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Challenges and unanswered questions in STEMI management
Accepted Manuscript Challenges and unanswered questions in STEMI management Athanasios Koutsoukis, Ioannis Kanakakis PII:
S1109-9666(18)30536-0
DOI:
https://doi.org/10.1016/j.hjc.2019.01.001
Reference:
HJC 371
To appear in:
Hellenic Journal of Cardiology
Received Date: 11 November 2018 Revised Date:
23 December 2018
Accepted Date: 3 January 2019
Please cite this article as: Koutsoukis A, Kanakakis I, Challenges and unanswered questions in STEMI management, Hellenic Journal of Cardiology, https://doi.org/10.1016/j.hjc.2019.01.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title : Challenges and unanswered questions in STEMI management
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Authors : Athanasios Koutsoukis1, Ioannis Kanakakis1
1. Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece
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Corresponding author: Ioannis Kanakakis, [email protected]
Address : Department of Clinical Therapeutics, Alexandra Hospital,
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Leoforos Vasilissis Sofias 80,11528, Athens.
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Title:
Challenges and unanswered questions in STEMI management
Introduction
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Acute coronary syndromes (ACS) remain the first cause of mortality in developed countries despite the progress made over the last decades. Event though the recent SWEDEHEART registy has shown that mortality and morbidity have declined over the last three decades, this decline still doesn’t apply in situations such as cardiogenic shock or ACS with cardiopulmonary resuscitation that still have an unacceptably high mortality1.
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The recently published guidelines of the European Society of Cardiology, clearly indicate that primary percutaneous coronary intervention (pPCI) is the treatment of choice for STEMI patients
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within indicated time frames2. In these new guidelines, an upgraded recommendation is suggested regarding the use of drug-eluting stents over bare metal stents, complete revascularization, use of enoxaparin and early hospital discharge. On the other hand, thrombus aspiration and bivalirudin utilization, were downgraded. Despite these advances in STEMI management, several challenges and
1. Time limitations in pPCI
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important areas of uncertainty exist. This review will address several of these issues.
The majority of STEMI patients who die from cardiac arrest, die at the very early stages of myocardial infarction, usually before arriving to the hospital3. The need for rapid access to emergency medical care remains a major problem. The majority of time loss occurs from the onset of symptoms to
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first medical contact (FMC). In the first published paper of the “Stent for life” (SFL) initiative, the median time from symptom onset to FMC (defined as the time of the diagnostic ECG) in different
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countries, ranged from 60 to 210 minutes 4. In Greece the same time interval (patient delay) varied between 142 and 125 minutes5. Public campaigns are needed in order to decrease patient delay. The SFL initiative launched a public awareness campaign some years ago with the following message: “You can SAVE A LIFE by knowing the signs of a heart attack and acting quickly to call emergency medical services, so that the best treatment can be received in the fastest possible time frame”. In a previous study, despite an 18-month intervention , time from symptom onset to hospital arrival did not differ between intervention and reference groups ,despite increased EMS use6.
ACCEPTED MANUSCRIPT Guidelines suggest that the time of STEMI diagnosis is the time zero to choose the reperfusion strategy. STEMI patients should undergo PCI if the anticipated delay from ECG diagnosis to reperfusion is <120 minutes. The selection of this time interval as the cut-off to choose PCI over fibrinolysis is based on old data coming from registries and trials with different designs in terms of cut-
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off point. The identification of the optimal cut-off point in order to choose the best reperfusion strategy, remains a challenge. Pinto et al showed that any mortality benefit of pPCI was lost when the time delay to pPCI was 114 minutes or more7. In 192.500 patients in the National Registry of Myocardial
infrarction, the reduction of pPCI benefit was associated with patient’s characteristics. For example, the benefit of pPCI was nullified for young patients with large anterior infarct with a delay >60 minutes
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and in older patients with non-anterior infarction and a delay>180 min7. The STREAM trial was designed with a cut-off point of 60 minutes. In this study, the pharmacoinvasive stategy had similar
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rates of death, shock, congestive heart failure or reinfarction at 30 days compared to pPCI, when applied in STEMI patients presenting early after symptom onset8.
According to the STEMI guidelines, time delay should be recorded as well as the proportion of patients receiving pPCI within the recommended times (ECG diagnosis to wire crossing of infarctrelated artety within 90 minutes or within 60 minutes when patients present directly to PCI-capable centers). These target delays are quality indicators and they differ from the time interval of 120 minutes
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which is useful in selecting pPCI over fibrinolysis2.
2. Reduction of myocardial infarct (MI) size
For STEMI patients, the most effective therapy for preventing heart failure and reducing MI size is
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timely reperfusion mainly by pPCI. Despite prompt reperfusion, a significant number of patients (about 10%) develop heart failure at one year post -MI. The negative effect of the “myocardial reperfusion
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injury” (RI) is the main target in the effort to reduce MI size. Several novel cardioprotective therapies such as the blockade of the mitochondrial permeability transition pore, therapeutic hypothermia, iv. metoprolol before pPCI, have shown promising results in MI size reduction9,10. In the METOCARD-CNIC study, early intravenous metopropol (15 mg) in patients with anterior STEMI and no signs of heart failure, resulted in smaller infarct size in CMR at 5-7 days (25.6 g vs 30 g, p= 0.012) and higher ejection fraction in 6 months (48.7% vs 45%, p= 0.018)11. The EARLYBAMI trial that included anterior and non-anterior infarcts, did not show metoprolol to reduce infarct size in CMR, however CMR was perfrormed in only half of the patients (55%)12.
ACCEPTED MANUSCRIPT Cyclosporine A inhibits the opening of the mitochondrial permeability transition pore and in early animal studies showed to decrease infarct size. However, in the CYCLE study, a single intravenous cyclosporine A bolus just before primary percutaneous coronary intervention had no effect on ST-segment resolution or hs-cTnT, and did not improve clinical outcomes or LV remodeling up to 6
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months13. The use of vasodilators has also been proposed as a measure to prevent RI. However, in the REFLO-STUDY, high-dose intracoronary adenosine and sodium nitroprusside failed to reduce MVO and MI size in a cohort of 247 reperfused STEMI patients14.
A patient-level pooled analysis of six randomized trials of endovascular cooling during primary
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PCI in STEMI, showed a significant reduction in infarct size in patients with anterior STEMI who were cooled to<35°C at the time of reperfusion15. The COOL-AMI EU trial, a multi-centered and
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randomized trial is running at the moment and will assess the role of hypothermia in the context of STEMI14. In the COOL-AMI EU pilot trial the presence of MVO was high and not different between hypothermia and control group (74% vs. 77%, p=0.79) as assessed by CMR in 4-6 days16. GP IIb/IIIa inhibitors may be useful in reducing no-reflow or thrombus burden as a bailout treatment, however they are not indicated as routine treatment in STEMI2. Deferred stenting has also been proposed as a mean to prevent MVO and reduce microvascular
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dysfuction post-MI. However in the DANAMI3-DEFER trial, routine deferred stenting was associated with a high risk of target vessel failure (TVR)17
The existing data suggest that efficient strategies to reduce reperfusion injury are still lacking
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prevent RI.
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and further studies are needed in this field. Table 1 presents of synopsis of studied treatments to
3. Management of cardiogenic shock Emergency revascularization is the mainstay treatment in cardiogenic shock. The latest ESC/EACTS Revascularization guidelines, no longer recommend complete revascularization in the setting of STEMI and multivessel disease complicated by cardiogenic shock18 .The CULPRIT-SHOCK trial showed a reduced 30 day risk of composite all cause mortality or renal failure with PCI of the culprit lesion only. This early benefit comes with the price of increases in repeat revascularization and
ACCEPTED MANUSCRIPT rehospitalization for congestive heart failure and no difference in all cause mortality in one year follow up19. The utility of mechanical circulatory support in the acute phase of cardiogenic shock still remains unanswered. The routine use of intra-aortic balloon counterpulsation is no longer indicated as the
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IABP-SHOCK II trial showed no benefit in 30 day mortality18. Data concerning the use of other percutaneous left ventricular assist devices are still insufficient to justify their routine use in this setting according to the latest european guidelines.
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4. Antithrombotic treatment
Anticoagulants and dual antiplatelet treatment (DAPT) are the main pharmacological therapy in
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STEMI. Despite major advances in this field, important issues remain unanswered:
a) What is the best time for the loading dose of oral P2Y12 inhibitors?
Pretreatment, defined as administration of the loading dose before assessment of coronary anatomy, provides stronger platelet inhibition at the time of PPCI, however the benefit from this strategy is still unclear. The previous and the recent STEMI guidelines recommend pretreatement with
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P2Y12 inhibitors, but the evidence from randomized control trials to support this strategy is weak2. There is no specific STEMI trial for clopidogrel and few patients were pre-treated with prasugrel in the TRITON-TIMI 38 trial20. The ATLANTIC trial (prehospital loading ticagrelor dose) was negative for the primary endpoint of ST segment resolution on ECG and TIMI 3 flow of the IRA (infarct-related
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artery) on angiography21.
The SWEDHEART registry, an observational, all comers-study, also evaluated ticagrelor
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pretreatment compared with treatment given in the catheterization laboratory in 7443 patients with STEMI. Overall no benefit of ticagrelor pretreatment was observed on a composite end point of mortality, myocardial infarction, and stent thrombosis at 30 days. Although there was a higher percentage of clopidogrel pretreament in the in-hospital ticagrelor population, results were the same after removing this population from the analysis22. A recent meta-analysis in nearly 10.000 STEMI patients examined the effect of early versus delayed P2Y12 inhibition. The “early strategy” was defined as administration of the P2Y12 inhibitors before arrival in the catheterisation laboratory, in comparison with the same drugs administered after
ACCEPTED MANUSCRIPT arrival in the catheterisation laboratory (delayed strategy) or administration in the catheterisation laboratory before PCI of rapidly acting P2Y12 inhibitors (i.e.,intravenous P2Y12 inhibitors or prasugrel or ticagrelor) in comparison with clopidogrel used in the control arm (delayed strategy). Early platelet inhibition with potent P2Y12 inhibitors versus delayed platelet inhibition by clopidogrel relative risk reduction of MI with no impact on mortality23.
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was associated with a significant 27 % relative risk reduction of MACE mainly driven by the 29%
These date suggest that adequate P2Y12 inhibition during pPCI should be regarded as a key element when deciding the type and the timing of antiplatelet therapy administered in STEMI24. Moreover, considering the incremental impact of FMC-to-PCI time delay on longterm mortality, patients with an
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expected FMC-to-PCI exceeding one hour, may have a greater benefit from early potent antiplatelet
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agent administration25.
b) What is the role of potent P2Y12 inhibitors in patients undergoing fibrinolysis? For patients undergoing fibrinolysis and subsequent PCI, clopidogrel is the P2Y12 inhibitor of choice, administered as a loading dose of 300 mg in patients <75 years old and without loading dose (75 mg/day) in patients >75 years2. Although potent P2Y12 inhibitors have not been properly tested in
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patients undergoing fibrinolysis, recent guidelines propose that in these patients clopidogrel can be switched to ticagrelor after 48h, which is an arbitrarily chosen time point, with a weak level of recommendation (IIbC)2. In the TREAT trial, patients that underwent thrombolysis were randomized to receive ticagrelor or clopidogrel as soon as possible and no longer that 24h. Median time to ticagrelor
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loading dose was 11 hours. 89% of the patients were pretreated with clopidogrel 300 mg before randomization. The trial showed that converting to ticagrelor late after initial exposure to clopidogrel
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in the context of thrombolysis, appears safe, as defined by a noninferior difference in major bleeding in 30 days26. However the question of concomitant use of ticagrelor with lytic therapy in the acute phase remains unanswered.
c) Triple or double therapy in Atrial fibrillation (AF) patients with STEMI and PCI ? Latest guidelines recommend that when a patient with non-valvular AF requires anticoagulation and antiplatelet treatment , a NOAC should be preferred over VKA18. The PIONEER trial and
ACCEPTED MANUSCRIPT the more recent RE-DUAL trial compared a NOAC plus single antiplatelet therapy with triple therapy with a VKA plus DAPT and consistently showed significantly lower bleeding risks with the dual antithrombotic regimen with no negative effect on the ischemic end-points. When dabigatran is used, the 150 mgx2 dose may be preferred over the lower dose (110mgx2) and when rivaroxaban is
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used the 15 mgx1 dose may be preferred over the 20 mg dose27.The ongoing AUGUSTUS and ENTRUST-AF-PCI trials investigate the role of apixaban and edoxaban respectively, in this clinical setting 28,29.
In the PIONNER and REDUAL trials only a small percentage of the patients involved was under ticagrelor (4% and 11% respectively). The use of ticagrelor instead of clopidogrel is
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contrandicated in the AF setting according to the recent european guidelines17. However a recent north american position paper suggests that ticagrelor may represent a reasonable choice in patients with high
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ischemic/thrombotic risk and low bleeding risk, although the authors admit that further data on the use of ticagrelor in conjuction with OAC is needed30.
In the same position paper an advanced approach regarding the use of double antithrombotic treatment (OAC plus P2Y12 inhibitor) is adopted, different from the current european point of view. More specifically, european recommendations suggest that triple therapy should be administered in most patients with AF and PCI for at least one month and up to 3-6 months depending on the ischemic
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risk, as this is calculated by the SYNTAX score, GRACE score, history of stent thrombosis, number and length of stents etc. The use of double antithrombotic treatment from day one is reserved only for patients at very high bleeding risk. On the contrary the North-American view is that the majority of patients should be treated with double antithrombotic therapy after hospital discharge. The role of triple month)30.
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therapy is limited for patients at high ischemic risk and for a limited period of time (rarely over 1
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The above suggest that with the recent advances in interventional cardiology such as the use of new generation stents with thinner struts and lower risk of thrombosis, the overall benefit for the patient may be mainly driven by a reduction in bleeding complications. Less bleeding is also associated with improved quality of life in patients receiving antithrombotic treatment31. Another challenge is the minimum and maximum duration of the double antithrombotic treatment. European guidelines recommend the continuation of clopidogrel for at least twelve months. On the other hand, a shorter duration (6 months) for low ischemic risk patients at high bleeding risk may be considered in the North-american expert consensus paper. As for the maximum duration , the
ACCEPTED MANUSCRIPT OAC-Alone trial, that sought to compare the strategy OAC alone vs OAC plus antiplatelet beyond 12 months post-PCI, was underpowered and inconclusive32. Further studies are needed in this area in order to adress this issue.
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5. Post- STEMI Risk stratification Despite the high rate of sudden death after myocardial infarction among patients with a low ejection fraction, implantable cardioverter–defibrillators are contraindicated less than 40 days after myocardial infarction. Also management of patients presenting VT or VF early during the STEMI course is not clear. An ICD or the temporary use of a WCD may be considered during that period in
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selected patients (incomplete revascularization, pre-existing LVEF dysfunction, occurrence of
arrhythmias 48 h after the onset of ACS) (IIb recommendation)33. However in the recently published
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VEST trial the wearable cardioverter–defibrillator failed to reduce the primary outcome of arrhythmic death among patients with a recent myocardial infarction and an ejection fraction of 35%, although there was a reduction in overall mortality in the intervention group34. Better risk stratification tools are needed in order to identify and treat appropriately patients at high risk for sudden cardiac death post-
6. Non-IRA management
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MI.
Patients undergoing primary PCI benefit from full revascularization, but the optimal timing of treatment and the optimal criteria to guide PCI (angiography, FFR or plaque morphology) is not known.
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The 2015 Complete Versus Lesion-Only Primary PCI Trial (CvLPRIT) randomized patients with STEMI and multi-vessel disease on index angiography to culprit lesion-only revascularization or
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complete revascularization. At 12 months, patients randomized to complete revascularization had an 11% absolute reduction in MACE35. Also in the DANAMI-PRIMULTI3 and the COMPARE-ACUTE trial, patients with STEMI and multivessel disease, that underwent complete revascularization guided by FFR measurements had significantly reduced risk of future events compared with no further invasive intervention after primary PCI 36,37. Although functional assessment of coronary lesions (FFR, iFR) is a powerful tool to guide revascularization, concerns about variability of these measurements in the acute phase of myocardial infarction exist. One recent study suggests that when iFR is used in the acute setting and indicates that
ACCEPTED MANUSCRIPT a non culprit stenosis is not haemodynamically significant, the need for revascularization will be unlikely38. However, in the same study, approximately one-third of the lesions that were hemodynamically significant by acute iFR (<0.90) were no longer hemodynamically significant when
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evaluated by follow-up iFR.
7. Role of b-blocker and ACE inhibitor treatment in patients with normal ejection fraction post STEMI
Recent guidelines suggest that routine administration of beta-blockers in all post-STEMI
patients should be considered especially in patients with left ventricular systolic dysfunction (LVSD).
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However, its clinical value for patient without overt heart failure (HF) or LVSD is unclear. In a cohort study of 91,895 patients with ST-segment elevation myocardial infarction, patients who did not have
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HF or LVSD as recorded in the hospital, the use of b-blockers was not associated with a lower risk of death at any time point up to 1 year39. The use of ACE inhibitors in this group is also an issue needing further research.
8. Special populations
Gender in STEMI seems to be a factor that defines prognosis. The ISACS-TC registry, analyzed
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a total of 2,657 women and 6,177 men that were hospitalized and treated for STEMI between 2010 and 201640. Women <60 years old appear to have worse outcomes than men, based on 30-day mortality, which was significantly higher in women than in men (11.6% versus 6.0%). Also mortality remained higher in women even in the group of patients who underwent percutaneous coronary intervention
years.
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(PCI; 7.1% versus 3.3%). This difference in mortality was not observed in the group of patients >60
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Age is a primordial risk factor for cardiovascular disease. In recent registries, the percentage of octagenarians undergoing pPCI reaches 10%. The rate of procedural complications, in-hospital and long-term all cause mortality after MI is higher in this population compared with a younger population41.However, there is no upper age limit for reperfusion and especially pPCI2 . Attention should be made in choosing the appropriate type and dosing of antithrombotic treatment in order to avoid bleeding complications42 . Cancer survivors is a growing population, due to advances in cancer treatment. Cardiovascular disease and cancer share common risk factors and cardiotoxicity of cancer treatment can lead to
ACCEPTED MANUSCRIPT accelerated coronary heart disease and myocardial infarction43,44. Little is known about the appropriate management of cancer patients with STEMI. Data are scarce and treatment strategies are based on expert opinions or consensus documents44,45. It seems however that the beneficial effect of pPCI in STEMI and guideline based treatment in reducing cardiac mortality is preserved in this population,
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although noncardiac mortality is significantly higher46. Thrombocytopenia and coagulation anomalies are frequent in this population. According to the existing consensus document, potent P2Y12 inhibitors should be avoided with platelets <50.000/ ml, and DAPT with clopidogrel may be used when platelets
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are between 30.000-50.000/ml. Aspirin monotherapy can be maintained if platelets are >10.000/ml 45 .
Conclusion-Key points
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STEMI management has always been one of the greatest challenges in cardiovascular medicine. Reduction in time delays, identification of treatment strategies against myocardial reperfusion injury, optimization of antithrombotic treatment, reduction of bleeding complications, better risk stratification tools, adequate cardioprotective treatment and complete revascularization are key steps that will aid us
i.v. Metoprolol Hypothermia
Study
Effect on Reperfusion injury
METOCARD-CNIC
Reduction of myocardial infarct size
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Treatment
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further improve outcomes in STEMI patients.
COOL-AMI
Pivotal trial running
CYCLE
No effect on outcomes or LV remodelling
i.c. Adenosine and nitrprusside
REFLO
No effect on MVO
GP IIb/IIIa
Antoniucci D. et al47
Bailout treatment in no-reflow or large thrombotic burden
Deferred stenting
DANAMI3-DEFER
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Cyclosporine A
Routine use of deferred stenting was associated with higher risk of TVR. Table 1. Treatment strategies to prevent reperfusion injury. I.v=intravenous, i.c. = intracoronary, TVR= Target vessel failure
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31. Res LCS, Lubberts B, Shah SH, DiGiovanni CW. Health-related quality of life after adverse bleeding events associated with antithrombotic drug therapy – A systematic review. Hell J Cardiol [Internet]. 2018;8–15. Available from: https://doi.org/10.1016/j.hjc.2018.06.012 32. Matsumura-Nakano Y, Shizuta S, Komasa A, et al. An open-label randomized trial comparing oral anticoagulation with and without single antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond one year after coronary stent implantation: the OAC-ALONE study. Circulation 2018;Epub ahead of print. 33. Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac deathThe Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2015 Nov 1;36(41):2793–867. http://dx.doi.org/10.1093/eurheartj/ehv316
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34. Olgin, JE., Pletcher, MJ., Vittinghoff, E. et al. (2018). Wearable cardioverter defibrillator after myocardial infarction. N Engl J Med 379: 1205-1215.
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35. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol. 2015;65(10):963-72. 36. Engstrøm, Thomas et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3— PRIMULTI): an open-label, randomised controlled trial.The Lancet , Volume 386 , Issue 9994 , 665 – 671
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37. Smits, PC., Abdel-Wahab, M., Neumann, F. et al. (2017). Fractional flow reserve guided multivessel angioplasty in myocardial infarction. N Engl J Med 376: 1234-1244.
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38. Thim, T., Gotberg, M., Frobert, O. et al. (2017). Nonculprit stenosis evaluation using instantaneous wave-free ratio in patients with st-segment elevation myocardial infarction. JACC Cardiovasc Interv 10: 2528-2535. 39. Dondo, TB., Hall, M., West, RM. et al. (2017). B-blockers and mortality after acute myocardial infarction in patients without heart failure or ventricular dysfunction. Journal of the American College of Cardiology 69: 2710-2720.
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40. Cenko, E., Yoon, J. et al. Sex differences in outcomes after STEMI: effect modification by treatment strategy and age. JAMA Intern. Med. https://doi.org/10.1001/jamainternmed.2018.0514 (2018)
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41.Bromage, D. I., Jones, D. A., Rathod, K. S., Grout, C., Bilal Iqbal, M., Lim, P., … Wragg, A. (2016). Outcome of 1051 octogenarian patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: Observational cohort from the London heart attack group. Journal of the American Heart Association, 5(6), 1–11. https://doi.org/10.1161/JAHA.115.003027
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42. Alexander KP, Chen AY, Roe MT et al. , CRUSADE Investigators. Excess dosing of antiplatelet and antithrombin agents in the treatment of nonST-segment elevation acute coronary syndromes. JAMA 2005;294(24):3108–3116 43. Koene RJ, Prizment AE, Blaes A, Konety SH. Shared risk factors in cardiovascular disease and cancer.Circulation 2016;133:1104–14. https://doi.org/10.1161/CIRCULATIONAHA.115.020406; PMID: 26976915 44. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines. Eur Heart J 2016;37:2768–01.
ACCEPTED MANUSCRIPT 45. Iliescu CA, Grines CL, Herrmann J, et al. SCAI expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia intervencionista). Catheter Cardiovasc Interv 2016;87:E202–23. https://doi.org/10.1002/ccd.26379; PMID: 26756277.
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46. Wang, F., Gulati, R., Lennon, et al. (2016). Cancer History Portends Worse Acute and Long-term Noncardiac (but Not Cardiac) Mortality After Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction. Mayo Clinic Proceedings, 91(12), 1680–1692. https://doi.org/10.1016/j.mayocp.2016.06.029
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47. Antoniucci D, Rodriguez A, Hempel A, et al. A randomized trial comparing primary infarct artery stenting with or without abciximab in acute myocardial infarction. J Am Coll Cardiol. 2003;42(11):1879e1886
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Title: “Challenges and unanswered questions in STEMI management”
Key points Patient delay remains a determining factor of total ischemic time. Delays in treatment reduce the benefits of primary PCI.
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Novel treatment and strategies to reduce myocardial infarct size are needed.
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Important issues in antithrombotic treatment -What is the best time for the loading dose of P2Y12 inhibitors? -What is the role of potent P2Y12 inhibitors in fibrinolysis? -Triple or double antithrombotic therapy in AF and STEMI with PCI?
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Risk stratification for sudden cardiac death after STEMI remains problematic.
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Optimal strategy for non-IRA management is still to be defined.
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Uncertain benefits of b-blockers and ACE inhibitors in STEMI patients without heart failure or left ventricular systolic dysfunction.
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S1109-9666(18)30536-0
DOI:
https://doi.org/10.1016/j.hjc.2019.01.001
Reference:
HJC 371
To appear in:
Hellenic Journal of Cardiology
Received Date: 11 November 2018 Revised Date:
23 December 2018
Accepted Date: 3 January 2019
Please cite this article as: Koutsoukis A, Kanakakis I, Challenges and unanswered questions in STEMI management, Hellenic Journal of Cardiology, https://doi.org/10.1016/j.hjc.2019.01.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title : Challenges and unanswered questions in STEMI management
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Authors : Athanasios Koutsoukis1, Ioannis Kanakakis1
1. Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece
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Corresponding author: Ioannis Kanakakis, [email protected]
Address : Department of Clinical Therapeutics, Alexandra Hospital,
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Leoforos Vasilissis Sofias 80,11528, Athens.
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Title:
Challenges and unanswered questions in STEMI management
Introduction
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Acute coronary syndromes (ACS) remain the first cause of mortality in developed countries despite the progress made over the last decades. Event though the recent SWEDEHEART registy has shown that mortality and morbidity have declined over the last three decades, this decline still doesn’t apply in situations such as cardiogenic shock or ACS with cardiopulmonary resuscitation that still have an unacceptably high mortality1.
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The recently published guidelines of the European Society of Cardiology, clearly indicate that primary percutaneous coronary intervention (pPCI) is the treatment of choice for STEMI patients
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within indicated time frames2. In these new guidelines, an upgraded recommendation is suggested regarding the use of drug-eluting stents over bare metal stents, complete revascularization, use of enoxaparin and early hospital discharge. On the other hand, thrombus aspiration and bivalirudin utilization, were downgraded. Despite these advances in STEMI management, several challenges and
1. Time limitations in pPCI
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important areas of uncertainty exist. This review will address several of these issues.
The majority of STEMI patients who die from cardiac arrest, die at the very early stages of myocardial infarction, usually before arriving to the hospital3. The need for rapid access to emergency medical care remains a major problem. The majority of time loss occurs from the onset of symptoms to
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first medical contact (FMC). In the first published paper of the “Stent for life” (SFL) initiative, the median time from symptom onset to FMC (defined as the time of the diagnostic ECG) in different
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countries, ranged from 60 to 210 minutes 4. In Greece the same time interval (patient delay) varied between 142 and 125 minutes5. Public campaigns are needed in order to decrease patient delay. The SFL initiative launched a public awareness campaign some years ago with the following message: “You can SAVE A LIFE by knowing the signs of a heart attack and acting quickly to call emergency medical services, so that the best treatment can be received in the fastest possible time frame”. In a previous study, despite an 18-month intervention , time from symptom onset to hospital arrival did not differ between intervention and reference groups ,despite increased EMS use6.
ACCEPTED MANUSCRIPT Guidelines suggest that the time of STEMI diagnosis is the time zero to choose the reperfusion strategy. STEMI patients should undergo PCI if the anticipated delay from ECG diagnosis to reperfusion is <120 minutes. The selection of this time interval as the cut-off to choose PCI over fibrinolysis is based on old data coming from registries and trials with different designs in terms of cut-
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off point. The identification of the optimal cut-off point in order to choose the best reperfusion strategy, remains a challenge. Pinto et al showed that any mortality benefit of pPCI was lost when the time delay to pPCI was 114 minutes or more7. In 192.500 patients in the National Registry of Myocardial
infrarction, the reduction of pPCI benefit was associated with patient’s characteristics. For example, the benefit of pPCI was nullified for young patients with large anterior infarct with a delay >60 minutes
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and in older patients with non-anterior infarction and a delay>180 min7. The STREAM trial was designed with a cut-off point of 60 minutes. In this study, the pharmacoinvasive stategy had similar
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rates of death, shock, congestive heart failure or reinfarction at 30 days compared to pPCI, when applied in STEMI patients presenting early after symptom onset8.
According to the STEMI guidelines, time delay should be recorded as well as the proportion of patients receiving pPCI within the recommended times (ECG diagnosis to wire crossing of infarctrelated artety within 90 minutes or within 60 minutes when patients present directly to PCI-capable centers). These target delays are quality indicators and they differ from the time interval of 120 minutes
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which is useful in selecting pPCI over fibrinolysis2.
2. Reduction of myocardial infarct (MI) size
For STEMI patients, the most effective therapy for preventing heart failure and reducing MI size is
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timely reperfusion mainly by pPCI. Despite prompt reperfusion, a significant number of patients (about 10%) develop heart failure at one year post -MI. The negative effect of the “myocardial reperfusion
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injury” (RI) is the main target in the effort to reduce MI size. Several novel cardioprotective therapies such as the blockade of the mitochondrial permeability transition pore, therapeutic hypothermia, iv. metoprolol before pPCI, have shown promising results in MI size reduction9,10. In the METOCARD-CNIC study, early intravenous metopropol (15 mg) in patients with anterior STEMI and no signs of heart failure, resulted in smaller infarct size in CMR at 5-7 days (25.6 g vs 30 g, p= 0.012) and higher ejection fraction in 6 months (48.7% vs 45%, p= 0.018)11. The EARLYBAMI trial that included anterior and non-anterior infarcts, did not show metoprolol to reduce infarct size in CMR, however CMR was perfrormed in only half of the patients (55%)12.
ACCEPTED MANUSCRIPT Cyclosporine A inhibits the opening of the mitochondrial permeability transition pore and in early animal studies showed to decrease infarct size. However, in the CYCLE study, a single intravenous cyclosporine A bolus just before primary percutaneous coronary intervention had no effect on ST-segment resolution or hs-cTnT, and did not improve clinical outcomes or LV remodeling up to 6
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months13. The use of vasodilators has also been proposed as a measure to prevent RI. However, in the REFLO-STUDY, high-dose intracoronary adenosine and sodium nitroprusside failed to reduce MVO and MI size in a cohort of 247 reperfused STEMI patients14.
A patient-level pooled analysis of six randomized trials of endovascular cooling during primary
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PCI in STEMI, showed a significant reduction in infarct size in patients with anterior STEMI who were cooled to<35°C at the time of reperfusion15. The COOL-AMI EU trial, a multi-centered and
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randomized trial is running at the moment and will assess the role of hypothermia in the context of STEMI14. In the COOL-AMI EU pilot trial the presence of MVO was high and not different between hypothermia and control group (74% vs. 77%, p=0.79) as assessed by CMR in 4-6 days16. GP IIb/IIIa inhibitors may be useful in reducing no-reflow or thrombus burden as a bailout treatment, however they are not indicated as routine treatment in STEMI2. Deferred stenting has also been proposed as a mean to prevent MVO and reduce microvascular
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dysfuction post-MI. However in the DANAMI3-DEFER trial, routine deferred stenting was associated with a high risk of target vessel failure (TVR)17
The existing data suggest that efficient strategies to reduce reperfusion injury are still lacking
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prevent RI.
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and further studies are needed in this field. Table 1 presents of synopsis of studied treatments to
3. Management of cardiogenic shock Emergency revascularization is the mainstay treatment in cardiogenic shock. The latest ESC/EACTS Revascularization guidelines, no longer recommend complete revascularization in the setting of STEMI and multivessel disease complicated by cardiogenic shock18 .The CULPRIT-SHOCK trial showed a reduced 30 day risk of composite all cause mortality or renal failure with PCI of the culprit lesion only. This early benefit comes with the price of increases in repeat revascularization and
ACCEPTED MANUSCRIPT rehospitalization for congestive heart failure and no difference in all cause mortality in one year follow up19. The utility of mechanical circulatory support in the acute phase of cardiogenic shock still remains unanswered. The routine use of intra-aortic balloon counterpulsation is no longer indicated as the
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IABP-SHOCK II trial showed no benefit in 30 day mortality18. Data concerning the use of other percutaneous left ventricular assist devices are still insufficient to justify their routine use in this setting according to the latest european guidelines.
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4. Antithrombotic treatment
Anticoagulants and dual antiplatelet treatment (DAPT) are the main pharmacological therapy in
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STEMI. Despite major advances in this field, important issues remain unanswered:
a) What is the best time for the loading dose of oral P2Y12 inhibitors?
Pretreatment, defined as administration of the loading dose before assessment of coronary anatomy, provides stronger platelet inhibition at the time of PPCI, however the benefit from this strategy is still unclear. The previous and the recent STEMI guidelines recommend pretreatement with
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P2Y12 inhibitors, but the evidence from randomized control trials to support this strategy is weak2. There is no specific STEMI trial for clopidogrel and few patients were pre-treated with prasugrel in the TRITON-TIMI 38 trial20. The ATLANTIC trial (prehospital loading ticagrelor dose) was negative for the primary endpoint of ST segment resolution on ECG and TIMI 3 flow of the IRA (infarct-related
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artery) on angiography21.
The SWEDHEART registry, an observational, all comers-study, also evaluated ticagrelor
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pretreatment compared with treatment given in the catheterization laboratory in 7443 patients with STEMI. Overall no benefit of ticagrelor pretreatment was observed on a composite end point of mortality, myocardial infarction, and stent thrombosis at 30 days. Although there was a higher percentage of clopidogrel pretreament in the in-hospital ticagrelor population, results were the same after removing this population from the analysis22. A recent meta-analysis in nearly 10.000 STEMI patients examined the effect of early versus delayed P2Y12 inhibition. The “early strategy” was defined as administration of the P2Y12 inhibitors before arrival in the catheterisation laboratory, in comparison with the same drugs administered after
ACCEPTED MANUSCRIPT arrival in the catheterisation laboratory (delayed strategy) or administration in the catheterisation laboratory before PCI of rapidly acting P2Y12 inhibitors (i.e.,intravenous P2Y12 inhibitors or prasugrel or ticagrelor) in comparison with clopidogrel used in the control arm (delayed strategy). Early platelet inhibition with potent P2Y12 inhibitors versus delayed platelet inhibition by clopidogrel relative risk reduction of MI with no impact on mortality23.
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was associated with a significant 27 % relative risk reduction of MACE mainly driven by the 29%
These date suggest that adequate P2Y12 inhibition during pPCI should be regarded as a key element when deciding the type and the timing of antiplatelet therapy administered in STEMI24. Moreover, considering the incremental impact of FMC-to-PCI time delay on longterm mortality, patients with an
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expected FMC-to-PCI exceeding one hour, may have a greater benefit from early potent antiplatelet
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agent administration25.
b) What is the role of potent P2Y12 inhibitors in patients undergoing fibrinolysis? For patients undergoing fibrinolysis and subsequent PCI, clopidogrel is the P2Y12 inhibitor of choice, administered as a loading dose of 300 mg in patients <75 years old and without loading dose (75 mg/day) in patients >75 years2. Although potent P2Y12 inhibitors have not been properly tested in
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patients undergoing fibrinolysis, recent guidelines propose that in these patients clopidogrel can be switched to ticagrelor after 48h, which is an arbitrarily chosen time point, with a weak level of recommendation (IIbC)2. In the TREAT trial, patients that underwent thrombolysis were randomized to receive ticagrelor or clopidogrel as soon as possible and no longer that 24h. Median time to ticagrelor
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loading dose was 11 hours. 89% of the patients were pretreated with clopidogrel 300 mg before randomization. The trial showed that converting to ticagrelor late after initial exposure to clopidogrel
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in the context of thrombolysis, appears safe, as defined by a noninferior difference in major bleeding in 30 days26. However the question of concomitant use of ticagrelor with lytic therapy in the acute phase remains unanswered.
c) Triple or double therapy in Atrial fibrillation (AF) patients with STEMI and PCI ? Latest guidelines recommend that when a patient with non-valvular AF requires anticoagulation and antiplatelet treatment , a NOAC should be preferred over VKA18. The PIONEER trial and
ACCEPTED MANUSCRIPT the more recent RE-DUAL trial compared a NOAC plus single antiplatelet therapy with triple therapy with a VKA plus DAPT and consistently showed significantly lower bleeding risks with the dual antithrombotic regimen with no negative effect on the ischemic end-points. When dabigatran is used, the 150 mgx2 dose may be preferred over the lower dose (110mgx2) and when rivaroxaban is
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used the 15 mgx1 dose may be preferred over the 20 mg dose27.The ongoing AUGUSTUS and ENTRUST-AF-PCI trials investigate the role of apixaban and edoxaban respectively, in this clinical setting 28,29.
In the PIONNER and REDUAL trials only a small percentage of the patients involved was under ticagrelor (4% and 11% respectively). The use of ticagrelor instead of clopidogrel is
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contrandicated in the AF setting according to the recent european guidelines17. However a recent north american position paper suggests that ticagrelor may represent a reasonable choice in patients with high
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ischemic/thrombotic risk and low bleeding risk, although the authors admit that further data on the use of ticagrelor in conjuction with OAC is needed30.
In the same position paper an advanced approach regarding the use of double antithrombotic treatment (OAC plus P2Y12 inhibitor) is adopted, different from the current european point of view. More specifically, european recommendations suggest that triple therapy should be administered in most patients with AF and PCI for at least one month and up to 3-6 months depending on the ischemic
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risk, as this is calculated by the SYNTAX score, GRACE score, history of stent thrombosis, number and length of stents etc. The use of double antithrombotic treatment from day one is reserved only for patients at very high bleeding risk. On the contrary the North-American view is that the majority of patients should be treated with double antithrombotic therapy after hospital discharge. The role of triple month)30.
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therapy is limited for patients at high ischemic risk and for a limited period of time (rarely over 1
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The above suggest that with the recent advances in interventional cardiology such as the use of new generation stents with thinner struts and lower risk of thrombosis, the overall benefit for the patient may be mainly driven by a reduction in bleeding complications. Less bleeding is also associated with improved quality of life in patients receiving antithrombotic treatment31. Another challenge is the minimum and maximum duration of the double antithrombotic treatment. European guidelines recommend the continuation of clopidogrel for at least twelve months. On the other hand, a shorter duration (6 months) for low ischemic risk patients at high bleeding risk may be considered in the North-american expert consensus paper. As for the maximum duration , the
ACCEPTED MANUSCRIPT OAC-Alone trial, that sought to compare the strategy OAC alone vs OAC plus antiplatelet beyond 12 months post-PCI, was underpowered and inconclusive32. Further studies are needed in this area in order to adress this issue.
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5. Post- STEMI Risk stratification Despite the high rate of sudden death after myocardial infarction among patients with a low ejection fraction, implantable cardioverter–defibrillators are contraindicated less than 40 days after myocardial infarction. Also management of patients presenting VT or VF early during the STEMI course is not clear. An ICD or the temporary use of a WCD may be considered during that period in
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selected patients (incomplete revascularization, pre-existing LVEF dysfunction, occurrence of
arrhythmias 48 h after the onset of ACS) (IIb recommendation)33. However in the recently published
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VEST trial the wearable cardioverter–defibrillator failed to reduce the primary outcome of arrhythmic death among patients with a recent myocardial infarction and an ejection fraction of 35%, although there was a reduction in overall mortality in the intervention group34. Better risk stratification tools are needed in order to identify and treat appropriately patients at high risk for sudden cardiac death post-
6. Non-IRA management
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MI.
Patients undergoing primary PCI benefit from full revascularization, but the optimal timing of treatment and the optimal criteria to guide PCI (angiography, FFR or plaque morphology) is not known.
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The 2015 Complete Versus Lesion-Only Primary PCI Trial (CvLPRIT) randomized patients with STEMI and multi-vessel disease on index angiography to culprit lesion-only revascularization or
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complete revascularization. At 12 months, patients randomized to complete revascularization had an 11% absolute reduction in MACE35. Also in the DANAMI-PRIMULTI3 and the COMPARE-ACUTE trial, patients with STEMI and multivessel disease, that underwent complete revascularization guided by FFR measurements had significantly reduced risk of future events compared with no further invasive intervention after primary PCI 36,37. Although functional assessment of coronary lesions (FFR, iFR) is a powerful tool to guide revascularization, concerns about variability of these measurements in the acute phase of myocardial infarction exist. One recent study suggests that when iFR is used in the acute setting and indicates that
ACCEPTED MANUSCRIPT a non culprit stenosis is not haemodynamically significant, the need for revascularization will be unlikely38. However, in the same study, approximately one-third of the lesions that were hemodynamically significant by acute iFR (<0.90) were no longer hemodynamically significant when
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evaluated by follow-up iFR.
7. Role of b-blocker and ACE inhibitor treatment in patients with normal ejection fraction post STEMI
Recent guidelines suggest that routine administration of beta-blockers in all post-STEMI
patients should be considered especially in patients with left ventricular systolic dysfunction (LVSD).
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However, its clinical value for patient without overt heart failure (HF) or LVSD is unclear. In a cohort study of 91,895 patients with ST-segment elevation myocardial infarction, patients who did not have
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HF or LVSD as recorded in the hospital, the use of b-blockers was not associated with a lower risk of death at any time point up to 1 year39. The use of ACE inhibitors in this group is also an issue needing further research.
8. Special populations
Gender in STEMI seems to be a factor that defines prognosis. The ISACS-TC registry, analyzed
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a total of 2,657 women and 6,177 men that were hospitalized and treated for STEMI between 2010 and 201640. Women <60 years old appear to have worse outcomes than men, based on 30-day mortality, which was significantly higher in women than in men (11.6% versus 6.0%). Also mortality remained higher in women even in the group of patients who underwent percutaneous coronary intervention
years.
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(PCI; 7.1% versus 3.3%). This difference in mortality was not observed in the group of patients >60
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Age is a primordial risk factor for cardiovascular disease. In recent registries, the percentage of octagenarians undergoing pPCI reaches 10%. The rate of procedural complications, in-hospital and long-term all cause mortality after MI is higher in this population compared with a younger population41.However, there is no upper age limit for reperfusion and especially pPCI2 . Attention should be made in choosing the appropriate type and dosing of antithrombotic treatment in order to avoid bleeding complications42 . Cancer survivors is a growing population, due to advances in cancer treatment. Cardiovascular disease and cancer share common risk factors and cardiotoxicity of cancer treatment can lead to
ACCEPTED MANUSCRIPT accelerated coronary heart disease and myocardial infarction43,44. Little is known about the appropriate management of cancer patients with STEMI. Data are scarce and treatment strategies are based on expert opinions or consensus documents44,45. It seems however that the beneficial effect of pPCI in STEMI and guideline based treatment in reducing cardiac mortality is preserved in this population,
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although noncardiac mortality is significantly higher46. Thrombocytopenia and coagulation anomalies are frequent in this population. According to the existing consensus document, potent P2Y12 inhibitors should be avoided with platelets <50.000/ ml, and DAPT with clopidogrel may be used when platelets
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are between 30.000-50.000/ml. Aspirin monotherapy can be maintained if platelets are >10.000/ml 45 .
Conclusion-Key points
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STEMI management has always been one of the greatest challenges in cardiovascular medicine. Reduction in time delays, identification of treatment strategies against myocardial reperfusion injury, optimization of antithrombotic treatment, reduction of bleeding complications, better risk stratification tools, adequate cardioprotective treatment and complete revascularization are key steps that will aid us
i.v. Metoprolol Hypothermia
Study
Effect on Reperfusion injury
METOCARD-CNIC
Reduction of myocardial infarct size
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Treatment
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further improve outcomes in STEMI patients.
COOL-AMI
Pivotal trial running
CYCLE
No effect on outcomes or LV remodelling
i.c. Adenosine and nitrprusside
REFLO
No effect on MVO
GP IIb/IIIa
Antoniucci D. et al47
Bailout treatment in no-reflow or large thrombotic burden
Deferred stenting
DANAMI3-DEFER
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Cyclosporine A
Routine use of deferred stenting was associated with higher risk of TVR. Table 1. Treatment strategies to prevent reperfusion injury. I.v=intravenous, i.c. = intracoronary, TVR= Target vessel failure
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References
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12. Roolvink V, Ibanez B, Ottervanger JP, et al. Early Administration of Intravenous Beta-Blockers in Patients With ST-Elevation Myocardial Infarction Before Primary PCI. J Am Coll Cardiol 2016;67:2705-15
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ACCEPTED MANUSCRIPT 23. Bellemain-Appaix, A., Begue, C., Bhatt, DL. et al. (2018). The efficacy of early versus delayed P2Y12 inhibition in percutaneous coronary intervention for st-elevation myocardial infarction: a systematic review and meta-analysis. EuroIntervention 14: 78-85. 24. Mangiacapra, F. and Di Sciascio, G. (2018). P2Y12 inhibition in STEMI: early, strong or both?. EuroIntervention 14: 25-27.
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29. Vranckx P, Lewalter T, Valgimigli M, Tijssen JG, Reimitz P-E, Eckardt L, et al. Evaluation of the safety and efficacy of an edoxaban-based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the ENTRUST-AF PCI trial. Am Heart J. United States; 2018 Feb;196:105–12 30. Angiolillo Dominick J, Goodman Shaun G, Bhatt Deepak L et al. (2018). Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention. Circulation 138: 527-536.
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ACCEPTED MANUSCRIPT 45. Iliescu CA, Grines CL, Herrmann J, et al. SCAI expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia intervencionista). Catheter Cardiovasc Interv 2016;87:E202–23. https://doi.org/10.1002/ccd.26379; PMID: 26756277.
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Title: “Challenges and unanswered questions in STEMI management”
Key points Patient delay remains a determining factor of total ischemic time. Delays in treatment reduce the benefits of primary PCI.
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Novel treatment and strategies to reduce myocardial infarct size are needed.
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Important issues in antithrombotic treatment -What is the best time for the loading dose of P2Y12 inhibitors? -What is the role of potent P2Y12 inhibitors in fibrinolysis? -Triple or double antithrombotic therapy in AF and STEMI with PCI?
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Risk stratification for sudden cardiac death after STEMI remains problematic.
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Optimal strategy for non-IRA management is still to be defined.
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Uncertain benefits of b-blockers and ACE inhibitors in STEMI patients without heart failure or left ventricular systolic dysfunction.
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