In the study looking at cardiac CT angiography (CTA) using perfusion scintigraphy as the reference standard (1), cardiac CTA had a sensitivity of 75%, specificity of 98%, positive predictive value of 68%, and negative predictive value of 99%. The authors concluded that cardiac CTA had a moderate sensitivity, a moderate positive predictive value, high specificity and a high negative predictive value.
In the study looking at cardiac CT angiography (CTA) using perfusion scintigraphy as the reference standard (1), cardiac CTA had a sensitivity of 75%, specificity of 98%, positive predictive value of 68%, and negative predictive value of 99%. The authors concluded that cardiac CTA had a moderate sensitivity, a moderate positive predictive value, high specificity and a high negative predictive value.
What is wrong with this picture?
At the extremes of prevalence, predictive values are profoundly affected. In this case, disease prevalence was 20/366 (5%). With this prevalence, just about any test is going to have a high negative predictive value. A clearer way to represent their data would be to report, at a minimum, the normalized predictive values where the disease prevalence is set to 50%.
The clinical implications of normalizing predictive values are obvious by looking at contingency tables of their original data (Table 1), and comparing this with a 50% prevalence normalized contingency table (Table 2). The sensitivity and specificity of the test is not affected by a change in prevalence. However, the normalized positive predictive value is 97% (up from 68%) and the normalized negative predictive value is 80% (down from 99%).
This normalization is important. It allows a meaningful interpretation of predictive values, and enables the comparison of predictive values from various research studies and across different imaging modalities.
The clinical implication of their research? Cardiac CTA, when positive, is highly meaningful and almost always represents true disease. A negative cardiac CTA is reassuring, but should not be relied upon exclusively to rule out such a serious condition.
Reference: 1. Rubinshtein R, Miller TD, Williamson EE et al. Detection of Myocardial Infarction by Dual-Source Coronary Computer Tomography Angiography Using Quantitated Myocardial Scintigraphy as the Reference Standard. Heart 2009 Feb 5; 0: hrt.2008.158618v1 [Epub ahead of print].
Einstein's editorial(1)on radiation risk from coronary artery imaging (December 2008) rightly emphasises that the effective radiation dose from a radiographic examination is intended to be applied to a population rather than to the individual. This is not an easy concept, and makes it difficult to relate the dose to the risk/benefit decision that it required of the IRMER practitioner. It is easy enough to avoid radiation of a no...
Einstein's editorial(1)on radiation risk from coronary artery imaging (December 2008) rightly emphasises that the effective radiation dose from a radiographic examination is intended to be applied to a population rather than to the individual. This is not an easy concept, and makes it difficult to relate the dose to the risk/benefit decision that it required of the IRMER practitioner. It is easy enough to avoid radiation of a non- radiographic test is available, but is anyone truly capable of comparing the risks of catheter coronary angiography in terms of its invasive nature with the extra radiation risk of a CT study?
The companion editorial by Hamon and Nolan2 on radial artery access for PCI provides another example to debate. They make a sound argument that the risk of bleeding complications is less from the radial route than from the femoral, despite greater skill and experience being required. They do not mention radiation, but Einstein points out that the radial route entails a higher dose. What then of a planned PCI in a man of 45 (who may well survive the latent period of cancer induction), who is lean and therefore very unlikely to have a bleed from the femoral approach? Is the reduction in radiation dose important enough to mandate that this patient should have his PCI from the femoral route? If not, why not?
I suspect that very few cardiac radiographic investigations are refused on a basis of radiation dose alone. We seek to mitigate the problem by using as little radiation as is reasonably achievable, a laudable stance, even though the resultant images should hover just above the non-diagnostic level. Some comfort can be had from those who doubt the official line that stochastic effects have no threshold3.
1. Einstein AJ. Radiation risk from coronary artery disease imaging: how do different diagnostic tests compare? Heart 2008;94:1519-1521
2. Hamon M, Nolan J. Should radial artery access be the “gold standard” for PCI? Heart 2008;94:1530-1532
3. Pollycove M. The Issue of the Decade: Hormesis. Eur J Nuclear Medicine 1995;22:399 – 401
We read with interest the study by Dr. Gale and colleagues.[1] We
fully agree with the authors that age, heart rate, and systolic blood
pressure are among the most powerful prognosticators in acute coronary
syndromes (ACS).[2,3] However, we believe that several key issues deserve
clarification.
First, by dichotomizing continuous variables such as creatin...
We read with interest the study by Dr. Gale and colleagues.[1] We
fully agree with the authors that age, heart rate, and systolic blood
pressure are among the most powerful prognosticators in acute coronary
syndromes (ACS).[2,3] However, we believe that several key issues deserve
clarification.
First, by dichotomizing continuous variables such as creatinine and
Killip class (e.g. Killip class II and IV would be considered equivalent
as “cardiac failure”), substantial prognostic information would be lost,
so that performance of risk scores consisting of such variables would be
underestimated. Furthermore, by not using the coefficients derived from
the original risk scores (i.e. the logistic regression models were re-
constructed),[1] this study essentially compares the predictive value of
various combinations of clinical variables, rather than the actual risk
scores per se.
Second, it is critical to recognize the inherent trade-offs between
discrimination and calibration.[4] An established prognosticator with an
adjusted odds ratio of 2, for example, may change the patient risk
category, and yet add minimally to the c-index. Because risk scores were
designed to predict different clinical outcomes at various time points, it
is not feasible to directly compare their calibration---thus, comparative
studies have focused on discrimination (c-statistic).[1,5,6] Nevertheless,
calibration remains an important consideration in medical decision
making,[4] and especially in informing patients and their families about
prognosis.
Third, the electrocardiogram, troponin, and creatinine are
inexpensive, routine standard investigations in ACS, and are not
“difficult-to-obtain” at all. These readily accessible data can be easily
incorporated into risk assessment. It should be noted that practically,
even a “simple” (such as the Simple Risk Index: heart rate x [age/10]2 /
systolic blood pressure) risk score (except perhaps the TIMI risk score
for non-ST elevation ACS, which comprises of 7 dichotomous variables[7])
requires the use of a calculator. For example, the “linear predictor for
30-day mortality” (which will likely require a calculator) of the EMMACE
model in Table 5 only provides the log odds but not the actual probability
of death.[1] Therefore, the clinical utility of a risk score hinges on the
ease of application at the bedside (e.g. PDA or web-based calculators are
available for GRACE, Framingham, Reynolds risk scores) rather than the
mere number of predictor variables.
We recognize that in some situations (e.g. in the ambulance), a very
simple risk score (e.g. consisting of only a few dichotomous variables)
may help to triage ACS patients more effectively. Nevertheless, in many
clinical settings, a more “sophisticated” risk score can afford improved
accuracy without sacrificing ease of application. Physicians should
realize that these apparently “complex” risk scores can enhance risk
stratification, and are in fact quite easy to use.[6,8] We contend that a
useful risk score should be “as simple as possible, but not simpler”.
REFERENCES
1. Gale CP, Manda SO, Weston CF, Birkhead JS, Batin PD, Hall AS.
Evaluation of risk scores for risk stratification of acute coronary
syndromes in the Myocardial Infarction National Audit Project (MINAP)
database. Heart 2009;95:221-227.
2. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon
CP, Van De Werf F, Avezum A, Goodman SG, Flather MD, Fox KA. Predictors of
hospital mortality in the global registry of acute coronary events. Arch
Intern Med 2003;163:2345-2353.
3. Boersma E, Pieper KS, Steyerberg EW, Wilcox RG, Chang WC, Lee KL,
Akkerhuis KM, Harrington RA, Deckers JW, Armstrong PW, Lincoff AM, Califf
RM, Topol EJ, Simoons ML. Predictors of outcome in patients with acute
coronary syndromes without persistent ST-segment elevation. Results from
an international trial of 9461 patients. The PURSUIT Investigators.
Circulation 2000;101:2557-2567.
4. Cook NR. Use and misuse of the receiver operating characteristic
curve in risk prediction. Circulation 2007;115:928-935.
5. Yan AT, Jong P, Yan RT, Tan M, Fitchett D, Chow CM, Roe MT, Pieper
KS, Langer A, Goodman SG. Clinical trial--derived risk model may not
generalize to real-world patients with acute coronary syndrome. Am Heart J
2004;148:1020-1027.
6. Yan AT, Yan RT, Tan M, Casanova A, Labinaz M, Sridhar K, Fitchett
DH, Langer A, Goodman SG. Risk scores for risk stratification in acute
coronary syndromes: useful but simpler is not necessarily better. Eur
Heart J 2007;28:1072-1078.
7. Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G,
Mautner B, Corbalan R, Radley D, Braunwald E. The TIMI risk score for
unstable angina/non-ST elevation MI: A method for prognostication and
therapeutic decision making. JAMA 2000;284:835-842.
8. Manfrini O, Bugiardini R. Barriers to clinical risk scores
adoption. Eur Heart J 2007;28:1045-1046.
Dear Editor,
The recent article by Davies and colleagues (1) discussed the role of
aorta in directing coronary circulation. They mainly treated the subject
from the viewpoint of blood pressure, however, there remains a further
point which needs to be clarified: namely, the coronary blood flow. The
aorta serves predominantly as a cushioning reservoir of blood during
systole, and thereafter expelling it to the peripheral c...
Dear Editor,
The recent article by Davies and colleagues (1) discussed the role of
aorta in directing coronary circulation. They mainly treated the subject
from the viewpoint of blood pressure, however, there remains a further
point which needs to be clarified: namely, the coronary blood flow. The
aorta serves predominantly as a cushioning reservoir of blood during
systole, and thereafter expelling it to the peripheral circulation during
diastole (reservoir function). One of the most important organs to be
supplied blood in diastole is the heart. A decreased aortic compliance
therefore increases the risk of subendocardial ischemia (2), and recent
studies have also shown a relationship between the aortic reservoir
function and ischemic heart disease (3,4). Moreover, a rigid aorta
increases the afterload of the heart. Therefore, a coronary supply-demand
imbalance of the heart could thus occur, even if the diastolic blood
pressure is maintained.
We previously analyzed the aortic reservoir function in pediatric patients
after undergoing an arterial switch operation, whose ascending aorta was
dilated and its distensibility had markedly decreased, similarly to that
observed in elderly individuals. (5-7). Their pulse pressure had also
increased in comparison to normal subjects (5). However, their
subendocardial viability ratio, which means the coronary supply-demand
balance of the heart, was the same as that observed in the control group.
Their subendocardial viability ratio closely correlated with the
percentage of the diastolic runoff, which is the percentage of the
diastolic blood flow to a total cardiac output (r = 0.872, p <0.0001).
The reason why the aortic reservoir function was maintained in patients
with a decreased aortic distensibility may be due to the fact that the
aorta was dilated. Although its distensibility decreased, an expanded
aorta may therefore be able to store enough blood during systole, which
resembles the compensation of a failing heart; namely, although the left
ventricular ejection fraction decreases, the increased left ventricular
end-diastolic volume can maintain a sufficient cardiac output. The
coronary supply-demand balance is crucial for life. As a result, various
types of compensatory mechanisms are thus considered to exist.
Regarding coronary circulation, the importance of the aortic diastolic
blood pressure (coronary driving pressure) cannot therefore be
overemphasized. However, the coronary blood flow, and the coronary supply-
demand balance should also be taken into consideration when analyzing this
problem.
References
1. Davies JE, Parker KH, Francis DP, et al.
What is the role of the aorta in directing coronary blood flow?
Heart. 2008;94:1545-1547
2. Watanabe H, Ohtsuka S, Kakihana M, et al.
Coronary circulation in dogs with an experimental decrease in aortic
compliance.
J Am Coll Cardiol 1993;21:1497-1506
3.Franklin S, Larson M, Khan S, et al.
Does the relation of blood pressure to coronary heart disease risk change
with aging?: The Framingham Heart Study.
Circulation 2001;103:1245-1249
4.Sisso H, Stampfer M, Rosner B, et al.
Systolic and diastolic blood pressure, pulse pressure, and mean arterial
pressure as predictors of cardiovascular disease risk in men.
Hypertension 2000;36:801-807
5.Murakami T, Takei K, Ueno M, et al.
Aortic reservoir function after arterial switch operation in elementary
school-aged children.
Circ J. 2008;72:1291-1295
6.Sievers H, Lange P, Arensman F, et al.
Influence of two-stage anatomic correction on size and distensibility of
the anatomic pulmonary/functional aortic root in patients with simple
transposition of the great arteries.
Circulation. 1984;70:202-208
7.Murakami T, Nakazawa M, Momma K, et al.
Impaired distensibility of neoaorta after arterial switch procedure.
Ann Thorac Surg. 2000;70:1907-1910
I read with great interest the paper by Raphael et al. in Heart regarding the seemingly paradoxical effect of high blood pressure (BP) and improved survival in chronic heart failure (1). Shortly after this was accepted/available on online and typically characteristic of the tempo of research, was the publication by Grigorian-Shamagian L et al. who followed up 1062 patients with chronic heart failure (CHF) for a mean of 1.9 ye...
I read with great interest the paper by Raphael et al. in Heart regarding the seemingly paradoxical effect of high blood pressure (BP) and improved survival in chronic heart failure (1). Shortly after this was accepted/available on online and typically characteristic of the tempo of research, was the publication by Grigorian-Shamagian L et al. who followed up 1062 patients with chronic heart failure (CHF) for a mean of 1.9 years and analysed changes in BP with survival. They also found an independent association between low baseline systolic blood pressure (SBP) and non sudden cardiac death, but interestingly changes in SBP during the following year did not influence survival, regardless of baseline SBP. The authors comment that
because the beneficial effects of drugs associated with increased survival (in their study angiotensin converting enzyme inhibitors and beta blockers) seem to be independent of their effects on SBP then changes in SBP should probably not influence the decision to use such drugs or continue their administration. They continue by saying that future studies should specifically investigate the effects of relevant drugs on BP and survival among patients with heart failure and low BP and whether the beneficial effects of drugs with known mortality benefit may be jeopardized by the concomitant use of BP lowering drugs with no such proven survival benefits.
(1)Raphael CE, Whinnett ZI, Davies JE, et al. Quantifying the paradoxical effect of higher systolic blood pressure on mortality in chronic heart failure. Heart. 2009;95:56-62.
(2)Grigorian-Shamagian L, Gonzalez-Juanatey JR, Vazquez R et al. Association of blood pressure and its evolving changes with survival of patients with heart failure. J Cardiac Fail 2008;14:561-568.
The
guidance on drug-eluting stents by Richarson et al. (1) is a typical
application of the value-based approach that NICE systematically uses to
examine costs and benefits of innovative treatments.
The
guidance on drug-eluting stents by Richarson et al. (1) is a typical
application of the value-based approach that NICE systematically uses to
examine costs and benefits of innovative treatments.
In
countries like Italy
where national regulatory agencies do not use any value-based approach in their
approval process, appraisals on whether or not innovative interventions are
value for money are left to individual researchers or to the work of scientific
societies. While the impact of such unofficial appraisals is admittedly low,
one advantage is that the speed of completion of these analyses is faster.
With
respect to Italian costing data, Table 1 summarises the value-based data of 4
innovative treatments in the area of interventional cardiology published in the
website of an Italian scientific society. The real price (RP) and the
value-based price (VBP) are reported for each of these 4 devices and compared
with one another. One point of strength of this analysis is the speed of
availability of the information in relation to the date of publication of the
original clinical data (e.g. reference 3).
These
comparisons of RP versus VBP show a remarkable heterogeneity that both
decision-makers and clinicians are generally unaware of. Extreme situations
include, on the one hand, carotideal filters (that are currently paid for much
more than their value-based price) and, on the other hand, drug-eluting stents
in acute myocardial infarction (that could claim, according to value-based
principles, a nearly ten-fold increase in their price if their favourable
impact on survival is confirmed by further studies).
Regardless
of whether or not individual countries have incorporated value-based analysis
in their regulatory approval process, it becomes increasingly clear that all
health-care professionals will have to gain more and more familiarity with
these issues in the near future; many of them will probably be called to
discussing value-based data and even to understanding why agreement or
discrepancies are found between RP and VBP. From this perspective, the case of
drug-eluting stents used for their on-label indications or acute myocardial
infarction is particularly interesting.
References
1.
Richardson J, Stevens A, Barnett D, Longson C. Drug-eluting stents for the
treatment of coronary artery disease: NICE technology appraisal guidance. Heart.
2008 Sep 3. [Epub ahead of print]
2. Trippoli S. Definizione del
prezzo dei dispositivi medici innovativi sulla base del rapporto costo
efficacia (abstract),XXIX Congresso Nazionale SIIFO, Napoli, 12 - 15
October 2008
3. Mauri L, Silbaugh TS, Garg P, Wolf RE,
Zelevinsky K, Lovett A, Varma MR, Zhou Z, Normand SL. Drug-eluting or bare-metal stents for acute
myocardial infarction- N Engl J Med 2008;359:1330-42.
Table 1. Innovative devices for
interventional cardiology: value-based information published
in the website of the Osservatorio Innovazione#.
Incremental benefit
Real price
(RP)
Value-based price (VBP)
Comparison
Drug-eluting stents for on-label indications*
Avoidance of 5.7 revascularisations for every
100 patients
EUR 1,600##
EUR 961
RP > VBP
Left ventricular assist device (Heartmate)
for end-stage heart failure
Survival gain of
9 to 16 months
per patient
EUR 75,000*
EUR 45, 000
to
82,426
RP ≈ VBP
Protective filters in carotideal stenting
Avoidance of 0.7 ipsilateral strokes for
every 100 patients
EUR 1,100*
EUR 300
RP > VBP
Drug eluting stents in acute myocardial
infarction
Survival gain of 2.65 months per patient
EUR 1,412**
EUR 13,567
RP < VBP
# All but
one of these examples have been published over the past months in the website
In their review on statin use in controversial subgroups, Drs. Jukema
and Bergheanu [1] comment on the protective role of statin therapy in the
elderly at risk for cardiovascular events. We do not share that same
optimism, since statin therapy in this group has increased cancer at the
expense of decreasing cardiovascular disease. Moreover, recent
investigations offer insight why this might occur.
In their review on statin use in controversial subgroups, Drs. Jukema
and Bergheanu [1] comment on the protective role of statin therapy in the
elderly at risk for cardiovascular events. We do not share that same
optimism, since statin therapy in this group has increased cancer at the
expense of decreasing cardiovascular disease. Moreover, recent
investigations offer insight why this might occur.
Importantly, the PROspective Study of Pravastatin in the Elderly at
Risk (PROSPER) trial [2] is the only large randomized study that has
specifically investigated a statin compared to placebo for the prevention
of cardiovascular disease in the elderly at high risk for subsequent
cardiovascular disease events. The mean age at trial entry was 75 years
and the trial duration was 3.2 years. Cancer incidence was significantly
increased in the statin treated subjects, resulting in an increase in
cancer mortality equal in magnitude to the decrease in cardiovascular
mortality, leaving all-cause mortality unchanged.
Statins are immunosuppressive and have been shown to increase the
numbers and functionality of peripheral regulatory T cells (Tregs) in vivo
by increasing the transcription factor forkhead box P3 [3]. This might
impair host innate [4] and adaptive [5] antitumour immune responses,
culminating in increased cancer incidence. Expectedly, increased Treg
numbers in many solid tumours predict a worse survival prognosis [5].
The elderly might be particularly subject to adverse outcomes from
the immunosuppressive effects of statin therapy, since they are already
relatively immunosuppressed due to aging [6] and much more likely to
harbor micrometastatic foci of dormant tumour cells [7]. The delicate
balance between tumour dormancy and growth might be altered favoring
growth, in the face of a statin induced increase in Treg numbers and
functionality [8]. This is important, since statin trials have largely
excluded individuals with prevalent or remote cancer. However, in
practice, statins are commonly used, regardless of a history of cancer.
Until well designed prospective trials demonstrate that statin
therapy in the elderly decreases all-cause mortality without increasing
cancer mortality, we favor emphasizing non-immunosuppressive modalities
for the prevention of cardiovascular disease in this age group. These
include, but are not limited to, diet, exercise, anti-platelet agents and
blood pressure control.
References
[1] Jukema JW, Bergheanu SC. Statins: established indications and
controversial subgroups. Heart 2008; 94: 1656-1662.
[2] Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly
individuals at risk of vascular disease (PROSPER): a randomised controlled
trial. Lancet 2002; 360: 1623-1630.
[3] Mausner-Fainberg K, Luboshits G, Mor A, et al. The effect of HMG-
CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells.
Atherosclerosis 2008; 197: 829-839.
[4] Tiemessen MM, Jagger AL, Evans HG, et al. CD4+CD25+Foxp3+
regulatory T cells induce alternative activation of human
monocytes/macrophages. Proc Natl Acad Sci USA 2007; 104: 19446-19451.
[5] Yakirevich E, Resnick MB. Regulatory T lymphocytes: pivotal
components of the host antitumor response. J Clin Oncol 2007; 25: 2506-
2508.
I am grateful to Dr De Belder for his thoughtful response to my original comments. Ordinarily I would leave the author the last say however Dr De Belder has raised fresh issues that merit a response. I will address those issues.
The possibility of clinical benefit in the form of mortality and morbidity reducti...
I am grateful to Dr De Belder for his thoughtful response to my original comments. Ordinarily I would leave the author the last say however Dr De Belder has raised fresh issues that merit a response. I will address those issues.
The possibility of clinical benefit in the form of mortality and morbidity reduction does not by itself permit the conclusion that there is benefit. The idea that, where there is equipoise, the presumption must be in favour of treatment is certainly one that a fee-payer can validly challenge.
NICE is not an independent body. It is a creature of statue.It was created on the 26th February 1999 by order of the Secretary of State for Health.1 NICE is subject to directions given by the Secretary of State for Health.2 By instruction 2(f) of these instructions one function of NICE is:
“to look into and consider, for the purpose of advising the Secretary of State with regard to possible improvements in the provision of health services and in the effective use of available resources…”
Thus NICE is an organ to advise the Secretary of State for Health in relation to some of the decisions that are necessary to discharge their duty to provide a national healthcare service.3 To deal with NICE is to indirectly engage with political decision-making. The broad inclusiveness, general transparency and sheer power of the process evidence this fact. Whilst NICE does purport to stand free of political interference in its processes it’s substantive role cannot be independent of Government.
The existence of an affordability gap is a consequence of health care rationing. A recent report of the House of Commons select Committee on Health looking at NICE recommended inter alia:
“NICE has a vital role to play in the rationing arrangements and, working with Government, should make clear to the public how and why such decisions are made.”4
In their response the Government accepted that:
“It is … clear that there is a vital role for NICE in the rationing of healthcare and in encouraging best clinical practice.”5
One place for clinicians to engage is therefore to face the reality of rationing and to engage the public, their patients and the healthcare system to address how this reality can be faced practically. There are no easy answers here.
The value of the treatment to the patient is extremely important. However on the generally utilitarian NICE approach only the fee-payer’s perception of the value of the treatment to patients in general is taken into account. The decision making process is not sensitive to individual patient preferences.
One way in which individual patient preferences can be taken into account, at least for those patients able to partially fund their own treatment is to consider a co-payment option. This has been recently accepted for some forms of cancer treatment.6 In principle this can also operate in relation to the choice of bare metal versus drug-eluting stents.
The logical basis for this is that the clinical evaluation for treatments within the “affordability gap” differs when compared to the clinical evaluation for treatments that lie outside this gap. Outside the affordability gap the clinician simply asks themselves what is the most powerful evidence-based treatment available? Within the affordability gap the clinician is caught by the choice between the best available evidence-based treatment and the treatment option the fee-payer will fund. By definition these two are different and the funded treatment has lesser clinical efficacy.
Where an alternative funding source is available a personal choice is faced by the NHS clinician:
(1) loyalty to NICE, the NHS and to the current system; or
(2) loyalty to the duty the doctor owes to their individual patient.
Here the fee-payer is the Government advised by NICE. Notice how the choice is faced by the NHS clinician is a consequence of the rationing option selected by the fee-payer.
If the alternative source of funding is the patient then we find that, in the affordability gap, there is no moral reason not to permit the patient to pay a top-up fee and to use the drug-eluting stent. The full argument is made in the paper cited by Dr De Belder.7
This is another point at which both clinicians and their representative bodies, e.g. the British Cardiac Society, can engage in the ongoing debate.
References
1 National Institute for Clinical Excellence (Establishment and Constitution) Order 1999,No. 220
2 Directionsand Consolidating Directions to the National Institute for Health and Clinical Excellence 2005.
(www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsLegislation/DH_4109216)and amended in 2007.
3 S.1 NHS Act 1977
4 First Report from the Health Committee, Session 2007-08, HC 27 at para247
5 The Government's Response to the Health Select Committee's First Report of Session 2007-08 on the National Institute for Health and Clinical Excellence. Cm 7331at p.2
6 Richards M. Improving access to medicines for NHS patients. www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_089927
7 Mohindra RK; Hall JA. Desmond's non-NICE choice: dilemmas from drug-eluting stents in the affordability gap. Clinical Ethics 2006;1(2):105-8(4)
The paper of De Bruyne B, Sarma J. [1] reads very well as a tutorial
on how to use FFR in a variety of clinical circumstances. However, there
are several inaccurate statements in this tutorial and important aspects
of coronary physiology are completely neglected. A major misconception is
the underlying assumption of the tutorial as expressed by Fig. 1 [1].
It is erroneous and misleading to regard the coronary s...
The paper of De Bruyne B, Sarma J. [1] reads very well as a tutorial
on how to use FFR in a variety of clinical circumstances. However, there
are several inaccurate statements in this tutorial and important aspects
of coronary physiology are completely neglected. A major misconception is
the underlying assumption of the tutorial as expressed by Fig. 1 [1].
It is erroneous and misleading to regard the coronary system as being
linear, i.e. presenting the coronary pressure-flow relation as straight
and passing through the origin of the pressure flow plot. The course of
such a relationship implies the claim that coronary flow is zero only when
coronary pressure is zero. This is simply not the case. Early on it has
been documented that in a beating heart and in the absence of collateral
flow 1) the pressure-flow relation is concave towards the flow axis for
lower pressures, 2) the pressure at which flow stops is higher than
coronary venous pressure and 3) the pressure flow relation in the
physiological pressure range may be approximated as incremental linear but
its extrapolated intercept with the pressure axis, Pzf, corresponds to a
value equal to about half of the mean left ventricular pressure[2,3]. Pzf
may easily be as high as 25 mmHg. The reasons for these characteristic
features of the coronary pressure-flow relation are simple: 1) vessels are
not rigid pipes but elastic tubes that change diameter when vascular
pressure is altered and 2) compressive forces related to heart contraction
affect especially the hydraulic conductivity of the inner layers of the
myocardial wall [4]. All these aspects were recently discussed in a Basic
Science for Clinicians paper [5] but apparently went unnoticed by the
authors of this tutorial.
Is all this basic science literature not relevant to the clinical
case? Of course it is, since continue to work on a false paradigm forms a
serious impediment of clinical scientific progress. Would as a result FFR
be useless as a clinical index? Of course not since the usefulness of FFR
in some conditions is supported by several clinical epidemiological
studies. However, clinical usefulness is not proof of the underlying
assumptions of FFR.
The tutorial is presumptuous at several places but especially when it
claims that FFR combined with angiography ‘emerges as the only true
‘‘all-in-one’’ approach’ of studying coronary patophysiology in
the clinic. Adding flow-velocity measurement to the pressure measurement,
a technology that is available now for some years, allows to distinguish
between stenosis resistance and microvascular resistance [6,7] which
cannot be done by FFR because the needed assumption that stenosis
resistance and microvascular resistance are independent of flow, pressure
and myocardial function is plain wrong.
This author is certainly respectful to the FFR principle and many of
its clinical applications. This letter would not have been written if the
authors had followed the acceptable procedure of making the reader aware
of the basic physiological literature and stipulated that their tutorial
was based on assumptions in order to improve readability of the paper.
However, this letter seems needed since misconceptions are presented as
facts.
1) De Bruyne B and Sarma J. Fractional flow reserve: a review
Heart 2008; 94: 949-959
2) Downey JM, Kirk Inhibition of coronary blood flow by a vascular
waterfall mechanism. ES. Circ Res. 1975;36:753-60.
3) Hoffman JI, Spaan JA Pressure-flow relations in coronary
circulation. Physiol Rev. 1990;70:331-90.
4) Fokkema DS, VanTeeffelen JW, Dekker S, Vergroesen I, Reitsma JB,
Spaan JA. Diastolic time fraction as a determinant of subendocardial
perfusion. Am J Physiol Heart Circ Physiol. 2005 ;288:H2450-6
5) Spaan JA, Piek JJ, Hoffman JI, Siebes M. Circulation.
Physiological basis of clinically used coronary hemodynamic indices. 2006
24;113(3):446-55.
6) Siebes M, Verhoeff BJ, Meuwissen M, de Winter RJ, Spaan JA, Piek
JJ. Single-wire pressure and flow velocity measurement to quantify
coronary stenosis hemodynamics and effects of percutaneous interventions.
Circulation. 2004 Feb 17;109(6):756-62.
7) Verhoeff BJ, Siebes M, Meuwissen M, Atasever B, Voskuil M, de
Winter RJ, Koch KT, Tijssen JG, Spaan JA, Piek JJ. Influence of
percutaneous coronary intervention on coronary microvascular resistance
index. Circulation. 2005 Jan 4;111(1):76-82.
Riezebos et al. have published an elegant study trying to inform a
critically important question on the optimal timing of patients admitted
with a non-ST elevantion ACS suitable for revascularization. In this study
which despite being multicentric had a very slow recruitment rate, the
main difficulty lies in understanding the value of cardiac enzyme
measurements as an outcome, given that patients were considered to have a...
Riezebos et al. have published an elegant study trying to inform a
critically important question on the optimal timing of patients admitted
with a non-ST elevantion ACS suitable for revascularization. In this study
which despite being multicentric had a very slow recruitment rate, the
main difficulty lies in understanding the value of cardiac enzyme
measurements as an outcome, given that patients were considered to have an
MI if the CK-MB was elevated above x1. If these endpoints were entirely
removed, then the event rates are identical both at an early and
intermediate timepoint of 6 months. Perhaps an LVEF or cardiac MRI measure
of size of infarct would be the ideal method of assessment. Certainly if
patient orientated measures were used - length of stay, rehospitalisation,
further procedures, other late events, quality of life and functional
status at 6 months - these measures would fare equally or an advantage to
an early revascularization strategy for measures such as length of stay.
Furhtermore the recruitment period of upto 2007 practice may not reflect
the higher loading doses of clopidogrel commonly used and also often these
medications are now prescribed in the ambulance en route to the
interventional centre. These factors impose an important limitation to the
interpretation of the OPTIMA trial, whose concept is still valid for a
decision making larger trial based on more complete assessment of infarct
size.
In the study looking at cardiac CT angiography (CTA) using perfusion scintigraphy as the reference standard (1), cardiac CTA had a sensitivity of 75%, specificity of 98%, positive predictive value of 68%, and negative predictive value of 99%. The authors concluded that cardiac CTA had a moderate sensitivity, a moderate positive predictive value, high specificity and a high negative predictive value.
What is wrong with thi...
What Constitutes a Simple and Useful Risk Score?
We read with interest the study by Dr. Gale and colleagues.[1] We fully agree with the authors that age, heart rate, and systolic blood pressure are among the most powerful prognosticators in acute coronary syndromes (ACS).[2,3] However, we believe that several key issues deserve clarification.
First, by dichotomizing continuous variables such as creatin...
Dear Editor, The recent article by Davies and colleagues (1) discussed the role of aorta in directing coronary circulation. They mainly treated the subject from the viewpoint of blood pressure, however, there remains a further point which needs to be clarified: namely, the coronary blood flow. The aorta serves predominantly as a cushioning reservoir of blood during systole, and thereafter expelling it to the peripheral c...
I read with great interest the paper by Raphael et al. in Heart regarding the seemingly paradoxical effect of high blood pressure (BP) and improved survival in chronic heart failure (1). Shortly after this was accepted/available on online and typically characteristic of the tempo of research, was the publication by Grigorian-Shamagian L et al. who followed up 1062 patients with chronic heart failure (CHF) for a mean of 1.9 ye...
The guidance on drug-eluting stents by Richarson et al. (1) is a typical application of the value-based approach that NICE systematically uses to examine costs and benefits of innovative treatments.
...
In their review on statin use in controversial subgroups, Drs. Jukema and Bergheanu [1] comment on the protective role of statin therapy in the elderly at risk for cardiovascular events. We do not share that same optimism, since statin therapy in this group has increased cancer at the expense of decreasing cardiovascular disease. Moreover, recent investigations offer insight why this might occur.
Importantly, th...
I am grateful to Dr De Belder for his thoughtful response to my original comments. Ordinarily I would leave the author the last say however Dr De Belder has raised fresh issues that merit a response. I will address those issues.
The possibility of clinical benefit in the form of mortality and morbidity reducti...
The paper of De Bruyne B, Sarma J. [1] reads very well as a tutorial on how to use FFR in a variety of clinical circumstances. However, there are several inaccurate statements in this tutorial and important aspects of coronary physiology are completely neglected. A major misconception is the underlying assumption of the tutorial as expressed by Fig. 1 [1].
It is erroneous and misleading to regard the coronary s...
Riezebos et al. have published an elegant study trying to inform a critically important question on the optimal timing of patients admitted with a non-ST elevantion ACS suitable for revascularization. In this study which despite being multicentric had a very slow recruitment rate, the main difficulty lies in understanding the value of cardiac enzyme measurements as an outcome, given that patients were considered to have a...
Pages