Author + information
- Received February 4, 1999
- Revision received May 18, 1999
- Accepted June 29, 1999
- Published online November 1, 1999.
- Peter N Ruygrok, MBChBa,* (, )
- Rein Melkert, PhDa,
- Marie-Angèle M Morel, BSca,
- John A Ormiston, MBChBa,
- Frits W Bär, MDa,
- Francisco Fernandez-Avilès, MDa,
- Harry Suryapranata, MD, PhD, FACCa,
- Keith D Dawkins, MD, FACCa,
- Claude Hanet, MDa,
- Patrick W Serruys, MD, PhD, FACCa,
- on behalf of the Benestent II Investigators Cardialysis Rotterdam The Netherlands
- ↵*Reprint requests and correspondence: Dr. Peter Ruygrok, Catheterization Laboratory, Green Lane Hospital, Green Lane West, Epsom, Auckland, New Zealand
This study was performed to assess whether angiography six months after coronary balloon angioplasty or stent implantation has an influence on clinical management and one-year outcome.
The Benestent II study randomized 827 patients to balloon angioplasty or stent implantation. A subrandomization was undertaken allocating patients to six-month clinical follow-up (CF) or clinical and angiographic follow-up (AF).
Seven hundred and six patients (349 CF and 357 AF) had no intercurrent angiography, so that restenosis and disease progression elsewhere remained unknown until the time of six-month follow-up. These two groups, which were well matched at enrolment, were compared with respect to symptoms, medication and major cardiac events defined as death, myocardial infarction and need for revascularization at six and 12 months.
At six-month follow-up, 53 (15%) of the CF and 76 (21%) of the AF patients had stable angina (p = 0.041), while 5 (1%) and 4 (1%) had symptoms of unstable angina. At 12-month follow-up, 44 (13%) patients in both groups had stable angina, and only 1 patient in the CF group had unstable angina. Seventy-seven patients (27 CF and 50 AF; p < 0.01) had major cardiac events between 6 and 12 months. Of the 349 patients in the CF group, 21 underwent repeat percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery between 6 and 12 months, compared with 44 of the 357 patients in the AF group (relative risk 2.05 [1.24 to 3.37], p = 0.003).
Patients who had AF six months after balloon angioplasty or stent implantation experienced more repeat revascularization procedures than those who had CF. They also had significantly more angina at six-month follow-up but this may be due to bias.
Since the introduction of percutaneous transluminal coronary angioplasty (PTCA) by Andreas Gruentzig in 1977 (1)and intracoronary stenting less than a decade later (2), there has been a plethora of studies, randomized and nonrandomized, that have explored equipment and technique refinements. These studies have guided angioplasty to the safe and effective procedure we practice today (3). In order to arrive at this state, clinical researchers in coronary angioplasty have relied on the goodwill and trust of their patients. Many studies have requested a follow-up angiogram six months after enrollment (4,5)in order to assess the rate of restenosis. Additionally, some centers continue to advocate angiography routinely six months after angioplasty (6). Such a procedure has an associated risk of morbidity and mortality, and albeit small (7–9), those centers may wish to consider discontinuing this practice. The dilemma of whether to reintervene in a patient who is asymptomatic but has angiographic evidence of restenosis often arises. The question of whether reintervention is beneficial or detrimental to such a patient, if the only indication for angiography was to comply with a research protocol, is often asked (10). The Benestent II study randomized 827 patients to stent implantation or conventional balloon angioplasty (11). A subrandomization was performed with 416 patients allocated six-month clinical follow-up (CF) alone and 411 allocated both angiographic and clinical review. The differences between these groups in terms of management and outcome are explored in this paper.
Patient selection and procedure
Eight hundred and twenty-seven patients with stable and unstable angina (Braunwald class I and II), and one or more de novo lesions measuring less than 18 mm in length in native coronary arteries >3 mm in diameter, were randomized to balloon angioplasty or heparin-coated Palmaz-Schatz stent implantation according to the Benestent II study protocol (11). All patients received aspirin for at least six months, and those that were stented received ticlopidine 250 mg daily for one month.
Patients were reviewed after 15 days, 6 months and 12 months, and clinical data, which included symptomatic status, examination findings, medication, clinical events and an assessment of quality of life, were recorded. Additionally, at the time of recruitment, a subrandomization was undertaken, assigning half the patients to a follow-up angiogram six months after the initial procedure. The protocol required a clinical review before angiography in those who were assigned to the angiographic follow-up (AF) group.
A detailed analysis was undertaken in order to determine whether six-month angiography, and thus knowledge of the coronary anatomy, influenced the decision to perform a further intervention, independent of the patient’s clinical status, and whether such a decision influenced the occurrence of clinical events in the subsequent six months. All patients were included who at six-month review had not undergone intercurrent angiography, repeat PTCA, coronary artery bypass graft surgery (CABG) or had died. Those who had suffered a myocardial infarction (MI), whether it be Q or non-Q wave, were included provided they did not undergo angiography between recruitment and six-month review. These patients were divided according to whether they were randomized to clinical only or clinical and AF, and their baseline demographic characteristics, angiographic characteristics, anginal status and intensity of medication were compared, looking for significant differences. The reintervention rates and event rates over the subsequent six months, and clinical status at one year after the index intervention, were then compared for the two groups. A subanalysis was also performed according to whether patients were randomized to balloon or stent angioplasty.
Continuous variables are expressed as mean ± standard deviation and were compared using the Student ttest. The Fisher exact test was used for categorical variables. Discrete variables are expressed as counts or percentages and are compared in terms of relative risks, with 95% confidence intervals calculated by the formula of Greenland and Robins. All statistical tests were two-tailed. Event-free survival distribution was estimated according to the Kaplan-Meier method, and the overall incidence of major adverse cardiac events was tested using the log-rank test.
Seven hundred and six patients of the 827 (85%) randomized to the Benestent study reached six-month follow-up without intercurrent angiography, coronary revascularization (surgery or angioplasty) or death. Of these patients, 349 had been randomly assigned to CF alone (thus no scheduled angiogram) and 357 to additional AF, six months after recruitment. The baseline characteristics of these two groups are displayed in Table 1. There were no significant differences.
Seventy-seven major adverse cardiac events, defined as death, MI, coronary bypass surgery or repeat percutaneous intervention between 6 and 12 months after recruitment, occurred in 72 patients. These events were divided according to randomization and are shown in Table 2. Although death MI rates were similar in the two groups, there were significantly more revascularization procedures, 45 in 44 patients in the AF group (one patient underwent rePTCA the day before coronary bypass surgery), compared with 21 procedures in CF group (relative risk [RR] 2.05 [1.24 to 3.37], p = 0.003) (Fig. 1). Was there clinical justification for the additional procedures? Table 3shows patient symptoms and medication at both six-month and one-year follow-up. At six months, a significantly greater number of patients (p = 0.041) were reported to suffer symptoms in the AF group, and there was a trend toward a greater amount of antianginal medication. By 12 months, 83% of patients were free of angina with an equal incidence in both groups.
To show whether it was in fact the patients that had symptoms that experienced events, predominantly revascularization, between 6 and 12 months after recruitment, their symptomatic status at six months is displayed in Table 4. Of those in the CF group who had a subsequent event, 46% had symptoms at six months, while in the AF group, 70% had symptoms at six months. The timing of revascularization procedures is also of interest. Figure 1displays the time of occurrence of these events for both groups. Most occurred soon after six-month follow-up in both groups.
To determine whether the knowledge that a patient had received a stent or balloon angioplasty alone influenced the decision to reintervene in those with angiographic evidence for restenosis, we analyzed the data according to treatment modality. There was no significant difference in events; however, there was a trend toward a greater number of rePTCAs in the stent group compared with the balloon group, in those randomized to AF (Table 5).
The Benestent II study randomized 827 patients to balloon angioplasty or stent implantation with a heparin-coated stent followed by one month of antiplatelet therapy with ticlopidine. The study found that stent implantation resulted in less restenosis (16% stent group, 30% balloon group, p = 0.0008) and fewer clinical events compared with the balloon group, with no significant difference in overall cost (11).
A subrandomization was undertaken assigning patients to CF alone or an additional angiogram six months after the procedure. The rationale for this subrandomization was to document the natural course of coronary artery disease and the behavior of interventional cardiologists in order to assess the real cost effectiveness of both balloon and stent treatment arms, as well as the gathering of objective evidence that one treatment was superior to another in the prevention of restenosis. The unique data from this subrandomization has allowed us to explore the question of whether knowledge of the coronary anatomy influences patient management and outcome. We have observed a significantly greater number of revascularization procedures in the AF group compared with the CF group (45 vs. 21). It is clear that events, which were predominantly revascularization procedures, were temporally related to the six-month angiogram in that group. Did these patients have significantly more symptoms? Our data suggest that this was the case; however, we believe this information should be treated with caution. The same cardiologist often performed the angiography and completed the case record forms; therefore, interpretation of a patient’s symptoms may have been biased by the angiographic findings. If this is indeed a true observation, one would also expect significantly more medication, a more objective observation, in the AF group. This was not the case, although a trend in this direction was observed.
It is likely that as coronary angioplasty, with refinements in both equipment and technique, has become a safer procedure, cardiologists have become more comfortable treating significant restenoses in the asymptomatic patient rather than “leaving them be.” Interestingly, a greater number of redilations were performed within a stented restenotic segment rather than one that had undergone balloon angioplasty alone, suggesting interventionists felt more secure redilating within a stent. It is likely that not only cardiologists but also cardiac surgeons, truly believe that the gap between management of symptomatic and asymptomatic stenoses should be narrowed (12,13)as the complication rates of performing such procedures continue to diminish, tipping the risk-benefit balance in favor of repeat intervention. The nature of the restenotic process, and the possibility of regression of asymptomatic and minimally symptomatic restenoses after the six-month follow-up angiogram, remains an important issue. It has been observed that lesion regression at the dilated site occurs late after balloon angioplasty (14)and also after stent implantation (15). Angioscopic studies in a selected group of patients have found that the neointima that appeared thick and nontransparent until six months after stent implantation became thin and transparent by three years after angioplasty, confirming neointimal regression (16). Additionally, it has been shown that patients with minimal symptoms experience a very low clinical event rate in the short term if an angiographically intermediate lesion is shown to be functionally insignificant by using techniques such as coronary pressure measurement and myocardial fractional flow reserve (17). These data suggest that a new conservative approach could be considered in patients with minimal symptoms and lesions of moderate severity.
None of the study patients experienced a complication as a result of the per-protocol follow-up angiogram, suggesting that the procedure is safe and that it is ethically reasonable to include follow-up angiography in a research protocol. There are long-term risks such as chance of malignancy resulting from radiation; however, patient dose in a limited study is similar to the annual background radiation dose (18).
The group of patients who underwent six-month follow-up angiography clearly underwent twice as many repeat interventions. There appeared, however, to be no adverse effect in terms of events. At 12 months after the initial intervention, the symptoms of angina and amount of antianginal medication was similar in both groups. If there truly were greater symptoms in the angiography group at six months, then angiography and subsequent reintervention conferred a beneficial effect.
Revascularization procedures were significantly more common in those patients having AF than in those having CF alone. The apparent greater number of symptoms in those having AF should be interpreted with caution, as it may be due to bias. The performance of angiography six months after intervention did not result in an adverse outcome in terms of death, MI and symptoms of angina in the subsequent six months.
We would like to acknowledge the dedication and skill of the physicians, nurses and technicians who treated and cared for patients recruited into the Benestent II study.
☆ The Benestent II Study was supported by a grant from CORDIS/Johnson & Johnson Interventional systems (Warren, New Jersey) and Sanofi (Paris, France).
This work was presented in part at the XXth Congress of the European Society of Cardiology, Vienna, Austria, August 1998.
- angiographic follow-up
- coronary artery bypass graft surgery
- clinical follow-up
- myocardial infarction
- percutaneous transluminal coronary angioplasty
- Received February 4, 1999.
- Revision received May 18, 1999.
- Accepted June 29, 1999.
- American College of Cardiology
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- Serruys P.W
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