- Email: [email protected]
Six-month outcomes of percutaneous transluminal coronary angioplasty in hypertensive patients: Results from the ROSETTA registry
Six-month outcomes of percutaneous transluminal coronary angioplasty in hypertensive patients: Results from the ROSETTA registry Janius Tsang, BSc,a Richard Sheppard, MD,c Koon Hou Mak, MD,d David Brown, MD,e Thao Huynh, MD,b David Schechter, MD,f and Mark J. Eisenberg, MD, MPHa for the ROSETTA Investigators Montreal, Quebec, Canada, Singapore, Bronx, NY, and Jerusalem, Israel
Purpose Hypertension is an important risk factor for coronary artery disease. However, the impact of hypertension on the outcomes of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) is unknown. Our purpose was to evaluate the association between hypertension and adverse outcomes and repeat cardiac procedures during the 6-month period after PTCA.
Methods We studied 791 patients who were enrolled in the Routine Versus Selective Exercise Treadmill Testing After Angioplasty (ROSETTA) registry. This registry is a prospective multicenter study examining the use of functional testing after a successful PTCA.
Results We compared 411 hypertensive patients (mean age 60.1 ± 10 years, 31.1% female) with 380 normotensive patients (mean age 59.1 ± 12 years, 16.2% female). Patients with hypertension had a higher 6-month rate of composite clinical events (unstable angina, myocardial infarction, death) than did normotensive patients (16.5% vs 10.5%, P = .017). In addition, there was a trend for hypertensive patients to have higher rates of cardiac procedures (angiography, repeat PTCA, coronary artery bypass graft surgery) compared with normotensive patients (19.8% vs 14.9%, P = .074). However, functional testing after PTCA was lower among hypertensive subjects (44.4% vs 54.0%, P = .008). Among the 411 hypertensive patients, a regression analysis showed that several variables were independently associated with increased 6-month adverse event rates, including pre-PTCA Killip class III-IV (odds ratio [OR] 5.7, 95% CI 1.7-19.0), Canadian Cardiovascular Society angina class III-IV (OR 2.1, 95% CI 1.1-4.2), unstable angina as the reason for PTCA (OR 2.3, 95% CI 1.2-4.3), peripheral vascular disease (OR 3.2, 95% CI 1.5-6.4), PTCA of a bypass graft (OR 3.1, 95% CI 1.2-7.6), and calcium antagonist usage at admission for the index PTCA (OR 1.9, 95% CI 1.1-3.4). Conclusions During the 6-month period after a successful PTCA, patients with hypertension have significantly higher adverse event rates than do those without hypertension. Several clinical variables may help identify which hypertensive patients are at higher risk for clinical events. (Am Heart J 2002;143:124-9.)
More than 500,000 percutaneous transluminal coronary angioplasty (PTCA) procedures are performed each year in North America.1,2 Despite the proved safety and efficacy of PTCA, identifying patients at high risk for adverse outcomes is still problematic.3,4 Hypertension is a known risk factor for coronary artery disease, but little is known From the aJewish General Hospital and the bMontreal General Hospital, McGill University, and the cRoyal Victoria Hospital, Montreal, Quebec, Canada, the dNational Heart Center, Singapore, the eAlbert Einstein College of Medicine, Bronx, NY, and the fHadassah Hospital, Jerusalem, Israel. M. J. E. is a research scholar of the Heart and Stroke Foundation of Canada. Submitted October 13, 2000; accepted August 31, 2001. Reprint requests: Mark J. Eisenberg, MD, MPH, Divisions of Cardiology and Clinical Epidemiology, Jewish General Hospital/McGill University, 3755 Cote Ste Catherine Rd, Suite A-118, Montreal, Quebec H3T 1E2, Canada. E-mail: [email protected] Copyright © 2002 by Mosby, Inc. 0002-8703/2002/$35.00 + 0 4/1/120290 doi:10.1067/mhj.2002.120290
about the prognosis of hypertensive patients during the 6 months after a successful PTCA.4 Previous studies2,5 have examined the 5- and 10-year outcomes of patients who have undergone a successful PTCA, but none have looked specifically at outcomes during the critical 6 months after a PTCA. During this 6-month period, patients have up to a 20% to 30% risk of restenosis and a subsequently increased risk of adverse cardiac events in this time.6,7 In addition, recent studies suggest that hypertensive patients have altered endothelial dysfunction that may be associated with the likelihood of restenosis after PTCA.8,9 Thus we compared the 6-month incidence of clinical events and follow-up cardiac procedures among hypertensive and normotensive patients who had a successful PTCA.
Methods The patient population was composed of 791 patients who underwent successful PTCA and who were enrolled in the
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Routine Versus Selective Exercise Treadmill Testing After Angioplasty (ROSETTA) registry. The ROSETTA registry prospectively collected data on patients recruited from 13 centers in 5 countries (Australia, Canada, Israel, Singapore, United States) (see Appendix). Information on ischemic events (unstable angina, myocardial infarction [MI], cardiac death) and repeat cardiac procedures (angiography, PTCA, coronary artery bypass graft [CABG] surgery,) were collected for each patient. Unstable angina was defined as angina requiring one or more hospitalizations during the first 6 months after the procedure. Myocardial infarction was defined by clinical, electrocardiographic, and enzyme criteria. Cardiac death was defined as any one of the following: sudden death, death after resuscitation, death from congestive heart failure, or death from definite, probable, or possible MI.
Entry criteria The study included 791 patients who were enrolled in the ROSETTA registry between February 1, 1996, and December 31, 1997. Six-month follow-up was complete by the end of June 1998. For the majority of the patients, enrollment in the study took place immediately after PTCA and before discharge from the hospital. The Ethics Committee at each institution approved the study, and written informed consent was obtained before patient enrollment. Patients were included in the study if they had successfully undergone PTCA of at least one coronary lesion. Successful PTCA was defined as reduction of 1 lesion from a stenosis of ≥60% to a residual of <50% with a minimum absolute reduction of 20% (by visual assessment). Patients were eligible no matter which of the currently accepted technologies were used (eg, PTCA, rotational atherectomy, directional atherectomy, laser atherectomy, stenting). Moreover, patients with multilesion or multivessel PTCA and patients with lesions treated in saphenous vein or arterial bypass grafts were also eligible for enrollment. Patients were excluded if they (1) were participating in conflicting clinical studies, (2) had contraindications to repeat cardiac procedures (angiography, PTCA, CABG), (3) had contraindications to or inability to undergo follow-up functional testing, (4) had a medical condition with a prognosis of <1 year, or (5) were unlikely to be available for 6-month follow-up.
Follow-up Clinical follow-up data were obtained 6 months after PTCA. For information on functional testing, clinical events, and cardiac procedures, the research nurses at each center contacted patients by telephone. End point documentation for tests or events that occurred at other institutions was also obtained.
Statistical analysis Patients were divided into 2 groups: those with or without hypertension. Research nurses at each center determined a patient’s hypertensive status through chart review. We then compared the baseline clinical and procedural characteristics among hypertensive and normotensive subjects. The rates of functional tests, repeat cardiac procedures, and clinical events that occurred during the 6-month follow-up period were also examined. Clinical events included unstable angina, MI, cardiac death, and all-cause mortality. The occurrence of a com-
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Table I. Clinical characteristics of 791 patients undergoing successful PTCA in the ROSETTA registry No. of patients (%)
Age (y ± SD) Male sex Hyperlipidemia Pre-PTCA coronary artery disease Single vessel Multivessel History of coronary artery disease Obesity Diabetes mellitus Current smoker Cerebral vascular accident Peripheral vascular disease Congestive heart failure Killip class III/IV Canadian Cardiovascular Society angina class III-IV History of angina Prior MI Prior PTCA Prior CABG Medication use at admission β-Blockers Calcium antagonists Nitrates Angiotensin-converting enzyme inhibitors Diuretics
Hypertensive (n = 411)
Normotensive (n = 380)
62.1 ± 10.1 283 (68.9) 238 (57.9)
59.1 ± 11.7 320 (83.8) 215 (56.6)
160 (38.9) 251 (61.1) 186 (45.5) 121 (29.4) 119 (29.0) 82 (20.0) 38 (9.2) 55 (13.4) 39 (9.5) 15 (3.7) 231 (56.5)
165 (43.3) 216 (56.7) 184 (48.5) 98 (25.7) 61 (16.0) 78 (20.4) 13 (3.4) 30 (7.9) 22 (5.8) 8 (2.1) 168 (44.1)
297 (72.3) 181 (44.3) 117 (28.5) 72 (17.5)
256 (67.0) 187 (49.1) 93 (24.3) 59 (15.4)
(51.6) (42.8) (44.5) (35.4)
(46.7) (23.6) (38.6) (15.0)
(17.5)
(4.5)
posite end point, defined as any of the above events, was also compared between the 2 groups. Repeat cardiac procedures included angiographies, PTCAs, and CABGs that occurred after the index PTCA. Finally, baseline characteristics were analyzed by logistic regression for predictors of outcome within the hypertensive population. Those characteristics that had P values <.10 by univariate analysis were then entered into a multivariate logistic analysis. Continuous values are presented as the mean ± SD, and dichotomous values are presented as percentages. All statistical tests were 2 tailed, and a P value ≤.05 was considered to be statistically significant.
Results Baseline clinical characteristics Table I shows the baseline clinical characteristics of hypertensive and normotensive patients. The hypertensive patient group was older than the normotensive group (62.1 ± 10 years vs 59.1 ± 12 years, P < .0001) and included a higher percentage of female subjects (31.1% vs 16.2%, P < .0001). Hypertensive patients were also more likely to have other risk factors for coronary artery disease, such as diabetes (29.0% vs 16.0%, P < .0001), history of a cerebrovascular accident
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126 Tsang et al
Figure 1
Adverse clinical outcomes among 411 hypertensive and 380 normotensive patients in the ROSETTA registry during the 6 months after a successful PTCA. NS, Not significant.
Table II. Procedural characteristics of 791 patients undergoing successful PTCA in the ROSETTA registry No. of patients
Multilesion PTCA Multivessel PTCA PTCA of a bypass graft Atherectomy Stenting Lesion severity (mean ± SD) Before (%) After (%) Post–Thrombolysis in Myocardial Infarction flow grade 3 2 0-1 Reason for PTCA Stable angina Unstable angina Acute or recent MI
Hypertensive (n = 411)
Normotensive (n = 380)
129 (31.3) 61 (14.8) 28 (6.8) 33 (8.0) 248 (60.3)
101 (26.5) 57 (15.0) 19 (5.0) 14 (3.7) 213 (55.6)
87.6 ± 10.9 8.7 ± 11.3
87.8 ± 10.6 8.4 ± 11.5
403 (98.1) 5 (1.2) 3 (0.72)
369 (96.9) 11 (2.9) 1 (0.26)
24.6 (101) 40.1 (165) 13.9 (57)
25.3 (96) 29.8 (113) 17.4 (66)
(9.2% vs 3.4%, P = .0004), peripheral vascular disease (13.4% vs 7.9%, P = .01), and congestive heart failure (9.5% vs 5.8%, P = .06). In addition, they were more likely to have more severe angina at admission (Canadian Cardiovascular Society angina class III or IV) (56.5% vs 44.1%, P = .0006).
Angiographic and procedural characteristics The angiographic and procedural characteristics of the hypertensive and normotensive groups were similar, with the exception of atherectomy use (Table II). Hypertensive patients were significantly more likely to undergo atherectomy than those without hypertension (8.0% vs 3.7%, P = .01). Most patients had a PTCA of a single lesion and a single vessel and had similar lesion severity. Hypertensive and normotensive patients also had mostly similar reasons for undergoing the index PTCA, but hypertensive subjects were more likely to have had unstable angina as the primary reason for the index PTCA (40.1% vs 29.8%, P = .002).
Clinical events and follow-up procedures We examined the rates of adverse clinical events and found that hypertensive patients were significantly more likely to have unstable angina during the 6 months after PTCA (14.7% vs 9.0%, P = .015) (Figure 1). The increased likelihood of unstable angina among hypertensive subjects also contributed to the higher incidence of the composite end point (P = .017). In addition, patients with hypertension tended to have a higher rate of MI (P = .11). Hypertensive patients were also much more likely to undergo repeat angiography and revascularization procedures than normotensive patients were during the 6 months after the index PTCA (19.8% vs 14.9%, P = .07) (Figure 2). However, despite the increased adverse event rate and the increased rate of repeat cardiac procedures, hypertensive patients were less likely to
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Figure 2
Use of cardiac procedures among 411 hypertensive and 380 normotensive patients in the ROSETTA registry during the 6 months after a successful PTCA.
undergo post-PTCA functional testing than were normotensive patients (44.4% vs 54.0%, P = .008).
Predictors of clinical events in hypertensive patients We identified several baseline characteristics that were independently associated with adverse clinical events within the hypertensive population (Table III). These characteristics included Killip class III-IV (46.7% vs 15.4%, odds ratio 5.7, 95% CI 1.7-19.0), Canadian Cardiovascular Society angina class III/IV (22.5% vs 9.0%, OR 2.1, 95% CI 1.1-4.2), unstable angina as the reason for PTCA (24.8% vs 11.0%, OR 2.3, 95% CI 1.2-4.3), peripheral vascular disease (30.9% vs 14.3%, OR 3.2, 95% CI 1.5-6.4), PTCA of a bypass graft (39.3% vs 14.9%, OR 3.1, 95% CI 1.2-7.6), and calcium antagonist use at admission (21.2% vs 12.4%, OR 1.9, 95% CI 1.1-3.4)
Discussion This study was designed to examine the incidence of clinical events and the use of follow-up cardiac procedures among hypertensive patients during the 6 months after a successful PTCA. We found that, among patients undergoing PTCA, those with hypertension have a significantly higher incidence of clinical events compared with normotensive patients. In addition, although hyper-
Table III. Univariate and multivariate analyses of clinical and procedural characteristics versus follow-up clinical events among 411 hypertensive patients undergoing successful PTCA in the ROSETTA registry
Univariate analysis Calcium antagonist at admission Calcium antagonist at discharge Canadian Cardiovascular Society angina class III/IV Congestive heart failure Diuretic use at discharge Killip class III/IV Peripheral vascular disease Previous CABG PTCA of 1 bypass graft Unstable angina as primary reason for PTCA Multivariate analysis Calcium antagonist at admission Canadian Cardiovascular Society angina class II/IV Killip class III/IV Peripheral vascular disease PTCA of 1 bypass graft Unstable angina as primary reason for PTCA
Odds ratio
95% CI
P value
1.9 1.7 2.9
1.1-3.2 1.0-2.8 1.6-5.4
.02 .07 .0004
3.3 2.9 4.8 2.7 1.9 3.7 2.7
1.6-6.7 1.6-5.4 1.7-13.7 1.4-5.1 1.0-3.6 1.6-8.3 1.6-4.6
.001 .0008 .003 .003 .04 .002 .0003
1.9 2.1
1.1-3.4 1.1-4.2
.03 .03
5.7 3.2 3.1 2.3
1.7-19.0 1.5-6.4 1.2-7.6 1.2-4.3
.005 .002 .01 .01
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128 Tsang et al
tensive patients underwent more repeat cardiac procedures, they also underwent less post-PTCA functional testing during the 6-month follow-up compared with normotensive patients. There are several possible explanations for these differences among hypertensive and normotensive patients. First, at the time of the PTCA, hypertensive patients were generally in a poorer state of health, with greater numbers of patients with Canadian Cardiovascular society Angina Class III-IV, congestive heart failure, and peripheral vascular disease. As a result, their worse clinical status might have contributed to the increased rate of adverse clinical events and repeat cardiac procedures. The reduced functional status of such patients might also contribute to the less frequent use of functional testing among hypertensive as opposed to normotensive subjects. However, patients who were unable to undergo any functional testing were excluded from the ROSETTA registry. Consequently, the lower post-PTCA functional testing rate among hypertensive patients suggests that they may not have been screened sufficiently after PTCA, contributing to the increased 6-month event rates. A second possible explanation for our results may be that hypertension often coexists with diabetes mellitus, and this association can contribute to the increased risk of clinical events and repeat procedures. The prevalence of hypertension among diabetic patients is at least twice that among the general population.10 Furthermore, diabetes mellitus and hypertension act synergistically to increase significantly the risk of adverse cardiac events.11 In a review of studies done between 1980 and 1996, Grossman and Messerli12 found that the risk of cardiac disease was twice as great in individuals with both risk factors than in those with either one. Moreover, several trials have demonstrated a greater incidence of adverse events in diabetic hypertensive patients than in diabetic normotensive patients.12 In a study of post-PTCA patients, diabetes and hypertension were found to be independent predictors of 5- to 19-year survival.2,5 Last, comorbidity other than diabetes among hypertensive subjects may also include left ventricular hypertrophy, hyperlipidemia, obesity, and smoking. Echocardiographically determined left ventricular hypertrophy and diastolic dysfunction are often indicative of poorer prognosis in these patients.13,14 Furthermore, hyperlipidemia is also known to be associated with adverse outcomes because the presence of hyperlipidemia can accelerate atherogenic processes in patients with hypertension.15 However, multivariate regression analysis of the ROSETTA population did not show that these comorbid conditions were significantly associated with post-PTCA outcomes. This result is most likely because the ROSETTA study included a relatively healthy group of patients. Fewer than one third of the patients were obese, only slightly more than half were hyperlipi-
demic, and 40% had single-vessel coronary artery disease. Consequently, the comorbid conditions that are traditionally associated with poor outcomes did not turn out to be strong predictors of adverse outcomes among hypertensive patients in the ROSETTA study.
Clinical implications Our results have several clinical implications. First, because hypertension often has accompanying comorbid conditions, clinicians should strongly consider any of these high-risk characteristics and comorbidities when treating their hypertensive patients with PTCA. In hypertensive patients with diabetes mellitus, high fasting plasma glucose levels (>13.4 mmol/L) have been shown to be significantly associated with increased rates of MI.16 Controlling hyperglycemia was found to lower the risk of MI, although the reduction was borderline of significance.17 Similarly, tight blood pressure regulation in hypertensive patients with type 2 diabetes mellitus decreases the rates of diabetesrelated mortality and morbidity.18 Second, the screening of hypertensive patients at risk of adverse clinical events after PTCA may be improved by increasing the rates of functional testing after PTCA. In our study, hypertensive patients underwent less frequent functional testing during the 6 months after their index PTCAs. Because there was less testing done in this group of patients, some of them may not have been identified as having a higher risk for a clinical event. Consequently, the lower testing rate may have contributed to the higher proportion of patients who had unstable angina or the composite end point. More frequent use of such functional tests after PTCA in hypertensive patients might identify and allow for earlier treatment of a group of high-risk patients. Finally, the significant risk factors that our regression model identified should be a useful tool in risk stratifying hypertensive patients before PTCA. Hypertensive patients with severe angina, congestive heart failure, a bypass graft vessel, peripheral vascular disease, or calcium channel antagonist usage have factors associated with worse clinical outcomes. Consequently, these groups of hypertensive patients may benefit from closer surveillance during the 6 months after PTCA.
Limitations Our study has several potential limitations. First, the examination of hypertensive patients was not an a priori hypothesis of the ROSETTA registry. This study was an ancillary study based on a subgroup analysis of a prospective registry. As a result, we did not collect the exact blood pressures of patients or the indications for their medication use. However, the potential for misclassification in our study is low for 2 reasons. Research nurses at each center performed thorough chart reviews to complete the data forms. Consequently, a
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patient’s hypertensive status was based on blood pressure measurements in the charts and not solely on patient recall. In addition, the difference in outcomes of the normotensive and hypertensive groups also counts against potential misclassification bias. If there had been a large number of hypertensive subjects misclassified as normotensive or vice versa, then the clinical outcomes of the 2 patient groups would be similar. Second, the study design did not include information on the prevalence of left ventricular hypertrophy among the hypertensive patients. We would have been better able to determine prognosis in these patients if we had echocardiographically determined the extent of left ventricular hypertrophy. Because of these limitations, the findings from this study should be validated in a prospective study aimed specifically at hypertensive patients and the potential effect of endothelial dysfunction on postangioplasty outcomes.
Conclusion In this study, we found that patients with hypertension are more likely to undergo repeat cardiac procedures and adverse clinical events 6 months after PTCA. The poorer state of health at baseline, the presence of comorbidities such as left ventricular hypertrophy and diabetes mellitus, and the involvement of endothelial dysfunction were factors that likely contributed to the increased event rates we saw in our study. In addition, because hypertensive patients underwent fewer functional tests after PTCA, patients at higher risk for adverse events may have not been properly identified, eventually contributing to the higher adverse outcome rates. Hypertensive patients could benefit from a more aggressive treatment strategy that involves increasing functional testing and management of comorbid conditions such as diabetes mellitus and endothelial dysfunction. Ultimately, the issues raised from this observational study need to be examined further in a prospective investigation.
Tsang et al 129
6.
7.
8.
9.
10.
11.
12. 13. 14. 15. 16.
17.
18.
nary balloon angioplasty (the LDCMC registry): Lady Davis Carmel Medical Center. Am J Cardiol 1998;82:547-53. Baim DS. Percutaneous coronary revascularization. In: Brawnwald E, Fauci AS, Kasper DL, et al. Harrison’s principles of internal medicine. 15th ed. New York: McGraw-Hill; 2001;1377-442. Sabatine MS, O’Gara PT, Lilly LS. Ischemic heart disease. In: Lilly LS, editor. Pathophysiology of heart disease. 2nd ed. Baltimore: Lippincott, Williams & Wilkins; 1997;119-44. Wu TC, Chen YH, Chen JW, et al. Impaired forearm reactive hyperemia is related to late restenosis after coronary stenting. Am J Cardiol 2000;85:1071-6. Schiffrin EL, Intengan HD, Thibault G, et al. Clinical significance of endothelin in cardiovascular disease. Curr Opin Cardiol 1997;12: 354-67. Meurice T, Vallet B, Bauters C, et al. Role of endothelial cells in restenosis after coronary angioplasty. Fund Clin Pharmacol 1996; 10:234-42. Wilson PW. An epidemiologic perspective of systemic hypertension, ischemic heart disease, and heart failure. Am J Cardiol 1997;80:38J. Grossman E, Messerli FH. Diabetic and hypertensive heart disease. Ann Intern Med 1996;125:304-10. Berkenboom G. Bradykinin and the therapeutic actions of angiotensinconverting enzyme inhibitors. Am J Cardiol 1998;82:11-3S. Kahan T. The importance of left ventricular hypertrophy in human hypertension. J Hypertension 1998;16:S23-9. Henry PD, Cabello OA, Chen CH. Hypercholesterolemia and endothelial dysfunction. Curr Opin Lipidol 1995;6:190-5. Adler AI, Neil AW, Manley SE, et al. Hyperglycemia and hyperinsulinemia at diagnosis of diabetes and their association with subsequent cardiovascular disease in the United Kingdom Prospective Diabetes Study (UKPDS 47). Am Heart J 1999;138:S353-9. UKPDS Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 32). Lancet 1998; 352:837-53. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:701-13.
Appendix Clinical Center Investigators:
References 1. Keelan ET, Nunez BD, Grill DE, et al. Comparison of immediate and long-term outcome of coronary angioplasty performed for unstable angina and rest pain in men and women. Mayo Clin Proc 1997;72:5-12. 2. Hasdai D, Bell MR, Grill DE, et al. Outcome ≥10 years after successful percutaneous transluminal coronary angioplasty. Am J Cardiol 1997;79:1005-11. 3. Gurlek A, Dagalp Z, Oral D, et al. Restenosis after transluminal coronary angioplasty: a risk factor analysis. J Cardvasc Risk 1995; 2:51-5. 4. Mick MJ, Piedmonte MR, Arnold AM, et al. Risk stratification for long-term outcome after elective coronary angioplasty: a multivariate analysis of 5,000 patients. J Am Coll Cardiol 1994;24:74-80. 5. Halon DA, Merdler A, Flugelman MY, et al. Importance of diabetes mellitus and systemic hypertension rather than completeness of revascularization in determining long-term outcome after coro-
Concord Hospital, Sydney, Australia: D. Brieger; The Royal Melbourne Hospital, Parkville, Australia: J. Lefkovits, P. Singh; Jewish General Hospital, Montreal, Quebec, Canada: M. Eisenberg, P. Garzon, J. Tsang, L. Dragatakis, R. Schlesinger, E. Shalit, D. Beauvais; Montreal General Hospital, Montreal, Quebec, Canada: T. Huynh, L. Pilote, C. Boudreault; Royal Victoria Hospital, Montreal, Quebec, Canada: M. Smilovitch, R. Sheppard, A. Serpa; Hadassah Hospital, Jerusalem, Israel: D. Schechter, H. Witt; National Heart Center, Singapore: K. H. Mak; University of California at San Diego Medical Center, San Diego, Calif: D. L. Brown, E. Mahmud; St Joseph’s Hospital, Omaha, Neb: M. Del Core; University of Texas Health Center at Tyler, Tyler, Tex: U. Deligonul, S. Collins; St Luke’s Regional Medical Center, Boise, Idaho, R. Duerr; Medical College of Virginia, Richmond, Va: E. Goudreau, K. Hall, R. O’Brien; New York Veterans Administration Medical Center, New York, NY: S. Sedlis, M. Saric.
Purpose Hypertension is an important risk factor for coronary artery disease. However, the impact of hypertension on the outcomes of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) is unknown. Our purpose was to evaluate the association between hypertension and adverse outcomes and repeat cardiac procedures during the 6-month period after PTCA.
Methods We studied 791 patients who were enrolled in the Routine Versus Selective Exercise Treadmill Testing After Angioplasty (ROSETTA) registry. This registry is a prospective multicenter study examining the use of functional testing after a successful PTCA.
Results We compared 411 hypertensive patients (mean age 60.1 ± 10 years, 31.1% female) with 380 normotensive patients (mean age 59.1 ± 12 years, 16.2% female). Patients with hypertension had a higher 6-month rate of composite clinical events (unstable angina, myocardial infarction, death) than did normotensive patients (16.5% vs 10.5%, P = .017). In addition, there was a trend for hypertensive patients to have higher rates of cardiac procedures (angiography, repeat PTCA, coronary artery bypass graft surgery) compared with normotensive patients (19.8% vs 14.9%, P = .074). However, functional testing after PTCA was lower among hypertensive subjects (44.4% vs 54.0%, P = .008). Among the 411 hypertensive patients, a regression analysis showed that several variables were independently associated with increased 6-month adverse event rates, including pre-PTCA Killip class III-IV (odds ratio [OR] 5.7, 95% CI 1.7-19.0), Canadian Cardiovascular Society angina class III-IV (OR 2.1, 95% CI 1.1-4.2), unstable angina as the reason for PTCA (OR 2.3, 95% CI 1.2-4.3), peripheral vascular disease (OR 3.2, 95% CI 1.5-6.4), PTCA of a bypass graft (OR 3.1, 95% CI 1.2-7.6), and calcium antagonist usage at admission for the index PTCA (OR 1.9, 95% CI 1.1-3.4). Conclusions During the 6-month period after a successful PTCA, patients with hypertension have significantly higher adverse event rates than do those without hypertension. Several clinical variables may help identify which hypertensive patients are at higher risk for clinical events. (Am Heart J 2002;143:124-9.)
More than 500,000 percutaneous transluminal coronary angioplasty (PTCA) procedures are performed each year in North America.1,2 Despite the proved safety and efficacy of PTCA, identifying patients at high risk for adverse outcomes is still problematic.3,4 Hypertension is a known risk factor for coronary artery disease, but little is known From the aJewish General Hospital and the bMontreal General Hospital, McGill University, and the cRoyal Victoria Hospital, Montreal, Quebec, Canada, the dNational Heart Center, Singapore, the eAlbert Einstein College of Medicine, Bronx, NY, and the fHadassah Hospital, Jerusalem, Israel. M. J. E. is a research scholar of the Heart and Stroke Foundation of Canada. Submitted October 13, 2000; accepted August 31, 2001. Reprint requests: Mark J. Eisenberg, MD, MPH, Divisions of Cardiology and Clinical Epidemiology, Jewish General Hospital/McGill University, 3755 Cote Ste Catherine Rd, Suite A-118, Montreal, Quebec H3T 1E2, Canada. E-mail: [email protected] Copyright © 2002 by Mosby, Inc. 0002-8703/2002/$35.00 + 0 4/1/120290 doi:10.1067/mhj.2002.120290
about the prognosis of hypertensive patients during the 6 months after a successful PTCA.4 Previous studies2,5 have examined the 5- and 10-year outcomes of patients who have undergone a successful PTCA, but none have looked specifically at outcomes during the critical 6 months after a PTCA. During this 6-month period, patients have up to a 20% to 30% risk of restenosis and a subsequently increased risk of adverse cardiac events in this time.6,7 In addition, recent studies suggest that hypertensive patients have altered endothelial dysfunction that may be associated with the likelihood of restenosis after PTCA.8,9 Thus we compared the 6-month incidence of clinical events and follow-up cardiac procedures among hypertensive and normotensive patients who had a successful PTCA.
Methods The patient population was composed of 791 patients who underwent successful PTCA and who were enrolled in the
American Heart Journal Volume 143, Number 1
Routine Versus Selective Exercise Treadmill Testing After Angioplasty (ROSETTA) registry. The ROSETTA registry prospectively collected data on patients recruited from 13 centers in 5 countries (Australia, Canada, Israel, Singapore, United States) (see Appendix). Information on ischemic events (unstable angina, myocardial infarction [MI], cardiac death) and repeat cardiac procedures (angiography, PTCA, coronary artery bypass graft [CABG] surgery,) were collected for each patient. Unstable angina was defined as angina requiring one or more hospitalizations during the first 6 months after the procedure. Myocardial infarction was defined by clinical, electrocardiographic, and enzyme criteria. Cardiac death was defined as any one of the following: sudden death, death after resuscitation, death from congestive heart failure, or death from definite, probable, or possible MI.
Entry criteria The study included 791 patients who were enrolled in the ROSETTA registry between February 1, 1996, and December 31, 1997. Six-month follow-up was complete by the end of June 1998. For the majority of the patients, enrollment in the study took place immediately after PTCA and before discharge from the hospital. The Ethics Committee at each institution approved the study, and written informed consent was obtained before patient enrollment. Patients were included in the study if they had successfully undergone PTCA of at least one coronary lesion. Successful PTCA was defined as reduction of 1 lesion from a stenosis of ≥60% to a residual of <50% with a minimum absolute reduction of 20% (by visual assessment). Patients were eligible no matter which of the currently accepted technologies were used (eg, PTCA, rotational atherectomy, directional atherectomy, laser atherectomy, stenting). Moreover, patients with multilesion or multivessel PTCA and patients with lesions treated in saphenous vein or arterial bypass grafts were also eligible for enrollment. Patients were excluded if they (1) were participating in conflicting clinical studies, (2) had contraindications to repeat cardiac procedures (angiography, PTCA, CABG), (3) had contraindications to or inability to undergo follow-up functional testing, (4) had a medical condition with a prognosis of <1 year, or (5) were unlikely to be available for 6-month follow-up.
Follow-up Clinical follow-up data were obtained 6 months after PTCA. For information on functional testing, clinical events, and cardiac procedures, the research nurses at each center contacted patients by telephone. End point documentation for tests or events that occurred at other institutions was also obtained.
Statistical analysis Patients were divided into 2 groups: those with or without hypertension. Research nurses at each center determined a patient’s hypertensive status through chart review. We then compared the baseline clinical and procedural characteristics among hypertensive and normotensive subjects. The rates of functional tests, repeat cardiac procedures, and clinical events that occurred during the 6-month follow-up period were also examined. Clinical events included unstable angina, MI, cardiac death, and all-cause mortality. The occurrence of a com-
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Table I. Clinical characteristics of 791 patients undergoing successful PTCA in the ROSETTA registry No. of patients (%)
Age (y ± SD) Male sex Hyperlipidemia Pre-PTCA coronary artery disease Single vessel Multivessel History of coronary artery disease Obesity Diabetes mellitus Current smoker Cerebral vascular accident Peripheral vascular disease Congestive heart failure Killip class III/IV Canadian Cardiovascular Society angina class III-IV History of angina Prior MI Prior PTCA Prior CABG Medication use at admission β-Blockers Calcium antagonists Nitrates Angiotensin-converting enzyme inhibitors Diuretics
Hypertensive (n = 411)
Normotensive (n = 380)
62.1 ± 10.1 283 (68.9) 238 (57.9)
59.1 ± 11.7 320 (83.8) 215 (56.6)
160 (38.9) 251 (61.1) 186 (45.5) 121 (29.4) 119 (29.0) 82 (20.0) 38 (9.2) 55 (13.4) 39 (9.5) 15 (3.7) 231 (56.5)
165 (43.3) 216 (56.7) 184 (48.5) 98 (25.7) 61 (16.0) 78 (20.4) 13 (3.4) 30 (7.9) 22 (5.8) 8 (2.1) 168 (44.1)
297 (72.3) 181 (44.3) 117 (28.5) 72 (17.5)
256 (67.0) 187 (49.1) 93 (24.3) 59 (15.4)
(51.6) (42.8) (44.5) (35.4)
(46.7) (23.6) (38.6) (15.0)
(17.5)
(4.5)
posite end point, defined as any of the above events, was also compared between the 2 groups. Repeat cardiac procedures included angiographies, PTCAs, and CABGs that occurred after the index PTCA. Finally, baseline characteristics were analyzed by logistic regression for predictors of outcome within the hypertensive population. Those characteristics that had P values <.10 by univariate analysis were then entered into a multivariate logistic analysis. Continuous values are presented as the mean ± SD, and dichotomous values are presented as percentages. All statistical tests were 2 tailed, and a P value ≤.05 was considered to be statistically significant.
Results Baseline clinical characteristics Table I shows the baseline clinical characteristics of hypertensive and normotensive patients. The hypertensive patient group was older than the normotensive group (62.1 ± 10 years vs 59.1 ± 12 years, P < .0001) and included a higher percentage of female subjects (31.1% vs 16.2%, P < .0001). Hypertensive patients were also more likely to have other risk factors for coronary artery disease, such as diabetes (29.0% vs 16.0%, P < .0001), history of a cerebrovascular accident
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126 Tsang et al
Figure 1
Adverse clinical outcomes among 411 hypertensive and 380 normotensive patients in the ROSETTA registry during the 6 months after a successful PTCA. NS, Not significant.
Table II. Procedural characteristics of 791 patients undergoing successful PTCA in the ROSETTA registry No. of patients
Multilesion PTCA Multivessel PTCA PTCA of a bypass graft Atherectomy Stenting Lesion severity (mean ± SD) Before (%) After (%) Post–Thrombolysis in Myocardial Infarction flow grade 3 2 0-1 Reason for PTCA Stable angina Unstable angina Acute or recent MI
Hypertensive (n = 411)
Normotensive (n = 380)
129 (31.3) 61 (14.8) 28 (6.8) 33 (8.0) 248 (60.3)
101 (26.5) 57 (15.0) 19 (5.0) 14 (3.7) 213 (55.6)
87.6 ± 10.9 8.7 ± 11.3
87.8 ± 10.6 8.4 ± 11.5
403 (98.1) 5 (1.2) 3 (0.72)
369 (96.9) 11 (2.9) 1 (0.26)
24.6 (101) 40.1 (165) 13.9 (57)
25.3 (96) 29.8 (113) 17.4 (66)
(9.2% vs 3.4%, P = .0004), peripheral vascular disease (13.4% vs 7.9%, P = .01), and congestive heart failure (9.5% vs 5.8%, P = .06). In addition, they were more likely to have more severe angina at admission (Canadian Cardiovascular Society angina class III or IV) (56.5% vs 44.1%, P = .0006).
Angiographic and procedural characteristics The angiographic and procedural characteristics of the hypertensive and normotensive groups were similar, with the exception of atherectomy use (Table II). Hypertensive patients were significantly more likely to undergo atherectomy than those without hypertension (8.0% vs 3.7%, P = .01). Most patients had a PTCA of a single lesion and a single vessel and had similar lesion severity. Hypertensive and normotensive patients also had mostly similar reasons for undergoing the index PTCA, but hypertensive subjects were more likely to have had unstable angina as the primary reason for the index PTCA (40.1% vs 29.8%, P = .002).
Clinical events and follow-up procedures We examined the rates of adverse clinical events and found that hypertensive patients were significantly more likely to have unstable angina during the 6 months after PTCA (14.7% vs 9.0%, P = .015) (Figure 1). The increased likelihood of unstable angina among hypertensive subjects also contributed to the higher incidence of the composite end point (P = .017). In addition, patients with hypertension tended to have a higher rate of MI (P = .11). Hypertensive patients were also much more likely to undergo repeat angiography and revascularization procedures than normotensive patients were during the 6 months after the index PTCA (19.8% vs 14.9%, P = .07) (Figure 2). However, despite the increased adverse event rate and the increased rate of repeat cardiac procedures, hypertensive patients were less likely to
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Figure 2
Use of cardiac procedures among 411 hypertensive and 380 normotensive patients in the ROSETTA registry during the 6 months after a successful PTCA.
undergo post-PTCA functional testing than were normotensive patients (44.4% vs 54.0%, P = .008).
Predictors of clinical events in hypertensive patients We identified several baseline characteristics that were independently associated with adverse clinical events within the hypertensive population (Table III). These characteristics included Killip class III-IV (46.7% vs 15.4%, odds ratio 5.7, 95% CI 1.7-19.0), Canadian Cardiovascular Society angina class III/IV (22.5% vs 9.0%, OR 2.1, 95% CI 1.1-4.2), unstable angina as the reason for PTCA (24.8% vs 11.0%, OR 2.3, 95% CI 1.2-4.3), peripheral vascular disease (30.9% vs 14.3%, OR 3.2, 95% CI 1.5-6.4), PTCA of a bypass graft (39.3% vs 14.9%, OR 3.1, 95% CI 1.2-7.6), and calcium antagonist use at admission (21.2% vs 12.4%, OR 1.9, 95% CI 1.1-3.4)
Discussion This study was designed to examine the incidence of clinical events and the use of follow-up cardiac procedures among hypertensive patients during the 6 months after a successful PTCA. We found that, among patients undergoing PTCA, those with hypertension have a significantly higher incidence of clinical events compared with normotensive patients. In addition, although hyper-
Table III. Univariate and multivariate analyses of clinical and procedural characteristics versus follow-up clinical events among 411 hypertensive patients undergoing successful PTCA in the ROSETTA registry
Univariate analysis Calcium antagonist at admission Calcium antagonist at discharge Canadian Cardiovascular Society angina class III/IV Congestive heart failure Diuretic use at discharge Killip class III/IV Peripheral vascular disease Previous CABG PTCA of 1 bypass graft Unstable angina as primary reason for PTCA Multivariate analysis Calcium antagonist at admission Canadian Cardiovascular Society angina class II/IV Killip class III/IV Peripheral vascular disease PTCA of 1 bypass graft Unstable angina as primary reason for PTCA
Odds ratio
95% CI
P value
1.9 1.7 2.9
1.1-3.2 1.0-2.8 1.6-5.4
.02 .07 .0004
3.3 2.9 4.8 2.7 1.9 3.7 2.7
1.6-6.7 1.6-5.4 1.7-13.7 1.4-5.1 1.0-3.6 1.6-8.3 1.6-4.6
.001 .0008 .003 .003 .04 .002 .0003
1.9 2.1
1.1-3.4 1.1-4.2
.03 .03
5.7 3.2 3.1 2.3
1.7-19.0 1.5-6.4 1.2-7.6 1.2-4.3
.005 .002 .01 .01
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tensive patients underwent more repeat cardiac procedures, they also underwent less post-PTCA functional testing during the 6-month follow-up compared with normotensive patients. There are several possible explanations for these differences among hypertensive and normotensive patients. First, at the time of the PTCA, hypertensive patients were generally in a poorer state of health, with greater numbers of patients with Canadian Cardiovascular society Angina Class III-IV, congestive heart failure, and peripheral vascular disease. As a result, their worse clinical status might have contributed to the increased rate of adverse clinical events and repeat cardiac procedures. The reduced functional status of such patients might also contribute to the less frequent use of functional testing among hypertensive as opposed to normotensive subjects. However, patients who were unable to undergo any functional testing were excluded from the ROSETTA registry. Consequently, the lower post-PTCA functional testing rate among hypertensive patients suggests that they may not have been screened sufficiently after PTCA, contributing to the increased 6-month event rates. A second possible explanation for our results may be that hypertension often coexists with diabetes mellitus, and this association can contribute to the increased risk of clinical events and repeat procedures. The prevalence of hypertension among diabetic patients is at least twice that among the general population.10 Furthermore, diabetes mellitus and hypertension act synergistically to increase significantly the risk of adverse cardiac events.11 In a review of studies done between 1980 and 1996, Grossman and Messerli12 found that the risk of cardiac disease was twice as great in individuals with both risk factors than in those with either one. Moreover, several trials have demonstrated a greater incidence of adverse events in diabetic hypertensive patients than in diabetic normotensive patients.12 In a study of post-PTCA patients, diabetes and hypertension were found to be independent predictors of 5- to 19-year survival.2,5 Last, comorbidity other than diabetes among hypertensive subjects may also include left ventricular hypertrophy, hyperlipidemia, obesity, and smoking. Echocardiographically determined left ventricular hypertrophy and diastolic dysfunction are often indicative of poorer prognosis in these patients.13,14 Furthermore, hyperlipidemia is also known to be associated with adverse outcomes because the presence of hyperlipidemia can accelerate atherogenic processes in patients with hypertension.15 However, multivariate regression analysis of the ROSETTA population did not show that these comorbid conditions were significantly associated with post-PTCA outcomes. This result is most likely because the ROSETTA study included a relatively healthy group of patients. Fewer than one third of the patients were obese, only slightly more than half were hyperlipi-
demic, and 40% had single-vessel coronary artery disease. Consequently, the comorbid conditions that are traditionally associated with poor outcomes did not turn out to be strong predictors of adverse outcomes among hypertensive patients in the ROSETTA study.
Clinical implications Our results have several clinical implications. First, because hypertension often has accompanying comorbid conditions, clinicians should strongly consider any of these high-risk characteristics and comorbidities when treating their hypertensive patients with PTCA. In hypertensive patients with diabetes mellitus, high fasting plasma glucose levels (>13.4 mmol/L) have been shown to be significantly associated with increased rates of MI.16 Controlling hyperglycemia was found to lower the risk of MI, although the reduction was borderline of significance.17 Similarly, tight blood pressure regulation in hypertensive patients with type 2 diabetes mellitus decreases the rates of diabetesrelated mortality and morbidity.18 Second, the screening of hypertensive patients at risk of adverse clinical events after PTCA may be improved by increasing the rates of functional testing after PTCA. In our study, hypertensive patients underwent less frequent functional testing during the 6 months after their index PTCAs. Because there was less testing done in this group of patients, some of them may not have been identified as having a higher risk for a clinical event. Consequently, the lower testing rate may have contributed to the higher proportion of patients who had unstable angina or the composite end point. More frequent use of such functional tests after PTCA in hypertensive patients might identify and allow for earlier treatment of a group of high-risk patients. Finally, the significant risk factors that our regression model identified should be a useful tool in risk stratifying hypertensive patients before PTCA. Hypertensive patients with severe angina, congestive heart failure, a bypass graft vessel, peripheral vascular disease, or calcium channel antagonist usage have factors associated with worse clinical outcomes. Consequently, these groups of hypertensive patients may benefit from closer surveillance during the 6 months after PTCA.
Limitations Our study has several potential limitations. First, the examination of hypertensive patients was not an a priori hypothesis of the ROSETTA registry. This study was an ancillary study based on a subgroup analysis of a prospective registry. As a result, we did not collect the exact blood pressures of patients or the indications for their medication use. However, the potential for misclassification in our study is low for 2 reasons. Research nurses at each center performed thorough chart reviews to complete the data forms. Consequently, a
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patient’s hypertensive status was based on blood pressure measurements in the charts and not solely on patient recall. In addition, the difference in outcomes of the normotensive and hypertensive groups also counts against potential misclassification bias. If there had been a large number of hypertensive subjects misclassified as normotensive or vice versa, then the clinical outcomes of the 2 patient groups would be similar. Second, the study design did not include information on the prevalence of left ventricular hypertrophy among the hypertensive patients. We would have been better able to determine prognosis in these patients if we had echocardiographically determined the extent of left ventricular hypertrophy. Because of these limitations, the findings from this study should be validated in a prospective study aimed specifically at hypertensive patients and the potential effect of endothelial dysfunction on postangioplasty outcomes.
Conclusion In this study, we found that patients with hypertension are more likely to undergo repeat cardiac procedures and adverse clinical events 6 months after PTCA. The poorer state of health at baseline, the presence of comorbidities such as left ventricular hypertrophy and diabetes mellitus, and the involvement of endothelial dysfunction were factors that likely contributed to the increased event rates we saw in our study. In addition, because hypertensive patients underwent fewer functional tests after PTCA, patients at higher risk for adverse events may have not been properly identified, eventually contributing to the higher adverse outcome rates. Hypertensive patients could benefit from a more aggressive treatment strategy that involves increasing functional testing and management of comorbid conditions such as diabetes mellitus and endothelial dysfunction. Ultimately, the issues raised from this observational study need to be examined further in a prospective investigation.
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7.
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12. 13. 14. 15. 16.
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Appendix Clinical Center Investigators:
References 1. Keelan ET, Nunez BD, Grill DE, et al. Comparison of immediate and long-term outcome of coronary angioplasty performed for unstable angina and rest pain in men and women. Mayo Clin Proc 1997;72:5-12. 2. Hasdai D, Bell MR, Grill DE, et al. Outcome ≥10 years after successful percutaneous transluminal coronary angioplasty. Am J Cardiol 1997;79:1005-11. 3. Gurlek A, Dagalp Z, Oral D, et al. Restenosis after transluminal coronary angioplasty: a risk factor analysis. J Cardvasc Risk 1995; 2:51-5. 4. Mick MJ, Piedmonte MR, Arnold AM, et al. Risk stratification for long-term outcome after elective coronary angioplasty: a multivariate analysis of 5,000 patients. J Am Coll Cardiol 1994;24:74-80. 5. Halon DA, Merdler A, Flugelman MY, et al. Importance of diabetes mellitus and systemic hypertension rather than completeness of revascularization in determining long-term outcome after coro-
Concord Hospital, Sydney, Australia: D. Brieger; The Royal Melbourne Hospital, Parkville, Australia: J. Lefkovits, P. Singh; Jewish General Hospital, Montreal, Quebec, Canada: M. Eisenberg, P. Garzon, J. Tsang, L. Dragatakis, R. Schlesinger, E. Shalit, D. Beauvais; Montreal General Hospital, Montreal, Quebec, Canada: T. Huynh, L. Pilote, C. Boudreault; Royal Victoria Hospital, Montreal, Quebec, Canada: M. Smilovitch, R. Sheppard, A. Serpa; Hadassah Hospital, Jerusalem, Israel: D. Schechter, H. Witt; National Heart Center, Singapore: K. H. Mak; University of California at San Diego Medical Center, San Diego, Calif: D. L. Brown, E. Mahmud; St Joseph’s Hospital, Omaha, Neb: M. Del Core; University of Texas Health Center at Tyler, Tyler, Tex: U. Deligonul, S. Collins; St Luke’s Regional Medical Center, Boise, Idaho, R. Duerr; Medical College of Virginia, Richmond, Va: E. Goudreau, K. Hall, R. O’Brien; New York Veterans Administration Medical Center, New York, NY: S. Sedlis, M. Saric.