(Circulation. 1998;98:2855-2859.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports* |
Dipyridamole Stress Echocardiography for Risk Stratification in Hypertensive Patients With Chest Pain
From the Cardiovascular Unit, Hospital of Lucca, Italy.
Correspondence to Lauro Cortigiani, MD, Unità Operativa di Malattie Cardiovascolari, Ospedale Campo di Marte, 55032 Lucca, Italy.
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Abstract |
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Background—The noninvasive prognostic assessment of coronary artery disease (CAD) in hypertensive patients represents an unresolved task to date. In this study, we investigated the value of dipyridamole stress echocardiography in risk stratification of hypertensive patients with chest pain and unknown CAD.
Methods and Results—Dipyridamole stress
echocardiography was performed in 257 hypertensives
(110 men; age, 63±9 years) complaining of chest pain and without a
history of CAD. No major complications occurred. Four tests were
interrupted prematurely because of side effects, with 98.4%
feasibility of test. A positive echocardiographic
response was found in 72 patients (27 during the low-dose [
0.56
mg/kg] and 45 during the high-dose [>0.56 mg/kg]). During the
follow-up (32±18 months), 27 cardiac events occurred: 3 deaths, 8
infarctions, and 16 cases of unstable angina. Moreover, 27 patients
underwent coronary revascularization. At
multivariate analysis, the positive
echocardiographic result (OR, 5.5; 95% CI, 1.4 to
16.6) was the only predictor of hard cardiac events (death,
infarction). Considering spontaneous cardiac events (death, infarction,
and unstable angina) as end points, the positive
echocardiographic result (OR, 4.2; 95% CI, 1.8 to 9.6)
and family history of CAD (OR, 4.2; 95% CI, 1.5 to 6.9) were
independently associated with prognosis. The 3-year survival rates for
the negative and the positive populations were, respectively, 97% and
87% (P=0.0019) considering hard cardiac events and 96%
and 74% (P=0.0000) considering spontaneous cardiac
events.
Conclusions—Dipyridamole stress echocardiography is safe, highly feasible, and effective in risk stratification of hypertensives with chest pain and unknown CAD. At present, it represents an attractive option for prognostic assessment of this clinically defined population.
Key Words: echocardiography • dipyridamole • prognosis • hypertension • coronary disease
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Introduction |
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The noninvasive prognostic assessment of hypertensive patients with chest pain is a particularly important goal in daily clinical practice, because hypertension is one of the major cardiovascular risk factors.1 However, it represents an unresolved problem to date. In fact, traditional exercise-dependent techniques, such as electrocardiography2 3 4 and perfusion scintigraphy,5 6 7 have suboptimal diagnostic specificity in patients with systemic hypertension and therefore lack capability to adequately categorize patients into low- and high-risk subgroups. In recent years, echocardiography combined with physical or pharmacological stress has attracted growing interest for diagnostic purposes in hypertensive patients, having shown higher specificity without loss in sensitivity compared with both exercise electrocardiography8 9 10 and perfusion scintigraphy.11 Nevertheless, the prognostic value of stress echocardiography in hypertensives remains to be determined.
On the basis of these data, we sought to investigate the value of dipyridamole stress echocardiography in risk stratification of hypertensive patients referred for chest pain who had unknown coronary artery disease (CAD).
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Methods |
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Patients
The study population was represented by 257 patients (110 men, 147 women; age, 63±9 years [mean±SD]) with mild to moderate hypertension who underwent dipyridamole stress echocardiography for evaluation of chest pain between October 1990 and April 1997. No patient had known CAD, as defined by history of myocardial infarction, unstable angina, coronary revascularization, and/or angiographically assessed stenosis >50% of any of the 3 coronary arteries or their major branches. Furthermore, no patient had significant valvular disease or dilated or hypertrophic cardiomyopathy. All patients had interpretable echocardiographic images both in the resting condition and during stress testing.
Hypertension was defined by systolic pressure 
140 mm Hg
and/or diastolic pressure 90 mm Hg in >1
determination and/or treatment with antihypertensive
therapy.12
At the time of the test, all patients were receiving antihypertensive
drugs, consisting of diuretics, ACE inhibitors, and
-blockers individually or in combination at the dosage adequate to
obtain blood pressure control. In 245 patients (95%), stress testing
was performed after washout of antianginal drugs, discontinuing
ß-blockers for 48 hours and long-acting nitrates and calcium
channel blockers for 24 hours before the test. In the remaining 12
patients (5%), the test was performed under therapy with ß-blockers
(n=5), calcium channel blockers (n=8), and/or nitrates (n=7). Moreover,
no patient took phylline-containing drugs or beverages for 24
hours.
Stress Protocol
Dipyridamole was administered
intravenously according to the high-dosage protocol (up to
0.84 mg/kg over 10 minutes).13 Starting in April 1993, the
stress protocol was modified with the coadministration of atropine (up
to 1 mg over 4 minutes).14
A 2-dimensional echocardiogram and 12-lead ECG were continuously monitored during the test and until the heart rate had returned to baseline value±10% during the recovery phase. Cuff blood pressure and the ECG were recorded every minute.
Criteria for test interruption were onset of obvious new wall motion
abnormalities, severe chest pain, horizontal or downsloping ST-segment
depression 2 mm, ST-segment elevation 1.5 mm,
symptomatic hypotension, supraventricular or
ventricular tachyarrhythmias, and
intolerable symptoms. Intravenous aminophylline (up to 240
mg) was immediately available to reverse the effects of
dipyridamole.
Echocardiographic Analysis
Echocardiographic images were obtained
continuously from the standard apical and parasternal views with
commercially available instruments (Sonos 2000, Hewlett Packard;
Sonotron 800, Vingmed; Ultramark-7, ATL). From 1990 to 1995, images
were recorded continuously on S-VHS videotape recorders
(Panasonic MD 830; Panasonic 7330) for off-line visual
analysis; starting in 1996, images were also recorded by
use of a quad-screen cine-loop system. Images were evaluated by 2
independent observers. In case of disagreement, a third observer
evaluated the images, and his or her judgment was binding.
Regional wall motion was semiquantitatively assessed in a 16-segment model of the left ventricle.15 A 4-point score was assigned to each segment as follows: 1=normal, 2=hypokinesia, 3=akinesia, and 4=dyskinesia. A wall motion score index (WMSI), obtained by dividing the sum of individual segment scores by the number of segments considered, was calculated both at baseline and at the peak of drug infusion.
The result of a test was considered positive when any new regional wall motion abnormalities or worsening of preexisting ones was detected.
The test was defined as positive at low or at high dose when new wall
motion abnormalities appeared after 0.56 mg/kg or >0.56 mg/kg of
dipyridamole, respectively, had been infused.
In our experience, the intraobserver and interobserver reproducibility in stress echo readings is 92% and 89%, respectively, as previously described.16
ECG Analysis
ECG changes were considered to be ischemic if an
ST-segment shift 0.1 mV from baseline at 80 ms after the J point
occurred in at least 2 contiguous leads.
In the case of right bundle-branch block, the ST-segment shift was
considered to be significant when it also occurred in lead
V5 and/or
V6.17 ECG changes were not taken as
criteria for positivity of the test in the absence of induced new wall
motion abnormalities; however, the development of ST-segment depression
2 mm or ST-segment elevation 1.5 mm was considered to be
significant enough for interruption of the test. In patients with left
bundle-branch block, preexisting ST-segment depression 0.1 mV, or
paced rhythm as well as in patients taking digitalis or antiarrhythmic
medications, ECG changes were considered nondiagnostic.
Follow-Up Data
Follow-up data were obtained from review of the patient's
hospital chart, contact with the patient's physician, telephone
interview with the patient, and periodic visits in our outpatient
clinic. The follow-up data were available for all patients. The
clinical events recorded during the follow-up were cardiac and
noncardiac deaths, myocardial infarction, unstable angina, and
coronary revascularization procedures
(surgery or angioplasty).
The cause of death was established from hospital or physician records; death was attributed to a cardiac origin in the case of documentation of significant arrhythmias and/or cardiac arrest, congestive heart failure, or myocardial infarction. Moreover, any death that occurred suddenly out of hospital was ascribed to a cardiac cause. The diagnosis of acute myocardial infarction was made on the basis of symptoms, ECG changes, and cardiac enzyme level increases. Unstable angina was defined by angina at rest or change in pattern of preexisting angina requiring hospitalization.
Statistical Analysis
Values were expressed as mean±SD for continuous variables
and as frequency and percentage for categorical variables.
Continuous variables were compared by Student's unpaired
t test, and differences of categorical variables were
assessed by the 
2 test. The Kaplan-Meier
method was used for estimation of infarction-free survival and of
event-free survival. For survival analysis, only 1 event was
considered in each patient. When patients underwent coronary
revascularization, they were censored at the time
of the procedure. Likewise, when patients died of noncardiac causes,
they were censored at the time of death.
The differences of the survival curves were analyzed by the log-rank test.
The capability of certain variables to predict subsequent outcome
was assessed by the Cox proportional hazard model using
univariate and stepwise multivariate
analysis (SPSS for Windows, 1995). The differences in risk were
expressed as ORs with the corresponding 95% CIs. The analysis
included the following variables: age (<65 or 65 years), sex,
family history of CAD, hypercholesterolemia,
cigarette smoking, diabetes, dipyridamole stress
echocardiographic result (positive/negative), dose of
drug to induce echocardiographic positivity, WMSI at
peak of drug infusion, rest-stress WMSI variation
(representing an integrated estimation of the extent and
severity of wall motion abnormalities), ECG changes during the test,
and angina during the test.
A value of P<0.05 was considered statistically significant.
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Results |
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Feasibility and Side Effects
No major complications occurred during dipyridamole stress echocardiography. Of 257 tests, 4 were interrupted prematurely because of the appearance of limiting side effects, consisting of severe chest pain in the absence of new wall motion abnormalities (n=2), symptomatic hypotension (n=1), and atrial fibrillation (n=1). Therefore, the overall feasibility of the test was 98.4%. All side effects were reversed by aminophylline administration. The results of these 4 patients who did not complete the stress protocol were included in the analysis, and the tests were considered negative for ischemia.
Stress Echocardiography Results
Atropine was added to dipyridamole in 100 patients
(39%). The following changes in hemodynamic profile
were documented at peak of stress: increment of heart rate from 70±12
to 109±17 bpm, reduction of systolic blood pressure from
142±20 to 139±23 mm Hg, reduction of diastolic
blood pressure from 84±10 to 77±12 mm Hg, and increment of
rate-pressure product from 10 568±7181 to 15 225±3744.
Echocardiographic positivity was identified in 72 patients (28%), 27 during the low and 45 during the high dose (11 patients during atropine administration). In the positive population, the WMSI increased from 1.05±0.11 in resting conditions to 1.36±0.19 at peak of drug infusion.
Of the remaining 185 patients with negative stress testing results, 38 (21%) developed an isolated ST-segment depression during dipyridamole infusion.
The clinical characteristics and the baseline and stress
echocardiography results for the study population
are illustrated in Table 1
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Follow-Up Data
During a follow-up of 32±18 months, there were 27 cardiac events
(3 deaths, 8 myocardial infarctions, and 16 cases of unstable angina)
and 5 deaths of noncardiac causes (4 cancer and 1 stroke). Moreover, 27
patients underwent coronary
revascularization with either surgery (n=18) or
angioplasty (n=9), 22 within 3 months (mean, 1.4±1.0 months) and 5
after 3 months (mean, 12.6±17.6 months) from stress testing. Patients
with positive echocardiographic results who underwent
coronary revascularization were found to
have a greater frequency of low-dose than high-dose positivity (52%
versus 24%; P=0.018) and higher rest-stress WMSI variation
in comparison with patients treated conservatively (0.40±0.17 versus
0.26±0.10; P<0.001). Table 2
summarizes the incidence of cardiac events and
revascularization procedures in the positive and in
the negative population.
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The incidence of cardiac events in the negative population was similar for patients evaluated with (n=89) and without (n=96) atropine (6.7 versus 5.2%; P=NS).
Finally, no event occurred among 38 patients who developed ECG but not echocardiographic positive response during stress testing.
Survival Analysis
Considering hard cardiac events (death, myocardial infarction) as
end points, the following variables showed a decremental prognostic
power at univariate analysis: positive
echocardiographic result (P=0.0060),
rest-stress WMSI variation (P=0.0076), low-dose positive
echocardiographic result (P=0.0176), and
peak-stress WMSI (P=0.0235) (Table 3). At multivariate
analysis, the positive echocardiographic result
(OR, 5.5; 95% CI, 1.4 to 16.6; P=0.0143) was the only
variable independently correlated with prognosis.
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When spontaneous cardiac events (death, myocardial infarction,
and unstable angina) were considered as end points, the strongest
univariate predictor of outcome was the positive
echocardiographic result (P=0.0000),
followed by rest-stress WMSI variation (P=0.0006), family
history of CAD (P=0.0009), peak-stress WMSI
(P=0.0084), low-dose positive
echocardiographic result (P=0.0148), and ECG
changes during the test (P=0.0073) (Table 4). At multivariate
analysis, the prognostic importance of a positive
echocardiographic result (OR, 4.2; 95% CI, 1.8 to 9.6;
P=0.0007) and family history of CAD (OR, 4.2; 95% CI, 1.5
to 6.9; P=0.0034) was independent and additive.
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The 3-year survival rates for the negative and the positive
populations were 97% and 87%, respectively (P=0.0019)
considering hard cardiac events (Figure 1) and 96% and 74%
(P=0.0000) considering spontaneous cardiac events (Figure 2).
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Discussion |
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The results of our study show that dipyridamole stress echocardiography is safe and highly feasible in hypertensive patients, because no complications and a very low incidence of limiting side effects were observed during the test, in keeping with the larger experiences reported by multicenter studies that collected data from thousands of unselected patients.18 Moreover, our results demonstrate first the effectiveness of dipyridamole stress echocardiography in risk stratification of hypertensive patients with chest pain, on the basis of presence/absence of the induced new wall motion abnormalities. In particular, a negative echocardiographic result was found to be associated with only 3% and 4% event rates over 3 years of follow-up when hard and spontaneous cardiac events, respectively, were considered as end points.
Stress-Test Technique
Recent studies have demonstrated that in hypertensive patients,
pharmacological stress echocardiography shows an
accuracy at least comparable to that of myocardial
scintigraphy, with a superior specificity11
and a similar sensitivity.11 19 These data, coupled with
the larger availability and lower cost in comparison with nuclear
medicine, make pharmacological stress
echocardiography an attractive option for
evaluation of hypertensive patients complaining of chest pain.
Among pharmacological stressors, dipyridamole and dobutamine are the most popular, and it is now clearly established that they have similar accuracy20 as well as the capability of prognostic stratification.21 22 In the present study, the choice to use dipyridamole instead of dobutamine was suggested by superior safety,18 23 24 feasibility,20 intrinsic technical simplicity,25 26 and last but not least, the lower cost of dipyridamole in Italy.
Clinical Implications
Although the results of this study emphasize the prognostic
importance of dipyridamole stress
echocardiography in hypertensive patients, this
imaging technique is not to be considered an alternative but rather
complementary to exercise ECG testing, which remains the first choice
in the screening phase, in that it is
physiological, simpler, and very low cost and
provides a high negative predictive value in patients with chest pain
and unknown CAD, similar to that shown by dipyridamole
stress echocardiography.27 The latter
can be recommended in selected conditions, such as in patients with
equivocal or ischemic ECG response during
exercise2 3 4 and those unable to exercise or with an
uninterpretable ECG. In our opinion, the application of this strategy
can have a beneficial effect in the cost-effectiveness of management of
CAD in patients with arterial hypertension.
Limitations of the Study
Because this was an observational study, coronary
revascularization was performed on the basis of
stress-test results and the individual clinical condition.
Consequently, revascularization procedures were
much more frequent in patients with inducible ischemia,
particularly when it was identified as severe in the time and space
domain (ie, low-dose, high rest-stress WMSI variation). It is
presumable that this dropout process may have lowered the positive
predictive value of the test for hard end points, although the
echocardiographic evidence of ischemia was
found to be a very strong and independent predictor of outcome.
The stress protocol was not performed with coadministration of atropine in all patients, because atropine was introduced in the clinical practice14 when the study was started. Nevertheless, the prognosis in the negative population did not differ between patients evaluated with or without atropine. This is not surprising, because atropine administration induces a step-up in sensitivity of dipyridamole stress echocardiography, particularly in patients with single-vessel disease,14 20 who represent a well-recognized low-risk population.28 29
The influence of left ventricular hypertrophy on the echocardiographic response to stress, as well as its prognostic implications, was not evaluated. However, it has been found that stress echocardiography has similar accuracy in hypertensive patients with and without left ventricular hypertrophy.10 Moreover, left ventricular hypertrophy is a strong prognostic predictor, independent of the presence of organic CAD in catheterized patients,30 as well as of inducible ischemia during dipyridamole stress echocardiography in patients with uncomplicated myocardial infarction and 1-vessel disease.31
Received May 22, 1998; revision received August 13, 1998; accepted September 15, 1998.
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