CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Direct Stenting for Stable Angina Pectoris Is Associated With Reduced Periprocedural Microcirculatory Injury Compared With Stenting After Pre-Dilation
Thomas Cuisset, MD,
Michalis Hamilos, MD,
Narbeh Melikian, MD,
Eric Wyffels, MD,
Jaydeep Sarma, MD,
Giovanna Sarno, MD,
Emanuele Barbato, MD,
Jozef Bartunek, MD,
William Wijns, MD, PhD* and
Bernard De Bruyne, MD, PhD
Cardiovascular Center, OLV Hospital, Aalst, Belgium.
Manuscript received September 18, 2007;
revised manuscript received November 6, 2007,
accepted November 13, 2007.
* Reprint requests and correspondence: Dr. William Wijns, Cardiovascular Center Aalst, Moorselbaan 164, B 9300 Aalst, Belgium. (Email: William.Wijns{at}village.uunet.be).
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Abstract
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Objectives: We conducted a randomized study to compare the effect of direct stenting (DS) and conventional stenting (CS) on post-procedural index of microcirculatory resistance (IMR) values.
Background: Direct stenting has been suggested to reduce periprocedural microcirculatory injury compared with stenting that follows pre-dilation (CS). The index of microcirculatory resistance is a sensitive invasive marker of coronary microvascular resistance.
Methods: Fifty patients admitted for elective percutaneous coronary intervention (PCI) were included. All patients had stable angina (Canadian Cardiovascular Society class <IV) related to a lesion suitable for DS and were randomized to DS (n = 25) or CS (n = 25). Baseline demographics and clinical and procedural data were comparable in both groups. An intracoronary pressure/temperature sensor-tipped guide wire was used. Thermodilution curves were obtained at baseline and during maximal hyperemia achieved by infusion of intravenous adenosine. The index of microcirculatory resistance was calculated from the ratio of the mean distal coronary pressure at maximal hyperemia to the inverse of mean hyperemic transit time.
Results: After otherwise-uneventful PCI, patients treated with CS had significantly greater IMR (DS 13 ± 3, CS 24 ± 14; p < 0.01) and tended to have greater post-PCI troponin T values (DS 0.035 ± 0.04, CS 0.17 ± 0.02; p = 0.07). In the whole sample, 20% of patients had post-PCI troponin release (troponin T >0.03 ng/ml). Patients with troponin elevation had significantly greater post-PCI IMR values than patients without troponin elevation: 24.7 ± 13.2 versus 16.9 ± 10.2; p = 0.04.
Conclusions: In patients undergoing successful coronary stenting for stable angina, DS is associated with reduced microvascular dysfunction induced by PCI as compared with CS.
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Abbreviations and Acronyms
| | CFR = coronary flow reserve | | CS = conventional stenting | | DS = direct stenting | | FFR = fractional flow reserve | | IMR = index of microcirculatory resistance | | MI = myocardial infarction | | PCI = percutaneous coronary intervention | | Tmn
= mean transit time |
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Stents are now deployed in as many as 95% of all percutaneous coronary interventions (PCIs). Improvements in balloon and stent technology have permitted the development of the "direct stenting" (DS) strategy (stent delivery without pre-dilation) instead of conventional stenting (CS), that is, stent implantation after balloon pre-dilation. Several studies demonstrated this technique to be feasible and safe in selected cases resulting in reduced procedural costs, duration, and radiation exposure (1). However, in randomized trials, the DS technique showed similar results to standard CS for long-term clinical outcome (2–13). Experimental and indirect clinical data support the concept of reduced wall damage and distal embolization when stent deployment is performed without balloon pre-dilation (14,15). These data suggest a benefit of DS over CS in terms of reduced post-procedural microvascular impairment. The index of microcirculatory resistance (IMR) is validated as a novel invasive index of microcirculatory resistance for assessing the status of the microcirculation independently of the epicardial area (16). The IMR is derived from distal coronary pressure and hyperemic mean transit time (16–18). We conducted a prospective and randomized study to evaluate the benefit of DS, in comparison with CS, on microvascular impairment assessed by post-PCI IMR values and troponin release in elective PCI for stable angina.
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Methods
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Trial design and randomization.
This was a randomized, prospective, single-center study. Patients were randomized either to DS or CS procedure in a 1:1 ratio.
Patient and lesion selection.
Between March and July 2007, 50 patients (age >18 years) with stable angina or a positive functional study with a planned PCI procedure of a single de novo lesion >50% and <100% diameter stenosis in a native coronary artery were randomized. The invasive physiological assessment of the lesion had to confirm the hemodynamic significance of the lesion severity with a fractional flow reserve (FFR) <0.80. All included lesions were deemed suitable for both DS and CS according to 2 independent interventionalists. Exclusion criteria were left ventricular ejection fraction <30%, acute coronary syndrome in the previous month, previous myocardial infarction (MI) in the target vessel–related territory, positive biomarkers before PCI, chronic total occlusion, intrastent restenosis, bifurcation with side branch >2 mm, ostial lesion, lesions with extensive calcifications or containing thrombus, and contraindications to adenosine. The study protocol was approved by the institutional ethics committee of OLV Hospital, and patients gave informed consent for participation and data collection.
Adjunctive medications.
Antiplatelet therapy was administered with a loading dose of 600 mg of clopidogrel and 500 mg of aspirin the day before the procedure regardless of background therapy. During catheterization, all patients received intravenous heparin bolus sufficient to attain an activated clotting time of 250 to 300 s. Use of glycoprotein IIb/IIIa antagonists was left to the physician’s discretion.
Cardiac catheterization protocol.
Coronary physiological indexes (coronary flow reserve [CFR], IMR, and FFR) were measured in each patient before (FFR only) and after PCI (all indexes) using previously described principles and methods (16–18). An intracoronary pressure/temperature sensor-tipped guide wire (Radi pressure wire, Certus-Radi Medical Systems, Uppsala, Sweden) was used to measure distal coronary pressure and to derive thermodilution curves. Thermodilution curves were obtained (in triplicate) from a hand-held, 3-ml brisk (<0.25 s) injection of room temperature saline at baseline and at maximal hyperemia (Fig. 1). Maximal hyperemia was achieved by infusion of 140 µg/kg/min of adenosine via the femoral vein. Mean transit time (Tmn) at baseline and maximal hyperemia were derived from thermodilution curves. Simultaneous recordings of mean aortic pressure (from the guiding catheter) and mean distal coronary pressure (from the distal pressure sensor) were also made at baseline and maximal hyperemia. We calculated CFR from the ratio of hyperemic to baseline Tmn. We calculated IMR from the ratio of the mean distal coronary pressure at maximal hyperemia to the inverse of mean hyperemic Tmn. We calculated FFR from the ratio of distal to proximal pressures at maximal hyperemia (Fig. 1).
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Figure 1 Measurement of Post-PCI IMR After PCI
IMR = Pd hyperhemia · Tmn hyperhemia. (A) Patient A undergoing direct stenting with low post-PCI IMR value and no troponin release. (B) Patient B undergoing conventional stenting with higher post-PCI IMR value and troponin release (troponin T = 0.042 ng/ml). CFR = coronary flow reserve; FFR = fractional flow reserve; IMR = index of microcirculatory resistance; Pa = arterial pressure; PCI = percutaneous coronary intervention; Pd = distal pressure; Tmn = mean transit time.
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Statistical analysis.
Statistical analysis was performed with the Graphpad Prism Software (v. 4.00, Graphpad Software Inc., San Diego, California). An estimate of mean post-PCI values of IMR was obtained from the published literature (16–18). We calculated that at least 20 patients should be included in each group to detect a difference of 30% between the DS and the CS group (alpha 0.05, beta 0.20, and statistical power 0.80). Therefore, we targeted a sample of 25 patients per group. Continuous variables were presented as mean ± SD. Unpaired t test or Mann-Whitney U test were used to analyse differences in continuous variables. The Fisher exact or chi-square test was used to analyze differences between categorical variables. Pearson correlation coefficients (2-sided) were derived to assess the relationship between IMR, CFR, and FFR and continuous baseline variables. A stepwise multiple regression model was produced to identify independent determinants of IMR. Data were evaluated using an intent-to-treat analysis. Statistical significance was set at p values <0.05.
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Results
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Patient characteristics.
Among the 25 patients randomized to DS, 24 eventually underwent successful DS. Baseline demographics and clinical and biological data were similar in both groups (Table 1). Angiographic data, pre-PCI FFR, minimum lumen diameter, and percentage of stenosis were comparable in both groups (Table 2).
Physiological measurements.
After PCI, physiological parameters were successfully obtained in all patients. Fractional flow reserve values were similar in both groups, and IMR values were significantly lower in patients undergoing DS than CS: 13 ± 3 and 24 ± 14, respectively, p < 0.01 (Table 2, Fig. 2). By using multivariate analysis integrating baseline clinical, biological, and procedural parameters, we found that the presence or absence of pre-dilation was the only independent determinant of post-PCI IMR (odds ratio 11.1, 95% confidence interval 5.0 to 17.1, p = 0.01).
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Figure 2 Distribution of IMR Values Among Patients Undergoing DS or CS According to Post-PCI Troponin Values
Closed circles = troponin positive; open circles = troponin negative. CS = conventional stenting; DS = direct stenting; IMR = index of microcirculatory resistance; PCI = percutaneous coronary intervention.
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In the whole sample, we observed a moderate negative correlation between IMR and CFR (r = –0.38, p = 0.006) (Fig. 3A), but there was no correlation between IMR and FFR (r = 0.15; p = 0.10) (Fig. 3B). Interestingly, the post-PCI CFR values were not significantly different between the DS and CS groups: 3.3 ± 1.6 and 3 ± 1.9, respectively (p = 0.64) (Table 2).
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Figure 3 Relationship Between Individual IMR Values and Corresponding CFR and FFR Post-PCI
(A) Correlation between post-PCI IMR and CFR values, r = –0.38, p = 0.006. (B) Correlation between post-PCI IMR and FFR values, r = 0.15, p = 0.1. Abbreviations as in Figures 1 and 2.
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Figure 1 represents 2 cases of successful PCI without any electrocardiographic (ECG) changes, recurrent chest pain, side branch loss, or other periprocedural complications. Patient A was treated for stable angina in a mid-right coronary artery (RCA) with direct stenting (3 mm diameter, 15 mm length) at 12 atmospheres and after dilation with short noncompliant balloon (3 mm diameter, 9 mm length). Post-PCI IMR was 9 (Fig. 1A), and there was no post-PCI troponin elevation. Patient B was planned for elective PCI of a distal RCA stenosis. He underwent conventional stenting with pre-dilation (2.5 mm diameter, 12 mm length) followed by stent deployment (3 mm diameter, 13 mm length). Post-PCI IMR was 54, and he exhibited post-PCI troponin elevation (troponin T = 0.042). These cases illustrate the high sensitivity of IMR and troponin T for detection of microvascular injury, even in the absence of any clinical symptoms or ECG changes.
Periprocedural MI and ECG changes.
After PCI, 20% of patients (n = 10) had troponin T elevation >0.03 ng/ml (3 times the 99th percentile of the normal population). Patients undergoing DS tended to have lower periprocedural MI than those with CS, with mean values of post-PCI troponin T of 0.035 ± 0.04 and 0.17 ± 0.02, respectively (p = 0.07). Mean post-PCI IMR values were significantly greater in patients with periprocedural MI (n = 10) than in patients without (n = 40): 24.7 ± 13.3 and 16.9 ± 10.2 respectively (p = 0.04).
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Discussion
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The results of the present study suggest a benefit of DS over CS in elective PCI based on lower levels of post-PCI microvascular resistance. In addition, patients with periprocedural troponin release had higher IMR values after PCI. Microvascular embolization during PCI identified by post-PCI troponin T release has been shown to be associated with increased mortality (19). A recent study that used intracoronary Doppler wire measurements has shown that periprocedural troponin elevation is significantly associated with microembolism and that crossing the stenosis with balloon or stent over the guidewire was a critical phase associated with intracoronary microemboli (20). Accordingly, we have hypothesized a potential benefit of DS over CS for reduction of periprocedural microembolization. Coronary flow reserve has been evaluated to assess post-PCI embolization. However, Hori et al. (21,22) showed that impaired CFR post-PCI was also related to increased baseline average peak velocity related to adenosine release during PCI. Likewise, in our study, CFR measurements were unable to identify a benefit of DS over CS with respect to rates of PCI-related microvascular injury because the prolonged hyperemia that follows the repeated ischemic episodes caused by PCI makes it difficult to obtain thermodilution curves in a basal state, which confounds post-PCI CFR values. Recently, IMR has been proposed as a new invasive marker to assess the microvascular coronary bed (16–18). This marker was used to assess microcirculation in different clinical settings, such as reperfusion in acute MI (23) and after heart transplantation (24). In the present study, significantly greater IMR values were measured in patients with post-PCI troponin release. We found that IMR was increased in a number of cases not showing troponin release, indicating that microvascular injury after PCI can occur in the absence of detectable significant myonecrosis. The debate between DS and CS has not yet been resolved. The potential disadvantages and risks of DS remain clear: higher risk of failure to cross with DS, which can lead to stent loss, temporary acute coronary occlusion, or trauma at the coronary ostium and inadequate choice of stent diameter or length. Direct stenting also has been associated with potential advantages: reduced procedural cost, use of contrast agent and X-ray time (2,13), and reduction in total ischemic time. Direct stenting also could be associated with reduced vessel wall injury that can cause dissections, thrombosis, and distal embolization, in particular at the stent edges (14). Indeed, in specific lesion subsets such as PCI of the saphenous venous graft, Webb et al. (25) have shown less distal embolization with DS versus CS. Most of the available clinical studies have been conducted with bare-metal stents. With the introduction of drug-eluting stents, concerns arose that DS would possibly damage the polymer coating and change or diminish the efficacy of the programmed drug release. A post-hoc analysis of the TAXUS II trial has shown that DS with the polymer-based paclitaxel-eluting TAXUS stent (Boston Scientific Corporation, Natick, Massachusetts) is feasible, safe, and equally effective (26). Recently, other studies have randomly compared DS and CS with drug-eluting stents. In these studies (13,27), DS has been associated with less neointimal hyperplasia near the distal stent edge (13) and resulted in a significantly lower rate of target lesion revascularization over a 12-month follow-up period compared with balloon pre-dilation followed by stenting (27). In the present study, using IMR as a novel and sensitive invasive marker of microcirculatory injury, we have shown that DS was associated with lower values of IMR, which tended to result in lower rates of post-PCI troponin release compared with CS.
Study limitations.
The length of time these microvascular disturbances persist and their prognostic significance, if any in absence of troponin increase, are not known. The sample size is relatively small, and randomization groups may not be entirely balanced.
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Conclusions
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The results of the present study suggested a lower rate of microvascular injury, evaluated with IMR, after otherwise uncomplicated DS versus CS. These data suggest that DS may be the preferred implantation technique in suitable patients undergoing elective PCI for stable angina pectoris.
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References
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Abstract
Methods