In my review on risk stratification in acute coronary syndromes,
"diagnostic value" was used conventionally to refer to the ability of
predischarge tests to predict future coronary events, particularly death
and myocardial infarction.
In response to the 3 additional points:
1. Cost-effectiveness Underwood et al are correct to caution me on
statements of cost-effectiveness. My contention was (...
1. Cost-effectiveness Underwood et al are correct to caution me on
statements of cost-effectiveness. My contention was (and remains) that
predischarge stress testing is usually as effective as perfusion imaging
for risk stratification and costs less. The superior quality of SPECT
compared with conventional perfusion imaging may confer some advantage
(see below) but the considerable capital costs involved will inevitably
limit its application.
2. Exercise ECG versus Perfusion Imaging Underwood et al are
incorrect to infer superiority of predischarge perfusion imaging from the
data presented in the metaanalysis of Shaw et al (1). Cardiac event rates
were higher in the studies of myocardial perfusion imaging, readily
accounting for the apparent difference between positive predictive values
for these diagnostic tests. It is for the same reason, incidentally, that
both tests appear to perform better in patients who have not received
thrombolytic therapy. Shaw emphasises in her metaanalysis that both the
exercise ECG and the radionuclide perfusion scan are blunt tools for risk
stratification and my algorithm recommends use of either test, without
expressing a preference. Underwood et al draw attention to 3 papers
comparing the exercise ECG with SPECT imaging that post-dated ShawÆs
metaanalysis (2-4). Two showed some advantage for SPECT imaging although
positive predictive values for events after hospital discharge appeared
low (specific data not provided), confirming previous reports (2-3). The
other was a small (n=71) retrospective series, in which the only
multivariate predictor of death and recurrent infarction was LV ejection
fraction (4). Only when the endpoint was extended to incorporate unstable
angina and heart failure did perfusion imaging provide independent
prognostic information. Set against the 36 studies (16,960 patients)
included in ShawÆs metaanalysis, the additional 3 selected by Underwood et
al are not overly persuasive but suggest that SPECT technology may have an
edge over the exercise ECG for risk stratification.
3. Incremental value of perfusion imaging Although one of the
studies quoted by Underwood et al found that SPECT perfusion imaging was
not independently predictive of death and recurrent infarction if LV
ejection fraction was included in the multivariate model (4), they quote
another in which incremental value was demonstrated (5). Data for stress
testing are similarly contradictory. For this reason I recommended
application of these tests (exercise ECG or perfusion scan) only in
patients with advanced LV dysfunction (LVEF <_40 in="in" whom="whom" risk="risk" is="is" greatest.="greatest." unpublished="unpublished" data="data" for="for" our="our" own="own" low="low" patients="patients" discharged="discharged" with="with" lvef="lvef"/>40% by GUSTO criteria (6)) show the estimated risk of death in
the first year is only 3.8% (2.1-5.4%) and of death and recurrent
infarction 9.8% (7.1-12.4%). The idea that these relatively low risk
survivors of acute myocardial infarction would benefit from further risk
stratification using perfusion imaging (or stress tesing) seems barely
credible. This does not of course mean that the tests should not be done
but it does mean that incautious predictions of "cost-effectiveness" may
In summary, SPECT imaging may offer a small advantage over the
exercise ECG for detection of residual ischaemia in patients with acute
coronary syndromes, although it remains a blunt tool for risk
stratification. Speaking from the perspective of the coronary care unit,
there is no doubt that the availability and low cost of exercise testing
(as opposed to the relative nonavailabiltiy and high cost of SPECT
imaging) will make it a more practical solution for predischarge risk
stratification in most centres. However, perfusion imaging is a
reasonable, perhaps better, alternative in those units able to provide a
predischarge service for upward of 700 coronary patients per year, and my
algorithm allows for this.
Adam D Timmis MD, FRCP
1. Shaw LJ, Peterson ED, Kesler K, Hasselblad V, Califf RM. A
metaanalysis of predischarge risk stratification after acute myocardial
infarction with stress electrocardiographic, myocardial perfusion, and
ventricular function imaging. Am J Cardiol 1996;78:1327-37.
2. Travin MI, Dessouki A, Cameron T, Heller GV. Use of exercise
technetium-99m sestamibi SPECT imaging to detect residual ischemia and for
risk stratification after acute myocardial infarction Am J Cardiol
3. Brown KA, Heller GV, Landin RS, Shaw LJ, Beller GA, Pasquale MJ,
Haber SB. Early dipyridamole (99m)Tc-sestamibi single photon emission
computed tomographic imaging 2 to 4 days after acute myocardial infarction
predicts in-hospital and postdischarge cardiac events: comparison with
submaximal exercise imaging. Circulation 1999;100:2060-6.
4. Dakik HA, Mahmarian JJ, Kimball KT, Koutelou MG, Medrano R, Verani
MS. Prognostic value of exercise 201Tl tomography in patients treated with
thrombolytic therapy during acute myocardial infarction. Circulation.
5. Mahmarian JJ, Mahmarian AC, Marks GF, Pratt CM, Verani MS. Role of
adenosine thallium-201 tomography for defining long-term risk in patients
after acute myocardial infarction. J Am Coll Cardiol 1995;25:1333-40.
First, there are no formal studies of the cost-effectiveness of risk stratification after infarction, and in their absence it is not warranted to extrapolate from the effectiveness and cost of individual tests to a statement on cost-effectiveness. To do so ignores induced costs (for instance when an abnormal exercise ECG leads to angiography without subsequent intervention), it ignores the relatively high failure rate of the exercise ECG after infarction (submaximal exercise, abnormal resting ECG, etc), and it ignores the need for further investigation in the chronic phase (such as myocardial perfusion imaging if this has not already been performed). For the diagnosis of coronary artery disease, there is now powerful evidence to indicate that strategies that include myocardial perfusion imaging are more cost effective than those that do not. Because diagnosis involves the detection of ischaemia and because persistent ischaemia after infarction is a key factor in prognosis, it is likely that formal studies of cost effectiveness of risk stratification would provide similar results.
Second, although the positive predictive value of any form of pre-discharge non-invasive testing is low, Dr Timmis ignores the superior positive predictive value of perfusion imaging compared with the exercise ECG in patients who have not received thrombolysis (13% versus 9% for death and 24% versus 18% for death or reinfarction). Since the distinction between patients who have and who have not received thrombolysis is mainly the size of their infarcts, it seems to us that a test that is capable of assessing infarct size and prognosis in those with large infarcts should not be cast aside so easily. Shaw and colleagues also emphasised the relatively poor quality of the studies available. For instance, three quarters of the studies were retrospective and one third reported fewer than 5 deaths, and they recognised the need for further studies to provide more reliable information. Further high quality studies are now available and we believe that the weight of evidence is that perfusion imaging is more effective than the exercise ECG for risk stratification after myocardial infarction.
Numerous studies have shown that inducible perfusion abnormalities are more common than ST segment changes on the exercise ECG. This extends observations from the era before thrombolysis when an inducible thallium defect was shown to be better than the exercise ECG for detecting and localising ischaemia and for identifying multi-vessel disease. However, because thrombolysis has reduced the event rate after infarction, there are those who argue that the event rate is now so low that myocardial perfusion imaging is less valuable after infarction than it was.  However these studies included a relatively low risk group with younger patients, preserved left ventricular function, and a low prevalence of multi-vessel disease. The higher risk patients were excluded because they mainly went straight to angiography and revascularisation and it is precisely these who would have been best identified by myocardial perfusion imaging if doubt remained after clinical assessment. In addition, selection bias was operating against perfusion imaging because when it was performed the results were used to guide intervention and hence to exclude the patient from follow-up. It is not surprising that non-invasive testing was not found to be valuable in the few remaining low risk patients.
In better designed studies there is now ample evidence that perfusion imaging is a valuable tool for risk stratification after infarction. Dakik and colleagues reported that a predischarge exercise myocardial perfusion scan in patients who had received thombolysis provided incremental prognostic information over and above clinical and ejection fraction data. In contrast, none of the variables from the exercise ECG contributed to the assessment of prognosis. Similarly, Travin and colleagues found that myocardial perfusion imaging within 14 days of infarction frequently revealed residual ischaemia and was better than clinical and exercise ECG variables in identifying patients at high risk. More recently, Brown and colleagues reported a multi-centre trial in patients with first acute infarction. Three hundred and thirty nine patients were randomised to early (2 to 4 days) dipyridamole myocardial perfusion imaging followed by predischarge (6 to 12 days) sub-maximal exercise imaging, and 112 patients were randomised to submaximal predischarge imaging alone. The findings of the early perfusion study were not available to the responsible physicians and hence patient management was not affected. Early dipyridamole imaging was safe and was predictive of both in-hospital and late cardiac events, and it was a stronger predictor than predischarge submaximal exercise ECG or submaximal exercise perfusion imaging. This prognostic value was independent of thrombolytic status.
Third, with regard to the influence of left ventricular function on prognostic power, Mahmarian and colleagues compared adenosine perfusion imaging and ejection fraction after infarction and found them to have complementary roles. They found that even patients with an ejection fraction greater than 40% were further stratified into low and high risk groups by the extent of the inducible perfusion defect. This study and the guidelines of the American College of Physicians contradict Dr Timmis's recommendation that further risk stratification is not required in asymptomatic patients with an ejection fraction greater than 40%. Indeed, the ACP guidelines suggest that these are the patients in whom non-invasive risk stratification is most successful.
With the growing pressure to reduce costs but maintain quality of care, accurate risk stratification at an early stage using myocardial perfusion imaging with vasodilator stress in all but the highest risk patients could have important benefits. Low risk patients could be discharged earlier than those at a higher risk and in-hospital cardiac events might be prevented. Because of the complementary role of perfusion and functional information, it is conceivable that combined assessment of both using gated SPECT could be highly effective in routine use, particularly since left ventricular end systolic volume appears to be more powerful in prognostic terms than ejection fraction alone.
In summary, we believe that there is sufficient evidence to modify Dr Timmis's algorithm to require early myocardial perfusion imaging rather than exercise ECG in all but the highest risk patients assessed by clinical criteria, and to include patients with relatively preserved LVEF in this strategy. We predict that such an approach will be cost-effective.
S Richard Underwood, MD, FRCP, FRCR, FESC
Imperial College School of Medicine
Royal Brompton Hospital
Sydney St, London SW3 6NP
Constantinos Anagnostopoulos MD, PhD
Royal Brompton Hospital
Sydney St, London SW3 6NP
Leslee J Shaw PhD
Emory University School of Medicine
1518 Clifton Road NE, Rm638
Atlanta, Georgia 30322, USA
1 Timmis A. Acute coronary syndromes: risk stratification. Heart 2000;83:241-6.
2 Shaw LJ, Peterson ED, Kesler K, et al. A metaanalysis of predischarge risk stratification after acute myocardial infarction with stress electrocardiographic, myocardial perfusion and ventricular function imaging. Am J Cardiol 1996;78:1327-37.
3 Underwood SR, Godman B, Salyani S, et al. Economics of myocardial perfusion imaging in Europe: the EMPIRE study. Eur Heart J 1999;20:157-66.
4 Shaw LJ, Hachamovitch R, Berman DS, et al. The economic consequences of available diagnostic and prognostic strategies for the evaluation of stable angina patients: an observational assessment of the value of precatheterisation ischaemia. J Am Coll Cardiol 1999;33:661-9.
5 Tilkemeier PL, Guiney TE, LaRaia PJ, et al. Prognostic value of predischarge low-level exercise thallium testing after thrombolytic treatment of acute myocardial infarction. Am J Cardiol 1990;66:1203-7.
6 Haber HL, Beller GA, Watson DD, et al. Exercise thallium-201 scintigraphy after thrombolytic therapy with or without angioplasty for acute myocardial infarction. Am J Cardiol 1993;71:1257-61.
7 Dakik HA, Mahmarian JJ, Kimball KT, et al. Prognostic value of exercise 201Tl tomography in patients treated with thrombolytic therapy during acute myocardial infarction. Circulation 1996;94:2735-42.
8 Miller TD, Gersh BJ, Christian TF, et al. Limited prognostic value of thallium-201 exercise treadmill testing early after myocardial infarction in patients treated with thrombolysis. Am Heart J 1995;130:259-66.
9 Travin MI, Dessouki A, Cameron T, et al. Use of exercise technetium-99m sestamibi SPECT imaging to detect residual ischemia and for risk stratification after acute myocardial infarction. Am J Cardiol 1995;75:665-9.
10 Brown KA, Heller GV, Landin RS, et al. Early dipyridamole (99m)Tc-sestamibi single photon emission computed tomographic imaging 2 to 4 days after acute myocardial infarction predicts in-hospital and postdischarge cardiac events: comparison with submaximal exercise imaging. Circulation 1999;100:2060-6.
11 Mahmarian JJ, Mahmarian AC, Marks GF, et al. Role of adenosine thallium-201 tomography for defining long-term risk in patients after acute myocardial infarction. J Am Coll Cardiol 1995;25:1333-40.
12 Peterson ED, Shaw LJ, Kesler K, et al. Clinical guideline: part II. Risk stratification after myocardial infarction. Ann Intern Med 1997;126:561-82.