Allen Jeremias

Stent Thrombosis After Successful Sirolimus-Eluting Stent Implantation

Background—Stent thrombosis (ST) is a rare but devastating complication of coronary stent implantation, occurring in 0.5% to 1.9% of patients with bare metal stents. The incidence of ST with drug-eluting stents is less well studied, particularly among patients outside of clinical trials. Methods and Results—The aim of this study was to evaluate the incidence and potential risk factors for ST in patients receiving sirolimus-eluting stents (SES) in the “real world” after commercial release in the United States in April 2003. All 652 patients who underwent SES implantation (776 lesions treated) at our institution between April and October 2003 were followed up prospectively after the procedure (median follow-up 100 days). During that period, 7 patients (1.1%, 95% CI 0.4% to 2.2%) developed ST within a range of 2 to 13 days, and 1 patient had an ST-elevation myocardial infarction on day 39 with evidence of thrombus within the SES at angiography. Patients with an ST had significantly smaller final nominal balloon diameters (2.75 versus 3.00 mm, P =0.04), and in 4 (57%) of the 7 patients with ST versus 1.7% of patients without ST (P <0.001), antiplatelet therapy had been discontinued after the procedure. Among the ST patients, 1 died and 5 had myocardial infarctions. Conclusions—In this single-center experience, the incidence of ST after SES implantation was ≈1%, which is within the expected range of bare metal stents. The discontinuation of antiplatelet therapy was strongly associated with the development of ST in this patient population.

Narrative Review: Alternative Causes for Elevated Cardiac Troponin Levels when Acute Coronary Syndromes Are Excluded

In September 2000, the Joint European Society of Cardiology/American College of Cardiology (ESC/ACC) Committee proposed a new definition of myocardial infarction based predominantly on the detection of the cardiospecific biomarkers troponin T and troponin I in the appropriate clinical setting (1). The rationale of including troponin assays in the diagnostic pathway was based on the assumption that myocardial necrosis, regardless of its magnitude, should be characterized as a myocardial infarction. Contemporary troponin assays are quite sensitive and can detect even very small episodes of myocardial necrosis (<1 g). The Committees recommendation for the diagnosis of myocardial infarction based on troponin elevation categorizes a cohort of patients whose values exceed the 99th percentile of a reference control group with an acceptable imprecision (coefficient of variation) of 10% or less. Unfortunately, few assays in current clinical use meet this standard. It has therefore been proposed that an increase in cardiac troponin levels above the 10% coefficient of variation be considered indicative of myocardial injury (2). Given that numerous troponin assays are commercially available and in clinical use, each individual laboratory should confirm the range of reference values in their specific setting and define the value that is considered a significant troponin elevation. The ESC/ACC Committee consensus document states that any amount of myocardial damage implies an impaired clinical outcome for the patient and there is no discernible threshold below which an elevated value of cardiac troponin would be deemed harmless (1). This view is also reflected in the updated 2002 ACC/American Heart Association (AHA) practice guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction (3). However, the ACC/AHA guidelines do indicate that the myocardial necrosis signified by troponin elevation may not necessarily be due to atherosclerotic coronary artery disease and that myocardial infarction should therefore be diagnosed in conjunction with other supportive evidence. The implementation of these new guidelines in clinical practice has led to a substantial increase in the frequency of myocardial infarction diagnosis. For example, among 2181 patients presenting with chest pain to an inner-city tertiary care center, diagnoses of myocardial infarction based on cardiac troponin level increased up to 195% as compared with diagnoses made according to creatine kinase-MB criteria (4). Mortality at 30 days was significantly higher among patients with elevated troponin levels at presentation than among patients with no biomarkers detected, but it was not as high as among patients with elevated creatine kinase-MB levels. In several studies of acute coronary syndromes, troponin elevation has likewise been associated with a worse prognosis (5). Furthermore, the risk for subsequent death appears to be related to the degree of troponin elevation: There is a statistically significant increase in mortality with increasing levels of troponin, and the relative risk for death is 7.8 in the group with the highest troponin levels (6). While the presence of thrombus and impaired epicardial blood flow are both associated with troponin elevation (7, 8), impaired myocardial perfusion is a more robust and independent predictor of troponin elevation among patients with acute coronary syndromes (9). Among patients with a high pretest probability or clinical suspicion of thrombotic coronary artery disease, the diagnostic and prognostic value of troponin is clear. However, troponin testing is now also being used as a screening tool among patients with a low pretest probability of thrombotic coronary artery disease. Given the high sensitivity of cardiac troponin for detecting even minimal myocardial-cell necrosis, these markers may become positive even in the absence of thrombotic acute coronary syndromes. This may occasionally be related to a spurious troponin elevation (usually easily detectable by obtaining a second sample) but may also be due to several nonthrombotic cardiac and systemic diseases. In many instances, these troponin elevations may arise from demand ischemia, with or even without significant coronary artery disease or microcirculatory dysfunction, rather than supply-side thrombotic ischemia. For example, among 1000 consecutive patients presenting to the emergency department of a large urban hospital, troponin I level was elevated on admission in 112 patients, and 45% of these patients had a final diagnosis other than acute coronary syndrome (10). Given the high sensitivity but low specificity among these patients with a low pretest probability of disease, the detection of even minimal troponin elevation may divert attention from the true underlying clinical problem and may lead to unnecessary cardiac evaluation, including invasive testing. The goal of this article is to review potential causes of troponin elevation that are unrelated to coronary thrombosis (Table) and to provide guidance on the evaluation and management of patients with nonthrombotic troponin elevation. Table. Nonthrombotic Causes and Presumed Mechanism for Elevated Cardiac Troponin Level Cardiac Troponins Cardiac troponins are regulatory proteins that control the calcium-mediated interaction of actin and myosin. The troponin complex consists of 3 subunits: troponin T, which binds to tropomyosin and facilitates contraction; troponin I, which binds to actin and inhibits actin-myosin interactions; and troponin C, which binds to calcium ions (11). The amino acid sequences of the skeletal and cardiac isoforms of cardiac troponin T and troponin I are sufficiently dissimilar and therefore detectable by monoclonal antibody-based assays (3). Troponin C is not used clinically because both cardiac and smooth muscle share troponin C isoforms. The release of cardiac troponin from the myocyte to the blood can be due to reversible or irreversible cell damage. In prolonged ischemia, cells are irreversibly damaged as the cell membrane degrades, followed by the gradual release of myofibril-bound cytosolic complexes (11). However, the notion that troponin is increased only after irreversible myocardial necrosis has recently been challenged by the observation that some patients with unstable angina have only transient troponin elevations, with values returning to baseline within a few hours (12). This pattern of troponin increase may not be consistent with permanent myocardial damage. It is, therefore, conceivable that myocardial troponin can also be released in the setting of increased membrane permeability. For example, it is thought that myocardial depressive factors (released in the setting of sepsis and other inflammatory states) cause degradation of free troponin in situ to lower-molecular-weight fragments (13). With increased membrane permeability, those smaller troponin fragments could be released into the systemic circulation. In this setting, myocyte damage may not be permanent, and thus cell necrosis does not occur. This notion is also supported by the clinical observation that myocardial depression during sepsis is a fully reversible process in most surviving patients (14). Nonthrombotic Mechanisms of Troponin Elevation Demand Ischemia The concept of demand ischemia without significant coronary artery disease refers to a mismatch between myocardial oxygen demand and supply in the absence of flow-limiting epicardial stenosis. Although theoretically the same pathophysiologic principle may be valid in the presence of coronary artery disease, it may be more difficult to identify the predominant mechanism that accounts for myocardial ischemia in that clinical scenario. Myocardial oxygen demand frequently increases in the setting of sepsis or septic shock and the systemic inflammatory response syndrome (15-17), hypotension or hypovolemia (18), and atrial fibrillation or other tachyarrhythmias (19, 20). All of these clinical scenarios are either due to or can lead to tachycardia with various loading conditions on the heart. This increases myocardial oxygen demand while decreasing myocardial oxygen supply by shortening diastolic time, a period during which the majority of the myocardial perfusion occurs. In addition, sepsis and other systemic inflammatory processes may lead to myocardial depression, greatly increased oxygen consumption, reduced perfusion pressure, and decreased oxygen delivery to the heart, ultimately resulting in the release of troponin into the systemic circulation (16). Among 20 septic patients treated in an intensive care unit, 85% were noted to have elevated troponin levels (16). The majority (59%) had no evidence of significant coronary artery disease. Similarly, Guest and colleagues found that elevated cardiac troponin level is a common finding among critically ill patients and is associated with a significant increase in mortality (15). In a more recent study, Ammann and colleagues evaluated 58 patients who were admitted to the intensive care unit for diagnoses other than acute coronary syndromes (17). Among the 55% of patients with elevated troponin levels, tumor necrosis factor-, interleukin-6, and C-reactive protein levels were significantly higher than among patients with undetectable troponin, and mortality was fourfold higher in the troponin-positive group. Of note, significant coronary artery disease was excluded in 72% of troponin-positive patients. Thus, troponin elevation among patients with sepsis and the systemic inflammatory response syndrome with or without shock in the intensive care unit setting is common and largely affects patients without significant coronary artery disease. Troponin elevation is associated with a worse prognosis, but whether any cardiovascular intervention could improve outcomes among these patients is unclear. Although a causal relationship has yet to be established, infl

Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve: the RESOLVE study.

OBJECTIVES This study sought to examine the diagnostic accuracy of the instantaneous wave-free ratio (iFR) and resting distal coronary artery pressure/aortic pressure (Pd/Pa) with respect to hyperemic fractional flow reserve (FFR) in a core laboratory-based multicenter collaborative study. BACKGROUND FFR is an index of the severity of coronary stenosis that has been clinically validated in 3 prospective randomized trials. iFR and Pd/Pa are nonhyperemic pressure-derived indices of the severity of stenosis with discordant reports regarding their accuracy with respect to FFR. METHODS iFR, resting Pd/Pa, and FFR were measured in 1,768 patients from 15 clinical sites. An independent physiology core laboratory performed blinded off-line analysis of all raw data. The primary objectives were to determine specific iFR and Pd/Pa thresholds with ≥90% accuracy in predicting ischemic versus nonischemic FFR (on the basis of an FFR cut point of 0.80) and the proportion of patients falling beyond those thresholds. RESULTS Of 1,974 submitted lesions, 381 (19.3%) were excluded because of suboptimal acquisition, leaving 1,593 for final analysis. On receiver-operating characteristic analysis, the optimal iFR cut point for FFR ≤0.80 was 0.90 (C statistic: 0.81 [95% confidence interval: 0.79 to 0.83]; overall accuracy: 80.4%) and for Pd/Pa was 0.92 (C statistic: 0.82 [95% confidence interval: 0.80 to 0.84]; overall accuracy: 81.5%), with no significant difference between these resting measures. iFR and Pd/Pa had ≥90% accuracy to predict a positive or negative FFR in 64.9% (62.6% to 67.3%) and 48.3% (45.6% to 50.5%) of lesions, respectively. CONCLUSIONS This comprehensive core laboratory analysis comparing iFR and Pd/Pa with FFR demonstrated an overall accuracy of ~80% for both nonhyperemic indices, which can be improved to ≥90% in a subset of lesions. Clinical outcome studies are required to determine whether the use of iFR or Pd/Pa might obviate the need for hyperemia in selected patients.

Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI

Background Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave‐free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR. Methods We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR‐guided or FFR‐guided coronary revascularization. The primary end point was the 1‐year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk. Results At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, ‐0.2 percentage points; 95% confidence interval [CI], ‐2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001). Conclusions Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE‐FLAIR ClinicalTrials.gov number, NCT02053038.)

Frequency of major noncardiac surgery and subsequent adverse events in the year after drug-eluting stent placement results from the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) Registry.

OBJECTIVES This study sought to determine the frequency of noncardiac surgery and adverse post-operative events among patients who recently received a drug-eluting stent (DES) following noncardiac surgery. BACKGROUND Little is known about frequency of and risks associated with noncardiac surgery after DES implantation. METHODS In the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) registry, consecutive patients who underwent attempted stent placement at 42 hospitals between July 2004 and September 2005 were enrolled and followed for 1 year. In this study, we analyzed patients who received ≥ 1 DES to determine the frequency of noncardiac surgery and cardiac death, myocardial infarction, or stent thrombosis in the following week. RESULTS Among 4,637 DES recipients, 206 (4.4%) underwent major noncardiac surgery in the following year (median days to surgery: 179 [interquartile range 112 to 266 days; range 13 to 360 days]). Overall, stent use averaged 1.5 per patient. The most frequent operations were orthopedic (36%), abdominal (31%), and vascular (20%). Compared with patients who did not undergo surgery, those who did were older, more likely to be women, and have had a prior stroke; the frequencies of prior myocardial infarction, prior coronary artery bypass graft, and diabetes were similar, as were left ventricular ejection fraction and indication for percutaneous coronary intervention. In the 7 days after surgery, 4 patients had a cardiac death, myocardial infarction, or stent thrombosis (1.9% [exact 95% confidence interval (CI): 0.5% to 4.9%]). The risk of the composite outcome was increased 27-fold in the week following noncardiac surgery compared with any other week after stent implantation (hazard ratio [HR]: 27.3 [95% CI: 10.0 to 74.2], p < 0.001). CONCLUSIONS The frequency of major noncardiac surgery in the year after DES placement is >4%. Although the overall risk of adverse outcomes was less than previously reported when surgery is performed months after DES placement, it is significantly increased in the week after major noncardiac surgery.

The utility of troponin measurement to detect myocardial infarction: review of the current findings

Myocardial infarction (MI) is defined by the presence of myocardial necrosis in combination with clinical evidence of myocardial ischemia. Cardiac troponins are regulatory proteins within the myocardium that are released into the circulation when damage to the myocyte has occurred. Therefore, serum troponin is an exquisitely sensitive marker of myocardial injury and is necessary for establishing the diagnosis of MI. High-sensitivity troponin assays are improving the diagnostic accuracy and rapid detection of myocardial infarction. The early identification of MI is vital for the institution of anti-thrombotic therapy to limit myocardial damage and preserve cardiac function. Troponin has both diagnostic and prognostic significance in the setting of acute coronary syndrome (ACS). Increased troponin levels in the absence of ACS should prompt an evaluation for an alternative, non-thrombotic mechanism of troponin elevation and direct management at the underlying cause. This review describes the role of troponin in the evaluation of patients with suspected myocardial infarction.

The impact of revascularization on mortality in patients with nonacute coronary artery disease

BACKGROUND Although early revascularization improves outcomes for patients with acute coronary syndromes, the role of revascularization for patients with nonacute coronary artery disease is controversial. The objective of this meta-analysis was to compare surgical or percutaneous revascularization with medical therapy alone to determine the impact of revascularization on death and nonfatal myocardial infarction in patients with coronary artery disease. METHODS The Medline and Cochrane Central Register of Controlled Trials databases were searched to identify randomized trials of coronary revascularization (either surgical or percutaneous) versus medical therapy alone in patients with nonacute coronary disease reporting the individual outcomes of death or nonfatal myocardial infarction reported at a minimum follow-up of 1 year. A random effects model was used to calculate odds ratios (OR) for the 2 prespecified outcomes. RESULTS Twenty-eight studies published from 1977 to 2007 were identified for inclusion in the analysis; the revascularization modality was percutaneous coronary intervention in 17 studies, coronary bypass grafting in 6 studies, and either strategy in 5 studies. Follow-up ranged from 1 to 10 years with a median of 3 years. The 28 trials enrolled 13,121 patients, of whom 6476 were randomized to revascularization and 6645 were randomized to medical therapy alone. The OR for revascularization versus medical therapy for mortality was 0.74 (95% confidence interval [CI], 0.63-0.88). A stratified analysis according to revascularization mode revealed both bypass grafting (OR 0.62; 95% CI, 0.50-0.77) and percutaneous intervention (OR 0.82; 95% CI, 0.68-0.99) to be superior to medical therapy with respect to mortality. Revascularization was not associated with a significant reduction in nonfatal myocardial infarction compared with medical therapy (OR 0.91; 95% CI, 0.72-1.15). CONCLUSION Revascularization by coronary bypass surgery or percutaneous intervention in conjunction with medical therapy in patients with nonacute coronary artery disease is associated with significantly improved survival compared with medical therapy alone.

Expert Consensus Statement on the Use of Fractional Flow Reserve, Intravascular Ultrasound, and Optical Coherence Tomography: A Consensus Statement of the Society of Cardiovascular Angiography and Interventions

The rationale for use of intracoronary physiology assessment and imaging arises from the limitations of coronary angiography, the traditional method for determining the severity of coronary stenoses. The visual assessment of percent diameter reduction has significant interobserver variability [1–3], even among experienced angiographers [4]. Computer-assisted quantitative coronary angiography only marginally improves diagnostic accuracy and its estimate of functional significance [5]. Fractional flow reserve (FFR) is used to determine the functional significance of a coronary stenosis [6]. Intravascular ultrasound (IVUS) offers excellent visualization of intraluminal and transmural coronary anatomy. Optical coherence tomography (OCT) further improves vascular visualization. There is now persuasive evidence regarding intracoronary diagnostic lesion assessments using physiology and anatomy. These adjunctive diagnostic procedures may influence the decision for coronary revascularization, guide the performance of percutaneous coronary interventions (PCI), and optimize procedural outcomes. There are substantial long-term outcome data showing benefit associated with FFR-guided decision-making. However, these techniques are underutilized in contemporary practice: the rates of use of IVUS and FFR during PCI for intermediate coronary stenoses (40–70% diameter stenosis) are 20.3% and 6.1% respectively [7]. In 2011, the ACCF/AHA/SCAI PCI guidelines [8] assigned levels of evidence for the use of these modalities in various clinical situations (Table T1 I). The purpose of this consensus statement is to review recent studies, to develop a consensus of how these

Continuum of Vasodilator Stress From Rest to Contrast Medium to Adenosine Hyperemia for Fractional Flow Reserve Assessment

OBJECTIVES This study compared the diagnostic performance with adenosine-derived fractional flow reserve (FFR) ≤0.8 of contrast-based FFR (cFFR), resting distal pressure (Pd)/aortic pressure (Pa), and the instantaneous wave-free ratio (iFR). BACKGROUND FFR objectively identifies lesions that benefit from medical therapy versus revascularization. However, FFR requires maximal vasodilation, usually achieved with adenosine. Radiographic contrast injection causes submaximal coronary hyperemia. Therefore, intracoronary contrast could provide an easy and inexpensive tool for predicting FFR. METHODS We recruited patients undergoing routine FFR assessment and made paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, cFFR, and FFR). Contrast medium and dose were per local practice, as was the dose of intracoronary adenosine. Operators were encouraged to perform both intracoronary and intravenous adenosine assessments and a final drift check to assess wire calibration. A central core lab analyzed blinded pressure tracings in a standardized fashion. RESULTS A total of 763 subjects were enrolled from 12 international centers. Contrast volume was 8 ± 2 ml per measurement, and 8 different contrast media were used. Repeated measurements of each metric showed a bias <0.005, but a lower SD (less variability) for cFFR than resting indexes. Although Pd/Pa and iFR demonstrated equivalent performance against FFR ≤0.8 (78.5% vs. 79.9% accuracy; p = 0.78; area under the receiver-operating characteristic curve: 0.875 vs. 0.881; p = 0.35), cFFR improved both metrics (85.8% accuracy and 0.930 area; p < 0.001 for each) with an optimal binary threshold of 0.83. A hybrid decision-making strategy using cFFR required adenosine less often than when based on either Pd/Pa or iFR. CONCLUSIONS cFFR provides diagnostic performance superior to that of Pd/Pa or iFR for predicting FFR. For clinical scenarios or health care systems in which adenosine is contraindicated or prohibitively expensive, cFFR offers a universal technique to simplify invasive coronary physiological assessments. Yet FFR remains the reference standard for diagnostic certainty as even cFFR reached only ∼85% agreement.

Prevalence and prognostic significance of preprocedural cardiac troponin elevation among patients with stable coronary artery disease undergoing percutaneous coronary intervention: results from the evaluation of drug eluting stents and ischemic events registry.

Background— Although cardiac troponin (cTn) elevation is associated with periprocedural complications during percutaneous coronary intervention (PCI) in the setting of acute coronary syndromes, the prevalence and prognostic significance of preprocedural cTn elevation among patients with stable coronary artery disease undergoing PCI are unknown. Methods and Results— Between July 2004 and September 2006, 7592 consecutive patients who underwent attempted stent placement at 47 hospitals throughout the United States were enrolled in a prospective multicenter registry. We analyzed the frequency of an elevated cTn immediately before PCI and its relationship to in-hospital and 1-year outcomes among patients who underwent PCI for either stable angina or a positive stress test. Among the stable coronary artery disease population (n=2382, 31.4%), 142 (6.0%) had a cTn level above the upper limit of normal before the procedure. Compared with patients who had normal baseline cTn, patients with elevated cTn had a higher rate of in-hospital death or myocardial infarction (13.4% versus 5.6%; P<0.001) and a trend toward higher rates of urgent repeat PCI (1.4% versus 0.2%; P=0.06). In multivariable analyses adjusted for demographic, clinical, angiographic, and procedural factors, baseline cTn elevation remained independently associated with the composite of death or myocardial infarction at hospital discharge (odds ratio, 2.1; 95% confidence interval, 1.2 to 3.8; P=0.01) and at the 1-year follow-up (odds ratio, 2.0; 95% confidence interval, 1.2 to 3.3; P=0.005). Conclusions— Baseline elevation of cTn is relatively common among patients with stable coronary artery disease undergoing PCI and is an independent prognostic indicator of ischemic complications. If these data are confirmed in future studies, consideration should be given to routine testing of cTn before performance of PCI in this patient population.