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ST elevation myocardial infarction: recent advances and updates
Leila Ganjehei*,1, Urmiya Mamoon Rashid2, Sara Payami3 & Andrew Kim Saal4
ABSTRACT ST elevation myocardial infarction (STEMI) remains a leading cause of morbidity, mortality and disability worldwide. Statistically, a trend towards improvements in morbidity and mortality has been consistent over the years, which is attributed primarily to the modification of risk factors, healthier lifestyles, treatment advances and better management of door-to-balloon times via STEMI systems. However, a major challenge in the coming years will be the baby boomers (born between the years 1946 and 1964) coming into old age. The first baby boomers turned 65 in year 2011. As the baby boomers age in the coming years, the incidence of coronary heart disease is likely to increase, and so there will be a greater need to have major advances in the management of coronary heart disease in order to deal with this additional incidence. The scope of this article is to review recent advances in the management of STEMI and to provide an updated overview. Statistical background According to the American Heart Association (AHA), the estimated annual incidence of myocardial infarction (MI) is 525,000 new attacks and 190,000 recurrent attacks [1] . The average age at first MI is 64.7 years for men and 72.2 years for women. Approximately 80% of people who die of coronary heart disease (CHD) are ≥65 years of age. Approximately every 44 s, an American will have a MI. The mortality rate increases for every 30 min that elapse before a patient with ST elevation MI (STEMI) is recognized and treated. The estimated average number of years of life lost by virtue of an MI is 16.6 [1] . In 2009, the overall CHD death rate was 116.1 per 100,000 individuals. From 1999 to 2009, the annual death rate attributable to CHD declined by 40.3%. In an analysis of 46,086 hospitalizations for acute coronary syndrome (ACS), the percentage of MI cases with ST-segment elevation decreased from 48.5 to 24% between 1999 and 2008 [2] . Over the last decade, in-hospital acute MI (AMI) mortality rates declined for every age/sex group except for males aged 70% STR on ECG at 90-min post-PCI)
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Review Ganjehei, Rashid, Payami & Saal compared with 54% in the nitroprusside and 51% in the saline groups (p = 0.009 and 0.75, respectively, vs saline). Angiographic MVO occurred in 18% of the adenosine group compared with 24% of the nitroprusside and 30% of the saline groups (p = 0.06 and 0.37, respectively, vs saline). MACEs occurred in 10% of the adenosine, 14% of the nitroprusside and 20% of the control patients (p = 0.08 and 0.29, respectively, vs saline). The study concluded that, in patients with STEMI treated by PCI and TA, the additional intracoronary administration of adenosine but not nitroprusside resulted in a significant improvement in MVO, as assessed by STR, compared with saline treatment. One recently concluded small, randomized, placebocontrolled trial studied intracoronary adenosine versus placebo in 70 AMI patients undergoing PCI [23] . Improvements in clinical outcome were significant in the adenosine group compared with placebo as evidenced by the resolution of ST segment (p < 0.01) and MBG 3 (p ≤ 0.05). TIMI3 flow following PCI showed borderline improvements in the adenosine group versus placebo. A composite end-point of death, recurrent MI, HF and target vessel revascularization at the 1-year follow-up was significantly lower in the adenosine group compared with placebo (p ≤ 0.05). Pretreatment with nitrites
Siddiqi et al. studied the effects of sodium nitrite on reducing myocardial injury on 229 STEMI patients in comparison with placebo in a randomized safety/efficacy trial [24] . A total of 70 μM of sodium nitrite injected 5 min prior to pPCI showed no difference in infarct size (by cardiac magnetic resonance [CMR]) between the treatment and placebo groups at 6–8 days (effect size: -0.7%; 95% CI: -2.2–0.7; p = 0.34) and 6 months after the injection. Other potential therapies of note that may have cardioprotective effects and could increase myocardial salvage include the incretin hormone (GLP-1), sitagliptin, FX06, melatonin, glucose, insulin, potassium (as the glucose–insulin–potassium [GIK] combination) combination therapy, KAI-9803 and therapeutic hypothermia. The incretin effect
GLP-1 (an incretin hormone), is released in the gut and causes an amplification of insulin activity in response to nutrients when given orally,
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but not intravenously [25] . GLP-1 is seen to have a cardioprotective effect via its effects on changes in blood pressure, endothelial function, body weight, cardiac metabolism, lipid metabolism, LV function and atherosclerosis, as well as its response (increased levels) to ischemia-driven reperfusion injury [26] . The most recent evidence of the role of GLP-1 (exenatide) in reducing reperfusion injury in pPCI STEMI patients was provided by Lonborg and colleagues [27] . A total of 172 STEMI patients (TIMI flow 0/1) were randomized to either intravenous exenatide or placebo. CMR showed that patients in the exenatide group exhibited significantly higher myocardial salvage indices compared with the placebo group (0.71 ± 0.13 vs 0.62 ± 0.16; p = 0.003). Infarct size in relation to area at risk was also smaller in the exenatide group compared with the placebo group (0.30 ± 0.15 vs 0.39 ± 0.15; p = 0.003). A post hoc analysis of the same study stratified the patients according to median system delay (132 min) [28] . The results showed that short system delay in the exenatide group was associated with a 30% reduction in final infarct size, whereas the cardioprotective effect of exenatide was not seen in patients with long system delay. Another incretin-related compound, sitagliptin, competitively inhibits the enzyme DPP-4. This enzyme breaks down the incretin GLP-1. Sitagliptin therefore prevents this breakdown of GLP-1 and is able to increase the secretion of insulin, as well the suppression of glucagon from the pancreas. In addition to its hypoglycemic effect, sitagliptin is also observed to have cardioprotective effects through lowering blood pressure, improving lipemia, reducing inflammatory markers and oxidative stress, improving endothelial function and reducing platelet aggregation [29] . With respect to its CV outcomes, sitagliptin is currently being evaluated in the TECOS study (NCT00790205). FX06
FX06 is a novel, naturally occurring small peptide derived from the human fibrin sequence. FX06 has been shown to reduce reperfusion injury and thereby reduce infarct size in animal models [30] . Its cardioprotective effect on humans was assessed in the F.I.R.E. study [31] . In this study, 234 pPCI STEMI patients were randomized to either an intravenous bolus of FX06 or placebo at the time of reperfusion. Infarct size was assessed via the measurement of the necrotic core zone and by LGE cardiac
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ST elevation myocardial infarction: recent advances & updates magnetic resonance imaging (CMR) at 5 days and 4 months following MI. On day 5, no significant difference in LGE zone was seen between the two groups (p = 0.207); however, the necrotic core zone was significantly reduced in the FX06 group compared with placebo (-58%; p < 0.025). By 4 months, the difference in scar sizes was no longer significant. MVO was present in 27.6% of the FX06 patients compared with 37.5% of the placebo group patients (p = 0.093). A post hoc analysis looked into the impact of time to therapy in the same cohort of the F.I.R.E study, stratified according to presentation status and the presence or absence of collaterals [32] . The esults showed no correlation of time to therapy with infarct size at 5–7 days post-MI; however, at 4 months, a significant reduction in infarct size was seen, as assessed by both LGE (0.3 vs 2.4%; p = 0.038) and necrotic core zone (8.0 vs 16%; p = 0.032) in patients who presented early (75 years of age group during the trial, and therefore an amendment to the trial was instated. After this amendment, this particular patient group received half the original bolus dose of tenecteplase and the rate of intracranial hemorrhage came down to 0.5%
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in the fibrinolysis group versus 0.3% in the pPCI group (p = 0.45). No difference in nonintracranial bleeding was found between the two groups. The results of the STREAM trial suggest a clinical model to follow during STEMI. If diagnosed in the field and with no PCI-equipped facility nearby, one should administer full-dose fibrinolysis with consideration of a half dose in patients who are >75 years of age, followed by transfer to a PCI hospital. For STEMI patients diagnosed in the field with a PCI hospital nearby, pPCI is the appropriate option. Follow-up 1-year mortality data from the STREAM trial were presented in the AHA 2013 conference, showing that STEMI patients randomized to be treated with either a pharmacoinvasive approach (bolus tenecteplase, clopidogrel and enoxaprin) or pPCI demonstrated no significant differences in all-cause death (6.7 vs 5.9%; p = 0.52) and cardiac death (4 vs 4.1%; p = 0.93) at the 1-year follow-up and the pharmacoinvasive approach was rendered as effective as pPCI with regards to the 1-year mortality outcome [95] . The mechanisms of action of various pharmacological agents along the coagulation pathway are depicted in Figure 1. ●●Devices
PCI is now the recommended method of mechanical reperfusion in STEMI and is preferred over thrombolysis when available. The choices for PCI have evolved rapidly over the last decade or so. Simple balloon angioplasty was replaced by BMSs, and restenosis complications secondary to neointimal formation paved way for drug-eluting stents (DESs). The idea behind DESs is for them to deliver an antiproliferative/antineoplastic agent in a sustained fashion over time into the lumen in order to prevent neointimal formation while maintaining the patency of the lumen, thereby reducing the risk of restenosis. However, clinical and epidemiological evidence suggests that DESs have been associated with very late (3–5 years) stent thrombosis [96] . A meta-analysis of 15 randomized controlled trials of 7867 STEMI patients compared first-generation DESs with BMSs [97] . The results showed that the risk of stent thrombosis with DESs revealed a variation over time (RR in the first year: 0.80, 95% CI: 0.58–1.12; RR in subsequent years: 2.10, 95% CI: 1.20–3.69). The interaction between the RR of stent thrombosis and time was found to be positive (p = 0.009 for the interaction).
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Extrinsic pathway (tissue injury)
Intrinsic pathway (surface contact)
Rivaroxaban
XIIa
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Plaque rupture (collagen)
Aspirin
Fondaparinux XI
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ADP Clopidogrel Prasugel Ticagrelor Cangrelor
Tissue factor
Xa
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Platelet activation Bivalirudin
ATIII Prothrombin (II)
Heparin LMWH
VII TXA2
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VIIa
ATIII
Abciximab Eptifibatide Tirofiban
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ATIII
Platelet aggregation Fibrinogen (I)
Fibrinolytics
Fibrin (Ia)
XIIIa
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Thrombus stable clot
Figure 1. Pharmacological reperfusion: mechanisms of action of pharmacological agents along coagulation pathway.
The results were similar for definite or probable stent thrombosis (p = 0.015 for the interaction). The need for target vessel revascularization was less frequent in DESs versus BMSs (RR: 0.51; 95% CI: 0.43–0.61). Further analysis revealed a trend towards greater benefit during the first year (RR: 0.46; 95% CI: 0.38–0.55) compared with subsequent years (RR: 0.75; 95% CI: 0.59–0.94; p = 0.007 for the interaction). Another recent meta-analysis of seven randomized trials showed that sirolimus-eluting stents (SESs) at a median follow-up of 3 years significantly reduced the risk of target vessel revascularization without increasing mortality, reinfarction and early-to-late stent thrombosis as compared with BMSs [98] . However, following the first year, SESs failed to further reduce target vessel revascularization (OR: 1.06; 95% CI: 0.64–1.74; p = 0.83) and also raised the risk of very late stent thrombosis (OR: 2.81; 95% CI: 1.33–5.92; p = 0.007).
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Stents eluting everolimus from a permanent polymer have been shown to significantly reduce stent thrombosis, target vessel revascularization and MI compared with stents not eluting everolimus (i.e., eluting paclitaxel/sirolimus instead) in a meta-analysis of 13 randomized trials with a mean follow-up of 22 months [99] . Sawada and colleagues studied arterial healing responses for the first time in STEMI patients who received either everolimus-eluting stents (EESs) or SES [100] . At 7 months, optical coherence tomography showed considerable suppression of neointimal proliferation in target lesions in both EES and SES groups; however, the EES group showed greater neointimal thickness compared with the SES group (94.8 ± 88.8 μm vs 65.6 ± 63.3 μm; p ≤ 0.0001). Furthermore, the EES group compared with the SES group significantly less frequently left uncovered struts (2.7 vs 15.7%; p ≤ 0.0001) and malapposed struts (0.7 vs 2.3%; p ≤ 0.0001) and the incidence rate of intrastent
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ST elevation myocardial infarction: recent advances & updates thrombosis in EESs was lower than with SESs (22.7 vs 63.6%; p = 0.05). DESs are composed of three parts: the stent platform (usually a metal alloy frame), the coating (usually a polymer that holds and elutes the drug) and the drug. Second-generation DESs have evolved from improvemens in all of the components of the stent structure. Contemporary alloys, polymer coatings with better biocompatibility, the use of polymer coatings that are biodegradable and the development of antineoplastic drugs that are less toxic may address the short- and long-term safety issues that were seen with BMSs and first-generation DESs. A meta-analysis of second-generation DESs with biodegradable polymers showed not only better safety, but also better efficacy compared with durable polymer SESs over a follow-up of up to 4 years [101] . Notably, the risk of very late stent thrombosis was lower with biodegradable polymer DESs compared with durable polymer SESs (HR: 0.22; 95% CI: 0.08–0.61; p = 0.004). A recent study conducted on everolimus-eluting bioresorbable vascular scaffolds showed for the first time that such a stent may be safe, particularly in STEMI patients [102] . The 53 ± 45.9 day follow-up showed no MACEs, as well as no acute or subacute stent thromboses. By nature of their design, biodegradable polymers seem to not only protect against early stent thrombosis, but also appear to negate late prothrombotic and proinflammatory complications [103,104] . In cases of in-stent restenosis, drug-eluting balloons (DEBs) have been the focus of attention as a potential optimal treatment strategy. A recent meta-analysis of five randomized trials (n = 801 patients, comparing DEBs with either balloon angioplasty or DESs as controls) showed that DEBs reduce the risk of MACEs compared with control treatment (RR: 0.46; 95% CI: 0.31–0.70; p < 0.001) [105] . Further analysis showed that DEB treatment compared with control treatment also carried a lower risk for target lesion revascularization (p = 0.006) and in-segment restenosis (p ≤ 0.001). The risk of stent thrombosis, however, did not show any difference between the two groups (p = 0.891). The ZEUS trial studied the comparison of DESs and BMSs in a unique set of patients with high bleeding and thrombosis, but low restenosis risk [106] . In this trial, 1606 patients were randomized to either Endeavor zotarolimuseluting stents (ZESs) or BMSs and were given customized dual antiplatelet therapy based on
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clinical risk, irrespective of the type of stent placement. In totoal, 52% of high-bleeding-risk patients received dual antiplatelet therapy for 30 days, 17% of high-thrombotic-risk patients received the therapy for 6 months and 31% of low-restenosis-risk patients received the therapy for 30 days if there was the presence of stable coronary artery disease or 6 months if there was the presence of ACS. The results showed fewer MACEs in the ZES group compared with the BMS group (17.5 vs 22.1%; p = 0.011), suggesting the Endeavor ZES to be the possible stent of choice in patients who are either intolerant or refuse long-term dual antiplatelet therapy. Recent studies comparing various stents in STEMI patients are summarized in Table 1. Vascular access: femoral versus radial PCI PCI is the primary treatment of choice in STEMI and leads to significantly better clinical outcomes. However, bleeding remains a major concern and may hamper an otherwise successful procedure. In addition to finding safer pharmacological thrombolytic therapies, there has also been a focus on accessing the coronary system via extrafemoral routes, with the most notable among these being radial artery access. An alternative access site such as the radial artery may ultimately lead to reduced vascular complications through reductions in bleeding and is regarded to be a safe technique. Several meta-analyses have supported the preferential use of radial access in STEMI PCI, as evidenced by lower bleeding complications and improved clinical outcomes [120–124] . The most recent meta-analysis covered the literature from 1990 to 2012 and included both randomized (n = 15) and nonrandomized trials (n = 15) comparing radial (n = 10,052) with femoral access (n = 19,142) in STEMI PCI patients [125] . The final analysis demonstrated a significant reduction in the primary end point (short-term [30-day] mortality) for the radial compared with the femoral approach (5.2 vs 10.3%; OR: 0.55; 95% CI: 0.40–0.76; p < 0.001; p for heterogeneity = 0.97). The differences remained significant in both randomized trials and observational studies (p < 0.001). Similarly, a significant reduction in major bleeding complications was seen with the radial approach as compared with the femoral approach (1.9 vs 4.7%; OR: 0.38; 95% CI: 0.31–0.47; p < 0.0001; p het = 0.17). The difference again remained significant in both randomized trials (p < 0.001) and observational
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Prospective registry analysis
Randomized, multicenter, all-comer, noninferiority trial
Velders et al. – (2013)
Christiansen SORT-OUT V et al. (2013)
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Abluminal biodegradable polymer BES vs durable polymer EES (COMPARE II)
Effect of BES with biodegradable polymer vs BMS on cardiovascular events among patients with acute myocardial infarction (COMFORTABLE AMI) EES vs BMS in STEMI Multicenter, (EXAMINATION) prospective, randomized controlled trial
Smits et al. (2013)
Raber et al. (2012)
STEMI
1498
1161
2707
2468
931
EES vs BMS
Biodegradable polymer BES vs BMS
Biodegradable polymer BES vs durable polymer EES
Biodegradable polymer BES vs permanent polymer SES
EES vs E-ZES
1.6–3.1 years
F/up
Combination of all-cause death, any recurrent MI and any revascularization
MACEs, composite of cardiac death, target vessel reinfarction and TLR
1 year
1 year
Composite of safety 9 months–1 year (cardiac death, MI and definite stent thrombosis) and efficacy (TVR) Composite of safety 1 year (cardiac death and nonfatal MI) and efficacy (TVR)
Composite of cardiac death, target vessel-related MI and TLR
End point/ outcome
Ref.
EES vs BMS: primary end point: 11.9 vs 14.2% (difference -2.34%; 95% CI: -5.75–1.07; p = 0.19); definite stent thrombosis: 0.5 vs 1.9% (p = 0.019); definite or probable stent thrombosis: 0.9 vs 2.5% (p = 0.019)
BES vs BMS: MACE at 1 year: 4.3 vs 8.7% (HR: 0.49; 95% CI: 0.30–0.80; p = 0.004); definite stent thrombosis: 0.9 vs 2.1% (HR: 0.42; 95% CI: 0.15–1.19; p = 0.1)
[111]
[110]
EES vs E-ZES: primary [107] end point: 9.7 vs 13.7% (HR: 0.64; 95% CI: 0.42–0.99); definite stent thrombosis: 1.1 vs 1.9% (p = 0.19) BES vs SES: primary end [108] point: 4.1 vs 3.1% (p = 0.06 for noninferiority); stent thrombosis at 1 year: 0.7 vs 0.2% (p = 0.034) BES vs EES: primary [109] end point: 5.2 vs 4.8% (RR: 1.07; 95% CI: 0.75–1.52; p = 0.0001 for noninferiority)
Results
ACS: Acute coronary syndrome; BA: Balloon angioplasty; BAS: Bioactive stent; BES: Biolimus-eluting stent; BMS: Bare metal stent; CAD: Coronary artery disease; DES: Drug-eluting stent; EES: Everolimus-eluting stent; E-ZES: Endeavor® zotarolimus-eluting stent; F/up: Follow-up; HR: Hazard ratio; MACE: Major adverse coronary event; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PEB: Paclitaxel-eluting balloon; PES: Paclitaxel-eluting stent; RR: Risk ratio; SES: Sirolimus-eluting stent; STEMI: ST elevation myocardial infarction; TIMI: Thrombolysis in myocardial infarction; TLR: Target lesion revascularization; TVF: Target vessel failure; TVR: Target vessel revascularization; ZES: Zotarolimus-eluting stent.
Sabate et al. (2012)
STEMI
Eligible dubjects Subjects Device(s) (n) studied
Stable CAD, ACS, at least one coronary artery lesion (>50% stenosis) Open-label, PCI patients prospective, (age >18 years, randomized, life expectancy controlled, >5 years, noninferiority trial reference vessel diameter 2.0–4.0 mm, willingness for 5-year F/up) Prospective, STEMI randomized, single-blinded, controlled trial
Study design
Study (year) Parent study
Table 1. Recent studies comparing intracoronary stents in ST elevation myocardial infarction patients.
Review Ganjehei, Rashid, Payami & Saal
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STEMI
Prospective, STEMI randomized study
Prospective, randomized noninferiority study
STEMI
STEMI
433
827
425
2665
End point/ outcome
F/up
Polyethylene terephthalate micronet mesh stent (MGuard™) vs conventional stents (DESs/BMSs)
BAS vs EES
Titaniumnitride-oxidecoated BAS vs PES 1 year
5 years
Rate of complete 60–90 min post(≥70%) ST-segment PCI resolution
MACEs, composite of cardiac death, recurrent MI or ischemia-induced TLR Composite of cardiac death, nonfatal MI or ischemia-driven TLR
EES vs BMS; BES Device-oriented 1 year vs BMS composite of cardiac death, target vessel reinfarction and TLR; patient-oriented composite of death, reinfarction and any revascularization
Eligible dubjects Subjects Device(s) (n) studied
Ref.
DES vs BMS: device[112] oriented composite (RR: 0.58; 95% CI: 0.43–0.79; p = 0.0004); patientoriented composite (RR: 0.78; 95% CI: 0.63–0.96; p = 0.02); acute definite stent thrombosis (RR: 0.38, 95% CI: 0.17–0.85; p = 0.02); 1-year definite stent thrombosis (RR 0.35; 95% CI: 0.16–0.75; p = 0.006) BAS vs PES: primary [113] end point: 16.4 vs 25.1% (p = 0.03); definite stent thrombosis: 0.9 vs 7.1% (p = 0.001) BAS vs EES: primary [114] end point: 9.6 vs 9.0% (HR: 1.04; 95% CI: 0.81–1.32; p = 0.81 and p = 0.001 for noninferiority); nonfatal MI: 2.2 vs 5.9% (p = 0.007) MGuard vs DES/BMS: [115] ST-segment resolution: 57.8 vs 44.7% (difference: 13.2%; 95% CI: 3.1–23.3%; p = 0.008); TIMI 3 flow: 91.7 vs 82.9% (p = 0.006)
Results
ACS: Acute coronary syndrome; BA: Balloon angioplasty; BAS: Bioactive stent; BES: Biolimus-eluting stent; BMS: Bare metal stent; CAD: Coronary artery disease; DES: Drug-eluting stent; EES: Everolimus-eluting stent; E-ZES: Endeavor® zotarolimus-eluting stent; F/up: Follow-up; HR: Hazard ratio; MACE: Major adverse coronary event; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PEB: Paclitaxel-eluting balloon; PES: Paclitaxel-eluting stent; RR: Risk ratio; SES: Sirolimus-eluting stent; STEMI: ST elevation myocardial infarction; TIMI: Thrombolysis in myocardial infarction; TLR: Target lesion revascularization; TVF: Target vessel failure; TVR: Target vessel revascularization; ZES: Zotarolimus-eluting stent.
MASTER
BASE-ACS
Karjalainen et al. (2012)
Stone et al. (2012)
TITAX-AMI
Tuomainen et al. (2012)
Randomized controlled trial
EXAMINATION and Pooled analysis COMFORTABLE-AMI
Study design
Sabate et al. (2012)
Study (year) Parent study
Table 1. Recent studies comparing intracoronary stents in ST elevation myocardial infarction patients (cont.).
ST elevation myocardial infarction: recent advances & updates
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SORT-OUT VI
DUTCH PEERS (TWENTE II)
SORT-OUT VI (2013)
TWENTE II (2013)
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Chronic, stable 2999 CAD or ACS patients with at least one coronary leasion of ≥50% stenosis PCI patients with 1811 DES implantation
Patients aged >18 years with restenosis of ≥50% post-DES implantation
1707
Cobalt chromium ZES vs platinum chromium EES
Permanent polymer ZES vs biodegradable BES
F/up
Composite TVF (cardiac death, TVR and MI)
1 year
MACEs (composite 12 months of cardiac death, MI and TLR)
6–8 months
MACEs (composite Up to 5 years of cardiac death, MI and TVR)
PEB vs PES vs BA Diameter stenosis at F/up angiography
Biodegradable polymer BES vs durable polymer SES
End point/ outcome
ZES vs EES; TVF: 6.1 vs 5.2% (p = 0.006 inferiority); definite or probable stent thrombosis: 0.6 vs 0.9% (p = 0.4)
BES vs SES: MACEs: 18.7 vs 22.6% (p = 0.05); definite stent thrombosis: RR: 0.62 (p = 0.09); very late definite stent thrombosis: RR: 0.20 (p = 0.004) PEB vs PES: primary end point: 38.0 vs 37.4% (p = 0.007 for noninferiority); PEB and PES vs BA: primary end point: p ≤ 0.0001 for superiority for both comparisons ZES vs BES: MACEs: 5.3 vs 5.1% (p = 0.006 for noninferiority)
Results
ACS: Acute coronary syndrome; BA: Balloon angioplasty; BAS: Bioactive stent; BES: Biolimus-eluting stent; BMS: Bare metal stent; CAD: Coronary artery disease; DES: Drug-eluting stent; EES: Everolimus-eluting stent; E-ZES: Endeavor® zotarolimus-eluting stent; F/up: Follow-up; HR: Hazard ratio; MACE: Major adverse coronary event; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PEB: Paclitaxel-eluting balloon; PES: Paclitaxel-eluting stent; RR: Risk ratio; SES: Sirolimus-eluting stent; STEMI: ST elevation myocardial infarction; TIMI: Thrombolysis in myocardial infarction; TLR: Target lesion revascularization; TVF: Target vessel failure; TVR: Target vessel revascularization; ZES: Zotarolimus-eluting stent.
Multicenter, prospective, single-blinded, randomized controlled trial
Prospective, randomized, allcomer trial
PEBs, PESs and BA Randomized, in patients with open-label trial restenosis after implantation of a DES (ISAR-DESIRE 3)
Byrne et al. (2013)
Multicenter, All-comers, real all-comer, world patients randomized, assessor-blind noninferiority trial
Serruys et al. LEADERS (2012)
Eligible dubjects Subjects Device(s) (n) studied
Study design
Study (year) Parent study
Table 1. Recent studies comparing intracoronary stents in ST elevation myocardial infarction patients (cont.).
[119]
[118]
[117]
[116]
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ST elevation myocardial infarction: recent advances & updates studies (p < 0.0001). The analysis concluded radial approach to be associated with reductions in mortality and bleeding complications. RIFLE-STEACS was a randomized, multicenter trial from Europe that compared transradial with transfemoral access for the prediction of better clinical outcomes [126] . The trial was conducted in four centers with high-volume operators (>150 PCIs/year). A randomized cohort of 1001 STEMI patients at 30 days showed that the primary end point of NACEs (composite of cardiac death, stroke, MI, target lesion revascularization and bleeding) occurred in 13.6% of patients in the radial arm compared with 21% in the femoral arm (p = 0.003). Radial access was also found to be associated with significantly lower rates of cardiac death (5.2 vs 9.2%; p = 0.020) and bleeding (7.8 vs 12.2%; p = 0.026) and shorter hospital stays (p = 0.03) compared with femoral access. The reduction in bleeding was predominantly attributed to reductions in access site bleeds (47%). The STEMI-R ADI A L trial assessed 707 STEMI patients undergoing pPCI, who were randomized to femoral or radial access PCI [127] . Only high-volume radialists (>200 PCIs/year) were included in the study. The results showed that 58% fewer 30-day NACEs (MACEs plus major bleeding) occurred in the radial arm compared with the femoral arm (4.6 vs 11.0%; p = 0.0028). However, the difference in MACEs alone was not significant (3.5% in the radial arm vs 4.2% in the femoral arm; p = 0.7). The rates of 30-day bleeding and access site complications were 80% lower in patients with radial PCI compared with femoral PCI (1.4 vs 7.2%; p = 0.0001). Furthermore, a lower contrast volume had to be used with radial access, and lengths of stay in the intensive care unit were shorter (2.5 days for the radial access group vs 3.0 days for the femoral access group; p = 0.0016). The overall mortality rates were 2.3 and 3.1% in the radial and femoral arms, respectively; this was not statistically significant, which was attributed to the study being underpowered for death. The study researchers concluded that a significant net clinical benefit in STEMI radial access PCI patients was most pronounced in patients who presented within 12 h. The evidence so far suggests that the radial approach to PCI improves clinical outcomes, reduces bleeding complications, increases patient comfort and reduces the length of stay in hospital. However, most of these effects are more
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pronounced when this procedure is carried out in high-volume centers and is directly related to the operator’s experience. A more widespread use of this access site for PCI and more operator experience over time may cause this procedure to become a default access site in future. Diagnostic updates A substudy of TRITON TIMI 38 trial [128] analyzed a subpopulation of ACS patients from the parent trial [129] , who presented with isolated anterior (V1–V4) ST-segment depression (1198/13,608) as documented by 12-lead ECG. All of these patients underwent angiograms, and the study investigators were able to assess the angiographic as well as the clinical outcomes in the said patient population. Further breakdown of the 1198 patients revealed that 26.2% of them actually had an occluded culprit artery (TIMI flow grade 0/1) and positive troponin marker, now diagnosed as STEMI. The rest of the patient population had a patent culprit artery (TIMI flow grade 2/3 for both), with positive troponin (53.5%) and negative troponin (20.3%) now classified as non-STEMI and unstable angina, respectively. Of the patients with occluded culprit arteries, the left circumflex artery was most commonly implicated (48.4%), followed by the left anterior descending (33.8%) and the right coronary arteries (17.8%). At the 30-day followup, the composite of death and MI was found to be significantly higher in occluded artery patients (8.6%) compared with those with marker-positive patent culprit arteries (6.3%) and marker-negative patent culprit arteryies (three-way p = 0.006). The ECG-to-PCI time for the occluded artery patients was 29.4 h, meaning fewer patients in this category went through urgent catheterization, which might explain the worse clinical outcome. The questionable sensitivity of 12-lead ECG in diagnosing anterior segment depression ACS led to the idea of considering all anterior ST-segment depression patients as having STEMI and treating them accordingly. Although not new, one possible approach is the use of the 80-lead or PRIME® (Verathon Inc., WA, USA) ECG vest in order to enhance the sensitivity of ECG diagnosis. Its outcome is displayed as a vector and gives a 360° view of the electrical activity of heart. The additional electrodes enhance the ability to find the suspected ST-segment vector and classify it as an AMI. The 80-lead ECG was approved for use by the FDA in 2002. The OCCULT-MI trial showed
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Review Ganjehei, Rashid, Payami & Saal that, in patients without ST elevation on 12-lead ECG, an 80-lead ECG diagnosed more patients with MI (sensitivity: 19.4 vs 10.7%, p = 0.0014; specificity: 93.9 vs 96.4%, p = 0.0005) or ACS (sensitivity: 12.3 vs 7.1%, p = 0.0025; specificity: 93.7 vs 96.4%, p = 0.0005) compared with 12-lead ECG [130] . Despite the significant sensitivity advantage of 80-lead over 12-lead ECG, the cost–effectiveness also needs some consideration. While a more traditional 12-lead ECG costs approximately 35 cents, the 80-lead ECG vest costs approximately US$80 and is not reusable. Another plausible alternative for improving ACS diagnosis is to enhance the sensitivity of 12-lead ECG by adding leads V7, V8 and V9, thereby expanding the selection of patients requiring timely reperfusion [131,132] . Stem cell therapy Despite of all the advances and efforts in minimizing myocardial damage following STEMI, even ideal management leaves at least some sort of irreversible damage to the myocardial tissue, that may lead to HF. Efforts to regenerate the lost tissue are currently underway and have met with conflicting results so far. The majority of the clinical trials have employed autologous bone marrow stem cells for this purpose, anticipating an improvement in cardiac function and consequently lower morbidity and mortality. The main focus of stem cell therapy is to prevent or reverse the remodeling of the LV following ischemic episodes. A meta-analysis of 33 randomized controlled trials conducted on 1765 subjects treated with bone marrow cell (BMC) therapy found no significant improvement in mortality (RR: 0.70; 95% CI: 0.40–1.21) or morbidity (reinfarction: RR: 0.67, 95% CI: 0.40–1.13; hospital readmission: RR: 0.87, 95% CI: 0.56–1.35); restenosis: RR: 0.90, 95% CI: 0.61–1.31; or target vessel revascularization: RR: 0.83, 95% CI: 0.62–1.11) when compared with placebo [133] . Short-term follow-up analysis, however, did reveal a significant improvement in LVEF in the treatment group (weighted mean difference: 2.87; 95% CI: 2.00–3.73) that was maintained for 12–61 months (weighted mean difference: 3.75; 95% CI: 2.57–4.93), along with significant improvement in LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV) and infarct size over long-term follow-up in some studies. A positive correlation was also observed between the dose and timing of treatment and the effect on LVEF.
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Another recently concluded meta-analysis showed that intracoronary BMC therapy compared with controls led to a significant improvement in LVEF (2.23%; p ≤ 0.001) and LVESV (-4.81 ml; p ≤ 0.001) at 6 months and maintained this effect at the 12-month followup (LVEF change: 1.90%; LVESV: -9.41 ml; p < 0.001 for both). The effects on LVEDV and infarct size, however, remained inconclusive [134] . The analysis also showed that the BMC-treated group showed a statistically significant reduction in recurrent AMI (RR: 0.44; 95% CI: 0.24– 0.79; p = 0.007) and readmission for HF, unstable angina or chest pain (RR: 0.59; 95% CI: 0.35–0.98; p = 0.04). Intracoronary BMC therapy was concluded to demonstrate moderate improvements in LVEF, as well as reductions in LVESV both at the 6- and 12-month follow-up. LVEDV and infarct size, however, did not show any improvement. The results of late-breaking stem cell trials, presented at the Scientific Sessions of the AHA 2012 and 2013 conferences, showed mixed results. The SCIPIO trial was a Phase I trial in which 18 post-MI patients with LVEF 75th High plasma sMAC is an percentile): all-cause mortality, HR: 1.81 independent predictor of all-cause (95% CI: 1.06–3.06; p = 0.029); MACEs, mortality and MACEs in STEMI PCI HR: 1.70 (95% CI: 1.16–2.48; p = 0.006) patients. Cut-off level of sMAC >75th percentile miR-133a ≥ median vs miR-133a Median miR-133a concentration: < median group: MACEs, 20 vs 9% 33.4; miR-133a adds prognostic (p = 0.025); CMR markers: infarct size value to STEMI patients, but not (p < 0.001), MVO (p < 0.001), myocardial independently beyond CMR salvage index (p < 0.001) markers of clinical prognosis LVEF < MPV vs LVEF > 50% MPV: ↑MPV, troponin I and WBC count 9.5 ± 1.1 fl vs 8.8 ± 0.8 fl (p = 0.001); on admission in anterior STEMI troponin I: 30 ± 29 ng/ml vs 12.2 ± 15.1 patients undergoing PCI is ng/ml (p = 0.001); WBC count: 12.3 ± associated with impaired LV systolic 3.8 ×109/l vs 10.6 ± 3.4 ×109/l (p = 0.027) function
[149]
[148]
Ref.
[150]
hs-CRP independent predictor of F/u outcome in NSTEMI, but not STEMI patients, Cut-off level of hs-CRP: 1.1 mg/dl Fetuin-A in combination with CRP is associated with CV death in ACS patients
Comments
Significant association between ↑TB and adjusted in-hospital CV mortality risk following PCI. Cut-off level of TB >0.9 mg/dl
CV mortality: overall, 10%; ↓fetuin-A, 17%; ↑CRP, 18%; ↓fetuin-A plus ↑CRP, 23% (p < 0.01); neither ↓fetuin-A nor ↑CRP, 5% Multivariate: ↑TB (>0.9 mg/dl) and in-hospital CV mortality risk, OR: 3.24 (95% CI: 1.27–8.27; p = 0.014); long-term mortality, no difference between ↑TB and ↓TB groups ↑ vs ↓ Lp-PLA2: 30-day MACEs: 24.2 vs 3.0% (p = 0.001); logistic regression: Lp-PLA2 for MACEs, OR: 1.011 (95% CI: 1.001–1.013; p = 0.037)
Combination of hs-CRP NSTEMI (HR: 1.217; 95% CI: cardiac death and MI 1.093–1.356; p ≤ 0.001)
End point
↓: Decreased; ↑: Increased; ACS: Acute coronary syndrome; AUC: Area under curve; CAD: Coronary artery disease; CEM: Content of erythrocyte membrane; CHF: Congestive heart failure; CMR: Cardiac magnetic resonance; cMRI: Cardiac magnetic resonance imaging; CV: Cardiovascular; EDV: End-diastolic volume; eGFR: Estimated glomerular filtration rate; ESR: Erythrocyte sedimentation rate; F/u: Follow-up; GGT: γ-glutamyl transferase; GRACE: Global Registry of Acute Coronary Events; HF: Heart failure; HR: Hazard ratio; hs-CRP: High-sensitivity CRP; Lp-PLA2: Lipoprotein associated phospholipase A2; LV: Left ventricular; LVEDV: Left ventricular end-diastolic volume; LVEF: Left ventricular ejection fraction; MA: Microalbuminuria; MACE: Major adverse coronary event; MBG: Myocardial blush grade; MI: Myocardial infarction; MMP-9: Matrix metalloproteinase-9; MPO: Myeloperoxidase; MPV: Mean platelet volume; MV: Multivariate; MVO: Microvascular obstruction; NA: Normoalbuminuria; NGAL: Neutrophil gelatinase-associated lipocalin; NP: Natriuretic peptide; NSTEMI: Non-ST elevation myocardial infarction; OPG: Osteoprotegerin; OR: Odds ratio; PCI: Percutaneous coronary intervention; ROC: Receiver operating characteristic; RR: Relative risk; SA: Stable angina; sMAC: Soluble membrane attack complex; STEMI: ST elevation myocardial infarction; sTNFR: Soluble TNF receptor; STR: ST-segment resolution; TB: Total bilirubin; TIMI: Thrombolysis in myocardial infarction; TMPG: Thrombolysis in myocardial infarction myocardial perfusion grade; UAER: Urinary albumin extraction rate; WBC: White blood cell.
Anterior STEMI PCI (97)
STEMI PCI (725)
Lindberg sMAC et al. (2012)
30 days
STEMI PCI (1624) After PCI and 26.2 months (mean)
First anterior STEMI PCI (100)
TB
Stankovic Lp-PLA2 et al. (2012)
Gul et al. (2013)
ACS-STEMI (404), 1 year ACS-NSTEMI (350)
Fetuin-A
Lim et al. (2013)
19.8 months
ACS (151, 47% STEMI)
Raposeiras hs-CRP Roubin et al. (2013)
Follow-up
Patient population (n)
Marker
Study (year)
Table 3. Recent studies on biomarkers of prognostic value in ST elevation myocardial infarction patients.
Review Ganjehei, Rashid, Payami & Saal
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STEMI (73)
Kaya et al. (2012)
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MACEs (cardiac death, reinfarction, new angina, HF, revascularization) All-cause mortality, repeat MI, HF
Systolic dysfunction, death
Severity of CAD assessed by Gensini score
End point
Multivariate analysis: ↑MPO: MACEs, OR: 3.843 (95% CI: 1.625–6.563; p = 0.003)
CEM levels are positively correlated with severity of CAD
CEM levels ↑ in STEMI vs NSTEMI (p = 0.012) and SA (p < 0.001); NSTEMI vs SA (p < 0.001); CEM levels and severity of CAD by Gensini score: r = 0.714 (p < 0.001) IL-6+/IL-10+ vs IL-6 -/IL-10+ STEMI: systolic dysfunction at discharge: 36.1 vs 19.2% (p = 0.06); death at 6 months: 11.1 vs 0% (p = 0.0005)
27 months
↑ESR at admission independently correlated with worse long-term prognosis in STEMI F/u. Cut-off level of ESR ≥33 mm/h ↓miR-150 levels are associated with LV remodeling after STEMI. miR-150 (AUC: 0.74) is a better predictor of LV remodeling than pro-BNP (AUC: 0.60)
↑OPG levels independently correlate with worse long-term prognosis in STEMI F/u
STEMI patients with simultaneous ↑ of IL-6 and IL-10 show worse clinical outcomes compared with STEMI patients who do not have a simultaneous elevation ↑MPO levels independently correlate with worse prognosis at 2 years of STEMI F/u
Comments
Results
Multivariate analysis: ↑OPG: death, HR: 1.28 (95% CI: 1.03–1.59; p = 0.03); repeat MI, HR: 1.30 (95% CI: 1.00–1.68; p = 0.05); admission with HF, HR: 1.50 (95% CI: 1.18–1.90; p = 0.001) In-hospital and Myocardial perfusion Angiographic reperfusion: ↑ vs ↓ ESR: 1 year mean TIMI frame count: 25.5 ± 6.5 vs 20.4 ± 5.2 (p = 0.01); TMPG 0–2: 55 vs 29% (p = 0.01) Predischarge LV remodeling (↑ Patients with remodeling (ΔEDV >0) and 4–6 months in LVEDV between vs without remodeling (ΔEDV ≤0): discharge and F/u, miR-150 levels: twofold less (p = 0.03); ΔEDV >0) miR-150 reclassified 54% of patients misclassified by BNP (p = 0.03) and 59% misclassified by multiparameter clinical model (p = 0.02)
25 ± 16 months
At discharge and 6 months
Samples collected prior to angiography
Follow-up
[160]
[159]
[158]
[157]
[156]
[155]
Ref.
↓: Decreased; ↑: Increased; ACS: Acute coronary syndrome; AUC: Area under curve; CAD: Coronary artery disease; CEM: Content of erythrocyte membrane; CHF: Congestive heart failure; CMR: Cardiac magnetic resonance; cMRI: Cardiac magnetic resonance imaging; CV: Cardiovascular; EDV: End-diastolic volume; eGFR: Estimated glomerular filtration rate; ESR: Erythrocyte sedimentation rate; F/u: Follow-up; GGT: γ-glutamyl transferase; GRACE: Global Registry of Acute Coronary Events; HF: Heart failure; HR: Hazard ratio; hs-CRP: High-sensitivity CRP; Lp-PLA2: Lipoprotein associated phospholipase A2; LV: Left ventricular; LVEDV: Left ventricular end-diastolic volume; LVEF: Left ventricular ejection fraction; MA: Microalbuminuria; MACE: Major adverse coronary event; MBG: Myocardial blush grade; MI: Myocardial infarction; MMP-9: Matrix metalloproteinase-9; MPO: Myeloperoxidase; MPV: Mean platelet volume; MV: Multivariate; MVO: Microvascular obstruction; NA: Normoalbuminuria; NGAL: Neutrophil gelatinase-associated lipocalin; NP: Natriuretic peptide; NSTEMI: Non-ST elevation myocardial infarction; OPG: Osteoprotegerin; OR: Odds ratio; PCI: Percutaneous coronary intervention; ROC: Receiver operating characteristic; RR: Relative risk; SA: Stable angina; sMAC: Soluble membrane attack complex; STEMI: ST elevation myocardial infarction; sTNFR: Soluble TNF receptor; STR: ST-segment resolution; TB: Total bilirubin; TIMI: Thrombolysis in myocardial infarction; TMPG: Thrombolysis in myocardial infarction myocardial perfusion grade; UAER: Urinary albumin extraction rate; WBC: White blood cell.
STEMI (90)
STEMI PCI (140)
Fatih Ozlu ESR et al. (2012)
Devaux miR-150 et al. (2013)
STEMI PCI (716)
Pedersen OPG et al. (2012)
MPO
STEMI (109)
Ammirati IL-6+, IL-6 -, IL-10+ et al. (2012) cytokines
Patient population (n)
STEMI, NSTEMI, SA (136)
Marker
Zhong Total cholesterol et al. (2012) CEM
Study (year)
Table 3. Recent studies on biomarkers of prognostic value in ST elevation myocardial infarction patients (cont.).
ST elevation myocardial infarction: recent advances & updates
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STEMI PCI (80)
4–6 months
In-hospital
Multimarker risk score correlates with angiographic, ECG and CMR mechanistic markers of outcomes
↑serum GGT at admission independently predicts inhospital MACEs in STEMI patients undergoing PCI ↑YKL-40 and leukocyte count independently predict inhospital MACEs in STEMI patients undergoing PCI
↓eGFR
ST elevation myocardial infarction: recent advances and updates
Leila Ganjehei*,1, Urmiya Mamoon Rashid2, Sara Payami3 & Andrew Kim Saal4
ABSTRACT ST elevation myocardial infarction (STEMI) remains a leading cause of morbidity, mortality and disability worldwide. Statistically, a trend towards improvements in morbidity and mortality has been consistent over the years, which is attributed primarily to the modification of risk factors, healthier lifestyles, treatment advances and better management of door-to-balloon times via STEMI systems. However, a major challenge in the coming years will be the baby boomers (born between the years 1946 and 1964) coming into old age. The first baby boomers turned 65 in year 2011. As the baby boomers age in the coming years, the incidence of coronary heart disease is likely to increase, and so there will be a greater need to have major advances in the management of coronary heart disease in order to deal with this additional incidence. The scope of this article is to review recent advances in the management of STEMI and to provide an updated overview. Statistical background According to the American Heart Association (AHA), the estimated annual incidence of myocardial infarction (MI) is 525,000 new attacks and 190,000 recurrent attacks [1] . The average age at first MI is 64.7 years for men and 72.2 years for women. Approximately 80% of people who die of coronary heart disease (CHD) are ≥65 years of age. Approximately every 44 s, an American will have a MI. The mortality rate increases for every 30 min that elapse before a patient with ST elevation MI (STEMI) is recognized and treated. The estimated average number of years of life lost by virtue of an MI is 16.6 [1] . In 2009, the overall CHD death rate was 116.1 per 100,000 individuals. From 1999 to 2009, the annual death rate attributable to CHD declined by 40.3%. In an analysis of 46,086 hospitalizations for acute coronary syndrome (ACS), the percentage of MI cases with ST-segment elevation decreased from 48.5 to 24% between 1999 and 2008 [2] . Over the last decade, in-hospital acute MI (AMI) mortality rates declined for every age/sex group except for males aged 70% STR on ECG at 90-min post-PCI)
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Review Ganjehei, Rashid, Payami & Saal compared with 54% in the nitroprusside and 51% in the saline groups (p = 0.009 and 0.75, respectively, vs saline). Angiographic MVO occurred in 18% of the adenosine group compared with 24% of the nitroprusside and 30% of the saline groups (p = 0.06 and 0.37, respectively, vs saline). MACEs occurred in 10% of the adenosine, 14% of the nitroprusside and 20% of the control patients (p = 0.08 and 0.29, respectively, vs saline). The study concluded that, in patients with STEMI treated by PCI and TA, the additional intracoronary administration of adenosine but not nitroprusside resulted in a significant improvement in MVO, as assessed by STR, compared with saline treatment. One recently concluded small, randomized, placebocontrolled trial studied intracoronary adenosine versus placebo in 70 AMI patients undergoing PCI [23] . Improvements in clinical outcome were significant in the adenosine group compared with placebo as evidenced by the resolution of ST segment (p < 0.01) and MBG 3 (p ≤ 0.05). TIMI3 flow following PCI showed borderline improvements in the adenosine group versus placebo. A composite end-point of death, recurrent MI, HF and target vessel revascularization at the 1-year follow-up was significantly lower in the adenosine group compared with placebo (p ≤ 0.05). Pretreatment with nitrites
Siddiqi et al. studied the effects of sodium nitrite on reducing myocardial injury on 229 STEMI patients in comparison with placebo in a randomized safety/efficacy trial [24] . A total of 70 μM of sodium nitrite injected 5 min prior to pPCI showed no difference in infarct size (by cardiac magnetic resonance [CMR]) between the treatment and placebo groups at 6–8 days (effect size: -0.7%; 95% CI: -2.2–0.7; p = 0.34) and 6 months after the injection. Other potential therapies of note that may have cardioprotective effects and could increase myocardial salvage include the incretin hormone (GLP-1), sitagliptin, FX06, melatonin, glucose, insulin, potassium (as the glucose–insulin–potassium [GIK] combination) combination therapy, KAI-9803 and therapeutic hypothermia. The incretin effect
GLP-1 (an incretin hormone), is released in the gut and causes an amplification of insulin activity in response to nutrients when given orally,
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but not intravenously [25] . GLP-1 is seen to have a cardioprotective effect via its effects on changes in blood pressure, endothelial function, body weight, cardiac metabolism, lipid metabolism, LV function and atherosclerosis, as well as its response (increased levels) to ischemia-driven reperfusion injury [26] . The most recent evidence of the role of GLP-1 (exenatide) in reducing reperfusion injury in pPCI STEMI patients was provided by Lonborg and colleagues [27] . A total of 172 STEMI patients (TIMI flow 0/1) were randomized to either intravenous exenatide or placebo. CMR showed that patients in the exenatide group exhibited significantly higher myocardial salvage indices compared with the placebo group (0.71 ± 0.13 vs 0.62 ± 0.16; p = 0.003). Infarct size in relation to area at risk was also smaller in the exenatide group compared with the placebo group (0.30 ± 0.15 vs 0.39 ± 0.15; p = 0.003). A post hoc analysis of the same study stratified the patients according to median system delay (132 min) [28] . The results showed that short system delay in the exenatide group was associated with a 30% reduction in final infarct size, whereas the cardioprotective effect of exenatide was not seen in patients with long system delay. Another incretin-related compound, sitagliptin, competitively inhibits the enzyme DPP-4. This enzyme breaks down the incretin GLP-1. Sitagliptin therefore prevents this breakdown of GLP-1 and is able to increase the secretion of insulin, as well the suppression of glucagon from the pancreas. In addition to its hypoglycemic effect, sitagliptin is also observed to have cardioprotective effects through lowering blood pressure, improving lipemia, reducing inflammatory markers and oxidative stress, improving endothelial function and reducing platelet aggregation [29] . With respect to its CV outcomes, sitagliptin is currently being evaluated in the TECOS study (NCT00790205). FX06
FX06 is a novel, naturally occurring small peptide derived from the human fibrin sequence. FX06 has been shown to reduce reperfusion injury and thereby reduce infarct size in animal models [30] . Its cardioprotective effect on humans was assessed in the F.I.R.E. study [31] . In this study, 234 pPCI STEMI patients were randomized to either an intravenous bolus of FX06 or placebo at the time of reperfusion. Infarct size was assessed via the measurement of the necrotic core zone and by LGE cardiac
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ST elevation myocardial infarction: recent advances & updates magnetic resonance imaging (CMR) at 5 days and 4 months following MI. On day 5, no significant difference in LGE zone was seen between the two groups (p = 0.207); however, the necrotic core zone was significantly reduced in the FX06 group compared with placebo (-58%; p < 0.025). By 4 months, the difference in scar sizes was no longer significant. MVO was present in 27.6% of the FX06 patients compared with 37.5% of the placebo group patients (p = 0.093). A post hoc analysis looked into the impact of time to therapy in the same cohort of the F.I.R.E study, stratified according to presentation status and the presence or absence of collaterals [32] . The esults showed no correlation of time to therapy with infarct size at 5–7 days post-MI; however, at 4 months, a significant reduction in infarct size was seen, as assessed by both LGE (0.3 vs 2.4%; p = 0.038) and necrotic core zone (8.0 vs 16%; p = 0.032) in patients who presented early (75 years of age group during the trial, and therefore an amendment to the trial was instated. After this amendment, this particular patient group received half the original bolus dose of tenecteplase and the rate of intracranial hemorrhage came down to 0.5%
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in the fibrinolysis group versus 0.3% in the pPCI group (p = 0.45). No difference in nonintracranial bleeding was found between the two groups. The results of the STREAM trial suggest a clinical model to follow during STEMI. If diagnosed in the field and with no PCI-equipped facility nearby, one should administer full-dose fibrinolysis with consideration of a half dose in patients who are >75 years of age, followed by transfer to a PCI hospital. For STEMI patients diagnosed in the field with a PCI hospital nearby, pPCI is the appropriate option. Follow-up 1-year mortality data from the STREAM trial were presented in the AHA 2013 conference, showing that STEMI patients randomized to be treated with either a pharmacoinvasive approach (bolus tenecteplase, clopidogrel and enoxaprin) or pPCI demonstrated no significant differences in all-cause death (6.7 vs 5.9%; p = 0.52) and cardiac death (4 vs 4.1%; p = 0.93) at the 1-year follow-up and the pharmacoinvasive approach was rendered as effective as pPCI with regards to the 1-year mortality outcome [95] . The mechanisms of action of various pharmacological agents along the coagulation pathway are depicted in Figure 1. ●●Devices
PCI is now the recommended method of mechanical reperfusion in STEMI and is preferred over thrombolysis when available. The choices for PCI have evolved rapidly over the last decade or so. Simple balloon angioplasty was replaced by BMSs, and restenosis complications secondary to neointimal formation paved way for drug-eluting stents (DESs). The idea behind DESs is for them to deliver an antiproliferative/antineoplastic agent in a sustained fashion over time into the lumen in order to prevent neointimal formation while maintaining the patency of the lumen, thereby reducing the risk of restenosis. However, clinical and epidemiological evidence suggests that DESs have been associated with very late (3–5 years) stent thrombosis [96] . A meta-analysis of 15 randomized controlled trials of 7867 STEMI patients compared first-generation DESs with BMSs [97] . The results showed that the risk of stent thrombosis with DESs revealed a variation over time (RR in the first year: 0.80, 95% CI: 0.58–1.12; RR in subsequent years: 2.10, 95% CI: 1.20–3.69). The interaction between the RR of stent thrombosis and time was found to be positive (p = 0.009 for the interaction).
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Extrinsic pathway (tissue injury)
Intrinsic pathway (surface contact)
Rivaroxaban
XIIa
XII
Plaque rupture (collagen)
Aspirin
Fondaparinux XI
XIa
IX
ADP Clopidogrel Prasugel Ticagrelor Cangrelor
Tissue factor
Xa
X
Platelet activation Bivalirudin
ATIII Prothrombin (II)
Heparin LMWH
VII TXA2
IXa
X Heparin LMWH
VIIa
ATIII
Abciximab Eptifibatide Tirofiban
Thrombin (IIa)
ATIII
Platelet aggregation Fibrinogen (I)
Fibrinolytics
Fibrin (Ia)
XIIIa
XIII
Thrombus stable clot
Figure 1. Pharmacological reperfusion: mechanisms of action of pharmacological agents along coagulation pathway.
The results were similar for definite or probable stent thrombosis (p = 0.015 for the interaction). The need for target vessel revascularization was less frequent in DESs versus BMSs (RR: 0.51; 95% CI: 0.43–0.61). Further analysis revealed a trend towards greater benefit during the first year (RR: 0.46; 95% CI: 0.38–0.55) compared with subsequent years (RR: 0.75; 95% CI: 0.59–0.94; p = 0.007 for the interaction). Another recent meta-analysis of seven randomized trials showed that sirolimus-eluting stents (SESs) at a median follow-up of 3 years significantly reduced the risk of target vessel revascularization without increasing mortality, reinfarction and early-to-late stent thrombosis as compared with BMSs [98] . However, following the first year, SESs failed to further reduce target vessel revascularization (OR: 1.06; 95% CI: 0.64–1.74; p = 0.83) and also raised the risk of very late stent thrombosis (OR: 2.81; 95% CI: 1.33–5.92; p = 0.007).
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Stents eluting everolimus from a permanent polymer have been shown to significantly reduce stent thrombosis, target vessel revascularization and MI compared with stents not eluting everolimus (i.e., eluting paclitaxel/sirolimus instead) in a meta-analysis of 13 randomized trials with a mean follow-up of 22 months [99] . Sawada and colleagues studied arterial healing responses for the first time in STEMI patients who received either everolimus-eluting stents (EESs) or SES [100] . At 7 months, optical coherence tomography showed considerable suppression of neointimal proliferation in target lesions in both EES and SES groups; however, the EES group showed greater neointimal thickness compared with the SES group (94.8 ± 88.8 μm vs 65.6 ± 63.3 μm; p ≤ 0.0001). Furthermore, the EES group compared with the SES group significantly less frequently left uncovered struts (2.7 vs 15.7%; p ≤ 0.0001) and malapposed struts (0.7 vs 2.3%; p ≤ 0.0001) and the incidence rate of intrastent
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ST elevation myocardial infarction: recent advances & updates thrombosis in EESs was lower than with SESs (22.7 vs 63.6%; p = 0.05). DESs are composed of three parts: the stent platform (usually a metal alloy frame), the coating (usually a polymer that holds and elutes the drug) and the drug. Second-generation DESs have evolved from improvemens in all of the components of the stent structure. Contemporary alloys, polymer coatings with better biocompatibility, the use of polymer coatings that are biodegradable and the development of antineoplastic drugs that are less toxic may address the short- and long-term safety issues that were seen with BMSs and first-generation DESs. A meta-analysis of second-generation DESs with biodegradable polymers showed not only better safety, but also better efficacy compared with durable polymer SESs over a follow-up of up to 4 years [101] . Notably, the risk of very late stent thrombosis was lower with biodegradable polymer DESs compared with durable polymer SESs (HR: 0.22; 95% CI: 0.08–0.61; p = 0.004). A recent study conducted on everolimus-eluting bioresorbable vascular scaffolds showed for the first time that such a stent may be safe, particularly in STEMI patients [102] . The 53 ± 45.9 day follow-up showed no MACEs, as well as no acute or subacute stent thromboses. By nature of their design, biodegradable polymers seem to not only protect against early stent thrombosis, but also appear to negate late prothrombotic and proinflammatory complications [103,104] . In cases of in-stent restenosis, drug-eluting balloons (DEBs) have been the focus of attention as a potential optimal treatment strategy. A recent meta-analysis of five randomized trials (n = 801 patients, comparing DEBs with either balloon angioplasty or DESs as controls) showed that DEBs reduce the risk of MACEs compared with control treatment (RR: 0.46; 95% CI: 0.31–0.70; p < 0.001) [105] . Further analysis showed that DEB treatment compared with control treatment also carried a lower risk for target lesion revascularization (p = 0.006) and in-segment restenosis (p ≤ 0.001). The risk of stent thrombosis, however, did not show any difference between the two groups (p = 0.891). The ZEUS trial studied the comparison of DESs and BMSs in a unique set of patients with high bleeding and thrombosis, but low restenosis risk [106] . In this trial, 1606 patients were randomized to either Endeavor zotarolimuseluting stents (ZESs) or BMSs and were given customized dual antiplatelet therapy based on
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clinical risk, irrespective of the type of stent placement. In totoal, 52% of high-bleeding-risk patients received dual antiplatelet therapy for 30 days, 17% of high-thrombotic-risk patients received the therapy for 6 months and 31% of low-restenosis-risk patients received the therapy for 30 days if there was the presence of stable coronary artery disease or 6 months if there was the presence of ACS. The results showed fewer MACEs in the ZES group compared with the BMS group (17.5 vs 22.1%; p = 0.011), suggesting the Endeavor ZES to be the possible stent of choice in patients who are either intolerant or refuse long-term dual antiplatelet therapy. Recent studies comparing various stents in STEMI patients are summarized in Table 1. Vascular access: femoral versus radial PCI PCI is the primary treatment of choice in STEMI and leads to significantly better clinical outcomes. However, bleeding remains a major concern and may hamper an otherwise successful procedure. In addition to finding safer pharmacological thrombolytic therapies, there has also been a focus on accessing the coronary system via extrafemoral routes, with the most notable among these being radial artery access. An alternative access site such as the radial artery may ultimately lead to reduced vascular complications through reductions in bleeding and is regarded to be a safe technique. Several meta-analyses have supported the preferential use of radial access in STEMI PCI, as evidenced by lower bleeding complications and improved clinical outcomes [120–124] . The most recent meta-analysis covered the literature from 1990 to 2012 and included both randomized (n = 15) and nonrandomized trials (n = 15) comparing radial (n = 10,052) with femoral access (n = 19,142) in STEMI PCI patients [125] . The final analysis demonstrated a significant reduction in the primary end point (short-term [30-day] mortality) for the radial compared with the femoral approach (5.2 vs 10.3%; OR: 0.55; 95% CI: 0.40–0.76; p < 0.001; p for heterogeneity = 0.97). The differences remained significant in both randomized trials and observational studies (p < 0.001). Similarly, a significant reduction in major bleeding complications was seen with the radial approach as compared with the femoral approach (1.9 vs 4.7%; OR: 0.38; 95% CI: 0.31–0.47; p < 0.0001; p het = 0.17). The difference again remained significant in both randomized trials (p < 0.001) and observational
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Prospective registry analysis
Randomized, multicenter, all-comer, noninferiority trial
Velders et al. – (2013)
Christiansen SORT-OUT V et al. (2013)
Future Cardiol. (2014) 10(5)
Abluminal biodegradable polymer BES vs durable polymer EES (COMPARE II)
Effect of BES with biodegradable polymer vs BMS on cardiovascular events among patients with acute myocardial infarction (COMFORTABLE AMI) EES vs BMS in STEMI Multicenter, (EXAMINATION) prospective, randomized controlled trial
Smits et al. (2013)
Raber et al. (2012)
STEMI
1498
1161
2707
2468
931
EES vs BMS
Biodegradable polymer BES vs BMS
Biodegradable polymer BES vs durable polymer EES
Biodegradable polymer BES vs permanent polymer SES
EES vs E-ZES
1.6–3.1 years
F/up
Combination of all-cause death, any recurrent MI and any revascularization
MACEs, composite of cardiac death, target vessel reinfarction and TLR
1 year
1 year
Composite of safety 9 months–1 year (cardiac death, MI and definite stent thrombosis) and efficacy (TVR) Composite of safety 1 year (cardiac death and nonfatal MI) and efficacy (TVR)
Composite of cardiac death, target vessel-related MI and TLR
End point/ outcome
Ref.
EES vs BMS: primary end point: 11.9 vs 14.2% (difference -2.34%; 95% CI: -5.75–1.07; p = 0.19); definite stent thrombosis: 0.5 vs 1.9% (p = 0.019); definite or probable stent thrombosis: 0.9 vs 2.5% (p = 0.019)
BES vs BMS: MACE at 1 year: 4.3 vs 8.7% (HR: 0.49; 95% CI: 0.30–0.80; p = 0.004); definite stent thrombosis: 0.9 vs 2.1% (HR: 0.42; 95% CI: 0.15–1.19; p = 0.1)
[111]
[110]
EES vs E-ZES: primary [107] end point: 9.7 vs 13.7% (HR: 0.64; 95% CI: 0.42–0.99); definite stent thrombosis: 1.1 vs 1.9% (p = 0.19) BES vs SES: primary end [108] point: 4.1 vs 3.1% (p = 0.06 for noninferiority); stent thrombosis at 1 year: 0.7 vs 0.2% (p = 0.034) BES vs EES: primary [109] end point: 5.2 vs 4.8% (RR: 1.07; 95% CI: 0.75–1.52; p = 0.0001 for noninferiority)
Results
ACS: Acute coronary syndrome; BA: Balloon angioplasty; BAS: Bioactive stent; BES: Biolimus-eluting stent; BMS: Bare metal stent; CAD: Coronary artery disease; DES: Drug-eluting stent; EES: Everolimus-eluting stent; E-ZES: Endeavor® zotarolimus-eluting stent; F/up: Follow-up; HR: Hazard ratio; MACE: Major adverse coronary event; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PEB: Paclitaxel-eluting balloon; PES: Paclitaxel-eluting stent; RR: Risk ratio; SES: Sirolimus-eluting stent; STEMI: ST elevation myocardial infarction; TIMI: Thrombolysis in myocardial infarction; TLR: Target lesion revascularization; TVF: Target vessel failure; TVR: Target vessel revascularization; ZES: Zotarolimus-eluting stent.
Sabate et al. (2012)
STEMI
Eligible dubjects Subjects Device(s) (n) studied
Stable CAD, ACS, at least one coronary artery lesion (>50% stenosis) Open-label, PCI patients prospective, (age >18 years, randomized, life expectancy controlled, >5 years, noninferiority trial reference vessel diameter 2.0–4.0 mm, willingness for 5-year F/up) Prospective, STEMI randomized, single-blinded, controlled trial
Study design
Study (year) Parent study
Table 1. Recent studies comparing intracoronary stents in ST elevation myocardial infarction patients.
Review Ganjehei, Rashid, Payami & Saal
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future science group
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STEMI
Prospective, STEMI randomized study
Prospective, randomized noninferiority study
STEMI
STEMI
433
827
425
2665
End point/ outcome
F/up
Polyethylene terephthalate micronet mesh stent (MGuard™) vs conventional stents (DESs/BMSs)
BAS vs EES
Titaniumnitride-oxidecoated BAS vs PES 1 year
5 years
Rate of complete 60–90 min post(≥70%) ST-segment PCI resolution
MACEs, composite of cardiac death, recurrent MI or ischemia-induced TLR Composite of cardiac death, nonfatal MI or ischemia-driven TLR
EES vs BMS; BES Device-oriented 1 year vs BMS composite of cardiac death, target vessel reinfarction and TLR; patient-oriented composite of death, reinfarction and any revascularization
Eligible dubjects Subjects Device(s) (n) studied
Ref.
DES vs BMS: device[112] oriented composite (RR: 0.58; 95% CI: 0.43–0.79; p = 0.0004); patientoriented composite (RR: 0.78; 95% CI: 0.63–0.96; p = 0.02); acute definite stent thrombosis (RR: 0.38, 95% CI: 0.17–0.85; p = 0.02); 1-year definite stent thrombosis (RR 0.35; 95% CI: 0.16–0.75; p = 0.006) BAS vs PES: primary [113] end point: 16.4 vs 25.1% (p = 0.03); definite stent thrombosis: 0.9 vs 7.1% (p = 0.001) BAS vs EES: primary [114] end point: 9.6 vs 9.0% (HR: 1.04; 95% CI: 0.81–1.32; p = 0.81 and p = 0.001 for noninferiority); nonfatal MI: 2.2 vs 5.9% (p = 0.007) MGuard vs DES/BMS: [115] ST-segment resolution: 57.8 vs 44.7% (difference: 13.2%; 95% CI: 3.1–23.3%; p = 0.008); TIMI 3 flow: 91.7 vs 82.9% (p = 0.006)
Results
ACS: Acute coronary syndrome; BA: Balloon angioplasty; BAS: Bioactive stent; BES: Biolimus-eluting stent; BMS: Bare metal stent; CAD: Coronary artery disease; DES: Drug-eluting stent; EES: Everolimus-eluting stent; E-ZES: Endeavor® zotarolimus-eluting stent; F/up: Follow-up; HR: Hazard ratio; MACE: Major adverse coronary event; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PEB: Paclitaxel-eluting balloon; PES: Paclitaxel-eluting stent; RR: Risk ratio; SES: Sirolimus-eluting stent; STEMI: ST elevation myocardial infarction; TIMI: Thrombolysis in myocardial infarction; TLR: Target lesion revascularization; TVF: Target vessel failure; TVR: Target vessel revascularization; ZES: Zotarolimus-eluting stent.
MASTER
BASE-ACS
Karjalainen et al. (2012)
Stone et al. (2012)
TITAX-AMI
Tuomainen et al. (2012)
Randomized controlled trial
EXAMINATION and Pooled analysis COMFORTABLE-AMI
Study design
Sabate et al. (2012)
Study (year) Parent study
Table 1. Recent studies comparing intracoronary stents in ST elevation myocardial infarction patients (cont.).
ST elevation myocardial infarction: recent advances & updates
Review
647
648
SORT-OUT VI
DUTCH PEERS (TWENTE II)
SORT-OUT VI (2013)
TWENTE II (2013)
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402
Chronic, stable 2999 CAD or ACS patients with at least one coronary leasion of ≥50% stenosis PCI patients with 1811 DES implantation
Patients aged >18 years with restenosis of ≥50% post-DES implantation
1707
Cobalt chromium ZES vs platinum chromium EES
Permanent polymer ZES vs biodegradable BES
F/up
Composite TVF (cardiac death, TVR and MI)
1 year
MACEs (composite 12 months of cardiac death, MI and TLR)
6–8 months
MACEs (composite Up to 5 years of cardiac death, MI and TVR)
PEB vs PES vs BA Diameter stenosis at F/up angiography
Biodegradable polymer BES vs durable polymer SES
End point/ outcome
ZES vs EES; TVF: 6.1 vs 5.2% (p = 0.006 inferiority); definite or probable stent thrombosis: 0.6 vs 0.9% (p = 0.4)
BES vs SES: MACEs: 18.7 vs 22.6% (p = 0.05); definite stent thrombosis: RR: 0.62 (p = 0.09); very late definite stent thrombosis: RR: 0.20 (p = 0.004) PEB vs PES: primary end point: 38.0 vs 37.4% (p = 0.007 for noninferiority); PEB and PES vs BA: primary end point: p ≤ 0.0001 for superiority for both comparisons ZES vs BES: MACEs: 5.3 vs 5.1% (p = 0.006 for noninferiority)
Results
ACS: Acute coronary syndrome; BA: Balloon angioplasty; BAS: Bioactive stent; BES: Biolimus-eluting stent; BMS: Bare metal stent; CAD: Coronary artery disease; DES: Drug-eluting stent; EES: Everolimus-eluting stent; E-ZES: Endeavor® zotarolimus-eluting stent; F/up: Follow-up; HR: Hazard ratio; MACE: Major adverse coronary event; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PEB: Paclitaxel-eluting balloon; PES: Paclitaxel-eluting stent; RR: Risk ratio; SES: Sirolimus-eluting stent; STEMI: ST elevation myocardial infarction; TIMI: Thrombolysis in myocardial infarction; TLR: Target lesion revascularization; TVF: Target vessel failure; TVR: Target vessel revascularization; ZES: Zotarolimus-eluting stent.
Multicenter, prospective, single-blinded, randomized controlled trial
Prospective, randomized, allcomer trial
PEBs, PESs and BA Randomized, in patients with open-label trial restenosis after implantation of a DES (ISAR-DESIRE 3)
Byrne et al. (2013)
Multicenter, All-comers, real all-comer, world patients randomized, assessor-blind noninferiority trial
Serruys et al. LEADERS (2012)
Eligible dubjects Subjects Device(s) (n) studied
Study design
Study (year) Parent study
Table 1. Recent studies comparing intracoronary stents in ST elevation myocardial infarction patients (cont.).
[119]
[118]
[117]
[116]
Ref.
Review Ganjehei, Rashid, Payami & Saal
future science group
ST elevation myocardial infarction: recent advances & updates studies (p < 0.0001). The analysis concluded radial approach to be associated with reductions in mortality and bleeding complications. RIFLE-STEACS was a randomized, multicenter trial from Europe that compared transradial with transfemoral access for the prediction of better clinical outcomes [126] . The trial was conducted in four centers with high-volume operators (>150 PCIs/year). A randomized cohort of 1001 STEMI patients at 30 days showed that the primary end point of NACEs (composite of cardiac death, stroke, MI, target lesion revascularization and bleeding) occurred in 13.6% of patients in the radial arm compared with 21% in the femoral arm (p = 0.003). Radial access was also found to be associated with significantly lower rates of cardiac death (5.2 vs 9.2%; p = 0.020) and bleeding (7.8 vs 12.2%; p = 0.026) and shorter hospital stays (p = 0.03) compared with femoral access. The reduction in bleeding was predominantly attributed to reductions in access site bleeds (47%). The STEMI-R ADI A L trial assessed 707 STEMI patients undergoing pPCI, who were randomized to femoral or radial access PCI [127] . Only high-volume radialists (>200 PCIs/year) were included in the study. The results showed that 58% fewer 30-day NACEs (MACEs plus major bleeding) occurred in the radial arm compared with the femoral arm (4.6 vs 11.0%; p = 0.0028). However, the difference in MACEs alone was not significant (3.5% in the radial arm vs 4.2% in the femoral arm; p = 0.7). The rates of 30-day bleeding and access site complications were 80% lower in patients with radial PCI compared with femoral PCI (1.4 vs 7.2%; p = 0.0001). Furthermore, a lower contrast volume had to be used with radial access, and lengths of stay in the intensive care unit were shorter (2.5 days for the radial access group vs 3.0 days for the femoral access group; p = 0.0016). The overall mortality rates were 2.3 and 3.1% in the radial and femoral arms, respectively; this was not statistically significant, which was attributed to the study being underpowered for death. The study researchers concluded that a significant net clinical benefit in STEMI radial access PCI patients was most pronounced in patients who presented within 12 h. The evidence so far suggests that the radial approach to PCI improves clinical outcomes, reduces bleeding complications, increases patient comfort and reduces the length of stay in hospital. However, most of these effects are more
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pronounced when this procedure is carried out in high-volume centers and is directly related to the operator’s experience. A more widespread use of this access site for PCI and more operator experience over time may cause this procedure to become a default access site in future. Diagnostic updates A substudy of TRITON TIMI 38 trial [128] analyzed a subpopulation of ACS patients from the parent trial [129] , who presented with isolated anterior (V1–V4) ST-segment depression (1198/13,608) as documented by 12-lead ECG. All of these patients underwent angiograms, and the study investigators were able to assess the angiographic as well as the clinical outcomes in the said patient population. Further breakdown of the 1198 patients revealed that 26.2% of them actually had an occluded culprit artery (TIMI flow grade 0/1) and positive troponin marker, now diagnosed as STEMI. The rest of the patient population had a patent culprit artery (TIMI flow grade 2/3 for both), with positive troponin (53.5%) and negative troponin (20.3%) now classified as non-STEMI and unstable angina, respectively. Of the patients with occluded culprit arteries, the left circumflex artery was most commonly implicated (48.4%), followed by the left anterior descending (33.8%) and the right coronary arteries (17.8%). At the 30-day followup, the composite of death and MI was found to be significantly higher in occluded artery patients (8.6%) compared with those with marker-positive patent culprit arteries (6.3%) and marker-negative patent culprit arteryies (three-way p = 0.006). The ECG-to-PCI time for the occluded artery patients was 29.4 h, meaning fewer patients in this category went through urgent catheterization, which might explain the worse clinical outcome. The questionable sensitivity of 12-lead ECG in diagnosing anterior segment depression ACS led to the idea of considering all anterior ST-segment depression patients as having STEMI and treating them accordingly. Although not new, one possible approach is the use of the 80-lead or PRIME® (Verathon Inc., WA, USA) ECG vest in order to enhance the sensitivity of ECG diagnosis. Its outcome is displayed as a vector and gives a 360° view of the electrical activity of heart. The additional electrodes enhance the ability to find the suspected ST-segment vector and classify it as an AMI. The 80-lead ECG was approved for use by the FDA in 2002. The OCCULT-MI trial showed
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Review Ganjehei, Rashid, Payami & Saal that, in patients without ST elevation on 12-lead ECG, an 80-lead ECG diagnosed more patients with MI (sensitivity: 19.4 vs 10.7%, p = 0.0014; specificity: 93.9 vs 96.4%, p = 0.0005) or ACS (sensitivity: 12.3 vs 7.1%, p = 0.0025; specificity: 93.7 vs 96.4%, p = 0.0005) compared with 12-lead ECG [130] . Despite the significant sensitivity advantage of 80-lead over 12-lead ECG, the cost–effectiveness also needs some consideration. While a more traditional 12-lead ECG costs approximately 35 cents, the 80-lead ECG vest costs approximately US$80 and is not reusable. Another plausible alternative for improving ACS diagnosis is to enhance the sensitivity of 12-lead ECG by adding leads V7, V8 and V9, thereby expanding the selection of patients requiring timely reperfusion [131,132] . Stem cell therapy Despite of all the advances and efforts in minimizing myocardial damage following STEMI, even ideal management leaves at least some sort of irreversible damage to the myocardial tissue, that may lead to HF. Efforts to regenerate the lost tissue are currently underway and have met with conflicting results so far. The majority of the clinical trials have employed autologous bone marrow stem cells for this purpose, anticipating an improvement in cardiac function and consequently lower morbidity and mortality. The main focus of stem cell therapy is to prevent or reverse the remodeling of the LV following ischemic episodes. A meta-analysis of 33 randomized controlled trials conducted on 1765 subjects treated with bone marrow cell (BMC) therapy found no significant improvement in mortality (RR: 0.70; 95% CI: 0.40–1.21) or morbidity (reinfarction: RR: 0.67, 95% CI: 0.40–1.13; hospital readmission: RR: 0.87, 95% CI: 0.56–1.35); restenosis: RR: 0.90, 95% CI: 0.61–1.31; or target vessel revascularization: RR: 0.83, 95% CI: 0.62–1.11) when compared with placebo [133] . Short-term follow-up analysis, however, did reveal a significant improvement in LVEF in the treatment group (weighted mean difference: 2.87; 95% CI: 2.00–3.73) that was maintained for 12–61 months (weighted mean difference: 3.75; 95% CI: 2.57–4.93), along with significant improvement in LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV) and infarct size over long-term follow-up in some studies. A positive correlation was also observed between the dose and timing of treatment and the effect on LVEF.
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Another recently concluded meta-analysis showed that intracoronary BMC therapy compared with controls led to a significant improvement in LVEF (2.23%; p ≤ 0.001) and LVESV (-4.81 ml; p ≤ 0.001) at 6 months and maintained this effect at the 12-month followup (LVEF change: 1.90%; LVESV: -9.41 ml; p < 0.001 for both). The effects on LVEDV and infarct size, however, remained inconclusive [134] . The analysis also showed that the BMC-treated group showed a statistically significant reduction in recurrent AMI (RR: 0.44; 95% CI: 0.24– 0.79; p = 0.007) and readmission for HF, unstable angina or chest pain (RR: 0.59; 95% CI: 0.35–0.98; p = 0.04). Intracoronary BMC therapy was concluded to demonstrate moderate improvements in LVEF, as well as reductions in LVESV both at the 6- and 12-month follow-up. LVEDV and infarct size, however, did not show any improvement. The results of late-breaking stem cell trials, presented at the Scientific Sessions of the AHA 2012 and 2013 conferences, showed mixed results. The SCIPIO trial was a Phase I trial in which 18 post-MI patients with LVEF 75th High plasma sMAC is an percentile): all-cause mortality, HR: 1.81 independent predictor of all-cause (95% CI: 1.06–3.06; p = 0.029); MACEs, mortality and MACEs in STEMI PCI HR: 1.70 (95% CI: 1.16–2.48; p = 0.006) patients. Cut-off level of sMAC >75th percentile miR-133a ≥ median vs miR-133a Median miR-133a concentration: < median group: MACEs, 20 vs 9% 33.4; miR-133a adds prognostic (p = 0.025); CMR markers: infarct size value to STEMI patients, but not (p < 0.001), MVO (p < 0.001), myocardial independently beyond CMR salvage index (p < 0.001) markers of clinical prognosis LVEF < MPV vs LVEF > 50% MPV: ↑MPV, troponin I and WBC count 9.5 ± 1.1 fl vs 8.8 ± 0.8 fl (p = 0.001); on admission in anterior STEMI troponin I: 30 ± 29 ng/ml vs 12.2 ± 15.1 patients undergoing PCI is ng/ml (p = 0.001); WBC count: 12.3 ± associated with impaired LV systolic 3.8 ×109/l vs 10.6 ± 3.4 ×109/l (p = 0.027) function
[149]
[148]
Ref.
[150]
hs-CRP independent predictor of F/u outcome in NSTEMI, but not STEMI patients, Cut-off level of hs-CRP: 1.1 mg/dl Fetuin-A in combination with CRP is associated with CV death in ACS patients
Comments
Significant association between ↑TB and adjusted in-hospital CV mortality risk following PCI. Cut-off level of TB >0.9 mg/dl
CV mortality: overall, 10%; ↓fetuin-A, 17%; ↑CRP, 18%; ↓fetuin-A plus ↑CRP, 23% (p < 0.01); neither ↓fetuin-A nor ↑CRP, 5% Multivariate: ↑TB (>0.9 mg/dl) and in-hospital CV mortality risk, OR: 3.24 (95% CI: 1.27–8.27; p = 0.014); long-term mortality, no difference between ↑TB and ↓TB groups ↑ vs ↓ Lp-PLA2: 30-day MACEs: 24.2 vs 3.0% (p = 0.001); logistic regression: Lp-PLA2 for MACEs, OR: 1.011 (95% CI: 1.001–1.013; p = 0.037)
Combination of hs-CRP NSTEMI (HR: 1.217; 95% CI: cardiac death and MI 1.093–1.356; p ≤ 0.001)
End point
↓: Decreased; ↑: Increased; ACS: Acute coronary syndrome; AUC: Area under curve; CAD: Coronary artery disease; CEM: Content of erythrocyte membrane; CHF: Congestive heart failure; CMR: Cardiac magnetic resonance; cMRI: Cardiac magnetic resonance imaging; CV: Cardiovascular; EDV: End-diastolic volume; eGFR: Estimated glomerular filtration rate; ESR: Erythrocyte sedimentation rate; F/u: Follow-up; GGT: γ-glutamyl transferase; GRACE: Global Registry of Acute Coronary Events; HF: Heart failure; HR: Hazard ratio; hs-CRP: High-sensitivity CRP; Lp-PLA2: Lipoprotein associated phospholipase A2; LV: Left ventricular; LVEDV: Left ventricular end-diastolic volume; LVEF: Left ventricular ejection fraction; MA: Microalbuminuria; MACE: Major adverse coronary event; MBG: Myocardial blush grade; MI: Myocardial infarction; MMP-9: Matrix metalloproteinase-9; MPO: Myeloperoxidase; MPV: Mean platelet volume; MV: Multivariate; MVO: Microvascular obstruction; NA: Normoalbuminuria; NGAL: Neutrophil gelatinase-associated lipocalin; NP: Natriuretic peptide; NSTEMI: Non-ST elevation myocardial infarction; OPG: Osteoprotegerin; OR: Odds ratio; PCI: Percutaneous coronary intervention; ROC: Receiver operating characteristic; RR: Relative risk; SA: Stable angina; sMAC: Soluble membrane attack complex; STEMI: ST elevation myocardial infarction; sTNFR: Soluble TNF receptor; STR: ST-segment resolution; TB: Total bilirubin; TIMI: Thrombolysis in myocardial infarction; TMPG: Thrombolysis in myocardial infarction myocardial perfusion grade; UAER: Urinary albumin extraction rate; WBC: White blood cell.
Anterior STEMI PCI (97)
STEMI PCI (725)
Lindberg sMAC et al. (2012)
30 days
STEMI PCI (1624) After PCI and 26.2 months (mean)
First anterior STEMI PCI (100)
TB
Stankovic Lp-PLA2 et al. (2012)
Gul et al. (2013)
ACS-STEMI (404), 1 year ACS-NSTEMI (350)
Fetuin-A
Lim et al. (2013)
19.8 months
ACS (151, 47% STEMI)
Raposeiras hs-CRP Roubin et al. (2013)
Follow-up
Patient population (n)
Marker
Study (year)
Table 3. Recent studies on biomarkers of prognostic value in ST elevation myocardial infarction patients.
Review Ganjehei, Rashid, Payami & Saal
future science group
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STEMI (73)
Kaya et al. (2012)
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MACEs (cardiac death, reinfarction, new angina, HF, revascularization) All-cause mortality, repeat MI, HF
Systolic dysfunction, death
Severity of CAD assessed by Gensini score
End point
Multivariate analysis: ↑MPO: MACEs, OR: 3.843 (95% CI: 1.625–6.563; p = 0.003)
CEM levels are positively correlated with severity of CAD
CEM levels ↑ in STEMI vs NSTEMI (p = 0.012) and SA (p < 0.001); NSTEMI vs SA (p < 0.001); CEM levels and severity of CAD by Gensini score: r = 0.714 (p < 0.001) IL-6+/IL-10+ vs IL-6 -/IL-10+ STEMI: systolic dysfunction at discharge: 36.1 vs 19.2% (p = 0.06); death at 6 months: 11.1 vs 0% (p = 0.0005)
27 months
↑ESR at admission independently correlated with worse long-term prognosis in STEMI F/u. Cut-off level of ESR ≥33 mm/h ↓miR-150 levels are associated with LV remodeling after STEMI. miR-150 (AUC: 0.74) is a better predictor of LV remodeling than pro-BNP (AUC: 0.60)
↑OPG levels independently correlate with worse long-term prognosis in STEMI F/u
STEMI patients with simultaneous ↑ of IL-6 and IL-10 show worse clinical outcomes compared with STEMI patients who do not have a simultaneous elevation ↑MPO levels independently correlate with worse prognosis at 2 years of STEMI F/u
Comments
Results
Multivariate analysis: ↑OPG: death, HR: 1.28 (95% CI: 1.03–1.59; p = 0.03); repeat MI, HR: 1.30 (95% CI: 1.00–1.68; p = 0.05); admission with HF, HR: 1.50 (95% CI: 1.18–1.90; p = 0.001) In-hospital and Myocardial perfusion Angiographic reperfusion: ↑ vs ↓ ESR: 1 year mean TIMI frame count: 25.5 ± 6.5 vs 20.4 ± 5.2 (p = 0.01); TMPG 0–2: 55 vs 29% (p = 0.01) Predischarge LV remodeling (↑ Patients with remodeling (ΔEDV >0) and 4–6 months in LVEDV between vs without remodeling (ΔEDV ≤0): discharge and F/u, miR-150 levels: twofold less (p = 0.03); ΔEDV >0) miR-150 reclassified 54% of patients misclassified by BNP (p = 0.03) and 59% misclassified by multiparameter clinical model (p = 0.02)
25 ± 16 months
At discharge and 6 months
Samples collected prior to angiography
Follow-up
[160]
[159]
[158]
[157]
[156]
[155]
Ref.
↓: Decreased; ↑: Increased; ACS: Acute coronary syndrome; AUC: Area under curve; CAD: Coronary artery disease; CEM: Content of erythrocyte membrane; CHF: Congestive heart failure; CMR: Cardiac magnetic resonance; cMRI: Cardiac magnetic resonance imaging; CV: Cardiovascular; EDV: End-diastolic volume; eGFR: Estimated glomerular filtration rate; ESR: Erythrocyte sedimentation rate; F/u: Follow-up; GGT: γ-glutamyl transferase; GRACE: Global Registry of Acute Coronary Events; HF: Heart failure; HR: Hazard ratio; hs-CRP: High-sensitivity CRP; Lp-PLA2: Lipoprotein associated phospholipase A2; LV: Left ventricular; LVEDV: Left ventricular end-diastolic volume; LVEF: Left ventricular ejection fraction; MA: Microalbuminuria; MACE: Major adverse coronary event; MBG: Myocardial blush grade; MI: Myocardial infarction; MMP-9: Matrix metalloproteinase-9; MPO: Myeloperoxidase; MPV: Mean platelet volume; MV: Multivariate; MVO: Microvascular obstruction; NA: Normoalbuminuria; NGAL: Neutrophil gelatinase-associated lipocalin; NP: Natriuretic peptide; NSTEMI: Non-ST elevation myocardial infarction; OPG: Osteoprotegerin; OR: Odds ratio; PCI: Percutaneous coronary intervention; ROC: Receiver operating characteristic; RR: Relative risk; SA: Stable angina; sMAC: Soluble membrane attack complex; STEMI: ST elevation myocardial infarction; sTNFR: Soluble TNF receptor; STR: ST-segment resolution; TB: Total bilirubin; TIMI: Thrombolysis in myocardial infarction; TMPG: Thrombolysis in myocardial infarction myocardial perfusion grade; UAER: Urinary albumin extraction rate; WBC: White blood cell.
STEMI (90)
STEMI PCI (140)
Fatih Ozlu ESR et al. (2012)
Devaux miR-150 et al. (2013)
STEMI PCI (716)
Pedersen OPG et al. (2012)
MPO
STEMI (109)
Ammirati IL-6+, IL-6 -, IL-10+ et al. (2012) cytokines
Patient population (n)
STEMI, NSTEMI, SA (136)
Marker
Zhong Total cholesterol et al. (2012) CEM
Study (year)
Table 3. Recent studies on biomarkers of prognostic value in ST elevation myocardial infarction patients (cont.).
ST elevation myocardial infarction: recent advances & updates
Review
655
656
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STEMI PCI (80)
4–6 months
In-hospital
Multimarker risk score correlates with angiographic, ECG and CMR mechanistic markers of outcomes
↑serum GGT at admission independently predicts inhospital MACEs in STEMI patients undergoing PCI ↑YKL-40 and leukocyte count independently predict inhospital MACEs in STEMI patients undergoing PCI
↓eGFR
