Cerebral Embolic Protection during Transcatheter Aortic-Valve Replacement.

BACKGROUND: Transcatheter aortic-valve replacement (TAVR) for the treatment of aortic stenosis can lead to embolization of debris. Capture of debris by devices that provide cerebral embolic protection (CEP) may reduce the risk of stroke. METHODS: We randomly assigned patients with aortic stenosis in a 1:1 ratio to undergo transfemoral TAVR with CEP (CEP group) or without CEP (control group). The primary end point was stroke within 72 hours after TAVR or before discharge (whichever came first) in the intention-to-treat population. Disabling stroke, death, transient ischemic attack, delirium, major or minor vascular complications at the CEP access site, and acute kidney injury were also assessed. A neurology professional examined all the patients at baseline and after TAVR. RESULTS: A total of 3000 patients across North America, Europe, and Australia underwent randomization; 1501 were assigned to the CEP group and 1499 to the control group. A CEP device was successfully deployed in 1406 of the 1489 patients (94.4%) in whom an attempt was made. The incidence of stroke within 72 hours after TAVR or before discharge did not differ significantly between the CEP group and the control group (2.3% vs. 2.9%; difference, -0.6 percentage points; 95% confidence interval, -1.7 to 0.5; P = 0.30). Disabling stroke occurred in 0.5% of the patients in the CEP group and in 1.3% of those in the control group. There were no substantial differences between the CEP group and the control group in the percentage of patients who died (0.5% vs. 0.3%); had a stroke, a transient ischemic attack, or delirium (3.1% vs. 3.7%); or had acute kidney injury (0.5% vs. 0.5%). One patient (0.1%) had a vascular complication at the CEP access site. CONCLUSIONS: Among patients with aortic stenosis undergoing transfemoral TAVR, the use of CEP did not have a significant effect on the incidence of periprocedural stroke, but on the basis of the 95% confidence interval around this outcome, the results may not rule out a benefit of CEP during TAVR. (Funded by Boston Scientific; PROTECTED TAVR ClinicalTrials.gov number, NCT04149535.).

Circadian and gender effects on repolarization in healthy adults: a study using harmonic regression analysis.

BACKGROUND: Sudden cardiac death and myocardial infarction have a circadian variation with a peak incidence in the early morning hours. Increased dispersion of repolarization facilitates the development of conduction delay necessary to induce sustained arrhythmia. Both QT-dispersion and T-wave peak to T-wave end (TpTe) have been proposed as markers of dispersion of myocardial repolarization. METHODS: Forty healthy adults (20 women), age 35-67 years old, with normal EKGs, echocardiograms, stress tests, and tilt-table tests were analyzed during a 27-hour hospital stay. EKGs were done at eight different time points. QT-intervals, QT-dispersion, and TpTe were measured at each time point. Harmonic regression was used to model circadian periodicity, P < 0.05 was considered significant. RESULTS: The composite QT-interval was longer in women than in men (416 + or - 17 msec vs 411 + or - 20 msec, respectively, P = 0.006). The QT-dispersion among all leads was greater in men than women (37 + or - 13 msec vs 30 + or - 11 msec, respectively, P < 0.0001); a similar difference was found in the precordial leads. Harmonic regression showed that QT-dispersion had a significant circadian variation, primarily in men. In men, the maximum QT-dispersion occurred at 6 AM (45 + or - 15 msec). TpTe also had a significant circadian variation that was not affected by gender in the majority of leads. CONCLUSIONS: A circadian variation exists in the dispersion of myocardial repolarization, as measured by both TpTe and QT-dispersion. Men and women have a different circadian variation pattern. Further studies regarding the mechanisms and clinical implications are needed.

Presence of carotid and peripheral arterial disease in patients with left main disease.

Left main (LM) coronary disease, carotid artery disease, and peripheral arterial disease each reflects advanced atherosclerosis. The frequency of their coexistence in the same patient has not been fully elucidated. All coronary angiograms obtained at the Cleveland Clinic from November 2003 to October 2005 were analyzed for presence of LM stenosis > or =50%. Patients with previous coronary artery bypass graft surgery were excluded. Patients with available carotid ultrasound and ankle-brachial indexes formed the analysis cohorts. A total of 10,298 coronary angiograms were obtained in 9,715 patients. There were 186 patients with LM disease and 1,913 patients without LM disease with carotid artery ultrasound data. There were 29 patients with LM disease and 604 patients without LM disease with available ankle-brachial indexes. Patients with significant LM disease more frequently had associated carotid stenosis > or =60% compared with patients without LM disease (31.2% vs 15.2%, p <0.0001). Patients with LM disease had lower mean ankle-brachial indexes compared with patients without LM disease (0.78 vs 0.87, p = 0.042). In conclusion, compared with patients without LM disease, patients with LM disease have a higher burden of advanced atherosclerosis as evidenced by a higher prevalence of significant carotid stenosis and lower ankle-brachial indexes.

In unstable angina or non-ST-segment acute coronary syndrome, should patients with multivessel coronary artery disease undergo multivessel or culprit-only stenting?

OBJECTIVES: We examined the safety and efficacy of nonculprit multivessel compared with culprit-only stenting in patients with multivessel disease presenting with unstable angina or non-ST-segment elevation myocardial infarction (non-ST-segment elevation acute coronary syndromes [NSTE-ACS]). BACKGROUND: In patients presenting with NSTE-ACS, multivessel coronary artery disease (CAD) is associated with adverse outcome. METHODS: Patients with multivessel CAD and NSTE-ACS that underwent percutaneous coronary intervention were included. The culprit lesion was defined by reviewing each patient's angiographic report, electrocardiogram, echocardiogram and, if available, nuclear stress test. All patients had at least 2 vessels with > or =50% stenosis, and the angiographic severity of CAD was assessed using the Duke Prognostic Angiographic Score. Patients with coronary bypass grafts, chronic total occlusions, and those with uncertain culprit lesions were excluded. Our end point was the composite of death, myocardial infarction, or any target vessel revascularization. RESULTS: From January 1995 to June 2005, 1,240 patients with ACS and multivessel CAD underwent percutaneous coronary intervention with bare-metal stenting and met our study criteria. Of these, 479 underwent multivessel and 761 underwent culprit-only stenting. There were 442 events during a median follow-up of 2.3 years. Multivessel intervention was associated with lower death, myocardial infarction, or revascularization after both adjusting for baseline and angiographic characteristics (hazard ratio 0.80; 95% confidence interval 0.64 to 0.99; p = 0.04) and propensity matched analysis (hazard ratio 0.67; 95% confidence interval 0.51 to 0.88; p = 0.004). CONCLUSIONS: In patients with multivessel CAD presenting with NSTE-ACS, multivessel intervention was significantly associated with a lower revascularization rate, which translated to a lower incidence of the composite end point compared with culprit-only stenting.

Impaired myocardial perfusion score and inflammatory markers in patients undergoing primary angioplasty for acute myocardial infarction

BACKGROUND: Microcirculatory dysfunction during acute myocardial infarction is mediated by various mechanisms including inflammation, thrombus, or plaque embolization. We hypothesize that patients with acute myocardial infarction and admission Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion grade (TMP) < 2 had increased inflammatory status as measured by high sensitivity C-reactive protein (hs-CRP). METHODS: From January 2002 to December 2003, 166 patients (178 lesions) were referred for primary percutaneous coronary intervention. Patients were stratified based on pre-PCI TMP < 2 or TMP 2. Univariate and multivariate predictors of in-hospital and 30-day death were determined with logistic regression. RESULTS: Pre-PCI TMP < 2 was found in 66% vs 34% with TMP 2 (P < .001). Hs-CRP levels were high in both groups but not significantly different (37.9 +/- 6 vs 33.7 +/- 6 mg/L, P = .63). Patients with TMP < 2 had higher WBC (12.83 +/-4.55 x 10(-3) vs 10.83 +/- 3.00 x 10(-3), P = .04), lower ejection fraction (40 +/- 11% vs 46 +/- 12%, P < .001), and higher admission CK-MB levels (116 +/- 13 ng/mL vs 55 +/- 13 ng/mL, P = .006). Death occurred in 12% in the poorTMP group vs 1.8% in the good TMP group (P = .03). Advanced age, use of an intra-aortic balloon pump, and elevated admission WBC were independently associated with in-hospital and 30-day death. CONCLUSIONS: High hs-CRP levels were not associated with impaired myocardial perfusion score. Microcirculatory impairment may be related to an increased inflammatory process, independent from high hs-CRP levels.

Use of platelet glycoprotein IIb/IIIa inhibitors in saphenous vein graft percutaneous coronary intervention and clinical outcomes.

Platelet glycoprotein (GP) IIb/IIIa inhibitors are widely used in percutaneous coronary intervention (PCI). Previous studies have suggested that they do not offer benefit in saphenous vein graft PCI. Nonetheless, their use remains widespread during vein graft angioplasty. We retrospectively analyzed 1,537 patients who underwent saphenous vein graft PCI. Patients who received a GP IIb/IIIa inhibitor (n = 941) were compared with those who did not receive any GP IIb/IIIa inhibitor (n = 596). The primary end point was myonecrosis after PCI (creatine kinase-MB level >3 times the upper reference limit). The incidence of myonecrosis after PCI was similar between the group that received GP IIb/IIIa and the group that did not (odds ratio for GP IIb/IIIa use 1.39, 95% confidence interval 0.97 to 2.00, p = 0.07). Propensity-adjusted analysis demonstrated no significant difference in myonecrosis after PCI, in-hospital mortality, Q-wave myocardial infarction, or bleeding (blood transfusion, retroperitoneal bleed, or hematoma) between the 2 groups. In an analysis restricted to patients who were treated with an emboli protection device, GP IIb/IIIa use was not associated with decreased myonecrosis after PCI (this was also the case for patients who were not treated with an emboli protection device). Unadjusted survival (mean follow-up 5.5 +/- 0.1 years) was similar between the group that received GP IIb/IIIa and the group that did not (log-rank test, p = 0.89). There was no difference in survival after adjusting for the propensity to receive a GP IIb/IIIa inhibitor (adjusted odds ratio for GP IIb/IIIa use 0.92, 95% confidence interval 0.69 to 1.23, p = 0.59). In conclusion, adjunctive use of platelet GP IIb/IIIa inhibitors in saphenous vein graft PCI does not appear to be associated with less myonecrosis or improved survival.

Relation of C-reactive protein level and long-term risk of death or myocardial infarction following percutaneous coronary intervention with a sirolimus-eluting stent.

Previous observations in the bare metal stent (BMS) era have demonstrated an association between a high preprocedural C-reactive protein (CRP) level and an increased incidence of death or myocardial infarction after percutaneous coronary intervention (PCI). We hypothesized that PCI with sirolimus-eluting stents (SESs) would result in a smaller increase in CRP compared with BMSs and that a high CRP level before PCI would be associated with a higher incidence of death or myocardial infarction at 12 months, regardless of the type of stent implanted. We analyzed patients who underwent PCI with stenting at the Cleveland Clinic Foundation. Patients who received BMSs and SESs were analyzed separately by categorizing them into low and high CRP groups based on whether their CRP level before PCI was above or below the median for each group. The increase in CRP that occurred with PCI was termed DeltaCRP. In total, 652 patients were included in the analysis. Median DeltaCRP was smaller in the SES group than in the BMS group (1.5 vs 0.7 mg/L, p = 0.009). In the BMS group, patients with a CRP level above the median before PCI had a higher incidence of 12-month death or myocardial infarction compared with patients with a CRP level below the median (11.3% vs 1.6%, p = 0.002). The same relation was present in the SES group, i.e., patients with a higher CRP level had a higher incidence of 12-month death or myocardial infarction compared with patients with a low CRP level (6.3% vs 1.0%, p = 0.005) and a higher 12-month mortality (5.2% vs 0%, p = 0.001). Multivariate logistic regression analysis demonstrated that the CRP level above the median before PCI was associated with a higher 12-month incidence of death or myocardial infarction, independent of the type of stent used, or DeltaCRP. In conclusion, PCI in the SES era causes a smaller increase in CRP compared with the BMS era. A high CRP level before PCI is independently associated with a higher risk of long-term death or myocardial infarction. This finding was present in the BMS and SES groups and highlights the need for aggressive risk-factor modification after PCI.

Lack of effect of enteric coating on aspirin-induced inhibition of platelet aggregation in healthy volunteers.

BACKGROUND: Aspirin inhibits platelet aggregation and is widely used in the treatment of cardiovascular disease. Some individuals are less responsive to aspirin's antiplatelet effect, a phenomenon termed aspirin resistance. It is not known whether the antiplatelet effect is fully preserved with the enteric-coated (EC) formulation. METHODS: We performed a prospective randomized trial of 50 healthy volunteers using a crossover design to compare the EC with the standard aspirin formulations. The subjects received a 7-day course of each aspirin formulation (81-mg) (Bayer Corporation, Morristown, NJ) separated by a 3-week washout period. Platelet function was measured before and after each course using optical aggregometry (with arachidonic acid and adenosine diphosphate as agonists) and a point-of-care platelet assay. RESULTS: The assays were reproducible, and the variation in baseline platelet function was small to moderate between the subjects. There was no difference in the extent of platelet inhibition between the EC and standard formulations with any of the 3 assays. With the point-of-care platelet assay, the mean aspirin effect favoring the standard formulation (more aggregation inhibition) compared with the EC formulation was 1.6% +/- 15.8% (P = .60 for difference between the formulations). The corresponding optical aggregometry values were -3.4% +/- 39.5% (P = .97) and -1.4% +/- 16.6% (P = .75) for arachidonic acid and adenosine diphosphate, respectively. CONCLUSIONS: Compared with standard aspirin, EC aspirin appears to exhibit similar inhibition of platelet aggregation in healthy volunteers. Furthermore, point-of-care platelet assessment correlated well with the gold standard of laboratory-based optical platelet aggregometry.

Primary percutaneous coronary intervention vs. fibrinolytic therapy for acute ST-elevation myocardial infarction in the elderly.

Advanced age is associated with worse prognosis among patients with acute ST-elevation myocardial infarction. Many eligible elderly patients with acute ST-elevation myocardial infarction, however, do not receive any reperfusion therapy at all. The risk of intracranial hemorrhage complicating fibrinolytic therapy increases with age. Furthermore, routine adjunctive stenting has made coronary angioplasty safer. In total, primary percutaneous coronary intervention is the preferred reperfusion strategy among elderly patients with acute ST-elevation myocardial infarction, provided that it can be performed without excessive delay. The break-even incremental delay with primary percutaneous coronary intervention compared with fibrinolytic therapy is not clear at this point and will need to be elucidated by future investigation.

Impaired myocardial perfusion score and inflammatory markers in patients undergoing primary angioplasty for acute myocardial infarction.

BACKGROUND: Microcirculatory dysfunction during acute myocardial infarction is mediated by various mechanisms including inflammation, thrombus, or plaque embolization. We hypothesize that patients with acute myocardial infarction and admission Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion grade (TMP) < 2 had increased inflammatory status as measured by high sensitivity C-reactive protein (hs-CRP). METHODS: From January 2002 to December 2003, 166 patients (178 lesions) were referred for primary percutaneous coronary intervention. Patients were stratified based on pre-PCI TMP < 2 or TMP 2. Univariate and multivariate predictors of in-hospital and 30-day death were determined with logistic regression. RESULTS: Pre-PCI TMP < 2 was found in 66% vs 34% with TMP 2 (P < .001). Hs-CRP levels were high in both groups but not significantly different (37.9 +/- 6 vs 33.7 +/- 6 mg/L, P = .63). Patients with TMP < 2 had higher WBC (12.83 +/-4.55 x 10(-3) vs 10.83 +/- 3.00 x 10(-3), P = .04), lower ejection fraction (40 +/- 11% vs 46 +/- 12%, P < .001), and higher admission CK-MB levels (116 +/- 13 ng/mL vs 55 +/- 13 ng/mL, P = .006). Death occurred in 12% in the poorTMP group vs 1.8% in the good TMP group (P = .03). Advanced age, use of an intra-aortic balloon pump, and elevated admission WBC were independently associated with in-hospital and 30-day death. CONCLUSIONS: High hs-CRP levels were not associated with impaired myocardial perfusion score. Microcirculatory impairment may be related to an increased inflammatory process, independent from high hs-CRP levels.

Primary percutaneous coronary intervention for acute MI: improving access and outcomes.

Patients with acute myocardial infarction (MI) with ST-segment elevation have better outcomes with primary percutaneous coronary intervention (PCI) than with fibrinolytic therapy. Multiple clinical trials in the past 10 years have addressed ways to improve PCI as primary therapy for acute MI. Logistic strategies to improve access to PCI are being studied.

Relation of myocardial perfusion to mortality after primary percutaneous coronary intervention.

In patients who undergo primary percutaneous coronary intervention (PCI), poor post-PCI myocardial blush is associated with increased mortality, even when epicardial perfusion is adequate. This observation has important implications for the methods of evaluating primary PCI results and the strategies used to improve myocardial reperfusion.

Safety of stress testing during the evolution of unstable angina pectoris or non-ST-elevation myocardial infarction.

Patients (n = 1,106) were chosen from the conservative arm of the Treat Angina with aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS-TIMI) 18 trial. Only 1 patient had a myocardial infarction and another died on the day of stress testing (mortality 0.12%). In patients with unstable angina pectoris or non-ST-elevation myocardial infarction treated with aspirin, heparin, and tirofiban, performance of an exercise or a pharmacologic stress test in selected patients within 48 to 72 hours after admission appears to be associated with a low risk of complications.

Association of the timing of ST-segment resolution with TIMI myocardial perfusion grade in acute myocardial infarction.

BACKGROUND: More complete ST-segment resolution (ST res) in acute myocardial infarction (MI) has been associated with better epicardial and myocardial reperfusion as assessed with the Thrombolysis in Myocardial Infarction (TIMI) flow grade (TFG) and the TIMI myocardial perfusion grade (TMPG), respectively. However, no data exist comparing the speed of ST resolution on continuous electrocardiogram (ECG) monitoring with the TMPG on coronary angiography. We hypothesized that delayed ST res is associated with impaired TMPGs. METHODS: Continuous 12-lead ECG recordings and 60-minute angiographic data were analyzed in 120 patients with acute MI who received tenectaplase monotherapy or combination therapy with low-dose tenectaplase and eptifibatide in the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial. RESULTS: More rapid ST res on continuous ECG monitoring was associated with improved TMPGs on coronary angiography performed 60 minutes after study drug administration. For TMPG 3, the median time to ST resolution was 53 minutes. For TMPG 2, 1, and 0, the corresponding times were 64 minutes, 80 minutes, and 106 minutes, respectively (P =.01 for trend). Likewise, more rapid ST res was also associated with faster epicardial flow. For TFG 3, the median time to ST resolution was 46 minutes, compared with 109 minutes for TIMI flow grades 0 to 2 (P =.001). The corresponding times for a corrected TIMI frame count < or =40 versus >40 were 52 minutes and 112 minutes, respectively (P <.001). CONCLUSIONS: Although the static ECG has been associated with epicardial and myocardial blood flow in the past, this study extends these observations to demonstrate that more rapid ST res on continuous ECG monitoring is associated with improved myocardial perfusion after thrombolytic administration.

Association of a pulsatile blood flow pattern on coronary arteriography and short-term clinical outcomes in acute myocardial infarction.

OBJECTIVES: We hypothesized that recognition of systolic flow reversal (pulsatile flow) after thrombolytic administration on coronary angiography is associated with angiographic and electrocardiogram findings reflecting impaired myocardial perfusion, as well as poorer clinical outcomes. BACKGROUND: Reversal of systolic flow on Doppler velocity wire recordings has been associated with impaired tissue perfusion on myocardial contrast echocardiography in the setting of myocardial infarction (MI). METHODS: Patients (n = 1,062) with a patent infarct-related artery were drawn from the Thrombolysis In Myocardial Infarction (TIMI) 10, TIMI 14, and Integrillin and Tenecteplase acute MI trials. RESULTS: Pulsatile flow (systolic flow reversal with cessation of antegrade contrast-dye motion or frank reversal of contrast-dye motion during systole) at 60 min after fibrinolytic administration was present in 11.0% of patients. Pulsatile flow was associated with higher corrected TIMI frame counts (slower epicardial flow) (median 40.1 frames, IQ 30 of 63 vs. 30 frames, interquartile 22 of 42, p < 0.0001), a closed microvasculature (TIMI myocardial perfusion grades 0 of 1, 57.1% vs. 37.8%, p = 0.03) and less complete (> or =70%) ST-segment resolution (23.5% vs. 58.9%, p = 0.008). Patients with pulsatile flow had a higher risk of death or reinfarction at 30 days (10.3% vs. 5.0%, p = 0.019). After controlling for age, pulse, blood pressure, anterior MI location, epicardial flow, and creatine kinase, pulsatile flow remained associated with an increased risk of death/MI (odds ratio 3.1, p = 0.006). CONCLUSIONS: A pulsatile pattern of flow is associated with impaired myocardial perfusion and poorer clinical outcomes independent of the velocity of antegrade flow in the epicardial artery. This simple and easily identifiable angiographic flow pattern may be useful in clinical risk stratification.

Evaluation of the association of proximal coronary culprit artery lesion location with clinical outcomes in acute myocardial infarction.

Impaired coronary artery blood flow and left anterior descending (LAD) artery culprit location are angiographic variables that have been associated with poorer outcomes after fibrinolytic administration in patients with acute myocardial infarction (AMI). We hypothesized that culprit lesion location in the proximal portion of the culprit artery would also be associated with poorer clinical outcomes compared with a mid or distal location. Lesion location and clinical outcomes were evaluated in 2,488 patients from the Thrombolysis In Myocardial Infarction (TIMI) 4, 10A, 10B, and 14 trials. Proximal lesions were located before or at the first major branch of the parent artery, mid lesions were between the first and the second major branches, and all other lesions were classified as distal. Proximal lesions were associated with a higher incidence of in-hospital death or recurrent AMI compared with mid or distal lesions (10.5% [n = 478] vs 6.1% [n = 1,498] vs 3.7% [n = 511], p <0.001), and they were associated with a higher rate of in-hospital death (6.7% [n = 478] vs 3.2% [n = 1,498] vs 2.5% [n = 511], p = 0.001). In a multiple logistic regression model adjusting for TIMI flow grade, age, gender, and pulse, the planimetered distance from the ostium to the LAD culprit lesion was associated with 30-day death or recurrent AMI (odds ratio 0.79 per centimeter increase in distance down the artery, p = 0.01). Proximal culprit lesion location is associated with an increased risk of adverse outcomes after fibrinolytic administration, which is likely due to a larger area of subtended myocardium. In patients with a LAD culprit lesion, proximal lesion location is a multivariate correlate of adverse outcomes even after adjustment for coronary blood flow and other covariates.