Circulation : Clinical Summaries

Initial trials comparing stenting with balloon angioplasty demonstrated improved angiographic and clinical outcomes with the former.1–3 The main clinical problem with bare metal stents (BMS) became the development of in-stent restenosis.4–6 Early data suggested that drug-eluting stents (DES) could mitigate, if not abolish, this problem.7–9 Since the approval of DES, these devices have become the predominant stents used in percutaneous coronary interventions, regardless of indication. As of September 2007, the Cypher sirolimus-eluting stent (SES) (Cordis Johnson & Johnson, Miami Lakes, Fla) had been deployed in >3 million patients worldwide,10 and the millionth Taxus paclitaxel-eluting stent (PES) (Boston Scientific, Natick, Mass) was implanted as of January 2005.11 Over the past 2 years, numerous reports of very late stent thrombosis (ST) with first-generation DES have surfaced. This highly morbid complication and data suggesting that death and myocardial infarction (MI) may be more common with DES12,13 have altered the focus of trials and registries working to determine optimal DES use. There is a hope that second-generation DES will be less prone to ST as a result of differences in drug, stent design, and polymer. Medtronic, Inc (Minneapolis, Minn) presented safety and efficacy data to a public meeting of the US Food and Drug Administration (FDA) Circulatory System Devices Panel (CSDP) in October 2007 on its Endeavor zotarolimus-eluting stent (ZES), seeking approval for the indication of treating de novo native coronary lesions ≤27 mm with reference vessel diameters of 2.5 to 3.5 mm. The FDA asked the CSDP to determine whether the data presented demonstrated a reasonable level of safety and effectiveness, with clinical benefits clearly outweighing short- and long-term risks of ZES use. Important efficacy end points included ischemia-driven target lesion revascularization (TLR) or target vessel revascularization (TVR); safety end points included death, MI, and ST. The …

Fibrinolytic therapy has been an important means of establishing reperfusion for decades. However, limitations to the use of thrombolytic therapy include perceived or definite contraindications, intracranial bleeding, inability to establish Thrombosis In Myocardial Infarction (TIMI-3) flow in many patients, and high rates of recurrent ischemia and reocclusion. Accordingly, primary percutaneous coronary intervention (PCI) has emerged as the preferred reperfusion strategy. Nearly all acute myocardial infarction (AMI) patients are eligible for emergency catheterization. Knowledge of the coronary anatomy allows immediate triage to surgery, medical therapy, or primary PCI, when appropriate, and results in earlier hospital discharge compared to thrombolytic therapy.1 Primary PCI establishes TIMI-3 flow in >90% of patients and is associated with reduced rates of recurrent ischemia and reocclusion. With the addition of stenting, reocclusion has been further reduced to 5% at routine 6-month angiography.2,3 Small studies have suggested that pharmacological adjuncts to PCI such as abciximab may improve myocardial perfusion and limit infarct size4,5 without the risk of bleeding observed with thrombolytic therapy.6 Finally, new technologies such as coronary thrombectomy, distal projection, and systemic cooling are easily applied in the catheterization laboratory and may further improve myocardial perfusion and infarct size. Although primary PCI has been in use for more than 25 years, the first trials randomizing PCI to intravenous thrombolytics therapy were not published until 1993.7 A meta-analysis of the first 10 randomized trials demonstrated a reduction in death, reinfarction, and stroke with primary PCI in all subgroups, but the greatest absolute benefit was observed in high-risk patients.8 On the basis of these early results, many experienced interventionalists were no longer willing to randomize patients to thrombolytic therapy. Therefore, the next decade of research was focused on perfecting the primary PCI technique, with studies randomizing patients to intraaortic balloon pumps, stents, glycoprotein …

Two-by-two factorial comparison of high-bolus-dose tirofiban followed by standard infusion versus abciximab and sirolimus-eluting versus bare-metal stent implantation in patients with acute myocardial infarction: Design and rationale for the MULTI-STRATEGY trial

Implantation of drug eluting stents (DES) has become a standard treatment of patients undergoing percutaneous coronary intervention (PCI). Incomplete strut coverage is a potential risk factor for late stent thrombosis. Optical coherence tomography (OCT) enables in vivo identification of incomplete neointimal coverage. Study included 62 patients after sirolimus eluting stents (SES) or paclitaxel eluting stents (PES) implantation. OCT examination was performed at least 24 months after the initial procedure (35.4± 9.4 months). In cross-sectional still frames selected from each 1 mm of analyzed stents a total number of visible struts and number of struts with or without complete neointimal coverage was assessed. Measurements of neointimal coverage, presented as a mean thickness of tissue, were performed. Patients were followed up for 3 years and the frequency ofmajor adverse cardiac events was recorded. In the analyzed 28 SES and 37 PES 9998 struts were identified. Complete neointimalcoverage was observed in 83.5% and 79.2% of SES and PES struts respectively (p = 0.48).There was no difference in incidence of not covered or malapposed struts between SES and PES groups. Mean thickness of the tissue covering SES struts was 0.165 ± 0.095 mm, and 0.157 ± 0.121 mm for PES. The mean neointimal thickness difference (SES vs. PES) was notstatistically significant. In a 36 months follow-up 1 death was observed - potentially attributed to stent thrombosis. A long term OCT follow-up after DES implantation shows high incidence ofuncovered struts regardless of the stent type. Clinical significance of this finding remains questionable and requires further large scale trials.

Recently, the use of sirolimus-eluting stents (SES) has been demonstrated to significantly reduce the rate of adverse events among selected patients with ST-segment elevation acute myocardial infarction (STEMI). We present real-world experience from a single center registry evaluating the safety and efficacy of primary percutaneous coronary intervention (PCI) in unselected patients with STEMI using SES. Clinical outcome at 300-day follow-up in two cohorts of 225 consecutive patients who underwent bare metal stent (BMS) (January 2004-February 2005, n = 123) or SES (March 2005-December 2006, n = 102) implantation was examined. The primary endpoint was a composite of major adverse cardiovascular events (MACE: death, nonfatal reinfarction, and target vessel revascularization [TVR]). The incidence of short-term MACE was similar between the SES group and BMS group (30-day rate of MACE: 4.9% versus 8.9%, P = 0.30). Angiographically documented stent thrombosis within 30 days after primary PCI was not diagnosed in any patient in the SES group and occurred in 1 patient treated with BMS (0 versus 0.8%, P = 1.0). At 300 days, SES implantation significantly reduced the incidence of MACE (7.8% versus 22.8%, hazard ratio [HR] 0.32 [95% confidence interval (CI) 0.15 to 0.71], P = 0.005), mainly due to a marked reduction in the risk of TVR (1.0% versus 17.1%, HR 0.05 [95% CI 0.01 to 0.39], P < 0.001). There was no new onset of documented stent thrombosis between 30 and 300 days in either group. Thus, this real-world registry confirmed the safety and efficacy of SES with remarkably lower rates of TVR and MACE in the setting of primary PCI for unselected patients with STEMI in a real-world scenario.

268 Study of 30 Days Mortality in a Contemporary Population Of Elderly Patients Undergoing Primary Percutaneous Intervention in Acute ST Elevation MI

Fibrinolytic therapy (FT) and primary percutaneous coronary intervention (PCI) are both well-accepted reperfusion therapies in ST-segment elevation myocardial infarction (STEMI). The evidence of randomized clinical trials indicates a relatively modest difference in 30-day mortality (≈1%) in favor of primary PCI over fibrin-specific FT and was based on very timely primary PCI (ie, a primary PCI–related delay of 40 minutes [door-to-balloon less door-to-needle time]).1 Longer delays to primary PCI, which are far more frequent in clinical practice,2 are associated with attenuated benefit or no benefit at all, particularly when compared with fibrin-specific FT.3,4 The benefit of timely primary PCI over FT is likely to especially apply to higher-risk patients.5,6 Irrespective of the method of reperfusion, the potential for myocardial salvage and better clinical outcome is inversely proportional to ischemic time or its only available clinical surrogate, symptom duration.7–12 These considerations underpin the notion expressed in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of STEMI that timely reperfusion therapy is likely more important in determining outcome than whether FT or primary PCI is the chosen reperfusion method.13 Response by Armstrong et al p 1310 The ACC/AHA STEMI guidelines highlight the time point of 3 hours of symptom duration in guiding the choice of reperfusion therapy. They state that if symptom duration is <3 hours, no preference exists between FT and primary PCI provided that treatment is timely (for FT, door-to-needle time <30 minutes; for primary PCI, door-to-balloon time <90 minutes and ≤60 minutes between estimated needle time and estimated balloon time). However, if symptom duration exceeds 3 hours, these guidelines favor primary PCI over FT, again provided that primary PCI can be performed in a timely fashion.13 This article reexamines the evidence that may or may not be the basis …

Primary percutaneous coronary intervention (PPCI) is recommended by the European Society of Cardiology (ESC) treatment guidelines as the preferred treatment for ST-elevation acute myocardial infarction (STEMI) whenever it is available within 90–120 minutes of the first medical contact. A survey conducted in 2008 in 51 ESC countries found that the annual incidence of hospital admissions for acute myocardial infarction is around 1,900 patients per million population, with an incidence of STEMI of about 800 per million. It showed that STEMI patients’ access to reperfusion therapy and the use of PPCI or thrombolysis (TL) vary considerably between countries. Northern, western and central Europe already have well-developed PPCI services, offering PPCI to 60–90 % of all STEMI patients. Southern Europe and the Balkans are still predominantly using TL. Where this is the case, a higher proportion of patients are left without any reperfusion treatment. The survey concluded that a nationwide PPCI strategy results in more patients being offered reperfusion therapy. To address the inequalities in STEMI patients’ access to life-saving PPCI, and to support the implementation of the ESC STEMI treatment guidelines in Europe, the Stent for Life (SFL) Initiative was launched jointly by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) and EuroPCR in 2008. National cardiac societies from Bulgaria, France, Greece, Serbia, Spain and Turkey signed the SFL Declaration at the ESC Congress in Barcelona in 2009. The aim of the SFL Initiative is to improve the delivery of, and STEMI patients’ access to, life-saving PPCI and thereby reduce mortality and morbidity. Currently, 10 national cardiac societies support the SFL Initiative in their respective countries. SFL national action programmes have been developed and are being implemented in several countries. The formation of regional PPCI networks involving emergency medical services, non-percutaneous coronary intervention hospitals and PPCI centres is considered to be a critical success factor in implementing PPCI services effectively. This article describes examples of how SFL countries are progressing in implementing their national programmes, thus increasing PPCI penetration in Europe.

There are limited data on the long-term safety and efficacy profile of coronary stent implantation in patients with stable coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). We aimed to assess the 4-year clinical outcome in patients who received a bare-metal stent (BMS), sirolimus-eluting stent (SES), or a paclitaxel-eluting stent (PES) for the percutaneous treatment of stable angina in our center during 2000-2005. In the study period, a total of 2,449 consecutive patients (BMS = 1,005; SES = 373; and PES = 1071) underwent a PCI as part of three historical PCI-cohorts for stable angina and were routinely followed for the occurrence of major adverse cardiac events (MACE). At 4 years follow-up, 264 BMS patients (26.8%) had a MACE, compared to 75 SES patients (20.9%) and 199 PES patients (23.9%). Multivariate analysis showed that SES and PES were superior to BMS with respect to MACE [hazard ratio (HR) = 0.62, 95% confidence interval (CI): 0.47-0.81; HR = 0.67, 95% CI: 0.55-0.82, respectively]. The occurrence of MACE was significantly lower in the SES and PES population, primarily due to less target-vessel revascularization (TVR) procedures (HR = 0.53, 95% CI: 0.37-0.75; HR = 0.71, 95% CI: 0.62-0.81, respectively). The occurrence of early, late, and very late stent thrombosis was equally rare with each stent type. There were no significant differences between SES and PES on death, myocardial infarction, TVR, and MACE. These findings suggest that SES and PES result in decreased TVR procedures and MACE compared to BMS at 4 years follow-up. SES or PES implantation should be the preferred choice over BMS for patients with stable CAD undergoing PCI.

DRUG-ELUTING STENTS ARE A MAJOR ADVANCE IN PERcutaneous coronary intervention (PCI) because they reduce the need for repeat target lesion revascularization several-fold compared with bare-metal stents. Early randomized clinical trials separately testing sirolimus-eluting stents and paclitaxel-eluting stents against their bare-metal counterparts demonstrated that rates of target lesion revascularization were reduced from approximately 10% to 15% to approximately 4% to 5%, whereas the rates of death, myocardial infarction, and stent thrombosis were similar between bare-metal and drug-eluting stents. Because these studies were performed for device regulatory approval, they enrolled patients and lesions with relatively low risk for restenosis and adverse events. Subsequent head-to-head trials of sirolimusand paclitaxel-eluting stents in cohorts with a broader risk profile have provided inconsistent results; some trials have suggested equivalent rates of target lesion revascularization for these stents, whereas others have reported superiority of sirolimus-eluting stents. Initial clinical trials in any area of medicine are primarily designed to test efficacy (ie, is the drug or device beneficial under ideal conditions?) rather than to test effectiveness or relevance (ie, is the drug or device beneficial in everyday practice?). Phase 4 (postapproval) studies are expected to be conducted to help bridge this gap while monitoring safety. The sirolimus-eluting stent was the first to become clinically available, and early postapproval data from the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry showed that the unrestricted use of sirolimus-eluting stents in the real world was safe and effective in reducing target lesion revascularization as well as major adverse cardiac events at 1 year compared with bare-metal stents—findings similar to the regulatory approval studies. Subsequently, observational data from the Taxus-Stent Evaluated At Rotterdam Cardiology Hospital (T-SEARCH) registry suggested that the unrestricted use of paclitaxel-eluting stents was safe and associated with a similar adjusted outcome when indirectly compared with sirolimus-eluting stents. There was an “inferior trend” in crude outcome observed with paclitaxel-eluting stents—although this finding was attributed to higher-risk characteristics among patients receiving such stents, since practice had become comfortable with a wider application of drug-eluting stents over time. Thereafter, a number of small, direct-comparison trials were reported, with most individually observing a similar outcome for patients receiving sirolimusvs paclitaxeleluting stents. On the other hand, a meta-analysis of 16 such randomized head-to-head trials determined sirolimuseluting stents to be superior to paclitaxel-eluting stents with regards to target lesion revascularization and stent thrombosis. Likewise, a collaborative network meta-analysis of 38 trials including 18 023 patients and having a follow-up of up to 4 years also suggested that sirolimus-eluting stents provided a clinical advantage over paclitaxel-eluting stents. The discordance in findings among some trials and subsets of patients (eg, those with diabetes) has been confusing and challenging to interpret. In this issue of JAMA, Galloe and colleagues aim to add clarity and relevance to the issue by comparing outcome among patients randomized to receive sirolimusvs paclitaxel-eluting stents in a study design reflecting everyday clinical practice by including unselected patients and by using symptom-driven clinical end points. They report in this large-scale practical randomized trial that there were no significant differences in clinical outcomes between patients receiving sirolimusand paclitaxel-eluting stents. Their preliminary data were included in the recent meta-analyses and can now be further examined. A noteworthy feature of the study by Galloe et al is that it is the largest randomized direct comparison of these drug-eluting stents; yet with low event rates and the challenges presented by enrollment of all-comers, it has several limitations that need to be considered. First, the study randomized less than a third (27.7%) of potentially eligible patients, which suggests that the cohort may not be as unselected as the authors intended. This raises some concern of selection bias and generalizability of the results and is compounded by the observation that clinical outcomes were worse among patients who were eligible for en-

Safety and efficacy of everolimus-eluting stents compared with first-generation drug-eluting stents in patients undergoing primary percutaneous coronary intervention.

The paclitaxel-eluting stent (PES) and sirolimus-eluting stent (SES) are first-generation drug-eluting stents (DES) that have been the most widely used; however, it is unclear whether there are differences in the long-term safety and efficacy between the 2 stents. The long-term effectiveness of DES in unselected people with diabetes is also currently unclear. Moreover, the possibility of late catch-up is suggested in the DES population. This study is an 8-center collaborative network analysis of all comers who received SES and PES. All patients who received SES and PES from February 2003 to October 2006 were enrolled. We analyzed 9315 patients (33.3% with diabetes) treated with SES or PES in the major 8 centers representing whole area of Korea. The primary end point was a major adverse cardiac event (MACE) composite of overall death, myocardial infarction, and target lesion revascularization. All analyses were performed using multivariable, adjusted models and propensity score-matching methods. Long-term MACE for 5 years were significantly lower in the SES than the PES group (13.3% versus 15.6%; hazard ratio, 0.82; 95% confidence interval, 0.71 to 0.96; P=0.01), which was mainly driven by the difference of MACE within the first year (hazard ratio, 0.73; 95% CI, 0.59 to 0.90; P=0.003), but the rate of MACE between 1 and 5 years in the landmark analysis was not different between the 2 stents (1.9 versus 2.0%/yr). In the subpopulation of people with diabetes, in contrast to the whole population, PES was comparable to SES in terms of any clinical outcome, both within the first year and from 1 to 5 years (MACE for 5 years, 20.3 versus 17.9%; MACE within the first year, 9.6 versus 8.2%; MACE 1 to 5 years, 2.9 versus 2.6%/yr). The PES was inferior to the SES in the clinical follow-up of more than 9000 patients' cohort for 5 years, which was mainly driven by the difference in the first year. In the subpopulation of people with diabetes that showed higher MACE than people without diabetes, however, PES was comparable to SES in any clinical outcome for 5 years. Although these 2 stents are not frequently used as before, the data would be useful to expect the long-term clinical course of the current DES.

Sirolimus-eluting versus paclitaxel-eluting stents in diabetic and non-diabetic patients within sirolimus-eluting stent restenosis: Results from the ISAR-DESIRE 2 trial

How does the risk of cardiovascular disease (CVD) vary with type and age of menopause? Earlier surgical menopause (e.g. <45 years) poses additional increased risk of incident CVD events, compared to women with natural menopause at the same age, and HRT use reduced the risk of CVD in women with early surgical menopause. Earlier age at menopause has been linked to an increased risk of CVD mortality and all-cause mortality, but the extent that this risk of CVD varies by type of menopause and the role of postmenopausal HRT use in reducing this risk is unclear. Pooled individual-level data of 203767 postmenopausal women from 10 observational studies that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium were included in the analysis. Postmenopausal women who had reported menopause (type and age of menopause) and information on non-fatal CVD events were included. Type of menopause (natural menopause and surgical menopause) and age at menopause (categorised as <35, 35-39, 40-44, 45-49, 50-54 and ≥55 years) were exposures of interest. Natural menopause was defined as absence of menstruation over a period of 12 months (no hysterectomy and/or oophorectomy) and surgical menopause as removal of both ovaries. The study outcome was the first non-fatal CVD (defined as either incident coronary heart disease (CHD) or stroke) event ascertained from hospital medical records or self-reported. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CI for non-fatal CVD events associated with natural menopause and surgical menopause. Compared with natural menopause, surgical menopause was associated with over 20% higher risk of CVD (HR 1.22, 95% CI 1.16-1.28). After the stratified analysis by age at menopause, a graded relationship for incident CVD was observed with lower age at menopause in both types of natural and surgical menopause. There was also a significant interaction between type of menopause and age at menopause (P < 0.001). Compared with natural menopause at 50-54 years, women with surgical menopause before 35 (2.55, 2.22-2.94) and 35-39 years (1.91, 1.71-2.14) had higher risk of CVD than those with natural menopause (1.59, 1.23-2.05 and 1.51, 1.33-1.72, respectively). Women who experienced surgical menopause at earlier age (<50 years) and took HRT had lower risk of incident CHD than those who were not users of HRT. Self-reported data on type and age of menopause, no information on indication for the surgery (e.g. endometriosis and fibroids) and the exclusion of fatal CVD events may bias our results. In clinical practice, women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures and early diagnosis of CVD. Our findings also suggested that timing of menopause should be considered as an important factor in risk assessment of CVD for women. The findings on CVD lend some support to the position that elective bilateral oophorectomy (surgical menopause) at hysterectomy for benign diseases should be discouraged based on an increased risk of CVD. InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844). There are no competing interests.

A randomized comparison of sirolimus- vs. paclitaxel-eluting stents for treatment of bifurcation lesions by single stent and kissing balloon: Results of the SINGLE KISS trial