Restenosis after percutaneous transluminal coronary angioplasty (PTCA): A report from the PTCA registry of the national heart, lung, and blood institute

Restenosis After Percutaneous Transluminal Coronary Angioplasty (PTCA): A Report from the PTCA Registry of the National Heart, Lung, and Blood Institute DAVID R. HOLMES, Jr., MD, RONALD E. VLIETSTRA, MB, ChB, HUGH C. SMITH, MD, GEORGE W. VETROVEC, MD, KENNETH M. KENT, MD, MICHAEL J. COWLEY, MD, DAVID P. FAXON, MD, ANDREAS R. GRUENTZIG, MD, SHERYL F. KELSEY, PhD, KATHERINE M. DETRE, MD, PhD, MARK J. VAN RADEN, MA, and MICHAEL B. MOCK, MD

The results of follow-up angiography in patients from 27 clinical centers enrolled in the PTCA Registry were analyzed to evaluate restenosis after PTCA. Of 665 patients with successful PTCA, 557 (64%) had follow-up angiography (median follow-up 166 days). Restenosis, defined as an increase of at least 30 % from the Immediate post-PTCA stenosis to the follow-up stenosis or a loss of at least 50% of the gain achieved at PTCA, was seen in 167 patients (33.6%). The incidence of restenosis in patients who underwent follow-up angiography was highest

within the first 5 months afler PTCA. Restenosis was found in 56% of patients with definite or probable angina after PTCA and in 14% of patients without angina after PTCA. Twenty-four percent of patlents with restenosis did not have either definite or probable angina. Multivariate analysis selected 4 factors associated with increased rate of restenosk male sex, PTCA of bypass graft stenosis, severity of angina before PTCA and no history of MI before PTCA. (Am J Cardiol 1964;53:77C_61C)

PTCA was first performed in 1977 by Gruntzig.lJ The techniques, clinical experience, and evolution have been documented in the NHLBI PTCA Registry, which was established in 1979.3y4The Registry data confirm that increased operator experience improves the success rate and lessens the incidence of complications. Other sources document the expansion of selection criteria beyond subtotal l-vessel CAD to include multivessel disease, bypass graft stenoses, and total coronary artery occlusions.5-11 One major aspect of PTCA remains to be defined: the problem of restenosis.ll-l6 So far, information on this has been limited by the relatively few patients reported and the relatively low percentage of patients undergoing follow-up angiography. This report from the NHLBI PTCA Registry focuses on the problem of restenosis: incidence, temporal sequence, and risk factors.

Methods From its inception in 1979 to its closing on September 30, 1982, the NHLBI PTCA Registry4 enrolled 3,079 patients from 105 clinical centers. Three criteria were applied to select patients in the present study: (1) The patient must have undergone a first PTCA before October 1,1981, making him or her eligible for l-year follow-up. Excluded from the study were patients who had undergone PTCA according to specialized protocols, for example, PTCA with the application of streptokinase and PTCA during or within 3 weeks of acute myocardial infarction. (2) The patient must have had a successful outcome as defined by the Registry: an improvement of at least 20% in the diameter from pre-PTCA value to the value at discharge from the hospital, without having to undergo CABG. For patients with PTCA of multiple lesions, the first stenosis to be dilated (usually the most severe) was analyzed. (3) The results of follow-up angiography must have been reported. Because the angiographic follow-up rate in the Registry differed greatly according to clinical center, the present study was limited to 27 centers that had angiographic follow-up rates of at least 74% of their successful cases. This study attempted to obtain an angiographic assessment at l-year follow-up. However, 42% of the restudies were per-

Address for reprints: David R. Holmes, Jr., MD, Mayo Clinic, 200 First Street, SW, Rochester, Minnesota 55905.

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RESTENOSIS

TABLE I

AFTER PTCA

Clinical Variables Assessed in Patients with Restenosis After PTCA

Clinical Variables

Age Sex Canadian Heart functional class Time since onset of chest pain New onset of chest pain Rest angina Unstable angina History of diabetes mellitus History of increased cholesterol History of Ml History of hypertension History of smoking

Coronary Anatomy and Left Ventricular Function Extent of CAD ( l-, 2 - and 3-vessel CAD) Left ventricular function (ejection fraction) Left ventricular function (regional wall motion abnormalities) Pre-PTCA stenosis

formed at 6 months or less. When more than 1 follow-up angiographic report was available, the one that provided the longest follow-up was evaluated. In addition, the follow-up study used for comparison was the angiogram that preceded any subsequent revascularization procedures, such as repeat PTCA or coronary artery bypass surgery. Definition of restenosis: To accommodate different angiographic definitions already in use, 4 definitions of restenosis were initially tested: (1) an increase of at least 30% from the immediate post-PTCA stenosis to the follow-up PTCA stenosis; (2) an immediate post-PTCA stenosis of less than 50% that increased to 270% at follow-up; (3) an increase in stenosis at follow-up to 10% below predilatation stenosis or higher; and (4) a loss of at least 50% of the gain achieved at PTCA. Several clinical variables were assessed for each patient (Table I). Statistical analysis was performed using univariate and multivariate techniques to test the association between risk factors and restenosis. The statistical analysis included chi-square testing of the proportion of patients with restenosis by categories of various risk factors. When risk factors with more than 2 levels were considered, a chi-square test for linear trend also was performed. For multivariate analysis, a stepwise logistic regression was used with outcome as whether or not a patient had restenosis. TABLE II

Baseline Clinical Characteristics of Patients Who Had Follow-Up Anglograms with Restenosis After PTCA Patients n

Males* Females* Angina pectoris Calnadian Heart class:

111 IV 1-vessel CAD Multivessel CAD Left main CAD Single stenosis dilated RCA LMCA Circumflex LAD Bypass graft Multiple stenoses dilated

450 107 549 17 171 211 138 467 a3 7 529

%

ai 19 98.6

3z.i 3719 24.8 83.8 14.9 1.3 95.0

(“(I (23)

($:$

(9::; 28

(‘,;::;T 5.0

(4.3);

Mean age 5 1.2 years. t Values in parentheses are based on the 529 Single-attempt PTCAs. LAD = left anterior descending artery; LMCA = left main coronary artery; RCA = right coronary artery. l

Dilatation Variables

Post-PTCA Variables

Lesion dilated Pre- and post-PTCA gradient Number of inflations Maximal inflation pressure Post-PTCA stenosis Presence of coronary dissection Morphology of the lesion Eccentricity of the lesion

Medications: aspirin, dipyridamole, fi blockers, calcium antagonists, and nitrates

Results

Twenty-seven clinical centers with a total of 665 eligible patients met the selection criteria. Follow-up angiography was performed in 557 of these patients (84%). The center-specific follow-up angiography rates ranged from 74 to 100%. The clinical characteristics of the 557 patients were similar to those of other patients enrolled in the NHLBI PTCA Registry (Table II). When all 4 angiographic definitions were used, 187 patients (33.6%) were identified as having restenosis (Fig. 1). As can be seen, restenosis defined as 230% increase (definition 1) or a loss of 50% of the gain (definition 4) identified all patients. Four patients had restenosis categorized by definition 1 but not by definition 4, and 22 patients had restenosis categorized by definition 4 but not by definition 1. With definition 1, re-

stenosis was documented in 165 patients (29.6%). With definition 4, restenosis was documented in 183 patients (32.8%). For analysis of risk factors, patients with restenosis by either definition 1 or 4 were classified as having restenosis. The follow-up angiographic results are shown in Figure 2. The changes in stenosis from baseline to follow-up were distributed around a mean increase of 12%. The mode of the change distribution is 0, followed by changes most frequent between f10 from the postPTCA lesion sizes. Small differences are probably caused by variability in measurement and do not represent true changes. This necessitated the clinically more plausible definitions of restenosis as described above. The median time for follow-up angiography was 188 days. A definite relationship was noted between the timing of follow-up angiography and the incidence of restenosis (Fig. 3). The incidence of restenosis in patients who underwent angiography was highest within the first 5 months after PTCA. The indication for follow-up angiography may be different in patients with restenosis. In these patients, the indication was often the return of angina pectoris. Of patients who underwent follow-up angiography during the first 5 months after PTCA, 81% had chest pain, compared with 38% of those who underwent follow-up angiography more than 5 months after PTCA. Of the 557 patients who underwent follow-up angiography, 252 (45%) had chest pain judged to be definite

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patients

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so 60 40 20 n 12345676

9-12

Time to FU angiogram,

=-12

months

FIGURE 3. Distribution of patients with and without restenosis after PTCA according to time to follow-up (FU) angiography. FIGURE 1. Four definitions of restenosis after PTCA, showing overlapping of numbers of patients in each category. Two additional patients had restenosis by definitions 2 and 4 but not by definition 1 or 3. See text for definitions.

Pts. with definite probable

or

Pts. without

chest

pain

angina

(N=252)

(N=272)

20 16 16 14 12 %

10 8 6 4 2 0 100

-60

-60

Restenosis

-40

PO

0

No change

20_1

40

60

60

100

FIGURE 4. Relation between symptoms and restenosis rate.

Improvement

FIGURE 2. Follow-up angiographic results in all 557 patients. Angiographic results represent the difference between follow-up angiographic stenosis and stenosis immediately after PTCA. Restenosis indicated here is by definition 1, that is, at least a 30% increase from stenosis immediately after PTCA to stenosis at follow-up.

or probable angina pectoris. Two hundred seventy-two patients (49%) had no chest pain. (In 5 patients, information as to the presence or absence of chest pain was unknown.) In patients with definite or probable angina, restenosis was documented in 56%, compared with 14% for patients without chest pain (Fig. 4). Of all patients with restenosis, 24% did not have probable or definite angina pectoris. Within each center, no change in the rate of restenosis was noted over time; that is, the restenosis rate for patients who underwent PTCA early during a center’s experience was similar to that for patients undergoing PTCA late during that center’s experience. Four variables were significantly (p
than did patients who did not have onset of angina within 2 months (44% vs 29%). In addition to these 4 factors, other variables were less strongly associated with increased restenosis rates (p <0.05) (Table III): short time since onset of angina, history of MI or diabetes mellitus and severity of initial stenosis. Multivariate analysis was performed on variables that were significant with univariate analysis as well as on 7 variables that showed less significance with univariate testing (0.05 < p < 0.15): Canadian Heart class III or IV, multivessel CAD, ejection fraction greater than 50%, presence of unstable angina, bypass graft stenosis, inflation pressure greater than 7 atm, and final stenosis more than 30% of the luminal diameter. Multivariate analyses were performed in subgroups because of large numbers of missing data, especially pressure gradients and medications. In the subsets of patients with all of these variables present, neither pre- nor post-PTCA gradient nor medications were selected by the program. Therefore, multivariate analysis was performed in a larger subset of 439 patients who had data on the risk factors other than gradients and medications. In these 439 patients, 4 factors were significantly associated with an increased incidence of restenosis: men had increased restenosis rates; bypass graft stenosis, Canadian Heart class III or IV angina pectoris, and no history of MI were characteristics also selected. No drug combination was associated with a decreased incidence of restenosis.

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TABLE III

AFTER PTCA

Univariate Analysis of Risk Factors for Restenosis After PTCA’

Factor Sex Male Female Initial aradient <46 mm Hg 40-59 mm Hg 60-79 mm Hg 180 mm Hg Final gradient <20 mm Hg 20-39 mm Ha 240 mm Hg New-onset angina No Yes Mo$s since first chest pain 6-12 212 History of MI No Yes History of diabetes mellitus No Yes Initial stenosis <70% 70-90% 91-100% l

n

% of Restenosis

450 107

36 22

p Value

Increased Restenosis


Males


Large gradient before PTCA


Large gradient after PTCA

370 149


New onset

268 146 131

<0.05

Short duration

412 126

<0.05

No MI

<0.05

Diabetes

<0.05 for linear trend

More severe stenosis before PTCA

2;: 133 24 317 114 23

31 3:

496 43

32 47

3:: 134

35 39

For each factor, the total number of patients in whom the information was available was used for analysis.

Discussion Restenosis after PTCA remains one of the most difficult problems with the procedure. Restenosis is difficult to define. Various angiographic criteria have been used. However, angiographic results range from evidence of small changes that may be errors in measurement to larger, more significant changes. Reported restenosis rates range from 20 to 35%.11-18 Analysis has been complicated by the lack of complete angiographic follow-up data. In addition, reported series have been small, thus limiting the analyses of multiple variables and patient subsets. Theoretically, the most valid approach would be the strict adherence to a protocol that involves routine follow-up angiography in all patients. However, this has not been feasible in practice. The patients analyzed in this study were selected from centers with the highest repeat angiography rates (overall 84%). Obviously, patients with restenosis are clinically different from those without restenosis: they returned earlier for repeat angiography and had a higher incidence of angina at follow-up angiography. Many of the patients with restenosis underwent angiography for clinical indications; for example, return of angina pectoris. Therefore, more patients with restenosis probably return for follow-up angiography than do asymptomatic patients. Such a difference could contribute to the high restenosis rates of 29 to 33% obtained here, although these rates are similar to reported rates from smaller series.12-l7 The selection of centers with high follow-up angiography rates was intended to minimize this selection bias as much as possible. The evaluation of restenosis requires that the follow-up angiography

rates be high, because even though most patients with restenosis are symptomatic, about one-fourth do not have either definite or probable angina. In assessing risk factors for the development of restenosis, angiographic definition and documentation is essential. From a clinical standpoint, however, an angiographic definition may not be ideal. For example, a patient with a stenosis of 90% before PTCA and an immediate stenosis of 10% after PTCA may have a stenosis of 40% at follow-up. Although this represents a significant change, the patient remains without a hemodynamically significant stenosis and should be free of ischemic symptoms. After PTCA in these patients with follow-up angiograms, 24% of patients who had angiographic evidence of restenosis were asymptomatic. From an angiographic standpoint, the second definition of restenosis may be more clinically meaningful in that immediately after PTCA, there was a hemodynamically insignificant stenosis (stenosis 60% luminal diameter), and at follow-up, a hemodynamically significant stenosis (170% luminal diameter) was documented. With this definition, a hemodynamically significant restenosis was documented in 25% of the patients in our series. The cause of restenosis is not known. Pre-PTCA clinical variables, details of the procedure itself, and therapeutic pre- and postdilatation regimens may all affect restenosis rates. In our study using multivariate analysis, the strongest association with restenosis was male sex, followed by dilatation of bypass graft stenoses, Canadian Heart class III or IV angina at baseline, and no history of MI. All of these variables could relate to as yet undefined underlying anatomic or pathophysiologic differences in these patients, including differences

June 15. 1984

in the composition of the atheromatous plaque. Univariate comparisons revealed other variables associated with restenosis. These included actual dilatation variables such as gradient before and after PTCA. A major area of investigation in patients undergoing PTCA involves the use of medications designed to reduce restenosis.1g,20 A wide variety of regimens are being tested. Antiplatelet regimens with aspirin and dipyridamole reduce both early and late vein graft closure.21,22 Warfarin also has been tried after PTCA, but has not been effective.lg The medication regimens in this series included an tiplatelets, anticoagulants, calcium antagonists, and nitrates; none was associated with decreased rates of restenosis. However, the specific protocols used were not controlled with respect to adequate dosage and timing of medications and monitoring of compliance. In a previous study from our institution, the administration of aspirin and dipyridamole had to be carefully controlled before a decrease in vein graft occlusion was noted.21T22These conditions may not have been met in the patients in the present study. Also, other drugs should be tried, for instance, sulfinpyrazone,20 in a more carefully controlled fashion. Finally, the cause of restenosis may not involve platelet mechanisms, but may depend on smooth muscle cell elements, hemodynamic forces, and other as yet undefined factors that are not amenable to current drug treatment. The NHLBI PTCA Registry may not be the ideal means for studying restenosis. The Registry was not designed initially to investigate restenosis. Therefore, follow-up management and medications were not standardized by protocol. Nevertheless, it has the largest systematic follow-up on patients who have undergone PTCA. Based on the data on the patients in this series, several comments can be made: angiographic evidence of restenosis occurs in approximately one-third of patients undergoing PTCA; restenosis is usually associated with and documented in patients with recurrent angina pectoris after PTCA, although approximately onefourth of patients with restenosis are asymptomatic; and most patients with restenosis and angina undergo follow-up angiography within 5 months after PTCA. Although a typical clinical presentation can be identified, that is, a man with recent onset of severe angina pectoris but without a history of MI who has had a successful PTCA but returns within 5 months for recurrence of angina, much variability remains unexplained. While these risk factors significantly increase the probability of restenosis, they do not explain the phenomenon, although this has not been studied in sufficient detail with properly controlled regimens necessary to come to a final conclusion. Finally, the restenosis rates reported herein are occurring despite the use of various anti-

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platelet regimens. The effect of these antiplatelet regimens, however, has not been studied in sufficient detail with properly controlled regimens necessary to reach a final conclusion. References 1. Gruntzig A. Transluminal dilatation of coronary-artery stenosis (letter to the editor). Lancet 1978;1:263. 2. Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979; 301: 61-68. 3. Kent KM, Bentivoglio LG, Block PC, Cowley MJ, Dorros G, Gosselin AJ, Gruentzig A, Myler RK, Simpson J, Stertzer SH, Williams DO, Bourassa MG, Kelsey SF, Detre KM, Mullin S, Passamani E. NHLBI Percutaneous Transluminal Coronary Angioplasty (PTCA) Registry: four years experience (abstr). Am J Cardiol 1982;49:904. 4. Kent KM, Bentivoglio LG, Block PC, Cowley MJ, Dorros G, Gosselin AJ, Gruntzig A, Myler RK, Simpson J, Stertrer SH, Williams DO, Fisher L, Gillespie MJ, Detre K, Kelsey S, Mullin SM, Mock MB. Percutaneous transluminal coronary angioplasty: report from the Registry of the National Heart, Lung, and Blood Institute. Am J Cardiol 1982:49:201 l-2020. 5. Stertzer S, Dorros G, Myler R, Cowley M, Williams D, Kent K. Complex transluminal angioplasty in multivessel coronary artery disease (abstr). Am J Cardiol 1982;49:904. 6. Hartzler Go. Rutherford BD. McConahav DR. Srmultaneous multiole lesion coronary angioplasty-a preferred therapy for patients with multiple vessel disease (abstr). Circulation 1982;66:suppl ll:ll-5. 7. Holmes DR Jr, Vlietstra RE, Reeder GS, Bresnahan JF, Smith HC, Bove AA, Schaff HV. Elective percutaneous transluminai coronary angioplasty of total coronary arterial occlusions not associated with acute infarction (abstr). J Am C&l Cardiol 1983;1:656. 0. Ford WB, Wholey MH, Zikria EA, Somadani SR, Sullivan ME. Percutaneous transluminal dilation of aortocoronarv SaDhenOuS vein bvoass arafts. Chest I. _ 1981;79:529-535. 9. Block PC, Palacios IF, Wholey MH, O’Toole J. Percutaneous transluminal angioplasty of stenotic coronary artery bypass grafts (abstr). Circulation 1981;64:suppl IV:IV-109. 10. Douglas JS Jr, Gruentxig AR, King SB Ill, Hollman J. Long-term results of percutaneous transluminal angioplasty for aorto-coronary saphenous vein araft stenosis (abstr). Circulation 1982:66:suool ll:il-124. 11. Vlietstra RE, Holmes DR Jr, Reeder GS,, Mock MB, Smith HC, Bove AA, Bresnahan JF, Piehler JM. Balloon angroplasty in multivessel coronary artery disease. Mayo Clin Proc 1983;58:563-567. 12. Hollman J, Gruentrlg A, Meier B, Bradford J, Galan K. Factors affecting recurrence after successful coronary angioplasty (abstr). J Am Coll Cardiol 1983;1:644. 13. Dangoisse V, Guiteras Val P, David PR, Lesperance J, CrCpeau J, Dyrda I, Bourassa MG. Recurrence of stenosis after successful percutaneous transluminal coronary angioplasty (PTCA) (abstr). Circulation 1982;66:suppl ll:ll-331. 14. Jutxky KR, Berte LE, Alderman EL, Ratts J, Simpson JB. Coronary restenosis rates in a consecutive patient series one Year post successful angioplasty (abstr). Circulation 1982;66:suppl ll:ll-331. 15. Holmes DR Jr, Vlietstra RE, Smith HC, Vetrovec GW, Cowley MJ, Kent KM, Detre KM, Myler R. Restenosis following percutaneous transluminal coronary angioplasty (PTCA): a report from the NHLBI PTCA Registry (abstr). Am J Cardiol 1982;49:905. 16. Scholl JM, David PR, Chaitman BR, Lesperance J, Crepeau J, Dyrda I, Bourassa MG. Recurrence of stenosis following percutaneous transluminal coronary angioplasty (abstr). Circulation 1981~64:suppl IV:IV-193. 17. David PR, Waters DD, Scholl JM, Crepeau J, Szlachcic J, LespL?rance J, Hudon G, Bourassa MG. Percutaneous transluminal coronary angioplasty in patients with variant angina. Circulation 1982;66:695-702. 16. Holmes DR Jr, Vlietstra RE, Mock MB, Smith HC, Cowley MJ, Kent KM, Detre KM. Follow-up of patients undergoing percutaneous transluminal coronary angioplasty (PTCA): a report from the NHLBI PTCA Registry (abstr). Am J Cardiol 1982;49:916. 19. Thornton MA, Gruentzig AR, Hollman J, King S Ill, Douglas J. Coumadin vs. aspirin in prevention of recurrence after transluminal coronary angioplasty-a randomized study (abstr). Circulation 1982;66:suppl ll:ll-262. 20. Sanborn TA, Faxon DP, Haudenschild C, Gottsman SB, Ryan TJ. Sulfinpyrazone inhibition of restenosis after experimental angioplasty (abstr). J Am Coil Cardiol 1983:1:644. 21. Chesebro JH, Clements IP, Fusler V, Elveback LR, Smith HC, Bardsley WT. Frye RL, Holmes DR Jr, Vlietstra RE, Pluth JR, Wallace RB, Puga FJ, Drszulak TA, Piehler JM, Schaff HV, Danielson GK. A platelet-inhibitordrug trial in coronary-artery bypass operations: benefit of perioperative diovridamole and aspirin therapy on early postoperative vein-graft patency. -N Errol J Med 1982:307:73-78. 22. Ch&bro JH, Fester V, Clements IP? Elveback LR, Smith HC, Frye RL, Pluth JR, Schaff HV. Perioperative drpyridamole plus aspirin therapy improves early aortocoronary vein graft patency with a continued late effect on individual grafts (abstr). J Am Coll Cardiol 1983;1:618. I