Selecting A Treatment Modality In Acute Coronary Syndrome

Article Author:
Luka Petrovic
Article Editor:
Lovely Chhabra
Updated:
6/28/2019 12:09:24 PM
PubMed Link:
Selecting A Treatment Modality In Acute Coronary Syndrome

Introduction

Acute coronary syndrome (ACS) is one of the manifestations of ischemic heart disease.[1][2] The term is used to describe any constellation of symptoms that suggests that acute myocardial ischemia is occurring.[1] ACS encompasses the following clinical entities: unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). The most common mechanism for acute myocardial ischemia represents coronary artery plaque rupture that results in thrombosis and leads to either partial or complete occlusion of the coronary artery.[3] Other mechanisms of acute myocardial ischemia requiring acknowledgment in the current era where effective medical therapy significantly decreased the risk of plaque rupture are plaque erosion, microvascular disease, vasospasm, and restenosis after stenting due to implication for alternative therapeutic strategies.[4] The basis for UA and NSTEMI differentiation is the presence of biomarkers of myocardial damage (cardiac-specific troponins) in the blood sample of patients with NSTEMI and the lack of those in patients with UA. STEMI refers to acute coronary syndrome accompanied with ST elevations in the ECG with concomitant or subsequent appearance of biomarkers of myocardial injury.[5] The estimated prevalence of coronary artery disease in the USA, including myocardial infarction (MI), is around 6% of the population.[6] In 2008, a report stated the incidence rate of STEMI in the USA was about 50 per 100000 and showing a decreasing trend when compared to earlier years.[7] National registry of MI reported 2.5 million cases of MI between 1990 and 2006 and additionally demonstrated an increase in the proportion of the cases caused by NSTEMI from 14.2% to 59.1% during the registry timeframe.[8] Numerous factors influence the mortality of patients with STEMI, but the details of these epidemiologic characteristics are beyond the scope of this document. Certain angiography registries report 1-year mortality in STEMI patients to be generally around 10%.[9][10] Some studies demonstrate that short term mortality in patients with NSTEMI is lower than patients with STEMI, but as the follow up extends to 2 years, mortality rates become comparable.[11]

Function

Treatment of ACS can be broken down into several groups of medications that improve survival, decrease recurrent ischemic events, and provide symptomatic relief. Choosing adequate treatment modality in ACS involves several critical decisions. It is essential to distinguish STEMI patients from those who are experiencing NSTEMI or UA. This distinction further impacts the priorities, timing, and selection of pharmacotherapy used in different patients with ACS.

First, is a review of the choice of treatment modalities in patients with STEMI. In this group of patients, the most important objective is to provide timely reperfusion modality with the goal of ischemic time being less than 120 minutes. Ischemic time refers to time from onset of symptoms to the administration of reperfusion therapy. Reperfusion therapy can be a fibrinolytic agent or a form of percutaneous coronary intervention (PCI). The choice of the reperfusion strategy will depend on the estimation of the time that will be necessary for the administration of reperfusion therapy. In the case of fibrinolysis that time is referred to as door-to-needle, while in the case of PCI, it is door-to-balloon time. PCI is the preferred reperfusion strategy in all patients with STEMI presenting within 12 hours of symptom onset with the condition that it must be done 120 minutes from STEMI diagnosis.[7] Apart from promptly restoring the coronary flow by reopening the culprit artery, it also provides definitive diagnostic modality for a comprehensive assessment of coronary anatomy, hemodynamic data, determines the need for CABG and provides prognostic data related to short-term and long-term mortality by calculating TIMI flow grade or TIMI frame count.[12] PCI should also be considered in patients presenting with symptoms that last more than 12 hours, which also have clinical evidence of ongoing ischemia, hemodynamic instability, malignant arrhythmias, or heart failure. The detailed discussion about the choice of vascular access, revascularization technique, and the optimal type of stent, along with the approach to non-culprit lesions is out of the scope of this review. Briefly, European guidelines from 2017 indicate that the stent deplyment should be into the culprit artery, and a drug-eluting stent (DES) is preferable to a bare metal stent (BMS) for primary PCI. Also, radial access may be preferred over femoral access when performed by an experienced operator.[7]

Fibrinolysis should be a consideration if the patient first presents to a non-PCI capable facility and the anticipated time from first medical contact to the performance of primary PCI exceeds 120 min (this 120-minute duration usually accounts for a 30-minute door in-door out time (DIDO) time goal at the non-PCI capable facility). Upon deciding about whether or not to use fibrinolysis, it should preferably occur within the first 30 minutes of the first medical contact. This strategy can be achieved either as prehospital fibrinolysis by the EMS or within 30 minutes of arriving at a non-PCI capable facility (door to needle time). Contraindications to fibrinolysis require prompt review if this strategy is an option. Absolute contraindications are any previous intracranial hemorrhage, ischemic stroke in the past 3 months, central nervous system neoplasm or arteriovenous malformation, major head trauma or surgery within the past month, known active bleeding or bleeding diathesis (with exception of menses), suspected aortic dissection, severe uncontrolled hypertension unresponsive to emergent medical therapy and use of streptokinase in the last 6 months.[7] Some relative contraindications include a history of chronic poorly controlled hypertension, recent surgery in the last 3 months, ischemic stroke more than 3 months ago, traumatic or prolonged CPR and any other unspecified intracranial pathology. Some factors merit consdieration when considering fibrinolysis based on the available evidence from the recent clinical studies. Mortality reduction in patients with STEMI who are undergoing fibrinolysis is the highest within the first 4 hours, being around 80% after 2 hours and less than 20% after 4 hours of symptom onset.[13] Patients with developed collateral circulation may have more significant benefit beyond the 2-hour timeframe when compared to patients without collateral circulation. CAPTIM trial compared pre-hospital fibrinolysis with PCI in patients with STEMI and found that patients who received treatment with pre-hospital fibrinolysis within 2 hours of symptoms onset had better survival when compared to PCI strategy.[14] Based on STREAM trial, prehospital fibrinolysis provides similar efficacy when compared to PCI in patients with STEMI who presented within 3 hours and were unable to get PCI within 1 hour but with a higher rate of intracranial bleeding.[15][16] An overview of nine randomized trials published by Fibrinolytic Therapy Trialist collaborative group suggests that characteristics of patients who derive the least benefit from fibrinolysis are those with a delayed presentation (over 13 to 24 hours of symptom onset), elderly (age greater than 75 years), inferior ST elevations, and uncontrolled hypertension (systolic blood pressure (BP) more than 175 mmHg).[17] Thus, as a general framework, it seems that patients who present with early onset of symptoms, but with a significant anticipated delay in transportation to a PCI-capable facility should get fibrinolytic treatment in the absence of absolute contraindications.  While on the other hand, patients who present with onset of symptoms longer than 12 hours and absence of hemodynamic instability and evidence of ongoing ischemia of a large amount of myocardium, should not receive fibrinolysis due to a likely lack of significant benefit. Other cases require evaluation on a case by case basis with careful consideration of risks and benefits. Upon deciding for a fibrinolytic strategy, agents that are fibrin-specific and given as a bolus (such as tenecteplase and reteplase) are preferred to other agents due to demonstrated lower risk of intracerebral bleeding and are more convenient to use.[18][19]

Concomitantly with the decision of reperfusion strategy, it is of paramount importance to institute appropriate antiplatelet and anticoagulation treatment in patients with STEMI. Differences in approach exist depending on the selected reperfusion strategy. In all patients, regardless if they are undergoing PCI or fibrinolysis, aspirin should be administered as early as possible.[20][21][22] The aspirin loading dose should be oral 162 to 325mg. The already chosen reperfusion strategy influences the choice of the second antiplatelet agent. In patients undergoing primary PCI, current evidence supports the use of oral ticagrelor with a loading dose of 180mg and maintenance dose of 90 mg twice daily or oral prasugrel with a loading dose of 60 mg and maintenance dose of 10 mg daily or clopidogrel with a 600 mg loading dose with subsequent dosing of 75 mg daily.[22][23][24][25] Contraindications to prasugrel include a history of ischemic stroke and/or transient ischemic attack.[25][26] IV formulation of P2Y12 cangrelor could be an option in situations where quick on and off action of platelet inhibition is required and especially in patients who have not been pretreated with oral ADP antagonists,[27][28] or in situations where patients cannot absorb orally. In regards to the timing of initial dose of P2Y12 in patients with STEMI undergoing PCI, current guidelines support a loading dose with the diagnosis of STEMI, although there exists a substantial variation in practice. Namely, giving the initial loading dose during PCI, after delineation of the coronary anatomy. Finally, GpIIb/IIIa inhibitors are useful in certain patients. Evidence to support the use of intravenous GP IIb/IIIa receptor antagonists in STEMI was largely established before the use of oral dual antiplatelet therapy. Although prior several studies have failed to show a significant benefit of “upstream” GP IIb/IIIa receptor antagonists use before primary PCI in the setting of dual antiplatelet therapy with either intravenous heparin or bivalirudin, its role is restricted to the use of abciximab based on a meta-analysis which suggested that adjunctive abciximab may be useful in this setting. The adjunctive use of GP IIb/IIIa agents at the time of PCI can be considered in selective situations and on a case to case basis especially for patients with a large thrombus burden or inadequate P2Y12 antagonist loading. In those receiving bivalirudin, the routine adjunctive use of GP IIb/IIIa inhibitors is not recommended, except for “bail-out” therapy in selected cases.[29][30][31]

In patients with STEMI who are undergoing fibrinolysis, clopidogrel is the recommended P2Y12 inhibitor.[32][33] Based on trials that evaluated the use of clopidogrel in this clinical setting, loading dose in this scenario is 300 mg, administered as soon as possible, followed by maintenance of 75 mg daily. In patients who are older than 75 yrs, only 75mg of clopidogrel is the recommended loading dose. Ticagrelor and prasugrel have not been sufficiently investigated in these patients and are not recommended as the adjunctive loading therapy, as there might be an increased bleeding risk given the higher potency of these agents. TREAT trial suggests that ticagrelor may be potentially safe in patients with ACS pretreated with clopidogrel who underwent fibrinolytic therapy when administered around 12 hours after the clopidogrel dose.[34] The use of GpIIb/IIIa inhibitors in patients with STEMI who are undergoing fibrinolysis is not recommended.[7]

Anticoagulant agents for consideration in patients with STEMI undergoing primary PCI are unfractionated heparin (UFH), low molecular weight heparin (LMWH) and bivalirudin.[7] Early evidence for the efficacy of UFH in patients with STEMI comes from the pre-fibrinolytic era. With the introduction of fibrinolysis, the publication of ISIS-2 and subsequent introduction of aspirin, the risk and benefit from the addition of UFH to fibrinolytic agents changed, but most of the evidence points out to small, but the significant net benefit of UFH when combined with aspirin versus aspirin alone in patients treated with fibrinolysis.[12] The well known, small, randomized trial that compared UFH to enoxaparin was ATOLL trial.[35] Around 900 STEMI patients, who received therapy with aspirin, clopidogrel and Gp IIb/IIIAa inhibitors (in about 80% of patients) were randomized to UFH versus enoxaparin before primary PCI, and the primary outcome of death, MI complications, procedure failure or major bleeding showed a non-significant reduction in the enoxaparin group. Data from this trial cannot be extrapolated to patients not treated with GpIIb/IIIa inhibitors and patients treated with ticagrelor or prasugrel. A meta-analysis took place in 2012, which included a large number of trials demonstrated that enoxaparin was superior to UFH, although the study had limitations due to the inclusion of data from non-randomized trials too. A meta-analysis by Hai-Long et al. in 2018.[36][37] demonstrated reduced incidence of MI and death in patients with STEMI treated with enoxaparin compared to UFH, without a difference in major bleeding. At present, the latest European Society guidelines for STEMI recommend UFH as the preferred agent, but enoxaparin remains a reasonable safe and alternate consideration. The studies which evaluated bivalirudin use in patients with STEMI undergoing PCI demonstrated a higher incidence of stent thrombosis.[38] A subgroup of large observational SWEDEHEART study included STEMI patients treated with UFH compared to bivalirudin and demonstrated similar rates of early stent thrombosis, while patients treated with UFH had increased mortality.[39] Due to limited evidence for routine use of bivalirudin, currently, it remains a safe option to use bivalirudin in patients with heparin-induced thrombocytopenia.

For patients with STEMI who are undergoing fibrinolysis, anticoagulant is necessary until revascularization occurs. If there is no planned revascularization, it should be administered at least 48 hours, up to 8 days.[12][7] Trials such as ASSENT 3 and ExTRACT-TIMI 25 demonstrated the benefit of enoxaparin when compared to UFH, although the latter study showed increased non-cerebral bleeding complications in patients treated with enoxaparin. The study also included patients with creatinine clearance less than 30 mL/min and patients older than 75, with appropriate dose adjustment.[40][41] It seems reasonable to prefer enoxaparin over UFH in patients with STEMI undergoing fibrinolysis, although guidelines suggest class I recommendation for both agents.[12][7]

Other general pharmacologic therapy that needs to be chosen and considered in all patients with STEMI includes beta blockers, nitrates, analgesics, inhibitors of the renin-angiotensin-aldosterone system (RAAS).

All patients with STEMI should receive a beta blocker in the absence of contraindications.[12][7] Absolute contraindications for beta blockers in the acute phase include hypotension, acute heart failure, AV block, or severe bradycardia. In the absence of contraindications, the decision comes to whether the patient needs to receive immediate IV beta blocker or an oral beta blocker within 24 hours of diagnosis. In patients treated with fibrinolysis, early IV beta blocker administration is the favored approach due to the observed reduction of acute malignant ventricular arrhythmias.[42][43][44] In patients who are undergoing primary PCI, evidence regarding early IV administration of beta blocker and beneficial short and long-term effect is inconsistent, thus, due to the potential for adverse effects, routine use in such manner is discouraged. Regardless, in every patient with STEMI, early IV beta-blocker therapy may be considered in hemodynamically stable patients, have hypertension, ongoing ischemia, or an arrhythmia that would benefit from early beta-blockade.[12][7] Commonly used agent in patients undergoing fibrinolysis or primary PCI is metoprolol. Based on the CAPRICORN trial, patients who have transient or permanent left ventricular (LV) dysfunction after STEMI should preferably receive carvedilol.[45]

Routine use of nitrates in patients with STEMI is not a strong recommendation unless used for anginal relief.[7][46] Nitrates should be used in STEMI patients during the acute phase for the treatment of chest pain due to ischemia, treatment of acute hypertension, or as a vasodilator for treatment of acute LV failure. Contraindications include use of phosphodiesterase inhibitors in the past 48 hours, marked hypotension with systolic blood pressure less than 90 mmHg and suspected right ventricular (RV) infarction. The agent used in the acute phase is nitroglycerin. The formulation is usually sublingual, but intravenous formulation is an option in patients with waxing and waning chest pain, and patients with acute LV failure.

Analgesic treatment in patients with STEMI is important to reduce pain, which can lead to sympathetic hyperactivity, which further impairs myocardial oxygen demand. The recommended agent is IV morphine, and it should not be used routinely, but in those patients with severe chest pain, not responding to nitrates and patients whose presentation is complicated by acute pulmonary edema. Side effects of bradycardia and hypotension require monitoring.

Oxygen is indicated in patients in patients with hypoxemia evidenced by oxygen saturation less than 90% or arterial blood partial pressure of oxygen less than 60 mmHg.[47]

There is strong evidence that RAAS inhibitors, specifically ACE inhibitors, are beneficial in patients with STEMI.[12][7] These agents should be considered in all STEMI patients, and unequivocally given to the ones with LV dysfunction, diabetes, or hypertension.[12][7] In patients who cannot tolerate ACE inhibitors, angiotensin receptor blocker (ARB) should be the alternative. These agents are usually started after 24 hours from admission, or during index hospitalization and in most of the patients continued indefinitely. Mineralocorticoid receptor antagonists, such as eplerenone, have a well-established indication in patients with STEMI who have LV dysfunction and are already on a RAAS inhibitor and a beta blocker.[12][7][48][49][50][51] Contraindications include acute renal failure, chronic renal failure with creatinine above 2.5 mg/dL, and hyperkalemia.

Lipid-lowering agents are indicated in the treatment of STEMI.[12][7] The choice has to be high-intensity statin, with careful risk and benefit assessment in populations with increased risk of side effects (patients with liver failure, elderly above age 75 yrs, previous side effects). The goal of treatment is a reduction in LDL more than 50% from baseline. Thus it is important to check lipid levels in patients with STEMI on admission. The timing of initiation of statin treatment has been investigated in the SECURE-PCI trial, and showed a trend toward a beneficial effect of early initiation of statin treatment in a subset of patients with STEMI, but data demonstrates no strong statistical significance.[52] Given the absence of harm in administering statin therapy early, it is reasonable to administer a statin as soon as possible following the diagnosis of STEMI. Agents preferably used in this setting are atorvastatin or rosuvastatin. Based on data from the IMPROVE-IT trial, ezetimibe should be a consideration in patients with intolerance or contraindication to statin treatment.[53] Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a group of medications that lower LDL. Two largest trials evaluating this group of medications were FOURIER and ODYSSEY trial. Both trials demonstrated a reduction in major adverse cardiovascular events when addimg these agents to statin therapy.[53][54] The ODYSSEY trial involved patients who had ACS within 12 months of enrollment into the study. The major limitation of these agents remains cost. Regardless, they should be considered in patients on optimal statin therapy after STEMI, with the inability to achieve adequate reduction in LDL when assessed on outpatient follow up.

The principal difference in the management of UA/NSTEMI compared to STEMI is that the initial choice of treatment modality focuses on medical management with anti-ischemic, antiplatelet, anticoagulant and analgesic therapy, all with the goal to minimize ischemia and prevent complications, while simultaneously deciding on the timing and appropriateness of coronary angiography versus non-invasive testing and the type of revascularization strategy.

First decision to make is whether the patient needs a coronary angiography versus a form on non-invasive functional testing (such as myocardial perfusion imaging or stress echocardiography). Generally, patients with UA/NSTEMI can undergo an early invasive strategy or an ischemia-guided (i.e., selective invasive) approach. The early invasive strategy involves coronary angiography performed within 48 hours of presentation, and subsequent PCI, CABG or medical therapy alone, depending on the characteristics of coronary anatomy. The ischemia-guided approach puts medical management as a priority, while coronary angiography would be the choice in patients exhibiting clinical signs and symptoms of ischemia (e.g., non-resolving chest pain, arrhythmic events, etc.), hemodynamic instability or have positive non-invasive testing. When making this initial modality choice, one should keep in mind that early invasive strategy is not recommended in two groups of patients: 1) patients who have extensive, severe comorbidities, where risk of revascularization outweighs the benefit and 2) patients who have chest pain, but low clinical likelihood of ACS with negative cardiac biomarkers [55]. Literature suggests that early invasive strategy provides improved mortality and reduction in non-fatal MI.[56][57][58][59][60] Given the available evidence, clinicians should pursue an early invasive strategy in patients with NSTEMI, in the absence of contraindications. Upon mkaing the decision for early invasive strategy, it is critical to identify certain higher risk features of the patient that would warrant a coronary angiography sooner, rather than later.[11] These include cardiogenic shock, recurrent or ongoing chest pain refractory to medical treatment, mechanical complications of MI, acute heart failure, prior CABG, prior PCI within six months of presentation with the clinical suspicion of in-stent restenosis or patients with GRACE score greater than 140.[11]

Antiplatelet agents have well-established benefit in UA/NSTEMI patients.[61][62][63] After the diagnosis of UA/NSTEMI has been made or highly suspected, all patients should receive aspirin and subsequently continued on a daily maintenance dose.[21][64][21] In addition to aspirin, all patients with UA/NSTEMI should receive therapy with a P2Y12 inhibitor.[65][66][11] The choice and timing of administration of the second antiplatelet agent will depend on whether early invasive strategy or ischemia-guided strategy was the choice and whether PCI, CABG, or medical management is the chosen option. PLATO and TRITON TIMI-38 trial have demonstrated more potent inhibition of platelets by ticagrelor and prasugrel when compared to clopidogrel, respectively. Thus for most patients, ticagrelor or prasugrel are the first choices of the second antiplatelet agents, but bearing in mind certain important caveats. In TRITON TIMI 38 trial, prasugrel has been shown to have less efficacy and increased risk of bleeding in patients who were over 75 years old, had a body weight less than 65kg or had a history of TIA or stroke.[23] These patients should not receive prasugrel. Also, patients who will not undergo PCI after coronary angiography should not receive prasugrel.[11] PRAGUE-18 trial demonstrated no difference in efficacy and safety between prasugrel and clopidogrel in patients with ACS undergoing PCI.[24] It is important to note that PLATO trial included a subset of patients who were undergoing PCI, CABG, or treated medically.[22]  Based upon the results of the PLATO trial, it is recommended to use 81 mg aspirin dosing for long-term maintenance when using ticagrelor as the second P2Y12 agent.  Higher dosing of aspirin (162 to 325 mg) may attenuate the efficacy of ticagrelor.  Clopidogrel should be considered as initial therapy if there is a concern regarding cost and access to ticagrelor or prasugrel, or the patient is at increased risk of bleeding. In the subset of patients who are undergoing ischemia-guided strategy, the initial choice of second antiplatelet agent should be ticagrelor, with clopidogrel considered for the same reason as for patients undergoing early-invasive strategy.[22] Prasugrel should be avoided in this group of patients because the TRILOGY ACS trial demonstrated that prasugrel is associated with slightly increased risk of bleeding when compared to clopidogrel in patients who are not undergoing primary PCI.[26] This data makes ticagrelor safer option in patients undergoing an ischemia-guided approach when it is still unknown whether PCI will take place or not. Regardless of the initial strategy, a certain subset of patients with UA/NSTEMI will require CABG as a form of revascularization after defining coronary anatomy. These patients will, by that time, usually receive both aspirin and a P2Y12 inhibitor. The reocmmendation is that that clopidogrel and ticagrelor should be held for five days before surgery, while prasugrel should be held seven days before the surgery.[11][55][67] Aspirin should not be interrupted for CABG.[11][55][67] Consideration to stop aspirin 3 to 5 days preoperatively is an option in patients with a significant risk of bleeding who are refusing blood transfusions.[11] Ultimately, unstable patients with UA/NSTEMI who have anatomy more suitable for CABG, have evidence of ongoing ischemia or hemodynamic instability, should be considered for emergent CABG regardless of antiplatelet therapy.

Given the complexities in predicting how the revascularization strategy will change, depending on the clinical scenario and coronary anatomy, the timing of the P2Y12 inhibitor administration has been debated, due to concern for potentially delaying CABG, if such type of revascularization is needed. Based on the current European and American guidelines, both recommend that P2Y12 inhibitor is administered as promptly as possible after the diagnosis of UA/NSTEMI.[11][55][67] In real-world practice, it is not unusual that P2Y12 inhibitor administration occurs in selected individuals at the time of coronary angiography with identification of coronary anatomy and the formulation of a revascularization plan.  Although major trials that evaluated the use of ticagrelor, prasugrel and clopidogrel in ACS patients did include patients where a P2Y12 inhibitor was administered during coronary angiography and sometimes even after, current guidelines do not recommend this practice, and it remains upon the discretion of the interventional cardiologist on a case-by-case basis.  It would be reasonable to say that P2Y12 administration may be delayed if the clinical suspicion for underlying multivessel disease and need for surgical revascularization remains high. 

Finally, there is limited use of GpIIb/IIIa inhibitors in patients with UA/NSTEMI.[68][69] These involve patients who are very likely to undergo CABG (e.g., the ones with already known high-risk coronary anatomy, high-risk patients with hemodynamic instability and ongoing ischemia), where GpIIb/IIIa inhibitor can be used before administering P2Y12 inhibitor until defining a clear operative plan. The other group where such therapy should be a consideration includes patients with thrombotic complications during coronary angiography.[68][69][70]

In the absence of absolute contraindication, anticoagulation is indicated in all patients with UA/NSTEMI once the diagnosis is made.[11][55][71] Enoxaparin, UFH, and fondaparinux are listed as class I of recommendation for this purpose.[11][55][67] Enoxaparin and fondaparinux should be avoided in patients with severe renal failure. Data from the SYNERGY trial demonstrated non-inferiority of enoxaparin when compared to UFH in terms of efficacy, with the expense of a modest increase in bleeding risk [72][73]. On the other hand, a meta-analysis published eight years after the SYNERGY trial reported a superior effect of enoxaparin when compared to UFH in reducing mortality and bleeding outcomes during PCI in patients with ACS.[37] The benefit was observed mostly in patients with STEMI. OASIS-5 study has demonstrated non-inferiority in the efficacy of fondaparinux compared to enoxaparin, with a better bleeding risk profile.[74] An important caveat was an increased risk of catheter-related thrombosis during PCI, which was successfully mitigated by intraprocedural UFH administration.[74][75]  Based on these observations, a reasonable approach would be that in patients undergoing early invasive strategy, where PCI is expected, anticoagulant of choice should be UFH, while enoxaparin could be an option in the absence of bleeding risk and renal failure. Fondaparinux should be considered in patients with higher bleeding risk, in the absence of advanced renal failure, but would mandate intraprocedural UFH administration to prevent intra-procedural catheter thrombosis. In patients who are managed by ischemia-guided strategy and PCI is unlikely to happen, fondaparinux offers optimal safety profile, while observations from ESSENCE and TIMI 11B trial suggest that enoxaparin in this clinical scenario should be favored when compared to UFH.[76][77] Bivalirudin is recommended as an anticoagulant agent in patients with UA/NSTEMI who have heparin-induced thrombocytopenia. Otherwise, bivalirudin offers a questionable benefit to a very small group of patients. Those patients would have characteristics that favor strong inclination to add GpIIb/IIIa inhibitors and at the same time would have to be at increased risk of bleeding. In that situation given non-inferiority in ischemic risk and lower incidence of bleeding with bivalirudin monotherapy compared to LMWH or UFH+GpIIb/IIIa, bivalirudin would be a choice.[68] Anticoagulation in the acute phase of UA/NSTEMI treatment is discontinued after revascularization or in the case when no revascularization is performed, discontinuation performed after at least 48 hours.[11][55][71]

Symptomatic therapy with nitrates, morphine, and beta blockers in the acute phase of UA/NSTEMI, resembles that of patients with STEMI, as described above. High-intensity statin therapy is the recommendation for all patients with UA/NSTEMI and should be initiated as early as possible after admission to the hospital.[11][78][79][80] ACE inhibitors should be started as a long-term therapy after UA/NSTEMI in patients with LV dysfunction, hypertension, or DM2, while ARBs should be the choice in the case where ACE inhibitor tolerance is an issue.[81][82][83][84][85] Beta-blockers have well known, proven efficacy in patients with UA/NSTEMI who have LV dysfunction.[45][86][87][88][89] Even though beta blockers dosing is a long term therapy for all patients with UA/NSTEMI, there has been no contemporary randomized controlled trial to assess its use in patients without LV dysfunction.[11] Long-term treatment with mineralocorticoid receptor antagonist (such as eplerenone or spironolactone) is recommended in patients with UA/NSTEMI and LVEF less than 40% and heart failure or diabetes.[48][49][50] Dual antiplatelet therapy (DAPT) in patients after ACS, should ideally be continued for 12 months, regardless if they underwent fibrinolysis, CABG, or PCI and irrespective of what type of stent is placed.[90] If patients who are on DAPT develop a high bleeding risk or sustain significant bleeding, discontinuation of P2Y12 inhibitor after six months is reasonable, and the recent guidelines support this approach.

Issues of Concern

One of the significant issues in the management of patients who had ACS is the optimal strategy to balance ischemic risk and bleeding risk in patients who require long-term anticoagulation due to another specific indication, as these patients already require antiplatelet therapy post-ACS. This type of treatment has the name triple therapy. In the most recent ACC/AHA guideline on UA/NSTEMI, the recommendation is that patients who had ACS and underwent PCI should receive triple therapy, but with making every effort to minimize the duration to limit the risk of bleeding.[55] Literature reports unequivocally increased risk of bleeding in patients who are on triple therapy when compared to DAPT or single antiplatelet agent.[55][91][92] Several strategies have been proposed to mitigate those risks. These include the use of clinical calculators such as HAS-BLED to assess bleeding risk, evaluating the appropriateness of indication for anticoagulation, targeting INR to 2-2.5 when using warfarin, the use of clopidogrel instead of more potent P2Y12 inhibitors and the use of proton pump inhibitors in patients with a prior history or at risk of gastrointestinal bleeding.[90] The most recent guidelines for the management of ACS recommend that triple therapy continues for six months following PCI in patients with lower bleeding risk, assessed by HAS-BLED score is equal or less than 2, followed by an oral anticoagulant (OAC) and clopidogrel or aspirin for the remaining 6 months.[7][11][55] In patients with HAS-BLED score of 3 and above, the recommendation is that triple therapy should be administered for one month, followed by an oral anticoagulant (OAC) and clopidogrel or aspirin for the total duration of 12 months. The choice of OAC involves a vitamin K antagonist (VKA) or a non-VKA oral anticoagulant (NOAC), based on patients preference and other socioeconomic factors. The decision between aspirin and clopidogrel during the period of treatment with OAC and one antiplatelet agent depends on the balance of ischemic risks such as complex coronary stenting, left main disease, bifurcation lesions, diabetic patients and bleeding risks such as a history of major bleeding and predisposition for future bleeding events. After 12 months of the described treatment, the guidelines recommend that OAC should be continued as a monotherapy indefinitely for the original indication.[7][11][55] In patients with ACS who did not undergo revascularization or have undergone CABG, the recommendation is that dual therapy involving OAC and aspirin or clopidogrel should continue for 12 months, and after completing that time, OAC should remain in place. Patients with high ischemic risk regardless of the type of revascularization may continue OAC and aspirin beyond the 12-month time frame. Several recent trial results have disputed the concept of triple therapy and examined the effect of OAC along with P2Y12 inhibitor in patients with ACS who are undergoing PCI.[93][94][95][96] WOEST, PIONEER-AF, RE-DUAL[96] and AUGUSTUS trials have examined the efficacy and safety of warfarin, rivaroxaban, dabigatran, and apixaban, respectively, in conjunction with clopidogrel for treatment of patients with ACS who underwent PCI, compared to treatment with triple therapy.[93][95][96][97] Based on the reported results, it appears that dual therapy with an anticoagulant agent and P2Y12 inhibitor when compared to triple therapy, significantly decreases the bleeding risk, while ischemic and thromboembolic risk remains unchanged. Based on these studies, new practice-changing guidelines are warranted, and the data requires interpretation for safe use in clinical practice. The ongoing ENTRUST-PCI study (NCT02866175) will provide data on edoxaban in this type of clinical scenario. It is worth noting that patients who are receiving anticoagulation for mechanical valve, should exclusively be on warfarin, while the antiplatelet regimen strategy is essentially the same as described above.

Clinical Significance

Special attention needs to be devoted to a particular subset of patients who present with cardiogenic shock following ACS. Cardiogenic shock as a complication of ACS is most commonly the consequence of LV failure, while other causes include mechanical complications such as ventricular septal defect, papillary muscle rupture, and RV failure.[98] In-hospital mortality rates, once cardiogenic shock occurs, are 40 to 60%, and prompt revascularization is one of the interventions that potentially can provide benefit.[98][99] Such patients require immediate attention and rapid institution of inotropes or vasopressors, mechanical circulatory support, and an effective revascularization strategy.[100] Contemporary trials suggest that revascularization should take place as early as possible and if PCI is the chosen strategy, culprit vessel should be revascularized as opposed to multivessel PCI.[101][102] Patients with RV infarction can have a clinical presentation of cardiogenic shock. In such patients, special care should be taken to avoid worsening hypotension due to medications such as nitrates, morphine, and diuretics (that may be otherwise routinely used in patients with myocardial infarction and LV dysfunction). Patients with RV infarction benefit from volume expansion that will increase RV preload and subsequent cardiac output.[103]

Other Issues

There are several subgroups of patients with UA/NSTEMI that are at higher risk of adverse outcomes. Those include elderly patients (age 75 or older), women, patients with diabetes mellitus (DM), and chronic kidney disease (CKD).[11] Patients older than 75 yrs have a higher incidence and prevalence of adverse outcomes, increased risk of bleeding, and are more likely to present with atypical symptoms.[6][104][105][106] Practical suggestions to decrease the risk of bleeding in elderly include use of low dose aspirin, avoidance of prasugrel, consideration for the use of bivalirudin as an anticoagulant and avoidance of abciximab if there is a need for the use of GpIIb/IIIa inhibitor.[107] It merits noting that in the absence of comorbidities that are a potential contraindication for revascularization, advanced age alone should not determine that the patient does not need early invasive strategy or revascularization.[55] Multiple studies have shown that women, when compared to men present with atypical symptoms, tend to have more comorbidities and have a lower likelihood of being referred for coronary angiography.[60][105][108] These findings warrant implementation for raising awareness of cardiovascular risk in women, and adherence to the guidelines for the treatment of UA/NSTEMI regardless of sex.[109] Given worse outcomes in patients with DM who present with UA/NSTEMI,[110] it is important to note that certain choices in treatment modality must merit consideration. Limited data show benefit of more potent antiplatelet agents, such as prasugrel,[111] along with favoring early invasive strategy in patients with DM, and preference of CABG compared to PCI in diabetic patients with complex coronary artery disease.[11][112] Patients with CKD who present with UA/NSTEMI are at increased risk of recurrent ischemic events, stent thrombosis, and post-PCI ischemic events.[113][114][115] Patients with advanced CKD stage IV or V usually get excluded from most of the clinical studies. A meta-analysis involving UA/NSTEMI patients with CKD has demonstrated favorable outcomes with an early invasive strategy.[59] Data suggest that CABG is the preferred option of revascularization in patients with CKD who have multivessel CAD and acceptable surgical risk, while if PCI is selected, DES is preferable over BMS.[11]

Enhancing Healthcare Team Outcomes

Many interventions and treatments have been proven so far to improve outcomes in patients with ACS. Still, given the emerging new evidence, heterogeneity in the population of patients with ACS and complexity in optimal decision making in the management of these patients, a robust multidisciplinary and streamlined system is necessary to keep improving outcomes. The highly coordinated care of patients with ACS, especially those with STEMI, starts early, with the first contact with emergency medical services (EMS) or the first contact with the emergency department. It is crucial that regardless of the type of the initial medical contact, an electrocardiogram (ECG) needs to take place in less than 10 minutes, and the initial diagnosis made.[7][116][117] If a STEMI is suspected, it is necessary to provide ECG monitoring with the capacity of defibrillation.[7][118][119] Given these requirements, success in outcomes will depend on adequate prehospital care resources and prompt access to the healthcare facility. It requires efficient transportation, trained personnel, availability of therapeutics, and ability of optimal communication with the healthcare providers in the corresponding hospital, which enables early activation of the cardiac catheterization lab.[120][121][122][123] Given the proven benefit of timely evaluation of patients with STEMI, avoiding treatment delays is necessary at all cost. There should be a system with meticulous tracking of target times for the institution of quality improvement. It is essential to raise awareness of the symptoms of ACS is raised in the general population for the avoidance of patient-related treatment delays.[124][125][126]

It is essential to create a geographic area of responsibility to transport patients to a PCI-capable center in a timely fashion, where the cardiac catheterization lab is available 24 hours a day, seven days per week, and where healthcare personnel has clear written protocols that facilitate risk stratification and management.[127][128][129][130] In geographic areas where timely transport to a PCI-capable facility is not possible, there is a need for a clear protocol for prehospital or early hospital fibrinolysis.[131][132][133] The care coordination continues upon patient admission in the hospital, and it is necessary that hospitals provide infrastructure in the form of coronary care units (CCU) or intensive care units (ICU), along with the units that have the capability of continuous monitoring and specialized care for patients with ACS.[134] A coordinated discharge of the patient is of paramount importance after the acute phase of treatment, medical stabilization, and optimal hospital stay. Apart from the medication reconciliation and confirmation that the patient will be able to receive the medications, interventions including smoking cessation, nutrition education, weight control, and exercise-based cardiac rehabilitation are strongly advised.[135][136][137] To reduce the gap between the ideal care and the real world care of patients with ACS,[138][139] establishing quality indicators is recommended with the goal to serve as a foundation for quality improvement interventions.[140]

ACS therapy modality selection requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


References

[1] Kumar A,Cannon CP, Acute coronary syndromes: diagnosis and management, part I. Mayo Clinic proceedings. 2009 Oct;     [PubMed PMID: 19797781]
[2] Libby P, Mechanisms of acute coronary syndromes and their implications for therapy. The New England journal of medicine. 2013 May 23;     [PubMed PMID: 23697515]
[3] Makki N,Brennan TM,Girotra S, Acute coronary syndrome. Journal of intensive care medicine. 2015 May;     [PubMed PMID: 24047692]
[4] Crea F,Libby P, Acute Coronary Syndromes: The Way Forward From Mechanisms to Precision Treatment. Circulation. 2017 Sep 19;     [PubMed PMID: 28923905]
[5] O'Gara PT,Kushner FG,Ascheim DD,Casey DE Jr,Chung MK,de Lemos JA,Ettinger SM,Fang JC,Fesmire FM,Franklin BA,Granger CB,Krumholz HM,Linderbaum JA,Morrow DA,Newby LK,Ornato JP,Ou N,Radford MJ,Tamis-Holland JE,Tommaso CL,Tracy CM,Woo YJ,Zhao DX, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2013 Jan 29;     [PubMed PMID: 23256914]
[6] Mozaffarian D,Benjamin EJ,Go AS,Arnett DK,Blaha MJ,Cushman M,de Ferranti S,Despr�s JP,Fullerton HJ,Howard VJ,Huffman MD,Judd SE,Kissela BM,Lackland DT,Lichtman JH,Lisabeth LD,Liu S,Mackey RH,Matchar DB,McGuire DK,Mohler ER 3rd,Moy CS,Muntner P,Mussolino ME,Nasir K,Neumar RW,Nichol G,Palaniappan L,Pandey DK,Reeves MJ,Rodriguez CJ,Sorlie PD,Stein J,Towfighi A,Turan TN,Virani SS,Willey JZ,Woo D,Yeh RW,Turner MB, Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015 Jan 27;     [PubMed PMID: 25520374]
[7] Ibanez B,James S,Agewall S,Antunes MJ,Bucciarelli-Ducci C,Bueno H,Caforio ALP,Crea F,Goudevenos JA,Halvorsen S,Hindricks G,Kastrati A,Lenzen MJ,Prescott E,Roffi M,Valgimigli M,Varenhorst C,Vranckx P,Widimsk� P, 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European heart journal. 2018 Jan 7;     [PubMed PMID: 28886621]
[8] Rogers WJ,Frederick PD,Stoehr E,Canto JG,Ornato JP,Gibson CM,Pollack CV Jr,Gore JM,Chandra-Strobos N,Peterson ED,French WJ, Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. American heart journal. 2008 Dec;     [PubMed PMID: 19032996]
[9] Fokkema ML,James SK,Albertsson P,Akerblom A,Calais F,Eriksson P,Jensen J,Nilsson T,de Smet BJ,Sj�gren I,Thorvinger B,Lagerqvist B, Population trends in percutaneous coronary intervention: 20-year results from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry). Journal of the American College of Cardiology. 2013 Mar 26;     [PubMed PMID: 23500325]
[10] Pedersen F,Butrymovich V,Kelb�k H,Wachtell K,Helqvist S,Kastrup J,Holmvang L,Clemmensen P,Engstr�m T,Grande P,Saunam�ki K,J�rgensen E, Short- and long-term cause of death in patients treated with primary PCI for STEMI. Journal of the American College of Cardiology. 2014 Nov 18-25;     [PubMed PMID: 25457398]
[11] Roffi M,Patrono C,Collet JP,Mueller C,Valgimigli M,Andreotti F,Bax JJ,Borger MA,Brotons C,Chew DP,Gencer B,Hasenfuss G,Kjeldsen K,Lancellotti P,Landmesser U,Mehilli J,Mukherjee D,Storey RF,Windecker S, 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). European heart journal. 2016 Jan 14;     [PubMed PMID: 26320110]
[12] O'Gara PT,Kushner FG,Ascheim DD,Casey DE Jr,Chung MK,de Lemos JA,Ettinger SM,Fang JC,Fesmire FM,Franklin BA,Granger CB,Krumholz HM,Linderbaum JA,Morrow DA,Newby LK,Ornato JP,Ou N,Radford MJ,Tamis-Holland JE,Tommaso CL,Tracy CM,Woo YJ,Zhao DX,Anderson JL,Jacobs AK,Halperin JL,Albert NM,Brindis RG,Creager MA,DeMets D,Guyton RA,Hochman JS,Kovacs RJ,Kushner FG,Ohman EM,Stevenson WG,Yancy CW, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Jan 29;     [PubMed PMID: 23247304]
[13] Gersh BJ,Stone GW,White HD,Holmes DR Jr, Pharmacological facilitation of primary percutaneous coronary intervention for acute myocardial infarction: is the slope of the curve the shape of the future? JAMA. 2005 Feb 23;     [PubMed PMID: 15728169]
[14] Bonnefoy E,Steg PG,Boutitie F,Dubien PY,Lapostolle F,Roncalli J,Dissait F,Vanzetto G,Leizorowicz A,Kirkorian G,Mercier C,McFadden EP,Touboul P, Comparison of primary angioplasty and pre-hospital fibrinolysis in acute myocardial infarction (CAPTIM) trial: a 5-year follow-up. European heart journal. 2009 Jul;     [PubMed PMID: 19429632]
[15] Armstrong PW,Gershlick AH,Goldstein P,Wilcox R,Danays T,Lambert Y,Sulimov V,Rosell Ortiz F,Ostojic M,Welsh RC,Carvalho AC,Nanas J,Arntz HR,Halvorsen S,Huber K,Grajek S,Fresco C,Bluhmki E,Regelin A,Vandenberghe K,Bogaerts K,Van de Werf F, Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. The New England journal of medicine. 2013 Apr 11;     [PubMed PMID: 23473396]
[16] Lassen JF,B�tker HE,Terkelsen CJ, Timely and optimal treatment of patients with STEMI. Nature reviews. Cardiology. 2013 Jan;     [PubMed PMID: 23165072]
[17] Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Lancet (London, England). 1994 Feb 5;     [PubMed PMID: 7905143]
[18] Van de Werf F, The history of coronary reperfusion. European heart journal. 2014 Oct 1;     [PubMed PMID: 25024409]
[19] Halvorsen S,Huber K, The role of fibrinolysis in the era of primary percutaneous coronary intervention. Thrombosis and haemostasis. 2011 Mar;     [PubMed PMID: 21136014]
[20] Baigent C,Collins R,Appleby P,Parish S,Sleight P,Peto R, ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. BMJ (Clinical research ed.). 1998 May 2;     [PubMed PMID: 9563981]
[21] Mehta SR,Tanguay JF,Eikelboom JW,Jolly SS,Joyner CD,Granger CB,Faxon DP,Rupprecht HJ,Budaj A,Avezum A,Widimsky P,Steg PG,Bassand JP,Montalescot G,Macaya C,Di Pasquale G,Niemela K,Ajani AE,White HD,Chrolavicius S,Gao P,Fox KA,Yusuf S, Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet (London, England). 2010 Oct 9;     [PubMed PMID: 20817281]
[22] Wallentin L,Becker RC,Budaj A,Cannon CP,Emanuelsson H,Held C,Horrow J,Husted S,James S,Katus H,Mahaffey KW,Scirica BM,Skene A,Steg PG,Storey RF,Harrington RA,Freij A,Thors�n M, Ticagrelor versus clopidogrel in patients with acute coronary syndromes. The New England journal of medicine. 2009 Sep 10;     [PubMed PMID: 19717846]
[23] Montalescot G,Wiviott SD,Braunwald E,Murphy SA,Gibson CM,McCabe CH,Antman EM, Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet (London, England). 2009 Feb 28;     [PubMed PMID: 19249633]
[24] Motovska Z,Hlinomaz O,Miklik R,Hromadka M,Varvarovsky I,Dusek J,Knot J,Jarkovsky J,Kala P,Rokyta R,Tousek F,Kramarikova P,Majtan B,Simek S,Branny M,Mrozek J,Cervinka P,Ostransky J,Widimsky P, Prasugrel Versus Ticagrelor in Patients With Acute Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention: Multicenter Randomized PRAGUE-18 Study. Circulation. 2016 Nov 22;     [PubMed PMID: 27576777]
[25] Wiviott SD,Braunwald E,McCabe CH,Montalescot G,Ruzyllo W,Gottlieb S,Neumann FJ,Ardissino D,De Servi S,Murphy SA,Riesmeyer J,Weerakkody G,Gibson CM,Antman EM, Prasugrel versus clopidogrel in patients with acute coronary syndromes. The New England journal of medicine. 2007 Nov 15;     [PubMed PMID: 17982182]
[26] Roe MT,Armstrong PW,Fox KA,White HD,Prabhakaran D,Goodman SG,Cornel JH,Bhatt DL,Clemmensen P,Martinez F,Ardissino D,Nicolau JC,Boden WE,Gurbel PA,Ruzyllo W,Dalby AJ,McGuire DK,Leiva-Pons JL,Parkhomenko A,Gottlieb S,Topacio GO,Hamm C,Pavlides G,Goudev AR,Oto A,Tseng CD,Merkely B,Gasparovic V,Corbalan R,Cintez? M,McLendon RC,Winters KJ,Brown EB,Lokhnygina Y,Aylward PE,Huber K,Hochman JS,Ohman EM, Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. The New England journal of medicine. 2012 Oct 4;     [PubMed PMID: 22920930]
[27] Bhatt DL,Stone GW,Mahaffey KW,Gibson CM,Steg PG,Hamm CW,Price MJ,Leonardi S,Gallup D,Bramucci E,Radke PW,Widimsk� P,Tousek F,Tauth J,Spriggs D,McLaurin BT,Angiolillo DJ,G�n�reux P,Liu T,Prats J,Todd M,Skerjanec S,White HD,Harrington RA, Effect of platelet inhibition with cangrelor during PCI on ischemic events. The New England journal of medicine. 2013 Apr 4;     [PubMed PMID: 23473369]
[28] Steg PG,Bhatt DL,Hamm CW,Stone GW,Gibson CM,Mahaffey KW,Leonardi S,Liu T,Skerjanec S,Day JR,Iwaoka RS,Stuckey TD,Gogia HS,Gruberg L,French WJ,White HD,Harrington RA, Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet (London, England). 2013 Dec 14;     [PubMed PMID: 24011551]
[29] De Luca G,Suryapranata H,Stone GW,Antoniucci D,Tcheng JE,Neumann FJ,Van de Werf F,Antman EM,Topol EJ, Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA. 2005 Apr 13;     [PubMed PMID: 15827315]
[30] Stone GW,Witzenbichler B,Guagliumi G,Peruga JZ,Brodie BR,Dudek D,Kornowski R,Hartmann F,Gersh BJ,Pocock SJ,Dangas G,Wong SC,Kirtane AJ,Parise H,Mehran R, Bivalirudin during primary PCI in acute myocardial infarction. The New England journal of medicine. 2008 May 22;     [PubMed PMID: 18499566]
[31] Steg PG,van 't Hof A,Hamm CW,Clemmensen P,Lapostolle F,Coste P,Ten Berg J,Van Grunsven P,Eggink GJ,Nibbe L,Zeymer U,Campo dell' Orto M,Nef H,Steinmetz J,Soulat L,Huber K,Deliargyris EN,Bernstein D,Schuette D,Prats J,Clayton T,Pocock S,Hamon M,Goldstein P, Bivalirudin started during emergency transport for primary PCI. The New England journal of medicine. 2013 Dec 5;     [PubMed PMID: 24171490]
[32] Sabatine MS,Cannon CP,Gibson CM,L�pez-Send�n JL,Montalescot G,Theroux P,Claeys MJ,Cools F,Hill KA,Skene AM,McCabe CH,Braunwald E, Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. The New England journal of medicine. 2005 Mar 24;     [PubMed PMID: 15758000]
[33] Chen ZM,Jiang LX,Chen YP,Xie JX,Pan HC,Peto R,Collins R,Liu LS, Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet (London, England). 2005 Nov 5;     [PubMed PMID: 16271642]
[34] Berwanger O,Nicolau JC,Carvalho AC,Jiang L,Goodman SG,Nicholls SJ,Parkhomenko A,Averkov O,Tajer C,Malaga G,Saraiva JFK,Fonseca FA,De Luca FA,Guimaraes HP,de Barros E Silva PGM,Damiani LP,Paisani DM,Lasagno CMR,Candido CT,Valeis N,Moia DDF,Piegas LS,Granger CB,White HD,Lopes RD, Ticagrelor vs Clopidogrel After Fibrinolytic Therapy in Patients With ST-Elevation Myocardial Infarction: A Randomized Clinical Trial. JAMA cardiology. 2018 May 1;     [PubMed PMID: 29525822]
[35] Montalescot G,Zeymer U,Silvain J,Boulanger B,Cohen M,Goldstein P,Ecollan P,Combes X,Huber K,Pollack C Jr,B�nezet JF,Stibbe O,Filippi E,Teiger E,Cayla G,Elhadad S,Adnet F,Chouihed T,Gallula S,Greffet A,Aout M,Collet JP,Vicaut E, Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial. Lancet (London, England). 2011 Aug 20;     [PubMed PMID: 21856483]
[36] Hai-Long W,Xiao-Hua P,Jian-Jun Y, The Efficacy and Safety of Enoxaparin: A Meta-analysis. Open medicine (Warsaw, Poland). 2018;     [PubMed PMID: 30211318]
[37] Silvain J,Beygui F,Barth�l�my O,Pollack C Jr,Cohen M,Zeymer U,Huber K,Goldstein P,Cayla G,Collet JP,Vicaut E,Montalescot G, Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ (Clinical research ed.). 2012 Feb 3;     [PubMed PMID: 22306479]
[38] Valgimigli M,Frigoli E,Leonardi S,Rothenb�hler M,Gagnor A,Calabr� P,Garducci S,Rubartelli P,Briguori C,And� G,Repetto A,Limbruno U,Garbo R,Sganzerla P,Russo F,Lupi A,Cortese B,Ausiello A,Ierna S,Esposito G,Presbitero P,Santarelli A,Sardella G,Varbella F,Tresoldi S,de Cesare N,Rigattieri S,Zingarelli A,Tosi P,van 't Hof A,Boccuzzi G,Omerovic E,Sabat� M,Heg D,J�ni P,Vranckx P, Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes. The New England journal of medicine. 2015 Sep 10;     [PubMed PMID: 26324049]
[39] Grimfj�rd P,Erlinge D,Koul S,Lagerqvist B,Svennblad B,Varenhorst C,James SK, Unfractionated heparin versus bivalirudin in patients undergoing primary percutaneous coronary intervention: a SWEDEHEART study. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2017 Mar 20;     [PubMed PMID: 28044990]
[40] Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet (London, England). 2001 Aug 25;     [PubMed PMID: 11530146]
[41] Antman EM,Morrow DA,McCabe CH,Jiang F,White HD,Fox KA,Sharma D,Chew P,Braunwald E, Enoxaparin versus unfractionated heparin as antithrombin therapy in patients receiving fibrinolysis for ST-elevation myocardial infarction. Design and rationale for the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction study 25 (ExTRACT-TIMI 25). American heart journal. 2005 Feb;     [PubMed PMID: 15846258]
[42] Chen ZM,Pan HC,Chen YP,Peto R,Collins R,Jiang LX,Xie JX,Liu LS, Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet (London, England). 2005 Nov 5;     [PubMed PMID: 16271643]
[43] Pfisterer M,Cox JL,Granger CB,Brener SJ,Naylor CD,Califf RM,van de Werf F,Stebbins AL,Lee KL,Topol EJ,Armstrong PW, Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA (alteplase) for Occluded Coronary Arteries. Journal of the American College of Cardiology. 1998 Sep;     [PubMed PMID: 9741504]
[44] Chatterjee S,Chaudhuri D,Vedanthan R,Fuster V,Ibanez B,Bangalore S,Mukherjee D, Early intravenous beta-blockers in patients with acute coronary syndrome--a meta-analysis of randomized trials. International journal of cardiology. 2013 Sep 30;     [PubMed PMID: 23168009]
[45] Dargie HJ, Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet (London, England). 2001 May 5;     [PubMed PMID: 11356434]
[46] ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet (London, England). 1995 Mar 18;     [PubMed PMID: 7661937]
[47] Hofmann R,James SK,Jernberg T,Lindahl B,Erlinge D,Witt N,Arefalk G,Frick M,Alfredsson J,Nilsson L,Ravn-Fischer A,Omerovic E,Kellerth T,Sparv D,Ekelund U,Linder R,Ekstr�m M,Lauermann J,Haaga U,Pernow J,�stlund O,Herlitz J,Svensson L, Oxygen Therapy in Suspected Acute Myocardial Infarction. The New England journal of medicine. 2017 Sep 28;     [PubMed PMID: 28844200]
[48] Pitt B,Remme W,Zannad F,Neaton J,Martinez F,Roniker B,Bittman R,Hurley S,Kleiman J,Gatlin M, Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. The New England journal of medicine. 2003 Apr 3;     [PubMed PMID: 12668699]
[49] Pitt B,Zannad F,Remme WJ,Cody R,Castaigne A,Perez A,Palensky J,Wittes J, The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. The New England journal of medicine. 1999 Sep 2;     [PubMed PMID: 10471456]
[50] Zannad F,McMurray JJ,Krum H,van Veldhuisen DJ,Swedberg K,Shi H,Vincent J,Pocock SJ,Pitt B, Eplerenone in patients with systolic heart failure and mild symptoms. The New England journal of medicine. 2011 Jan 6;     [PubMed PMID: 21073363]
[51] Girerd N,Collier T,Pocock S,Krum H,McMurray JJ,Swedberg K,Van Veldhuisen DJ,Vincent J,Pitt B,Zannad F, Clinical benefits of eplerenone in patients with systolic heart failure and mild symptoms when initiated shortly after hospital discharge: analysis from the EMPHASIS-HF trial. European heart journal. 2015 Sep 7;     [PubMed PMID: 26093641]
[52] Berwanger O,Santucci EV,de Barros E Silva PGM,Jesu�no IA,Damiani LP,Barbosa LM,Santos RHN,Laranjeira LN,Egydio FM,Borges de Oliveira JA,Dall Orto FTC,Beraldo de Andrade P,Bienert IRC,Bosso CE,Mangione JA,Polanczyk CA,Sousa AGMR,Kalil RAK,Santos LM,Sposito AC,Rech RL,Sousa ACS,Baldissera F,Nascimento BR,Giraldez RRCV,Cavalcanti AB,Pereira SB,Mattos LA,Armaganijan LV,Guimar�es HP,Sousa JEMR,Alexander JH,Granger CB,Lopes RD, Effect of Loading Dose of Atorvastatin Prior to Planned Percutaneous Coronary Intervention on Major Adverse Cardiovascular Events in Acute Coronary Syndrome: The SECURE-PCI Randomized Clinical Trial. JAMA. 2018 Apr 3;     [PubMed PMID: 29525821]
[53] Szarek M,White HD,Schwartz GG,Alings M,Bhatt DL,Bittner VA,Chiang CE,Diaz R,Edelberg JM,Goodman SG,Hanotin C,Harrington RA,Jukema JW,Kimura T,Kiss RG,Lecorps G,Mahaffey KW,Moryusef A,Pordy R,Roe MT,Tricoci P,Xavier D,Zeiher AM,Steg PG, Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial. Journal of the American College of Cardiology. 2019 Feb 5;     [PubMed PMID: 30428396]
[54] Sabatine MS,Giugliano RP,Keech AC,Honarpour N,Wiviott SD,Murphy SA,Kuder JF,Wang H,Liu T,Wasserman SM,Sever PS,Pedersen TR, Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine. 2017 May 4;     [PubMed PMID: 28304224]
[55] Amsterdam EA,Wenger NK,Brindis RG,Casey DE Jr,Ganiats TG,Holmes DR Jr,Jaffe AS,Jneid H,Kelly RF,Kontos MC,Levine GN,Liebson PR,Mukherjee D,Peterson ED,Sabatine MS,Smalling RW,Zieman SJ, 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2014 Dec 23;     [PubMed PMID: 25260718]
[56] Bavry AA,Kumbhani DJ,Rassi AN,Bhatt DL,Askari AT, Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials. Journal of the American College of Cardiology. 2006 Oct 3;     [PubMed PMID: 17010789]
[57] Fox KA,Clayton TC,Damman P,Pocock SJ,de Winter RJ,Tijssen JG,Lagerqvist B,Wallentin L, Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data. Journal of the American College of Cardiology. 2010 Jun 1;     [PubMed PMID: 20359842]
[58] Savonitto S,Cavallini C,Petronio AS,Murena E,Antonicelli R,Sacco A,Steffenino G,Bonechi F,Mossuti E,Manari A,Tolaro S,Toso A,Daniotti A,Piscione F,Morici N,Cesana BM,Jori MC,De Servi S, Early aggressive versus initially conservative treatment in elderly patients with non-ST-segment elevation acute coronary syndrome: a randomized controlled trial. JACC. Cardiovascular interventions. 2012 Sep;     [PubMed PMID: 22995877]
[59] Charytan DM,Wallentin L,Lagerqvist B,Spacek R,De Winter RJ,Stern NM,Braunwald E,Cannon CP,Choudhry NK, Early angiography in patients with chronic kidney disease: a collaborative systematic review. Clinical journal of the American Society of Nephrology : CJASN. 2009 Jun;     [PubMed PMID: 19423566]
[60] Alfredsson J,Lindb�ck J,Wallentin L,Swahn E, Similar outcome with an invasive strategy in men and women with non-ST-elevation acute coronary syndromes: from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). European heart journal. 2011 Dec;     [PubMed PMID: 21911338]
[61] Baigent C,Blackwell L,Collins R,Emberson J,Godwin J,Peto R,Buring J,Hennekens C,Kearney P,Meade T,Patrono C,Roncaglioni MC,Zanchetti A, Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet (London, England). 2009 May 30;     [PubMed PMID: 19482214]
[62] Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet (London, England). 1990 Oct 6;     [PubMed PMID: 1976875]
[63] Lewis HD Jr,Davis JW,Archibald DG,Steinke WE,Smitherman TC,Doherty JE 3rd,Schnaper HW,LeWinter MM,Linares E,Pouget JM,Sabharwal SC,Chesler E,DeMots H, Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. The New England journal of medicine. 1983 Aug 18;     [PubMed PMID: 6135989]
[64] Fanaroff AC,Kaltenbach LA,Peterson ED,Akhter MW,Effron MB,Henry TD,Wang TY, Antiplatelet Therapy Changes for Patients With Myocardial Infarction With Recurrent Ischemic Events: Insights Into Contemporary Practice From the TRANSLATE-ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) Study. Journal of the American Heart Association. 2018 Feb 8;     [PubMed PMID: 29437596]
[65] Yusuf S,Zhao F,Mehta SR,Chrolavicius S,Tognoni G,Fox KK, Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. The New England journal of medicine. 2001 Aug 16;     [PubMed PMID: 11519503]
[66] Mehta SR,Yusuf S,Peters RJ,Bertrand ME,Lewis BS,Natarajan MK,Malmberg K,Rupprecht H,Zhao F,Chrolavicius S,Copland I,Fox KA, Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet (London, England). 2001 Aug 18;     [PubMed PMID: 11520521]
[67] Kristensen SD,Knuuti J,Saraste A,Anker S,B�tker HE,Hert SD,Ford I,Gonzalez-Juanatey JR,Gorenek B,Heyndrickx GR,Hoeft A,Huber K,Iung B,Kjeldsen KP,Longrois D,L�scher TF,Pierard L,Pocock S,Price S,Roffi M,Sirnes PA,Sousa-Uva M,Voudris V,Funck-Brentano C, 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). European heart journal. 2014 Sep 14;     [PubMed PMID: 25086026]
[68] Stone GW,Bertrand ME,Moses JW,Ohman EM,Lincoff AM,Ware JH,Pocock SJ,McLaurin BT,Cox DA,Jafar MZ,Chandna H,Hartmann F,Leisch F,Strasser RH,Desaga M,Stuckey TD,Zelman RB,Lieber IH,Cohen DJ,Mehran R,White HD, Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY Timing trial. JAMA. 2007 Feb 14;     [PubMed PMID: 17299194]
[69] Giugliano RP,White JA,Bode C,Armstrong PW,Montalescot G,Lewis BS,van 't Hof A,Berdan LG,Lee KL,Strony JT,Hildemann S,Veltri E,Van de Werf F,Braunwald E,Harrington RA,Califf RM,Newby LK, Early versus delayed, provisional eptifibatide in acute coronary syndromes. The New England journal of medicine. 2009 May 21;     [PubMed PMID: 19332455]
[70] Kastrati A,Mehilli J,Neumann FJ,Dotzer F,ten Berg J,Bollwein H,Graf I,Ibrahim M,Pache J,Seyfarth M,Sch�hlen H,Dirschinger J,Berger PB,Sch�mig A, Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA. 2006 Apr 5;     [PubMed PMID: 16533938]
[71] Eikelboom JW,Anand SS,Malmberg K,Weitz JI,Ginsberg JS,Yusuf S, Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet (London, England). 2000 Jun 3;     [PubMed PMID: 10859038]
[72] Ferguson JJ,Califf RM,Antman EM,Cohen M,Grines CL,Goodman S,Kereiakes DJ,Langer A,Mahaffey KW,Nessel CC,Armstrong PW,Avezum A,Aylward P,Becker RC,Biasucci L,Borzak S,Col J,Frey MJ,Fry E,Gulba DC,Guneri S,Gurfinkel E,Harrington R,Hochman JS,Kleiman NS,Leon MB,Lopez-Sendon JL,Pepine CJ,Ruzyllo W,Steinhubl SR,Teirstein PS,Toro-Figueroa L,White H, Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004 Jul 7;     [PubMed PMID: 15238590]
[73] Mahaffey KW,Cohen M,Garg J,Antman E,Kleiman NS,Goodman SG,Berdan LG,Reist CJ,Langer A,White HD,Aylward PE,Col JJ,Ferguson JJ 3rd,Califf RM, High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in the SYNERGY trial. JAMA. 2005 Nov 23;     [PubMed PMID: 16304073]
[74] Yusuf S,Mehta SR,Chrolavicius S,Afzal R,Pogue J,Granger CB,Budaj A,Peters RJ,Bassand JP,Wallentin L,Joyner C,Fox KA, Comparison of fondaparinux and enoxaparin in acute coronary syndromes. The New England journal of medicine. 2006 Apr 6;     [PubMed PMID: 16537663]
[75] Steg PG,Mehta S,Jolly S,Xavier D,Rupprecht HJ,Lopez-Sendon JL,Chrolavicius S,Rao SV,Granger CB,Pogue J,Laing S,Yusuf S, Fondaparinux with UnfracTionated heparin dUring Revascularization in Acute coronary syndromes (FUTURA/OASIS 8): a randomized trial of intravenous unfractionated heparin during percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux. American heart journal. 2010 Dec;     [PubMed PMID: 21146654]
[76] Demers C, ESSENCE trial results: breaking new ground. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events. The Canadian journal of cardiology. 1998 Aug;     [PubMed PMID: 9779028]
[77] Antman EM,McCabe CH,Gurfinkel EP,Turpie AG,Bernink PJ,Salein D,Bayes De Luna A,Fox K,Lablanche JM,Radley D,Premmereur J,Braunwald E, Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation. 1999 Oct 12;     [PubMed PMID: 10517729]
[78] Cannon CP,Braunwald E,McCabe CH,Rader DJ,Rouleau JL,Belder R,Joyal SV,Hill KA,Pfeffer MA,Skene AM, Intensive versus moderate lipid lowering with statins after acute coronary syndromes. The New England journal of medicine. 2004 Apr 8;     [PubMed PMID: 15007110]
[79] Baigent C,Blackwell L,Emberson J,Holland LE,Reith C,Bhala N,Peto R,Barnes EH,Keech A,Simes J,Collins R, Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet (London, England). 2010 Nov 13;     [PubMed PMID: 21067804]
[80] LaRosa JC,Grundy SM,Waters DD,Shear C,Barter P,Fruchart JC,Gotto AM,Greten H,Kastelein JJ,Shepherd J,Wenger NK, Intensive lipid lowering with atorvastatin in patients with stable coronary disease. The New England journal of medicine. 2005 Apr 7;     [PubMed PMID: 15755765]
[81] Pfeffer MA,Braunwald E,Moy� LA,Basta L,Brown EJ Jr,Cuddy TE,Davis BR,Geltman EM,Goldman S,Flaker GC, Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. The New England journal of medicine. 1992 Sep 3;     [PubMed PMID: 1386652]
[82] Pfeffer MA,McMurray JJ,Velazquez EJ,Rouleau JL,K�ber L,Maggioni AP,Solomon SD,Swedberg K,Van de Werf F,White H,Leimberger JD,Henis M,Edwards S,Zelenkofske S,Sellers MA,Califf RM, Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. The New England journal of medicine. 2003 Nov 13;     [PubMed PMID: 14610160]
[83] Granger CB,McMurray JJ,Yusuf S,Held P,Michelson EL,Olofsson B,Ostergren J,Pfeffer MA,Swedberg K, Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet (London, England). 2003 Sep 6;     [PubMed PMID: 13678870]
[84] Yusuf S,Teo KK,Pogue J,Dyal L,Copland I,Schumacher H,Dagenais G,Sleight P,Anderson C, Telmisartan, ramipril, or both in patients at high risk for vascular events. The New England journal of medicine. 2008 Apr 10;     [PubMed PMID: 18378520]
[85] Yusuf S,Sleight P,Pogue J,Bosch J,Davies R,Dagenais G, Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The New England journal of medicine. 2000 Jan 20;     [PubMed PMID: 10639539]
[86] The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet (London, England). 1999 Jan 2;     [PubMed PMID: 10023943]
[87] Packer M,Coats AJ,Fowler MB,Katus HA,Krum H,Mohacsi P,Rouleau JL,Tendera M,Castaigne A,Roecker EB,Schultz MK,DeMets DL, Effect of carvedilol on survival in severe chronic heart failure. The New England journal of medicine. 2001 May 31;     [PubMed PMID: 11386263]
[88] Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet (London, England). 1999 Jun 12;     [PubMed PMID: 10376614]
[89] Flather MD,Shibata MC,Coats AJ,Van Veldhuisen DJ,Parkhomenko A,Borbola J,Cohen-Solal A,Dumitrascu D,Ferrari R,Lechat P,Soler-Soler J,Tavazzi L,Spinarova L,Toman J,B�hm M,Anker SD,Thompson SG,Poole-Wilson PA, Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). European heart journal. 2005 Feb;     [PubMed PMID: 15642700]
[90] Levine GN,Bates ER,Bittl JA,Brindis RG,Fihn SD,Fleisher LA,Granger CB,Lange RA,Mack MJ,Mauri L,Mehran R,Mukherjee D,Newby LK,O'Gara PT,Sabatine MS,Smith PK,Smith SC Jr,Halperin JL,Levine GN,Al-Khatib SM,Birtcher KK,Bozkurt B,Brindis RG,Cigarroa JE,Curtis LH,Fleisher LA,Gentile F,Gidding S,Hlatky MA,Ikonomidis JS,Joglar JA,Pressler SJ,Wijeysundera DN, 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. The Journal of thoracic and cardiovascular surgery. 2016 Nov;     [PubMed PMID: 27751237]
[91] Kim JH,Newby LK,Clare RM,Shaw LK,Lodge AJ,Smith PK,Jolicoeur EM,Rao SV,Becker RC,Mark DB,Granger CB, Clopidogrel use and bleeding after coronary artery bypass graft surgery. American heart journal. 2008 Nov;     [PubMed PMID: 19061702]
[92] Fox KA,Mehta SR,Peters R,Zhao F,Lakkis N,Gersh BJ,Yusuf S, Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation. 2004 Sep 7;     [PubMed PMID: 15313956]
[93] Dewilde WJ,Oirbans T,Verheugt FW,Kelder JC,De Smet BJ,Herrman JP,Adriaenssens T,Vrolix M,Heestermans AA,Vis MM,Tijsen JG,van 't Hof AW,ten Berg JM, Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet (London, England). 2013 Mar 30;     [PubMed PMID: 23415013]
[94] Fiedler KA,Maeng M,Mehilli J,Schulz-Sch�pke S,Byrne RA,Sibbing D,Hoppmann P,Schneider S,Fusaro M,Ott I,Kristensen SD,Ibrahim T,Massberg S,Schunkert H,Laugwitz KL,Kastrati A,Sarafoff N, Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial. Journal of the American College of Cardiology. 2015 Apr 28;     [PubMed PMID: 25908066]
[95] Gibson CM,Mehran R,Bode C,Halperin J,Verheugt F,Wildgoose P,van Eickels M,Lip GY,Cohen M,Husted S,Peterson E,Fox K, An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). American heart journal. 2015 Apr;     [PubMed PMID: 25819853]
[96] Cannon CP,Bhatt DL,Oldgren J,Lip GYH,Ellis SG,Kimura T,Maeng M,Merkely B,Zeymer U,Gropper S,Nordaby M,Kleine E,Harper R,Manassie J,Januzzi JL,Ten Berg JM,Steg PG,Hohnloser SH, Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. The New England journal of medicine. 2017 Oct 19;     [PubMed PMID: 28844193]
[97] Lopes RD,Heizer G,Aronson R,Vora AN,Massaro T,Mehran R,Goodman SG,Windecker S,Darius H,Li J,Averkov O,Bahit MC,Berwanger O,Budaj A,Hijazi Z,Parkhomenko A,Sinnaeve P,Storey RF,Thiele H,Vinereanu D,Granger CB,Alexander JH, Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. The New England journal of medicine. 2019 Apr 18;     [PubMed PMID: 30883055]
[98] Thiele H,Ohman EM,Desch S,Eitel I,de Waha S, Management of cardiogenic shock. European heart journal. 2015 May 21;     [PubMed PMID: 25732762]
[99] Stegman BM,Newby LK,Hochman JS,Ohman EM, Post-myocardial infarction cardiogenic shock is a systemic illness in need of systemic treatment: is therapeutic hypothermia one possibility? Journal of the American College of Cardiology. 2012 Feb 14;     [PubMed PMID: 22322079]
[100] Rihal CS,Naidu SS,Givertz MM,Szeto WY,Burke JA,Kapur NK,Kern M,Garratt KN,Goldstein JA,Dimas V,Tu T, 2015 SCAI/ACC/HFSA/STS Clinical Expert Consensus Statement on the Use of Percutaneous Mechanical Circulatory Support Devices in Cardiovascular Care (Endorsed by the American Heart Association, the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencion; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d'intervention). Journal of cardiac failure. 2015 Jun;     [PubMed PMID: 26036425]
[101] Bagai J,Brilakis ES, Update in the Management of Acute Coronary Syndrome Patients with Cardiogenic Shock. Current cardiology reports. 2019 Mar 4;     [PubMed PMID: 30828750]
[102] Thiele H,Akin I,Sandri M,Fuernau G,de Waha S,Meyer-Saraei R,Nordbeck P,Geisler T,Landmesser U,Skurk C,Fach A,Lapp H,Piek JJ,Noc M,Goslar T,Felix SB,Maier LS,Stepinska J,Oldroyd K,Serpytis P,Montalescot G,Barthelemy O,Huber K,Windecker S,Savonitto S,Torremante P,Vrints C,Schneider S,Desch S,Zeymer U, PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock. The New England journal of medicine. 2017 Dec 21;     [PubMed PMID: 29083953]
[103] O'Gara PT,Kushner FG,Ascheim DD,Casey DE Jr,Chung MK,de Lemos JA,Ettinger SM,Fang JC,Fesmire FM,Franklin BA,Granger CB,Krumholz HM,Linderbaum JA,Morrow DA,Newby LK,Ornato JP,Ou N,Radford MJ,Tamis-Holland JE,Tommaso CL,Tracy CM,Woo YJ,Zhao DX, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography     [PubMed PMID: 23299937]
[104] Gale CP,Cattle BA,Woolston A,Baxter PD,West TH,Simms AD,Blaxill J,Greenwood DC,Fox KA,West RM, Resolving inequalities in care? Reduced mortality in the elderly after acute coronary syndromes. The Myocardial Ischaemia National Audit Project 2003-2010. European heart journal. 2012 Mar;     [PubMed PMID: 22009446]
[105] Canto JG,Rogers WJ,Goldberg RJ,Peterson ED,Wenger NK,Vaccarino V,Kiefe CI,Frederick PD,Sopko G,Zheng ZJ, Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA. 2012 Feb 22;     [PubMed PMID: 22357832]
[106] Nguyen HL,Goldberg RJ,Gore JM,Fox KA,Eagle KA,Gurfinkel EP,Spencer FA,Reed G,Quill A,Anderson FA Jr, Age and sex differences, and changing trends, in the use of evidence-based therapies in acute coronary syndromes: perspectives from a multinational registry. Coronary artery disease. 2010 Sep;     [PubMed PMID: 20661139]
[107] Eisen A,Giugliano RP, Antiplatelet and Anticoagulation Treatment in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: Comparison of the Updated North American and European Guidelines. Cardiology in review. 2016 Jul-Aug;     [PubMed PMID: 26186386]
[108] Poon S,Goodman SG,Yan RT,Bugiardini R,Bierman AS,Eagle KA,Johnston N,Huynh T,Grondin FR,Schenck-Gustafsson K,Yan AT, Bridging the gender gap: Insights from a contemporary analysis of sex-related differences in the treatment and outcomes of patients with acute coronary syndromes. American heart journal. 2012 Jan;     [PubMed PMID: 22172438]
[109] Mehta LS,Beckie TM,DeVon HA,Grines CL,Krumholz HM,Johnson MN,Lindley KJ,Vaccarino V,Wang TY,Watson KE,Wenger NK, Acute Myocardial Infarction in Women: A Scientific Statement From the American Heart Association. Circulation. 2016 Mar 1;     [PubMed PMID: 26811316]
[110] Elbarouni B,Ismaeil N,Yan RT,Fox KA,Connelly KA,Baer C,DeYoung JP,Gallo R,Ramanathan K,Pesant Y,Leiter LA,Goodman SG,Yan AT, Temporal changes in the management and outcome of Canadian diabetic patients hospitalized for non-ST-elevation acute coronary syndromes. American heart journal. 2011 Aug;     [PubMed PMID: 21835297]
[111] Wiviott SD,Braunwald E,Angiolillo DJ,Meisel S,Dalby AJ,Verheugt FW,Goodman SG,Corbalan R,Purdy DA,Murphy SA,McCabe CH,Antman EM, Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation. 2008 Oct 14;     [PubMed PMID: 18757948]
[112] Farkouh ME,Domanski M,Sleeper LA,Siami FS,Dangas G,Mack M,Yang M,Cohen DJ,Rosenberg Y,Solomon SD,Desai AS,Gersh BJ,Magnuson EA,Lansky A,Boineau R,Weinberger J,Ramanathan K,Sousa JE,Rankin J,Bhargava B,Buse J,Hueb W,Smith CR,Muratov V,Bansilal S,King S 3rd,Bertrand M,Fuster V, Strategies for multivessel revascularization in patients with diabetes. The New England journal of medicine. 2012 Dec 20;     [PubMed PMID: 23121323]
[113] Morel O,Muller C,Jesel L,Moulin B,Hannedouche T, Impaired platelet P2Y12 inhibition by thienopyridines in chronic kidney disease: mechanisms, clinical relevance and pharmacological options. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2013 Aug;     [PubMed PMID: 23476040]
[114] Navarro MA,Gosch KL,Spertus JA,Rumsfeld JS,Ho PM, Chronic Kidney Disease and Health Status Outcomes Following Acute Myocardial Infarction. Journal of the American Heart Association. 2016 May 23;     [PubMed PMID: 27217497]
[115] Szummer K,Lundman P,Jacobson SH,Sch�n S,Lindb�ck J,Stenestrand U,Wallentin L,Jernberg T, Relation between renal function, presentation, use of therapies and in-hospital complications in acute coronary syndrome: data from the SWEDEHEART register. Journal of internal medicine. 2010 Jul;     [PubMed PMID: 20210836]
[116] Diercks DB,Peacock WF,Hiestand BC,Chen AY,Pollack CV Jr,Kirk JD,Smith SC Jr,Gibler WB,Ohman EM,Blomkalns AL,Newby LK,Hochman JS,Peterson ED,Roe MT, Frequency and consequences of recording an electrocardiogram >10 minutes after arrival in an emergency room in non-ST-segment elevation acute coronary syndromes (from the CRUSADE Initiative). The American journal of cardiology. 2006 Feb 15;     [PubMed PMID: 16461033]
[117] Rokos IC,French WJ,Koenig WJ,Stratton SJ,Nighswonger B,Strunk B,Jewell J,Mahmud E,Dunford JV,Hokanson J,Smith SW,Baran KW,Swor R,Berman A,Wilson BH,Aluko AO,Gross BW,Rostykus PS,Salvucci A,Dev V,McNally B,Manoukian SV,King SB 3rd, Integration of pre-hospital electrocardiograms and ST-elevation myocardial infarction receiving center (SRC) networks: impact on Door-to-Balloon times across 10 independent regions. JACC. Cardiovascular interventions. 2009 Apr;     [PubMed PMID: 19463447]
[118] O'Doherty M,Tayler DI,Quinn E,Vincent R,Chamberlain DA, Five hundred patients with myocardial infarction monitored within one hour of symptoms. British medical journal (Clinical research ed.). 1983 Apr 30;     [PubMed PMID: 6404481]
[119] Mehta RH,Starr AZ,Lopes RD,Hochman JS,Widimsky P,Pieper KS,Armstrong PW,Granger CB, Incidence of and outcomes associated with ventricular tachycardia or fibrillation in patients undergoing primary percutaneous coronary intervention. JAMA. 2009 May 6;     [PubMed PMID: 19417195]
[120] Terkelsen CJ,S�rensen JT,Maeng M,Jensen LO,Tilsted HH,Trautner S,Vach W,Johnsen SP,Thuesen L,Lassen JF, System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. JAMA. 2010 Aug 18;     [PubMed PMID: 20716739]
[121] Fordyce CB,Al-Khalidi HR,Jollis JG,Roettig ML,Gu J,Bagai A,Berger PB,Corbett CC,Dauerman HL,Fox K,Garvey JL,Henry TD,Rokos IC,Sherwood MW,Wilson BH,Granger CB, Association of Rapid Care Process Implementation on Reperfusion Times Across Multiple ST-Segment-Elevation Myocardial Infarction Networks. Circulation. Cardiovascular interventions. 2017 Jan;     [PubMed PMID: 28082714]
[122] Stowens JC,Sonnad SS,Rosenbaum RA, Using EMS Dispatch to Trigger STEMI Alerts Decreases Door-to-Balloon Times. The western journal of emergency medicine. 2015 May;     [PubMed PMID: 25987932]
[123] Squire BT,Tamayo-Sarver JH,Rashi P,Koenig W,Niemann JT, Effect of prehospital cardiac catheterization lab activation on door-to-balloon time, mortality, and false-positive activation. Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors. 2014 Jan-Mar;     [PubMed PMID: 24329031]
[124] Rathore SS,Curtis JP,Chen J,Wang Y,Nallamothu BK,Epstein AJ,Krumholz HM, Association of door-to-balloon time and mortality in patients admitted to hospital with ST elevation myocardial infarction: national cohort study. BMJ (Clinical research ed.). 2009 May 19;     [PubMed PMID: 19454739]
[125] Nielsen PH,Terkelsen CJ,Nielsen TT,Thuesen L,Krusell LR,Thayssen P,Kelbaek H,Abildgaard U,Villadsen AB,Andersen HR,Maeng M, System delay and timing of intervention in acute myocardial infarction (from the Danish Acute Myocardial Infarction-2 [DANAMI-2] trial). The American journal of cardiology. 2011 Sep 15;     [PubMed PMID: 21757183]
[126] Pinto DS,Kirtane AJ,Nallamothu BK,Murphy SA,Cohen DJ,Laham RJ,Cutlip DE,Bates ER,Frederick PD,Miller DP,Carrozza JP Jr,Antman EM,Cannon CP,Gibson CM, Hospital delays in reperfusion for ST-elevation myocardial infarction: implications when selecting a reperfusion strategy. Circulation. 2006 Nov 7;     [PubMed PMID: 17075010]
[127] Widimsky P,Wijns W,Fajadet J,de Belder M,Knot J,Aaberge L,Andrikopoulos G,Baz JA,Betriu A,Claeys M,Danchin N,Djambazov S,Erne P,Hartikainen J,Huber K,Kala P,Klinceva M,Kristensen SD,Ludman P,Ferre JM,Merkely B,Milicic D,Morais J,Noc M,Opolski G,Ostojic M,Radovanovic D,De Servi S,Stenestrand U,Studencan M,Tubaro M,Vasiljevic Z,Weidinger F,Witkowski A,Zeymer U, Reperfusion therapy for ST elevation acute myocardial infarction in Europe: description of the current situation in 30 countries. European heart journal. 2010 Apr;     [PubMed PMID: 19933242]
[128] Knot J,Widimsky P,Wijns W,Stenestrand U,Kristensen SD,Van' T Hof A,Weidinger F,Janzon M,N�rgaard BL,Soerensen JT,van de Wetering H,Thygesen K,Bergsten PA,Digerfeldt C,Potgieter A,Tomer N,Fajadet J, How to set up an effective national primary angioplasty network: lessons learned from five European countries. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2009 Aug;     [PubMed PMID: 19736153]
[129] Nallamothu BK,Krumholz HM,Ko DT,LaBresh KA,Rathore S,Roe MT,Schwamm L, Development of systems of care for ST-elevation myocardial infarction patients: gaps, barriers, and implications. Circulation. 2007 Jul 10;     [PubMed PMID: 17538036]
[130] Bagai A,Jollis JG,Dauerman HL,Peng SA,Rokos IC,Bates ER,French WJ,Granger CB,Roe MT, Emergency department bypass for ST-Segment-elevation myocardial infarction patients identified with a prehospital electrocardiogram: a report from the American Heart Association Mission: Lifeline program. Circulation. 2013 Jul 23;     [PubMed PMID: 23788525]
[131] Kalla K,Christ G,Karnik R,Malzer R,Norman G,Prachar H,Schreiber W,Unger G,Glogar HD,Kaff A,Laggner AN,Maurer G,Mlczoch J,Slany J,Weber HS,Huber K, Implementation of guidelines improves the standard of care: the Viennese registry on reperfusion strategies in ST-elevation myocardial infarction (Vienna STEMI registry). Circulation. 2006 May 23;     [PubMed PMID: 16702474]
[132] Henry TD,Sharkey SW,Burke MN,Chavez IJ,Graham KJ,Henry CR,Lips DL,Madison JD,Menssen KM,Mooney MR,Newell MC,Pedersen WR,Poulose AK,Traverse JH,Unger BT,Wang YL,Larson DM, A regional system to provide timely access to percutaneous coronary intervention for ST-elevation myocardial infarction. Circulation. 2007 Aug 14;     [PubMed PMID: 17673457]
[133] Le May MR,So DY,Dionne R,Glover CA,Froeschl MP,Wells GA,Davies RF,Sherrard HL,Maloney J,Marquis JF,O'Brien ER,Trickett J,Poirier P,Ryan SC,Ha A,Joseph PG,Labinaz M, A citywide protocol for primary PCI in ST-segment elevation myocardial infarction. The New England journal of medicine. 2008 Jan 17;     [PubMed PMID: 18199862]
[134] Hasin Y,Danchin N,Filippatos GS,Heras M,Janssens U,Leor J,Nahir M,Parkhomenko A,Thygesen K,Tubaro M,Wallentin LC,Zakke I, Recommendations for the structure, organization, and operation of intensive cardiac care units. European heart journal. 2005 Aug;     [PubMed PMID: 15781435]
[135] Piepoli MF,Hoes AW,Agewall S,Albus C,Brotons C,Catapano AL,Cooney MT,Corr� U,Cosyns B,Deaton C,Graham I,Hall MS,Hobbs FDR,L�chen ML,L�llgen H,Marques-Vidal P,Perk J,Prescott E,Redon J,Richter DJ,Sattar N,Smulders Y,Tiberi M,van der Worp HB,van Dis I,Verschuren WMM,Binno S, 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention     [PubMed PMID: 27222591]
[136] Anderson L,Oldridge N,Thompson DR,Zwisler AD,Rees K,Martin N,Taylor RS, Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease: Cochrane Systematic Review and Meta-Analysis. Journal of the American College of Cardiology. 2016 Jan 5;     [PubMed PMID: 26764059]
[137] Vaz-Carneiro A,Costa J, [Analysis of the Cochrane Review: Electronic Cigarettes for Smoking Cessation and Reduction. Cochrane Database Syst Rev. 2014,12: CD010216]. Acta medica portuguesa. 2015 Mar-Apr;     [PubMed PMID: 26061503]
[138] Fox KA,Goodman SG,Klein W,Brieger D,Steg PG,Dabbous O,Avezum A, Management of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE). European heart journal. 2002 Aug;     [PubMed PMID: 12127920]
[139] Lenfant C, Shattuck lecture--clinical research to clinical practice--lost in translation? The New England journal of medicine. 2003 Aug 28;     [PubMed PMID: 12944573]
[140] Schiele F,Gale CP,Bonnefoy E,Capuano F,Claeys MJ,Danchin N,Fox KA,Huber K,Iakobishvili Z,Lettino M,Quinn T,Rubini Gimenez M,B�tker HE,Swahn E,Timmis A,Tubaro M,Vrints C,Walker D,Zahger D,Zeymer U,Bueno H, Quality indicators for acute myocardial infarction: A position paper of the Acute Cardiovascular Care Association. European heart journal. Acute cardiovascular care. 2017 Feb;     [PubMed PMID: 27574334]