- Email: [email protected]
Editorials
EDITORIALS
More Dialysis Appears Beneficial for Pregnant ESRD Patients (at Least in Belgium) Related Articles, pp. 756 and 766
HE VERY detailed paper by Bagon et al1 from Belgium plus the report of the US registry by Okundaye et al,2 both of which appear in this issue, give some new insight into pregnancy during dialysis. It is also obvious that advantages exist in a small country (Belgium) versus a larger one (United States) when it comes to conducting national surveys. Belgium had a 100% response from its dialysis centers compared to only a 40% response rate in the US study. As the authors point out, marked improvement has been achieved in the results of patients who become pregnant after they are on dialysis. However, before we start doing infertility work-ups on all ESRD patients in their childbearing years, we need to recognize that because something can be done does not mean it should be done. For example, if a patient has a good chance to be transplanted, it is probably better to wait until after the transplant is successful before pursuing pregnancy. The reasons for this are at least threefold: ● Pregnancy posttransplant does not result in sensitization.3 ● Chances of a successful conception are much higher posttransplant.4 ● Fewer complications and/or birth abnormalities exist posttransplant.4 By contrast, if being pregnant during dialysis is the patient’s only chance to have a child, pregnancy should be considered with the recognition that it may not be successful or that there will be prematurity and perhaps fetal complications. Having considered these major problems, let me turn to what I find the most encouraging part of the Belgian study. The authors appear to show that if the amount of dialysis is increased by hours per week or Kt/V, birth weight improves. They interpret birth weight as a sign of less prematurity. This was supported by a similar but nonsignificant trend in the US data with better
T
infant survival in women dialyzed 20 or more hours per week.2 If we assume that more dialysis, as shown in Figure 4 of the Belgian paper, gives a higher birth weight and a longer gestational period, where does this leave us in countries that provide a standard payment for dialysis only three times a week? To answer this question, I called some highly placed sources at the US Health Care Financing Administration (HCFA). I explained that this information would soon be published and asked what their response would be if more frequent dialysis were ordered? Without making absolute commitments, they said the following: ● They were not aware of ever receiving a request for more frequent dialysis due to pregnancy in an ESRD patient. ● If acceptable scientific evidence exists, they do not see why payments for more frequent dialysis could not be covered. (One needs to realize this would be a rather rare request and would extend for only 10 to 15 weeks from the recognition of pregnancy until delivery at about 32 weeks.) ● The gate appears to be open. To go through that gate, however, one presumably would have to present the data from the two articles in this issue and hope for payment. I believe the articles in this month’s American Journal of Kidney Diseases show that a viable pregnancy is possible 50% of the time if additional dialysis is delivered. I would, however, recommend (pregnancy) during dialysis only if the patient could not receive a transplant. We need to remember that birth is merely the start of a long new journey. No studies exist that I am aware of to show how these children do longterm. Such studies need to be undertaken from this current base. —Alan R. Hull, MD Dallas Nephrology Associates Dallas, TX r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3105-0019$3.00/0
American Journal of Kidney Diseases, Vol 31, No 5 (May), 1998: pp 863-867
863
864
EDITORIALS
REFERENCES 1. Bagon JA, Vernaeve H, De Muylder X, Lafontaine J-J, Martens J, Roost GV: Pregnancy and dialysis. Am J Kidney Dis 31:756-765, 1998 2. Okundaye I, Abrinko P, Hou S: Registry of pregnancy in dialysis patients. Am J Kidney Dis 31:766-773, 1998
3. Sanfilippo F, Vaughn WK, Bollinger RR, Spees EK: Comparative effects of pregnancy, transfusion, and prior graft rejection on sensitization and renal transplant results. Transplantation 34:360-366, 1982 4. Davison JM: Dialysis, transplantation, and pregnancy. Am J Kidney Dis 17:127-132, 1991
New JNC-6 Guidelines
T
HE ALGORITHM for therapy of hypertension in the sixth report of the Joint National Committee (JNC-6)1 starts with lifestyle modifications alone for those patients at relatively low overall risk for cardiovascular-renal diseases and with drugs for those at higher risk. If lifestyle modifications are not sufficient to bring the blood pressure to below 140/90 mm Hg, three suggested pathways for the initial choice of therapy are as follows: 1. Diuretics or beta-blockers for those with uncomplicated hypertension. 2. Angiotensin-converting enzyme (ACE) inhibitors for diabetic patients with proteinuria; ACE and diuretics for patients with heart failure; -blockers and, if systolic dysfunction is present, ACE inhibitors after a heart attack; and diuretics or long-acting dihydropyridine calcium antagonists for systolic hypertension in the elderly. 3. Certain drugs that are not compelling but that provide favorable effects on concomitant conditions, such as an ␣-blocker for prostatism or a diuretic with osteoporosis. The latter recommendations are not supported by hard evidence from randomized controlled trials (RCTs), as are the first two recommendations, but they are supported by a great deal of clinical experience. The recommendation for diuretics or -blockers for uncomplicated hypertension in patients younger than 65 years is firmly based in evidence from multiple RCTs.2 Whether other choices will do as well will hopefully be known when some of the 30ⴙ comparative trials now in process are completed. The compelling indications are generally well r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3105-0020$3.00/0
recognized to be based on data from RCTs. The only exception may be the recommendation that if diuretics are not adequate or appropriate, a long-acting dihydropyridine calcium antagonist be used for elderly patients with systolic hypertension. That recommendation is based primarily on the recently published SYST-EUR trial3 in which almost 5,000 patients older than 60 years were given either placebo or a drug regimen based on the long-acting dihydropyridine calcium antagonist nitrendipine, starting with one 10 mg dose per day and increasing if needed to 20 to 40 mg in two doses a day in addition to an ACE inhibitor or a diuretic. Over a very short follow-up period averaging 2 years, patients given nitrendipine (the only drug needed in G60% of the patients) had a highly significant 42% reduction in strokes and a 26% reduction in cardiac end points (although the reductions in heart failure [29%] and myocardial infarction [30%] did not reach statistical significance). These data go along with a less well-controlled study from China in which long-acting nifedipine also reduced strokes in elderly patients with isolated systolic hypertension (ISH).4 In addition to studies with other long-acting dihydropyridines in heart failure in which coronary mortality was reduced,5,6 these data should allay the concerns that arose from the recognition that large doses of short-acting nifedipine increased mortality in postmyocardial infarction patients.7 Since nitrendipine, the calcium channel blocker (CCB) used in the SYST-EUR trial, is not marketed in the United States, JNC-6 recommends that the other available long-acting dihydropyridines be used. It should be noted that the nondihydropyridines diltiazem and verapamil and the new T-channel blocker mibefradil have not been
EDITORIALS
tested for primary protection; they are therefore not included in this ‘‘compelling’’ indication. The remainder of the algorithm fits prior JNC recommendations with the additional insistence that therapy be pushed to achieve the goal of blood pressure below 140/90 mm Hg. If that goal is not achieved with the first drug, usually titrated slowly up to a moderate dose, either another drug should be substituted or, if it was not the first choice, a diuretic should be added. In my experience over the past few years, many practitioners, including a few nephrologists, have dropped diuretics altogether or given woefully inadequate single daily doses of furosemide, a practice that may be even worse than prescribing no diuretic at all, since the practitioner may be misled into believing that the few hours of volume contraction provided by furosemide should be all that is needed to control hypertension.8 Regardless of the reasons why diuretics have been downplayed, their use is often essential, even more so in those hypertensive patients with renal insufficiency often seen by nephrologists. If the blood pressure remains uncontrolled after the administration of multiple drugs, referral to a ‘‘hypertension specialist’’ is recommended. At present, that individual is not identifiable other than by colleagues who know of the expertise of some practitioners in dealing with difficult hypertension. The American Society of Hypertension has begun an accrediting process, grandfathering those now so recognized and credentialing others through courses and an examination. JNC-6 provides appropriate recommendations for the treatment of hypertension, recommendations that are both evidence based and up to date. As more evidence becomes available, some of these recommendations may need to be changed; however, for now, they are appropriate. Lest practitioners be concerned that these guidelines will constrain their personal choices, recall the opening statement in JNC-61: ‘‘The committee recognizes that the responsible clinician’s judgement of the individual patient’s needs
865
remains paramount. Therefore, [these] guidelines should serve as a tool to be adapted and implemented in local and individual situations.’’ If used as intended, JNC-6 will prove helpful to all who provide care for hypertensive patients. —Norman M. Kaplan, MD Professor of Internal Medicine UT Southwestern Medical Center at Dallas Dallas, TX REFERENCES 1. Joint National Committee: The sixth report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure. Arch Intern Med 57:2413-2446, 1998 2. Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, Lemaitre RN, Wagner EH, Furberg CD: Health outcomes associated with antihypertensive therapies used as first-line agents: A systematic review and meta-analysis. JAMA 277:739-745, 1997 3. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 350:757-764, 1997 4. Gong L, Zhang W, Zhu Y, Kong D, Pag V, Ghadirian P, LeLorier J, Hamet P: Shanghai trial of nifedipine in the elderly (STONE). J Hypertens 14:1237-1245, 1996 5. Packer M, O’Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, Miller AB, Neuberg GW, Frid D, Wertheimer JH, Cropp AB, DeMets DL: Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective randomized amlodipine survival evaluation study group. N Engl J Med 335:1107-1114, 1996 6. Cohn JN, Ziesche S, Smith R, Anand I, Dunkman WB, Loeb H, Cintron G, Boden W, Baruch L, Rochin P, Loss L: Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Circulation 96:856-863, 1997 7. Furberg CD, Psaty BM, Meyer JV: Nifedipine: Doserelated increase in mortality in patients with coronary heart disease. Circulation 92:1326-1331, 1995 8. Kaplan NM: Treatment of hypertension: Drug therapy, in Clinical Hypertension (ed 7). Baltimore, MD, Williams & Wilkins, 1998, pp 181-263
866
EDITORIALS
JNC Redux ‘‘Who are you going to believe? Me or your own eyes?’’ —Groucho Marx
T
HE SIXTH REPORT of the Joint National Committee (JNC-6)1 appeared just about the same time that Siegel and Lopez2 reported in the Journal of the American Medical Association that nobody had listened to the previous set of guidelines. It seems highly likely that the response to this new set will be equally underwhelming. Why? Ignorance of the guidelines is one possibility. Another is that physicians don’t find them and the evidence they are based on persuasive. The report recommends (as did the previous one) diuretics and -blockers for the initial treatment of uncomplicated hypertension. The data show that this combination is effective in reducing morbidity and mortality from hypertension. Compared with what? With diuretics and angiotensin-converting enzyme (ACE) inhibitors? No, that comparison has not been made. Furthermore, many physicians remembered that JNC-43 allowed ACE inhibitors and calcium channel blockers as first-choice drugs. Apparently, between their fourth and fifth advisories, the hypertension experts decided that they should be bound by the limits of randomized controlled trials (RCTs). It is useful to reflect on what an RCT tells us. It differentiates between a treatment that doesn’t work and one that barely works and between treatments that differ very slightly. If the treatment is a great advance, its effect is so obvious that an RCT is not necessary. No one ever conducted a controlled study to determine that insulin lowers blood sugar, that morphine relieves pain, that aspirin reduces a fever, that diuretics increase urinary output, or that penicillin cures syphilis. Drugs that are truly effective do not require controlled studies. Look at the new treatments for the acquired immunodeficiency syndrome, which are clearly effective without the benefit of RCTs. It is virtually axiomatic that the effectiveness of a treatment is inversely proportional to the number of controlled
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3105-0021$3.00/0
studies that surround it. Consider oncology: one oncology group can devise more RCTs than scores of cardiology divisions, and cardiologists are not slouches when it comes to RCTs. We are inundated with pronunciamentos declaring the effectiveness of myriads of new treatments for breast cancer as well as the need for evermore early diagnosis of it, yet age-adjusted mortality for the disease hasn’t changed since 1930.4 Scores of RCTs have proved that early diagnosis and treatment of breast cancer prolong life, yet life has not been prolonged. Fire the statisticians for not getting the annual mortality data right. With respect to hypertension, one cannot say based on RCTs that the initial treatment of hypertension with an ACE inhibitor (and a diuretic if needed) will have an effect on morbidity and mortality that is as beneficial as the combination of a diuretic and a -blocker. However, the beneficial effects of ACE inhibitors on the heart, the kidney, and even the eye5 are so pronounced and the incidence of their side effects so low that it seems more than reasonable to use them as an initial treatment of uncomplicated hypertension. The only reason not to is that they are clearly more expensive than diuretics and -blockers. Physicians seem to have made up their minds about the beneficial effects of ACE inhibitors, based on what seems to be very good evidence. JNC-4 appeared to agree; JNC-5 and JNC-6 did not. What JNC-7 will decide, I do not know. RCTs clearly have their place, but the physician should not be their slave. —Neil A. Kurtzman, MD Editor-in-Chief REFERENCES 1. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: The sixth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 157:2413-2446, 1998 2. Siegel D, Lopez J: Trends in antihypertensive drug use in the United States. JAMA 278:1745-1748, 1997 3. Joint National Committee on Detection, Evaluation, and
EDITORIALS
Treatment of High Blood Pressure: The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 148:1023-1038, 1988 4. Landis SH, Murray T, Bolden F, Wright P: Cancer statistics, 1998. CA Cancer J Clin 48:6-29, 1998
867
5. Chaturvedi N, Sjolie A-K, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, Rogulja-Pepeonik Z, Fuller JH, and the EUCLID Study Group: Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. Lancet 351:28-31, 1998
More Dialysis Appears Beneficial for Pregnant ESRD Patients (at Least in Belgium) Related Articles, pp. 756 and 766
HE VERY detailed paper by Bagon et al1 from Belgium plus the report of the US registry by Okundaye et al,2 both of which appear in this issue, give some new insight into pregnancy during dialysis. It is also obvious that advantages exist in a small country (Belgium) versus a larger one (United States) when it comes to conducting national surveys. Belgium had a 100% response from its dialysis centers compared to only a 40% response rate in the US study. As the authors point out, marked improvement has been achieved in the results of patients who become pregnant after they are on dialysis. However, before we start doing infertility work-ups on all ESRD patients in their childbearing years, we need to recognize that because something can be done does not mean it should be done. For example, if a patient has a good chance to be transplanted, it is probably better to wait until after the transplant is successful before pursuing pregnancy. The reasons for this are at least threefold: ● Pregnancy posttransplant does not result in sensitization.3 ● Chances of a successful conception are much higher posttransplant.4 ● Fewer complications and/or birth abnormalities exist posttransplant.4 By contrast, if being pregnant during dialysis is the patient’s only chance to have a child, pregnancy should be considered with the recognition that it may not be successful or that there will be prematurity and perhaps fetal complications. Having considered these major problems, let me turn to what I find the most encouraging part of the Belgian study. The authors appear to show that if the amount of dialysis is increased by hours per week or Kt/V, birth weight improves. They interpret birth weight as a sign of less prematurity. This was supported by a similar but nonsignificant trend in the US data with better
T
infant survival in women dialyzed 20 or more hours per week.2 If we assume that more dialysis, as shown in Figure 4 of the Belgian paper, gives a higher birth weight and a longer gestational period, where does this leave us in countries that provide a standard payment for dialysis only three times a week? To answer this question, I called some highly placed sources at the US Health Care Financing Administration (HCFA). I explained that this information would soon be published and asked what their response would be if more frequent dialysis were ordered? Without making absolute commitments, they said the following: ● They were not aware of ever receiving a request for more frequent dialysis due to pregnancy in an ESRD patient. ● If acceptable scientific evidence exists, they do not see why payments for more frequent dialysis could not be covered. (One needs to realize this would be a rather rare request and would extend for only 10 to 15 weeks from the recognition of pregnancy until delivery at about 32 weeks.) ● The gate appears to be open. To go through that gate, however, one presumably would have to present the data from the two articles in this issue and hope for payment. I believe the articles in this month’s American Journal of Kidney Diseases show that a viable pregnancy is possible 50% of the time if additional dialysis is delivered. I would, however, recommend (pregnancy) during dialysis only if the patient could not receive a transplant. We need to remember that birth is merely the start of a long new journey. No studies exist that I am aware of to show how these children do longterm. Such studies need to be undertaken from this current base. —Alan R. Hull, MD Dallas Nephrology Associates Dallas, TX r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3105-0019$3.00/0
American Journal of Kidney Diseases, Vol 31, No 5 (May), 1998: pp 863-867
863
864
EDITORIALS
REFERENCES 1. Bagon JA, Vernaeve H, De Muylder X, Lafontaine J-J, Martens J, Roost GV: Pregnancy and dialysis. Am J Kidney Dis 31:756-765, 1998 2. Okundaye I, Abrinko P, Hou S: Registry of pregnancy in dialysis patients. Am J Kidney Dis 31:766-773, 1998
3. Sanfilippo F, Vaughn WK, Bollinger RR, Spees EK: Comparative effects of pregnancy, transfusion, and prior graft rejection on sensitization and renal transplant results. Transplantation 34:360-366, 1982 4. Davison JM: Dialysis, transplantation, and pregnancy. Am J Kidney Dis 17:127-132, 1991
New JNC-6 Guidelines
T
HE ALGORITHM for therapy of hypertension in the sixth report of the Joint National Committee (JNC-6)1 starts with lifestyle modifications alone for those patients at relatively low overall risk for cardiovascular-renal diseases and with drugs for those at higher risk. If lifestyle modifications are not sufficient to bring the blood pressure to below 140/90 mm Hg, three suggested pathways for the initial choice of therapy are as follows: 1. Diuretics or beta-blockers for those with uncomplicated hypertension. 2. Angiotensin-converting enzyme (ACE) inhibitors for diabetic patients with proteinuria; ACE and diuretics for patients with heart failure; -blockers and, if systolic dysfunction is present, ACE inhibitors after a heart attack; and diuretics or long-acting dihydropyridine calcium antagonists for systolic hypertension in the elderly. 3. Certain drugs that are not compelling but that provide favorable effects on concomitant conditions, such as an ␣-blocker for prostatism or a diuretic with osteoporosis. The latter recommendations are not supported by hard evidence from randomized controlled trials (RCTs), as are the first two recommendations, but they are supported by a great deal of clinical experience. The recommendation for diuretics or -blockers for uncomplicated hypertension in patients younger than 65 years is firmly based in evidence from multiple RCTs.2 Whether other choices will do as well will hopefully be known when some of the 30ⴙ comparative trials now in process are completed. The compelling indications are generally well r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3105-0020$3.00/0
recognized to be based on data from RCTs. The only exception may be the recommendation that if diuretics are not adequate or appropriate, a long-acting dihydropyridine calcium antagonist be used for elderly patients with systolic hypertension. That recommendation is based primarily on the recently published SYST-EUR trial3 in which almost 5,000 patients older than 60 years were given either placebo or a drug regimen based on the long-acting dihydropyridine calcium antagonist nitrendipine, starting with one 10 mg dose per day and increasing if needed to 20 to 40 mg in two doses a day in addition to an ACE inhibitor or a diuretic. Over a very short follow-up period averaging 2 years, patients given nitrendipine (the only drug needed in G60% of the patients) had a highly significant 42% reduction in strokes and a 26% reduction in cardiac end points (although the reductions in heart failure [29%] and myocardial infarction [30%] did not reach statistical significance). These data go along with a less well-controlled study from China in which long-acting nifedipine also reduced strokes in elderly patients with isolated systolic hypertension (ISH).4 In addition to studies with other long-acting dihydropyridines in heart failure in which coronary mortality was reduced,5,6 these data should allay the concerns that arose from the recognition that large doses of short-acting nifedipine increased mortality in postmyocardial infarction patients.7 Since nitrendipine, the calcium channel blocker (CCB) used in the SYST-EUR trial, is not marketed in the United States, JNC-6 recommends that the other available long-acting dihydropyridines be used. It should be noted that the nondihydropyridines diltiazem and verapamil and the new T-channel blocker mibefradil have not been
EDITORIALS
tested for primary protection; they are therefore not included in this ‘‘compelling’’ indication. The remainder of the algorithm fits prior JNC recommendations with the additional insistence that therapy be pushed to achieve the goal of blood pressure below 140/90 mm Hg. If that goal is not achieved with the first drug, usually titrated slowly up to a moderate dose, either another drug should be substituted or, if it was not the first choice, a diuretic should be added. In my experience over the past few years, many practitioners, including a few nephrologists, have dropped diuretics altogether or given woefully inadequate single daily doses of furosemide, a practice that may be even worse than prescribing no diuretic at all, since the practitioner may be misled into believing that the few hours of volume contraction provided by furosemide should be all that is needed to control hypertension.8 Regardless of the reasons why diuretics have been downplayed, their use is often essential, even more so in those hypertensive patients with renal insufficiency often seen by nephrologists. If the blood pressure remains uncontrolled after the administration of multiple drugs, referral to a ‘‘hypertension specialist’’ is recommended. At present, that individual is not identifiable other than by colleagues who know of the expertise of some practitioners in dealing with difficult hypertension. The American Society of Hypertension has begun an accrediting process, grandfathering those now so recognized and credentialing others through courses and an examination. JNC-6 provides appropriate recommendations for the treatment of hypertension, recommendations that are both evidence based and up to date. As more evidence becomes available, some of these recommendations may need to be changed; however, for now, they are appropriate. Lest practitioners be concerned that these guidelines will constrain their personal choices, recall the opening statement in JNC-61: ‘‘The committee recognizes that the responsible clinician’s judgement of the individual patient’s needs
865
remains paramount. Therefore, [these] guidelines should serve as a tool to be adapted and implemented in local and individual situations.’’ If used as intended, JNC-6 will prove helpful to all who provide care for hypertensive patients. —Norman M. Kaplan, MD Professor of Internal Medicine UT Southwestern Medical Center at Dallas Dallas, TX REFERENCES 1. Joint National Committee: The sixth report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure. Arch Intern Med 57:2413-2446, 1998 2. Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, Lemaitre RN, Wagner EH, Furberg CD: Health outcomes associated with antihypertensive therapies used as first-line agents: A systematic review and meta-analysis. JAMA 277:739-745, 1997 3. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 350:757-764, 1997 4. Gong L, Zhang W, Zhu Y, Kong D, Pag V, Ghadirian P, LeLorier J, Hamet P: Shanghai trial of nifedipine in the elderly (STONE). J Hypertens 14:1237-1245, 1996 5. Packer M, O’Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, Miller AB, Neuberg GW, Frid D, Wertheimer JH, Cropp AB, DeMets DL: Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective randomized amlodipine survival evaluation study group. N Engl J Med 335:1107-1114, 1996 6. Cohn JN, Ziesche S, Smith R, Anand I, Dunkman WB, Loeb H, Cintron G, Boden W, Baruch L, Rochin P, Loss L: Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Circulation 96:856-863, 1997 7. Furberg CD, Psaty BM, Meyer JV: Nifedipine: Doserelated increase in mortality in patients with coronary heart disease. Circulation 92:1326-1331, 1995 8. Kaplan NM: Treatment of hypertension: Drug therapy, in Clinical Hypertension (ed 7). Baltimore, MD, Williams & Wilkins, 1998, pp 181-263
866
EDITORIALS
JNC Redux ‘‘Who are you going to believe? Me or your own eyes?’’ —Groucho Marx
T
HE SIXTH REPORT of the Joint National Committee (JNC-6)1 appeared just about the same time that Siegel and Lopez2 reported in the Journal of the American Medical Association that nobody had listened to the previous set of guidelines. It seems highly likely that the response to this new set will be equally underwhelming. Why? Ignorance of the guidelines is one possibility. Another is that physicians don’t find them and the evidence they are based on persuasive. The report recommends (as did the previous one) diuretics and -blockers for the initial treatment of uncomplicated hypertension. The data show that this combination is effective in reducing morbidity and mortality from hypertension. Compared with what? With diuretics and angiotensin-converting enzyme (ACE) inhibitors? No, that comparison has not been made. Furthermore, many physicians remembered that JNC-43 allowed ACE inhibitors and calcium channel blockers as first-choice drugs. Apparently, between their fourth and fifth advisories, the hypertension experts decided that they should be bound by the limits of randomized controlled trials (RCTs). It is useful to reflect on what an RCT tells us. It differentiates between a treatment that doesn’t work and one that barely works and between treatments that differ very slightly. If the treatment is a great advance, its effect is so obvious that an RCT is not necessary. No one ever conducted a controlled study to determine that insulin lowers blood sugar, that morphine relieves pain, that aspirin reduces a fever, that diuretics increase urinary output, or that penicillin cures syphilis. Drugs that are truly effective do not require controlled studies. Look at the new treatments for the acquired immunodeficiency syndrome, which are clearly effective without the benefit of RCTs. It is virtually axiomatic that the effectiveness of a treatment is inversely proportional to the number of controlled
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3105-0021$3.00/0
studies that surround it. Consider oncology: one oncology group can devise more RCTs than scores of cardiology divisions, and cardiologists are not slouches when it comes to RCTs. We are inundated with pronunciamentos declaring the effectiveness of myriads of new treatments for breast cancer as well as the need for evermore early diagnosis of it, yet age-adjusted mortality for the disease hasn’t changed since 1930.4 Scores of RCTs have proved that early diagnosis and treatment of breast cancer prolong life, yet life has not been prolonged. Fire the statisticians for not getting the annual mortality data right. With respect to hypertension, one cannot say based on RCTs that the initial treatment of hypertension with an ACE inhibitor (and a diuretic if needed) will have an effect on morbidity and mortality that is as beneficial as the combination of a diuretic and a -blocker. However, the beneficial effects of ACE inhibitors on the heart, the kidney, and even the eye5 are so pronounced and the incidence of their side effects so low that it seems more than reasonable to use them as an initial treatment of uncomplicated hypertension. The only reason not to is that they are clearly more expensive than diuretics and -blockers. Physicians seem to have made up their minds about the beneficial effects of ACE inhibitors, based on what seems to be very good evidence. JNC-4 appeared to agree; JNC-5 and JNC-6 did not. What JNC-7 will decide, I do not know. RCTs clearly have their place, but the physician should not be their slave. —Neil A. Kurtzman, MD Editor-in-Chief REFERENCES 1. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: The sixth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 157:2413-2446, 1998 2. Siegel D, Lopez J: Trends in antihypertensive drug use in the United States. JAMA 278:1745-1748, 1997 3. Joint National Committee on Detection, Evaluation, and
EDITORIALS
Treatment of High Blood Pressure: The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 148:1023-1038, 1988 4. Landis SH, Murray T, Bolden F, Wright P: Cancer statistics, 1998. CA Cancer J Clin 48:6-29, 1998
867
5. Chaturvedi N, Sjolie A-K, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, Rogulja-Pepeonik Z, Fuller JH, and the EUCLID Study Group: Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. Lancet 351:28-31, 1998