The Unremitting Advances in STEMI Care and PCI
Pub Date: Wednesday, November 18, 2009
Author: Hani Jneid, MD
Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009. Published online before print, November 18, 2009. 10.1161/CIRCULATIONAHA.109.192663.
Ischemic heart disease remains the leading cause of mortality in the Western world. In particular, coronary artery disease (CAD) claims one of every five deaths in the United States and nearly one American suffers an acute ST-segment elevation myocardial infarction (STEMI) every minute.[1,2] Primary percutaneous coronary intervention (PCI) is the mainstay initial therapy for STEMI. It is, thus, not unexpected that a synopsis of the advances in both fields are published jointly, as in the current report. The 2009 Focused Updates of the guidelines on PCI for the management of patients with STEMI , a result of the collaborative efforts of the American Heart Association (AHA), American College of Cardiology Foundation (ACC), and Society for Cardiovascular Angiography and Interventions (SCAI), considered a plethora of studies and generated updated, well-balanced, and clinically-applicable recommendations. In this report, I provide a noncomprehensive synopsis of these recommendations and a critical reading of the associated evidence.
Prasugrel, a more potent and rapid-acting thienopyridine than clopidogrel, was incorporated in the current report  following the release of TRITON-TIMI 38  and its subsequent Food and Drug Administration approval (July 2009). TRITON-TIMI 38  was a pivotal randomized controlled trial (RCT) of 13,608 patients demonstrating a significant 19% reduction in the composite of cardiovascular death, myocardial infarction (MI), or stroke with prasugrel (60-mg loading followed by10-mg daily doses) compared with clopidogrel after a mean 15-months follow-up. This salubrious outcome, driven by a reduction in nonfatal MI, was observed as early as 3 days postrandomization, and was accompanied by notable reductions in the rates of ischemic events, urgent target vessel revascularization (TVR), and stent thrombosis (ST) in the prasugrel group. Despite an overall 32% increase in major bleeding with prasugrel (including thrombolysis in myocardial infarction (TIMI) major and life-threatening bleeding), the net clinical-benefit end point still favored prasugrel. Notably, stronger benefits were observed in high-risk patients, such as diabetics  and patients with anterior STEMI. The 2009 Focused Update , therefore, recommends the addition of prasugrel as an alternative choice to clopidogrel during primary PCI but cautioned against its use in those with a history of stroke or transient ischemic attack, as shown previously , and recommended its empiric discontinuation at least 7 days before planned CABG. TRITON-TIMI 38 enrolled moderate-to high-risk ACS patients scheduled to undergo PCI, of whom 26% had STEMI, and therefore did not apply to all ACS patients. The need for thienopyridine discontinuation before CABG may prevent the widespread adoption of prasugrel in the community, especially knowing the coronary anatomy (less relevant in patients undergoing primary PCI ), but may be overcome by the progressive adoption of platelet function testing to determine the degree of platelet inhibition and predict the timing of safe CABG surgery. Post-hoc analyses from TRITON-TIMI 38  identified two additional subgroups in whom prasugrel had no net favorable clinical benefit (patients greater than or equal to 75 years old and those who weighed less than 60 kg). It is also important to note that the comparator group was treated with the conventional 300-mg loading dose of clopidogrel [9,10], which achieves a slower peak effect, compared with a 600-mg loading dose, and which has been recently shown to be inferior to the upfront clopidogrel double-dosing regimen in the CURRENT-OASIS 7 trial.
The 2009 Focused Update  provides a review of the evidence pertaining to the timing of GP IIb/IIIa inhibitors and their comparative effectiveness. They concluded that the use of intravenous glycoprotein (GP) IIb/IIIa receptor inhibitors at the time of primary PCI can no longer be routinely recommended [12-14] and should be substituted with a more selective approach (as in the setting of a large thrombus burden or no thienopyridine pretreatment). In addition, the routine upstream use of GP IIb/IIIa inhibitors, as a facilitated approach prior to cath lab arrival for primary PCI [12,15] or in non-ST elevation acute coronary syndrome (NSTE-ACS) patients undergoing early angiography , is no longer recommended given the absence of benefits on ischemic end points [12,15,16] and the increased bleeding risk.[16,17] Among patients with NSTE-ACS, upstream use of GP IIb/IIIa inhibitors may be beneficial in diabetics, patients with elevated biomarker levels, patients more than 75 years old, and those undergoing PCI. These patient subgroups, identified on post-hoc analyses from EARLY-ACS , were previously confirmed by prior evidence. Newer data demonstrated similar efficacy of the small molecules (tirofiban or eptifibatide) and the chimeric monoclonal antibody abciximab in the setting of primary PCI.[19-21] The salutary outcomes associated with GP IIb/IIIa inhibitors in prior trials were predominantly driven by periprocedural MI reduction and appear to be attenuated nowadays by optimal background medical treatments (ex. statin, dual oral antiplatelet therapy, better anticoagulants), early invasive and timely reperfusion strategies, and better interventional techniques. In addition, the realization of the importance of including periprocedural bleeding in the assessment of outcomes after PCI  has diminished the net clinical benefits previously observed with GP IIb/IIIa inhibitors.
Along these lines, the use of the direct thrombin inhibitor, bivalirudin, during primary PCI has been adopted as an alternative to the combination of unfractionated heparin and GP IIb/IIIa inhibitors during primary PCI (on top of background dual oral antiplatelet therapy). This was derived from the landmark HORIZONS-AMI , a RCT of 3,602 STEMI patients undergoing primary PCI, demonstrating a lower incidence of net adverse clinical events at 30 days and 1 year with bivalirudin use (driven largely by a decrease in major bleeding).[14,23] Bivalirudin was associated with remarkably lower 30-day  and 1-year all-cause mortality rates , which was attributable to the greater contribution of major bleeding to mortality than reinfarction or ST, as shown by others. The salutary benefits of bivalirudin was unaffected by the use of preprocedural heparin or higher clopidogrel loading dose , although both predicted the occurrence of early ST with bivalirudin. In a 2x2 factorial design, HORIZONS-AMI  examined the use of the first-generation paclitaxel-eluting stent (a drug-eluting stent, DES) versus its bare-metal stent (BMS) counterpart during primary PCI for STEMI and demonstrated no intergroup differences in 12-month rates of mortality, MI, or ST, but a small reduction in TVR and in 13-month binary restenosis (hence, TVR was unaffected by angiographic follow-up). The safety and efficacy of DESs in the STEMI setting were also supported by a meta-analysis, including 3,605 patients from 11 trials, showing no difference in major adverse cardiovascular events, including ST, at 12-months follow-up and a significant reduction in TVR up to 24-months follow-up. The use of DESs is therefore endorsed as a reasonable alternative strategy to BMSs. However, the 2009 Focused Update  judiciously emphasized that stent use during primary PCI should take into consideration patients' compliance, concomitant use of oral anticoagulation, and the possible need for surgery during the ensuing year. Recently, the 2-year data from HORIZONS-AMI confirmed the persistent benefits of bivalirudin and DESs.
Another important guideline update pertains to PCI for left main (LM) CAD. The SYNTAX trial  assessed the optimal revascularization strategy in 1,800 patients with previously untreated three-vessel or LM CAD and found the PCI strategy (using paclitaxel-eluting stents) not to be noninferior to CABG with respect to the 12-month primary composite of major adverse cardiac or cerebrovascular events (MACCEs). This was driven by higher rates of repeat revascularization associated with PCI, although no differences in death or MI rates were observed and a small but significantly higher stroke rate was evident with CABG. The higher MACCEs rates associated with PCI were observed in patients in the highest SYNTAX scores and in those with two- and three-vessel CAD (the latter being a post-hoc finding that should be interpreted with caution). The 2-year follow-up data from SYNTAX  confirmed its earlier findings but further uncovered a significantly higher MI rate with PCI during this time period. Despite the all-comers design of SYNTAX, its applicability to routine clinical practice remains uncertain, given the inclusion of seasoned interventional cardiologists treating complex CAD (4.3 treated lesions/patient, 73% bifurcation, and one-third had a greater than 100 mm stent length). Patients treated with CABG also received suboptimal postrevascularization, which may bias the outcomes. Although CABG continues as the standard therapy for complex multivessel and/or LM CAD, PCI for LM CAD may be considered instead of CABG in patients with suitable coronary anatomy and/or high surgical risk. In the absence of supporting evidence, a 2-to 6-month angiographic follow-up after LM stenting is no longer recommended.
In addition to the aforementioned recommendations, the current report  endorsed a multitude of additional therapeutic strategies. An early invasive strategy (within 12 to 24 hours), but not an immediate invasive one, appears to be reasonable in high-risk NSTE-ACS patients.[30,31] Furthermore, based on the FAME study , showing superior 1-year outcomes and less use of stents per patient with the use of fractional flow reserve (FFR), FFR appears to be a reasonable strategy to complement angiography in order to determine the significance of intermediate coronary lesions and guide interventions in patients with stable multivessel CAD. This is especially important given recent reports showing that the majority of such patients do not have preceding noninvasive testing to document ischemia or target therapy. Following the finding in the NICE-SUGAR trial , which showed a morbidity benefit from intensive glucose control and a reduction in mortality for those who were in the intensive care unit for more than 3 days, and other studies , the 2009 Focused Update  also endorsed the use of an insulin-based regimen as a reasonable strategy to achieve and maintain a glucose level less than 180 mg/dL while avoiding hypoglycemia. An earlier AHA statement  called urgently for definitive trials to assess the best treatment strategies for glycemic control and define specific treatment targets. In addition, aspiration thrombectomy before PCI was associated with better myocardial reperfusion  and lower 1-year cardiac mortality  among STEMI patients undergoing primary PCI (on top of optimal medical therapies, including 600-mg clopidogrel loading dose and abciximab). This cheap and readily available technique, which was also associated with infarct size reduction , stands in contradistinction to mechanical thrombectomy and embolic protection, which were associated with increased harm or a neutral effect during primary PCI , respectively. Therefore, aspiration thrombectomy appears a reasonable strategy during primary PCI. Following the CARE study , finding no impact of various contrast media on the rates of contrast-induced nephropathy (CIN), the recommended choices of agents for patients with chronic kidney disease has been expanded to include isosmolar or low-osmolar agents (other than ioxaglate or iohexol).
Overall, Kushner and colleagues are to be congratulated on their efforts to critically evaluate the evidence and produce useful recommendations to guide clinicians. One can derive innumerable and noteworthy observations from their report. Notably, the contemporary 12- to15-months MACE rates following STEMI are in the range of 12% [5,23], which speak for the alarming residual burden of morbidity and mortality in these patients. It is reassuring, however, that the 2009 Focused Update  reported at least two strategies (bivalirudin use, aspiration thrombectomy) associated with small but significant reductions in mortality. Advances in therapies are therefore rapidly evolving. One should, however, constantly remember that the discovery of new pharmaceuticals and better therapeutic strategies should be accompanied by the adoption of older well-established therapies. The existing disparities in STEMI care [42,43] has been repetitively demonstrated and the chasm described in the Institute of Medicine report between the care we have and the care we could have  still applies best for the treatment of STEMI. Finally, while 47% of the decline in CAD mortality observed in this country since 1986 is attributable to treatments, only 10% are related to immediate therapies after ACS , which account for the majority of the recommendations in the current report. Secondary-prevention therapies along with lifestyle changes and risk-factor modification continue to impart the highest impact and are largely lacking.
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-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --