Factors influencing the indication of coronary angiography in patients presenting with chest pain unspecified: an analysis of two decades (1994-2014).

Guidelines for cardiac catheterization in patients with non-specific chest pain (NSCP) provide significant room for provider discretion, which has resulted in variability in the utilization of invasive coronary angiograms (CAs) and a high rate of normal angiograms. The overutilization of CAs in patients with NSCP and discharged without a diagnosis of coronary artery disease is an important issue in medical care quality. As a result, we sought to identify patient demographic, socioeconomic, and geographic factors that influenced the performance of a CA in patients with NSCP who were discharged without a diagnosis of coronary artery disease. We intended to establish reference data points for gauging the success of new initiatives for the evaluation of this patient population. In this 20-year retrospective cohort study (1994-2014), we examined 107 796 patients with NSCP from the Myocardial Infarction Data Acquisition System, a large statewide validated database that contains discharge data for all patients with cardiovascular disease admitted to every non-federal hospital in NJ. Patients were partitioned into two groups: those offered a CA (CA group; n = 12 541) and those that were not (No-CA group; n = 95 255). Geographic, demographic, and socioeconomic variables were compared between the two groups using multivariable logistic regression, which determined the predictive value of each categorical variable on the odds of receiving a CA. Whites were more likely than Blacks and other racial counterparts (19.7% vs. 5.6% and 16.5%, respectively; P < .001) to receive a CA. Geographically, patients who received a CA were more likely admitted to a large hospital compared to small- or medium-sized ones (12.5% vs. 8.9% and 9.7%, respectively; P < .05), a primary teaching institution rather than a teaching affiliate or community center (16.1 % vs. 14.3% and 9.1%, respectively; P < .001), and at a non-rural facility compared to a rural one (12.1% vs. 6.5%; P < .001). Lastly from a socioeconomic standpoint, patients with commercial insurance more often received a CA compared to those having Medicare or Medicaid/self-pay (13.7% vs. 9.5% and 6.0%, respectively; P < .001). The utilization of CA in patients with NSCP discharged without a diagnosis of coronary artery disease in NJ during the study period may be explained by differences in geographic, demographic, and socioeconomic factors. Patients with NSCP should be well scrutinized for CA eligibility, and reliable strategies are needed to reduce discretionary medical decisions and improve quality of care.

Slowing Progression of Cardiovascular Calcification With SNF472 in Patients on Hemodialysis: Results of a Randomized Phase 2b Study.

BACKGROUND: The high cardiovascular morbidity and mortality in patients with end-stage kidney disease could be partially caused by extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite. METHODS: This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium volume score and other measurements of cardiovascular calcification by computed tomography scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage kidney disease receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log coronary artery calcium volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least 1 dose of SNF472 or placebo and had an evaluable computed tomography scan after randomization. RESULTS: The mean change in coronary artery calcium volume score was 11% (95% CI, 7-15) for the combined SNF472 dose group and 20% (95% CI, 14-26) for the placebo group (P=0.016). SNF472 compared with placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5-24] versus 98% [95% CI, 77-123]; P<0.001) but not in the thoracic aorta (23% [95% CI, 16-30] versus 28% [95% CI, 19-38]; P=0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least 1 treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg, and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively. CONCLUSIONS: Compared with placebo, SNF472 significantly attenuated the progression of coronary artery calcium and aortic valve calcification in patients with end-stage kidney disease receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02966028.

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients.

BACKGROUND: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. METHODS: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). CONCLUSIONS: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.).

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers. METHODS: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication. RESULTS: The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. CONCLUSIONS: On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

Extended-Duration Betrixaban Reduces the Risk of Stroke Versus Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients: An APEX Trial Substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban).

BACKGROUND: Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). METHODS: Hospitalized acutely medically ill subjects (n=7513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35-42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10±4 days) for venous thromboprophylaxis. Stroke events were adjudicated by an independent, blinded event adjudication committee. RESULTS: The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32-0.96; P=0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30-0.94; P=0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26-0.90; P=0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24-0.87; P=0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin. CONCLUSIONS: Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01583218.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity.

BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).

The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial.

BACKGROUND: The APEX trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80-mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein inhibitor. METHODS: This analysis assessed the pharmacokinetics, efficacy, and safety of full- (80 mg) and reduced-dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. RESULTS: The median concentration of betrixaban among subjects administered the 80-mg dose was higher than that of the 40-mg dose (19 ng/mL vs 11 ng/mL, P<.001). In the primary analysis cohort 1 (d-dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism-related death) was significantly reduced among subjects treated with 80 mg of extended-duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction=0.26 [0.04-0.42], P=.023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction=0.30 [0.13-0.44], P=.001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin. CONCLUSIONS: The 80-mg betrixaban dose achieves higher plasma concentrations than the 40-mg dose and, in contrast to the 40-mg dose, is associated with improved efficacy across all cohorts relative to standard-dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects.

N-terminal pro-B-type natriuretic peptide and the risk of stroke among patients hospitalized with acute heart failure: an APEX trial substudy.

BACKGROUND: Among patients hospitalized with acute heart failure (HF), the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in short-term stroke prediction remains unclear. METHODS: In the APEX trial, 7513 patients hospitalized for an acute medical illness were randomized to receive either extended-duration betrixaban (80 mg once daily for 35-42 days) or standard-of-care enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. Baseline NT-proBNP concentrations were obtained in 3261 patients admitted for HF. Stroke events were adjudicated by an independent clinical events committee blinded to thromboprophylaxis allocation. The association of NT-proBNP level and other risk factors and biomarkers with stroke was assessed at 77 days after randomization. RESULTS: In univariate analysis, the risk of stroke at 77 days was associated with baseline NT-proBNP (HR 3.63 [95% CI 1.47-8.99]; P = 0.005), D-dimer (HR 2.73 [95% CI 1.03-7.20]; P = 0.043), and hsCRP (HR 3.03 [95% CI 1.36-6.75]; P = 0.007). In multivariable analysis adjusting for hsCRP and thromboprophylaxis, NT-proBNP was associated with the risk of stroke (adjusted HR 3.64 [95% CI 1.35-9.83]; P = 0.011). The interaction of NT-proBNP with the treatment effect was not significant (Pint = 0.30). CONCLUSIONS: Baseline NT-proBNP concentration was associated with short-term stroke among patients hospitalized with acute HF. Stroke risk assessment models should consider incorporation of NT-proBNP measurement.

Competing risk analysis in a large cardiovascular clinical trial: An APEX substudy.

Competing risk methods are time-to-event analyses that account for fatal and/or nonfatal events that may potentially alter or prevent a subject from experiencing the primary endpoint. Competing risk methods may provide a more accurate and less biased estimate of the incidence of an outcome but are rarely applied in cardiology trials. APEX investigated the efficacy of extended-duration betrixaban versus standard-duration enoxaparin to prevent a composite of symptomatic deep-vein thrombosis (proximal or distal), nonfatal pulmonary embolism, or venous thromboembolism (VTE)-related death in acute medically ill patients (n = 7513). The aim of the current analysis was to determine the efficacy of betrixaban vs standard-duration enoxaparin accounting for non-VTE-related deaths using the Fine and Gray method for competing risks. The proportion of non-VTE-related death was similar in both the betrixaban (133, 3.6%) and enoxaparin (136, 3.7%) arms, P = .85. Both the traditional Kaplan-Meier method and the Fine and Gray method accounting for non-VTE-related death as a competing risk showed equal reduction of VTE events when comparing betrixaban to enoxaparin (HR/SHR = 0.65, 95% 0.42-0.99, P = 0.046). Due to the similar proportion of non-VTE-related deaths in both treatment arms and the use of a univariate model, the Fine and Gray method provided identical results to the traditional Cox model. Using the Fine and Gray method in addition to the traditional Cox proportional hazards method can indicate whether the presence of a competing risk, which is dependent of the outcome, altered the risk estimate.

Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification.

Background: Patients receiving dialysis have high cardiovascular risk in part due to extensive vascular calcification. In the CaLIPSO study, infusion of hexasodium fytate (SNF472), the hexasodium salt of inositol hexaphosphate, for 52 weeks thrice weekly during hemodialysis significantly reduced progression of coronary artery calcification (CAC). This report examines pharmacokinetic/pharmacodynamic (PK/PD) and exposure-efficacy in CaLIPSO. Methods: We measured hexasodium fytate plasma concentrations (PK) by validated liquid chromatography-mass spectroscopy, and hydroxyapatite crystallization in plasma (PD) by validated spectrophotometry. Analyses included patients evaluable for PK, PD, and CAC change (per-protocol analysis). We developed a simple Emax model for maximum concentration (Cmax) and PD effect, and linear and non-linear Emax models for exposure-efficacy among individual average Cmax and absolute and percent changes in CAC score from baseline to week 52. Results: Among evaluable patients receiving placebo (n = 15), 300 mg (n = 20), or 600 mg (n = 20), average Cmax across visits was not quantifiable (<0.76 µM), 15 µM, and 46 µM, respectively. These results suggest a more-than-proportional increase, without accumulation, with a Cmax ratio of approximately 3 for the doses administered. Average inhibition of hydroxyapatite crystallization was 15%, 61%, and 75%, respectively, and similar across visits. Simple Emax models described 80% maximal effect at exposures >21.9 µM and a plateau in exposure-efficacy above the third quartile of Cmax (≥32 µM). Conclusion: Hexasodium fytate has exposure-dependent effects on hydroxyapatite crystallization and progression of cardiovascular calcification. Simple Emax models show robust relations among exposure, inhibition of hydroxyapatite crystallization, and change in CAC volume. Clinical Trial Registration: https://www.clinicaltrials.gov; identifier NCT02966028.

The CALCIPHYX study: a randomized, double-blind, placebo-controlled, Phase 3 clinical trial of SNF472 for the treatment of calciphylaxis.

BACKGROUND: Calcific uraemic arteriolopathy (CUA; calciphylaxis) is a rare disease seen predominantly in patients receiving dialysis. Calciphylaxis is characterized by poorly healing or non-healing wounds, and is associated with mortality, substantial morbidity related to infection and typically severe pain. In an open-label Phase 2 clinical trial, SNF472, a selective inhibitor of vascular calcification, was well-tolerated and associated with improvement in wound healing, reduction of wound-related pain and improvement in wound-related quality of life (QoL). Those results informed the design of the CALCIPHYX trial, an ongoing, randomized, placebo-controlled, Phase 3 trial of SNF472 for treatment of calciphylaxis. METHODS: In CALCIPHYX, 66 patients receiving haemodialysis who have an ulcerated calciphylaxis lesion will be randomized 1:1 to double-blind SNF472 (7 mg/kg intravenously) or placebo three times weekly for 12 weeks (Part 1), then receive open-label SNF472 for 12 weeks (Part 2). All patients will receive stable background care, which may include pain medications and sodium thiosulphate, in accordance with the clinical practices of each site. A statistically significant difference between the SNF472 and placebo groups for improvement of either primary endpoint at Week 12 will demonstrate efficacy of SNF472: change in Bates-Jensen Wound Assessment Tool-CUA (a quantitative wound assessment tool for evaluating calciphylaxis lesions) or change in pain visual analogue scale score. Additional endpoints will address wound-related QoL, qualitative changes in wounds, wound size, analgesic use and safety. CONCLUSIONS: This randomized, placebo-controlled Phase 3 clinical trial will examine the efficacy and safety of SNF472 in patients who have ulcerated calciphylaxis lesions. Patient recruitment is ongoing.

Trial design and baseline characteristics of CaLIPSO: a randomized, double-blind placebo-controlled trial of SNF472 in patients receiving haemodialysis with cardiovascular calcification.

BACKGROUND: The objective of CaLIPSO, a Phase 2b, randomized, double-blind, placebo-controlled clinical trial, is to test the hypothesis that myo-inositol hexaphosphate (SNF472) attenuates the progression of cardiovascular calcification in patients receiving maintenance haemodialysis. Here we report the trial design and baseline characteristics of trial participants. METHODS: Adult patients on maintenance haemodialysis (≥6 months) with an Agatston coronary artery calcium score, as measured by a multidetector computed tomography scanner, of 100-3500 U were enrolled. Patients were stratified by Agatston score (100-<400, 400-1000 or >1000 U) and randomized in a 1:1:1 ratio to receive placebo, SNF472 300 mg or SNF472 600 mg administered intravenously three times weekly during each haemodialysis session. RESULTS: Overall, 274 patients were randomized. The mean age of trial participants was 63.6 (standard deviation 8.9) years and 39% were women. The coronary artery, aorta and aortic valve median (25th-75th percentile) Agatston scores at baseline were 730 U (315-1435), 1728 U (625-4978) and 103 U (31-262), respectively, and the median (25th-75th percentile) calcium volume scores at baseline were 666 (310-1234), 1418 (536-4052) and 107 (38-278), respectively. Older age and diabetes mellitus were associated with higher calcium scores at baseline. CONCLUSIONS: The CaLIPSO trial enrolled patients on haemodialysis with pre-existent cardiovascular calcification to test the hypothesis that SNF472 attenuates its progression in the coronary arteries, aorta and aortic valve.

Effects of Myo-inositol Hexaphosphate (SNF472) on Bone Mineral Density in Patients Receiving Hemodialysis: An Analysis of the Randomized, Placebo-Controlled CaLIPSO Study.

BACKGROUND AND OBJECTIVES: In the CaLIPSO study, intravenous administration of SNF472 (300 or 600 mg) during hemodialysis significantly attenuated progression of coronary artery and aortic valve calcification. SNF472 selectively inhibits formation of hydroxyapatite, the final step in cardiovascular calcification. Because bone mineral is predominantly hydroxyapatite, we assessed changes in bone mineral density in CaLIPSO. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with coronary artery calcification at screening (Agatston score of 100-3500 U) were randomized 1:1:1 to receive placebo, 300 mg SNF472, or 600 mg SNF472 as an intravenous infusion during hemodialysis three times weekly for 52 weeks. Dual-energy x-ray absorptiometry (DXA) scans were obtained at baseline (screening) and end of treatment, and between-group changes from baseline were compared using analysis of covariance. RESULTS: Among 274 randomized patients, 202 had evaluable DXA scans at baseline and postrandomization (the DXA-modified intention-to-treat population). Mean (95% confidence interval) changes in total-hip bone mineral density from baseline to week 52 were -1.5% (-2.7% to -0.3%), -1.5% (-2.7% to -0.4%), and -2.5% (-3.8% to -1.2%) in the placebo, 300 mg SNF472, and 600 mg SNF472 groups, respectively. Mean (95% confidence interval) changes in femoral-neck bone mineral density from baseline to week 52 were -0.3% (-1.6% to 1.0%), -1.0% (-2.3% to 0.2%), and -2.6% (-4.0% to -1.3%), respectively. Regression analyses showed no correlation between change in coronary artery calcium volume and change in bone mineral density at either location. Changes in serum alkaline phosphatase, calcium, magnesium, phosphate, and intact parathyroid hormone levels were similar across treatment groups. Clinical fracture events were reported for four of 90, three of 92, and six of 91 patients in the placebo, 300 mg SNF472, and 600 mg SNF472 groups, respectively. CONCLUSIONS: Bone mineral density decreased modestly in all groups over 1 year. In the 600 mg SNF472 group, the reduction appeared more pronounced. Reported fractures were infrequent in all groups. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Effect of SNF472 on Progression of Cardiovascular Calcification in End-Stage-Renal-Disease (ESRD) Patients on Hemodialysis (HD), NCT02966028.

Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study.

OBJECTIVES: To evaluate the efficacy and safety of fixed-dose combinations of rosuvastatin and fenofibric acid (rosuvastatin/fenofibric acid) compared with simvastatin in patients with high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). BACKGROUND: Combination therapy with a statin and a fibrate is one of the treatment options to manage multiple lipid abnormalities in patients with hypercholesterolemia and elevated TGs. METHODS: In this randomized, double-blind study, patients (n = 474) with LDL-C > or =160 mg/dL and < or =240 mg/dL and TG > or =150 mg/dL and <400 mg/dL were treated for 8 weeks with simvastatin 40 mg, rosuvastatin/fenofibric acid 5 mg/135 mg, rosuvastatin/fenofibric acid 10 mg/135 mg, or rosuvastatin/fenofibric acid 20 mg/135 mg. Primary and secondary variables were mean percent changes in LDL-C comparing rosuvastatin/fenofibric acid 20 mg/135 mg with simvastatin 40 mg and rosuvastatin/fenofibric acid 10 mg/135 mg and rosuvastatin/fenofibric acid 5 mg/135 mg with simvastatin 40 mg, respectively. Additional efficacy variables included non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein (Apo) B, HDL-C, TG, and high-sensitivity C-reactive protein (hsCRP). Safety was evaluated based on data collected for adverse events (AEs), physical and electrocardiographic examinations, vital sign measurements, and clinical laboratory tests. RESULTS: Significantly greater reductions in LDL-C levels from baseline values were observed with the combination of rosuvastatin/fenofibric acid 20 mg/135 mg (-47.2%, p < 0.001), rosuvastatin/fenofibric acid 10 mg/135 mg (-46.0%, p < 0.001), and rosuvastatin/fenofibric acid 5 mg/135 mg (-38.9%, p = 0.007) than with simvastatin 40 mg (-32.8%). Significant (p < or = 0.04 for all comparisons) improvements in non-HDL-C, ApoB, HDL-C, TG, and hsCRP levels were also observed with each of the rosuvastatin/fenofibric acid doses as compared with simvastatin 40 mg. Treatment-related AEs and discontinuations due to AEs were similar across groups. The incidence of serious AEs was 0% with simvastatin 40 mg, 3.4% with rosuvastatin/fenofibric acid 5 mg/135 mg, 0.8% with rosuvastatin/fenofibric acid 10 mg/135 mg, and 2.5% with rosuvastatin/fenofibric acid 20 mg/135 mg. No cases of rhabdomyolysis or drug-related myopathy were reported. CONCLUSION: In patients with high LDL-C and TG levels, combination treatment with rosuvastatin/fenofibric acid was well tolerated, and each of the rosuvastatin/fenofibric acid doses produced greater reductions in LDL-C and improvements in other efficacy parameters, compared with simvastatin 40 mg. [Clinical trial is registered at www.clinicaltrials.gov NCT00812955.].

Left Pericardiophrenic Vein Pacing for Tachy-Brady Syndrome Due to an Obstructing Cardiac Angiosarcoma.

We describe a case of a permanent pacemaker lead placement via the left pericardiophrenic vein for the treatment of tachy-brady syndrome due to a primary cardiac angiosarcoma. (Level of Difficulty: Advanced.).

A novel assay to measure calcification propensity: from laboratory to humans.

Cardiovascular calcification (CVC) contributes to morbidity and mortality in patients undergoing dialysis. We examined the pharmacodynamic effects of SNF472, a calcification inhibitor, on plasma calcium phosphate crystallization using spectrometric measurements, and its correlations with effects on CVC in rats or humans. Rats (N = 38) injected with vitamin D (days 1-3) to induce CVC were infused with saline or SNF472 (days 1-12). Inhibition of CVC was 50-65% with SNF472 3 mg/kg and ~ 80% with SNF472 10 or 30 mg/kg. SNF472 dose-dependently inhibited calcium phosphate crystallization, which correlated with inhibition of CVC (r = 0.628, P = 0.005). In patients with calciphylaxis (N = 14), infusion of SNF472 (~ 7 mg/kg) during hemodialysis for 12 weeks inhibited calcium phosphate crystallization by nearly 70%. In patients with CVC (N = 274), infusion of SNF472 during hemodialysis for 52 weeks inhibited calcium phosphate crystallization (placebo: 15%; 300 mg: 61%; 600 mg: 75%), which correlated with inhibition of CVC (r = 0.401, P = 0.003). These findings show a direct correlation between inhibition of calcium phosphate crystallization in plasma and inhibition of CVC both in a rat model and in humans, supporting the use of the pharmacodynamic assay in clinical trials as a potentially predictive tool to evaluate the activity of calcification inhibitors.

Effects of SNF472, a Novel Inhibitor of Hydroxyapatite Crystallization in Patients Receiving Hemodialysis - Subgroup Analyses of the CALIPSO Trial.

INTRODUCTION: Coronary artery calcium (CAC) is highly prevalent and linked with poor outcomes in patients receiving maintenance hemodialysis, and its reduction may improve patient prognosis. SNF472, a selective inhibitor of hydroxyapatite crystallization, slows CAC progression in patients receiving maintenance hemodialysis. In this analysis, we assessed the efficacy of SNF472 in prespecified patient subgroups. METHODS: In a randomized clinical trial SNF472 300 mg, SNF472 600 mg, or placebo were infused thrice weekly in 91, 92, and 91 patients receiving maintenance hemodialysis and with CAC at baseline, respectively. In prespecified subanalyses, the percent change in CAC volume score (CACvs) from baseline to week 52 in modified intention-to-treat (mITT) and per-protocol (PP) populations was calculated in the following subgroups: age, sex, diabetes mellitus, dialysis vintage, prior atherosclerotic cardiovascular disease, baseline use of non-calcium and calcium-based phosphate binders, calcimimetics, activated vitamin D, warfarin, and statins. RESULTS: In the main trial, SNF472 significantly reduced CACvs progression compared with placebo (11% versus 20% mITT analyses; P = 0.016; 8% vs. 24% PP analyses; P < 0.001). Treatment differences for CACvs progression were similar across all subgroups, and all interaction P values were non-significant in mITT and PP analyses. CONCLUSIONS: SNF472 treatment for 52 weeks reduced CACvs progression compared with placebo in a broad range of patients receiving maintenance hemodialysis. Future studies will determine the impact of SNF472 on cardiovascular events in this population.

Mechanism of action of SNF472, a novel calcification inhibitor to treat vascular calcification and calciphylaxis.

BACKGROUND AND PURPOSE: No therapy is approved for vascular calcification or calcific uraemic arteriolopathy (calciphylaxis), which increases mortality and morbidity in patients undergoing dialysis. Deposition of hydroxyapatite (HAP) crystals in arterial walls is the common pathophysiologic mechanism. The mechanism of action of SNF472 to reduce HAP deposition in arterial walls was investigated. EXPERIMENTAL APPROACH: We examined SNF472 binding features (affinity, release kinetics and antagonism type) for HAP crystals in vitro, inhibition of calcification in excised vascular smooth muscle cells from rats and bone parameters in osteoblasts from dogs and rats. KEY RESULTS: SNF472 bound to HAP with affinity (KD ) of 1-10 µM and saturated HAP at 7.6 µM. SNF472 binding was fast (80% within 5 min) and insurmountable. SNF472 inhibited HAP crystal formation from 3.8 µM, with complete inhibition at 30.4 µM. SNF472 chelated free calcium with an EC50 of 539 µM. Chelation of free calcium was imperceptible for SNF472 1-10 µM in physiological calcium concentrations. The lowest concentration tested in vascular smooth muscle cells, 1 µM inhibited calcification by 67%. SNF472 showed no deleterious effects on bone mineralization in dogs or in rat osteoblasts. CONCLUSION AND IMPLICATIONS: These experiments show that SNF472 binds to HAP and inhibits further HAP crystallization. The EC50 for chelation of free calcium is 50-fold greater than a maximally effective SNF472 dose, supporting the selectivity of SNF472 for HAP. These findings indicate that SNF472 may have a future role in the treatment of vascular calcification and calcific uraemic arteriolopathy in patients undergoing dialysis.

Improvement in wound healing, pain, and quality of life after 12 weeks of SNF472 treatment: a phase 2 open-label study of patients with calciphylaxis.

BACKGROUND: Calciphylaxis in end-stage renal disease is characterized by painful necrotic skin ulcers and high mortality. There are no approved therapies. SNF472, an intravenous formulation of myo-inositol hexaphosphate, inhibits the formation and growth of hydroxyapatite crystals, the final common pathway in the pathogenesis of vascular calcification. METHODS: In this open-label, single-arm study, calciphylaxis patients on thrice-weekly hemodialysis and standard care, received intravenous SNF472 3 times per week for 12 weeks. The primary endpoint was wound healing assessed using the quantitative Bates-Jensen Wound Assessment Tool (BWAT). Pain visual analog scale (VAS), quality of life (wound-QoL), and qualitative wound image review were secondary endpoints. Quantitative changes from baseline were analyzed by paired t-tests using multiple imputation to account for missing observations. RESULTS: Fourteen patients received SNF472. Improvements from baseline to week 12 were observed for mean BWAT score (- 8.1; P < 0.001), pain VAS (- 23.6 mm; P = 0.015) and wound-QoL global score (- 0.90; P = 0.003). Of the 9 patients with ulcerated lesions at baseline who completed treatment, wound image review showed improvement for 7. SNF472 was well tolerated with no serious treatment-related adverse events. The most common adverse events were infections which occur frequently in patients on hemodialysis. None of these were considered as treatment-related. CONCLUSIONS: SNF472 was well-tolerated and improvements from baseline to week 12 in wound healing, pain, and quality of life were observed. A randomized, double-blind, placebo-controlled trial is planned to evaluate SNF472 in patients with calciphylaxis.