Risk stratification by stress echocardiography: a whiter shade of pale?

Please see page 205 for the article by Moreno et al. ( doi: 10.1016/j.euje.2003.11.008 ) to which this editorial pertains. In this issue of the Journal, Moreno et al. show the high negative predictive value of a negative dipyridamole stress echocardiogram in medically stabilized unstable angina. 1 The negative predictive value was, however, lower in male patients with previous myocardial infarction. This paper adds another significant piece of information on a 20 year old line of evidence supporting the efficiency of stress echo in risk stratification, and it also raises the important issue on the need to further improve the negative predictive value of stress echo in some clinically identifiable subsets. The paper written by Moreno et al. once again emphasizes what we learned during the past 25 years. The very coherent, simple and important conclusion is that stress echocardiographic test negativity makes the presence of a prognostically important organic coronary artery disease unlikely. 2 The excellent outcome associated with this response does not support the decision to proceed with coronary angiography and even less to go on with an anatomy-based revascularization. 3 On the contrary, a stress echocardiographic positivity identifies a group of patients at higher risk, in whom coronary angiography in view of an ischemia-driven revascularization is warranted. Moreno et al.'s paper is also interesting as it suggests that the negative predictive value of the test can be suboptimal in some subsets, since some events (even hard events) have occurred in male patients with previous myocardial infarction. There are several reasons for the suboptimal prediction of a negative stress echo. Firstly, it is very difficult for a stress test for ischemia to predict some “events”. The very same definition of “hard event” should be taken into account. The five deaths observed by Moreno et al. included one intracranial bleeding 1 month after, one sepsis 2 months after, and a stroke 19 months after testing. 1 Other cardiac events occur for phenomena (such as plaque fissuration, thrombosis and spasm) that are largely unrelated to the underlying plaque hemodynamic severity, which is mirrored in a positive stress echo. Stress test cannot reasonably and clearly predict such disparate events unrelated to the underlying coronary artery disease. This is asking too much for any form of stress testing, and we have to accept a certain degree of inability to predict all and every hard event. Secondly, most events occurred after 1 year from testing. It is probably wise to reassess the patient after 1 year. The situation can be changed substantially for the natural progression of coronary artery disease, and the test “warranty” may expire after 1 year. Thirdly, other parameters might be included in the evaluation of a negative stress echo response, such as the presence of anti-ischemic therapy at the time of testing and—as a potentially attractive new parameter—the coronary flow reserve on left anterior descending coronary artery. A recent work by Sicari et al. clearly showed that the presence of anti-ischemic therapy, at the time of testing, is important in modulating the prognostic impact of pharmacological stress echo. 5 Moreno et al. have evaluated patients often under antianginal treatment. Sicari et al. have demonstrated that, in presence of concomitant anti-ischemic therapy, a positive test is prognostically more malignant, and a negative test prognostically less benign. Another conceptually appealing approach to improve the negative predictive value is to add another variable to stress imaging: the coronary flow reserve evaluated on mid-distal left anterior descending coronary artery. With state-of-the-art technology and skilled operator, this may be easily achieved especially during vasodilator stress echo, and allows to have a semi-simultaneous, integrated assessment of flow and function. 6 This “dual imaging” approach allows to integrate coronary flow reserve assessment on the left anterior descending artery and the regional wall motion assessment into one test, and it is increasingly feasible with latest generation instruments. 6 This approach, not only allows to expand the diagnostic potential of the technique, 7 but also increases its prognostic potential. Particularly, the negative predictive value of a stress echo test for wall motion criteria is significantly higher in presence of a preserved coronary flow reserve. The clinical cardiologists might benefit from stress echo in the difficult task of risk stratification. As stated by Maseri, “identification of patients with known ischemic heart disease who are at low risk is important firstly, because it is reassuring for the patient; (…) and secondly, because it is difficult to demonstrate that even the most aggressive treatments can increase life expectancy when the latter is not reduced appreciably”. 8 The article written by Moreno et al. lends further support to the role of stress echo in this non-invasive stratification strategy. However, it also adds some important information. The stress echo response is not only in black-or-white, or in positive or negative. The positive response can be effectively titrated into a gamut of shades of grey, covering all possible risks—from lowest to highest. 4 A positivity of six akinetic–dyskinetic segments in a patient with resting ejection fraction <40% and evaluated under full anti-ischemic therapy is much more prognostically malignant than a positivity of two hypokinetic segments, with normal baseline function, in a test performed off therapy. Stress echo acts like a Newton's prism also for negative tests ( Fig. 1 ), destructuring the “homogeneous” low clinical risk of a “white” (negative) response into a spectrum of different risks, from relatively higher (male, previous myocardial infarction) to relatively lower (females, normal baseline function) risk. Further risk stratification will also be possible to obtain, taking into account time from stress testing, therapy at testing time, and coronary flow reserve on left anterior descending artery. Stress echo, compared to the perfusion scintigraphy, has the inherent advantage that serial testing does not induce cumulative biological damage in the patients, and therefore a policy of repeated follow-up testing is much more sustainable for the patient, the environment and the entire society. 9 All negative tests have a “white” risk code, but some—Moreno et al. 1 remind us—are whiter compared to others. The low risk of a negative stress echo in a patient with clinically stabilized unstable angina might be further stratified. Patients with a recent (<6 months) negative test off therapy, with normal baseline left ventricular function and with a preserved coronary flow reserve on left anterior descending artery by transthoracic echocardiography have a lower risk when compared to patients with old (>1 year) test, on antianginal therapy at the time of testing, abnormal baseline function and reduced coronary flow reserve. “ And so it was that later As the miller told his tale That her face at first just ghostly Turned a whiter shade of pale ” (Procol Harum “A whiter shade of pale”, 1967)