An "Inclisiran First" Strategy vs Usual Care in Patients With Atherosclerotic Cardiovascular Disease.

BACKGROUND: Most patients with atherosclerotic cardiovascular disease fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals. Twice-yearly inclisiran lowers LDL-C by ∼50% when added to statins. OBJECTIVES: This study evaluated the effectiveness of an "inclisiran first" implementation strategy (adding inclisiran immediately upon failure to reach LDL-C <70 mg/dL despite receiving maximally tolerated statins) vs representative usual care in U.S. patients with atherosclerotic cardiovascular disease. METHODS: VICTORION-INITIATE, a prospective, pragmatically designed trial, randomized patients 1:1 to inclisiran (284 mg at days 0, 90, and 270) plus usual care (lipid management at treating physician's discretion) vs usual care alone. Primary endpoints were percentage change in LDL-C from baseline and statin discontinuation rates. RESULTS: We randomized 450 patients (30.9% women, 12.4% Black, 15.3% Hispanic); mean baseline LDL-C was 97.4 mg/dL. The "inclisiran first" strategy led to significantly greater reductions in LDL-C from baseline to day 330 vs usual care (60.0% vs 7.0%; P < 0.001). Statin discontinuation rates with "inclisiran first" (6.0%) were noninferior vs usual care (16.7%). More "inclisiran first" patients achieved LDL-C goals vs usual care (<70 mg/dL: 81.8% vs 22.2%; <55 mg/dL: 71.6% vs 8.9%; P < 0.001). Treatment-emergent adverse event (TEAE) and serious TEAE rates compared similarly between treatment strategies (62.8% vs 53.7% and 11.5% vs 13.4%, respectively). Injection-site TEAEs and TEAEs causing treatment withdrawal occurred more commonly with "inclisiran first" than usual care (10.3% vs 0.0% and 2.6% vs 0.0%, respectively). CONCLUSIONS: An "inclisiran first" implementation strategy led to greater LDL-C lowering compared with usual care without discouraging statin use or raising new safety concerns. (A Randomized, Multicenter, Open-label Trial Comparing the Effectiveness of an "Inclisiran First" Implementation Strategy to Usual Care on LDL Cholesterol [LDL-C] in Patients With Atherosclerotic Cardiovascular Disease and Elevated LDL-C [≥70 mg/dL] Despite Receiving Maximally Tolerated Statin Therapy [VICTORION-INITIATE]; NCT04929249).

Safety and Efficacy of Renal Denervation in Patients Taking Antihypertensive Medications.

BACKGROUND: Renal denervation (RDN) reduces blood pressure (BP) in patients with uncontrolled hypertension in the absence of antihypertensive medications. OBJECTIVES: This trial assessed the safety and efficacy of RDN in the presence of antihypertensive medications. METHODS: SPYRAL HTN-ON MED is a prospective, randomized, sham-controlled, patient- and assessor-blinded trial enrolling patients from 56 clinical centers worldwide. Patients were prescribed 1 to 3 antihypertensive medications. Patients were randomized to radiofrequency RDN or sham control procedure. The primary efficacy endpoint was the baseline-adjusted change in mean 24-hour ambulatory systolic BP at 6 months between groups using a Bayesian trial design and analysis. RESULTS: The treatment difference in the mean 24-hour ambulatory systolic BP from baseline to 6 months between the RDN group (n = 206; -6.5 ± 10.7 mm Hg) and sham control group (n = 131; -4.5 ± 10.3 mm Hg) was -1.9 mm Hg (95% CI: -4.4 to 0.5 mm Hg; P = 0.12). There was no significant difference between groups in the primary efficacy analysis with a posterior probability of superiority of 0.51 (Bayesian treatment difference: -0.03 mm Hg [95% CI: -2.82 to 2.77 mm Hg]). However, there were changes and increases in medication intensity among sham control patients. RDN was associated with a reduction in office systolic BP compared with sham control at 6 months (adjusted treatment difference: -4.9 mm Hg; P = 0.0015). Night-time BP reductions and win ratio analysis also favored RDN. There was 1 adverse safety event among 253 assessed patients. CONCLUSIONS: There was no significant difference between groups in the primary analysis. However, multiple secondary endpoint analyses favored RDN over sham control. (SPYRAL HTN-ON MED Study [Global Clinical Study of Renal Denervation With the Symplicity Spyral Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications]; NCT02439775).

Renal Denervation: A Practical Guide for Health Professionals Managing Hypertension.

Growing evidence demonstrates the suitability of renal denervation in a broad population of patients; however, questions remain over its suitability and practical implementation. Given the rapidity of emerging data, this has been a challenging field for potential adopters to navigate. The purpose of this article is twofold: to provide navigation through emerging clinical data and evolving guidance; and to provide physicians with practical, evidence-based advice for identifying eligible patients and providing appropriate management in the pre- and postintervention settings. Although many of these recommendations are based on existing published guidance documents, we reflect equally on our own experiences of using this technology.

Sex Differences in Clinical Characteristics and Outcomes After Myocardial Infarction With Low Ejection Fraction: Insights From PARADISE-MI.

Background Studies demonstrated sex differences in outcomes following acute myocardial infarction, with women more likely to develop heart failure (HF). Sacubitril/valsartan has been shown to reduce cardiovascular death and HF hospitalizations in patients with HF with reduced ejection fraction. Methods and Results A total of 5661 patients (1363 women [24%]) with acute myocardial infarction complicated by reduced left ventricular ejection fraction (≤40%), pulmonary congestion, or both and ≥1 of 8 risk-augmenting factors were randomized to receive sacubitril/valsartan or ramipril. The primary outcome was cardiovascular death or incident HF. Baseline characteristics, clinical outcomes, and safety events were compared according to sex, a prespecified subgroup. Female participants were older and had more comorbidities. After multivariable adjustment, women and men were at similar risks for cardiovascular death or all-cause death. Women were more likely to have first HF hospitalization (hazard ratio [HR], 1.34 [95% CI, 1.05-1.70]; P=0.02) and total HF hospitalizations (HR, 1.39 [95% CI, 1.05-1.84]; P=0.02). Sex did not significantly modify the treatment effect of sacubitril/valsartan compared with ramipril on the primary outcome (P for interaction=0.11). Conclusions In contemporary patients who presented with reduced left ventricular ejection fraction, pulmonary congestion, or both, following acute myocardial infarction, women had a higher incidence of HF during follow-up. Sex did not modify the treatment effect of sacubitril/valsartan relative to ramipril. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02924727.

An occult iatrogenic pneumothorax as a cosmetic procedure complication.

A pneumothorax is the abnormal gas accumulation within the pleural space. We present a case of a patient with an occult iatrogenic pneumothorax who presented with symptomatic anemia that substantially improved after a transfusion, diverting the clinical suspicion. As a result, she developed acute respiratory distress, initially considered secondary to a possible pulmonary embolism vs. fat embolism. After computed tomography confirmed the diagnosis, a chest tube was inserted. This case emphasizes the importance of suspecting pneumothorax secondary to cosmetic procedures and using computed tomography as the first diagnostic tool in complex cases since chest x-rays can miss pneumothorax.

Alirocumab and Lipid Levels, Inflammatory Biomarkers, Metabolomics, and Safety in Patients Receiving Maintenance Dialysis: The ALIrocumab in DIALysis Study (A Phase 3 Trial to Evaluate the Efficacy and Safety of Biweekly Alirocumab in Patients on a Stable Dialysis Regimen).

Rationale & Objective: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab is used in the general population to treat dyslipidemia, but little is known about the effects of alirocumab on lipid levels, biomarkers, the metabolome, and safety in individuals receiving maintenance dialysis. Study Design: Patients receiving maintenance dialysis for at least 3 months and with a low-density lipoprotein cholesterol level of >70 mg/dL were treated with alirocumab for 12 weeks. Laboratory measurements, drug levels, and safety assessments were obtained at baseline and every 4 weeks during the trial. Setting & Participants: In an outpatient setting, 14 patients completed the trial. Intervention: The patients were treated with alirocumab at a full dose of 150 mg every 2 weeks for 12 weeks. The patients were asked to report any adverse events every 2 weeks. Outcomes: There were no unexpected adverse events or laboratory abnormalities in this population receiving dialysis. The drug levels were the same as those for a population not receiving dialysis. Results: Alirocumab resulted in a 45% reduction in the low-density lipoprotein cholesterol level (P = 0.005) and a 35% reduction in the apolipoprotein B level (P = 0.06). There were no significant decreases in the levels of triglycerides, C-reactive protein, fibrinogen, or other inflammatory biomarkers tested. There were significant decreases in the levels of 7 ceramide, 5 sphingomyelin, and 5 cholesterol ester species. Limitations: This study was performed in only 14 patients who were administered alirocumab for only 12 weeks. This study did not address alirocumab treatment in patients with chronic kidney disease not receiving maintenance dialysis. Conclusions: Individuals receiving maintenance dialysis had a similar response to the PCSK9 inhibitor alirocumab as patients not receiving dialysis. The levels of inflammatory biomarkers were not clearly decreased by alirocumab, but the levels of ceramides, sphingomyelins, and cholesterol esters were significantly reduced. Trial Registration: Clinical Trials.gov as NCT03480568.

Hypertension urgencies in the SPYRAL HTN-OFF MED Pivotal trial.

The SPYRAL HTN-OFF MED Pivotal trial ( https://clinicaltrials.gov/ct2/show/NCT02439749 ) demonstrated significant reductions in blood pressure (BP) after renal denervation (RDN) compared to sham control in the absence of anti-hypertensive medications. Prior to the 3-month primary endpoint, medications were immediately reinstated for patients who met escape criteria defined as office systolic BP (SBP) ≥ 180 mmHg or other safety concerns. Our objective was to compare the rate of hypertensive urgencies in RDN vs. sham control patients. Patients were enrolled with office SBP ≥ 150 and < 180 mmHg, office diastolic BP (DBP) ≥ 90 mmHg and mean 24 h SBP ≥ 140 and < 170 mmHg. Patients had been required to discontinue any anti-hypertensive medications and were randomized 1:1 to RDN or sham control. In this post-hoc analysis, cumulative incidence curves with Kaplan-Meier estimates of rate of patients meeting escape criteria were generated for RDN and sham control patients. There were 16 RDN (9.6%) and 28 sham control patients (17.0%) who met escape criteria between baseline and 3 months. There was a significantly higher rate of sham control patients meeting escape criteria compared to RDN for all escape patients (p = 0.032), as well as for patients with a hypertensive urgency with office SBP ≥ 180 mmHg (p = 0.046). Rate of escape was similar between RDN and sham control for patients without a measured BP exceeding 180 mmHg (p = 0.32). In the SPYRAL HTN-OFF MED Pivotal trial, RDN patients were less likely to experience hypertensive urgencies that required immediate use of anti-hypertensive medications compared to sham control.

Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.

BACKGROUND: Renal denervation has been shown to lower blood pressure in the presence of antihypertensive medications; however, long-term safety and efficacy data from randomised trials of renal denervation are lacking. In this pre-specified analysis of the SPYRAL HTN-ON MED study, we compared changes in blood pressure, antihypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group. METHODS: This randomised, single-blind, sham-controlled trial enrolled patients from 25 clinical centres in the USA, Germany, Japan, the UK, Australia, Austria, and Greece, with uncontrolled hypertension and office systolic blood pressure between 150 mm Hg and 180 mm Hg and diastolic blood pressure of 90 mm Hg or higher. Eligible patients had to have 24-h ambulatory systolic blood pressure between 140 mm Hg and less than 170 mm Hg, while taking one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned (1:1) to radiofrequency renal denervation or a sham control procedure. Patients and physicians were unmasked after 12-month follow-up and sham control patients could cross over after 12-month follow-up completion. The primary endpoint was the treatment difference in mean 24-h systolic blood pressure at 6 months between the renal denervation group and the sham control group. Statistical analyses were done on the intention-to-treat population. Long-term efficacy was assessed using ambulatory and office blood pressure measurements up to 36 months. Drug surveillance was used to assess medication use. Safety events were assessed up to 36 months. This trial is registered with ClinicalTrials.gov, NCT02439775; prospectively, an additional 260 patients are currently being randomly assigned as part of the SPYRAL HTN-ON MED Expansion trial. FINDINGS: Between July 22, 2015, and June 14, 2017, among 467 enrolled patients, 80 patients fulfilled the qualifying criteria and were randomly assigned to undergo renal denervation (n=38) or a sham control procedure (n=42). Mean ambulatory systolic and diastolic blood pressure were significantly reduced from baseline in the renal denervation group, and were significantly lower than the sham control group at 24 and 36 months, despite a similar treatment intensity of antihypertensive drugs. The medication burden at 36 months was 2·13 medications (SD 1·15) in the renal denervation group and 2·55 medications (2·19) in the sham control group (p=0·26). 24 (77%) of 31 patients in the renal denervation group and 25 (93%) of 27 patients in the sham control group adhered to medication at 36 months. At 36 months, the ambulatory systolic blood pressure reduction was -18·7 mm Hg (SD 12·4) for the renal denervation group (n=30) and -8·6 mm Hg (14·6) for the sham control group (n=32; adjusted treatment difference -10·0 mm Hg, 95% CI -16·6 to -3·3; p=0·0039). Treatment differences between the renal denervation group and sham control group at 36 months were -5·9 mm Hg (95% CI -10·1 to -1·8; p=0·0055) for mean ambulatory diastolic blood pressure, -11·0 mm Hg (-19·8 to -2·1; p=0·016) for morning systolic blood pressure, and -11·8 mm Hg (-19·0 to -4·7; p=0·0017) for night-time systolic blood pressure. There were no short-term or long-term safety issues associated with renal denervation. INTERPRETATION: Radiofrequency renal denervation compared with sham control produced a clinically meaningful and lasting blood pressure reduction up to 36 months of follow-up, independent of concomitant antihypertensive medications and without major safety events. Renal denervation could provide an adjunctive treatment modality in the management of patients with hypertension. FUNDING: Medtronic.

Assessing clinical and biomarker characteristics to optimize the benefits of sacubitril/valsartan in heart failure.

Of the various medical therapies for heart failure (HF), sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor that combines sacubitril, a pro-drug that is further metabolized to the neprilysin inhibitor sacubitrilat, and the angiotensin II type 1 receptor blocker valsartan. Inhibition of neprilysin and blockade of the angiotensin II type 1 receptor with sacubitril/valsartan increases vasoactive peptide levels, increasing vasodilation, natriuresis, and diuresis. Left ventricular ejection fraction (LVEF) is widely used to classify HF, to assist with clinical decision-making, for patient selection in HF clinical trials, and to optimize the benefits of sacubitril/valsartan in HF. However, as HF is a complex syndrome that occurs on a continuum of overlapping and changing phenotypes, patient classification based solely on LVEF becomes problematic. LVEF measurement can be imprecise, have low reproducibility, and often changes over time. LVEF may not accurately reflect inherent disease heterogeneity and complexity, and the addition of alternate criteria to LVEF may improve phenotyping of HF and help guide treatment choices. Sacubitril/valsartan may work, in part, by mechanisms that are not directly related to the LVEF. For example, this drug may exert antifibrotic and neurohumoral modulatory effects through inhibition or activation of several signaling pathways. In this review, we discuss markers of cardiac remodeling, fibrosis, systemic inflammation; activation of neurohormonal pathways, including the natriuretic system and the sympathetic nervous system; the presence of comorbidities; patient characteristics; hemodynamics; and HF signs and symptoms that may all be used to (1) better understand the mechanisms of action of sacubitril/valsartan and (2) help to identify subsets of patients who might benefit from treatment, regardless of LVEF.

Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction.

BACKGROUND: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking. METHODS: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first. RESULTS: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group. CONCLUSIONS: Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).

Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.

BACKGROUND: Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications. METHODS: In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the UK, and the USA, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02439749. FINDINGS: From June 25, 2015, to Oct 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was -3·9 mm Hg (Bayesian 95% credible interval -6·2 to -1·6) and for office systolic blood pressure the difference was -6·5 mm Hg (-9·6 to -3·5). No major device-related or procedural-related safety events occurred up to 3 months. INTERPRETATION: SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications. FUNDING: Medtronic.

Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial.

BACKGROUND: Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients with uncontrolled hypertension on antihypertensive medications with drug adherence testing. METHODS: In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20-80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing. FINDINGS: Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure -7·0 mm Hg, 95% CI -12·0 to -2·1; p=0·0059, 24 h diastolic blood pressure -4·3 mm Hg, -7·8 to -0·8; p=0.0174, office systolic blood pressure -6·6 mm Hg, -12·4 to -0·9; p=0·0250, and office diastolic blood pressure -4·2 mm Hg, -7·7 to -0·7; p=0·0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference -6·8 mm Hg, 95% CI -12·5 to -1·1; p=0·0205), 24 h systolic blood pressure (difference -7·4 mm Hg, -12·5 to -2·3; p=0·0051), office diastolic blood pressure (difference -3·5 mm Hg, -7·0 to -0·0; p=0·0478), and 24 h diastolic blood pressure (difference -4·1 mm Hg, -7·8 to -0·4; p=0·0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group. INTERPRETATION: Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common. FUNDING: Medtronic.

ApoCIII as a Cardiovascular Risk Factor and Modulation by the Novel Lipid-Lowering Agent Volanesorsen.

PURPOSE OF REVIEW: Apolipoprotein CIII (ApoCIII) is now recognized as a key regulator in severe hypertriglyceridemia, chylomicronemia, and conditions of triglyceride-rich lipoprotein (TRL) remnant excess due to its inhibition of lipoprotein lipase (LPL) and hepatic lipase, leading to decreased hepatic reuptake of TRLs, as well as enhanced synthesis and secretion of VLDL from the liver. ApoCIII gain-of-function mutations are associated with atherosclerosis and coronary heart disease (CHD), and contribute to the development of cardiometabolic syndrome, hypertriglyceridemia, and type 2 diabetes mellitus. Conversely, loss-of-function mutations in ApoCIII are associated with lower levels of plasma triglycerides (TG), attenuation of vascular inflammatory processes such as monocyte adhesion and endothelial dysfunction, and potentially, a reduction in the incidence and progression of atherosclerosis and cardioprotection. RECENT FINDINGS: Evidence is now emerging that volanesorsen, a second-generation antisense oligonucleotide drug targeting ApoCIII messenger RNA resulting in decreases in TG in patients with familial chylomicronemia syndrome, severe hypertriglyceridemia, and metabolic dyslipidemia with type 2 diabetes giving support to the hypothesis that ApoCIII is a powerful inhibitor of LPL, and when reduced, endogenous clearance of TRLs can result in substantial reductions in TG levels. Discovery of the ApoCIII inhibitor volanesorsen opens a new era of lipid-lowering drugs for reduction in TG and potentially for reduction in LDL-C. Herein, this review will provide an update on the pathophysiology of ApoCIII-linked atherosclerosis and the development of the first drug to target ApoCIII, volanesorsen, as a promising lipid-lowering agent.

Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial.

BACKGROUND: Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. METHODS: SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749. FINDINGS: Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5·5 mm Hg (95% CI -9·1 to -2·0; p=0·0031), 24-h DBP -4·8 mm Hg (-7·0 to -2·6; p<0·0001), office SBP -10·0 mm Hg (-15·1 to -4·9; p=0·0004), and office DBP -5·3 mm Hg (-7·8 to -2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP -0·5 mm Hg (95% CI -3·9 to 2·9; p=0·7644), 24-h DBP -0·4 mm Hg (-2·2 to 1·4; p=0·6448), office SBP -2·3 mm Hg (-6·1 to 1·6; p=0·2381), and office DBP -0·3 mm Hg (-2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5·0 mm Hg (95% CI -9·9 to -0·2; p=0·0414), 24-h DBP -4·4 mm Hg (-7·2 to -1·6; p=0·0024), office SBP -7·7 mm Hg (-14·0 to -1·5; p=0·0155), and office DBP -4·9 mm Hg (-8·5 to -1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group. INTERPRETATION: Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation. FUNDING: Medtronic.

Integrative Blood Pressure Response to Upright Tilt Post Renal Denervation.

BACKGROUND: Whether renal denervation (RDN) in patients with resistant hypertension normalizes blood pressure (BP) regulation in response to routine cardiovascular stimuli such as upright posture is unknown. We conducted an integrative study of BP regulation in patients with resistant hypertension who had received RDN to characterize autonomic circulatory control. METHODS: Twelve patients (60 ± 9 [SD] years, n = 10 males) who participated in the Symplicity HTN-3 trial were studied and compared to 2 age-matched normotensive (Norm) and hypertensive (unmedicated, HTN) control groups. BP, heart rate (HR), cardiac output (Qc), muscle sympathetic nerve activity (MSNA), and neurohormonal variables were measured supine, and 30° (5 minutes) and 60° (20 minutes) head-up-tilt (HUT). Total peripheral resistance (TPR) was calculated from mean arterial pressure and Qc. RESULTS: Despite treatment with RDN and 4.8 (range, 3-7) antihypertensive medications, the RDN had significantly higher supine systolic BP compared to Norm and HTN (149 ± 15 vs. 118 ± 6, 108 ± 8 mm Hg, P < 0.001). When supine, RDN had higher HR, TPR, MSNA, plasma norepinephrine, and effective arterial elastance compared to Norm. Plasma norepinephrine, Qc, and HR were also higher in the RDN vs. HTN. During HUT, BP remained higher in the RDN, due to increases in Qc, plasma norepinephrine, and aldosterone. CONCLUSION: We provide evidence of a possible mechanism by which BP remains elevated post RDN, with the observation of increased Qc and arterial stiffness, as well as plasma norepinephrine and aldosterone levels at approximately 2 years post treatment. These findings may be the consequence of incomplete ablation of sympathetic renal nerves or be related to other factors.

Repeat ablation and hospitalization following cryoballoon ablation of atrial fibrillation at a single tertiary medical center.

Cryoablation for atrial fibrillation (AF) has rapidly become a mainstream treatment for AF. In this report, 163 patients who had undergone a cryoablation procedure at one clinical center were contacted by telephone 33.1 ± 3.3 months after the procedure. All patients had received cryoablation of the pulmonary vein ostia, although concomitant procedures were performed at the same time in over 50% of the patients, including radiofrequency and/or cryoablation of other areas of the left atrium. Freedom from a repeat ablation procedure was 87%, while freedom from recurrent hospitalization for AF was 89%, as compared to previous reports of 65%. Of the 13 patients who had a repeat ablation procedure, only one was found to have a reconnection of pulmonary veins, while 4 were found to have atrial flutter. Cryoablation for AF produces a durable result in most patients out to 3 years with better outcomes than previously reported.

Probability of Accurate Heart Failure Diagnosis and the Implications for Hospital Readmissions.

Heart failure (HF) is a complex syndrome with inherent diagnostic challenges. We studied the scope of possibly inaccurately documented HF in a large health care system among patients assigned a primary diagnosis of HF at discharge. Through a retrospective record review and a classification schema developed from published guidelines, we assessed the probability of the documented HF diagnosis being accurate and determined factors associated with HF-related and non-HF-related hospital readmissions. An arbitration committee of 3 experts reviewed a subset of records to corroborate the results. We assigned a low probability of accurate diagnosis to 133 (19%) of the 712 patients. A subset of patients were also reviewed by an expert panel, which concluded that 13% to 35% of patients probably did not have HF (inter-rater agreement, kappa = 0.35). Low-probability HF was predictive of being readmitted more frequently for non-HF causes (p = 0.018), as well as documented arrhythmias (p = 0.023), and age >60 years (p = 0.006). Documented sleep apnea (p = 0.035), percutaneous coronary intervention (p = 0.006), non-white race (p = 0.047), and B-type natriuretic peptide >400 pg/ml (p = 0.007) were determined to be predictive of HF readmissions in this cohort. In conclusion, approximately 1 in 5 patients documented to have HF were found to have a low probability of actually having it. Moreover, the determination of low-probability HF was twice as likely to result in readmission for non-HF causes and, thus, should be considered a determinant for all-cause readmissions in this population.

Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial.

BACKGROUND: Ixmyelocel-T is an expanded, multicellular therapy produced from a patient's own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions. METHODS: In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1:1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01670981. FINDINGS: Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=66) or placebo (n=60). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary efficacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0·63 [95% CI 0·42-0·97]; p=0·0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p=0·0197). INTERPRETATION: To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes. FUNDING: Vericel Corporation.

The gender of authors in the Baylor Proceedings: a reflection of both current staff composition and lesser number of publications by female physicians.

Gender parity has been achieved in entrance to medical school, but women still constitute only 32% of the physicians licensed to practice in the state of Texas. Similarly, female physicians lag behind in scholarly publications. This gender imbalance appears to be improving, although parity has yet to be achieved in many journals. We could reliably obtain the gender of both the physician staff of the North Division of Baylor Scott & White Health and of the authors in Baylor University Medical Center Proceedings. Of the Baylor authors, 19% were female physicians, while 65% were male physicians (others were nonphysicians). The gender makeup of the total staff was 27% female and 73% male physicians. Thus, female authorship is only 70% as great as the number of female staff physicians. We suggest ways to encourage more women to submit publications.