Results
The derivation cohort included 273 consecutive SE with 90 females (33%)
and 183 males. Mean ± standard deviation (SD) age was 60±11 years. The
derivation cohort included 250 patients with non-ischemic SE and 23 with
tests suggestive of myocardial ischemia. All patients were followed up
for a mean 18±20 months.
The WMSI was calculated for both groups. The median WMSI for the
non-ischemic group was 1 (1-1) and was 1.65 (1.50-1.83) for the ischemic
cohort (p<0.0001 for the difference). The SV was estimated at
rest and post exercise and the ΔSV calculated. The mean ΔSV for the
non-ischemic group was 24.0ml (22.6 to 25.4) compared to 3.4ml (-1.1 to
8.2), p<0.0001 for the difference. A receiver operator curve
(ROC) analysis comparing non-ischemic and ischemic SE by ΔSV showed that
a ΔSV of less than 11ml had an optimal area under the curve (AUC) of
0.95, with a sensitivity of 95% and a specificity of 99%, p
< 0.0001) for myocardial ischemia. See Figure 3. Examples of
the Doppler tracings used to estimate the normal and abnormal ΔSV values
are shown in Figures 1 & 2.
Indexing for SV (SV divided by the body surface area) was also
performed. The ROC analysis using the Δ indexed SV
(ΔSVi) resulted in an optimal AUC of 0.78, with a
sensitivity of 72% and a specificity of 85%, p=0.001 (See Figure 4).
Based on these data, a cut-off value for a “normal ΔSV” was set as
>10ml. The ΔSVi was not used, as it
appeared to be a less discriminative measure.
To confirm there was no change in the LVOT diameter at the level of the
aortic valve before and after exercise, these measurements were taken
for all patients in the derivation cohort (n=273). The mean pre-exercise
diameter was 2.25cm (95% CI 2.24-2.27) and was 2.26cm (2.24-2.27)
post-stress, p=0.33, confirming that there was no significant change.
The validation cohort consisted of 1093 consecutive SE that were
available for analysis, with 376 females (34%) and 717 males. Mean ±
standard deviation (SD) age was 59±12 years. The baseline
characteristics are detailed in Table 1. There were 1000 patients with
non-ischemic SE, and 93 patients with SE suggestive of myocardial
ischemia. Total follow up was for 20,460 patients-months (up to 5 years
per patient, for a mean 37±23 months). The SV and CO data for
non-ischemic and ischemic stress echocardiograms are listed in Table 2.
The estimated SV was able to be performed in approximately 94% of
stress echocardiograms. Limiting factors included post exercise image
quality, inadequate Doppler envelopes (with subsequent inadequate VTI
measurement) and irregular electrical rhythms, especially bigeminy.
The mean maximum heart rate achieved by patients in the validation
cohort was 152±20bpm, which represented 98±19% of the MPHR. The mean
heart rate at the time the SV post was acquired was 108±38bpm, which was
68±25% of the maximum predicted heart rate. For the non-ischemic
patients, the heart rate was 108±39, and for the ischemic patients it
was 105±15, p=0.19 (see table 2).
Prognostic events for the follow-up period in the validation cohort were
subsequently analysed based on patient SV response to exercise, using
the ΔSV. Utilising the criteria from the derivation cohort, patients
were divided into two (2) groups: Group 1 had a normal ΔSV response to
exercise (>10ml) and group 2 had an abnormal ΔSV response
(≤10ml). The baseline characteristics of these two groups are detailed
in Table 3. The vast majority of the ischemic SE in were in group 2
(98% of the ischemic SE).
Multivariate Cox proportional hazard regression analysis demonstrated
that an abnormal ΔSV response (ΔSV ≤10ml) resulted in a hazard ratio
(HR) adjusted for age, sex, exercise capacity and Framingham risk score
of 10.3, with 95% confidence intervals (CI) of 5.6 to 19.1,
p<0.0001, for the combined adverse cardiac endpoints, adjusted
for age, gender, exercise capacity, ejection fraction and Framingham
risk score. The Kaplan Meier curves show early and on-going separation
(see Figure 6).
Cardiac deaths were rare events during follow up. None were seen in the
normal ΔSV group and three (3) noted in the abnormal ΔSV cohort.
Analysis of these limited data suggested a trend to increased mortality
in the abnormal ΔSV group with a HR of 12.4 (95% CI 0.85 to 18.0),
p=0.066.
The HR for subsequent invasive catherization based on a ΔSV ≤10ml was
4.92 (95% CI 3.76 to 6.45) p<0.0001, noting that the
overwhelming majority of these patients had an ischemic SE. These
patients were more likely to proceed to invasive catheterization on a
clinical basis, due to the SE result.
There were 99 patients who had an abnormal ΔSV response who had a
non-ischemic SE. These patients were shown to have increased risk
of an adverse cardiac event when compared to the 867 patients with a
non-ischemic SE who had a normal ΔSV exercise response. The HR was 3.2
with 95% CI 1.1-9.3, p=0.035. (see Figure 7) The majority of events
appeared to be ischemic in nature (angina pectoris or need for
percutaneous coronary intervention). Using a lack of adverse cardiac
outcomes as the baseline for a true negative test, the overall negative
predictive value for a normal SV response (ΔSV > 10ml) was
94%.