Detection of Restenosis After Elective Percutaneous Transluminal Coronary Angioplasty Using the Exercise Treadmill Test James R. Bengtson, MD, MPH, Daniel B. Mark, MD, MPH, Michael B. Honan, MD, David S. Rendall, PA-C, Tomoaki Hinohara, MD, Richard S. Stack, MD, Mark A. Hlatky, MD, Robert M. Califf, MD, Kerry L. Lee, PhD, and David B. Pryor, MD

To determine the vdue of a &month exercise trea4hliH test for detecting resteMsis after elective ~ba*--tmseadvepatientswitb~ PTCAkdwithutarecentmyocarcMinf~on W8ft!Stdid.AlllMgtlWt228patkntrWithOUt~

temd cwdiac events, early repeat revasada~tion . to bwdmig testing, 209 (92%) orcomtrunderwent fosow-up angiography, and 200 aiso hadafdowuptreadndgtestaml~thestudy pqdatim. Restenodr (175% lumbud diameter stemsis) occwred in SO patients (25%). Five with a Mghef vdab+eswereindivkkdlyaswc&ted liskofrest~angina (p = 0.0002),

examgina (p = O.OOOl), a positive treahnil test (p = O&08), more exercise ST deviation (p = 0.04) ad a lower maximum exerdse hem4 rate (p = 0.09). However, only exerciseinduced angina (p = 0.002), recurrent angina (p = 0.01)dapodtivetreadndWtest (p=O.O4)were ilhpeahtpredktorsofrestemnh.usingthese3 varidhs,patientsubsetscouhlbeidentifi8dwith re&moslrratesrangingfrom 11 to83%.Theexerd~~gtestaddedindcpcndcntinWmath tosymptomstatusabouttheliskofresteMsisafter ektive PTCA. Rev-, 2O%OffMhtS angina nor witbresteMsishadneitberexardse-induced ihia at Mow-up. For mare acante detection of restcnods, the exercise treadm3testmurtbe q@ementedbyamoredefiniUve test. (AmJCardM 199O;esCZ8-34)

From the Division of Cardiology, Department of Medicine, and the Division of Biometry, Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina. This study was supported in part by research grants HS-05635 and HS04873 from the National Center for Health Services Research: research grants HL-17670 and HL-36587 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland; and grants from the Andrew W. Mellon Foundation, New York, New York; and the Robert Wood Johnson Foundation, Princeton, New Jersey. Manuscript received December 28, 1988; revised manuscript received June 20, 1989, and accepted August 25. Address for reprints: James R. Bengtson, MD, MPH, Box 3254, Duke University Medical Center, Durham, North Carolina 27710.

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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

ince the first percutaneoustransluminal coronary angioplasty (PICA) was performed in 1977,’ it has been used as an alternative to bypass graft surgery or medical therapy for many patients with coronary artery disease.2Unfortunately, restenosisafter an initially successful FTCA remains a significant problem, occurring in 12 to a of patients within the first 6 months after the procedure.3-‘0Coronary angiography has been used to detect restenosisand to aid decision making about the need for further intervention. Serial angiograms, however, are time-consuming, costly and associatedwith risk. Several studies have examined the value of noninvasive testing, including thallium-201 imaging’ I-14 and exerciseradionuclide ventriculography,t5 for detecting restenosisafter successful FTCA. These tests are more expensiveand less readily available than standard treadmill exercise testing. Thus, it would be helpful to know whether clinicians can rely on a standard treadmill test, in addition to clinical symptoms,to follow patients after successfulFTCA. The accuracy of the test in this setting, however, remains incompletely defined. In addition, no previous evaluation of noninvasive testing for restenosishas had more than a 75% rate of follow-up angiography. This study examinesthe value of the exercisetreadmill test for detecting restenosis in a large consecutivepopulation of patients with successful elective PTCA and a high rate of angiographic follow-up.

S

METHODS PatkM m We identified 325 consecutive patients without a recent (16 weeks)myocardial infarction who underwent an elective FTCA for native core nary artery disease(stenosis175%) at Duke University Medical Center during a 1-year period (April 1986 to April 1987). Of these, 303 (93%) had a successfulprocedure and were considered potentially eligible for the Duke FTCA restenosisfollow-up protocol, involving a repeat coronary angiogram and an exercise treadmill test approximately 6 months after PICA (Figure 1). Thirty-two patients did not have follow-up angiography: 3 died (2 from cardiovascular causesand 1 by suicide), 9 had medical contraindications to repeat angiography (cerebrovasculardiseasein 4, renal failure in 3, severe congestiveheart failure in 1 and anticoagulation in l), 13 refused the test (or the referring physician refused), 4 lived out of state and 3 could not be contacted. Thus, 271 eligible patients (89%) had a repeat angiogram. In

32 patients, interim clinical events obviated the relevance of detecting restenosisby exercise testing: 5 patients had interval myocardial infarctions and 27 underwent repeat revascularization procedures (18 PTCA, 9 coronary artery bypasssurgery) after returning with recurrent symptoms before scheduled follow-up. Thirty additional patients were deemed ineligible for exercise testing becauseof unstable angina at the time of followup. Among the 209 remaining eligible patients, 200 (96%) had both follow-up catheterization and an exercise treadmill test and formed the final study population. Data tdecth and infomation system: The computerized medical information systemused in this study has been described in detail.‘” I* Before both PTCA and follow-up catheterization, each patient had a cardiac history, physical examination and a resting 12-lead electrocardiogram. Baselinerisk factors for coronary artery diseasewere defined as described previouslyr9:hypertension was a current systolic blood pressure >140 mm Hg or a history of hypertension; hyperlipidemia was the presenceof a fasting serum cholesterol level 1250 mg/dl or a history of hyperlipidemia; a family history was considered present if first-degree relatives had coronary artery diseasebefore age 60. Symptomsat the time of follow-up were classified as follows: (1) asymptomatic or nonanginal discomfort, defined as discomfort that clearly has a noncardiac etiology; (2) atypical angina, defined as discomfort that could not be clearly classified as either typical or nonanginal; and (3) typical angina, defined as discomfort reproducibly precipitated by increasedcardiac workload, located appropriately, visceral in quality and relieved promptly after removal of the precipitating factors or after useof nitroglycerin.20 Angina severity was assessedaccording to the Canadian Cardiovascular Society criteria.21 AneioQlartv~f0kw-W -w anew*y: PTCA was performed using an 8Fr thin wall guiding catheter and a low-profile balloon catheter. Successful PTCA was defined as a reduction in coronary luminal diameter stenosisimmediately after PTCA to 15m of luminal diameter, as determined visually by consensus of 12 experienced angiographers. Patients were routinely given heparin intravenously at the start of the PTCA procedure, and received aspirin (325 mg/day), dipyridamole (75 mg 3 times a day) and a calcium antagonist from the time of PTCA until follow-up.5 Follow-up coronary angiography was performed on an outpatient basis using the Judkins technique with 5Fr or 6Fr catheters. The luminal diameter stenosisat the site of the previously successfulPTCA was graded on an ordinal scale (0, I artery (n = 20), restenosiswas defined as recurrence of a 275% luminal narrowing in >l of the vessels. TraedmYl testingt Standard Bruce protocol exercise treadmill tests23*24 were performed on the same day as

the catheterization in all but 6 cases,and within 2 days in all patients. Patients receiving /3-adrenergicblocking drugs were instructed to taper the dosesso that no such drugs were being taken 2 days before testing. Exercise was continued until the target heart rate was achieved, or until the development of limiting symptoms (angina, dyspnea, fatigue or claudication), abnormalities of rhythm (ventricular tachycardia or frequent couplets) or marked and progressive ST-segment displacement (LO.20 mV in the presenceof typical angina or in the first stage of exercise). All test results were reviewed by one of the investigators independently of the clinical data and blinded to the outcome assessment.Any ST-segment deviation 10.10 mV relative to the baseline that occurred during or after exercise in 3 consecutive beats and that was horizontal or sloping away from the baseline at 0.08 second after the J point was measured to the nearest 0.05 mV using a calibrated grid. Each test was classified according to standardized criteria24 into one of the following interpretations: (1) positive, if the ST segment was horizontal or downslopingand was depressedLO. 10 mV from the resting electrocardiographic baseline at 0.08 second after the J point, or the ST segment was elevated 20.10 mV from the resting baseline in leads 325 Elrglble Eleclrve Angroplasly

303 Successful Electrve Angloplasly 3 Deaths 10 Medical Contraindcations to Follow-up Angrography 19 Wrthout Follow-up Angiography 271 With AnglographIc Follow-up 5 Myocardial

Infarctron

27 Repeal Revascularzatron Prior to 6-Month Follow-up (16 PTCA. 9 CABG) 30 Unstable Angrna AI 6-Monlh Follow-up 209 Ellgble For Follow-up T:eadml’l Test

200

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TABLE

I Baseline

Clinical

Characteristics*

Restenosis (n = 50) % Male sex Hypertension Diabetes mellitus Family history of premature heart disease Smoking history Hyperlipidernia History of myocardial infarction Age Ws)* ’ Data shorn

TABLE

II Baseline

No Significant Disease (n=lD4) %

37

74

33

72

68

65

28

56 18 62

23 8 35

50 17 76

45 15 61

43 14 59

19

58 38

32 19

70 41

14

28

21

59

53-66

56

9 31

29

ae Miars(25th

Other Significant Disease (n=46) %

57

55 49

46

51 20

49-65

59

50-65

19

to 75th pwcentlk).

Angiographic

Characteristics

Angioptasty artery IAD LAD/LCX LCX LCX/ RCA RCA LAD/RCA Number of diseased vessels

1 2 3 Ejection fraction*

Other Significant Disease (n =46) %

(n=lC!d)

%

26 3 8 2 10 1

52 6 16 4 20 2

21 1 11 1 11 1

46 2 24 2 24 2

44 4 15 6 34 1

42 4 14 6 33 1

32 13 5

64 26 10 49-m

17 19 10 54

37

85 19 0 59

82 18 0 5364

56

l Data shown are meckms (25th to 75th percenhle) LAD - left anterior descending: LCX = left circumflex;

No Significant Disease

Restenosis (n = 50) %

RCA = rght coronary

41

22 47-m

artery

I

without Q waves; (2) negative adequate, if the patient reached 85% of the maximal predicted heart rate without significant ST-segmentchanges;(3) negative inadequate or indeterminate, if there were no significant STsegmentchanges,but the patient failed to reach the predicted target heart rate, or if ST elevation occurred only in leads with pathologic Q waves; and (4) uninterpretable, in the presenceof left bundle branch block or an artificially paced rhythm. A previously derived treadmill angina index24 was used to describe exercise-inducedsymptoms; this index was assigneda value of 0 if angina was absent during exercise, 1 if angina occurred during exercise and 2 if angina was the reason the patient stopped exercising. Data mrk: Continuous variables were summarized with medians and quartile ranges (25th to 75th percentile). Patient groups were compared with respect to continuous variables using Kruskal-Wallis nonparametric analysis of variance, and discrete variables using &i-square analysis. Univariate and multivariate relations between restenosisand 5 predictor variables defined before the analysis were examined using a logistic regression mode1.2S~26 In a second analysis, the same variables were incorporated into an ordinal logistic regressionmodel to assessthe predictive value in estimating the number of major coronary arteries (0, 1, 2 or 3) 30

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with significant stenosesat follow-up cardiac catheterization. Comparison of the results of these 2 analyses provided an assessmentof the effect of significant lesions in other coronary vesselson the associationsbeing examined. The predictor variables examined were: recurrent angina1 symptoms (either typical or atypical) coded as a binary variable; the treadmill angina index; treadmill interpretation coded as 2 if positive, 1 if negative inadequate or indeterminate (uninterpretable tests were deleted from analysis) and 0 if negative adequate; the magnitude of exercise-induced ST deviation; and exerciseduration in seconds.In an exploratory fashion, the relation to restenosisof 2 additional variables, maximum heart rate achieved on the treadmill and exercise systolic blood pressure,was also examined. RESULTS

Restenosisof the PTCA lesion occurred in 98 (36%) of the 271 patients who had a successfulelective PTCA and had angiographic follow-up (with or without a treadmill test). Of the 200 patients who had both follow-up angiography and a treadmill exercise test, 50 (25%) had restenosisof the PTCA lesion, 46 (23%) had no restenosisbut had significant coronary diseasepresent at other sitesand 104 (52%) had no significant coronary stenoses.These 3 groups did not differ appreciably

TABLE

III Treadmill Test Results Other Significant Disease (n = 46) %

Restenosis (n=50) % Angina during test None Nonlimiting angina Test stopped due to angina Test interpretabon Negative Negative inadequate or indeterminate posibve uninterpretable ST-segment deviation (mV)* 0

0.10-0.19 023-0.30 Maximum heart rate+ Peak systolic blood pressure+ Exercise duratron (min)+ l

UninterpretaMe

tests &ted

30

No Signiftcant Disease (n = 104) %

60 20

37 5

80

10

11

94 7

90 7

10

20

4

9

3

3

15 16

30 32

22 9

48 20

59 24

57 23

17 2

34 4

14

30 2

17 4

16 4

31

65

31

15

31

10

69 22 9

83 13 4

83 13 4

2 136 170 6.2 (n = 7): 1 data shown are medms

1

4

4

112-149 158-200

142 184

4.4-8.6

123-155 155-200

7.1

140 177

5.2-8.8

7.2

123-153 l&s191 4.9-9.6

(25th to 75th percents!).

in age, gender or prevalenceof hypertension, diabetes, family history of premature heart disease,smoking history or hyperlipidemia (Table I). More patients in the group without restenosisbut with other significant stenoseshad a history of myocardial infarction compared with the other 2 groups. Slightly more patients with restenosishad left anterior descendinglesions, compared with the other 2 groups (p = 0.32) (Table II). The proportion of patients with multivessel diseaseon the baseline angiogram was highest in the group without restenosisbut with other significant stenoses(63%), intermediate in the group with restenosis(36%) and lowest in those without stenoses(18%) (p 1 vesselin 20 patients; the restenosis rate was slightly higher in this group (30%) than in those having l-vessel angioplasty (24%), but this difference was not significant (p = 0.62). The median ejection fraction was higher in the group without significant diseaseon the follow-up study (p = 0.007). Figure 2 showsthe distribution of angina1symptoms at the time of follow-up. Among 29 patients reporting typical angina1 symptoms at follow-up, 19 (66%) had restenosis,compared with 11 of 42 (26%) with atypical symptoms, and 20 of 129 (16%) without symptoms at follow-up (p l of these criteria to be present. Limitaths: Several limitations of our study should be noted. First, the association between any variable and restenosisis greatly influenced by the definition of restenosis.The useof a standard dichotomousdefinition (presentvs absent) for restenosismay have diluted some associationspresent in the data. Second, the ability to demonstratean associationbetweenany set of independent variables and restenosisis limited by the number of patients with restenosis.Our study population was large enough, however, to detect several strong predictors of restenosis.Finally, the relative prognostic importance of detected and undetected restenosis in this population could not be determined because most patients with restenosis were referred for repeat revascularization procedures.

Our study shows that in patients able to perform a follow-up treadmill test 6 months after elective PTCA, the presenceof exercise-inducedischemia improves the clinician’s ability to detect restenosis,beyond the contribution of the patient’s symptom status. The overall accuracy of the test, however, is only fair, as would be expected in a population with predominantly l-vessel disease,” and the test is negative in a substantial minority of patients with angiographic restenosis.A unique feature of this study is that 6-month follow-up exercise tests and repeat coronary angiograms were obtained in 88% of patients eligible for both studies after a successful PTCA, a much higher rate than any previous study of noninvasive testing to detect restenosis. Long-term reasnoeis rate: The restenosis rate in this group of patients undergoing elective PTCA is comparable to that found in other studies.3*5s2x The variability in rates reported in these studies can-be explained in part by differences in the definition of restenosis,2xand perhaps by variability in completenessof angiographic follow-up. In addition, the restenosisrate in a subsetof patients who were able to undergo exercise treadmill testing was lower than the rate in patients who were not tested, becausemost of the latter group underwent evaluation before their scheduledfollow-up date becauseof unstable angina. test result to restefwsis: Our Relationofresults are similar to those of previous studies that examined the ability of exercise testing to detect restenosis. Wijns et a1,t4for example, found in a group of 89 patients that the positive predictive value of either hori- REFERENCES zontal ST-segment depressionor angina occurring dur- 1. Gruentrig AR Transluminal dilatation of coronary artery stenosis. lancef ing the treadmill test was 50%, whereas the negative 19?8:f.263. DR and Vlintra RE. PTCA: current status and future trends. Mayo predictive value was 65%. Ernst et al” studied 25 pa- 2.Clin llolmcs Prm I986.61X65 X76. tients who underwent treadmill testing 4 to 8 months 3. Holmes DR. Vliesctra RF.. Smith 11C, Vetrova GW. Kent KM. Cowlcy MJ, Faxon DP. Gruentzip AR. Kel.wy SF. Detre KM, Van Raden MJ. Mock MB. after PTCA, and found a sensitivity of 75%, a specilic- Restencais after percutaneous transluminal coronary angioplasty: a report from ity of 85% and a positive predictive value of 50%. the PTCA Registry of National Hcar~. I.ung. and Blood Institute. ,4m J Car&o/ The substantial number of false negative results in I984:S3.77~‘-U/ c: AR. King SB. Schlumpf M. Siegenthaler W. Long-term follow-up this study is at least partially due to the large proportion 4.afterGruent7ig percutaneous transluminal coronary angioplasty: the early %unch expriof patients with I -vesseldisease,in whom the sensitivity ence. N LngI J Med 1987:316:/12?-1132. of treadmill testing is known to be lower.27Conversely, 5. Sm~onton CA. Mark DB. Hinohara T. Rendall DS. Phillips HR. Peter RH. Bchar VS. Kong Y. O’Callaghan WC;. Califf RM, Stack RS. Late re-stcnosis nearly half of the patients who had positive treadmill following emergent coronary angioplasty for acute myocardial infarction: comtests but were not found to have angiographic restenosis pariwn with clcctivc coronary angioplasry. JACC 1988:I /:698--705. Fcltz TA, Bal ET. van Bogcrijcn L. van den Berg E. (“false positive” treadmill tests) had other significant 6.&coopErnst CA,SMPG,Plukkervan HW.der Long-term angiqvaphic follow-up. cardiac events. and stenosesat the time of follow-up, which could have survival in patients undergoing prcutancous transluminal coronary angioplasty. caused an ischemic responseto exercise. Furthermore, Br ffeorr J 1987;57:22(1-225. 7. Kaltcnbach M. Kober G. Scherer D. Vallbracht C. Recurrence rate after the functional significance of a stenosis