Effectiveness of Clopidogrel vs Alternative P2Y12 Inhibitors Based on the ABCD-GENE Score.

BACKGROUND: An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear. OBJECTIVES: The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y12 inhibitor (prasugrel or ticagrelor) therapy after percutaneous coronary intervention (PCI). METHODS: A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y12 inhibitor treatment were included. The primary outcome was major atherothrombotic events (MAE) within 1 year after PCI. Cox regression was performed to assess event risk in clopidogrel-treated (reference) vs alternatively treated patients, with stabilized inverse probability weights derived from exposure propensity scores after stratifying by ABCD-GENE score and further by CYP2C19 loss-of-function (LOF) genotype. RESULTS: Among patients with scores <10 (n = 3,200), MAE was not different with alternative therapy vs clopidogrel (weighted HR: 0.89; 95% CI: 0.65-1.22; P = 0.475). The risk for MAE also did not significantly differ by treatment among patients with scores ≥10 (n = 1,135; weighted HR: 0.75; 95% CI: 0.51-1.11; P = 0.155). Among CYP2C19 LOF allele carriers, MAE risk appeared lower with alternative therapy in both the group with scores <10 (weighted HR: 0.50; 95% CI: 0.25-1.01; P = 0.052) and the group with scores ≥10 (weighted HR: 0.48; 95% CI: 0.29-0.80; P = 0.004), while there was no difference in the group with scores <10 and no LOF alleles (weighted HR: 1.03; 95% CI: 0.70-1.51; P = 0.885). CONCLUSIONS: These data support the use of alternative therapy over clopidogrel in CYP2C19 LOF allele carriers after PCI, regardless of ABCD-GENE score, while clopidogrel is as effective as alternative therapy in non-LOF patients with scores <10.

A case of ultra-prolonged intra-aortic balloon pump support via sheathless femoral access.

Background: An intra-aortic balloon pump (IABP) is a mechanical circulatory support platform with a relatively low complication rate. Axillary access is increasingly utilized to allow rehabilitation. Case summary: We present a case of femoral IABP inserted into the femoral artery percutaneously via a sheathless technique that allowed the patient to ambulate and physically rehabilitate over 102 days until cardiac transplantation. The patient was able to progress with the protocolized rehabilitation programme to up to 3500 ft walking distance. The IABP was removed at the time of transplantation without any vascular complications. Discussion: While axillary IABP offers an opportunity to rehabilitate, it has an unacceptably high complication rate, often resulting in vascular injury that adds morbidity to an acutely ill cohort. In this case, we found that sheathless femoral IABP access offered stability for a prolonged time while avoiding pain, bleeding, infection, and vascular injury. We hypothesize that this is due to less indwelling prosthetic material usage and also device flexibility, allowing conformation to the natural course of the femoral artery. We are encouraged by this case to use a sheathless access approach for patients expected to require prolonged IABP support.

Impact of the ABCD-GENE Score on Clopidogrel Clinical Effectiveness after PCI: A Multi-Site, Real-World Investigation.

The Age, Body mass index, Chronic kidney disease, Diabetes mellitus, and CYP2C19 GENEtic variants (ABCD-GENE) score was developed to identify patients at risk for diminished antiplatelet effects with clopidogrel after percutaneous coronary intervention (PCI). The objective of this study was to validate the ability of the ABCD-GENE score to predict the risk for atherothrombotic events in a diverse, real-world population of clopidogrel-treated patients who underwent PCI and received clinical CYP2C19 genotyping to guide antiplatelet therapy. A total of 2,341 adult patients who underwent PCI, were genotyped for CYP2C19, and received treatment with clopidogrel across four institutions were included (mean age 64 ± 12 years, 35% women, and 20% Black). The primary outcome was major atherothrombotic events, defined as the composite of all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina within 12 months following PCI. Major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, myocardial infarction, ischemic stroke, or stent thrombosis, was assessed as the secondary outcome. Outcomes were compared between patients with an ABCD-GENE score ≥ 10 vs. < 10. The risk of major atherothrombotic events was higher in patients with an ABCD-GENE score ≥ 10 (n = 505) vs. < 10 (n = 1,836; 24.6 vs. 14.7 events per 100 patient-years, adjusted hazard ratio (HR) 1.66, 95% confidence interval (CI), 1.23-2.25, P < 0.001). The risk for MACE was also higher among patients with a score ≥ 10 vs. < 10 (16.7 vs. 10.1 events per 100 patient-years, adjusted HR 1.59, 95% CI 1.11-2.30, P = 0.013). Our diverse, real-world data demonstrate diminished clopidogrel effectiveness in post-PCI patients with an ABCD-GENE score ≥ 10.

Massive Tension Hemothorax After Pacemaker Implantation.

A case of an 85-year-old male on apixaban and clopidogrel undergoing pacemaker implantation is described. After procedure he developed unilateral tension hemothorax and required emergent drainage and exploratory thoracotomy. No vascular, cardiac, or pulmonary source was identified. After multidisciplinary discussions, it was speculated that spontaneous intercostal vessel rupture due to forceful coughing and elevated blood pressure during the procedure was the most likely cause of bleeding.

Regadenoson, a selective A2A adenosine receptor agonist, causes dose-dependent increases in coronary blood flow velocity in humans.

BACKGROUND: Regadenoson is a selective A2A adenosine receptor agonist and vasodilator used to increase the heterogeneity of distribution of coronary blood flow during myocardial perfusion imaging. This study characterized the dose dependence of regadenoson-induced coronary hyperemia. METHODS AND RESULTS: An open-label, dose-escalation study of regadenoson (10-500 microg, rapid intravenous bolus) was performed in 34 subjects; in 4 additional subjects, the effect of aminophylline to reverse the response to regadenoson was determined. Intracoronary peak blood flow velocity in either the left anterior descending or left circumflex artery was measured by continuous Doppler signal recording, heart rate, central aortic blood pressure, and adverse effects were recorded. Regadenoson increased peak blood flow velocity by up to 3.4-fold in a dose-dependent manner. The mean duration of the increase in flow velocity of 2.5-fold or greater caused by 400 to 500 microg of regadenoson was 2.3 to 2.4 minutes. Regadenoson (400-500 microg) increased heart rate by up to 21 +/- 6 beats/min and decreased systolic blood pressure (-5 +/- 8 mm Hg to -24 +/- 16 mm Hg) and diastolic blood pressure (-8 +/- 4 mm Hg to -15 +/- 14 mm Hg). Aminophylline (100 mg) attenuated the increase in peak flow velocity but not tachycardia caused by 400 microg of regadenoson. CONCLUSION: The results of this study demonstrate the utility of regadenoson as a coronary vasodilator for myocardial perfusion imaging.

Phytoestrogens and coronary microvascular function in women with suspected myocardial ischemia: a report from the Women's Ischemia Syndrome Evaluation (WISE) Study.

AIMS: Soy phytoestrogens are popular, but information on their coronary effects in patients with suspected ischemic heart disease is limited. Accordingly, we investigated the relationship between blood phytoestrogen levels and coronary reactivity in women with suspected myocardial ischemia referred for coronary angiography. METHODS: Coronary flow velocity reserve (CFVR) and volumetric flow reserve (VFR) to adenosine (ADO) and nitroglycerin (NTG) (nonendothelial-dependent responses) and acetylcholine (ACH) (endothelial-dependent response) were assessed in 106 women from the Women's Ischemia Syndrome Evaluation (WISE). Blood phytoestrogen (daidzein and genistein) and estrogen (estradiol) levels were correlated with coronary reactivity measures. RESULTS: Participants were mostly postmenopausal (79%), mean age 56 years, and 24% had obstructive coronary artery disease (CAD) at angiography. Genistein blood levels were negatively correlated with nonendothelial-dependent coronary flow responses. The highest genistein tertile (>6.1 ng/mL) had a CFVR of 2.1 +/- 0.5 (mean +/- SD) and VFRADO of 1.0 +/- 0.6, and both were significantly (p= 0.0001) lower compared with the other genistein tertiles combined. Similar associations were noted for CFVR(NTG) and VFR(NTG) (p = 0.03 and p = 0.01, respectively). The highest genistein tertile was associated with lower CFVR(ACH) compared with the other tertiles (p = 0.03). In multivariable modeling, blood genistein levels were significant independent predictors of coronary flow responses to ADO. There were no significant correlations between coronary reactivity variables and daidzein or endogenous estrogen. CONCLUSIONS: In women with suspected myocardial ischemia, higher genistein blood levels are associated with impaired nonendothelial-dependent and endothelial-dependent coronary microvascular function.

Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Altered coronary reactivity is frequent in women with findings of myocardial ischemia without significant obstructive disease. This suggests a defect in coronary microvascular function. The adenosine-related component of this altered reactivity has been described in male and mixed gender populations, while the factors influencing this component of coronary reactivity in symptomatic women have received limited attention. Accordingly, the relationship between adenosine-related microvascular coronary reactivity and risk factors in symptomatic women evaluated for suspected ischemia remains uncertain. HYPOTHESIS: Abnormal coronary microvascular reactivity to adenosine is predicted by atherosclerosis risk factors in women. METHODS: As part of the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE), we investigated the relationship between risk factors and coronary microvascular reactivity as flow velocity reserve to intracoronary adenosine (CFVR(Ado)) in 210 women referred for angiography to evaluate suspected ischemia. RESULTS: Univariate analyses identified associations between CFVR(Ado) and multiple risk conditions; however, after adjusting for age, none remained significant. The best multivariable model using combinations of risk conditions to predict CFVR(Ado) yielded an R2 of only 0.18. CONCLUSIONS: Among women with suspected ischemia, risk factors account for <20% of observed variability in CFVR(Ado). Therefore, other as yet unidentified factors must primarily account for coronary microvascular reactivity to adenosine.

Some thoughts on the vasculopathy of women with ischemic heart disease.

Considerable experimental and clinical data indicate that sex has an important influence on cardiovascular physiology and pathology. This report integrates selected literature with new data from the Women's Ischemia Syndrome Evaluation (WISE) on vascular findings in women with ischemic heart disease (IHD) and how these findings differ from those in men. A number of common vascular disease-related conditions are either unique to (e.g., hypertensive disorders of pregnancy, gestational diabetes, peripartum dissection, polycystic ovarian syndrome, etc.) or more frequent (e.g., migraine, coronary spasm, lupus, vasculitis, Raynaud's phenomenon, etc.) in women than men. Post-menopausal women more frequently have many traditional vascular disease risk conditions (e.g., hypertension, diabetes, obesity, inactivity, and so on), and these conditions cluster more frequently in them than men. Considerable evidence supports the notion that, with these requisite conditions, women develop a more severe or somewhat different form of vascular disease than men. Structurally, women's coronary vessels are smaller in size and appear to contain more diffuse atherosclerosis, their aortas are stiffer (fibrosis, remodeling, and so on), and their microvessels appear to be more frequently dysfunctional compared with men. Functionally, women's vessels frequently show impaired vasodilator responses. Limitations of existing data and higher risks in women with acute myocardial infarction, need for revascularization, or heart failure create uncertainty about management. A better understanding of these findings should provide direction for new algorithms to improve management of the vasculopathy underlying IHD in women.

Impaired coronary vascular reactivity and functional capacity in women: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE) Study.

OBJECTIVES: We investigated the relationship between coronary vascular reactivity and functional capacity as assessed from the Duke Activity Status Index (DASI) in a cohort of women evaluated for suspected ischemia. BACKGROUND: Reduced functional capacity and impaired vascular reactivity are associated with poor prognosis, but an association between vascular reactivity and functional capacity is unknown. METHODS: A total of 190 women enrolled in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE) study had baseline clinical assessment and coronary artery flow velocity response to adenosine (CFVR(ado)). We compared these results with self-reported DASI metabolic equivalents (METs). RESULTS: Mean age was 55 +/- 11 years (range 21 to 83 years), and only 18% had coronary stenosis > or =50%. Women with a CFVR(ado) <2.5 (n = 98) had mean DASI of 15.1 +/- 13.6, compared to women (n = 92) with CFVR(ado) > or =2.5, whose mean DASI was 21.0 +/- 15.2 (p = 0.004). This relationship was maintained after adjusting for age and presence of coronary artery disease. CFVR(ado) of > or =2.5 was associated with a DASI of >20 (odds ratio 3.03, 95% confidence interval 1.56 to 5.90, p = 0.001). CONCLUSIONS: Women with reduced CFVR(ado) were significantly more likely to have reduced functional capacity. Impairment in coronary vascular function and reduced levels of activity may both play a role in the poorer prognosis observed in the WISE study women; however, the relationship between the two is still unclear.

Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Coronary vascular dysfunction has been linked to atherosclerosis and adverse cardiovascular outcomes in men, but these relationships have not been firmly established in women. METHODS AND RESULTS: As part of the Women's Ischemia Syndrome Evaluation (WISE) sponsored by the National Heart, Lung, and Blood Institute, 163 women referred for clinically indicated coronary angiography underwent coronary reactivity assessment with quantitative coronary angiography and intracoronary Doppler flow before and after intracoronary administration of acetylcholine, adenosine, and nitroglycerin and were then followed up for clinical outcomes. History of hypertension was present in 61%, dyslipidemia in 54%, diabetes in 26%, and current tobacco use in 21% of women enrolled. Seventy-five percent had no or only mild epicardial coronary artery disease (CAD). Over a median follow-up of 48 months, events occurred in 58 women. On bivariate analysis, women with an event had significantly less change in coronary cross-sectional area (DeltaCSA) in response to acetylcholine (P=0.0006) and nitroglycerin (P=0.04). In addition, women with abnormal coronary dilator response to acetylcholine had less time free from cardiovascular events (P=0.004). In multivariable analysis, after controlling for age, hypertension, diabetes, dyslipidemia, tobacco use, and CAD severity, %DeltaCSA with acetylcholine (P=0.001) independently predicted events. When the outcome was restricted to only death, myocardial infarction, congestive heart failure, and stroke, %DeltaCSA with acetylcholine remained a significant predictor (P=0.006). CONCLUSIONS: In women in this study, impaired coronary vasomotor response to acetylcholine was independently linked to adverse cardiovascular outcomes regardless of CAD severity.

Pharmacologic plaque passivation for the reduction of recurrent cardiac events in acute coronary syndromes.

Acute coronary syndrome (ACS) is often associated with the rupture of vulnerable atherosclerotic plaque, coronary thrombus formation, and abrupt limitation of blood flow, leading to adverse outcomes. Passivation of vulnerable plaque represents a therapeutic concept that has the potential to prevent or limit the magnitude of a new rupture in order to reduce the recurrence or severity of events. Plaque passivation can be defined as a process by which the structure or content of the atherosclerotic plaque is changed to reduce the risk of subsequent rupture and thrombosis. This may be achieved by using strategies that address different components of the plaque or the endothelium. The following factors can affect the susceptibility of plaque to rupture: macrophage infiltration; accumulation of inflammatory cells; paracrine secretion of enzymes that may cause degradation of the fibrous cap of coronary plaque; shear stress; circadian rhythm variation in stress hormone release; and infectious agents. The use of pharmacologic agents to reduce plaque vulnerability by passivation has been explored. Clinical studies demonstrate that lipid-modifying agents (e.g., statins), antiplatelet agents (acetylsalicylic acid, thienopyridines, thianopyridines, glycoprotein IIb/IIIa inhibitors), and antithrombotic agents (unfractionated heparin and low-molecular-weight heparin) can reduce the occurrence of acute coronary events in ACS patients. In addition, angiographic studies suggest that statins may also promote regression of atherosclerosis. Angiotensin-converting enzyme inhibitors, niacin, and calcium antagonists may also contribute to plaque passivation. This article reviews atherosclerotic plaque development and vulnerability and discusses some clinical studies highlighting the role of plaque passivation in the management of ACS patients.

Percutaneous coronary intervention versus medical therapy for coronary allograft vasculopathy. One center's experience.

BACKGROUND: Coronary allograft vasculopathy, a rapidly progressive form of atherosclerosis, remains the limiting factor in the long-term survival of heart transplant recipients. Some centers have attempted percutaneous coronary intervention to slow the disease process and thereby reduce mortality in these patients, but long-term follow-up data are scarce. We compared clinical outcomes in heart transplant recipients with coronary allograft vasculopathy who were treated either with percutaneous coronary intervention or with aggressive medical therapy alone. METHODS: A retrospective analysis of all heart transplant recipients at our institution who underwent surveillance coronary angiography for coronary allograft vasculopathy between 1995 and 2000 was performed. Patients with coronary allograft vasculopathy were stratified according to whether they received medical therapy or percutaneous coronary intervention. Baseline demographics, results of re-vascularization procedures and outcomes were analyzed. RESULTS: From 1995 to 2000, 301 patients underwent 602 coronary angiograms. Of the 79 patients who had angiographic evidence of coronary allograft vasculopathy, 53 were treated with aggressive medical therapy, while 26 underwent percutaneous coronary intervention in addition to aggressive medical therapy. At baseline, patients treated with aggressive medical therapy tended to be younger (54.6 +/- 13.8 years) than patients treated with percutaneous coronary intervention (62.6 +/- 7.6 years; p = 0.0079). Ejection fraction at time of diagnosis of coronary allograft vasculopathy was similar for both groups (medical therapy group, 44.4 +/- 13.4% vs percutaneous coronary intervention group, 47.2 +/- 12.7%; p = 0.38). In our cohort, heart transplant recipients with coronary allograft vasculopathy demonstrated greater mortality than heart transplant recipients without coronary allograft vasculopathy (p = 0.016). Patients who underwent percutaneous coronary intervention had a 60% re-stenosis rate at 6 months if they were treated with coronary angioplasty and an 18% re-stenosis rate if they received a coronary stent. Kaplan-Meier analysis showed no significant difference in survival in either treatment group at 1 year (80% for medical therapy group vs 95% for percutaneous coronary intervention group) or 3 years (68% for medical therapy group vs 79% for percutaneous coronary intervention group) after the angiographic diagnosis of coronary allograft vasculopathy. CONCLUSION: In this non-randomized trial, heart transplant recipients with coronary allograft vasculopathy were less likely to survive than patients without it. In addition, we found no statistical difference in mortality in heart transplant recipients with coronary allograft vasculopathy, regardless of whether they received percutaneous coronary intervention or aggressive medical therapy alone.

Angiographic patterns and the natural history of the vulnerable plaque.

Coronary angiography is the gold standard for the identification of obstructive coronary artery disease (CAD). The use of this diagnostic test in the evaluation of many clinical syndromes of CAD has yielded a wealth of angiographic data relative to the vulnerable atherosclerotic plaque. This chapter reviews these important data including the limitations of the angiogram in vulnerable plaque detection, angiographic patterns of complex plaques or "culprit lesions," and the natural history of the complex angiographic lesion.

Revisiting the culprit lesion in non-Q-wave myocardial infarction. Results from the VANQWISH trial angiographic core laboratory.

OBJECTIVE: We sought to determine the underlying coronary anatomy and characterize the culprit lesion after non-Q-wave myocardial infarction (NQWMI). BACKGROUND: Although the culprit lesion and infarct-related artery often are easily identified with coronary angiography after Q-wave MI, the culprit lesion after NQWMI has not been well characterized. Small retrospective studies have suggested that the absence of Q-waves on an electrocardiogram is due to incomplete occlusion of the infarct-related artery. METHODS: Coronary angiograms from 350 patients randomized to the early invasive strategy in the Veterans Affairs Non-Q-Wave Infarction Strategies in-Hospital (VANQWISH) trial were systematically analyzed in an angiographic core laboratory. A consensus panel identified the culprit lesion and the infarct-related artery using prespecified criteria for complex lesion morphology and acute versus chronic occlusions. Severity of angiographic disease and left ventricular function also were analyzed. Patients with a single identified culprit lesion were compared with those who had multiple apparent culprits and those without an identifiable culprit lesion. RESULTS: A single culprit lesion was identified in only 49% of patients undergoing early angiography after NQWMI. The majority of patients either had no identifiable culprit (37%) or multiple apparent culprit lesions (14%). A single incomplete occlusion of the infarct-related artery was found in only 36% of patients, and an isolated acute occlusion of the infarct-related artery occurred in 13%. Patients without an identifiable culprit lesion had severe coronary disease (obstructive coronary artery disease [CAD] in 84%) but no complex lesion morphology. There was no difference in angiographic severity of disease comparing patients with and without identifiable culprit lesions. Patients with a single incomplete occlusion of the infarct-related artery were more likely to undergo percutaneous transluminal coronary angioplasty than other patients, whereas patients with multiple culprit lesions were more frequently treated with coronary artery bypass grafting. CONCLUSIONS: Coronary angiography early after NQWMI frequently identifies severe obstructive CAD, but a single identifiable culprit lesion was identified in <50% of patients. Multiple culprit lesions were seen in 14% of patients. An angiographic culprit lesion could not be identified in more than one-third of patients undergoing coronary angiography as part of an invasive strategy.

Systolic compression of the left anterior descending coronary artery: a case series, review of the literature, and therapeutic options including stenting.

Six cases in our institution of various presentations of left anterior descending (LAD) myocardial bridging were found on coronary angiography. Generally a benign condition, this finding can result in ischemia or infarction as seen in some of our cases. We found one case in which the bridge resulted in an anterior myocardial infarction in an elderly patient, one case with fixed stenoses at the entry and exit point of the bridge causing ischemia, another with vasospasm within the bridged segment, one case in which the patient was referred for intervention of a fixed stenosis which after intracoronary nitroglycerin (NTG) was found to be an LAD bridge, another case in which the thallium myocardial perfusion scan revealed a reversible anterior defect, and finally one case with anginal chest pain despite a normal coronary flow reserve proximal and distal to the bridged segment. Our treatments varied from stenting in three patients to medical therapy in the remaining patients. We concluded that a thorough evaluation in this population should include functional testing for ischemia, intravascular ultrasound to assess wall thickness, and coronary flow reserve measurements in order to determine the significance of the these bridges. Stenting may have a role in select patients. However, additional studies are needed.