We wish to respond to criticisms of our paper on the cost
effectiveness of drug eluting stents (DES) by Martyn Thomas in his recent
editorial.
The criticisms are that:
• Our study is based on data of uncertain quality from one centre, which
may be biased, and report unusually low rates of diabetes and
revascularisation.
Processes of validation of our data are available on req...
We wish to respond to criticisms of our paper on the cost
effectiveness of drug eluting stents (DES) by Martyn Thomas in his recent
editorial.
The criticisms are that:
• Our study is based on data of uncertain quality from one centre, which
may be biased, and report unusually low rates of diabetes and
revascularisation.
Processes of validation of our data are available on request. Our
data is virtually complete – deaths are tracked, and in the past three
years, only two patients underwent a second revascularisation in another
north-west NHS hospital, all of which participate in a common audit.
Diabetes rates among Liverpool patients having PCI are comparable
with other regional hospitals (Blackpool 13%, Manchester RI 10%, South
Manchester 15%) and across the country. Some higher rates (e.g. Birmingham
and Leicester (20%) are probably due to ethnicity differences.
The British Cardiovascular Intervention Society (BCIS) audit for
2003[1] reported that only 4.3% of PCIs were required for restenosis,
though less than 20% of procedures then used DES. This is consistent with
an average risk of re-intervention without DES of 5-10%, confirming recent
gains made in both technology and expertise even without the use of DES.
An audit study from Leicester showed overall target lesion restenosis at
12 months of 4.9% for bare metal stents (BMS) and 2.8% for DES.[2] These
figures are therefore consistent with the rates from Liverpool quoted in
our study.
Thomas asks how many patients had LAD treated: the answer is 55%,
considerably higher than in the Sirius trial (44%) - there is no
systematic bias against treating patients with LAD with BMS.
We reaffirm that our data reflect common UK experience and practice,
which DES clinical trial populations clearly do not.
• We have not adequately considered risk factors identified in other
studies, in particular diabetes.
Thomas misses our point completely: when vessel architecture is also
considered, diabetes ceases to be an independent risk factor. Any increase
in re-stenosis related to diabetes is mediated indirectly through the
significant architecture variables.
• We make too much of protocol driven revascularisations in the
trials
It is for Thomas therefore to explain why the rate of "clinically
driven revascularisations" in BMS arms of trials (quoted by Thomas as
16.2% at twelve months) is so much higher than the BCIS audit identifies
as UK practice. The substantial effects of protocol driven angiograms on
revascularisation rates in the trials are widely acknowledged.[3]
• Our results are inconsistent with the previous literature on the
cost effectiveness of DES over BMS
The literature on this is wider and shows more varied results than
Thomas suggests. Greenberg et al. [4] for instance calculated that DES
were cost effective only if the revascularisation rate was 12% or more –
far higher than in most UK patients. Importantly, most studies were
undertaken with support from manufacturers or closely based on results of
clinical trials with very high revascularisation rates.
• We have rejected the efficacy of DES in lowering restenosis rates
in most patients
Thomas fails to understand the distinction between efficacy
(demonstrated in clinical trials), effectiveness and cost effectiveness
(real world practice). We fully accept that DES lower the rate of
restenosis, and probably by similar proportions in all patient groups.
But the absolute reduction in risk varies widely: a patient with 24% risk
of reintervention may have that risk reduced by 16% to just 8%, whereas
another patient with only a 6% risk has a much smaller gain of just 4%.
Clearly treating the former patient will give much better ‘value for
money’ than the latter. Accurate assessment of absolute risk in patients
undergoing PCI in UK (not in the trials) is fundamental to assessing DES
cost-effectiveness.
The real problem is price; every DES implanted costs the NHS £500+
extra. This is justified for a few patients with high risk of recurrence.
However, evidence is strong from reputable sources (including BCIS
themselves) that for most patients the extra costs are difficult to
justify, particularly if it means diverting scarce resources from other
patients. The cardiological community should focus on another objective:
persuading manufacturers to accept lower profits in return for secure long-term markets.
2) Jilaihawi H, Khan S, Kovac J
Low incidence of revascularisation of bare metal stents in the era of drug eluting stents: a single tertiary centre experience. Heart 2005; 91(Suppl 1): A5, 002
3) van Hout BA, Serruys PW, Lemos PA, van den Brand MJ, van Es GA, Lindeboom WK, Morice MC.
One year cost effectiveness of sirolimus eluting stents compared with bare metal stents in the treatment of single native de novo coronary lesions: an analysis from the RAVEL trial. Heart. 2005; 91: 507-12.
4) Greenberg D, Bakhai A, Cohen D.
Can we afford to eliminate restenosis?: Can we afford not to?. Journal of the American College of Cardiology 2004; 43: 513-518
In the letter by Olivetto et al. [1] the authors have highlighted two
potential limitations of our study firstly that fractional shortening may
not be a reliable measure of systolic function in hypertrophic
cardiomyopathy and that ejection fraction is better; and secondly, that
the cut off value for systolic impairment (...
In the letter by Olivetto et al. [1] the authors have highlighted two
potential limitations of our study firstly that fractional shortening may
not be a reliable measure of systolic function in hypertrophic
cardiomyopathy and that ejection fraction is better; and secondly, that
the cut off value for systolic impairment (<_25 may="may" have="have" been="been" too="too" low="low" resulting="resulting" in="in" an="an" underestimation="underestimation" of="of" the="the" prevalence="prevalence" systolic="systolic" impairment.="impairment." we="we" essentially="essentially" agree="agree" with="with" their="their" comments="comments" and="and" highlighted="highlighted" these="these" as="as" potential="potential" limitations="limitations" our="our" manuscript.2="manuscript.2" would="would" however="however" like="like" to="to" address="address" further="further" points.="points." p="p"/> The study cohort comprised 1080 patients evaluated over more than 10
years using a number of different echocardiography machines and evolving
technologies. In order to retrospectively analyse echo studies taken
during this period and determine the ejection fraction in those patients
in who this measurement was not originally determined would have resulted
in potentially inaccurate results and in our view would have been miss-
leading. Furthermore the measurement of ejection fraction in-itself also
has inherent limitations in patients with asymmetric ventricles. We
considered fractional shortening to be more reliable and reproducible
measure of systolic performance in this context.
We acknowledge that systolic impairment may be present in patients
with hypertropic cardiomyopathy and fractional shortening greater than
25%. However, we adopted a pragmatic approach using a well recognised cut
off value for the definition of systolic impairment. Although some
patients with systolic impairment may have been missed, we believe that we
were able to identify a group of patients that require early intervention
to prevent disease progression.
Finally we believe that the low annual incidence of systolic
impairment identified in our study compared to earlier ones possibly
reflects the identification of more asymptomatic cases. However as we
pointed out in this and a earlier study [2, 3], most patients with
hypertrophic cardiomyopathy appear to develop wall thinning over time i.e.
left ventricular remodelling and therefore a degree of systolic
impairment is likely to occur in most patients if followed for a long
enough period.
References
1. Olivotto I, Nistri S, Cecchi F. Systolic impairment in
hypertrophic cardiomyopathy, Heart 2005 (20 June).
2. Thaman R, Gimeno JR, Murphy RT, Kubo K, Sachdev B, Morgenssen J,
PM Elliott, WJ McKenna. Prevalence and Clinical significance of systolic
impairment in hyperrophic cardiomyopathy. Heart 2005; 91:920-925.
3. Thaman R, Gimeno JR, Reith S, Esteban MT, Limongelli G, Murphy RT,
Mist B, McKenna WJ, Elliott PM. Progressive left ventricular remodelling
in patients with hypertrophic cardiomyopathy and severe left ventricular
hypertrophy. J Am Coll Cardiol. 2004 Jul 21; 44(2):398-405.
In January’s edition of Heart we presented the fascinating case of a
patient with long QT syndrome who was refractory to conventional
pharmacological and pacing techniques.[1] Despite potassium and magnesium
supplements, beta-blockade, implantation of a single, then dual chamber
implantable cardioverter-defibrillator (ICD), amiodarone, nicorandil and
mexiletine; the patient continued to experience life-...
In January’s edition of Heart we presented the fascinating case of a
patient with long QT syndrome who was refractory to conventional
pharmacological and pacing techniques.[1] Despite potassium and magnesium
supplements, beta-blockade, implantation of a single, then dual chamber
implantable cardioverter-defibrillator (ICD), amiodarone, nicorandil and
mexiletine; the patient continued to experience life-threatening
ventricular tachyarrhythmias, receiving more than 700 ICD discharges over
a seven-month period. She was ultimately treated successfully with
bilateral thoracoscopic cervico-thoracic sympathectomies.
It has been over 23-months since her bilateral thoracoscopic cervico-
thoracic sympathectomies. I am pleased to report that she continues to
make good progress. She has only had one repeat hospital admission for an
episode of recurrent polymorphic ventricular tachycardia. This
fortunately settled spontaneously over a 48-hour period without any
alterations to her medication or ICD.
At the time of publication we were awaiting the result of mutation
screening of the genes KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A. This has now
revealed that the patient is heterozygous for a previously undescribed
mutation in intron 3 of the SCN5A gene (IVS3-5C>A)* dramatically
reducing the efficiency of the acceptor splice-site prior to exon 4. Most
likely the mutation results in the occurrence of exon skipping phenomena
and frame shifts leading to mRNA decay (haploinsufficiency) or the
synthesis of truncated protein variants. With reduced SCN5A channel
activity the patient would be expected to present with Brugada syndrome.
The synthesis of truncated variants with exclusion of some segments and
inclusion of other amino acids as a result of the synthesis of different
splice-variants could explain the deviation from the Brugada phenotype.[2]
Other mutations resulting in putative truncation of SCN5A, i.e. W156X and
L1786X, have had different phenotypes.[2][3] Furthermore,
haploinsufficiency of SCN5A in the mouse is associated with re-entrant
ventricular tachyarrhythmias.[4] The precise explanation for the LQT3
phenotype in this patient must await further molecular and functional
studies.
References
1. Turley AJ, Thambyrajah J, Harcombe AA. Bilateral Thoracoscopic Cervical
Sympathectomy For The Treatment Of Recurrent Polymorphic Ventricular
Tachycardia. Heart 2005;91:15-7.
2. Bezzina CR, Rook MB, Groenewegen WA et al. Compound heterozygosity for
mutations (w156X and R225W) in SCN5A associated with severe cardiac
conduction disturbance. Circ Res 2003;92:159-168.
3. Herfst IJ, Potet F, Bezzina CR et al. Na+ channel mutation leading to
loss of function and non-progressive conduction defects. J Mol Cell
Cardiol 2003;35:549-553.
4. Papadatos GA, Wallerstein PMR, Head CEG et al. Slowed conduction and
ventricular tachycardia after targeted disruption of the cardiac sodium
channel gene SCN5A. Proc Natl Acad Sci USA 2002;99:6210-6215.
*The mutation occurs in nucleotide no. 29298 in the genomic sequence
ensg00000183873 (www.ensembl.org). Exons are numbered from the exon
containing the start ATG codon at nucleotide no. 16967.
AJ Turley1, E Behr2, M Christiansen3, J Thambyrajah1 and AA Harcombe4
1 Cardiothoracic Division, The James Cook University Hospital,
Middlesbrough, UK
2 Cardiothoracic Unit, St George’s Hospital, London, UK
3 Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen,
Denmark
4 Cardiothoracic Division, Queens Medical Centre, Nottingham, UK
Correspondence to:
Dr AJ Turley BMedSci, MRCP
Cardiothoracic Division
The James Cook University Hospital
Marton Road, Middlesbrough.
TS4 3BW
England.
Tel. 01642 854623
Fax. 01642 854190
E-mail: Andrew.Turley{at}stees.nhs.uk
I read with interest the article on hypoxemia associated with aortic
root dilatation.[1] But this is not a new syndrome as Eicher et al.[1]
suggested. It is the platypnea-orthodeoxia syndrome first described in
1949 by Burchell et al.[2] Platypnea-orthodeoxia is a relatively
uncommon but often underdiagnosed syndrome [3] with striking clinical
manifestations, characterized by dyspnea relieved by assu...
I read with interest the article on hypoxemia associated with aortic
root dilatation.[1] But this is not a new syndrome as Eicher et al.[1]
suggested. It is the platypnea-orthodeoxia syndrome first described in
1949 by Burchell et al.[2] Platypnea-orthodeoxia is a relatively
uncommon but often underdiagnosed syndrome [3] with striking clinical
manifestations, characterized by dyspnea relieved by assumption of a
supine position and simultaneous deoxygenation following a change from a
recumbent to an upright position.
In 1949, Burchell and his colleagues from Mayo Clinic [2] described a
patient with a post-traumatic intrathoracic venous-arterial type of blood
shunt, who exhibited a threefold increase in ventilation and a 15-point
decrease in arterial oxygen saturation whenever the patient was in an
upright position. They actually did not use the term platypnea-
orthodeoxia in their presentation. It was Altman and Robin [4] who coined
the term platypnea in 1969. Everybody had been familiar with the term
‘orthopnea’ that was used to describe increased dyspnea in the recumbent
position relieved by sitting, which is, of course, a well-known, common
and important symptom of congestive heart failure. So Altman and Robin
[4] coined the term ‘platypnea’ or flat breathing, which is the reverse
symptom of dyspnea in an upright position relieved by recumbency. Then in
1976 Robin and coworkers [5] introduced and added the second term
‘orthodeoxia’ to this syndrome to describe accentuated arterial
deoxygenation following a change to an upright position from recumbency.
The most common etiological association in platypnea-orthodeoxia
nowadays is an interatrial right-to-left shunt, through either a patent
foramen ovale or an atrial septal defect or a fenestrated atrial septal
aneurysm. Under normal conditions, an interatrial communication allows
blood to shunt from left to right, due to a higher pressure in left atrium
than right atrium and a greater compliance of the right ventricle than the
left ventricle. Right-to-left interatrial shunting is usually associated
only with spontaneous or induced pulmonary hypertension. Therefore, in
the absence of a right-to-left pressure gradient, what is the mechanism
for a right-to-left shunt? Or put in another way, what causes water to
flow uphill [6]? Of course, a persistent Eustachian valve can cause
interatrial right-to-left shunting with a normal right atrial pressure.[7]
Platypnea-orthodeoxia could be explained on the basis of positional
modification of abnormal shunting. Standing upright could stretch the
interatrial communication, be it a patent foramen ovale, an atrial septal
defect, or a fenestrated atrial septal aneurysm, thus allowing more
streaming of venous blood from inferior vena cava through the defect,
whether or not a persistent Eustachian valve coexists.[8,9] This
redirection of flow caused by an anatomic distortion of the right atrium
or the atrial septum also might occur from aortic root dilatation or
aneurysm. An example of the former was nicely demonstrated on
transesophageal echocardiography in 2001 by Medina et al.[10]
Due to space constraint, I would not discuss all the other causes of
platypnea-orthodeoxia. I refer your readers to my original Editorial
Comment that was published in Catheterization and Cardiovascular
Interventions in May 1999.[11] Suffice to say that two conditions must
coexist to cause platypnea-orthodeoxia: (1) an anatomical component in the
form of an interatrial communication and (2) a functional component which
produces a deformity in the atrial septum and results in a redirection of
shunt flow with the assumption of an upright posture.
References
1. Eicher J-C, Bonniaud P, Baudouin N, et al: Hypoxaemia associated with
an enlarged aortic root: a new syndrome? Heart 2005;91:1030-1035.
2. Burchell HB, Helmholz HF Jr, Wood EH: Reflex orthostatic dyspnea
associated with pulmonary hypotension. Am J Physiol 1949;159:563-564.
3. Cheng TO: Platypnea-orthodeoxia and blockpnea as two unrecognized or
underdiagnosed causes of medically unexplained dyspnea. Chin Med J
2004;117:1116.
4. Altman M, Robin ED: Platypnea (diffuse Zone I phenomenon)? N Engl J
Med 1969;281:1347-1348.
5. Robin ED, Laman D, Horn BR, Theodore J: Platypnea related to
orthodeoxia caused by true vascular lung shunts. N Engl J Med
1965;294:941-943.
6. Cheng TO: Mechanism of platypnea-orthodeoxia: what causes water to flow
uphill? Circulation 2002;105:e47.
7. Bashour T, Kabbani S, Saalouke M, Cheng TO: Persistent Eustachian valve
causing severe cyanosis in atrial septal defect with normal right heart
pressures. Angiology 1983;34:79-83.
8. Cheng TO: reversible orthodeoxia. Ann Intern Med 1992;116:875.
9. Cheng TO: Platypnea-orthodeoxia due to interatrial right-to-left
shunting. Acta Cardiologica 1994;49:217.
10. Medina A, Suarez de Lezo J, Cabarello E, et al: Platypnea-orthodeoxia
due to aortic elongation. Circulation 2001;104:741.
11. Cheng TO: Platypnea-orthodeoxia syndrome: etiology, differential
diagnosis, and management. Cathet Cardiovasc Interv 1999;47:64-66.
I read with great interest the recent paper by Lip et al., indicating
that clinical congestive heart failure is an important determinant of
plasma concentrations of von Willebrand factor (vWf), a marker of
endothelial dysfunction, in a large cohort of patients with non-valvular
atrial fibrillation.[1]
It would be very interesting to know the rate of digoxin use in both
groups (with and without...
I read with great interest the recent paper by Lip et al., indicating
that clinical congestive heart failure is an important determinant of
plasma concentrations of von Willebrand factor (vWf), a marker of
endothelial dysfunction, in a large cohort of patients with non-valvular
atrial fibrillation.[1]
It would be very interesting to know the rate of digoxin use in both
groups (with and without heart failure), as one would anticipate a higher
rate of use among subjects with congestive heart failure. We have recently
reported that digoxin use was associated with increased levels of
circulating endothelial microparticles measured by flow cytometry in a
small population of patients with non-valvular atrial fibrillation, which
did not seem to depend on the underlying presence of clinical heart
failure in our study.[2] It is biologically plausible, although at
present unproven, that estimulation of cardiac glycoside receptors in
endothelial cells with subsequent increase in intracellular calcium might
induce the release of microparticles and affect other cellular responses.
Perhaps an analysis of the SPAF data regarding differences in vWF levels
among subjects with and without digoxin use and adjusting for the presence
of clinical heart failure or LV dysfunction will contribute to clarify
this issue.
References
1. Lip GY, Pearce LA, Chin BS, Conway DS, Hart RG. Effects of
congestive heart failure on plasma von Willebrand factor and soluble P-
selectin concentrations in patients with non-valvar atrial fibrillation.
Heart. 2005 Jun;91(6):759-63.
2. Chirinos JA, Castrellon A, Zambrano JP, Jy W, Horstman LL, Jiménez
JJ, Willens H, Castellanos A, Myerburg RJ, Ahn YS. Digoxin use is
associated with increased platelet and endothelial cell activation in
patients with non-valvular atrial fibrillation. Heart Rhythm
2005;2:525–529.
In discussion and exchange of ideas with colleagues (Europace, 2005)
there is a consensus among some of us performing CRT that a positive QRS
deflection in lead aVR and aVL is somewhat an indicator for "non-
responders" when that patient is implanted with an biventricular pacing
device.
This observation needs to be further scrutinized and varified by both
a prospective studies as well as with retrospective analys...
In discussion and exchange of ideas with colleagues (Europace, 2005)
there is a consensus among some of us performing CRT that a positive QRS
deflection in lead aVR and aVL is somewhat an indicator for "non-
responders" when that patient is implanted with an biventricular pacing
device.
This observation needs to be further scrutinized and varified by both
a prospective studies as well as with retrospective analysis of all "non-
responders" from CRT.
We should all remember our clinical skills and the evidence that
existed in B.T. (Before Troponin) times. I still take a convincing cardiac
history and suspicious ECG changes seriously and ignore the first
troponin, keeping the patient in at least 24 hours and measuring a second
troponin/creatinine kinase, or exercising the patient if further pain
occurs. We should all be wary of becoming too dependan...
We should all remember our clinical skills and the evidence that
existed in B.T. (Before Troponin) times. I still take a convincing cardiac
history and suspicious ECG changes seriously and ignore the first
troponin, keeping the patient in at least 24 hours and measuring a second
troponin/creatinine kinase, or exercising the patient if further pain
occurs. We should all be wary of becoming too dependant on perceived
panacea's like Troponin or d-dimer, and lead clinicians and academics must
constantly remind us to still examine the broad picture which is comprised
of many clues and not just one piece (albeit an important one) of the
puzzle.
We congratulate the authors on highlighting adverse prognostic indicators in patients with infective endocarditis. We recently examined predictors of mortality in 47 patients from our center who presented with paravalvular abscess formation - a complication of infective endocarditis (J Am Soc of Echocardiogr, in press). We found renal failure and neurologic
impairment as the determinants of survival in our smal...
We congratulate the authors on highlighting adverse prognostic indicators in patients with infective endocarditis. We recently examined predictors of mortality in 47 patients from our center who presented with paravalvular abscess formation - a complication of infective endocarditis (J Am Soc of Echocardiogr, in press). We found renal failure and neurologic
impairment as the determinants of survival in our small series of patients highlighting the similarities of the authors large series. Thus renal failure and altered mental status may indicate that an aggressive approach be taken with those with IE or its complication.
In their report, Thaman and co-workers state that left ventricular systolic impairment (SI), defined as a fractional shortening (FS) <_25 is="is" a="a" rare="rare" occurrence="occurrence" in="in" patients="patients" with="with" hypertrophic="hypertrophic" cardiomyopathy="cardiomyopathy" hcm.1="hcm.1" however="however" we="we" are="are" concerned="concerned" that="that" their="their" conclusions="conclusions" may="may" be="be" misleading="misleading" regard="regard" to="to" the="the" true="true" prevalence="prevalence" of="of" si="si" hcm="hcm" due="due" methodological="methodological" limitations.="limitations." first="first" all="all" fs="fs" not="not" regarded="regarded" as="as" reliable="reliable" index="index" systolic="systolic" function="function" especially="especially" asymmetric="asymmetric" ventricles="ventricles" patients.="patients." therefore="therefore" it="it" unfortunate="unfortunate" more="more" accurate="accurate" _2-d="_2-d" ejection="ejection" fraction="fraction" values="values" were="were" available="available" for="for" this="this" study.p="study.p" _="_"/>
Moreover, as suggested by the authors, the very strict definition employed for SI (FS<_25 might="might" have="have" led="led" to="to" significant="significant" underestimation="underestimation" of="of" systolic="systolic" impairment.="impairment." in="in" the="the" italian="italian" registry="registry" for="for" hcm="hcm" including="including" _1677="_1677" patients="patients" from="from" _40="_40" centres="centres" _2="_2" we="we" observed="observed" a="a" distribution="distribution" fs="fs" values="values" which="which" was="was" very="very" similar="similar" that="that" reported="reported" by="by" thaman="thaman" et="et" al.="al." _1="_1" with="with" mean="mean" _4110.="_4110." note="note" only="only" _7="_7" had="had" _="_" while="while" cut-off="cut-off" value="value" _25th="_25th" percentile="percentile" as="as" high="high" _34.="_34." among="among" _1491="_1491" whom="whom" follow-up="follow-up" data="data" available="available" average="average" _9.47.4="_9.47.4" years="years" likelihood="likelihood" heart="heart" failure-related="failure-related" death="death" inversely="inversely" related="related" fs.="fs." multivariate="multivariate" cox="cox" regression="regression" survival="survival" analysis="analysis" age="age" gender="gender" atrial="atrial" fibrillation="fibrillation" initial="initial" nyha="nyha" class="class" and="and" lv="lv" outflow="outflow" obstruction="obstruction"/>=30 mm Hg) as covariates, patients with FS <_34 i.e.="i.e." _="25th" percentile="percentile" had="had" an="an" almost="almost" _6-fold="_6-fold" increase="increase" in="in" risk="risk" compared="compared" to="to" patients="patients"/>34% (HR 5.8; 95%CI 1.2-27.8, p=0.028). Of note, in the group with FS <_34 heart-failure="heart-failure" related="related" mortality="mortality" was="was" comparable="comparable" between="between" patients="patients" _="25%" and="and"/>25% (p=0.33) (unpublished observations).
Therefore, we propose that SI, more broadly defined, is not uncommon in HCM, and that even FS values within the lower range of standard reference values may in fact identify patients with incipient SI and adverse long-term outcome due to progressive heart failure. To confine the recognition of SI to those patients in whom extreme degrees of dysfunction and remodelling have already occurred may result in an underestimation of the actual prevalence of SI in HCM, as well as in delayed institution of appropriate treatment [3].
References
1. Thaman R, Gimeno JR, Murphy RT, et al. Prevalence and clinical significance of systolic impairment in hypertrophic cardiomyopathy. Heart. 2005;91:920-5
2. Cecchi F, Olivotto I, Betocchi S, et al. The Italian registry for hypertrophic cardiomyopathy: a nationwide survey. Am Heart J, in press.
3. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J. 2005;26:1115-40.
In their article published last month, Stakos et al. (Heart 2005) found that both glipizide and metformin, when administered to non-diabetic African Americans with insulin resistance, lead to a significant increase in pulse wave velocity (PWV) when compared to placebo, and conclude that,
"…long term administration of oral antidiabetic glipizide or metformin to normoglycaemic African Americans with insulin re...
In their article published last month, Stakos et al. (Heart 2005) found that both glipizide and metformin, when administered to non-diabetic African Americans with insulin resistance, lead to a significant increase in pulse wave velocity (PWV) when compared to placebo, and conclude that,
"…long term administration of oral antidiabetic glipizide or metformin to normoglycaemic African Americans with insulin resistance may decrease the elastic properties of the aorta." Stakos et al. go on to state that, "On the basis of these observations, the use of glipizide, metformin, or both for the prevention of cardiovascular complication in normoglycaemic insulin resistant African Americans needs to be critically evaluated." On the surface, these observations and claims appear to be quite concerning. Indeed, PWV has been correlated with aortic distensibility, and an increase in PWV is associated with increased cardiovascular mortality and adverse events. However, does the article by Stakos et al. really demonstrate this to be true? There are several points which I think need to be addressed before the validity of the authors conclusions can be accepted.
First, the implication from this study is that the increase in PWV in normotensive, normolipidemic African Americans is associated with an increase in cardiovascular mortality. What the authors fail to mention however, is that PWV has been found to be associated with an increase in
cardiovascular mortality and events only in patients with end stage renal disease and/or hypertension. Studies in normotensive patients have failed to show a correlation between PWV and outcomes. It is inappropriate to extrapolate findings from one patient population (i.e. hypertension/ESRD) to another (normotensive African American women – see below). In addition, in studies performed on hypertensive patients and/or patients with ESRD, PWV has always been correlated with an increase in LVMI. Both
PWV and LVMI in these populations have been identified as independent predictors of cardiovascular complications. Indeed, LVMI has been found to be directly associated with PWV as PWV is a measure of arterial stiffness and increased afterload. In the study by Stakos et al., there is a highly significant decrease in LVMI in all groups regardless of the
change in PWV. The authors fail to reconcile this seeming contradiction.
Second, this is a study that is represented as a "randomized, placebo controlled trial…" However, if we examine the distribution of the study subjects we see marked disparities between groups – glipizide with an n=25, metformin with an n=57, placebo with an n=97. How is it possible for a truly randomized trial to have such differences in subject number? Did the authors want a 1:2:4 randomization strategy? If so, why did they not describe this and the reason why in the Methods section? The authors
state that since "…the shape of the active drug tablets (glipizide and metformin) is different…. We created an identical placebo tablet. Thus, the total number of placebo was at least two to three times larger for any active treatment." Also they state that at the beginning of the study, metformin was not approved by the FDA, and therefore "the metformin group was larger than the glipizide group." This implies that two separate randomizations occurred during the study, one for glipizide, and another for metformin. If so, one cannot combine the two control groups into one and compare it to each of the active groups. Rather, one should compare each active group to their respective control group. The authors do not give a reason for why this was not done.
Third, the authors show us baseline results and give us the number of subjects in each group, however they go on to say "a small number (about 13%) of subjects dropped out." The authors fail to account for these missing subjects in their paper – were the number of dropouts evenly distributed between groups? Was one group more affected by the dropouts
than another? Nowhere is this described in the body of the paper or in the associated figures and tables. This is a major lapse on the part of the authors. "About" 13% of 181 is equal to 24 patients – with group sizes of 25, 59 and 97, it is clear where and how these dropouts are distributed between the three groups will impact greatly on the interpretation of results. Should the majority of dropouts be concentrated in the active groups especially, the potential introduction of alpha and beta error becomes enormous.
Also, in their Methods section, the authors state that "African Americans usually have high concentrations of high density lipoprotein (HDL) cholesterol and low concentrations of triglyceride. For these reasons none of the participants were considered to have metabolic syndrome." One cannot take generalizations about an entire population and apply it to a specific subgroup and expect it to apply. Indeed, according
to their own findings (see Table 1 Baseline Characteristics), a significant number of their patients meet the ATP III guidelines for the Metabolic Syndrome – having >/= 3 of the following:
1) Waist size > 40 inches (102 cm) for men or > 35 inches (88 cm) for women
2) Fasting Triglyceride >/= 150 mg/dl (1.69 mmol/L)
3) HDL chol <40 mg/dl (1.04 mmol/L) men or <50 mg/dl (1.29 mmol/L)
women
4) BP >/= 130/85
5) Fasting glucose >/= 110 mg/dl (6.1 mmol/L)
Examination of Table 1 shows another important fact - the vast majority of patients in this study are women – 89% in the Glipizide group, 74% in the Metformin group, and 76% in the Placebo group. This is not mentioned or discussed in the paper. It is extremely dangerous to make generalized
statements regarding entire populations (i.e. all African Americans with insulin resistance) when the study in question is relevant to only a subgroup of that population (African American women – many with the Metabolic Syndrome).
Finally, one must weigh in all the evidence available in the literature, and not take just one piece of information. Many studies have been published demonstrating the potential cardioprotective effects of Metformin – normalizing endothelial function, decreasing insulin resistance, decreasing PAI-1 and CRP, increasing HDL – as well as evidence supporting a mortality benefit of Metformin in patients with coronary artery disease and diabetes. Should all previous literature be tossed aside due to the findings of one small and methodologically questionable study? Even if the findings of Stakos et al are found to be true, they are true of only a subgroup of a subgroup of a subgroup of people – African American women with insulin resistance and no diabetes.
John Kao, MD
Assistant Professor of Medicine
University of Illinois at Chicago
Director, Cardiac Cath Lab
Jesse Brown VA Hospital
Chief, Section of Cardiology
Jesse Brown VA Hospital
References
1. Guerin et al. "Impact of Aortic Stiffness Attenuation on Survival of Patients in End-Stage Renal Failure." Circulation. 2001;103:987-992
2. Laurent et al. "Aortic Stiffness Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Hypertensive Patients." Hypertension. 2001;37:1236-1241
3. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III), JAMA 285 (2001), pp. 2486–2497.
4. Kao J, Tobis J, McClellan RL, Heaton MR, Davis BR, Holmes DR Jr., Currier JW. METFORMIN TREATMENT IS ASSOCIATED WITH DECREASED CLINICAL EVENTS IN DIABETIC PATIENTS UNDERGOING PERCUTANEOUS INTERVENTION: A PRESTO
SUBSTUDY. American Journal of Cardiology 2004; 93: 1347-1350.
Dear Editor,
We wish to respond to criticisms of our paper on the cost effectiveness of drug eluting stents (DES) by Martyn Thomas in his recent editorial.
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