Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:In patients with CKD and end-stage kidney disease (ESKD), cardiac stress testing has low sensitivity and specificity for coronary disease. Alternate markers that are derived during the stress testing may enhance the predictive characteristic of stress testing. The objective was to examine the predictive characteristic of lung-to-heart ratio (LHR) in patients with CKD and ESKD. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS/METHODS:Retrospective parallel cohort of ESKD and CKD not on dialysis (CKD-ND) who underwent stress testing with nuclear myocardial perfusion imaging utilizing sestamibi tracer and regadenoson. Stress LHR was calculated by the processing software and reported. Patients were analyzed by tertile of LHR (≤0.28, 0.29-0.32, ≥0.33). The primary outcome was a composite of all-cause mortality, hospitalization for myocardial infarction or unstable angina, or revascularization. RESULTS:There were 144 CKD-ND and 145 ESKD patients. Patients with ESKD had greater comorbidity burden than CKD-ND. Stress tests were more often performed for pre-operative risk assessment among ESKD versus CKD-ND (53.8 vs. 5.6%, p < 0.001). ESKD patients more likely had ischemia identified on stress testing (19.3 vs. 8.3%, p = 0.001). Mean LHR was 0.31 (Standard deviation - SD: 0.09) and was similar across CKD-ND stages and ESKD. Primary outcome in the lowest (23%) and highest (33.3%) LHR tertile was higher than the middle tertile (12.8%); p = 0.005. This finding was similar between CKD-ND and ESKD and persisted in multivariable analysis. CONCLUSIONS:LHR ≤0.28 and ≥0.33 are independently associated with higher risk for death in patients with CKD-ND and ESKD. Future studies are warranted to understand the association of extreme LHR values and outcomes in this high-risk population.

Dual antiplatelet therapy (DAPT) is key for the prevention of recurrent ischemic events after percutaneous coronary intervention (PCI), however, it increases the risk of bleeding complications. While new generation drug-eluting stents have been shown superior to bare-metal stents after a short DAPT course, the optimal DAPT duration in patients at high bleeding risk (HBR) remains to be determined. TRIAL DESIGN: The XIENCE Short DAPT program consists of three prospective, single-arm studies (XIENCE 90, XIENCE 28 Global and XIENCE 28 USA) investigating 3- or 1-month DAPT durations in HBR patients undergoing PCI with the XIENCE stent. The XIENCE 90 study is being conducted in the US and enrolled 2047 subjects who discontinued DAPT at 3months if they were free from myocardial infarction (MI), repeat coronary revascularization, stroke, or stent thrombosis. The XIENCE 28 program includes the USA study, enrolling 642 patients in US and Canada, and the Global study, enrolling 963 patients in Europe and Asia. In XIENCE 28, patients were to discontinue DAPT at 1month post-PCI if event-free. The primary hypothesis for both XIENCE 90 and XIENCE 28 is that a short DAPT regimen will be non-inferior to a conventional DAPT duration with respect to the composite of all-cause death or MI. Patients enrolled in the prospective multicenter post-market XIENCE V USA study will be used as historical control group in a stratified propensity-adjusted analysis. CONCLUSIONS: The XIENCE Short DAPT Program will provide insights into the safety and efficacy of two abbreviated DAPT regimens of 3- and 1-month duration in a large cohort of HBR patients undergoing PCI with the XIENCE stent.

Background: Alport syndrome is a rare and serious inherited form of CKD affecting as many as 60,000 persons in the US with no specific therapies approved for its treatment.
Method(s): An international, multicenter, double-blind, placebo-controlled, randomized Phase 3 trial (CARDINAL; NCT03019185) evaluated the safety and efficacy of bardoxolone methyl (Bard) in patients with Alport syndrome 12 to 70 years of age with baseline eGFR 30-90 mL/min/1.73 m² and UACR<= 3500mg/g. As an exploratory endpoint, the trial assessed patient global impression of change (PGIC), a non-disease specific 7-point scale that asks patients to rate how much their illness has changed as very much/much/minimally improved (1, 2, and 3 pts), no change (4 pts), or minimally/much/ very much worse (5, 6, and 7 pts) after 48 and 100 weeks of treatment.
Result(s): A total of 157 patients were randomized to Bard (n=77) or placebo (n=80). In addition to significant on-treatment and off-treatment increases in mean eGFR relative to placebo (between-group differences of 7.7 +/- 2.1 [p=0.0005] at Week 100 and 4.3 +/- 1.9 mL/min/1.73 m² [p=0.023] at Week 104, respectively), Bard improved PGIC scores relative to placebo (lower values) after 48 and 100 weeks. Categorical summaries also showed more patients randomized to bardoxolone (34%) reported their condition had improved compared to those on placebo (19%) after 100 weeks of treatment.
Conclusion(s): In CARDINAL, Bard significantly preserved eGFR in patients with Alport syndrome and also resulted in improvements in how patients evaluated their wellbeing. (Figure Presented)

Renal denervation (RDN) is effective in lowering blood pressure (BP) in patients with hypertension. The issue remains how to best identify potential responders. Ambulatory BP monitoring may be useful. Baseline nighttime systolic BP (SBP) ≥136 mm Hg and its variability (SD) ≥12 mm Hg in DENER-HTN trial or 24-hour heart rate ≥73.5 bpm in SPYRAL HTN-OFF MED Trial were shown to predict the BP response to RDN. We applied these criteria to the patients with hypertension in the sham-controlled RADIANCE-HTN SOLO trial to predict the BP response to ultrasound RDN at 2 months while patients were maintained off medications. BP responders were defined as: clinical with 24-hour SBP <130 mm Hg (RDN: 22/64 versus sham: 7/58); meaningful with 24-hour SBP reduction ≥10 mm Hg (RDN: 24/64, sham: 7/58); and extreme with 24-hour SBP reduction above mean+2 SD of the SBP decrease in the sham group, that is, ≥16.5 mm Hg (RDN: 10/64 versus sham: 2/58). The predictive criteria reported above were tested for sensitivity, specificity, and positive and negative predictive values. The predictive value varied according to the definition of response, with the clinical definition being strongly influenced by regression to the mean. Baseline nighttime SBP and its variability, especially when combined, offered good specificity (>90% irrespective of definition) but low sensitivity (from 9.1% to 30% depending on the definition) to predict responders; the heart rate criterion had insufficient predictive value. This analysis suggests the potential role of nighttime SBP and its variability to predict BP response to RDN in patients with hypertension. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02649426.

OBJECTIVE:To describe from a non-interventional registry the short-term ischemic and hemorrhagic outcomes in patients with NSTEMI managed with a loading dose of a P2Y12 inhibitor (P2Y12i) given at least four hours prior to diagnostic angiography and delineation of coronary anatomy. Prior data on the effects of such "upstream loading" have been inconsistent. METHODS:In 53 US hospitals, we evaluated the in-hospital care and outcomes of patients with confirmed NSTEMI managed with an interventional strategy and loaded upstream (at least four hours before diagnostic angiography) with P2Y12 inhibitor therapy. Patients entered into the database were grouped into one of four cohorts for analysis: (1) overall cohort, (2) thienopyridine (clopidogrel or prasugrel) load, (3) ticagrelor load, and (4) ticagrelor-consistent. The fourth cohort is a subset of cohort 3 that received ticagrelor throughout the index hospital stay and at discharge. We evaluated in-hospital clinical course and ischemic and bleeding outcomes in all patients, and also 30-d outcomes in the ticagrelor-consistent cohort. RESULTS:A total of 3,355 patients were enrolled, of whom 1,087 had 30-day follow-up. The mean (+/-SD) age was 63.3+/-12.5 y and 62.6% were male. TIMI and GRACE scores placed these patients in the intermediate risk range and CRUSADE scores were in the moderate risk range. The loading dose in UPSTREAM was clopidogrel in 45.6%, ticagrelor in 53.6%, and prasugrel in 0.8%. The median upstream interval (loading dose to angiography) was 17:27 hours and did not change appreciably over the course of the data collection period (2/15 - 10/19). Access was radial in 48.6% and femoral in 51.4%. Post-angiography management was medical only in 32.3%, PCI in 59.4%, and CABG in 8.3%. Median LOS was 2.7d, and median time from angiography to CABG was 3.6d. In-hospital mortality was 0.51% and major bleeding (TIMI) was 0.24%; the in-hospital MACE rate was 0.7% and stent thrombosis occurred in 0.18%. No significant differences were seen between the ticagrelor and clopidogrel cohorts in hospital, but 16% received more than one P2Y12i in-hospital. On follow-up (93.2% response), 86.7% of patients reported taking ticagrelor as directed. CONCLUSION/CONCLUSIONS:Upstream loading of P2Y12 inhibitors was associated with very low rates of bleeding and short LOS in a large cohort of NSTEMI patients managed invasively.

Background /UNASSIGNED:Coronavirus disease 2019 (COVID-19) is associated with a coagulopathy favouring thrombosis over bleeding that imparts a poor prognosis. Clot in transit (CIT) is considered a rare entity and the most severe form of venous thromboembolism (VTE), carrying a higher mortality than isolated pulmonary embolism (PE). The incidence of this phenomenon in patients with COVID-19 infection is unknown and likely under-recognized. Case summary /UNASSIGNED:During the peak of the COVID-19 pandemic in New York City, a 70-year-old Hispanic female presented with syncope due to a saddle PE further complicated by a highly mobile CIT. Polymerase chain reaction was positive for COVID-19 infection, however, there was no evidence of lung parenchymal involvement or hyper-inflammation. Based on consensus from a multidisciplinary team, aspiration thrombectomy was attempted to treat this extreme case of VTE, however, the patient died during the procedure. Discussion /UNASSIGNED:This case raises awareness to the most catastrophic form of VTE, presenting in an early phase of COVID-19 infection without the typical hyper-inflammation and severe lung injury associated with development of COVID-related coagulopathy. It also serves to inform on the critical role echocardiography has in the comprehensive evaluation and re-evaluation of hospitalized patients with COVID-19, and the importance of a multidisciplinary organized approach in clinical decision-making for this complex and poorly understood disease and its sequelae.