and treatment of hypertension in older people. J Hum Hypertens 1997; 11: 271–76. Fayers PM, Hand DJ. Generalisation from phase III clinical trials: survival, quality of life, and health economics. Lancet 1997; 350: 1025–27.
SIR—The Syst-Eur study 1 results accord with those of the Systolic Hypertension in the Elderly Program (SHEP) trial, reported in 1991,2 and those from the Medical Research Council trial of treatment of hypertension in older adults:3 elderly patients with isolated systolic hypertension benefit from antihypertensive therapy. The main reason why the Syst-Eur investigators continued with a placebo group despite the positive SHEP results was centered around the importance of providing data on fatal cerebrovascular events and on overall and cardiovascular mortality. It is now clear, 6 years after the SHEP report, that the new trial (started in fact in 1989) falls short of providing the information aimed at. The final number of primary endpoints (114) is less than half those foreseen in the planning phase. The lack of power of the study had certainly been established earlier, by the same monitoring committee that applied the stopping rules in February, 1997, based on the same end-point used in SHEP— namely, stroke. The very broad 95% CIs around the estimates of mortality (–62/+39 for fatal stroke, –48/+2 for cardiovascular deaths, –33/+9 for total deaths) are only suggestive of a benefit. Continuing placebo-controlled trials against the right of clearly informed patients is nothing new. But, besides the basic concern reiterated in your recent editorial,4 is it possible here to raise another suspicion? The trial has been stopped—and the late decision is welcome for the patients—so that at least a positive, though not innovative, result would be available for at least one of the highly controversial calcium antagonists. In other words: have patients been protected from further placebo exposure by a delayed ethical concern or by more prosaic but highly effective market considerations? Our suspicions may never be allayed, but in
1633