Dr Levitt has raised a valuable point that the risk benefit
relationship of aspirin may vary with age as well as CHD risk and it is
worth re-evaluating the conclusions made in our paper [1].
He has however misunderstood the way in which we calculated benefit
from aspirin treatment. Because haemorrhagic strokes were not always
reported separately they had to be included in cardiovascular e...
Dr Levitt has raised a valuable point that the risk benefit
relationship of aspirin may vary with age as well as CHD risk and it is
worth re-evaluating the conclusions made in our paper [1].
He has however misunderstood the way in which we calculated benefit
from aspirin treatment. Because haemorrhagic strokes were not always
reported separately they had to be included in cardiovascular events along
with other causes of stroke and myocardial infarction (MI) when
calculating the benefit from aspirin treatment. Thus any increased risk
of haemorrhagic strokes in subjects treated with aspirin would be evident
as a diminution of observed relative risk reduction. If there is a marked
increase in aspirin induced haemorrhagic stroke with age this should be
seen as a variation in relative risk reduction with age. It is possible
that an increased risk of stroke could be offset by greater prevention of
MI in older people as seen in the US doctors study [2] but not the
Thrombosis Prevention Trial [3]. Overall there appears to be no
consistent variation in relative risk reduction with age when stroke and
MI are considered together [3, 4].
The evidence that the risk of extracranial bleeding caused by non-
steroidal anti-inflammatory drugs increases with age is stronger [5]. The
bulk of the patients in the studies from which we estimated the risk of
bleeding were in the age range 40 - 75 years. The Framingham study
excluded subjects above 75 years and risk estimation tools such as our
Table, based on Framingham, cannot be used to estimate risk for this age
group. Thus we are unable to make recommendations about aspirin use for
patients greater than 75 years of age. Within the age range 40 - 75 there
may well still be a gradient of risk of aspirin induced haemorrhage with
age [5] and use of a single figure may underestimate risk in older
subjects but overestimate it for younger subjects. Our analysis was
extremely conservative and, even allowing for an underestimate of risk of
extracranial bleeding in older subjects by 100% [5], a coronary heart
disease (CHD) event risk threshold for aspirin use of 1.5% per annum (15%
per 10 years) will still be above the upper 95% CI for the point at which
the benefit from aspirin in preventing CHD exceeds possible harm. For
younger subjects the point of intersection between the lines predicting
harm and benefit from aspirin treatment may occur at a lower CHD risk than
that indicated in our paper. The size of the absolute benefit achieved by
aspirin treatment at these low levels of CHD risk would be very small.
Regardless of the magnitude of the risk of haemorrhage, at CHD risk of 15%
over 10 years the NNT to prevent 1 MI is 44 over 5 years and treatment of
people with lower CHD risk may not be considered worthwhile.
Thus although the risk-benefit relationship of aspirin may well vary
with age as well as CHD risk we believe that benefit will outweigh harm
when the CHD risk is greater than 15% over 10 years in people up to 75
years of age. In younger people the safety of aspirin treatment may be
greater but it is still unlikely to be worthwhile until the risk of CHD
exceeds 15% over 10 years.
P R Jackson
References
(1) Sanmuganathan PS, Ghahramani P, Jackson PR et al Aspirin for primary
prevention of coronary heart disease: safety and absolute benefit related
to coronary risk derived from meta-analysis of randomised trials. Heart
2001;85:265-71.
(2) Steering Committee of the Physicians Health Study Research Group.
Final report on the aspirin component of the ongoing Physicians Health
Study. New Engl J Med 1989;321:129-35.
(3) Determination of who may derive most benefit from aspirin in primary
prevention: subgroup results from a randomised controlled trial. BMJ
2000;321:13-17.
(4) Kjeldsen SE, Kolloch RE, Leonetti G et al. Influence of gender and
age on preventing cardiovascular disease by antihypertensive treatment and
acetylsalicylic acid. The HOT study. J Hypertens 2000;18:629-42.
(5) McDonald TM, Morant SV, Robinson GC, Shield MJ, McGilchrist MM, Murray
FE, McDevitt DG. Association of upper gastrointestinal toxicity of non-
steroidal anti-inflammatory drugs with continued exposure: a cohort study.
BMJ 1997;315:1333-7.
Robin Norris and the SHARP Investigators are to be congratulated on
another study that is full of interest [1]. The new performance indicator
proposed is, indeed, very attractive. Quite correctly, the number of lives
saved by hospital thrombolysis is calculated using the figure of 30/1000
derived from hospital trials. But there is one point on which I must take
issue, and that is the additional life-saving fr...
Robin Norris and the SHARP Investigators are to be congratulated on
another study that is full of interest [1]. The new performance indicator
proposed is, indeed, very attractive. Quite correctly, the number of lives
saved by hospital thrombolysis is calculated using the figure of 30/1000
derived from hospital trials. But there is one point on which I must take
issue, and that is the additional life-saving from earlier thrombolysis.
Norris concludes that there is negligible (1.6/1000/h) benefit from
earlier thrombolysis, and thus makes no mention of the potential value of
prehospital thrombolysis. There is, however, a very serious methodological
flaw in estimating the time-related benefit from retrospective analysis of
hospital trials of thrombolysis versus placebo. In short, the sickest
patients get the earliest treatment, and the benefit of giving earlier
treatment is masked [2,3]. The only valid way of quantifying the time-
related benefit is by comparing prehospital with hospital treatment in a
randomised trial. Boersma [4] gives a meta-analysis of 8 such trials and
concludes that the benefit is 21/1000/h, more than 10 times greater than
the FTT estimate. More recently Morrison [5] has published a meta-analysis
of 6 of the 8 trials included by Boersma, and comes up with virtually the
same value of 2%/h.
The 60-minute call to needle standard in the National Service
Framework for coronary heart disease takes account of this evidence.
Although the NSF leaves open the question of how the standard is to be
achieved, the emphasis is necessarily shifting to prehospital
administration. In SHARP, in four self-selected, well-motivated hospitals,
only 51% of call to needle times were within 90 minutes, and thus a
minority would have been less than 60 minutes, and in 15 UK hospitals only
15% were within 60 minutes [6]. A different strategy from scoop and run to
the nearest hospital is clearly needed.
(1) Norris RM, on behalf of the Southern Heart Attack Response Project
(SHARP) Investigators. A new performance indicator for acute myocardial
infarction. Heart 2001;85:395-401.
(2) Rawles J. Problems in quantifying the benefit of earlier thrombolysis
in acute myocardial infarction. Pharmaceutical Medicine 1995;9:105-13.
(3) Rawles J. What is the likely benefit of earlier thrombolysis? Eur Heart
J 1996;17:991-5.
(4) Boersma E, Maas ACP, Simoons ML. Early thrombolytic treatment in acute
myocardial infarction: reappraisal of the golden hour. Lancet 1996;348:771
-5.
(5) Morrison LJ, Verbeek PR, McDonald AC, Sawadsky BV, Cook DJ. Mortality
and prehospital thrombolysis for acute myocardial infarction. A meta-
analysis. JAMA 2000;283:2686-92.
(6) Birkhead JS, on behalf of the Myocardial Infarction Audit Group. Trends
in the provision of thrombolytic treatment between 1993 and 1997. Heart
1999;82:438-42.
It seems that there is a potential flaw in the analysis by
Sanmuganathan, et al (1), of the relative risk benefit ratio in the use of
aspirin for the primary prevention of coronary artery disease. The
coronary risks are calculated using tables in which age is a major
determinant, but the risks of a bleeding complication are averaged over
all ages. Since bleeding complicat...
It seems that there is a potential flaw in the analysis by
Sanmuganathan, et al (1), of the relative risk benefit ratio in the use of
aspirin for the primary prevention of coronary artery disease. The
coronary risks are calculated using tables in which age is a major
determinant, but the risks of a bleeding complication are averaged over
all ages. Since bleeding complications almost certainly increase with
age, this would have the net effect of over-estimating the dangers of
aspirin use in younger patients, and under-estimating them in older ones.
For example, the study assumed an increased risk of hemorrhagic
stroke among aspirin users of 0.039%/year, a value taken from a recent
meta-analysis by He et al (2). But table 4 of that meta-analysis records
a risk of 0.029% in those under 64 and of 0.110% in those 64 and older.
This was not statistically significant, presumably due to the small number
of events, but this almost 4-fold difference would certainly appear to be
of clinical significance.
Determining the effect of age on non-cerebral major bleeds in aspirin
users is difficult. None of the 4 studies cited in the article provide
any information on bleeding rates at various ages and the literature in
general on this subject seems rather sparse. One study which at least
alluded to age differences was the Stroke Prevention in Atrial
Fibrillation II Study (3) which noted that major hemorrhages occurred in
0.9% of aspirin users under the age of 75 and in 1.6% of those over 75.
Unfortunately, there was no control group and for reasons that are
unclear, the bleeding risk in this study was 5 to 10 times as great as the
4 studies referenced by Sanmuganathan.
In any case, it would appear that one needs a table of bleeding risk
at various ages before one can safely advise aspirin use in the elderly.
1. Sanmuganathan PS, Ghahramani P, Jackson PR, et al. Aspirin for
primary prevention of coronary heart disease: safety and absolute benefit
related to coronary risk derived from meta-analysis of randomised trials.
Heart 2001; 85:265-271.
2. He J, Whelton PK, Vu B, et al. Aspirin and risk of hemorrhagic
stroke. A meta-analysis of randomized controlled trials. JAMA 1998;
280:1930-1935.
3. Warfarin versus aspirin for prevention of thromboembolism in
atrial fibrillation: stroke prevention in atrial fibrillation II study.
Lancet 1994; 343:687-691.
As John Rawles states, the benefit of prehospital thrombolysis could
be much greater than the FTT estimate for hospital treated patients of 1.6
lives/1000 treated per hour of delay [1]. Indeed, the "golden hour" [2]
may even be extended to the "golden two hours" as Rawles' own seminal work
suggests [3]. The point we were trying to make in the SHARP report [4] was
that 30/1000 is the most that can be ex...
As John Rawles states, the benefit of prehospital thrombolysis could
be much greater than the FTT estimate for hospital treated patients of 1.6
lives/1000 treated per hour of delay [1]. Indeed, the "golden hour" [2]
may even be extended to the "golden two hours" as Rawles' own seminal work
suggests [3]. The point we were trying to make in the SHARP report [4] was
that 30/1000 is the most that can be expected when streptokinase is
administered in hospital. Reduction in "door to needle times", important
as this may be for the process of care, cannot improve outcomes to any
significant degree.
Achievement of the NSF standard of a 60-minute call to needle time
may again improve process rather than outcome because the major component
of delay is not the call to needle time but the onset to call time. We
should be persevering with public educational campaigns with the message
"Chest pain lasting longer than 15 minutes. Call 999 for the ambulance".
Such campaigns have been abandoned far too early in the past; as with
advice to stop smoking, this message needs constant repetition. If most
patients acted on this advice, pre-hospital thrombolytic treatment could
save many extra lives.
Robin Norris
(1) Fibrinolytic Therapy Trialists (FTT) Collaborative Group.
Indications for fibrinolytic therapy in suspected acute myocardial
infarction; collaborative overview of early mortality and major morbidity
results from all randomised trials of more than 1000 patients. Lancet
1994; 343: 311-22.
(2) Boersma E, Maas ACP, Simoons ML et al. Early thrombolytic treatment in
acute myocardial infarction; reappraisal of the Golden Hour Lancet.
1996;348: 771-5.
(3) Rawles J What is the likely benefit of earlier thrombolysis? Eur Heart
J 1996; 17: 991-5.
(4) Norris RM on behalf of the Southern Heart Attack Response Project
(SHARP} Investigators.A New Performance Indicator for Acute Myocardial
Infarction. Heart 2001; 85: 395-401.
Berry and McMurray (Heart 2001;85:e8) report three of four cases of
serious adverse events in association with spironolactone linked to the
non-specific symptom of diarrhoea. As cited, Professor McMurray many years
ago reported the renal adverse effects of "diarrhoea" induced volume
depletion in conjunction with ACE inhibition as a simple case study. I may
have misinterpreted the recent report but I...
Berry and McMurray (Heart 2001;85:e8) report three of four cases of
serious adverse events in association with spironolactone linked to the
non-specific symptom of diarrhoea. As cited, Professor McMurray many years
ago reported the renal adverse effects of "diarrhoea" induced volume
depletion in conjunction with ACE inhibition as a simple case study. I may
have misinterpreted the recent report but I believe that this earlier
interpretation (and not the one described in the above article) remains
the correct origin of "pathology" in this present case study series.
The authors appear to imply that Spironolactone per se causes drug-
induced diarrhoea. While it is reasonable to speculate on this on the
basis of their few cases, it is not at all easy to deduce such causality
in a small and heterogeneous population of patients with heart failure,
particularly in the patients treated here with several diuretics. The
reason that the BNF does not note diarrhoea (rather than non-specific
"gastro intestinal disturbance") as a side effect of spironolactone
treatment is because this is, as yet, is not an associated adverse event
attributable to drug treatment rather than confounding by association.
This can be checked with the Medicines Control Agency and the manufacturer
of the proprietary brand (GD Searle). Perhaps specific population data can
be derived to address this by use of large-scale prescription event
monitoring systems[1] but it is important to note that this is not yet an
accepted association nor do these case reports define it as such.
There are many who regard the effect of spironolactone in end stage
CHF as wholly related to "more effective" diuresis.[2] Yet sodium and
volume depletion can be fraught with danger for the few patients who
qualify for this additional treatment (i.e. those and only those who
fulfil RALES end stage severity), as is well illustrated by Berry and
McMurray's case reports. I believe the cases presented can all be
individually related to volume depletion related to well-recognised drug
interactions (NSAID) and or multiple diuretic treatments in combination
with end stage cardiac and cardio renal pathology. This is a problem that
we recently noted in the Journal[3] for others, who in contrast to Berry
and McMurray, were keen to promote an aggressive and largely unmonitored
combination diuretic treatment[4] previously shown to be a source of
difficulty in controlled hospital studies far less community use.[5] Berry
and McMurray are absolutely right to caution against the unbridled use of
Spironolactone. In the same way surely 45% of their routine cardiology
patient discharges do not fit the RALES criteria? How did that happen in
their own Department?
In summary the adverse events noted relate more generally to the
detrimental impact of multiple diuretic treatments on the kidneys and
critical electrolyte balance. They show clearly how lives can be lost
almost entirely due to these issues of drug selection. The relationship of
Spironolactone with drug induced intestinal dysfunction and therefore
secondary rather than primary drug related sodium and fluid loss is an
interesting one but one whose primary step is not proven nor explained
here. More obviously the adverse events relate to diuretic induced fluid
and electrolyte loss and are therefore an extension of predicted
pharmacological effect rather than any new and undefined effect although
this remains possible? The correct caution here is to select the
appropriate patients for Spironolactone and not to think of it as a "cure
all" at all stages of the heart failure syndrome, which it clearly is not.
Careful supervision of renal function is required for all CHF patients but
particularly those who require combination diuresis whether for defined
diuretic resistance, because of the severity of disease (RALES patient
group) or by default. Combination diuretic pharmacology is a very well-
researched topic[6] not helped by unrestricted drug prescription which
obviously even occurs in a specialist heart failure unit.
Robert J. MacFadyen, Cardiac Unit (7th Floor), Highland Acute
Hospitals NHS Trust, Old Perth Road, Inverness IV2 3UJ
References
(1) Evans JM, MacDonald TM. Record-linkage for pharmacovigilance in Scotland. Br J Clin Pharmacol 1999;47:105-10.
(2) Bauersachs J, Fraccarollo D, Ertl G, Gretz N, Wehling M, Christ M. Striking increase of natriuresis by low dose Spironolactone in congestive heart failure only in combination with ACE inhibition: mechanistic evidence to support RALES. Circulation 2000;102:2325-8.
(3) MacFadyen RJ, Struthers AD. Diuretic use and abuse in systolic cardiac failure: a recipe for renal impairment? Heart 2000;83:468.
(4) Broadley AJM, Marshall AJ. Self-administration of Metolazone reduces readmissions with decompensated congestive cardiac failure. Heart 1999;82:397-8.
(5) Channer KS, McLean KA, Lawson-Matthew P, Richardson M. Combination diuretic treatment in severe heart failure: a randomised controlled trial. Br Heart J 1994;71:146-50.
(6) Brater DC. Resistance to loop diuretics. Why to happens and what to do about it. Drugs 1985;30:427-43.
We thank Dr. MacFadyen for his thoughtful comments on our report.
We were trying to draw to readers' attention, our observations that severe
renal dysfunction and hyperkalaemia can occur when spironolactone is added
to conventional therapy (and other, non-heart failure, drugs) in "real"
patients with heart failure, a phenomenon not described in the carefully
selected RALES population. Interesting...
We thank Dr. MacFadyen for his thoughtful comments on our report.
We were trying to draw to readers' attention, our observations that severe
renal dysfunction and hyperkalaemia can occur when spironolactone is added
to conventional therapy (and other, non-heart failure, drugs) in "real"
patients with heart failure, a phenomenon not described in the carefully
selected RALES population. Interestingly, similar concerns were recently
aired at the Scientific Sessions of the American Heart Association [1].
While augmentation of diuresis may be the simple explanation for our
findings, it has been argued that low dose spironolactone does not induce
a diuresis and acts in other ways [2]. We also wished to specifically
report the occurrence of diarrhoea with spironolactone, a possible adverse
event that we have now seen in several patients and one which has occurred
with delayed spironolactone rechallenge in two. Consequently, we think
this is a real rather than false association. We are surprised that Dr.
MacFadyen is surprised by our rate of use of spironolactone. One of the
most common reasons for admission to our Cardiology ward is severe, end-
stage, chronic heart failure and treatment with low dose spironolactone is
indicated in these patients. We are glad, however, that he agrees that
very careful monitoring of renal function is mandatory in patients
starting spironolactone for heart failure.
Reference List
(1) Bozkurt B, Geraci JM, Knowlton AA. Spironolactone use in heart
failure: Spiraling out of control? Circulation 2000;102:2002.
(2) Cody RJ, Pitt B, Perez A, Bettman R. The benefit of spironolactone in
the RALES Trial is not primarily due to a diuretic effect. Journal of the
American College of Cardiology 2000;35:212A-.
Macleod and Davey Smith suggest that the association that we found between psychological characteristics, particularly obsessionality and the somatic symptoms of anxiety on the one hand and fatal IHD on the other [1] were due to confounding by socio-economic factors. They suggest that we should have shown estimates before and after adjustment for social class.
We did discuss the adjustment for social class in the paper and p...
Macleod and Davey Smith suggest that the association that we found between psychological characteristics, particularly obsessionality and the somatic symptoms of anxiety on the one hand and fatal IHD on the other [1] were due to confounding by socio-economic factors. They suggest that we should have shown estimates before and after adjustment for social class.
We did discuss the adjustment for social class in the paper and pointed out this had relatively little effect on the association. We now show the results unadjusted, adjusted for other potential confounding factors and after adjustment for these factors and social class to demonstrate this point.
Phobic anxiety
Obsessionality
Somatic complaint
Total
Unadjusted
RR (95% CI)
P value
1.06 (0.99–1.14)
p=0.08
1.10 (1.04–1.16)
p=0.001
1.14 (1.08–1.21)
p=0.0001
1.26 (1.09–1.45)
p=0.002
Adjusted for age, smoking, BMI,
fibrinogen, factor VII, sys BP and cholesterol
RR (95% CI)
P value
1.07 (0.99–1.15)
p=0.08
1.08 (1.02–1.15)
p=0.007
1.09 (1.02–1.15)
p=0.007
1.28 (1.09–1.50)
p=0.002
Adjusted for age, smoking, BMI,
fibrinogen, factor VII, sys BP, cholesterol and social class
RR (95% CI)
P value
1.07 (0.99–1.15)
p=0.10
1.08 (1.02–1.15)
p=0.009
1.08 (1.02–1.15)
p=0.009
1.28 (1.09–1.50)
p=0.003
RR = Relative Risk of fatal IHD for a one point increase in each sub scale of the Crown Crisp Experiential Index and for a 10 point increase in the total score from Cox Model for fatal IHD.
Although the scores on a number of the sub-scales - phobic anxiety, obsessionality / obsessional neurosis and functional somatic complaint (physical symptoms of anxiety) - were significantly higher in those of lower social class the magnitude of the association was relatively small. For example, as we stated in the paper, the median score on the obsessionality /obsessional neurosis sub scale was 6 for men in social class ! and 7 for men in social class V. This is not to deny that poverty is a pervasive cause of ill-health or that public policies to reduce inequalities in health and wealth are to be commended [2]
All epidemiological studies are open to the possibility that associations may be due to residual confounding and ours in no exception. However, we think that socioeconomic differences are unlikely to be the explanation of the associations found in this case. Ultimately though the debate can only be settled by intervention studies. On this point both we and Macleod and Davey Smith are in agreement.
Andrew Haines
London School of Hygiene and Tropical Medicine
Jackie Cooper , T.W.Meade
MRC Epidemiology and Medical Care Unit , St Bartholomew's and the Royal London School of Medicine and Dentistry
References
(1) Haines A, Cooper, Meade TW Psychological characteristics and fatal ischaemic heart disease. Heart 2001;85:385-9
(2) Haines A. Heath I, Smith R. Joining together to combat poverty. BMJ 2000, 320: 1-2
Haines and colleagues present a further example from observational
epidemiology of an association between a psychosocial factor and
cardiovascular health (1). They suggest that this association is likely to
be causal - a suggestion apparently accepted by the popular press in their
reporting of this research (2).
However, given the non-specificity of the association between a range
of such factor...
Haines and colleagues present a further example from observational
epidemiology of an association between a psychosocial factor and
cardiovascular health (1). They suggest that this association is likely to
be causal - a suggestion apparently accepted by the popular press in their
reporting of this research (2).
However, given the non-specificity of the association between a range
of such factors - broadly those with a negative social connotation - and
an equally diverse group of pathological outcomes (3,4,5), some scepticism
seems appropriate. There are alternative explanations for these
relationships. The authors do not discuss an important one of these. In
their study, as with every published study that has reported such
relationships, adverse exposure in relation to the psychosocial factor was
associated with general social disadvantage. Adverse social position is
associated with poorer health thus a confounded, non-causal association
between any factor associated with adverse social position and poorer
health is to be expected (6). Furthermore since it is accepted that all
indices of social position, such as occupational class, are relatively
crude, adjustment for them in multivariate models may have little
influence (7,8). In their paper, Haines and colleagues do not show
estimates before and after adjustment for social class. Instead they show
fully adjusted estimates and since these are still conventionally
significant conclude that effects are independent of the adjustment
factors.
There is a political attractiveness to psychosocial, as opposed to
material, explanations for social inequalities in health. Such
explanations put responsibility at the level of the individual - in this
case for being too fussy - and distract from the role of economic policy
in creating material inequality (9).
In view of the importance of this issue we agree with the authors'
final paragraph. Observational epidemiology has taken us as far as it can
in relation to this question. Future research should concentrate on
experimental studies. If psychosocial interventions are truly a promising
strategy to improve cardiovascular health then this should be demonstrated
in randomised controlled trials.
Yours sincerely,
JOHN MACLEOD
Department of Primary Care and General Practice
University of Birmingham, B15 2TT
GEORGE DAVEY SMITH
Department of Social Medicine
University of Bristol, BS8 2PR
References
1. Haines A, Cooper J, Meade TW. Psychological characteristics and
fatal ischaemic heart disease. Heart 2001;85:385-389.
2. Meikle J. Fussing can double risk of heart attack. Guardian 2001,
March 15.
3. Kauhanen J, Kaplan GA, Cohen RD, Julkunen J, Salonen JT.
Alexthymia and risk of death in middle-aged men. Journal of Psychosomatic
Research 1996;41:541-549.
4. Bosma H, Schrijvers C, Mackenbach JP. Socioeconomic inequalities
in mortality and importance of perceived control: cohort study. BMJ
1999;319:1469-70.
5. Everson SA, Goldberg DE, Kaplan GA, Cohen RD, Pukkala E,
Tuomilehto J, Salonen JT. Hopelessness and Risk of Mortality and Incidence
of Myocardial Infarction and Cancer. Psychosomatic Medicine 1996;58:113-
121.
6. Davey Smith G, Dorling D. "I'm all right John": voting patterns
and mortality in England and Wales, 1981-92. BMJ 1996;313:1573-77.
7. Davey Smith G, Harding S. Is control at work the key to socio-
economic gradients in mortality? (letter) Lancet 1997;350:1369-70.
8. Phillips AN, Davey Smith G. How independent are independent
effects? Relative risk estimation when correlated exposures are measured
imprecisely. J Clin Epidemiol 1991;44:1223-31.
9. Lynch JW, Davey Smith G, Kaplan GA, House JS. Income inequality
and mortality: importance to health of individual income, psychosocial
environment, or material conditions. BMJ 2000; 320: 1200-1204.
The occurrence of drug-related prerenal uraemia and, hence,
hyperkalemia [1,2] is an entirely predictable outcome if the precaution
is not taken to reduce the dose of loop diuretics when sprironolactone is
added to existing angiotensin converting enzyme (ACE) inhibitor therapy.
This given the fact that the coprescription of all three modalities (ie
spironolactone, loop diuretics, and ACE inhibitors) can...
The occurrence of drug-related prerenal uraemia and, hence,
hyperkalemia [1,2] is an entirely predictable outcome if the precaution
is not taken to reduce the dose of loop diuretics when sprironolactone is
added to existing angiotensin converting enzyme (ACE) inhibitor therapy.
This given the fact that the coprescription of all three modalities (ie
spironolactone, loop diuretics, and ACE inhibitors) can powerfully augment
diuresis even to the extent of precipitating prerenal uraemia [3,4] as a
consequence of the enhancement of natriuresis arising from the synergism
between spironolactone and ACE inhibitors [5].
O M P Jolobe
References
(1) Berry C, McMurray JJV. Serious adverse events experienced by patients
with chronic heart failure taking spironolactone. Heart 2001;85:e8(April).
(2) Schepkens H, Vanholder R, Billouw J-M, Lamiere N. Life-threatening
hyperkalaemia during combined therapy with angiotensin-converting enzyme
inhibitors and spironolactone. An analysis of 25 cases. American Journal
of Medicine 2001;110:438-441.
(3) Ikram H, Lewis GRJ, Webster MWI, Richards AM, Nicholls MG, Crozier IG.
Combined spironolactone and converting enzyme inhibitor therapy for
refractory heart failure. Australian and New Zealand Journal of Medicine
1986;16:61-63.
(4) Jolobe OMP. Efficacy of low-dose captopril in addition to furosemide and
spironolactone in patients with decompensated liver disease during blunted
diuresis (letter). Journal of Hepatology 1993;19:321-322.
(5) Bauersachs J, Fraccarollo D, Ertl G, Gretz N, Wehling M, Christ M.
Striking increase of natriuresis by low-dose spironolactone in congestive
heart failure only in combination with ACE inhibitors. Mechanistic
evidence to support RALES. Circulation 2000;102:2325-2328.
,
When I received the September issue of Heart, I was pleased to read
an article by Galasko and colleagues (Heart 2001; 86:271-276) on the
prospective comparison of echocardiographic wall motion score index and
radionuclide ejection fraction in predicting outcome following acute
myocardial infarction. In their introduction, they indicated that no
study has directly compared wall motion score index and l...
,
When I received the September issue of Heart, I was pleased to read
an article by Galasko and colleagues (Heart 2001; 86:271-276) on the
prospective comparison of echocardiographic wall motion score index and
radionuclide ejection fraction in predicting outcome following acute
myocardial infarction. In their introduction, they indicated that no
study has directly compared wall motion score index and left ventricular
ejection fraction in the assessment of prognosis.
I would like to call to the attention of these authors that an article
published in Clinical Cardiology (24, 191-195) (2001) by Smock, Larson,
Brown and Conti entitled 'Early prediction of 30 day mortality after Q wave
myocardial infarction by echocardiographic assessment of left ventricular
function - a pilot investigation.'
In this cohort of 201 consecutive patients with Q wave myocardial
infarction, echocardiographic assessment of left ventricular ejection
fraction within the first 24 hours after onset of myocardial infarction
was a powerful predictor of 30 day mortality. Wall motion score index was
also highly predictive of 30 day mortality. The relationship between wall
motion score index and left ventricular ejection fraction and 30 day
mortality was analyzed and there was no statistical advantage of one
method over the other or of combining left ventricular ejection fraction
and wall motion score index to determine prognosis. We believe that
focusing on left ventricular ejection fractions is a more practical of the
two approaches to assess 30 day mortality within 24 hours of admission to
hospital.
I congratulate these investigators on an excellent piece of work and
certainly concur that evaluating ventricular function is an excellent way
to assess prognosis in patients early after a myocardial infarction.
Sincerely,
C. Richard Conti, MD, MACC
Eminent Scholar, Cardiology
Professor of Medicine
Dear Editor,
Dr Levitt has raised a valuable point that the risk benefit relationship of aspirin may vary with age as well as CHD risk and it is worth re-evaluating the conclusions made in our paper [1].
He has however misunderstood the way in which we calculated benefit from aspirin treatment. Because haemorrhagic strokes were not always reported separately they had to be included in cardiovascular e...
Robin Norris and the SHARP Investigators are to be congratulated on another study that is full of interest [1]. The new performance indicator proposed is, indeed, very attractive. Quite correctly, the number of lives saved by hospital thrombolysis is calculated using the figure of 30/1000 derived from hospital trials. But there is one point on which I must take issue, and that is the additional life-saving fr...
April 3, 2001
To the Editor:
It seems that there is a potential flaw in the analysis by Sanmuganathan, et al (1), of the relative risk benefit ratio in the use of aspirin for the primary prevention of coronary artery disease. The coronary risks are calculated using tables in which age is a major determinant, but the risks of a bleeding complication are averaged over all ages. Since bleeding complicat...
Dear Editor
As John Rawles states, the benefit of prehospital thrombolysis could be much greater than the FTT estimate for hospital treated patients of 1.6 lives/1000 treated per hour of delay [1]. Indeed, the "golden hour" [2] may even be extended to the "golden two hours" as Rawles' own seminal work suggests [3]. The point we were trying to make in the SHARP report [4] was that 30/1000 is the most that can be ex...
Dear Editor,
Berry and McMurray (Heart 2001;85:e8) report three of four cases of serious adverse events in association with spironolactone linked to the non-specific symptom of diarrhoea. As cited, Professor McMurray many years ago reported the renal adverse effects of "diarrhoea" induced volume depletion in conjunction with ACE inhibition as a simple case study. I may have misinterpreted the recent report but I...
Dear Editor,
We thank Dr. MacFadyen for his thoughtful comments on our report. We were trying to draw to readers' attention, our observations that severe renal dysfunction and hyperkalaemia can occur when spironolactone is added to conventional therapy (and other, non-heart failure, drugs) in "real" patients with heart failure, a phenomenon not described in the carefully selected RALES population. Interesting...
We did discuss the adjustment for social class in the paper and p...
Editor,
Haines and colleagues present a further example from observational epidemiology of an association between a psychosocial factor and cardiovascular health (1). They suggest that this association is likely to be causal - a suggestion apparently accepted by the popular press in their reporting of this research (2).
However, given the non-specificity of the association between a range of such factor...
The occurrence of drug-related prerenal uraemia and, hence, hyperkalemia [1,2] is an entirely predictable outcome if the precaution is not taken to reduce the dose of loop diuretics when sprironolactone is added to existing angiotensin converting enzyme (ACE) inhibitor therapy. This given the fact that the coprescription of all three modalities (ie spironolactone, loop diuretics, and ACE inhibitors) can...
Dear Editor
, When I received the September issue of Heart, I was pleased to read an article by Galasko and colleagues (Heart 2001; 86:271-276) on the prospective comparison of echocardiographic wall motion score index and radionuclide ejection fraction in predicting outcome following acute myocardial infarction. In their introduction, they indicated that no study has directly compared wall motion score index and l...
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