BACKGROUND:Hemostatic compression devices (HCDs) are routinely used following transradial catheterization to reduce bleeding risk. However, prolonged compression times can increase the likelihood of radial artery occlusion (RAO) and delay patient throughput in the cardiac catheterization laboratory (CCL). METHODS:At a single tertiary care center, we implemented an expedited HCD weaning protocol that halved the time to initial deflation for diagnostic procedures (from 120 to 60 min) and percutaneous coronary intervention (PCI) (from 240 to 120 min). This was a prospective, sequential pre-post implementation study in which patients were enrolled consecutively during each study phase. The protocol utilized expedited serial partial deflations to achieve faster hemostasis while maintaining safety. We recorded timestamps, HCD deflation details, and complications, defined as bleeding, severe hematomas, need for blood transfusion, surgical consultation, or unplanned admission. Rates of complications and times to HCD removal and CCL discharge were compared before and after protocol implementation. RESULTS:A total of 397 patients were included (original protocol n = 200; expedited protocol n = 197). In the entire cohort, mean time to HCD removal decreased from 192 ± 60 to 150 ± 48 min (p < 0.001), and mean time to CCL discharge decreased from 198 ± 54 to 162 ± 60 min (p < 0.001) with the expedited protocol. Rates of serious complications (0.5% vs. 0.0%; p = 0.320) and overall bleeding or hematoma (16.5% vs. 18.3%; p = 0.692) were similar between groups. In the PCI subgroup (n = 58), time to HCD removal (270 ± 30 vs. 210 ± 42 min; p < 0.001) and time to discharge (288 ± 30 vs. 234 ± 60 min; p < 0.001) were also significantly shortened with no serious complications reported. While bleeding events in PCI patients trended higher in the expedited group (8.3% vs. 23.5%; p = 0.171), the difference was not statistically significant. CONCLUSION:An expedited HCD weaning protocol safely reduced CCL length of stay in transradial catheterization without increasing bleeding or serious complications. This approach may improve procedural efficiency and patient throughput.

The ability to non-invasively measure left atrial pressure would facilitate the identification of patients at risk of pulmonary congestion and guide proactive heart failure care. Wearable cardiac monitors, which record single-lead electrocardiogram data, provide information that can be leveraged to infer left atrial pressures. We developed a deep neural network using single-lead electrocardiogram data to determine when the left atrial pressure is elevated. The model was developed and internally evaluated using a cohort of 6739 samples from the Massachusetts General Hospital (MGH) and externally validated on a cohort of 4620 samples from a second institution. We then evaluated model on patch-monitor electrocardiographic data on a small prospective cohort. The model achieves an area under the receiver operating characteristic curve of 0.80 for detecting elevated left atrial pressures on an internal holdout dataset from MGH and 0.76 on an external validation set from a second institution. A further prospective dataset was obtained using single-lead electrocardiogram data with a patch-monitor from patients who underwent right heart catheterization at MGH. Evaluation of the model on this dataset yielded an area under the receiver operating characteristic curve of 0.875 for identifying elevated left atrial pressures for electrocardiogram signals acquired close to the time of the right heart catheterization procedure. These results demonstrate the utility and the potential of ambulatory cardiac hemodynamic monitoring with electrocardiogram patch-monitors. Heart failure is a common disorder that is challenging to manage. Appearance of symptoms can be subtle and dangerous and there are few tools for clinicians to estimate when a patient is likely to experience an episode of heart failure. Current methods to detect elevated pressure in the heart (one sign of oncoming failure) are invasive and can only be performed in an inpatient setting. A non-invasive, quick method for detecting higher heart pressure would be helpful for identifying worsening heart failure in the home environment. For this reason, we developed a computer method to detect elevated pressures inside the heart using a non-invasive signal from a wearable patch monitor device, the electrocardiogram (ECG, or EKG). Our results show our method provides a reliable, non-invasive way to measure heart pressures using data that can be obtained in the outpatient setting. Schlesinger and Alam et al. utilize a deep neural network and single-lead electrocardiogram data to determine elevated left atrial pressure in patients. This work aims to identify patients at risk of pulmonary congestion and guide proactive heart failure care.

Background: Cardiac allograft vasculopathy (CAV) continues to be a major source of morbidity and mortality in heart transplant patients. Serial coronary angiography is the recommended modality to monitor for CAV after heart transplant. Research Question: We aimed to characterize the incidence and distribution of CAV on coronary angiography in heart transplant patients. Methods: In a cohort of 465 patients who had undergone orthotopic heart transplant at a single center, we identified 2451 associated coronary angiograms. Coronary stenosis lesions were extracted to perform CAV grading on each angiogram following the International Society of Heart and Lung Transplantation (ISHLT) grading system. Kaplan-Meier curves were generated for CAV incidence across gender and race. McNemar tests for paired proportions were used to compare involvement of different coronary arteries. Results: Among 465 patients (age 53.8±12.6 years, 26.9% female, 75.9% white), the mean±SD follow-up time was 5.8±4.5 years, with 2451 associated coronary angiograms (5.3±4.2 angiograms per patient). Over the follow-up period, 156 (33.5%) patients experienced CAV with an average time after transplant for CAV diagnosis of 4.2±3.5 years. CAV incidence ranged from 9.0% at the first angiogram at around one year from the transplant date, to 24.5% at the 5th angiogram at around 5 years from the transplant date. Of those diagnosed with CAV, 12 (7.7%) underwent PCI at time of initial diagnosis and 44 (28.2%) underwent PCI during the total follow-up period. At time of diagnosis, 137 (87.8%) patients had ISHLT Grade I, 14 (9.0%) patients had Grade II, and 5 (3.2%) had Grade III CAV. There were significant differences in vessel involvement with CAV at time of diagnosis – 3.8% presented with left main (LM), 66.0% with left anterior descending (LAD), 27.6% with left circumflex (LCx), and 39.1% with right coronary artery (RCA) involvement, including the branches of each. There was markedly more main vessel (88.4%) compared to branch vessel (26.3%) CAV reported, likely due to limitations of coronary angiography in visualizing small vessel CAV. CAV incidence and severity was not significantly different across sex or race. Conclusions: Within a large transplant patient cohort, CAV incidence was high and mostly reported in main vessels with the LAD being the most involved. Further work could be done to optimize earlier and more effective detection of CAV.

AbstractQuantifying hemodynamic severity in patients with heart failure (HF) is an integral part of clinical care. A key indicator of hemodynamic severity is the mean Pulmonary Capillary Wedge Pressure (mPCWP), which is ideally measured invasively. Accurate non-invasive estimates of the mPCWP in patients with heart failure would help identify individuals at the greatest risk of a HF exacerbation. We developed a deep learning model, HFNet, that uses the 12-lead electrocardiogram (ECG) together with age and sex to identify when the mPCWP > 18 mmHg in patients who have a prior diagnosis of HF. The model was developed using retrospective data from the Massachusetts General Hospital and evaluated on both an internal test set and an independent external validation set, from another institution. We developed an uncertainty score that identifies when model performance is likely to be poor, thereby helping clinicians gauge when to trust a given model prediction. HFNet AUROC for the task of estimating mPCWP > 18 mmHg was 0.8 $$2\pm$$ 2 ± 0.01 and 0.$$81\pm$$ 81 ± 0.01 on the internal and external datasets, respectively. The AUROC on predictions with the highest uncertainty are 0.50 $$\pm$$ ± 0.02 (internal) and 0.$$56\pm$$ 56 ± 0.04 (external), while the AUROC on predictions with the lowest uncertainty were 0.86 ± 0.01 (internal) and 0.82 ± 0.01 (external). Using estimates of the prevalence of mPCWP > 18 mmHg in patients with reduced ventricular function, and a decision threshold corresponding to an 80% sensitivity, the calculated positive predictive value (PPV) is 0.$$89\pm$$ 89 ± 0.01when the corresponding chest x-ray (CXR) is consistent with interstitial edema HF. When the CXR is not consistent with interstitial edema, the estimated PPV is 0.$$78\pm$$ 78 ± 0.02, again at an 80% sensitivity threshold. HFNet can accurately predict elevated mPCWP in patients with HF using the 12-lead ECG and age/sex. The method also identifies cohorts in which the model is more/less likely to produce accurate outputs.

Renal Denervation for Treatment of Hypertension: From High-Level Quality Evidence to Implementation in Clinical PracticeJournal of the Society for Cardiovascular Angiography & InterventionsVol. 2Issue 6101130PreviewAccording to the National Health and Nutrition Examination Survey, the rate of blood pressure control (<140/90 mm Hg) of adults in the United States has consistently declined over the past decade (2009-2012: 52.8%, 2013-2016: 51.3%, 2017-2020: 48.2%; P = .034).1 This unsatisfactorily high prevalence of uncontrolled hypertension paradoxically occurs despite the availability of safe, effective, and largely affordable antihypertensive drugs and lifestyle modifications. Thanks to clinical trials investigating device-based therapies for hypertension, which included objective assessment of medication adherence using highly accurate adherence testing of urine and/or plasma, nonadherence to medication has been identified as a major reason for uncontrolled hypertension. Full-Text PDF Open Access

Introduction: Despite the unique pathophysiology, clinical presentation, and disparities in care of women with coronary artery disease, sex-based differences in coronary morphology and their relation to disease remain poorly understood. Methods: We constructed a retrospective cohort of adult patients who underwent a coronary angiogram between 2000 and 2021 at Massachusetts General Hospital and compared dominance, branching, and coronary lesion location and severity at baseline between males and females. We mapped lesions over time and studied differences in risk of receiving a future intervention by sex of the patient and location of the lesion in the coronary tree. Results: 50,988 patients (age 65.7+12.8 years, 33.0% female) had a baseline coronary angiogram and 174,502 lesions were reported. Compared to males, females were less likely to have left or mixed dominance (15.7% vs. 17.4% p<0.001) and trifurcation of the left main (LM) (5.9% vs. 11.1%, p<0.001). Compared to males, females had more lesions reported in the left anterior descending (30.0% vs. 28.3%, p<0.001) and right coronary artery (26.5% vs. 24.4% p<0.001), and less lesions in branches - obtuse marginal, diagonal, posterior descending, and posterolateral (21.8% vs. 25.1%, p<0.001). Obstructive disease - defined as ≥50% stenosis in the LM or ≥70% stenosis in any other vessel - was less common in females (48.8% vs. 69.1% , p<0.001). 8,432 patients (age 65.8+11.0 years, 25.8% female) with 37,842 lesions were evaluated longitudinally over a median follow-up of 2.9 (IQR 0.9-6.7) years, excluding follow-up of ≤2 months. The adjusted hazard ratio for need for a future intervention was 1.16 (95% CI 1.08-1.25) in females as compared to males, but this varied significantly by location in the coronary tree and sex (Figure). Conclusions: Significant sex-based differences in coronary artery morphology, location, and disease distribution exist. Their interplay may inform future need for intervention.

Abstract Background The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used. Methods To better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions. Results A total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93% ≥ 2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE in > 2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors. Conclusions This independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 ( https://clinicaltrials.gov/ct2/show/NCT01207440 ).

As less invasive alternatives to surgical pulmonary valve replacement (PVR) are being refined and evaluated, there is a need for benchmark data concerning outcomes from surgical PVR.We examined in-hospital outcomes from surgical PVR in The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) and Adult Cardiac Surgery Database (STS-ACSD) between 2007 and 2013, with a focus on patients likely to be eligible for transcatheter PVR (ie, ≥ 5 years age and ≥ 30 kg). Patient characteristics, morbidity, and mortality were described.The STS-CHSD included 6,431 eligible patients with a median age of 17 years (interquartile range [IQR], 14–25 years). Preoperative comorbidities were uncommon: arrhythmia (1.7%), renal failure (0.1%), endocarditis (0.3%), neurologic deficit (0.8%), and diabetes (0.5%). In-hospital mortality was 0.9%. A major complication occurred in 2.2%. The STS-ACSD included 3,352 eligible patients; the median age was 41 years (IQR, 30–55 years). Preoperative comorbidities were more common: arrhythmia (24.3%), renal failure (3.8%), endocarditis (12.2%), cerebrovascular disease (7.9%), and diabetes (10.9%). In-hospital mortality was 4.1%. A major complication occurred in 20.9%.Contemporary outcomes from surgical PVR include a low risk of in-hospital death or major complications. Patients in the STS-ACSD are older and have an increased prevalence of preoperative factors, which may contribute to higher morbidity and mortality.

Radial artery occlusion (RAO) remains the Achilles' heel of transradial coronary procedures. Standard over lower systemic anticoagulation levels are believed to reduce RAO rates but this is ill-supported by scientific evidence. We compared whether standard in comparison with less intensive anticoagulation was superior in preventing vessel closure.The two arms of this analysis included 731 pooled patients with the same inclusion and exclusion criteria. We assessed forearm arterial access site occlusion rate by unfractionated heparin (UFH) dose in an individual participant data meta-analysis of this randomized study and of consecutive eligible patients from our previous trial. We randomized 308 consecutive patients undergoing transradial coronary angiography with 5 French (5Fr) catheters without need to crossover to receive 2500 or 5000 UFH units. The primary end-point was the ultrasonographically determined vessel occlusion rate. Incident RAOs in the randomized arm were 15.9% vs. 14%, in the low and standard UFH dose, respectively (p = 0.7). Corresponding figures for forearm arterial occlusion rates in the pooled population were 13.0% vs. 9.9% (relative risk: 1.3, 95% confidence interval — CI: 0.88–1.98; p = 0.2). Procedural and fluoroscopy duration was less than 15 and 3 min, respectively. The mean UFH dose difference was 3.52 (95% CI: − 0.45 to 7.49) units per kilo body weight between occluded (n = 84) and patent forearm arteries (n = 647); (p = 0.053).Incident forearm arterial occlusions were high despite using 5Fr catheters for a short-lasting procedure. Systemic anticoagulation with standard over lower UFH dose did not reduce the frequency of RAOs after coronary angiography.

HomeJournal of the American Heart AssociationVol. 10, No. 4Paclitaxel‐Coated Devices: Safety and Efficacy Are in the PVI of the Beholder Open AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toOpen AccessEditorialPDF/EPUBPaclitaxel‐Coated Devices: Safety and Efficacy Are in the PVI of the Beholder Douglas E. Drachman, and MD, and Joseph M. GarasicMD Douglas E. DrachmanDouglas E. Drachman * Correspondence to: Douglas E. Drachman, MD, Division of Cardiology, Massachusetts General Hospital, Gray‐Bigelow 800, 55 Fruit St, Boston, MA 02114. E‐mail: E-mail Address: [email protected] https://orcid.org/0000-0003-1538-5807 Vascular Medicine Section, , Division of Cardiology, , Massachusetts General Hospital, , Boston, , MA , and Joseph M. GarasicJoseph M. Garasic Vascular Medicine Section, , Division of Cardiology, , Massachusetts General Hospital, , Boston, , MA Originally published6 Feb 2021https://doi.org/10.1161/JAHA.120.020289Journal of the American Heart Association. 2021;10:e020289This article is a commentary on the followingSurvival and Causes of Death Among Veterans With Lower Extremity Revascularization With Paclitaxel‐Coated Devices: Insights From the Veterans Health AdministrationSince Charles Dotter and Melvin Judkins performed the first angioplasty in the superficial femoral artery >55 years ago, endovascular techniques have advanced dramatically, but remain plagued by associated vascular injury and consequent restenosis. Breakthroughs in balloon‐ or stent‐based drug delivery now permit the application of antirestenotic therapy, most often with the antiproliferative drug paclitaxel, directly to the treated arterial segment at the time of percutaneous vascular intervention (PVI). This technology was initially embraced in clinical practice given that the use of paclitaxel‐coated devices (PCDs) resulted in marked reduction of restenosis: paclitaxel drug‐eluting stents (DESs) have been shown to reduce the relative risk of restenosis or target lesion revascularization by 40% at 5 years; and paclitaxel drug‐coated balloon (DCB) therapies may improve primary patency rates to 69.5% at 3 years, compared with 45.1% with conventional, non–drug‐coated treatment.1, 2 Along with the widespread clinical application of PCDs to achieve durable outcomes in PVI, societal guidelines recommend PCDs for the treatment of femoropopliteal stenosis.3, 4Canary in the Coal Mine and Meta‐Analysis DataIn December 2018, however, the safety of PCDs was called to question when a meta‐analysis identified excess late mortality associated with PCDs in 28 randomized controlled trials (RCTs) involving 4663 patients. At 1 year, all‐cause mortality was indistinguishable between the 2 groups (2.3% with PCDs versus 2.3% with control). At 2 years, however, all‐cause mortality was significantly higher (7.2% versus 3.8%) in PCD‐treated patients (hazard ratio [HR] 1.68; 95% CI, 1.15–2.47); and at 5 years, excess all‐cause mortality was even greater in the PCD cohort (14.7% versus 8.1%; HR, 1.93; 95% CI, 1.27–2.93), with a number needed to harm of 14 patients. Although the precise mechanism of device toxicity was not elucidated by the meta‐analysis, a proposed dose‐response between paclitaxel exposure and mortality was identified, with 0.4±0.1% excess mortality per paclitaxel mg/y exposure (P<0.001).5The alarm raised by this single meta‐analysis has had dramatic and lasting repercussions in the clinical arena, although there has also been significant skepticism among interventional thought leaders about the validity of the study's findings. At its core, the lingering unanswered question is: are PCDs truly causal for the increased late mortality reported by Katsanos et al,5 or is this merely an association brought about by statistical, confounding, or other factors? On the basis of heterogeneous, aggregate (not patient‐level) data from 28 RCTs, the meta‐analysis could not provide a plausible mechanism to explain the late mortality signal, particularly because paclitaxel has been used for decades as a highly efficacious chemotherapeutic agent at orders of magnitude higher doses, without a previously recognized mortality signal. In addition, methodologic concerns challenge the validity of the study's findings. The RCTs were designed to assess efficacy end points, but not mortality end points, and aggregate data were therefore represented in an intention‐to‐treat, not as‐treated, manner. Significant subject crossover within the many included studies obscures the potential for any firm conclusions about causality between PCD use and mortality. Likewise, many patients in the RCTs were lost to follow‐up: at 1 year, data from 28 RCTs and 4663 patients were available; at 2 years, there were 12 RCTs and 2316 patients; at 5 years, only 3 RCTs and 863 patients remained, and the excess mortality of PCDs was only identified at 2 and 5 years, with winnowing, and perhaps confounded, patient populations for evaluation.The concern for PCD‐associated late mortality prompted the Food and Drug Administration to act swiftly, convening an emergency advisory panel and halting ongoing clinical investigations of PCD therapies, including the BASIL‐3 (Balloon Versus Stenting in Severe Ischaemia of the Leg‐3) and the SWEDEPAD (Swedish Drug‐Elution Trial in Peripheral Arterial Disease) clinical trials. Much attention has been given to the potential inadequacies of trial‐level versus patient‐level data, a relevant critique of the meta‐analysis by Katsanos et al.5 As a result, the Vascular InterVentional Advances Physicians research group obtained patient‐level data from device manufacturers for 8 RCTs involving 2185 subjects, and conducted a meta‐analysis of as‐treated rather than intention‐to‐treat outcomes, further enhancing the fidelity of the findings compared with the meta‐analysis by Katsanos et al.5 The Vascular InterVentional Advances Physicians meta‐analysis corroborated the presence of a 38% increase in relative risk for all‐cause mortality associated with PCDs at 5 years.6 As a result, in 2019, the Food and Drug Administration published a Letter to Health Care Providers recommending, in essence, that physicians reserve the use of PCDs for procedures at highest risk of restenosis, and that they discuss with their patients the potential risk of increased mortality associated with PCDs when considering treatment options.7Since the initial publication of the meta‐analysis by Katsanos et al,5 there has remained considerable uncertainty about the safety of PCDs, and an unmet need for clinician guidance. Virtually all subsequent evaluations of industry‐sponsored clinical programs and real‐world outcomes from nationwide data sets have not demonstrated excess mortality with PCDs. Reviewing these data provides context for the current state of knowledge, and informs perspective on the importance of the article by Gutierrez et al in this issue of the Journal of the American Heart Association (JAHA).8PCD Mortality in Industry‐Sponsored ProgramsIn 4 separate clinical programs with intermediate to long‐term follow‐up, akin to that seen in the meta‐analysis by Katsanos et al,5 independent evaluation of patient‐level data did not demonstrate excess mortality with PCDs.Ouriel et al examined all‐cause mortality in the 3 RCTs involving the Lutonix DCB. Among 1093 patients treated with DCB and 250 treated with uncoated balloon percutaneous transluminal angioplasty (PTA), the 5‐year all‐cause mortality HR was 1.01 (95% CI, 0.68–1.52).9Data from the IN.PACT Admiral DCB clinical program (2 RCTs and 2 single‐arm studies) were pooled, with 1837 patients treated with DCB and 143 treated with PTA. There was no dose‐dependent harm associated with low‐, mid‐, or high‐dose terciles of paclitaxel. All‐cause adjusted mortality at 5 years was 13.2% for DCB and 11.0% for PTA (P=0.188).10Data from the Stellarex low‐dose paclitaxel DCB platform included 2 RCTs, with 419 patients treated with DCB and 170 patients treated with PTA. Three‐year all‐cause mortality was 8.4% in the DCB cohort and 8.8% in the PTA cohort (P=0.86).11Patient‐level data from the Zilver PTX paclitaxel DES program included 336 patients treated with DESs and 143 patients in control cohorts. The 5‐year all‐cause mortality with DESs (19.1%) was not statistically different from control (17.1%; P=0.60).12National Data Set Analyses of PCD MortalitySeveral studies have examined the association of PCDs with all‐cause mortality in retrospective cohort studies using real‐world outcomes from national data registries.Using the Centers for Medicare and Medicaid Services nationwide data set, Secemsky and colleagues13 examined the outcomes of 16 560 patients who underwent femoropopliteal PVI in 2016. At a median follow‐up of 389 days, of the 5989 patients (36.2%) treated with PCDs, unadjusted all‐cause mortality was lower (32.5%) compared with patients who underwent PVI with non‐PCDs (34.3%; P=0.007). Following multivariable adjustment, the all‐cause mortality was not different between the groups (HR, 0.97; 95% CI, 0.91–1.04; P=0.43), a finding that was consistently demonstrated when considering patients treated with DCB alone, patients treated with DES alone or in combination with DCB, and patients in whom critical limb ischemia was present.13 Concerns with this assessment included that the use of administrative codes to identify patient characteristics and treatment is inevitably heterogeneous and may include unmeasurable confounding variables; the patient population treated in the database was entirely inpatients; there was an exceptionally high burden of critical limb ischemia (51%) in the Centers for Medicare and Medicaid Services data set, which is associated with such high mortality that any modest impact of PCD‐associated mortality may be overwhelmed by other clinical factors; and the Centers for Medicare and Medicaid Services evaluation had median follow‐up of 389 days, which was shorter than the 2‐ and 5‐year time points, where excess all‐cause mortality was identified in the meta‐analysis by Katsanos et al.14Another analysis of the Centers for Medicare and Medicaid Services data set included femoropopliteal PVI in outpatient and inpatient settings from 2015 to 2016. Of the 83 225 patients identified, DCB was used in 29% of PVI, with lower adjusted 1‐year all‐cause mortality compared with non‐DCB PVI (HR, 0.89; 95% CI, 0.84–0.94; P<0.001).15An evaluation of the Optum Database of 16 976 Medicare Advantage insured patients treated with femoropopliteal PVI between April 2015 and December 2017 found no significant difference between all‐cause mortality of the 26.4% treated with PCDs compared with 73.6% treated with non‐PCDs (adjusted HR, 1.03; 95% CI, 0.96–1.10; P=0.39) at median follow‐up of 2.66 years.16In the German nationwide BARMER health insurance program, 64 771 patients were identified who underwent femoropopliteal PVI from 2007 to 2015, with no statistically significant difference in all‐cause mortality between PCD PVI and those treated with non‐PCDs at exceptionally long median follow‐up of 7.6 years.17Clinical Trial Interim and Subgroup Analyses for PCD SafetyImmediately following the publication of the concerning meta‐analysis by Katsanos et al,5 the SWEDEPAD and BASIL‐3 clinical trials were halted. An unplanned interim analysis of all‐cause mortality in the SWEDEPAD clinical trial was conducted, and the findings were recently published. In this multicenter, randomized, open‐label registry study, 2289 patients had been enrolled, with 1149 receiving PCDs. At a median follow‐up of 2.49 years, all‐cause mortality was 25.5% in the PCD cohort and 24.6% in the non‐PCD cohort (HR, 1.06; 95% CI, 0.92–1.22). There was also no statistically significant difference between the 2 cohorts when stratified by claudication or critical limb ischemia clinical status.18A subgroup analysis of the efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with symptomatic peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities (VOYAGER PAD) clinical trial, evaluating PCD all‐cause mortality, was recently presented at the Transcatheter Cardiovascular Therapeutics Connect 2020 conference. VOYAGER PAD was an RCT examining the impact of rivaroxaban (2.5 mg twice daily) versus placebo in 6564 patients undergoing peripheral revascularization.19 In the subgroup analysis, Hess and colleagues examined the impact of PCDs on all‐cause mortality in the 4379 patients in the study who were treated with PVI, of whom 1358 (31%) were treated with PCDs. The weighted all‐cause mortality at 42 months was 12.1% in the PCD‐treated cohort and 12.6% in the non‐PCD cohort (HR, 0.95; 95% CI, 0.83–1.09; P=0.49). In a rigorous, adjudicated RCT with 99.6% ascertainment of vital status, there was no indication of excess mortality with PCD use compared with non‐PCD treatment of PVI.20Veterans' Health Administration Data Reviewed for PCD MortalityIn this issue of JAHA, Gutierrez et al8 present an observational retrospective cohort study from the Veterans Administration Corporate Data Warehouse, adding to the growing body of support from real‐world assessment of large data sets that do not disclose an increase in mortality associated with PCDs. Using International Classification of Diseases, Tenth Revision (ICD‐10), coding and Current Procedural Terminology and Healthcare Common Procedure Coding systems, 10 505 Veterans Administration–based patients were identified who underwent femoropopliteal PVI from October 1, 2015, to June 30, 2019. Of this cohort, 2265 patients (21.6%) underwent PCD‐based PVI, whereas 8240 patients (78.4%) were treated with a non‐PCD PVI. Atherectomy was performed more often in PCD (26.8%) versus non‐PCD (20.4%) procedures, raising the question whether within this nonrandomized population, patients treated with PCDs may have had more complex, severe, diffuse underlying PAD. Moreover, patients treated with PCDs had a higher rate of current tobacco use, valvular heart disease, and a critical limb ischemia presentation, suggesting a higher clinical risk substrate in the PCD cohort. Despite this specter, the study found no significant difference in survival rates of PCD and non‐PCD cohorts at 2 years (77.4% versus 79.7%) or at 3 years (70.7% versus 71.8%) with all‐cause mortality (HR, 1.06; 95% CI, 0.95–1.18; P=0.3013). Access to patient‐level data identified no difference in cause of death between PCD and non‐PCD cohorts: cardiovascular (34.0% PCD versus 39.7% non‐PCD; P=0.28); diabetes mellitus complications (13.0% PCD versus 13.5% non‐PCD; P>0.999); malignancy (11.8% PCD versus 11.0% non‐PCD; P=0.78); infection (9.5% PCD versus 8.5% non‐PCD; P = 0.78); as well as pulmonary, genitourinary, cerebrovascular, and gastrointestinal causes. The use of this Veterans Administration data set, which had no missing patient outcomes, and clearly characterized patient cause of death, adds considerable understanding to the debate about mortality associated with PCD‐based PVI.Notable limitations to this report include the fact that the study population was predominantly men (98.1%) and White individuals (73.5%), which may reduce the generalizability of the results. In addition, the primary results of this nonrandomized retrospective cohort analysis may be confounded by unknown variations in baseline patient characteristics, but many measured factors, if anything, may have predisposed to worse outcomes in the PCD cohort.8Conclusions and Future DirectionsAn extensive body of literature supports the use of PCD therapy for improved patency in femoropopliteal PVI. The findings of excess 2‐ and 5‐year all‐cause mortality associated with PCD use in the meta‐analysis by Katsanos et al5 have raised significant and appropriate concern in the interventional community, and have prompted a rapid and diligent call‐to‐arms evaluation of the findings. Such investigation must clarify the veracity of a truly causal relationship versus simple association, and provide guidance for PVI operators and patients alike. Since that time, the preponderance of data collected from patient‐level evaluation of industry clinical studies, retrospective analysis of administrative databases, subgroup analyses of clinical trials, and interim analysis of an ongoing randomized controlled open‐label trial of PCDs have all demonstrated no excess death associated with PCD use in femoropopliteal lower‐extremity intervention. The study by Gutierez and colleagues in this issue of JAHA advances our understanding by including a rigorous data set with complete and long‐term follow‐up, and specific details about cause of death, with no clear indication of causality or of a probable mechanism of PCD‐associated mortality.For now, the guidance from the Food and Drug Administration remains clear: reserve use of PCDs for anatomic and clinical situations where their efficacy may be most advantageous and where their risk is lowest, while participating in shared, individualized consideration of risk and benefit with our patients. With a growing body of data, including randomized controlled assessments on the horizon, our understanding of the safety and efficacy of PCDs continues to evolve, as will our optimal interventional strategies for the care of patients with symptomatic lower‐extremity peripheral artery disease.DisclosuresDr Drachman reports personal fees from Abbott Vascular, personal fees from Boston Scientific, personal fees from Broadview Ventures, personal fees from Cardiovascular Systems Inc, and personal fees from Cordis/Cardinal Health, outside the submitted work. Dr Garasic reports personal fees from ACI Clinical, personal fees from Bayer, personal fees from AbbVie, personal fees from Abbott, personal fees from Takeda, personal fees from Siemens, personal fees from Baim Institute, personal fees from Beaufort LLC, personal fees from Parexel, personal fees from Boehringer Ingelheim, other from Ostial Corporation, and other from Vertex Pharmaceuticals, outside the submitted work.Footnotes* Correspondence to: Douglas E. Drachman, MD, Division of Cardiology, Massachusetts General Hospital, Gray‐Bigelow 800, 55 Fruit St, Boston, MA 02114. E‐mail: [email protected]orgThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 4.See Article by Gutierrez et al.References1 Dake MD, Ansel GM, Jaff MR, Ohki T, Saxon RR, Smouse HB, Machan LS, Snyder SA, O'Leary EE, Ragheb AO, et al. 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Journal of the American Heart Association. 2021;10 February 16, 2021Vol 10, Issue 4Article InformationMetrics Download: 1,278 Copyright © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley BlackwellThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.https://doi.org/10.1161/JAHA.120.020289PMID: 33554617 Originally publishedFebruary 6, 2021 Keywordspaclitaxeldrug‐eluting balloonperipheral artery diseasedrug‐eluting stentEditorialsperipheral vascular diseasePDF download SubjectsStentRevascularizationPeripheral Vascular DiseaseRestenosisVascular Disease

Objectives In the PACE trial 5-year analysis evaluating use of ponatinib in patients with refractory chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia, a 25% incidence of AOEs was identified (Cortes, Blood 2018) using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs). We performed a retrospective review using a charter-based independent Adjudication Committee (AC) to better understand clinically relevant AOE rates in PACE. Methods The AC (3 cardiologists, 1 hematologist, and 1 neurologist) evaluated AOEs (identified using >500 terms) in PACE using established definitions developed by the American College of Cardiology/American Heart Association (ACC/AHA), US Food and Drug Administration (FDA), and Standardized Data Collection for Cardiovascular Trials Initiative (SCTI). The AC also reviewed patient profiles including event, severity, concomitant medication, and hospitalization data. These adjudicated results were compared with pre-adjudication MedDRA PT search results. The AC was blind to dose, dose modification, and investigator causality opinion. Events not associated with a cardiovascular etiology or that failed to meet the ACC/AHA, FDA, and SCTI definitions were determined by the AC not to be AOEs. Results This review included all 449 heavily pretreated patients with Ph+ leukemia enrolled in PACE (median age, 59 y; 47% female; 93% ≥2 tyrosine kinase inhibitors). At a median follow-up of 37.3 months, adjudicated AOEs occurred in 17.4% of the overall patient population compared with 24.7% pre-adjudication. The majority of the pre-adjudication serious AOEs were adjudicated as serious AOEs (20% pre-adjudication vs 16% adjudicated). The most common adjudicated AOE (>2%) was peripheral arterial occlusive disease. Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Analyses by baseline risk factors demonstrated that patients with the following baseline risk factors had higher incidence rates of adjudicated AOEs than those without ischemic cardiac disease, hypertension, hypercholesterolemia, and diabetes. Conclusions Independent AC review of the PACE trial identified a lower rate of clinically relevant AOEs than previously reported, suggesting an earlier possible overestimation that may not accurately reflect the risk of AOEs with ponatinib. The ongoing ponatinib dose-ranging OPTIC study will further evaluate dose-dependent AOE incidence rates. In the PACE trial 5-year analysis evaluating use of ponatinib in patients with refractory chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia, a 25% incidence of AOEs was identified (Cortes, Blood 2018) using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs). We performed a retrospective review using a charter-based independent Adjudication Committee (AC) to better understand clinically relevant AOE rates in PACE. The AC (3 cardiologists, 1 hematologist, and 1 neurologist) evaluated AOEs (identified using >500 terms) in PACE using established definitions developed by the American College of Cardiology/American Heart Association (ACC/AHA), US Food and Drug Administration (FDA), and Standardized Data Collection for Cardiovascular Trials Initiative (SCTI). The AC also reviewed patient profiles including event, severity, concomitant medication, and hospitalization data. These adjudicated results were compared with pre-adjudication MedDRA PT search results. The AC was blind to dose, dose modification, and investigator causality opinion. Events not associated with a cardiovascular etiology or that failed to meet the ACC/AHA, FDA, and SCTI definitions were determined by the AC not to be AOEs. This review included all 449 heavily pretreated patients with Ph+ leukemia enrolled in PACE (median age, 59 y; 47% female; 93% ≥2 tyrosine kinase inhibitors). At a median follow-up of 37.3 months, adjudicated AOEs occurred in 17.4% of the overall patient population compared with 24.7% pre-adjudication. The majority of the pre-adjudication serious AOEs were adjudicated as serious AOEs (20% pre-adjudication vs 16% adjudicated). The most common adjudicated AOE (>2%) was peripheral arterial occlusive disease. Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Analyses by baseline risk factors demonstrated that patients with the following baseline risk factors had higher incidence rates of adjudicated AOEs than those without ischemic cardiac disease, hypertension, hypercholesterolemia, and diabetes. Independent AC review of the PACE trial identified a lower rate of clinically relevant AOEs than previously reported, suggesting an earlier possible overestimation that may not accurately reflect the risk of AOEs with ponatinib. The ongoing ponatinib dose-ranging OPTIC study will further evaluate dose-dependent AOE incidence rates.

7550 Background: The final 5-year analysis of the PACE trial, which evaluated use of PON in pts with refractory chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia, identified a 25% incidence of AOEs (Cortes, Blood 2018) from a search utilizing > 400 preferred terms (PTs) defined by MedDRA and related to vascular ischemia or thrombosis. We performed a retrospective review using an independent Endpoint Adjudication Committee (EAC) to better understand clinically relevant AOE rates in PACE. Methods: The EAC consisted of 3 cardiologists, 1 hematologist, and 1 neurologist to review AOEs (identified using > 500 terms) in PACE using American College of Cardiology/American Heart Association (ACC/AHA) definitions for major adverse cardiovascular events (MACE), and to review pt profiles including event, severity, concomitant medication, and hospitalization data. These results were compared with MedDRA PT search results. The EAC was blind to dose, dose modification, and investigator causality opinion. Results: The PACE review included 449 heavily pretreated pts with Ph+ leukemia (median age, 59 y; 47% female; 93% ≥2 tyrosine kinase inhibitors). With median follow-up 37.3 mo in all pts, AOEs were identified by MedDRA PT search in 25% of pts and EAC-verified in 17% (Table). In each category listed in the table, the EAC verification identified fewer AOEs and serious AOEs. Serious AOEs were identified by MedDRA PT search in 20% of pts and EAC-verified in 16%. Events that were not associated with a cardiovascular etiology or failed to meet the MACE definition set forth by the ACC/AHA were determined by the EAC not to be an AOE. Conclusions: The independent EAC review showed a lower rate of clinically relevant AOEs than was reported in PACE, suggesting an earlier possible overestimation that may not accurately reflect the risk of AOEs with PON. The ongoing PON dose-ranging OPTIC study will further evaluate the PON risk:benefit profile. Clinical trial information: NCT01207440 . [Table: see text]

Background Kidney injury is common in patients with cardiovascular disease. Objectives We determined whether blood measurement of kidney injury molecule-1 (KIM-1), would predict kidney outcomes in patients undergoing angiographic procedures for various indications. Methods One thousand two hundred eight patients undergoing coronary and/or peripheral angiography were prospectively enrolled; blood was collected for KIM-1 measurement. Peri-procedural acute kidney injury (AKI) was defined as AKI within 48 hours of contrast exposure. Non-procedural AKI was defined as AKI beyond 48 hours. Development of chronic kidney disease (CKD) was defined as progression to an estimated glomerular filtration rate (eGFR) <60 milliliters/minute/1.73 m(2) by study conclusion. Univariate and multivariable Cox proportional hazards models were used to identify predictors of non-procedural AKI, while univariate and multivariable logistic regression analysis was used to evaluate peri-procedural AKI and predictors of progression to CKD. Results During mean follow up of 4 years, peri-procedural AKI occurred in 5.0%, non-procedural AKI in 27.3%, and 12.4% developed new reduction in eGFR <60 mL/min/1.73 m2. Higher KIM-1 concentrations were associated with prevalent comorbidities associated with risk in cardiovascular disease and worse left ventricular function. In adjusted analyses, elevated pre- and post-procedural KIM-1 concentrations predicted not only peri-procedural AKI (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.09-2.18, P = .01 and OR 1.54, 95% CI 1.10-2.15, P = .01, respectively) and non-procedural AKI (hazard ratio [HR] 1.49, 95% CI 1.24-1.78, P < .001 and HR 1.46, 95% CI 1.23-1.74, P < .001, respectively), but also progression to CKD (OR 1.99, 95% CI 1.32-2.99, P = .001 and OR 2.02, 95% CI 1.35-3.03, P = .001, respectively). Conclusions In a typical at-risk population undergoing coronary and/or peripheral angiography, blood concentrations of KIM-1 may predict incident pen-procedural and non-procedural AKI, as well as progression to to CKD.

Background Patients with diabetes mellitus (DM) are at substantial risk of developing peripheral artery disease (PAD). We recently developed a clinical/proteomic panel to predict obstructive PAD. In this study, we compare the accuracy of this panel for the diagnosis of PAD in patients with and without DM. Methods and results The HART PAD panel consists of one clinical variable (history of hypertension) and concentrations of six biomarkers (midkine, kidney injury molecule-1, interleukin-23, follicle-stimulating hormone, angiopoietin-1 and eotaxin-1). In a prospective cohort of 354 patients undergoing peripheral and/or coronary angiography, performance of this diagnostic panel to detect ≥50% stenosis in at least one peripheral vessel was assessed in patients with (n=94) and without DM (n=260). The model had an area under the receiver operating characteristic curve (AUC) of 0.85 for obstructive PAD. At optimal cut-off, the model had 84% sensitivity, 75% specificity, positive predictive value (PPV) of 84% and negative predictive value (NPV) of 75% for detection of PAD among patients with DM, similar as in those without DM. In those with DM, partitioning the model into five levels resulted in a PPV of 95% and NPV of 100% in the highest and lowest levels, respectively. Abnormal scores were associated with a shorter time to revascularisation during 4.3 years of follow-up. Conclusion A clinical/biomarker model can predict with high accuracy the presence of PAD among patients with DM. Trial registration number NCT00842868 .

Background Peripheral arterial disease (PAD) is a global health problem that is frequently underdiagnosed and undertreated. Noninvasive tools to predict the presence and severity of PAD have limitations including inaccuracy, cost, or need for intravenous contrast and ionizing radiation. Hypothesis A clinical/biomarker score may offer an attractive alternative diagnostic method for PAD. Methods In a prospective cohort of 354 patients referred for diagnostic peripheral and/or coronary angiography, predictors of ≥50% stenosis in ≥1 peripheral vessel (carotid/subclavian, renal, or lower extremity arteries) were identified from >50 clinical variables and 109 biomarkers. Machine learning identified variables predictive of obstructive PAD; a score derived from the final model was developed. Results The score consisted of 1 clinical variable (history of hypertension) and 6 biomarkers (midkine, kidney injury molecule‐1, interleukin‐23, follicle‐stimulating hormone, angiopoietin‐1, and eotaxin‐1). The model had an in‐sample area under the receiver operating characteristic curve of 0.85 for obstructive PAD and a cross‐validated area under the curve of 0.84; higher scores were associated with greater severity of angiographic stenosis. At optimal cutoff, the score had 65% sensitivity, 88% specificity, 76% positive predictive value (PPV), and 81% negative predictive value (NPV) for obstructive PAD and performed consistently across vascular territories. Partitioning the score into 5 levels resulted in a PPV of 86% and NPV of 98% in the highest and lowest levels, respectively. Elevated score was associated with shorter time to revascularization during 4.3 years of follow‐up. Conclusions A clinical/biomarker score demonstrates high accuracy for predicting the presence of PAD.

BACKGROUND Noninvasive models to predict the presence of coronary artery disease (CAD) may help reduce the societal burden of CAD.OBJECTIVES From a prospective registry of patients referred for coronary angiography, the goal of this study was to develop a clinical and biomarker score to predict the presence of significant CAD.METHODS In a training cohort of 649 subjects, predictors of >= 70% stenosis in at least 1 major coronary vessel were identified from >200 candidate variables, including 109 biomarkers. The final model was then validated in a separate cohort (n = 278).RESULTS The scoring system consisted of clinical variables (male sex and previous percutaneous coronary intervention) and 4 biomarkers (midkine, adiponectin, apolipoprotein C-I, and kidney injury molecule-1). In the training cohort, elevated scores were predictive of >= 70% stenosis in all subjects (odds ratio [ OR]: 9.74; p < 0.001), men (OR: 7.88; p < 0.001), women (OR: 24.8; p < 0.001), and those with no previous CAD (OR: 8.67; p < 0.001). In the validation cohort, the score had an area under the receiver-operating characteristic curve of 0.87 (p < 0.001) for coronary stenosis >= 70%. Higher scores were associated with greater severity of angiographic stenosis. At optimal cutoff, the score had 77% sensitivity, 84% specificity, and a positive predictive value of 90% for >= 70% stenosis. Partitioning the score into 5 levels allowed for identifying or excluding CAD with > 90% predictive value in 42% of subjects. An elevated score predicted incident acute myocardial infarction during 3.6 years of follow up (hazard ratio: 2.39; p < 0.001).CONCLUSIONS We described a clinical and biomarker score with high accuracy for predicting the presence of anatomically significant CAD. (The CASABLANCA Study: Catheter Sampled Blood Archive in Cardiovascular Diseases; NCT00842868) (C) 2017 by the American College of Cardiology Foundation.