Exercise, electrocardiographic and functional responses after percutaneous transluminal coronary angioplasty

Exercise, Electrocardiographicand FunctionalResponses After PercutaneousTransluminalCoronary Angioplasty DOUGLAS R. ROSING, MD, MARK J. VAN RADEN, MA, RITA M. MINCEMOYER, BS, ROBERT 0. BONOW, MD, MARTIAL G. BOURASSA,

MD, PAUL R. DAVID, MD,

CAROLYN J. EWELS, BS, KATHERINE M. DETRE, MD, DrPH, and KENNETH M. KENT, MD

Exercise testing after successful PTCA showed improved cardiac functional status on examination of electrocardiographic and symptomatic responses, myocardial perfusion and global and regional left ventricular function. Sixty-six patients were studied before and after persistently successful PTCA. Follow-up studies an average of 8 months after the successful procedure showed an incidence of abnormal testing of only 7% using both electrocardiographic and subjective symptomatic criteria during treadmill studies and no abnormal studies

with thallium scintigraphy. Radionuclide cineangiography demonstrated similar left ventricular ejection fractions at rest before and after PTCA, but an improvement of 9 f 10% (p X0.001) in the exercise ejection fraction at follow-up. However, 52 % of patients with paired data still had an abnormal radionuclide cineangiographic study after successful PTCA, raising the question of the presence of subclinical ischemia or a false-positive result.

It has been documented in the NHLBI Registry that angioplasty improves the anatomic appearance of coronary artery stenoses in PTCA in most patients who undergo this procedure.’ Although these results suggest that the subjective symptomatic improvement experienced by patients after successful angioplasty is due to improved coronary blood flow to ischemic myocardium, other explanations, such as a placebo effect or the infarction of ischemic tissue, are also possible. To demonstrate improved functional left ventricular myocardial perfusion after successful PTCA, several noninvasive tests were performed in patients in the NHLBI PTCA Registry. These studies used treadmill and bicycle exercise to evaluate exercise capacity, symptoms, myocardial perfusion, and electrocardiographic and global and segmental left ventricular function responses. The results of this testing form the subject of this report.

Methods

(Am J Cardiol 1984;53:36C-41C)

Patients: The makeup of the 3,079 patients in the PTCA Registry has been described.2 Of these patients, 1,878 had a successful procedure. To reduce the bias in the selection of patients who underwent follow-up studies, we used only data from centers that reported follow-up studies in at least 46% of the patients undergoing successful PTCA. This figure of 46% was selected to maximize the number of studies available for evaluation. From such centers, a baseline or folloyv-up exercise study was submitted to the Registry in 215 patients: 62 had absent or incomplete follow-up data, 37 had restenosis” of an originally successfully dilated lesion,3 19 had no follow-up angiography to assess restenosis and 19 had multivessel disease with incomplete revascularization at the time of PTCA. Thus, “pure” follow-up data were available in only 78 patients who underwent successful PTCA, 66 of whom had complete paired data. Two centers (the Montreal Heart Institute and the NHLBI) provided 55 of the patients (83%) with “pure” paired data. When clinically feasible, cardiac medication was discontinued 5 half-lives before exercise testing. Information is available regarding medication administration at the time of baseline examination but not at follow-up testing.

From the National institutes of Health, Bethesda, Maryland; the University of Pittsburgh, Pittsburgh, Pennsylvania; and the Montreal Heart Institute, Montreal, Quebec, Canada. Address for reprints: Douglas R. Rosing, MD, National Institutes of Health, Building 10 Room 7B-15, Bethesda, Maryland 20205.

An increase in stenosis 130% from the immediate post-PTCA result or the loss of at least half the initial gain in diameter. l

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June 15, 1984

45 r 40

35 r gj 30 !5 25 :

19

2ND

3RD

4TH

5TH

6TH

7TH

8TH

9TH

JOT”

, ,TH

12TH

13TH +

MONTH OF FOLLOW-UP STUDY FIGURE 1. Time of follow-up studies in 66 patients who had successful percutaneous transluminal coronary angioplasty and comprise the “pure” group with paired tests. The 13-month interval includes a few patients with follow-up occurring between 14 and 16 months.

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increase by at least 5 percentage points relative to the rest study. In all exercise studies, ejection fractions were obtained at maximal effort. Thus, in most patients, observations at follow-up were made at a higher level of exercise compared with the baseline. Statistical analyses: All statistical analyses were performed with the t and chi-square tests. The chi-square test for correlated proportions was employed for testing improvement in paired pre- and post-PTCA results. A p value <0.05 was considered statistically significant. All results are expressed as the mean f standard deviation unless otherwise stated. Agreement between the outcome of different types of functional exercise tests was measured by the kappa statistic, which measures the amount of agreement over that expected to result from chance alone. The maximal value of this statistic is 1. Values CO.40 have been characterized as having poor agreement beyond what might be expected by chance, values between 0.40 and 0.75 as having fair to good agreement, and values >0.75 as having excellent agreements Results

Treadmill exercise tests: Treadmill exercise tests used either the Bruce4 or a National Institutes of Health (NIH) protocol. According to the NIH protocol, speed is kept constant at 2.2 mph for the first 15 minutes, with the incline initially 0% and increasing 2.5% every 2.5 minutes. After 12.5 minutes the speed and incline are increased every 2.5 minutes to 2.3 mph, 12%; 2.7 mph, 14%; 3.1 mph, 16%; 3.5 mph, 18%; 3.9 mph, 20%; 4.7 mph, 20%; and 5.5 mph, 20%. Many patients exercised according to a modified Bruce protocol, which begins at 1.7 mph with a 5% incline for 3 minutes before beginning the standard Bruce protocol.4 The exercise tests were maximal tests; that is, they were symptom-, arrhythmia- or blood pressure-limited. Exercise duration was recorded and STsegment changes were analyzed. An exercise test was considered positive if at peak exercise or during the g-minute recovery period, (1) the slope of the ST segment was horizontal and the segment was elevated at least 1 mm and also elevated 1 mm or more relative to the rest recording; or (2) the slope of the ST segment was 10, the segment was depressed at least 1 mm and also depressed at least 1 mm relative to the recording at rest. Thallium scintigraphy: Thallium-201 myocardial scintigraphy was performed immediately after treadmill exercise and either at rest (3 patients) or during the redistribution phase after exercise. Protocol and methods were individualized for each institution. Investigators were asked to evaluate radioisotope distribution of the anterior, inferior and posterior aspects of the left ventricle for each phase of the test and to determine whether a perfusion defect was present in each area. “Uncertain” could also be checked for a given area. If any box was checked to indicate a defect with exercise and this defect represented a change from rest, the test result was considered positive. Radionuclide cineangiography: Radionuclide cineangiography was performed at rest and during supine bicycle exercise. All studies included in this section were performed at the NHLBI according to methods described.5 A modified left anterior oblique view was used and global ejection fraction as well as wall motion of the anterior, inferior and posterior segments was evaluated. For each segment, wall motion was designated normal, hypokinetic, akinetic or dyskinetic. Ejection fractions were determined at rest and during maximal exercise. A test result was positive when any type of wall motion abnormality was present in any of the 3 areas examined during exercise or the exercise ejection fraction did not

The distribution of the time from successful angioplasty to follow-up study is shown in Figure 1. The average time to follow-up was 245 days and the median time to follow-up was also 8 months. Because so few patients had paired data available for analysis, we believed it was important to determine whether the data of the patients included was representative of the entire group of patients from the institutions supplying results in at least 46% of their successful procedures. Thus, we compared the results of the treadmill exercise, thallium and radioisotope cineangiographic studies in various patient groups who had a baseline or follow-up study with those who had paired results recorded. Tables I and II show that the study results in the patients with paired data were similar to the results obtained in other patient groups undergoing these tests at baseline and follow-up with the exception of the treadmill exercise tests. With the treadmill studies, a significantly larger proportion of patients had positive baseline tests in the larger, unselected and in the restenosis and incompletely revascularized groups of patients. Treadmill tests: Forty-five patients who underwent successful PTCA had baseline and follow-up treadmill tests (Tables I and II). Only 15 patients (33%) had a positive test result before PTCA, whereas 3 patients (7%) had a positive result after a successful procedure (p
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TABLE I

Baseline Test Results

TABLE II

Follow-Up Test Results

A. All Successful Patients from Eligible Sites’ Exercise (n = 190) -___

Positive Negative Unknown

n

%

63 72 55

47 53

Thallium (n = 120) n ;: 33

Pure Groups from Eligible Sites

RNA (n = 76)

%

n

%

60 40 ...

55

92

16”

..:

Positive Neaative

Exercise

Thallium

RNA

(n = 58)

(n = 34)

(n = 34)

n

%

n

%

n

%

5:

9;

3;

9;

:8”

z:

B. Pure Groups from Eligible Sites+ Exercise (n = 66)

Positive Negative

Thallium (n = 41)

Pure Groups with Paired Data RNA (n = 37)

n

%

n

%

n

%

24

;:

22 19

53 48

35 2

95 5

Exercise (n = 45)

Positive Negative p value

Thallium (n = 28)

RNA (n = 31)

n

%

n

%

;“o

33 67

15 13

it

1

Exercise (n = 34) n Positive Negative p value

%

29 2

94 6 NS

D. Restenosis or Incomplete Revascularization

with Paired Data

Thallium (n = 17) %

21 13

n

%

13 4

:: NS

RNA (n = 8) n

RNA

(n = 45)

(n = 28)

(n = 31)

%

4;

9;

n 2:

%

n

%

10:

16 15

52 48

RNA = radionuclide cineangiogram.

n

NS

Thallium

n Positive Negative

C. Pure Groups with Paired Data+

Exercise

%

6 2 NS

NS = not significant; RNA = radionuclide cineangiogram. The number in parentheses represents the total number of successful patients from sites with 146% follow-up for that test. Percentages are based on those with known results only. + The number in parentheses are subsets of the patients in the preceding part A. These patients did not have restenosis of a successfully dilated lesion or incomplete revascularization of multivessel disl

ease. t p <0.05 for the difference between the patients in group C and those in group A (with the 45 patients in group C removed from group

TABLE Ill

Total Minutes on Test Baseline mean*+ Follow-u mean P Mean difference+ Median percent change Patients with 250% increase p value

Time on Exercise Test: Pure Group Patients with Paired Time Data Modified Bruce Protocol (n = 20)

NIH Protocol (n = 26)

1.9

7.6 f 3.1

9.5 f 7.6

7.2 f 2.7

10.5 f 2.8

19.4 f 6.5

2.9 f 3.5

9.9 f 7.6

Bruce Protocol (n = 6) 5.3 f

1.9 f

1.8

+2a%

33%

<0.05’

+31%

+127%

45%

58%

<0.01+


Total All Protocols (n = 52)

. +42%

47%

a Significance of improvement in mean time on test. + Values are mean f standard deviation.

A\

““3 p <0.05 and D.

for the difference

between

the patients

in groups C

The improvement in exercise capacity obtained after successful angioplasty is described in Table III. Almost half the patients had 50% or greater improvement in exercise capacity. In 12 of the 45 patients with paired data who underwent baseline treadmill testing, cardiac medication could not be safely discontinued. Table IV is a list of the number of patients who were receiving cardiac medication at the time of testing, which might have affected their exercise test results. If all 8 patients with a negative test result on propranolol or nitrates would have converted to a positive test result on discontinuation of medication, the sensitivity of the test would only have improved to 50%. Thallium scintigraphic studies: Twenty-eight patients who had successful PTCA underwent thallium scintigraphic perfusion studies before and after their procedure (Tables I and II). Fifteen patients (54%) had a positive test result at baseline, whereas no patient had

a positive test result after a successful procedure (p
Jwe

Seven patients had wall motion abnormalities at rest and 27 had wall motion abnormalities during their exercise study at the time of baseline testing (Table V). Twenty-six patients had an abnormal ejection fraction response to exercise. After successful PTCA, 16 patients (52%) had a positive study result (p <@.OOl compared with baseline study). Two patients still had a wall motion abnormality at rest; in 1 patient, who had had normal wall motion at baseline, a new abnormality developed after successful PTCA. Ten patients had at least I area of abnormality during exercise (Table V). Fifteen patients had an abnormal ejection fraction response to exercise after successful PTCA. In absolute terms, the rest ejection fraction at baseline was 54 f 6% and decreased to 50 f 11% (difference not significant [NS]) wit.h exercise. After successful PTCA, the rest ejection fraction of 52 f 7%, not significantly different, from the baseline rest value, increased to 60 f 8% (p
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THE AMEFllCAN JOURNAL OF CARDlOLOGv

TABLE IV

Medications Affecting Exercise Tests Pure Group with Paired Exercise Data Positive Test -__

Negative Test

Total

(n = 15)

ln = 30) ~~.~__~_._____

(n = 45)

__

%

n

%

1

7

c

0

1

2

3

20

8

27

11

25

730

202

730

3:

7:

n

Medication Diuretics or digitalis Propranalol or nitrates groups Neither Both group -

11 0

0 :

n

Diuretics or digitalis Propranalol or nitrates Both groups Neither group

Negative Test

Total

(n = 15)

(n = 13)

(n = 28)

n

%

2521

89:

0

0

0

0

11

73

8

62

19

68

0 4

0 27

0 5

0 38

0 9

0 32

Exercise Abnormalities

n

Baseline %

280

10 8

n

Follow-Up %

15 10 3

Resting Defects

n

%

28

100 0 0

z: 11

Exercise Defects

Follow-Up

Baseline

Defects (n)

n

%

n

%

0

24 6 :

77 19 :

28

90 10 :

RNA = radionuclide

cineangiogram.

%

0

RNA Test (n = 31)

1 3’

n

0

8

Baseline

%

radionuclide cineangiographic studies provided a much more sensitive marker of ischemia before successful angioplasty, but produced a large number of positive tests after the procedure. No patient underwent both thallium and radionuclide cineangiographic studies. Results in patients with restenosis or incomplete revascularization: Paired data were available for at least 1 exercise test in 19 patients with multivessel disease and incomplete revascularization as well as in 37 patients who experienced restenosiss of their successfully dilated obstruction. The results of functional

Follow-Up %

%

Positive Test

n

Rest Abnormalities

(n)

n

Pure Group with Paired Thallium Data

Thallium Test (n = 28)

Abnormalities

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I Baseline)

Distributions of Number of Thallium Abnormalities and Radionuclide Angiographic Defects: Pure Group Patients with Paired Data

Baseline

Volume 53

:0

n 1: :

Follow-Up %

n

%

13

21 6

68 19 13 0

z: 10

:

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EXERCISE RESPONSES AFTER ANGIOPLASTY

TABLE VI Functional Test Consistency: Pure Group

Using the development of angina during treadmill testing as an indicator of ischemia was more sensitive in detecting ischemia than were the tests based on ST-segment changes or thallium perfusion defects. The marked improvement in the results of treadmill (using either ST-segment changes or angina as end points) and thallium studies, with a low incidence of abnormal follow-up test results, indicates significant functional improvement after successful angioplasty and parallels the results of hemodynamic and angiographic findings1 as well as clinical responses.iO However, the finding of abnormal results with radionuclide cineangiographic studies in 52% of patients raises questions about the degree of success of the procedure. Although the percentage of patients with an abnormal radionuclide cineangiographic study remained high at the time of follow-up study (Table II), the exercise ejection fraction improved by 9 f 10% at follow-up (p
Patients with Multiple Tests Baseline Tests Treadmill and Thallium Tests (n = 32) Test results Pos, Pos, Neg, Neg,

Pos Neg Pos Neg

n

Treadmill and RNA Tests (n = 27)

%

n

7 7 :; 7 22 11 34 Kappa = 0.11

% 19 0 74 7

; 20 2 Kappa -

0

Follow-Up Tests Treadmill and Thallium Tests (n = 18) Test Results Pos, Pos, Neg, Neg,

Pos Neg Pos Neg

n

%

:

1:

Treadmill and RNA Tests (n = 30) n

%

: 15 15 Kappa -

1: 8: Kappa = 0.45

: 50 50 0

Neg = negative study; Pos = positive; RNA = radionuclide cineangiography.

studies in these patients before angioplasty and at the time of follow-up are presented in Tables I and VII. There was a statistically significantly greater incidence of positive follow-up treadmill and thallium studies in this subgroup compared to patients with persistent success. Although there was no statistically significant difference between the groups for radionuclide cineangiographic studies at follow-up, only 17% of patients with incomplete revascularization or restenosis demonstrated an improvement in their test results. Discussion

The results of various types of functional exercise testing performed before angioplasty in the present study are similar to results in comparable groups of patients with coronary artery disease not undergoing these procedures. 7-e Considering that 94% of these patients had l-vessel disease, the relatively low sensitivity of the treadmill and thallium studies was anticipated. TABLE VII

Functional Test Abnormalities in Patients with Restenosis or Incomplete Revascularization Compared with Those with Persistently Successful Percutaneous Transluminal Coronary Angioplasty Persistently Successful PTCA Positive Baseline Test

Exercise Thallium test Radionuclide cineangiographic test

:z 29

Improvement n

%

Positive Baseline Test

87 100 45

21 13 6

l

13 15 13

Incomplete Revascularization

Only patients with a positive study at baseline are included. f “ImprovemerWindicates a negative result at follow-up. NS = not significant. l

Improvement+ n

or Restenosis

%

Significance

33 15 17

p
June 15. 1984

term1 and is not meant to imply that successful angioplasty produces normal vessels. In the 31 patients who underwent radionuclide cineangiography before and after successful angioplasty, the average pressure gradient across the area dilated was 20 f 13 mm Hg immediately after PTCA, and the average angiographic stenosis was 21 f 14% at follow-up. Laboratory studies suggest that <70% luminal diameter stenoses should not interfere with myocardial perfusion,l” but these studies examined hyperemic flow in an anesthetized dog, and no data are available that evaluate the potential for low grade stenoses to produce myocardial ischemia in high flow situations in man. In addition, there is experimental evidence1”J4 that multiple noncritical stenoses can interfere with coronary blood flow, and it is presumed that patients undergoing successful PTCA, in addition to the dilated stenosis, may have other noncritical lesions in the same vessel. Finally, studies at the NIH have shown that successful PTCA improved diastolic function in patients, but 32% of patients still had an abnormal peak left ventricular filling rate or time to peak filling rate, or both. l5 Thus, abnormalities detected by follow-up radionuclide cineangiographic studies after successful angioplasty may represent abnormal myocardial blood flow responses and subclinical ischemia rather than false-positive study results.

References 1. Kent KM, Bentivoglio LG, Block PC, Cawley YJ, Dorros G, Gosselin AJ, Grtitizig A, Myler RK, Simpson J, Sterlrer SH, Williams DC, Fisher L, Glllesple MJ, Detre K, Kelsey S, Mullin SM, Mock MB. Percutaneous transluminal coronary angioplasty: report from the Registry of the National

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tieart, Lung, and Blood Institute. Am J Cardiol 1982;49:2011 -2020. 2. Detre KM, Myler RK, Kelsey SF, Van Raden M. To T, Mitchell H. Baseline characteristics of patients in the National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronarv Anaioplastv Reaistrv. Am J Cardiol _ ._ 1984;53:7C- 11c. 3. Holmes DR Jr, Vlietstra RE, Smith HC, Vetrovec GW, Kent KM, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF. Detre KM, Van Raden MJ, Mock MB. Restenosis after percutaneous translummal coronary angioplasty fPTCA): A report from the PTCA Reolstrv of the National Heart. Luno. .,. and blood Institube. Am J Cardiol 1984;?7C-‘8lC 4. Bruce RA. Exercise testina of oatients with coronarv heart dtsease. Prlnciples and normal standayds for evaluation. Ann bin Res 1971;3:323332 5. Borer JS, Bacharach SL, Green MV, Kent KM, Epstein SE, Johnston GS. Real-time radionuclide cineanaioaraohv in the noninvasive evaluation of global and regional left ventri&la; f&&ion at rest and during exercise in patients with coronary-artery disease. N Eng J Med 1977;296:839%844. 6. Fleiss JL. Statistical Methods for Rates and Propwttlons 2nd ed. New York: John Wiley, 1981:217-218. 7. Chaitman BR, Hanson JS. Comparative sensitivity and specificity of exercise electrocardiographic lead systems Am J Cardiol 1981;47:13351349. a. Massie BM, Botvinick EH, Brundage BH. Correlation of thallium-201 scintigrams with coronary anatomy: factors affecting region by region sensitivity. Am J Cardiol 1979;44:616-622. 9. Okada RD, Boucher CA, Strauss HW, Pohost GM. Exercise radionuclide imaaina approaches to coronarv, arterv, disease Am J Cardiol 1980:46: 1 I@-7264. 10. Kent KM, Bentivoglio LG, Block PC, Bourassa MG, Cowley MJ, Dorros G, Detre KM, Goaselin AJ, Gruentzig AR, Kelsey SF, Mock MB, Mullin SM, Passamani E, Myler RK, Simpson J. Sterlzer SH. Van Raden M. Williams DO. Long-term efficacy of pefcutaneous translumjnal coronary angioplasty (PTCA): Report from the National Heart, Lung. and Blood Institute PTCA Registry. Am J Cardiol 1984;53:48C-51C. 11. Bonow RO, Bacharach SL, Green MV, Kent KM, Rosing DR, Lipson LC, Leon MB, Epstein SE. Impaired left ventricular diastolic filling in patients with coronary artery disease: assessment with radionuclide ahgidgraphy. Circulation 1981:64:315-323. 12. DePuey EG, Boskovlc D, Krajcer 2, Leatherman L, Angelini P, Sonnemaker RE, Burdine JA, Springer A. Exercise radionuclide ventriculography in evaluating successful transluminal coronary angioplasty. Cathet & Cardiovasc Diagn 1983;9:153-166. 13. Gould KL, Lipscomb K. Effects of coronary stenoses on coronary flow reserve and resistance. Am J Cardiol 1974;34:48-55. 14. Karayannacos PE, Talukder N, Ing TS, Nerem RM, Roshon S, Vasko JS. The role of multiple non-critical arterial stenoses in the pathogenesis of ischemia. J Thorac Cardiovasc Surg 1977;73:458-469. 15. Bonow RO, Kent KM, Rosing DR, Lipson LC, Bacharach SL, Green MV, Epstein SE. Improved lefl ventricular diastolic filling in patients with coronary artery disease after percutaneous transluminal coronary angioplasty. Circulation 1982;66:1159-1167.