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Clinical Perspectives
ambulatory blood pressure readings are several beneficial in the elderly[11,12,25], making it important
mmHg lower than clinical blood pressures. Echocar- to screen for hypertension in this age group. The
diography can be useful since if left ventricular hyper- SHEP study evaluated patients aged over 60 years,
trophy is detected it places the patient in a higher risk the MRC studied patients aged 6574 years and the
group[22] and strongly favours the case of antihyper- STOP-Hypertension study patients aged 7084 years.
tensive therapy. Unfortunately electrocardiography, All demonstrated a reduction in cardiovascular mor-
although more widely available, is very insensitive for bidity or mortality in the actively treated group. It
detecting left ventricular hypertrophy[23] and so is should be appreciated, however, that the patients
often unhelpful in stratifying patients. Echocardiog- enrolled in these studies in general were fit elderly.
raphy is, unfortunately, still not widely available for Although the STOP-Hypertension study included
routine use in assessing suspected hypertensives. patients in their eighties, there remains uncertainty
Once a diagnosis of mild or borderline hyper- about whether the very elderly benefit from treat-
tension is made treatment dilemmas may follow. ment. The SHEP and MRC study suggested that
Although patients with diastolic blood pressures in treating isolated systolic hypertension (systolic blood
the range of 9099 mmHg have been found to benefit pressure >160 mmHg and diastolic blood pressure
from anti-hypertensive therapy, the magnitude of such <90 mmHg) was beneficial in this group of patients.
benefit is small and relates largely to the reduction in Therefore in patients in their 60s and 70s there is
the rate of stroke[7]. Some patients are not convinced convincing evidence that treatment of systolic blood
about the need for lifelong anti-hypertensive therapy pressure >160 mmHg and/or diastolic blood pressure
for such mildly elevated blood pressure values, >90 mmHg is beneficial. One complication is that in
especially if they are aware that their blood pressure is the elderly the frequency of drug side effects is higher.
higher when seen by a doctor than at other times. An In addition, with stiffer arteries there may be an
ambulatory blood pressure monitoring convincingly exaggerated alerting response to the clinic setting, so
demonstrating an elevated average blood pressure the argument for use of ambulatory blood pressure
level will often be helpful in supporting advice for the monitoring to confirm hypertension is even more
need to treat. It is important to stress, however, that cogent in the elderly population.
hypertension should not be assessed in isolation of
other cardiovascular risk factors. The presence of
other risk factors, such as advanced age, male sex, Secondary hypertension
smoking, hyperlipidaemia, diabetes mellitus or a
family history of cardiovascular disease argues for the Although the vast majority of cases of hypertension
recommendation of anti-hypertensive therapy more are essential, a variety of diseases can cause raised
rigorously and at lower thresholds, as does the pres- blood pressure. Most estimates place the prevalence
ence of end-organ damage, e.g. renal failure or left of secondary hypertension at less than 5% of an
ventricular hypertrophy. Many experts argue that the unselected hypertensive population, with renal dis-
thresholds for anti-hypertensive treatment should be ease being by far the most common. Most can be
a full 5 mmHg lower in diabetics. easily detected, but there remains a difficult 1% or so
If a decision is made not to treat a mild in whom special testing may be necessary to detect
hypertensive with drugs it is important that the blood the underlying cause and no consensus exists to guide
pressure is closely monitored. Additionally, lifestyle the clinician as to when or how he or she should look
advice is mandatory, as it should be for all hyperten- for an underlying cause. This is an area in which
sive patients. Reducing salt (and calorie, if over- evidence-based medicine is lacking to guide practice,
weight) intake, avoiding excessive alcohol, cessation and yet we all have to face this problem regularly. At
of smoking, avoiding a high saturated fat intake and what age and in what circumstances is special testing
taking regular exercise are all recommended[24]. required? History and examination may give clues to
the presence of an underlying disease such as renal
failure, renovascular disease, hyperaldosteronism,
Hypertension in the elderly phaeochromocytoma or aortic coarctation. Other
suggestive factors are early age of onset, lack of
Elderly patients are particularly important because family history, unusual course, early complications,
they have a very high prevalence of hypertension and or resistance to therapy. The use of ambulatory blood
a high absolute risk of cardiovascular complications. pressure monitoring can also give clues to the possi-
Earlier treatment studies had been based on middle- bility of secondary hypertension as detailed below.
aged subjects. However, more recent studies have Causes of secondary hypertension can be grouped
confirmed that blood pressure lowering is also into categories:
v Drug induced: cocaine, cyclosporin, erythro- 2. Chest X-ray: for coarctation, cardiomegaly.
poietin, non-steroidals, licorice derivatives, 3. Fundoscopy.
sympathomimetics, some antidepressants, oestro- 4. ECG.
gens and excess sodium chloride can all cause 5. Echocardiography would be very helpful but at
hypertension[26]. the moment it is not sufficiently available to be
v Renal disorders: chronic renal failure, nephritis, used in all subjects.
papillary necrosis, renovascular disease, renal tu- 6. Ambulatory blood pressure monitoring: this
mours and infections can all cause hypertension, should be considered in all hypertensives, as it
and renal function testing and imaging are import- can confirm hypertension, accurately document
ant tests. the severity, detect white coat hypertension, and
v Endocrine cause: diabetes, thyroid disorder, phaeo- give a pointer to an increased possibility of
chromocytoma, Conns syndrome, Cushings secondary hypertension (absence of fall in blood
disease, SAME (syndrome of apparent mineralo- pressure at night).
corticoid excess), glucocorticoid resistance, ac- Some have argued that routine hypertensives
romegaly, and others can cause hypertension and should not be offered this test on the grounds of
an endocrine cause should always be considered cost, but given the implications of life-long anti-
if the course of the hypertension is unusual or if hypertensive therapy the cost of a decent initial
associated features suggest the possibility. assessment is small in comparison to the life-time cost
v Cardiovascular causes: coarctation, Takayasus of an inaccurate initial assessment.
and other arterial stenotic disorders are rare causes. When should further investigation be insti-
Certain patients are at particularly high risk of tuted? In the presence of abnormalities detected in the
a secondary cause of hypertension and warrant routine procedures above, in the presence of height-
specific investigation. Such routine screening for ened clinical suspicion (e.g. extensive peripheral vas-
secondary causes usually consists of renal ultrasonog- cular disease makes renovascular hypertension much
raphy, 24 h urinary collection for catecholamines, more likely) or in patients presenting with definite
electrolyte estimation, plasma renin and aldosterone hypertension under the age of 30 years. The exact
measurement and a test for renal artery stenosis. choice of tests to exclude the individual cause of
History and examination findings may point towards secondary hypertension depend on the cause of
performing one or more of these, or occasionally suspicion, the availability of local renal imaging
other investigations, such as cortisol, thyroid function modalities and the specifics of the case.
or other specific endocrine testing. In addition, an
increase in serum creatinine after commencing
angiotensin-converting enzyme inhibitors may Renovascular hypertension
prompt investigations for renovascular disease. Hy-
pertension that is resistant (poor blood pressure con- Renal artery stenosis is rare in patients with mild
trol while on three or more antihypertensive agents) hypertension without any suggestive clinical clues and
more frequently has an underlying cause as does high in these patients there is little point in further inves-
blood pressure occurring in the young, particularly tigation[27]. In contrast, some patients have a very
when there is no family history of hypertension. high prevalence of renal artery stenosis. This includes
Another feature more recently associated with an those with accelerated or malignant hypertension,
increased prevalence of secondary hypertension is the those with renal asymmetry detected on non-invasive
detection of an absent fall in blood pressure at night assessment and those whose renal function deterior-
during 24 h ambulatory blood pressure monitoring ates on an angiotensin-converting enzyme inhibi-
despite an apparently good nights sleep by diary tor[28]. In these patients it seems worth proceeding
entry. This latter finding is not diagnostic but it raises directly to renal angiography since a negative non-
the suspicion of secondary hypertension and should invasive test would not be sufficient adequately to
trigger further consideration of this possibility. exclude an underlying renal artery stenosis. It is in the
A working rule is that routine investigation in in-between group of patients that non-invasive assess-
all new hypertensives should include: ment, as a screening method for those that require
1. Urea and electrolytes before and after commenc- further assessment with angiography, is important.
ing antihypertensive therapy. This helps detect Before fully investigating for renovascular hyperten-
endocrine causes, e.g. low potassium in Conns, sion the question of whether its detection would alter
renal failure and renovascular hypertension patient management should be raised e.g. if blood
(increase in creatinine after commencing ACE pressure is adequately controlled on drug therapy in
inhibitor). an elderly patient is there any reason to attempt renal
artery revascularization if a diagnosis of renal artery diagnose and treat hypertension and when to initiate
stenosis is made? Good reasons to exclude the diag- investigation for secondary hypertension. It is
nosis include hypertension that is uncontrolled on important to remember, however, that hypertension
drug therapy, deteriorating renal function and inter- can no longer be treated as a single, isolated risk
mittent acute episodes of pulmonary oedema. Other factor. It is important to perform a full cardiovascu-
indications might include unacceptable side-effects lar risk factor profiling on all patients, including
with drug therapy and a young age when renal artery assessment of smoking status and serum cholesterol.
stenosis due to fibromuscular hyperplasia is relatively The aim of management should be to reduce the
more common. This type of pathology responds well overall risk of future cardiovascular events.
to percutaneous transluminal renal angioplasty and J. MAYET
intervention may prevent life-long drug therapy. A. J. S. COATS
There is no universally agreed age at which screening Imperial College of Science, Technology and Medicine,
for secondary causes should become routine; ages of at the National Heart and Lung Institute and Royal
under 20 and under 25 have both been suggested[27,28] Brompton Hospital
although we favour a high index of suspicion ap- London, U.K.
proach under the age of 30 years. The elderly have a
particularly high incidence of renovascular disease,
usually due to atheromatous disease, but again, this References
diagnosis is only worth pursuing if it will influence
clinical management. [1] Collins R, Peto R, McMahon S et al. Blood pressure, stroke
and coronary heart disease. Part 2, short-term reductions in
Where a non-invasive test is required to screen blood pressure: overview of randomised drug trials in their
a patient prior to possible angiography, the test used epidemiological context. Lancet 1990; 335: 82738.
will depend largely on local expertise. Intravenous [2] McMahon S, Peto R, Cutler J et al. Blood pressure, stroke
and coronary heart disease. Part 1, prolonged differences in
pyelography (sensitivity 75%, specificity 86%), plasma blood pressure: prospective observational studies corrected for
renin activity (sensitivity 5080%, specificity 84%), regression dilution bias. Lancet 1990; 335: 76574.
captopril plasma renin activity (sensitivity 74%, [3] Evans JG, Pose G. Hypertension. Br Med Bull 1971; 27:
3742.
specificity 89%), captopril renography (sensitivity
[4] Petrie JC, OBrien ET, Littler WA, de Swiet M. Blood
93%, specificity 95%), Doppler renal artery ultra- pressure measurement. London: Br Med J, 1987.
sonography (sensitivity 90%, specificity 9095%) and [5] OBrien E, Atkins N, Mee F, Coyle D, Syed S. A new
magnetic resonance angiography (sensitivity 9095%, audiovisual technique for recording blood pressure in re-
search? The sphygmocorder. J Hypertens 1995; 13: 17347.
specificity 95%) have all been used. The figures quoted [6] Smith TDW, Clayton D. Individual variation between general
are derived from a review by Mann and Pickering[27] practitioners in labelling of hypertension. Br Med J 1990; 300:
and are a summary of many studies. These studies 745.
[7] Medical Research Council Working Party. MRC trial of
however, usually occur in centres with expertise in this treatment of mild hypertension: principal results. Br Med J
area, and so may be different in the real world. 1985; 291: 97104.
[8] Veterans Administration Cooperative Study Group on Anti-
hypertensive Agents. Effects of treatment on morbidity in
Mineralocorticoid hypertension hypertension. II. Results in patients with diastolic blood
pressure averaging 90 through 114 mmHg. JAMA 1970; 213:
It has been appreciated recently that mineralocorti- 114352.
[9] Hypertension Detection and Follow-up Program Cooperative
coid associated hypertension is more common than Group. Five-year findings of the hypertension detection and
previously thought. Milder cases of hyperaldos- follow-up program. I. Reduction in mortality of persons with
teronism can be treated medically and can have well high blood pressure, including mild hypertension. JAMA
1979; 242: 256271.
controlled hypertension for many years with mild [10] Australian National Blood Pressure Management Committee.
hypokalaemia. There has been a profusion of infor- The Australian Therapeutic trial in mild hypertension. Lancet
mation of the molecular defects in rare forms of 1980; I: 12617.
mineralocorticoid associated hypertension and more [11] SHEP Cooperative Research Group. Prevention of stroke by
antihypertensive drug treatment in older persons with isolated
subtle derangements of the steroid pathways seem systolic hypertension. JAMA 1991; 265: 25564.
likely to account for a greater proportion of cases of [12] Medical Research Council Working Party. MRC trial of
hypertension when we investigate this area in greater treatment of hypertension in older adults: principal results. Br
Med J 1992; 304: 40512.
detail with newer techniques. [13] Kannel WB, Dawber TR, McGee DL. Perspectives on systolic
hypertension: the Framingham study. Circulation 1986; 61:
117982.
Conclusion [14] 1993 guidelines for the management of hypertension: memo-
randum from a World Health Organization/International
We have highlighted some of the difficult areas Society of Hypertension meeting. J Hypertens 1993; 11: 905
in hypertension management, especially when to 18.
[15] The fifth report of the Joint National Committee on detection, [23] Devereux RB, Koren MJ, De Simone G, Okin PM, Kligfield
evaluation, and treatment of high blood pressure (JNC V). P. Methods for detection of left ventricular hypertrophy:
Arch Intern Med 1993; 153: 15483. application to hypertensive heart disease. Eur Heart J1993; 14
[16] Pickering TG. Blood pressure measurement and detection of (Suppl D): 815.
hypertension. Lancet 1994; 344: 315. [24] Sever PS, Beevers G, Bulpitt C et al. Management guidelines
[17] Gosse P, Promax H, Durandet P, Clementy J. White coat in essential hypertension: report of the second working part
hypertension: no harm for the heart. Hypertension 1993; 22: of the British Hypertension Society. Br Med J 1993; 306:
7669. 9837.
[18] Perloff D, Sokolow M, Cowan RM, Juster RP. Prognostic [25] Dahlof B, Lindholm LH, Hansson L, Scherston B, Ekbom T,
value of ambulatory blood pressure measurements: further Wester P-O. Morbidity and mortality in the Swedish Trial in
analyses. J Hypertens 1989; 7 (Suppl 3): S3S10. Old Patients with Hypertension (STOP-Hypertension). Lancet
[19] Verdecchia P, Porcellati C, Schillaci G et al. Ambulatory 1991; 338: 12815.
blood pressure: an independent predictor of prognosis in [26] Streeten DH, Anderson GH. Secondary hypertension. An
essential hypertension. Hypertension 1994; 24: 793801. overview of its causes and management. Drugs 1992; 43:
[20] Staessen JA, OBrien ET, Atkins N, Amery AK. Short report: 80519.
ambulatory blood pressure in normotensive compared with [27] Mann SJ, Pickering TG. Detection of renovascular hyperten-
hypertensive subjects. J Hypertens 1993; 11: 128997. sion. State of the art: 1992. Ann Intern Med 1992; 117:
[21] Coats AJS, Radaelli A, Clark SJ, Conway J, Sleight P. The 84553.
influence of ambulatory blood pressure monitoring on the [28] National High Blood Pressure Education Program Working
design and interpretation of trials in hypertension. J Hyper- Group. 1995 update of the working group reports on chronic
tens 1992; 10: 38591. renal failure and renovascular hypertension. Arch Intern Med
[22] Kannel WB. Left ventricular hypertrophy as a risk factor in 1996; 156: 193847.
arterial hypertension. Eur Heart J 1992; 13 (Suppl D): 828.
equally applicable to drug-treated and device-treated the number of expected deaths. Life-tables and
patients. We have offered suggestions for a more KaplanMeier curves only reflect the duration of
complicated description of events in implantable follow-up, the occurrence of death and time of cen-
cardioverter defibrillator patients[15], but complexity soring. There is no correction for the age at the time
creates a barrier, as in the case of other quoted of inclusion in the study. The standardized mortality
classification systems. If the code S14, D14 would ratio adjusts the mortality rate to eliminate the effects
limit the number of misclassifications to 5%[13], it of age, sex, and follow-up duration[28]. Thus, it con-
would be a handy tool in all trials and studies on tributes to a better comparison of outcomes in rand-
anti-arrhythmic treatment. omized and observational studies. It is a parameter to
be added to the standard patient characteristics, as
means and standard deviations of age and follow-up.
Survival analysis and other statistics in It is a pity that standard statistical packages do not
clinical medicine provide easy processing of the procedure.
are false positive errors that assign statistical benefit death[22,23]. Length and quality of life interfere with
to a given modality, when such benefit does not exist. cost/benefit considerations. In the MADIT patient
Type 2 errors are false negative errors: the observed population, the cost of implantable cardioverter de-
distinction is regarded as not significant (no benefit), fibrillator treatment per life-year saved was U.S.
whereas in reality a benefit exists. Type 2 errors can $27 000, and in the AVID study U.S. $114 000[35].
arise in circumstances in which the numbers of obser- Can survival and financial calculations ever
vations are too small: insufficient power of the study. offer a definite solution for individual patients in
Another report advocates type 3 and type 4 errors[31]. different socio-economic and philosophical back-
Type 3 errors are errors in which the risk of a given grounds? We believe not. We concur with Voltaire
medical or public health approach is under-estimated, that common sense is not so common, but the
undetected or not specifically sought, leading to an clinician hardly needs unbiased information, based
under-estimate of the risk-benefit balance. Type 4 on adequate and objective data analysis. The study of
errors arise because the risks of a given medical money is one in which complexity is used to disguise
intervention are over-estimated, leading to under-use truth or to evade it, but not to reveal it[36]. Let us
or abandonment of a useful intervention. It should be hope that clinical trials and practice will not suffer
emphasized that type 3 errors appear to be much from this syndrome, described by Galbraith[36].
more frequent than type 4 errors. This stems, in part, What should the practitioner do when a new
from the failure of medicine to establish effective treatment is described? The most concise answer
mechanisms for the rapid recognition and correction comes from Kassirer[37]. We cannot uncritically adopt
of errors. Most recorded medical history deals with the new strategy, but are obliged to use our inferential
triumphs of medicine. The disasters are usually in- skills to answer several questions. Is my patient
terred along with the victimpatients. The introduc- similar to the subjects studied? Is the magnitude of
tion into the field of anti-arrhythmic treatment, of the difference between the new treatment and the
notions as type 3 and type 4 errors, could offer existing one sufficient to justify a switch? Can the
interesting perspectives. results of the study be generalized to patients in my
Besides these classical errors, other misunder- practice and to the type and quality of care available
standings can arise from insufficient data analysis locally? Affirmative answers to these questions will
and/or presentation. Examples of these are: omission encourage a switch to the new therapy.
of simple absolute risks[23], omission of simple H. ECTOR
mortality data[11], conventional medical treatment H. HEIDBU } CHEL
without preset minimum requirements[21,32], one- F. VAN DE WERF
sided significance tests[22], inappropriate drug selec- University Hospital Gathuisberg
tion[11,33], and cumulation of results for different Leuven, Belgium
drugs in one group[11,21,34]. Discontinuation of anti-
arrhythmic drug treatment, especially when com-
pared to implantable cardioverter defibrillator References
therapy, can be a fatal error in high risk patient
groups. In the MADIT study[21,32], only 45% of the [1] Logan RL, Scott PJ. Uncertainty in clinical practice: impli-
cations for quality and costs of health care. Lancet 1996; 347:
patients with drug treatment were taking amiodarone 5958.
at the time of the last follow-up visit. Study medi- [2] Hellman S, Hellman DS. Problems of the randomized clinical
cation withdrawal in the placebo/amiodarone trial. N Engl J Med 1991; 324: 15859.
arm was 214/385% in EMIAT[23], 255/364% in [3] Ector H. Endpoints and trials: a matter of life and death.
PACE 1994; 17: 107981.
CAMIAT[22]. [4] Ector H, Rogers R, Rubens A, De Geest H. Classification of
death in patients under antiarrhythmic treatment. PACE
1993; 16: 22504.
[5] Epstein AE. AVID necessity. PACE 1993; 16: 17735.
Conclusions [6] Gottlieb SS. Dead is dead artificial definitions are no
substitute. Lancet 1997; 349: 6623.
The most provocative challenge in cardiology for the [7] Lewis JA, Machin D. Intention to treat who should use
next decade will be the attempt to delay sudden ITT? Br J Cancer 1993; 68: 64750.
[8] Sackett DL, Gent M. Controversy in counting and attrib-
death as long as possible. To replace this final event uting events in clinical trials. N Engl J Med 1979; 301:
by another terminal endpoint such as death from 141012.
heart failure, carcinoma, cerebrovascular accident, is [9] Epstein AE, Carlson MD, Fogoros RN, Higgins SL, Venditti
not at all attractive. The implantable cardiac de- FJ. Classification of death in antiarrhythmic trials. J Am Coll
Cardiol 1996; 27: 43342.
fibrillators cut deaths[34], by reverting sudden ar- [10] Kim SG, Fogoros RN, Furman S, Connolly SJ, Kuck KH,
rhythmic death. Amiodarone can prevent arrhythmic Moss AJ. Standardized reporting of ICD patient outcome: the
report of a North American Society of Pacing and Electro- frequent or repetitive ventricular premature depolarizations:
physiology Policy conference, February 910, 1993. PACE CAMIAT. Lancet 1997; 349: 67582.
1993; 16: 135862. [23] Julian DG, Camm AJ, Frangin G. et al. Randomized trial of
[11] Echt DS, Liebson PR, Mitchell LB et al. Mortality and effect of amiodarone on mortality in patients with left-
morbidity in patients receiving encainide, flecainide, or pla- ventricular dysfunction after recent myocardial infarction:
cebo. The cardiac arrhythmia suppression trial. N Engl J Med EMIAT. Lancet 1997; 349: 66774.
1991; 324: 7818. [24] Lee ET. Statistical methods for survival analysis, 2nd edn.
[12] Greene HL, Richardson DW, Barker AH et al.Classification New York: John Wiley & Sons, Inc., 1992 .
of deaths after myocardial infarction as arrhythmic or non- [25] Cox DR, Oakes D. Analysis of survival data. London,
arrhythmic (the cardiac arrhythmia pilot study). Am J Cardiol England: Chapman & Hall, 1992.
1989; 63: 16. [26] Whitehead J. The design and analysis of sequential clinical
[13] Hinkle Jr LE, Thaler HT. Clinical classification of cardiac trials, 2nd edn. Chichester, England: Ellis Horwood Limited,
deaths. Circulation 1982; 65: 45764. 1992 .
[14] Rogers R, Ector H, Rubens A, Timmermans C, Heidbuchel [27] Gardner MJ, Altman DG. Statistics with confidence. London,
H, De Geest H. Classification of death in patients England: British Medical Journal, 1989 .
under antiarrhythmic treatment. In: Aubert AE, Ector H, [28] Ector H, Jordaens L, Vanhaecke J. Survival analysis and
Stroobandt R, eds. Cardiac Pacing and Electrophysiology. clinical medicine. An observational comparison of the im-
Dodrecht, The Netherlands: Kluwer Academic Publishers, plantable cardioverter defibrillator, amiodarone treatment,
1994: 4148 . and heart transplantation. Eur Heart J 1996; 17: 14447.
[15] Ector H. Endpoints and trials: a matter of life and death. [29] Yusuf S, Garg R, Zucker D. Analyses by the intention-to-
Classification of death in patients under antiarrhythmic treat- treat principle in randomized trials and databases. PACE
ment. In: Oto AM, ed. Practice and Progress in Cardiac 1991; 14: 207882.
Pacing and Electrophysiology. Dordrecht, The Netherlands: [30] Fischer LD, Dixon DO, Herson J, Frankowski RK, Hearson
Kluwer Academic Publishers, 1996: 15 . MS, Peace KE. Intention to treat in clinical trials. In: Peace
[16] The Criteria Committee of the New York Heart Association. KE, ed. Statistical issues in drug research and development.
Nomenclature and Criteria for Diagnosis of Diseases of the New York: Marcel Dekker, 1990: 33150..
Heart and Great Vessels. Boston: Little, Brown and Com- [31] Robin ED, Lewiston NJ. Type 3 and type 4 errors in the
pany, 1973: 286 . statistical evaluation of clinical trials. Chest 1990; 98: 4635.
[17] Lown B, Wolf M. Approaches to sudden death from coronary [32] Friedman PL, Stevenson WG. Unsustained ventricular
heart disease. Circulation 1971; 44: 13042. tachycardia to treat or not to treat. N Engl J Med 1996;
[18] Lown B. Sudden cardiac death 1978. Circulation 1979; 60: 335: 19845.
15939. [33] Mason JW. A comparison of seven antiarrhythmic drugs in
[19] Passamani E. Clinical trials, are they ethical? N Engl J Med patients with ventricular tachyarrhythmias. N Engl J Med
1991; 324: 158992. 1993; 329: 4528.
[20] Feinstein AR. The limitations of randomized trials. Ann [34] McCarthy M. Implantable cardiac defibrillators cut deaths.
Intern Med 1983; 99: 54450. Lancet 1997; 349: 1225.
[21] Moss AJ, Hall WJ, Cannom DS et al. Improved survival with [35] Muschlin AI, Zipes DP. NASPE 18th Annual Scientific Ses-
an implanted debrillator in patients with coronary disease at sions, New Orleans, May 710, 1997.
high risk for ventricular arrhythmia. N Engl J Med 1996; 335: [36] Galbraith JK. Money. Whence it came, where it went. New
193340. York: Bantam Books, 1975: 6 .
[22] Cairns JA, Connolly SJ, Roberts R, Gent M. Randomized [37] Kassirer JP. Clinical trials and meta-analysis. What do they
trial of outcome after myocardial infarction in patients with do for us. N Engl J Med 1992; 327: 2734.