Interventional therapy of coronary artery disease in China: retrospective and perspective

Abstract

Coronary artery disease is the most common cardiovascular disease and constitutes the major cause of death in China. The interventional treatment of coronary artery disease has developed rapidly during the last decade, with the number of percutaneous coronary intervention (PCI) procedures being around 147 300 in the year of 2007. The number is expected to be elevated greatly in the coming years because of great improvement in national health care system and interventional expertise. This article reviews the current status of coronary intervention in China. REPERFUSION STRATEGY FOR ST-ELEVATION MYOCARDIAL INFARCTION During early phase of ST-elevation myocardial infarction (STEMI), current consensus is rapid and complete restoration of normal blood flow in the infarct-related artery (IRA).1 Myocardial salvage in this phase is critically time-dependent.2 Numerous randomized clinical trials demonstrated the superiority of primary PCI, as opposed to fibrinolytic therapy, especially when it is delivered within 90 minutes from patients' first medical contact.2,3The benefits of primary PCI are the greatest if it is performed in an expeditious manner after symptom onset. However, in daily practice, only a minority of patients with STEMI were treated by primary PCI within recommended door-to-balloon (D2B) time.4 Influence of ambulance use on early reperfusion In China, many patients with symptoms of STEMI are identified in an out-of-hospital setting, and management of patients with STEMI is centered on the fastest possible implementation of reperfusion therapy. Ambulance use may lead to more frequent and/or faster administration of early reperfusion for patients with acute chest pain.5 In a study including 498 consecutive patients with STEMI who were admitted within 12 hours of symptom onset to 19 hospitals in Beijing, Song et al6 observed that only 186 (37.3%) patients were transported to hospitals by an ambulance. The ambulance users had significantly shorter pre-hospital delay (90 minutes vs 130 minutes in non-users, P <0.001) and higher early reperfusion rate (85.5% vs 76.9%, P=0.015), mainly because of a greater proportion of patients undergone primary PCI (70.4% vs 60.9%, P=0.032). Importantly, ambulance use was associated with a significant reduction in median D2B time (120 minutes vs 145 minutes, P <0.001) and symptom onset-to-balloon (223 minutes vs 300 minutes, P <0.001). However, only 18% of patients received primary PCI within 90 minutes of hospital arrival. The overall rates of major adverse cardiac events (MACE) and in-hospital mortality were similar between the ambulance users and non-users.6 The study indicated that ambulances were underused by patients with STEMI in Beijing. New public health care system should be developed to facilitate an earlier reperfusion by using ambulances for patients with acute chest pain, especially those with STEMI. Putting it in perspective, patients with STEMI and their relatives or friends may call a centralized phone system for medical emergencies, and pre-hospital patients with STEMI are managed in ambulance with intensive care facilities and staffs, including on-site electrocardiographic recording and immediate initiation of medical treatment (such as administration of antiplatelet, anticoagulant or thrombolytic agents).7 Physician versus patient transfer PCI Previous studies indicated that even when transport was required, primary PCI remained a superior strategy to local thrombolysis.1-4,8 Recently, about 1000 hospitals have been equipped with angiography facilities but lack of qualified operators for independent PCI procedures in China. Patient transfer for primary PCI in clinical practice is time-consuming due to various reasons, and therefore, an inter-hospital transfer service system is desirable.9 Zhang et al10 conducted a prospective multicenter randomized trial comparing physician with patient transfer for primary PCI in 334 patients with acute STEMI. Despite similar procedural success rate and length of hospital stay in physician and patient transfer PCI, the physician transfer strategy provided shorter D2B time, lower cumulative composite of MACE, and improved MACE-free survival at 30-day follow-up. Different clinical pathways In China, clinical pathways for mechanical revascularization vary considerably among hospitals. How to standardize and improve hospital performance in triaging patients with acute STEMI in order to reduce reperfusion delay remains under investigation. A prospective, multicenter, randomized clinical trial comparing the effects of different clinical pathways of myocardial reperfusion after STEMI on D2B time and short-term outcomes has been reported.11 The rapid group consisted of 271 patients who were brought directly to catheterization laboratory from the emergency room, and the non-rapid group comprised 275 patients who were admitted initially to cardiac ward or coronary care unit (CCU) for electrocardiographic or hemodynamic monitoring or intensive medical therapy, and then underwent PCI. The results showed that the rapid approach had significantly shorter D2B time, with greater number of patients achieving reperfusion within 90 minutes. Peak CK-MB was significantly lower in the rapid group, as well as sum of ST segment resolution 2 hours after procedure. Although in-hospital cumulative MACE was not significantly different between the two groups, 30-day cumulative survival (94.5% vs 90.4%, P=0.036) and MACE-free survival rates (89.5% vs 84.1%, P=0.028) were significantly improved in the rapid group. Many patients with symptoms of STEMI are usually initially brought to the emergency room before receiving any treatment in China. With this regards, bypassing CCU/cardiac ward approach should be easier and more practical comparing with the strategy of bypassing emergency room.12 Such a standardized protocol and integrated clinical pathway, combining with other modifications proposed by D2B alliance, should be useful to further reduce ischemic time and improve the quality of early myocardial reperfusion and long-term clinical outcomes for STEMI patients. Tirofiban-facilitated PCI There is a continued debate as to whether a combined reperfusion regimen with platelet glycoprotein IIb/IIIa inhibitor provides additional benefit in optimal myocardial reperfusion for patients with acute STEMI. In the study by Shen et al13 which investigated the clinical benefits of adjunctive tirofiban therapy combined with primary PCI in patients with STEMI, 172 consecutive patients with STEMI presented within 12 hours of symptoms were randomly allocated to primary PCI combined with early (upstream group, n=57) or late administration of tirofiban (downstream group, n=57) or primary PCI treatment alone (control group, n=58). Compared with control group, the upstream and downstream groups had significantly higher rates of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow of IRA, TIMI grade 3 myocardial perfusion, corrected TIMI frame count (cTFC), and resolution of the sum of ST-segment elevation. Peak creatine kinase (CK)-MB and troponin I levels were lower and average hospital stay was shortened. The MACE rates were reduced at 30 days, and left ventricular ejection fraction was improved at 6 months. Further analysis demonstrated significantly better effects in favor of upstream strategy with regard to pre-procedure TIMI grade 3 flow, post-procedure cTFC, length of hospital stay, and 30-day and 6-month clinical outcomes. Multivariate Logistic analysis revealed that age >65 years (OR=342, P<0.01), tirofiban therapy (OÄ=0.56, P <0.05), and ejection fraction <0.50 during hospitalization (OR=2.56, P<0.01) were major independent predictors of MACE at 6-month clinical follow-up. There was no significant difference in hemorrhagic complications among the three groups. Likewise, Fu et al14 also showed that intravenous tirofiban, in addition to aspirin and clopidogrel in patients with STEMI undergoing primary PCI via trans-radial approach, can rapidly inhibit platelet aggregation, loosen occlusive thrombus, improve myocardial reperfusion, and reduce MACE rate without major bleeding complications. These findings supported the concept that early use of tirofiban in conjunction with aspirin, clopidogrel, and low molecular weight heparin in unselected patients with acute STEMI who underwent primary PCI could facilitate rapid restoration of blood flow supply particularly at the level of microcirculation, which favorably increased myocardial reperfusion, reduced muscle damage, and improved overall clinical outcomes of the patients. This strategy was also proven safe. Myocardial no-reflow Several experimental studies have demonstrated that pre-treatment with tirofiban, fosinopril or valsartan, and nicorandil, or post-treatment with statins, exerted a beneficial effect on myocardial no-reflow, through platelet inhibition, endothelial prevention, and adenosine triphosphate-sensitive K channel activation.15-17 Adenosine can reduce both structural and functional no-reflow, while calcium channel blockade can only reduce functional no-reflow.18 In the clinical studies, Zhao et al19 observed that chronic pretreatment with angiotensin converting enzyme inhibitors could preserve microvascular integrity and reduce no-reflow in patients with acute STEMI undergoing primary PCI. In contrast, similar slow flow/no-reflow rates were found using distal protection by either Diver CE or Guardwire Plus device, with comparable risk reduction of distal embolization and improvement of ST-segment resolution.20 PCI FOR HIGH-RISK PATIENTS With the wide use of drug-eluting stents (DES), the indications of PCI have been expanded largely by including patients with high-risk clinical and angiographic profiles. The procedure can be performed safely in elderly patients and has become an effective approach for symptomatic relief and prognostic improvement despite incomplete revascularization in many patients.21 Non-ST-elevation acute coronary syndrome Patients with non-ST-elevation acute coronary syndromes, including unstable angina and non-ST-elevation myocardial infarction, should undergo risk stratification based on clinical, biochemical, hemodynamic and angiographic features. PCI is usually recommended as the first therapeutic approach of choice, especially for those at high risk, and could be performed at the early stage of hospitalization with maximal anti-platelet and anti-coagulation protection. Revascularization has been shown to offer a better prognosis for patients with life-threatening condition, but conservative strategy may be reserved for those at low risk such as without recurrence of chest pain, no signs of heart failure, no ECG changes on 2 recordings at 6 to 12 hours, or no troponin elevation on 2 samples taken 6 to 12 hours apart22 PCI in the elderly The rapid growth of the elderly population has resulted in an increase in the number of the elderly being referred and considered for PCI. Advanced age independently predicts early and late mortality and MACE after PCI because of high-risk clinical profiles in the elderly. Ma et al23 recently reported the long-term outcome for a total of 80 patients aged 85 years or older with acute coronary syndromes undergoing stent-based PCI. Overall, the procedural success rate was 93.8% and occurrence of procedure-related complication was 17.5%. The incidence of in-hospital MACE tended to be higher in patients treated with bare-metal stents than those treated with DES (14.3% vs 6.8%, P=0.30). During 3-year follow-up, the overall MACE-free survival was 82.9% and the incidence of MACE was not significantly different between the two groups. Multivariate regression analysis showed that creatinine level and hypertension were major factors affecting long-term MACE rate for these very elderly patients.23 For patients aged 65 years or older with acute STEMI, the trans-radial approach for primary PCI is safe and feasible, and sirolimus-eluting stent implantation can be safely and effectively performed in these patients with a similar procedural success rate, a low complication rate, and excellent short-term outcomes compared with femoral approach.24 Diabetes Patients with diabetes often have more extensive coronary artery disease, poorer left ventricular function, and worse clinical outcomes after revascularization than the non-diabetic counterparts.25 The use of DES improves the overall results after PCI. Yang and his colleagues26 compared in-hospital and long-term outcomes between rapamycin- versus paclitaxel-eluting stents in Chinese diabetic patients with coronary artery disease. They revealed that both stents were associated with similar efficacy and safety during long-term follow-up. In a small cohort of diabetic patients with acute STEMI undergoing DES-based primary PCI, Zhang et al27 demonstrated similar early clinical outcomes in diabetic and non-diabetic patients, and a worse 1-year cumulative MACE-free survival in diabetic patients, suggesting that more effective diabetes-related management may be required to further improve the clinical outcomes of patients with diabetes suffering STEMI. Patients with renal insufficiency Numerous studies have shown that renal insufficiency is not uncommon in patients undergoing coronary revascularization. PCI in patients with renal insufficiency is feasible, but may be associated with poor long-term results even at the presence of mild-to-moderate renal dysfunction.28-30 Renal insufficiency was found to have a negative prognostic impact, similar to that of diabetes, on cardiovascular morbidity and mortality. In a large cohort study involving 1174 patients with successful DES-based PCI, all-cause mortality and MACE were prospectively compared between patients with moderate or severe renal insufficiency (defined as estimated creatinine clearance (CrCl) <60 ml/min) and those with normal or mildly impaired renal function.30 The study indicated that patients with at least moderate renal insufficiency were older and had lower hemoglobin and target vessel revascularization, and higher all-cause death, cardiac death, and occurrence of non-fatal myocardial infarction. Compared with normal renal function, hazard ratios of a composite of mortality and myocardial infarction were 1.079, 5.067, and 8.828 in patients with mild (CrCl 60-89 ml/min), moderate (CrCl 30-59 ml/min), and severe (CrCl <30 ml/min) renal insufficiency respectively. Moderate to severe renal insufficiency was also an independent risk factor for late stent thrombus after PCI with rapamycin-eluting stent implantation.31 PCI FOR COMPLEX LESIONS Unprotected left main artery disease The efficacy and safety of DES implantation for unprotected left main coronary artery (LMCA) lesions remain to be established in different clinical settings. Gao et al32 compared the results of 220 patients with unprotected LMCA treated with DES with those of another 224 patients treated with bare-metal stents in a Chinese registry. Despite more multivessel disease, bifurcation stenting, and in-hospital MACE in the DES recipients, the cumulative cardiac death, target vessel revascularization, overall MACE, and angiographic restenosis rates during 15-month follow-up were significantly lower in the DES group than those in the bare-metal stent group. This study suggested that DES implantation for unprotected LMCA disease appeared safe and effective in selected patients. Likewise, Han et al33 evaluated clinical effectiveness of DES for the treatment of unprotected LMCA stenosis using various stenting techniques. During 8-year follow-up, mortality, MACE rate, and stent thrombosis were 6.5%, 14.5%, and 0.7% respectively. Their findings also supported the safety of DES-based PCI for unprotected LMCA lesions. Bifurcation lesions The treatment strategy of DES-based PCI for bifurcation lesions has been improved, and generally, stent implantation in the main vessel only is recommended. When both main vessel and side branch were stented, several techniques were used to ensure coverage of entire ostium of a large side branch (lumen diameter >2.0-2.5 mm), and final kissing balloon inflation immediately after crush procedure was mandatory to reduce restenosis and improve clinical outcomes.34-36 Chen and his colleagues35,36 used double-kissing and double-crush (i.e. DK crush) technique to treat true bifurcation lesions. They observed that compared with classic crush approach, the DK crush technique had the potential of increasing final kissing balloon inflation rate and reducing stent thrombosis, with a further reduction of target lesion revascularization and cumulative MACE at 8 months. The differences of sirolimus- versus paclitaxel-eluting stents in reduction of restenosis and improvement of clinical outcomes at the setting of bifurcation PCI need further investigation.34,37 Chronic total occlusion Treatment of chronic total occlusion (CTO) may represent the last frontier for interventionists. Recent developments of PCI materials (guide-wires and micro-catheter), novel devices (tornus catheter), contra-lateral injection and retrograde approaches, and other techniques (paralleled wire, STAR technique) have allowed operators to tackle successfully complex cases of CTO in 70%-90%.38 The success rate was declined with long duration of occlusion, abrupt missing stump, bridging collaterals >15 mm in occluded length, moderate to severe calcification or tortuosity, and ostial or distal location of CTO. Procedural failures were mainly caused by inability of guide-wire or balloon to pass through the occlusion. Imaging guidance by intravascular ultrasound or CT angiography has been useful to increase the success rate of wire crossing, and multi-wire plaque crushing is effective in facilitating balloon catheter passing occluded sites.39 For patients with CTO, the clinical and angiographic outcomes post DES implantation are superior to those of bare-metal stenting. Calcification Calcified coronary lesions carry the risk of suboptimal stent expansion, subsequently leading to restenosis or stent thrombosis. In the "real-world" PCI practice, Li et al40 have obtained similar favorable results for both calcified and non-calcified lesions in terms of in-stent and in-segment restenosis, target lesion revascularization, and angiographic sub-acute and late thrombosis rate at 8-month follow-up. CHINA-MADE DRUG-ELUTING STENTS The number of PCI procedures incorporating DES placement grew exponentially, at present, accounting for more than 90% of PCI procedures overall. Since early 2003, 3 types of home-made DES have been used in China, namely durable polymer coated, rapamycin-eluting Firebird stent and Partner stent, and bio-degradable polymer coated, rapamycin-eluting Excel stent. These home-made DES are applied to patients with "on-label" or "off-label" indications in daily clinical practice, and have been shown to be equally effective compared with Cypher stents with regard to both angiographic and clinical outcomes during long-term follow-up.41 The Yingyi stent, a paclitaxel-eluting stent without polymer coating, is available soon. Lately, the platform of Firebird stent was modified by using cobalt alloyed metal instead of stainless steel (i.e. Firebird 2 stent) to increase radial strength and radiopacity, and reduce thickness of stent struts. Zhang et al42 and Xu et al43 conducted a prospective, historically controlled, and multi-center clinical trial to evaluate its safety and long-term efficacy. At 1-year follow-up, the use of Firebird 2TM stent resulted in 94% decrease in target lesion revascularization compared with that of a bare cobalt alloy Drive stent. Such a beneficial effect was maintained during 2-year follow-up. The cumulative 2-year MACE free survival was 98.5% and 66.7% for Firebird 2TM stent and bare cobalt alloy stent, respectively. None in Firebird 2TM stent group and one patient in bare cobalt alloy stent group had angiographic stent thrombosis. The effects of biodegradable polymer sirolimus-eluting Excel stent on 1-year outcome after PCI were evaluated initially in a pilot registry involving 100 consecutive patients. Dual anti-platelet therapy was maintained for 6 months after the procedure and then followed by aspirin alone infinitely. During 1-year follow-up, 4 patients reached primary end point due to in-stent restenosis, which was treated successfully by repeated PCI. Notably, no death, re-infarction, and stent thrombosis occurred. The multicenter registry of excel biodegradable drug eluting stent (CREATE) was a post-marketing surveillance multi-center, prospective study, which enrolled 2077 "real world" patients from 59 centers of 4 countries. All patients received exclusively Excel stents, and clopidogrel was discontinued 6 months after the procedure. The MACE rate was 3.1% and stent thrombosis was 0.87% at 18 months. Repeated angiography revealed mean in-stent lumen loss of 0.21 mm, with in-stent and in-segment restenosis rates of 3.8% and 6.7%, respectively. The results of CREATE registry have been presented in the Late Breaking Clinical Trials session at ACC 08i2 summit. Recently, clinical and angiographic outcomes were compared between Excel and Firebird stents during a "real world" PCI setting, and the results showed that both DES had reduced MACE and risk of restenosis similarly. SAFETY ISSUES OF DES One of the major safety concerns is late or very late DES thrombosis. Although the exact mechanism of DES thrombosis remains unknown, it identifies a subgroup of patients with STEMI with poor angiographic and early clinical outcomes, suggesting that the management of these patients should be improved. In an early report of China multicenter registry between January 2003 and December 2004, the incidence of stent thrombosis with DES and bare-metal stent was 0.77% and 0.75% respectively.44 Recently, Chen et al45 retrospectively analyzed the incidence of DES thrombosis during 2-year follow-up in a single center registry. Among 8190 consecutive patients who received dual anti-platelet therapy after stenting, the incidences of acute or sub-acute, late, and very late stent thrombosis were 0.49%, 0.63%, and 0.74% respectively, and those were similar for Cypher (n=2986), Taxus (n=1587), and Firebird (n=3617) stents. Numerous studies have shown that incomplete stent apposition occurred after DES implantation due to complex clinical profile, procedural factor, and lesion characteristics. Qian et al46 reported a 17% occurrence rate of incomplete stent apposition by intravascular ultrasound in patients who had undergone DES implantation for de novo lesions. During 34 months of follow-up, almost a quarter of these patients developed STEMI caused by very late stent thrombosis. Thus, incomplete stent apposition after DES implantation may confer a higher incidence of very late stent thrombosis, even with longstanding dual anti-platelet therapy after the procedures. Han et al47 compared short-term safety and efficacy between triple (cilostazol combined with clopidogrel and aspirin, n=1103) and dual (aspirin plus clopidogrel, n=2032) antiplatelet regimens in a large cohort. Despite similar rates of stent thrombosis (0.7% vs 1.0%) and major bleeding events (0.3% vs 0.2%), 30-day mortality (0.4% vs 1.6%, P <0.05) and MACE rate (1.3% vs 2.6%, P <0.05) were lower for triple regimen.