A rise in troponin, per se, is diagnostic of myocardial necrosis or injury but is not sufficient to define myocardial infarction (MI), which is myocardial necrosis secondary to myocardial ischemia. Additional clinical, ECG, or echocardiographic evidence of ischemia is needed to define MI (Figure 1.1). In fact, MI is defined as a troponin elevation above the 99th percentile of the reference limit (~0.03 ng/ml, depending on the assay) with a rise and/or fall pattern, along with any one of the following four features: (i) angina; (ii) new or dynamic ST-T abnormalities not explained by LVH or LBBB, or new Q waves; (iii) new wall motion abnormality on imaging; (iv) intracoronary thrombus on angiography.1,2 Isolated myocardial necrosis is common in critically ill patients and manifests as a troponin rise, sometimes with a rise and fall pattern, but no clinical or ECG features of MI. This troponin rise is not called MI but is called “non-MI troponin elevation” or “non-ischemic myocardial injury”. A rise or fall in troponin is necessary to define MI. A mild, chronically elevated but stable troponin may be seen in chronic heart failure, severe left ventricular hypertrophy, or advanced kidney disease. While having a prognostic value, this stable troponin rise is not diagnostic of MI. A fluctuating troponin pattern may be seen in myocarditis. Different cutoffs have been used to define a relevant troponin change, but, in general, a troponin that rises above the 99th percentile with a rise or fall of > 20% is characteristic of MI (50-80% cutoff is more applicable to low troponin levels <0.1 ng/ml).3 Type 1 or spontaneous MI is usually due to plaque rupture or erosion that promotes platelet aggregation, thrombus formation and microembolization of platelet aggregates. NSTEMI is a type 1 MI without persistent ST-segment elevation. STEMI is a type 1 MI with persistent (> 20 min), ischemic ST-segment elevation.1,4 For practical purposes, ischemic symptoms with ongoing ST-segment elevation of any duration are considered STEMI and treated as such. The diagnosis may be retrospectively changed to NSTEMI if ST elevation quickly resolves without reperfusion therapy, in < 20 minutes. Figure 1.1 Diagnosis and types of myocardial infarction. In NSTEMI, the thrombus is most often a platelet-rich non-occlusive thrombus. This contrasts with STEMI, which is due to an occlusive thrombus rich in platelets and fibrin. Also, NSTEMI usually has greater collateral flow to the infarct zone than STEMI. As a result of the diffuse inflammation and alteration of platelet aggregability, multiple plaque ruptures are seen in ~30–80% of MIs, although only one is usually considered the culprit.5 This shows the importance of medical therapy to “cool down” the diffuse process, and explains the high risk of MI recurrence within the following year even if the culprit plaque is stented.5 Occasionally, a ruptured plaque or, more commonly, an eroded plaque may lead to microembolization of platelets and thrombi and impaired coronary flow without any residual, angiographically significant lesion or thrombus. In this case, ischemia is related to severely increased O2 demands (demand/supply mismatch). The patient may have underlying CAD, but the coronary plaques are stable without acute rupture or thrombosis. Conversely, the patient may not have any underlying CAD, in which case troponin I usually remains < 1 ng/ml and the ECG and echo are unlikely to show ischemia.6–8 About half of patients with type 2 MI have underlying CAD. Cardiac mechanisms of type 2 MI include: severe hypertension, acute HF, arrhythmias, aortic stenosis/hypertrophic cardiomyopathy. Non-cardiac mechanisms of type 2 MI include: gastrointestinal bleed, severe anemia, sepsis, hypoxemia. Management of type 2 MI- The primary therapy is directed towards the primary insult (e.g., sepsis, anemia, severe HTN, tachyarrhythmia). Acute antithrombotic therapy and coronary angiography are not warranted. Ischemic work-up, by means of stress testing or coronary angiography, is electively performed, before or after discharge. For example, in a patient with gastrointestinal (GI) bleed and angina, the primary treatment consists of transfusion and GI therapy, e.g., endoscopic cauterization. Antithrombotic drugs should be avoided for at least few days, and, if possible, weeks. Depending on the ECG, the echo findings, and the severity of anemia, coronary angiography may not be required. For example, a mild troponin rise of 0.3 ng/ml without significant ECG abnormalities, occurring with acute and severe anemia, may not require coronary angiography. On the other hand, troponin rise with a nadir hemoglobin of 8–10 mg/dl and with ST changes often requires coronary angiography. Importance of differentiating the two subtypes of type 2 MI- A large European registry distinguished between type 2 MI with underlying CAD (CAD history or new CAD diagnosis during admission), and type 2 MI without underlying CAD.8 Half of patients with type 2 MI had no underlying CAD. In type 2 MI without CAD, troponin was <0.6 ng/ml, whereas with underlying CAD it could exceed 1 ng/ml. From a cardiovascular standpoint, the prognosis was impressively benign in patients with type 2 MI without underlying CAD, whose mean age was 72: no cardiac mortality and 0.8% overall mortality at 3 months. Conversely, patients with type 2 MI and underlying CAD had a cardiac mortality comparable to type 1 MI at 3 months (~4% vs. 5%), and an overall mortality higher than type 1 MI (9 vs 6%) (higher mortality related to older age [mean age 76], more comorbidities and higher BNP). Similar observations were made in other registries, except for the finding of a high non-cardiac mortality in all type 2 MIs.11,12 Thus, while the acute management of type 2 MI is the same regardless of underlying CAD, long-term management is dramatically different when underlying CAD is present and somewhat resembles the long-term management of type 1 MI (Table 1.1 ). Table 1.1 Tips in MI definition In this case, myocardial injury occurs because of a demand-supply imbalance similar to type 2 MI but less profound and with less CAD, or because of a direct cardiomyocyte injury (trauma, myocarditis, rhabdomyolysis, cytokines and neurohormones in shock, stroke, or post-operative states). This injury may be chronic with steady, chronic troponin elevation (e.g., advanced kidney disease or cardiomyopathy).* Therapy is directed towards the primary insult. The cardiac prognosis depends on the presence of CAD and is generally better than type 2 MI, as CAD is less likely.10 It was initially hypothesized by Prinzmetal and then demonstrated in a large series that coronary vasospasm and vasospastic angina most often occur in patients with significant CAD at the site of a significant and sometimes unstable atherosclerotic obstruction.13–15 In fact, a ruptured plaque is commonly accompanied by vasospasm, as the activated platelets and leukocytes release vasoconstrictors. Vasospasm also frequently occurs without obstructive coronary atherosclerosis and may lead to chronic vasospastic angina. In fact, in the current era, the term “coronary vasospasm” is mainly used to identify this “isolated coronary vasospasm” with no severe CAD. Indeed, isolated vasospasm is frequently the underlying disease process in patients with typical angina or MI yet no significant CAD.16–19 The diagnosis is definitely made when: (i) vasospasm is angiographically reproduced with provocative testing, along with (ii) symptoms and (iii) ST changes during testing. Endothelial dysfunction, which underlies isolated coronary vasospasm, may also occur at the microvascular level and manifest as diffuse microvascular constriction, not visible angiographically, or as insufficient microvascular dilatation during stress. About 6-10% of patients presenting with a picture of type 1 MI have normal coronary arteries or insignificant CAD (<50% obstructive; 50% being considered obstructive in MI, unlike the 70% cutoff in stable CAD). This prevalence is higher among women and younger patients; up to 15% of women presenting with a type 1 MI picture have no CAD.19–27 The picture is mostly a NSTEMI picture, but up to a third of cases are STEMI, and half of the patients have completely normal angiographic appearance of the coronary arteries.19 This phenomenon is coined MINOCA and may be due to any of the following processes:19,23 Troponin elevation is generally mild, <1 ng/ml, in overlooked type 2 MI, but may be severe in the other processes 1-4. Work-up with cardiac MRI – Cardiac MRI is a central investigation in MINOCA. In an analysis of all comers with MINOCA, MRI established the diagnosis in most patients (three main diagnoses: myocarditis 33%, infarction 24%, and takotsubo 16%);19 ~25% did not have significant MRI abnormality (myocardial injury too small, <1 gram?). In two studies of patients with severely elevated troponin (up to 27 ng/ml, mean 9 ng/ml) and unobstructed coronary arteries, cardiac MRI established the diagnosis in 90% of patients (myocarditis 60%, infarction 15%, and takotsubo ~14%).26,27 ** Other work-up- In a cohort of 145 women with MINOCA (median angiographic stenosis 30%), OCT showed plaque disruption in 46% of the cases, at times in an angiographically normal coronary segment and even in some patients with a fully normal coronary angiogram.20 An even higher prevalence of plaque disruption, >50%, was seen in another OCT study of men and women with MINOCA.21 MRI showed an ischemic pattern in most (75%) but not all of these plaque disruption cases. Yet MRI detected an ischemic pattern in an additional 25% of patients, missed by OCT, coronary vasospasm being the likely culprit in this subset. Half the time, ischemic edema was seen with no LGE. Regarding coronary artery vasospasm, one meta-analysis showed that vasospasm, macro- or microvascular, was inducible in 27% of patients with MINOCA, suggesting that it is a common pathogenetic mechanism in MINOCA.19 In a contemporary study of MINOCA patients, coronary vasospasm was induced in 46% of them.18 Beware of microvascular dysfunction diagnosis in MINOCA: microvascular dysfunction may be a consequence of the myocardial injury, not the cause of it. Thrombophilia was detected in 14% of MINOCA patients19 (but beware that factor V Leiden and factor II mutation are also prevalent in normal subjects, 5% and 2%, respectively). Prognosis- Most studies suggest that MI patients without significant CAD have good long-term outcomes,22–25 particularly if the coronary arteries are angiographically normal,22,24 with a 6-month risk of death of < 1% and death/MI of ~2%. One review suggests a more guarded prognosis, albeit better than MI with obstructive CAD with half of its 12-month mortality.19 The finding of plaque disruption on OCT does not dictate stenting if stenosis <50%, but rather aggressive antiplatelet and statin therapy. Unstable angina is traditionally defined as any of the following clinical presentations, with or without ECG evidence of ischemia and with a normal troponin: True resting angina of ACS will generally result in a troponin rise. In case of a serially negative troponin, and even more so, serially undetectable troponin (< 0.003–0.01 ng/ml), ACS is very unlikely, and the 30-day risk of coronary events is < 0.5%. 28–30 In the current era of sensitive troponin, resting chest pain is generally either MI or non-cardiac pain (+/- vasospastic angina), not unstable angina. In patients with a recent infarction (a few days earlier), the diagnosis of reinfarction relies on: Type 3 MI is defined as sudden death with preceding clinical and ECG features suggestive of MI, such as VF. In the post-PCI context, MI is diagnosed by a troponin elevation > 5× normal, along with ischemic ST changes or Q waves, new wall motion abnormality, or angiographic evidence of procedural complications.1 In patients with elevated baseline cardiac markers that are stable or falling, post-PCI MI is diagnosed by > 20% reincrease of the downward trending troponin to a value >5x normal, along with the other features (most studies use a 50% rather than a 20% cutoff in the post-PCI context). Note that spontaneous NSTEMI carries a much stronger prognostic value than post-PCI NSTEMI, despite the often mild biomarker elevation in the former (threefold higher mortality).33,34 In fact, in spontaneous NSTEMI, the adverse outcome is related not just to the minor myocardial injury but to the ruptured plaques that carry a high future risk of large infarctions. This is not the case in the controlled post-PCI MI. Along with data suggesting that only marked CK-MB elevation carries a prognostic value after PCI, an expert document has proposed the use of CK-MB ≥ 10× normal or troponin ≥70x normal to define post-PCI MI, rather than the mild troponin rise.34 In the post-CABG context, MI is diagnosed by a troponin elevation > 10× normal, associated with new Q waves or new wall motion abnormality.1 The following ECG findings are diagnostic of non-ST elevation ischemia: On the other hand, LVH and bundle branch blocks are not specific for ischemia and make the ECG less interpretable. They do predict an intermediate risk of in-hospital complications (vs. high risk for dynamic ST depression).4,39 As per ESC guidelines: “hemodynamically stable patients presenting with chest pain and LBBB only have a slightly higher risk of MI compared to patients without LBBB.“ Only 50% of patients with non-ST elevation ACS have an ischemic ECG,40 and 20% of NSTEMIs have an absolutely normal ECG.41,42 Yet, patients with ischemic ECG are higher-risk patients and most often have LAD or multivessel involvement. ECG performed during active chest pain has a higher sensitivity and specificity for detection of ischemia. However, even when performed during active ischemia, the ECG may not be diagnostic, particularly in left circumflex ischemia. In fact, up to 40% of acute LCx total occlusions and 10% of LAD or RCA occlusions are not associated with significant ST-T abnormalities, for various reasons: (i) the vessel may occlude progressively, allowing the development of robust collaterals that prevent ST elevation or even ST depression upon coronary occlusion; (ii) the ischemic area may not be well seen on the standard leads (especially posterior or lateral area); (iii) underlying LVH or bundle branch blocks may obscure new findings; a comparison with old ECGs is valuable. In general, ~15–20% of NSTEMIs are due to acute coronary occlusion, frequently LCx occlusion, and may be, pathophysiologically, STEMI-equivalents missed by the ECG and potentially evolving into Q waves.43 NSTEMI patients with acute coronary occlusion have a higher 30-day mortality than patients without an occluded culprit artery, probably related to delayed revascularization of a STEMI-equivalent.44 To improve the diagnostic yield of the ECG: Table 1.2 Clinical features of chest pain a Traditional CAD risk factors are only weakly predictive of the likelihood of ACS during a given presentation.36 For example, shoulder pain that mainly occurs with shoulder movements is unlikely angina, even in a diabetic patient with prior MI. Once ACS is otherwise diagnosed, diabetes and PAD do predict a higher ACS risk. b A new MR murmur in a patient with chest pain is considered ischemic MR until proven otherwise. c True angina and PE pain may seem reproducible with palpation, as the chest wall is hypersensitive in those conditions. A combination of multiple low-likelihood features (e.g., reproducible pain that is also positional and sharp), rather than a sole reliance on pain reproducibility, better defines the low-likelihood group.37,38 Whereas troponin I and T are also present in skeletal muscles, the muscular configuration is different and is not detected by the cardiac troponin assays. Cardiac troponin I and T are highly specific for a myocardial injury. However, this myocardial injury may not be secondary to a coronary event but to other insults (e.g., critical illness, HF, hypoxemia, hypotension), without additional clinical, ECG, or echocardiographic features of MI. High-sensitivity troponin (hs-troponin) assays have a much lower detection cutoff than the conventional, sensitive troponin assays (eg, detection cutoff = 0.005 ng/ml vs. 0.04 ng/ml); they detect troponin in ≥50% of healthy individuals, and in fact, some very-high-sensitivity assays can measure troponin in almost all individuals. This detection cutoff is not to be confused with MI cutoff of hs-troponin, which is close to that of conventional, sensitive troponin (~0.04 ng/ml). Yet, even MI cutoff is lower and more precise with hs-troponin, with precision at the 3rd decimal; also, this fine precision allows MI cutoff to be lower in women than men, as women normally have smaller myocardial mass and troponin values.45 Thus, hs-troponin slightly increases the diagnosis of MI in comparison to sensitive troponin (by ~20%). 4 More importantly, it rises earlier and allows delineation of a very low level within the non-MI range, allowing stratification of troponin values within this non-MI range (e.g., undetectable=very low risk). Note: to avoid the confusion of decimals, hs-troponin is reported as a whole number in ng/L (e.g., detection cutoff 5 ng/L); this may be divided by 1000 to provide a conventional ng/ml value. Troponin rises above MI cutoff within 3 hours of an episode of ischemia lasting > 20-30 min. Hs-troponin rises above detection cutoff rapidly, usually within 1 hour of ischemia.4 Kidney disease may be associated, per se, with a chronic mild elevation of troponin I. This is not related to reduced renal clearance of troponin, a marginal effect at best. It is rather due to the underlying myocardial hypertrophy, chronic CAD, and BP swings. This leads to a chronic ischemic imbalance, and, as a result, a chronic myocardial damage. Kinetics of troponin rise and decline- In MI, troponin peaks at 18-24 hours and remains elevated for 7-14 days. However, in small MI, troponin usually normalizes within 2–3 days. Note that the troponin peak and downslope are much slower than the upslope; thus, patients presenting late after an infarct may have a plateau pattern of stable troponin (Figure 1.2).1,2 In acutely reperfused infarcts (STEMI or NSTEMI), those markers peak earlier (e.g., 12–18 hours) and sometimes peak to higher values than if not reperfused, but decline faster. Hence, the total amount of biomarkers released, meaning the area under the curve, is much smaller, and the troponin elevation resolves more quickly (e.g., 4–5 days). The area under the curve, rather than the actual biomarker peak, correlates with the infarct size. Note on CK-MB- Troponin I or T is much more sensitive and specific than CK-MB. Frequently, NSTEMI is characterized by an elevated troponin and a normal CK-MB; CK-MB only rises with large MI, when troponin exceeds 0.5 ng/ml. CK-MB rises at 3-6 hours, peaks at 12-24 hours, and normalizes at 2-3 days. Overall, CK-MB testing is not recommended on a routine basis but has one potential application: in patients with marked troponin elevation and subacute symptom onset, CK-MB helps diagnose the age of the infarct (a normal CK-MB implies that MI is several days old). The absence of wall motion abnormalities during active chest pain argues against ischemia. For optimal sensitivity, the patient must have active ischemia while the test is performed. Wall motion abnormalities may persist after pain resolution in case of stunning or in case of subendocardial necrosis involving > 20% of the inner myocardial thickness (< 20% subendocardial necrosis or mild troponin rise may not lead to any discernible contractile abnormality).46 Conversely, wall motion abnormalities, when present, are not very specific for acute ischemia and may reflect an old infarct. However, the patient is already in at least an intermediate risk category. Figure 1.2 Kinetics of troponin release. Troponin rises above MI cutoff at 2-3 hours, then peaks and plateaus at ~24 hours. Note the slow decline that mimics a plateau pattern. Reperfused MI has a much narrower curve; the troponin area under the curve, rather than the peak, corresponds to the infarct size. An elevated troponin may be repeated every 8 hours until it trends down, to assess the area under the curve/infarct size. Strain echocardiography (global or regional) improves the sensitivity and negative predictive value of echo for ACS diagnosis in patients with normal initial troponin and non-diagnostic ECG (91%), even several hours after the chest pain episode, but is non-specific and has a poor positive predictive value (13% in one study).46 Acute resting nuclear scan, with the nuclear injection performed during active chest pain or within ~3 hours of the last chest pain episode, has an even higher sensitivity than echo in detecting ischemia. An abnormal resting scan, however, is not specific, as the defect may be an old infarct or an artifact. Only 25% of patients presenting with chest pain are eventually diagnosed with ACS. On the other hand, the ECG is normal in 20–37% of patients with ACS, and before the era of sensitive troponin, ~2-4% of patients discharged home with a presumed non-cardiac chest pain were eventually diagnosed with MI.42 According to multiple large registries and meta-analyses, a single undetectable or very low hs-troponin (eg, <0.005 ng/ml) is associated with <0.3% risk of acute MI and nearly 0% risk of cardiac death at 30 days28–30,45,47–55 Even 1-year events were very low at 0.6% in several registries, with a cardiac death ≤0.1%.28,47,51 This risk is further reduced in patients whose ECG is not suggestive of ischemia. Therefore, discharge is safe in those patients, at least as safe as in patients with negative stress tests, with no need for serial troponin measurement. For patients acutely presenting with chest pain and no other critical illness, ESC and multiple European investigators suggest checking hs-troponin at presentation and at 1 or 2 hours after presentation (0/1 or 0/2 strategy) (Figure 1.3).4,28–30,45,47–55 An undetectable hs-troponin, or a detectable hs-troponin with insignificant change at 1 or 2 hours rules out MI with >99.5% confidence. However, the issue is that a substantial proportion of patients who rule in for MI have non-MI troponin elevation or type 2 MI, rather than type 1 MI. ACS/type 1 MI is the diagnosis in 70-75% of the rule-in cases with no other critical illness, but is much lower in all comers (type 1 MI is the diagnosis in only 50% of patients with troponin up to 3-fold the upper reference limit).4 Note that the MI cutoff of hs-troponin is close to that of conventional troponin (eg, ~0.04 ng/ml), but is slightly lower and more precise than conventional troponin, with precision at the 3rd decimal, and the cutoff is lower in women than men with many assays.45 Thus, hs-troponin slightly increases the diagnosis of MI in comparison to conventional troponin (by 20%). More importantly, it allows delineation of a very low level and a very low risk population that cannot be delineated with conventional troponin and allows early and safe discharge of these very low risk patients. Based on this strategy, over 60% of patients may be discharged at presentation or 1 to 2 hours later. In fact, up to 50% of patients presenting with chest pain have undetectable or very low hs-troponin I (<0.005 ng/ml).51,52 If hs-troponin is not available or not used, conventional troponin is rechecked 3-6 hours after symptom onset (<3-6 hours from presentation) (ACC guidelines). Late troponin abnormality beyond 3 hours is rare, ~1%;4 rarely, troponin may need to be checked beyond 6 hours, in patients with worrisome ECG or recurrent severe symptoms (ACC).36 A negative conventional troponin is less reassuring than a low/undetectable hs-troponin, and thus, the patient frequently requires non-invasive testing for CAD; stress testing or coronary CT angiography may be performed after the second troponin, at 3-6 hours after symptom onset, or may be deferred up to 72 hours after discharge in patients with atypical symptoms and no prior CAD. The patient with persistent atypical chest pain and negative troponin has a low likelihood of CAD and may undergo stress testing while having the atypical pain. Figure 1.3 0/1-hour or 0/2-hour ESC algorithm using hs-troponin in patients presenting to the emergency department with suspected ACS. This example uses the cutoff values specific for Roche Elecsys hs-troponin T assay. Of note, with this assay, the 99 th percentile threshold is 22 ng/L in men, and 14 ng/L in women, yet 52 ng/L is chosen as the MI rule-in value. As per ESC, this is done to improve the positive predictive value for MI, particularly that the 99th percentile threshold varies with the population studied and is not highly specific. This algorithm may be applied to other hs-troponin assays using different cutoffs (Abbott hs-troponin I, rule-in value=64). Hs-troponin is expressed in ng/L, which may be divided by 1000 to obtain conventional values in ng/ml. Clinical scores (eg, HEART) do not improve the safety of this algorithm and unnecessarily reduce the proportion of patients ruled out.47 Most patients who rule out with the hs-troponin strategy have non-cardiac pain. Hence, further testing is not definitely required in patients who rule out with the hs-troponin strategy, particularly when hs-troponin is undetectable. Yet some of the rule-out patients have true angina, especially those with exertional chest pain. CTA or stress imaging (>stress ECG, as per ESC) remains necessary in exertional chest pain and in patients with intermediate hs-troponin findings: a normal or low-risk stress imaging suggests no CAD, microvascular disease, or low-risk CAD for which medical therapy is appropriate. Medical therapy is tailored to how much the physician believes the chest pain is anginal, based on the exertional component, and is somewhat comparable to the management of chronic CAD. As such, coronary angiography is performed in patients whose chest pain is: (i) predominantly exertional, and (ii) occurring during low levels of activity. Rule-in patients frequently require coronary angiogram, in the absence of a concomitant type 2 MI setting. In patients with elevated troponin, the most important step is to distinguish type 1 MI from secondary myocardial injury (which does not dictate acute antithrombotic therapy or coronary angiography). In a patient presenting with chest pain and no other obvious cardiac or systemic insult (HF, critical illness), any troponin elevation, even if mild (eg, 0.04 ng/ml), is a high-risk feature suggestive of type 1 MI and treated as such, with an initial invasive strategy. More severe troponin elevation or ischemic ST depression increases the likelihood of underlying CAD and, in this setting, type 1 MI (rather than MI secondary to an overlooked type 2 MI setting, hypertension, or microvascular disease). Per ESC guidelines, elevations up to 3-fold the upper reference limit (~0.15 ng/ml) have limited positive predictive value for type 1 MI (~50%). Conversely, “elevations beyond 5-fold the upper reference limit have high (>90%) positive predictive value for type 1 MI” (this corresponds to a troponin >0.25 ng/ml).4 Severe hypertension, elevated LVEDP from acute diastolic dysfunction, and vasospasm (micro- or macrovascular) are common causes of mild troponin elevation in patients with non-obstructed coronary arteries. All patients with elevated troponin are categorized as “high risk”, but additional features imply a further increase in risk and probability of type 1 MI, such as ischemic ST changes (more extensive disease), severe troponin rise >0.5-1 ng/ml,56 elevated BNP, or high-risk scores (TIMI risk score ≥ 3 or GRACE risk score >140*). Unstable angina- Some patients qualify for an initial invasive strategy even if troponin is below MI cutoff, and may be placed under the category of “unstable angina”, although “severe stable angina” is a better nomenclature (intermediate-risk ACS per ACC, low-risk ACS per ESC): Hs-troponin is usually detectable in those patients, albeit below MI cut-off. This resembles the hs-troponin behaviour after a stable angina episode or a positive exercise stress testing: hs-troponin rises to detectable levels but remains well below MI cutoff, even if stress-induced ischemia is severe. Ischemia must be sustained to induce a troponin rise above MI cutoff.57 Diabetes is associated with a higher risk of adverse outcomes in NSTEMI and in typical exertional angina, and thus, an invasive strategy may be considered even with the latter case. Women with negative troponin do not generally qualify for an initial invasive strategy, as there is evidence of harm with this strategy in low-risk women. There are 4 lines of therapy for NSTEMI: An initial invasive strategy implies that diagnostic coronary angiography and possible revascularization are performed within 72 hours of presentation, and within 24 hours in the highest risk subgroup. An initial or early invasive strategy does not equate with early PCI. It rather equates with early coronary angiography for risk stratification and subsequent management by PCI, CABG, or medical therapy according to the angiographic findings. It is an early intent to revascularize. In various clinical trials that managed ACS invasively, ~55–60% received PCI, ~15% received CABG, and 25% received medical therapy only.59–61 The initial invasive strategy is contrasted with the initial conservative/selective invasive strategy, in which the patient is treated medically and risk-stratified with stress testing, then invasively managed in case of recurrent true angina or high-risk stress test result. Three major trials (FRISC II, TACTICS-TIMI 18, RITA 3) established the benefit of an initial invasive strategy and showed that in high-risk ACS patients this strategy reduces the combined endpoint of death and MI in comparison to an initial conservative strategy, particularly in patients with positive troponin, ST-segment changes, or TIMI risk score ≥ 3 (50% reduction in death/MI in those subgroups in all three trials, with an absolute risk reduction of ~5% at 30 days and 1 year).62–64 The mortality was reduced at 1-year follow-up in the overall FRISC II trial (by ~40%, more so in the highest risk groups), and at 5-year follow-up in the overall RITA 3 trial. Those beneficial results were seen despite the narrow difference in revascularization rates between the initial invasive and initial conservative strategy. For example, in TACTICS, 60% of patients in the initial invasive strategy vs. 35% of patients in the initial conservative strategy received revascularization at 30 days, this difference becoming narrower over the course of 6–12 months. These trials did not address revascularization vs. no revascularization in high-risk ACS patients who angiographically qualify for revascularization, in which case revascularization is expected to show more striking benefits. These trials rather addressed the early intent to revascularize vs. the early intent to not revascularize. In trials where the difference in revascularization between groups was narrower, such as the ICTUS trial, the early invasive strategy could not show a benefit over the early conservative strategy (at 1 year, the revascularization rates were 79% vs. 54%).65 The results of the ICTUS trial do not imply a lack a benefit from revascularization, but rather that an initial conservative strategy with a later invasive strategy if needed, sometimes weeks later, may be appropriate in initially stabilized patients who are free of angina, particularly if they have multiple comorbidities and are not ideal candidates for revascularization (class IIb in ACC guidelines; not recommended in ESC guidelines). Timing of initial invasive strategy in NSTEMI: early invasive strategy <24 hours – The exact timing of the initial invasive strategy has been addressed in the TIMACS trial, where an “early” invasive strategy at < 24 hours was compared to a “delayed early” invasive strategy at 36 hours to 5 days (mainly 48–72 hours).61 The early invasive strategy did not reduce the rate of death/MI in the overall group but reduced it in the highest-risk group, with GRACE risk score >140. VERDICT trial reproduced similar findings.66 Thus, an “early” invasive strategy < 24 hours is reasonable in patients with a GRACE risk score > 140, but also in all patients with elevated troponin or dynamic ST changes, per ACC and ESC guidelines (class I recommendation ESC).4 Immediate invasive strategy <2 hours – Coronary angiography becomes “urgent” in the following, very-high risk cases: Large scale application of urgent coronary angiography (<2 hours) in all comers with NSTEMI did not improve death or MI (ABOARD and EARLY trials).67,68 Delayed initial invasive strategy <72 hours –This delay is acceptable in patients with negative troponin who nonetheless have typical exertional angina with unstable features (intermediate-risk ACS, paragraph III.C).36 Timing of invasive strategy in acute HF– In patients with ischemic ST abnormality, new Q waves, or severe troponin rise (>1 ng/ml), MI is presumed the cause of acute HF (type 1 MI) rather the result of it (type 2 MI). An invasive strategy is indicated and multivessel CAD is expected. Except in acute ST elevation, angiography and PCI are not warranted urgently, as supine positioning and contrast loading during angiography increase preload and aggravate HF, LVEDP and myocardial ischemia. Furthermore, procedural sedation blunts the compensatory vasoconstriction and tachycardia of pre-shock patients. These 3 factors may precipitate a downhill course of shock and massive pulmonary edema requiring urgent intubation in patients who were initially stable. Thus, in somewhat stable patients, coronary angiography is usually performed 1-3 days later, once proper diuresis has been achieved. Only unstable HF patients, such as those with shock or massive pulmonary edema already requiring mechanical ventilation, who also have ongoing deep ST depression, are treated with an immediate invasive strategy within 2 hours (per ESC and ACC).4,36 Typically, aspirin +/- one ADP-receptor antagonist (ticagrelor, clopidogrel) is started upon admission, upstream of catheterization.36 In the current era of potent ADP-receptor antagonists and quick catheterization <24 hours, upstream therapy with those agents does not seem necessary, and initiation during catheterization appears sufficient (ACCOAST, ISAR-REACT-5 trials).69,70 In fact, ESC guidelines recommend against routine pre-treatment with an ADP receptor antagonist (class III). Upstream IIb/IIIa inhibitor therapy is not beneficial.60,71,72 Figure 1.4 Platelet receptors and antiplatelet mechanisms of action. Cyclooxygenase 1 (COX-1) allows the synthesis of thromboxane A2 (TXA2), which acts on its platelet receptor, eventually activating the IIb/IIIa receptor. Aspirin irreversibly acetylates COX-1. While the pharmacokinetic half-life of aspirin is only ~20 min – 2 h, the pharmacodynamic effect of aspirin lasts the lifespan of the platelet (5–7 days). The platelet ADP receptor eventually leads to conformational activation of the IIb/IIIa receptors. Clopidogrel and prasugrel (thienopyridines) are prodrugs that get metabolized into the same active metabolite. This active metabolite irreversibly binds to the P2Y12 ADP receptor, extending the pharmacodynamic effect of these drugs to 5–7 days despite a half-life of 6 h. The prodrugs are metabolized by cytochromes (CYP), particularly CYP2C19; only 15% of clopidogrel vs. 100% of prasugrel is actively metabolized. This explains why prasugrel is a much more potent inhibitor of platelet aggregation (~75% vs. ~35% inhibition of platelet aggregation). Some patients have a CYP2C19 mutation that slows clopidogrel metabolism and preferentially increases its inactivation by esterases, translating into a poor or no response to clopidogrel. Prasugrel, on the other hand, has only one metabolic pathway, and will be metabolized by cytochromes regardless of how slow the metabolism is. Ticagrelor directly binds to the P2Y12 ADP receptor and reversibly inhibits it (the effect clears as the drug clears from plasma). Despite being a reversible ADP antagonist, the very potent ADP blockade and the long half-life translate into an antiplatelet effect that lasts 3–4 days (half-life ~15 h). Since it directly acts on its receptor, the response to ticagrelor is consistent and potent (~75% platelet inhibition), including in clopidogrel non-responders. Cangrelor is an intravenous ADP receptor antagonist that directly and reversibly binds to the ADP receptor. It inhibits 90% of the platelet aggregation. In contrast to ticagrelor, it has a short half-life of 5 min, which, in addition to the reversible receptor binding, leads to a very quick onset and offset of action. Thrombin is also a potent activator of platelet aggregation. Vorapaxar blocks the thrombin receptor. Cyclic AMP, promoted by cilostazol, inhibits platelet aggregation. The IIb/IIIa receptor is the final common pathway of platelet aggregation and allows linking of the platelets through fibrinogen molecules. Four anticoagulants are considered in NSTE-ACS: (i) unfractionated heparin (UFH), (ii) enoxaparin, (iii) bivalirudin, and (iv) fondaparinux. Upon admission, anticoagulation with any one of these four drugs should be initiated (class I recommendation). During PCI, either UFH or bivalirudin is used (Figures 1.5, 1.6; Table 1.3). Figure 1.5 Specific effects of the four anticoagulants. A heparin derivative induces a conformational change in antithrombin III (AT III), which, according to the size of the heparin–AT III complex, predominantly inactivates Xa or the active thrombin. UFH inactivates thrombin preferentially, while low-molecular-weight heparin (LMWH) inactivates Xa preferentially. The smaller fondaparinux molecule inactivates Xa exclusively. The inactivation of Xa eventually inhibits thrombin generation rather than thrombin activity. Heparin activates platelets directly by binding to them, which also triggers antiplatelet antibodies (HIT). The oral direct thrombin inhibitor (dabigatran) and the oral Xa antagonists (apixaban, rivaroxaban) are used to treat AF, not ACS. Figure 1.6 Summary of anticoagulant use in NSTE-ACS, before catheterization and during PCI. Operators who are not comfortable with performing PCI solely under the coverage of a prior subcutaneous dose of enoxaparin should avoid starting enoxaparin on admission and should use any of the other three agents upfront. Table 1.3 Summary of antithrombotic therapy in ACS. Note: Avoid switching between UFH and enoxaparin. The switch to bivalirudin is, however, appropriate. IV NTG is indicated for frequently recurrent angina, ongoing angina, or ischemia associated with hypertension or HF. Angina that is not relieved by 400 mcg of sublingual NTG may not be relieved by the smaller infusion dose of IV NTG (10–200 mcg/min); the latter may however be tried, in conjunction with β-blockers and antithrombotic therapy. IV NTG is initiated at 10 mcg/min and increased by 10 mcg/min every 3–5 minutes until symptoms are relieved or a limiting reduction of SBP < 100–110 mmHg occurs. Oral or topical nitrates (patch, paste) are acceptable alternatives in the absence of ongoing angina. After stabilization, IV NTG may be converted to an oral or topical nitrate, with a dosing that prevents tolerance and leaves a 12-hour nitrate-free interval (e.g., isosorbide dinitrate 10–40 mg or nitropaste 0.5–2 inches at 8 a.m., 2 p.m. and 8 p.m.). After coronary angiography, a decision is made for PCI vs. CABG vs. continuing medical therapy alone, as dictated by the coronary anatomy. If a decision is made to proceed with CABG, hold clopidogrel and ticagrelor for 5 days before surgery, if possible, and hold enoxaparin for 12–24 hours and eptifibatide for 4 hours before surgery. There are two types of patients within this group: Even if PCI is not performed, prescribe clopidogrel or ticagrelor for at least 1 month, and preferably 12 months. This applies to patients with significant CAD who are not revascularized, but also patients with insignificant CAD when moderate disease is present or plaque rupture is believed to be the underlying trigger.71 In addition, clopidogrel is beneficial in patients who undergo CABG in the context of ACS, where clopidogrel may be started a few days after CABG.87 In the absence of stenting, the ADP receptor antagonist is more readily stopped if needed (bleeding, surgical procedure). If PCI is performed, prescribe clopidogrel, prasugrel, or ticagrelor for 12 months, regardless of whether a bare-metal stent (BMS) or a drug-eluting stent (DES) is used. Prasugrel or ticagrelor is preferred by the ACC and ESC guidelines. De-escalation to clopidogrel may be done at 1 month if the bleeding risk is high (TOPIC trial). Does a longer duration of therapy (>12 months) provide extra benefit? (Table 1.4) According to the DAPT study, which included patients with MI (26%) or stable CAD undergoing DES placement, the continued administration of a thienopyridine between 1 year and 2.5 years reduced the MI risk in half during this time frame (from 4% to 2%). MI was reduced at the stent site (stent thrombosis) but also at distant lesions, where half of the events occur. This benefit was seen despite the short study duration (1.5 years) and despite the exclusion of patients who had a recurrent coronary event in the first year, the latter likely deriving an even larger benefit from continued thienopyridine administration.88 A benefit of prolonged therapy was also seen in a separate DAPT study addressing BMS patients. Interestingly, even beyond 1 year, and even with BMS, there was a ~1% risk of stent thrombosis after thienopyridine interruption, similar to DES. The pitfall of this prolonged therapy was an increase in bleeding, cancer diagnoses, and overall deaths (related to cancer and bleeding). Thus, continued thienopyridine therapy seems reasonable in patients who have a low bleeding risk (e.g., age < 75) and no suspicion of underlying malignancy; it is expected to be particularly beneficial in the high ischemic risk groups, such as recurrent MI, multiple complex PCIs, combined CAD + PAD, ischemic HF, or ongoing uncontrolled risk factors, such as smoking or diabetes.89,90 Another trial, CHARISMA, addressed prolonged dual antiplatelet therapy regardless of stenting and showed that patients with a prior MI, as opposed to stable CAD, benefited from extended dual antiplatelet therapy for up to 28 months, whether PCI was performed or not; the benefit was larger in patients with a prior MI and PAD.91 Figure 1.7 Duration of dual antiplatelet therapy (DAPT) according to ACC guidelines. Table 1.4 Long-term therapy >12 months may be considered based on the following: Conversely, is earlier interruption acceptable? The ADP receptor antagonist may be safely interrupted at 1 month with BMS, at 3 months with DES in the stable CAD setting,92–102 and at 6 months with DES in the ACS setting (DES registries and PRODIGY trial).92,93,95–102 Upon interruption between 6 and 12 months, there is a small risk of MI that is, nonetheless, likely similar to the low and steady risk at >12 months’ interruption, not higher.90,93,96,103 For those patients deemed at high risk of stent thrombosis or recurrent MI, the interruption of the ADP receptor antagonist is limited to < 7–10 days. In fact, the median time from clopidogrel interruption to stent thrombosis, when it rarely happens in the 1–6-month time interval after stent implantation, is 13.5 days.104,105 Several studies even suggest that 1–3 months of DAPT, followed by clopidogrel or ticagrelor monotherapy (aspirin discontinuation), may be sufficient after DES in both stable or unstable CAD (MASTER-DAPT, STOP DAPT-2 and SMART-Choice trials with clopidogrel).98–101 This is particularly true for ticagrelor monotherapy in ACS and complex anatomy; aspirin beyond 3 months nearly doubled major bleeding with no ischemic benefit (TWILIGHT and TICO trials).102 Three trials only used 1 month of DAPT in high-bleeding risk PCI patients, mostly ACS, and showed superior safety with DES vs BMS despite this short DAPT.98,99 As such, ESC guidelines allow, in ACS, a shorter DAPT duration of 3 months if high bleeding risk (class IIa). Beyond one year of PCI or MI, single therapy with oral anticoagulant is recommended (no aspirin nor clopidogrel) and appears to reduce mortality, bleeding and cardiovascular events compared to anticoagulant+single antiplatelet agent (AFIRE trial with rivaroxaban, and registry data).113,114 Figure 1.8 Antiplatelet therapy after PCI in patients who also require anticoagulation (AF, LV thrombus) (according to ESC and North American perspective 2021).112 Warfarin replaces NOAC in mechanical valves or mitral stenosis.
1
Non-ST-Segment Elevation Acute Coronary Syndrome
I. Definition, types of myocardial infarction, and pitfalls
A .Type 1 MI (spontaneous MI) = True acute coronary syndrome (ACS)
B. Type 2 MI (secondary MI) with or without underlying CAD
C. Non-ischemic myocardial injury (also called “non-MI troponin elevation”)
D .Coronary vasospasm and microvascular dysfunction
E. MI with non-obstructed coronary arteries (MINOCA)
F. Unstable angina
G. Additional notes: definition of reinfarction, type 3 MI, post-PCI MI (type 4 MI), and post-CABG MI (type 5 MI)
II. Clinical features, ECG, cardiac biomarkers, and echocardiography in ACS
A. Assess the clinical features of chest pain (Table 1.2)
B. ECG
Clinical features suggestive of angina
Typical angina is reproduced or worsened by exertion. In case of vasospasm, angina may occur only at rest or at night without an exertional component
Severe distress, deep fatigue, diaphoresis, jaw radiation, or severe nausea during pain is concerning for angina (the latter symptoms may occur without pain and are called “angina equivalents”)
Prior history of CAD or MI with typical angina or symptoms mimicking prior MIa
New MR murmurb
Clinical features suggestive of a low angina likelihood (the 3 Ps)
Chest pain that is P ositional or reproduced with certain chest/arm movements
P leuritic pain (↑ with inspiration or cough: suggests pleural or pericardial pain, or costochondritis)
P alpable pain localized at a fingertip area and fully reproduced with palpationc
Pain > 30–60 min with consistently negative troponin
Very brief pain < 15 s
C. Cardiac Troponin I or T
D. Echocardiography and acute resting nuclear scan
III. Initial approach to acute chest pain presentations and the use of conventional and high-sensitivity troponins
A. Assess for other serious causes of chest pain at least clinically, by chest X-ray and by ECG (always think of pulmonary embolism, aortic dissection, and pericarditis).
B. Use conventional troponin and hs-troponin for MI rule-in and rule-out
C. Stratification of patients who rule in for MI
IV. Management of NSTEMI
A. Initial invasive strategy
B. Antiplatelet therapy (Figure 1.4) (see Appendix 4 for a detailed discussion)
C. Anticoagulant therapy (see Appendix 4 for a detailed discussion)
D. Anti-ischemic therapy and other therapies
Antiplatelet therapy
1.Aspirin 325mg on admission to all, then 81 mg daily (after a 325mg first dose)
2.Clopidogrel 300mg or ticagrelor 180mg may be used on admission, but in the era of expedite catheterization <24 hours, ADP receptor antagonists are best reserved for downstream use, during PCI
3. After coronary angiography, if PCI is to be performed:
Add 300 mg of clopidogrel if 300 mg has already been given
or load with 600 mg of clopidogrel in the lab if no clopidogrel has been given
or load with prasugrel 60 mg (even if clopidogrel has been given)
or load with ticagrelor 180 mg (even if clopidogrel has been given)
or infuse IV cangrelor for 2 hours, not if patient already received P2Y12-antagonist, then load with oral P2Y12-antagonist as infusion finishes
GPI if PCI complications or heavy thrombus burden (bailout use of GPI)
Anticoagulant therapy
UFH pre-catheterization and during PCI
or UFH pre-catheterization and switch to bivalirudin during PCI
or Fondaparinux 2.5mg SQ once daily pre-catheterization, with standard-dose UFH or bivalirudin during PCI
or Enoxaparin pre-catheterization. If patient received 1 mg/kg SQ within 8h of PCI and has already received two doses of enoxaparin, no additional anticoagulation is needed during PCI (if enoxaparin was used 8–12 h ago or only one SQ dose was given, add 0.3 mg/kg IV during PCI; if enoxaparin was used >12h ago, give 0.5–0.75mg/kg IV bolus)
V. General procedural management after coronary angiography: PCI, CABG, or medical therapy only
A. CABG indications
B. PCI indications
C. Among patients with high-risk ACS managed invasively, ~25–30% do not undergo any revascularization after coronary angiography
VI. Discharge medications in NSTEMI
A. Antiplatelet and anticoagulant therapy
(1) age>75: -2; 65-75: -1;<65: 0
(2) smoking: +1; (3) diabetes: +1;
(4) stent in the setting of MI: +1; (5) recurrent event (prior PCI or MI): +1;
(6) stent <3 mm: +1; (7) HF or EF<30%: +2; (8) SVG stent: +2.
DAPT score ≥ +2 favors DAPT> 12 months, while age >75 argues against it.
PAD and CKD are additional markers of ischemic risk.112
3 vessels treated, ≥3 stents implanted ≥3 lesions treated, stent length >60 mm, bifurcation with 2 stents implanted, chronic total occlusion, left main, atherectomy
B. Other therapies
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