The prognostic value of heart rate response during vasodilator stress myocardial perfusion imaging in patients with end-stage renal disease undergoing renal transplantation.

BACKGROUND: In asymptomatic end-stage renal disease (ESRD) patients undergoing vasodilator stress myocardial perfusion imaging (MPI) prior to renal transplantation (RT), the impact of pre-transplant heart rate response (HRR) to vasodilator stress on post-RT outcomes is unknown. METHODS: We analyzed a retrospective cohort of asymptomatic patients with ESRD who underwent a vasodilator stress SPECT-MPI and subsequently received RT. Blunted HRR was defined as HRR <28% for regadenoson stress and <20% for adenosine stress. The primary endpoint was major adverse cardiac events (MACE), defined as cardiac death or myocardial infarction. Clinical risk was assessed using the sum of risk factors set forth by the AHA/ACCF consensus statement on the assessment of RT candidates. RESULTS: Among 352 subjects, 140 had an abnormal pre-transplant HRR. During a mean follow-up of 3.2 ± 2.0 years, 85 (24%) MACEs were observed. Blunted HRR was associated with increased MACE risk (hazard ratio 1.72; 95% confidence interval 1.12-2.63, P = 0.013), and remained significant after adjustment for gender, sum of AHA/ACCF risk factors, summed stress score, baseline heart rate, and ß-blocker use. HRR was predictive of MACE in patients with normal MPI and irrespective of clinical risk. Blunted HRR was associated with a significant increase in post-operative (30-day) MACE risk (17.9% vs 8.5%; P = 0.009). CONCLUSION: In asymptomatic ESRD patients being evaluated for RT, a blunted pre-transplant HRR was predictive of post-RT MACE. HRR may be a valuable tool in the risk assessment of RT candidates.

Validation of a clinical pathway to assess asymptomatic renal transplant candidates using myocardial perfusion imaging.

BACKGROUND: An AHA/ACCF scientific statement proposed 8 risk factors to assess the need for noninvasive coronary artery disease (CAD) surveillance in asymptomatic patients undergoing evaluation for kidney transplantation. The clinical application of these risk factors and the role of noninvasive testing in this context have not been defined. METHODS AND RESULTS: We retrospectively followed a cohort of 581 consecutive kidney transplant recipients of whom 401 had pre-transplant radionuclide myocardial perfusion imaging (MPI) and 90 had pre-transplant coronary angiography. The sum of pre-transplant AHA/ACCF risk factors (age >60 years, hypertension, diabetes, cardiovascular disease, dyslipidemia, smoking, dialysis >1 year, left ventricular hypertrophy) was calculated. MPI scans were analyzed by a "blinded" reader. Patients were followed for a mean of 3.7 ± 2.3 years post-transplant for major adverse cardiac events (MACE), defined as cardiac death or non-fatal myocardial infarction. The sum of risk factors was associated with modest discriminatory capacity for obstructive angiographic CAD (area under the curve [AUC], 0.70; P = 0.004), 30-day post-operative MACE (AUC, 0.60; P = 0.036), and long-term MACE (AUC, 0.63; P < 0.001). A threshold of ≥3 risk factors was optimal for identifying patients at risk. MPI provided incremental predictive value for obstructive CAD (P = 0.02) and long-term MACE (P = 0.04) but not post-operative MACE (P = 0.56). MPI was best predictive of long-term MACE in intermediate risk (3-4 risk factors) patients. CONCLUSIONS: Asymptomatic kidney transplant candidates with ≥3 AHA/ACCF risk factors are at increased cardiac risk, and should be considered for noninvasive CAD surveillance. Intermediate risk patients (3-4 factors) benefit the most from pre-transplant MPI to define long-term MACE risk.

The prognostic value of regadenoson SPECT myocardial perfusion imaging in patients with end-stage renal disease.

BACKGROUND: The prognostic value of regadenoson SPECT myocardial perfusion imaging (MPI) has not been specifically studied in patients with end-stage renal disease (ESRD). METHODS AND RESULTS: We prospectively followed ESRD patients enrolled in the ASSUAGE and ASSUAGE-CKD trials in which they received regadenoson-stress 99mTc-tetrofosmin SPECT-MPI. Images were semiquantitatively analyzed by an investigator blinded to clinical and outcome data. Patients were followed for cardiac death, myocardial infarction (MI), and coronary revascularization (CR). Revascularizations occurring >90 days post-MPI were considered "late" events. Survival analysis was performed using Cox regression models, adjusting for age, gender, diabetes, dyslipidemia, smoking, and known coronary artery disease. We analyzed 303 patients (mean age 54 years; 64% men), who were followed for 35 ± 10 months. Adjusting for clinical covariates, abnormal regadenoson-stress MPI (SSS ≥ 4) was associated with increased risk of the composite of cardiac death or MI (23.9% vs 14.4%; HR 1.88; CI 1.04-3.41; P = .037) and the composite of cardiac death, MI, or late CR (27.3% vs 16.7%; HR 1.80; CI 1.03-3.14; P = .039). Adjusting for clinical covariates, regadenoson-induced myocardial ischemia (SDS ≥ 2) was associated with increased rate of the composite endpoint of cardiac death, MI, or CR (33.3% vs 16.9%; HR 1.97; CI 1.19-3.27; P = .008). CONCLUSION: Regadenoson-stress SPECT-MPI provides a significant prognostic value in patients with ESRD. ESRD patients with normal SPECT-MPI have relatively high adverse event rates.

Derivation and validation of E/e' ratio as a parameter in the evaluation of left atrial appendage thrombus formation in patients with nonvalvular atrial fibrillation.

We sought to determine and prospectively validate, with concomitantly performed transthoracic (TTE) and transesophageal echocardiograms (TEE), a TTE-assessed E/e' threshold that can be useful in predicting left atrial appendage (LAA) thrombus in patients with nonvalvular atrial fibrillation (NVAF). The retrospective derivation cohort was comprised of 297 patients with NVAF with TTE performed within 1 year of TEE. The validation cohort was comprised of 266 prospectively enrolled patients with TTE performed immediately prior to TEE. LAA thrombus was detected by TEE in 6.4 % of patients in both cohorts. Receiver operating characteristic (ROC) analyses demonstrated a good discriminatory capacity of lateral E/e' in predicting LAA thrombus in the derivation cohort (AUC 0.72; CI 0.63-0.82; P = 0.001) which was confirmed in the validation cohort (AUC 0.83; CI 0.75-0.91; P < 0.001). In the derivation cohort, ROC curve point-coordinates identified E/e' thresholds of both 9.0 and 8.0 to be associated with 100 % sensitivity, with specificities of 36 and 30 %, respectively. An E/e' threshold of ≥8 was selected a priori for prospective validation, and was associated with 100 % sensitivity and 41 % specificity for LAA thrombus, with positive and negative predictive values of 10 and 100 %, respectively, and positive and negative likelihood ratios of 1.69 and 0, respectively. We determined and validated an E/e' threshold of 8 as a highly sensitive and useful parameter that can aid in identifying patients at very low risk for LAA thrombus and potentially obviate the need for a TEE prior to electrophysiology procedures and restoration of sinus rhythm.

Impact of Diastolic Function Parameters on the Risk for Left Atrial Appendage Thrombus in Patients with Nonvalvular Atrial Fibrillation: A Prospective Study.

BACKGROUND: In patients with nonvalvular atrial fibrillation (NVAF), the impact of left ventricular diastolic function on the risk for left atrial appendage (LAA) thrombus has not been prospectively studied. METHODS: At two academic medical centers, patients with NVAF were prospectively enrolled to undergo investigational transthoracic echocardiography immediately before clinically indicated transesophageal echocardiography. Mitral inflow E velocity and tissue Doppler septal and lateral mitral annulus velocities (e') were measured, and E/e' ratios were calculated. RESULTS: Among 266 subjects (mean age, 65 years; 32% women), 17 (6.4%) had LAA thrombus. Patients with LAA thrombus had a higher mean CHA2DS2-VASc score (4.6 ± 1.7 vs 3.0 ± 1.8, P < .001), a higher mean lateral E/e' ratio (19.4 ± 10.1 vs 10.2 ± 5.6, P < .001), and a lower mean lateral e' velocity (7.0 ± 3.2 vs 10.4 ± 3.7 cm/sec, P = .001). There was a good discriminative capacity for E/e' (area under the curve, 0.83; P < .001) and e' velocity (area under the curve, 0.76; P = .001). None of the patients with normal E/e' ratios or normal e' velocities had LAA thrombus. Both E/e' (odds ratio, 1.13 per point; 95% CI, 1.06-1.20; P < .001) and e' velocity (odds ratio, 0.76 per 1 cm/sec; 95% CI, 0.63-0.92; P = .005) provided independent and incremental predictive value beyond the CHA2DS2-VASc score; however, E/e' provided greater incremental value than e' velocity (P = .036). Analyses using septal and averaged E/e' and septal e' velocity yielded similar results. Diastolic function parameters were also associated with the presence and intensity of left atrial spontaneous echo contrast, a precursor of LAA thrombus. CONCLUSIONS: This prospective and concomitant evaluation of diastolic function and LAA thrombus in patients with NVAF demonstrates that E/e' ratio and e' velocity are associated with LAA thrombus, independent of CHA2DS2-VASc score, and may play a role in identifying patients at low risk for LAA thrombus. These data suggest that diastolic function assessment may improve stroke prediction in patients with NVAF.

Impact of B-type natriuretic peptide level on the risk of left atrial appendage thrombus in patients with nonvalvular atrial fibrillation: a prospective study.

BACKGROUND: The impact of B-type natriuretic peptide (BNP) level on the risk of left atrial appendage (LAA) thrombus in patients with nonvalvular atrial fibrillation (NVAF) has not been prospectively studied. METHODS: In two academic medical centers, we obtained BNP levels immediately prior to transesophageal echocardiogram performed to exclude LAA thrombus in patients with NVAF. RESULTS: Among 261 subjects (mean age 65 ± 12 years; 30 % women) with NVAF, 17 (6.5 %) had LAA thrombus and 85 (32.6 %) had at least mild spontaneous echo contrast (SEC). Mean BNP level was significantly higher in patients with LAA thrombus [775 ± 678 vs. 384 ± 537, P = 0.001]. Receiver operator characteristics analysis demonstrated that BNP has a good discriminatory capacity for LAA thrombus (area under the curve, 0.74; 95 % confidence interval [CI], 0.63-0.85; P = 0.001); BNP ≥ 67 pg/mL was 100 % sensitive and 20 % specific for LAA thrombus. Multivariate logistic regression analysis demonstrated that BNP was not independently associated with LAA thrombus (odds-ratio, 1.05 per 100 pg/mL increment; CI, 0.99-1.12; P = 0.127) after adjusting for CHA2DS2-VASc score; while the latter was independently associated with LAA thrombus after adjusting for BNP level (odds-ratio, 1.46 per CHA2DS2-VASc point; CI, 1.09-1.96; P = 0.011). Nonetheless, BNP was associated with SEC in univariate and multivariate analysis, after adjusting for the CHA2DS2-VASc score, (odds-ratio, 1.08; CI, 1.02-1.14; P = 0.005). CONCLUSIONS: BNP is predictive of SEC. However, it does not provide significant incremental value in the prediction of LAA thrombus.

Prognostic value of heart rate response during regadenoson stress myocardial perfusion imaging in patients with end stage renal disease.

BACKGROUND: Blunted heart rate response (HRR) to vasodilator stress agents is associated with worse outcomes. There are limited data assessing the effect of impaired HRR to regadenoson among patients with end-stage renal disease (ESRD) undergoing stress myocardial perfusion imaging (MPI). METHODS: We prospectively followed patients with ESRD enrolled in the ASSUAGE and ASSUAGE-CKD trials. HRR was defined as 100*(peak stress heart rate-resting heart rate)/resting heart rate. Study cohort was dichotomized to blunted and normal HRR groups according to an established median HRR value <28% or ≥28%, which were propensity-score matched based on 22 clinical and imaging covariates. The Primary endpoint was all-cause death. The secondary cardiac-specific endpoints included: (1) the composite endpoint of cardiac death or myocardial infarction; (2) the composite endpoint of cardiac death, myocardial infarction, or late (>90 days) coronary revascularization. RESULTS: There were 303 patients followed for 35 ± 10 months. In the entire cohort, there was a stepwise increase in the rates of death and all secondary endpoints with worsening HRR (P values ≤.001). Blunted HRR (<28%) was associated with increased risk of death (unadjusted hazard ratio 4.10 [1.98-8.46], P < .001) and all secondary endpoints (P ≤ .001). After multivariate adjustment, HRR remained an independent predictor of mortality and secondary endpoints whether used as continuous or dichotomous variable, and added incremental prognostic value for all-cause death (P = .046). Blunted HRR was associated with increased event rate among patients with normal myocardial perfusion (P = .001) and abnormal perfusion (P = .053). In the propensity-matched cohort of 132 patients (66 in each group), blunted HRR was associated with significant increase in all-cause death (21% vs. 5%, HR 5.09 [1.46-17.7], P=.011), and similarly for the secondary endpoints. CONCLUSION: Blunted HRR (<28%) to regadenoson is a strong and independent predictor of death and cardiovascular events in patients with ESRD and adds incremental prognostic value.

Severe chronic kidney disease as a predictor of benefit from aminophylline administration in patients undergoing regadenoson stress myocardial perfusion imaging: A substudy of the ASSUAGE and ASSUAGE-CKD trials.

BACKGROUND: Regadenoson is predominantly renally metabolized. Patients with severe chronic kidney disease (CKD) experience more frequent gastrointestinal adverse effects (AE) from regadenoson. Aminophylline use following regadenoson reduces the incidence of regadenoson-related AE. We investigated whether patients with severe CKD receive incremental benefit from aminophylline administration in reducing regadenoson AE. METHODS: We performed post hoc analysis of the pooled database of the ASSUAGE and ASSUAGE-CKD trials. These were randomized placebo-controlled clinical trials which tested the benefit of intravenous aminophylline vs placebo after regadenoson injection in patients undergoing a clinically indicated stress MPI. Patients were categorized into two treatment arms: aminophylline vs placebo; and two groups: Severe CKD (GFR < 30 mL·min(-1)/1.73 m(2) or dialysis) and Control (GFR ≥ 30 mL·min(-1)/1.73 m(2)). The study endpoints were gastrointestinal AE, non-gastrointestinal AE and composite of any regadenoson AE. RESULT: The pooled database of the two trials yielded 548 patients, of whom 274 patients received aminophylline and 274 received placebo. Aminophylline was associated with greater absolute risk reduction (ARR) in gastrointestinal AE among patients with severe CKD vs controls (25% vs 4%, p < .001). A significant interaction was identified between severe CKD and aminophylline in reducing gastrointestinal AE (p = .007), indicating greater reduction in gastrointestinal AE with aminophylline use among patients with severe CKD. Aminophylline use was associated with a trend toward greater ARR in any regadenoson-related AE (32% vs 21%, p = .08). CONCLUSION: Aminophylline is associated with incremental benefit in reducing gastrointestinal AE in patients with severe CKD undergoing regadenoson stress MPI. Potentially, this population could be targeted for prophylactic administration of aminophylline in order to improve their overall experience with the test.

The safety and tolerability of regadenoson in patients with end-stage renal disease: the first prospective evaluation.

BACKGROUND: There has not been any prospective evaluation of the safety and tolerability of regadenoson (REG)-stress in patients with end-stage renal disease (ESRD). METHODS: From the pooled database of two identically designed randomized, double-blinded, placebo-controlled clinical trials, ASSUAGE and ASSUAGE-CKD (IV-aminophylline vs placebo following REG-stress), we extracted the placebo-treated subjects to form 2 study groups: ESRD (dialysis or GFR < 15 mL/minute/1.73 m(2)) and control (GFR ≥ 30). The incidence of REG adverse effects and the hemodynamic and ECG responses to REG-stress were compared. RESULTS: We identified 146 ESRD subjects and 97 controls. There was no significant difference in the incidence of the composite of any REG adverse effect [ESRD 108 (74%) vs control 73 (75%), P = .82]. ESRD patients seem to have excess incidences of diarrhea [42 (29%) vs 14 (14%), P = .009] and fewer events of dizziness [28 (19%) vs 43 (44%), P < .001]. There were no serious adverse events in either group. There was no significant difference in the incidence of ST-segment deviation, tachyarrhythmias, atrioventricular block, or hypotension. CONCLUSION: This is the first prospective study to confirm the safety and tolerability of REG in patients with ESRD.

Attenuation of the side effect profile of regadenoson: a randomized double-blind placebo-controlled study with aminophylline in patients undergoing myocardial perfusion imaging and have severe chronic kidney disease--the ASSUAGE-CKD trial.

A subgroup analysis of the ASSUAGE trial suggested that the standardized intravenous aminophylline administration following regadenoson-stress leads to substantial attenuation of regadenoson adverse-effects in patients with severe chronic kidney disease (CKD). In a randomized, double-blinded, placebo-controlled clinical trial of patients with stage 4 and 5 CKD, we compared the frequency and severity of regadenoson adverse-effects in those who received 75 mg of intravenous aminophylline versus a matching placebo administered 90 s post-radioisotope injection. Consecutive 300 patients with severe CKD (36% women; 86% end-stage renal disease; age 55 (±13) years) were randomized to receive aminophylline (n = 150) or placebo (n = 150). In the aminophylline arm, there was 65% reduction in the incidence of the primary endpoint of diarrhea (9 (6.0%) vs. 26 (17.3%), P = 0.002), 51% reduction in the secondary endpoint of any regadenoson adverse-effect (47 (31.3%) vs. 96 (64%), P < 0.001) and 70% reduction in headache (16 (10.7%) vs. 54 (36%), P < 0.001). The stress protocol was better tolerated in the aminophylline group (P = 0.008). The quantitative summed difference score, as a measure of stress-induced ischemic burden, was similar between the study groups (P = 0.51). In conclusion, the routine standardized administration of intravenous aminophylline in patients with severe CKD substantially reduces the frequency and severity of the adverse-effects associated with regadenoson-stress without changing the ischemic burden. [NCT01336140].