Home Treatment for Active Cancer Patients With Low-Risk Pulmonary Embolism　- A Predetermined Companion Report From the ONCO PE Trial.

BACKGROUND: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.Methods and Results: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0-9.6%]) in the home treatment group and in 2 patients (1.8% [0.0-4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0-9.6%]), and 2 patients (3.0% [0.0-7.2%]) required hospitalization due to bleeding events. CONCLUSIONS: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.

Assessment of Pazopanib-Related Heart Failure in Patients With Advanced Soft Tissue Sarcoma　- A Single Institute Analysis.

BACKGROUND: Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This study determined the incidence and risk factors of HF following pazopanib treatment for STS at our Institute and the clinical outcomes.Methods and Results:This study retrospectively analyzed the cases of STS patients treated with pazopanib (n=151) between 2012 and 2020. HF occurred in 6 patients (3.9%) at the median onset of 137 (range 14-468) days after the treatment initiation. When their HF was diagnosed, pazopanib was interrupted in all 6 patients. No patients experienced HF-related death, and HF development was not a significant factor for poor overall survival. The cumulative doses of anthracyclines (>225 mg/m2) before pazopanib initiation (83% vs. 37%, P=0.031), pazopanib initiation at age ≥60 years (83% vs. 35%, P=0.026), and the baseline B-type natriuretic peptide (BNP) concentration (≥50 pg/mL) before pazopanib (67% vs. 11%, P=0.002) initiation were predictive factors for post-pazopanib treatment HF. CONCLUSIONS: The study findings highlight the effect of past anthracycline exposure and baseline BNP for pazopanib-associated HF. Although the study patients' clinical outcomes were generally favorable, periodic monitoring of cardiac function using ultrasonic echocardiography or serum markers is essential to detect events early and begin therapeutic intervention appropriately under a cardiologist's instructions.

A Rare Case of Reversible Cardiac Dysfunction Associated with Tegafur/Gimeracil/Oteracil (S-1) Therapy.

For the past 20 years, S-1 has been used in the treatment of many types of cancer. However, the clinical importance of myocardial dysfunction attributed to S-1 remains to be unclear. Thus, in this study, we report on a patient with myocardial dysfunction associated with S-1.S-1 postoperative chemotherapy for gastric cancer was included as a treatment for a 65-year-old man. On day 8, S-1 treatment was discontinued after the patient developed an oral ulcer. He was then admitted to the hospital because of diarrhea caused by S-1. At approximately the same time, he developed dyspnea, and his chest X-rays revealed perihilar vascular engorgement and cardiac enlargement. Although his brain natriuretic peptide was 595.8 pg/mL, troponin I and creatine phosphokinase were unremarkable. Electrocardiograms showed no change in atrial fibrillations or new ST-T wave change. As per his transthoracic echocardiogram, noted were expansion of the left ventricle, global hypokinesis, and reduced left ventricular ejection fraction (approximately 40%). The patient was then diagnosed with S-1-related myocardial dysfunction. Furosemide, human atrial natriuretic peptide, dobutamine, enalapril, spironolactone, and bisoprolol were administered. Thirteen days after being diagnosed with heart failure, his symptoms disappeared, his echocardiogram showed that the left ventricular ejection fraction had increased to 65%, and the cardiothoracic ratio improved to 47% according to his chest X-rays.S-1-related myocardial dysfunction may be reversible, as it can improve after approximately 2 weeks.

Cardiotoxicities of 5-Fluorouracil and Other Fluoropyrimidines.

OPINION STATEMENT: Fluoropyrimidine (FP) is used to treat a wide range of cancers; however, it is associated with drug-induced vascular toxicity, as well as angina pectoris and coronary spasm. FP has been administered for many years, although the incidence, mechanisms, and appropriate methods for managing its associated cardiovascular toxicities have not been clarified, and the management of these complications has not been standardized. This lack of evidence is not limited to FP. Many trials of anticancer agents have been conducted, excluding patients with heart diseases. Hence, there is a paucity of epidemiological data on cardiovascular adverse events caused by anticancer agents. There have been remarkable improvements in cancer treatment in recent years, with consequent improvements in prognosis. In this context, new cardiovascular toxicities related to new drugs have emerged. We are now compelled to respond to cardiovascular adverse events despite the lack of evidence regarding optimal management. The result has been establishment and rapid maturation of the new academic field of cardio-oncology. Despite the relative lack of evidence, we must review small pieces of evidence that have accumulated to date and make the utmost efforts to provide patients with effective evidence-based medical care. Simultaneously, we urgently need randomized clinical trials to build strong evidence.

Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity.

BACKGROUND: Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib. OBJECTIVE: To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity. METHODS: This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study. RESULTS: Compared with international normalized ratio at the baseline significant (P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing. CONCLUSION: In most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.

[Effects of Seven Tyrosine Kinase Inhibitors on the Anticoagulation Activity of Warfarin].

Several studies have reported increased anticoagulation effect of warfarin(WF)when combined with tyrosine kinase inhibitors(TKIs), such as gefitinib and erlotinib. However, effects of TKIs other than gefitinib and erlotinib on the anticoagulation effect of WF have not been clarified. To assess the degree and onset of prothrombin time-international normalized ratio (PT-INR)elevation and changes in WF daily doses in patients additionally receiving TKIs, this retrospective, single-center observational study compared PT-INR values and WF daily doses during WF treatment in the absence and presence of TKIs. Seven different TKIs(afatinib, alectinib, axitinib, crizotinib, pazopanib, regorafenib, and vandetanib)were prescribed during treatment with WF of venous thromboembolism in 10 cancer patients. Compared to baseline PT-INR, significant PT-INR elevations were observed in all patients during the combination therapy. The median PT-INR increased 1.6-fold from the baseline in the presence of TKIs(p<0.01), and the onset of PT-INR elevation was observed at a median of 18 days. As all patients receiving WF with the 7 TKIs showed PT-INR elevation, enhancement of the anticoagulation effect of WF in the presence of TKIs appears to be highly frequent. PT-INR should be carefully monitored, and adjusting the WF dosage may become necessary during the WF and TKI combination therapy.

[Effects of Tyrosine Kinase Inhibitors on Control of PT-INR in Patients Receiving Warfarin].

Few studies have evaluated the influence of anticancer drugs on the anticoagulation response to warfarin(WF). This retrospective, single-center, observationalstudy evaluated the changes in prothrombin time-internationalnormal ized ratio (PT-INR)in patients receiving a combination of WF and anticancer drugs. We compared(a)PT-INR changes between groups receiving WF and concomitantly started on either tyrosine kinase inhibitors(TKI)(WF+TKI group: n=14)or anticancer drugs other than TKI(WF+non-TKI group: n=20)and(b)PT-INR changes between groups that were started on WF concomitantly while receiving either TKI(TKI+WF group: n=16)or anticancer drugs other than TKI(non-TKI+WF group: n=13). (a)PT-INR changes were significantly larger in the WF+TKI group than in the WF+non-TKI group(2.23 vs 0.42, p<0.001). In the WF+TKI group, the WF dose was reduced after all 14 patients(100.0%)showed increased PT-INR.(b)PT-INR changes during the WF induction period were significantly larger in the TKI+WF group than in the non-TKI+WF group(2.18 vs 0.68, p<0.001). In the TKI+WF group, the WF dose was reduced after 12 patients(75.0%)showed increased PT-INR. It might be necessary to consider a reduction in WF dose when WF is administered in combination with TKIs.

Angiotensin II impairs endothelial nitric-oxide synthase bioavailability under free cholesterol-enriched conditions via intracellular free cholesterol-rich membrane microdomains.

Vascular endothelial function is impaired in hypercholesterolemia partly because of injury by modified LDL. In addition to modified LDL, free cholesterol (FC) is thought to play an important role in the development of endothelial dysfunction, although the precise mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms of endothelial dysfunction induced by an FC-rich environment. Loading cultured human aortic endothelial cells with FC induced the formation of vesicular structures composed of FC-rich membranes. Raft proteins such as phospho-caveolin-1 (Tyr-14) and small GTPase Rac were accumulated toward FC-rich membranes around vesicular structures. In the presence of these vesicles, angiotensin II-induced production of reactive oxygen species (ROS) was considerably enhanced. This ROS shifted endothelial NOS (eNOS) toward vesicle membranes and vesicles with a FC-rich domain trafficked toward perinuclear late endosomes/lysosomes, which resulted in the deterioration of eNOS Ser-1177 phosphorylation and NO production. Angiotensin II-induced ROS decreased the bioavailability of eNOS under the FC-enriched condition.

Trend of clinical outcome and surrogate markers during titration of ß-blocker in heart failure patients with reduced ejection fraction: relevance of achieved heart rate and ß-blocker dose.

BACKGROUND: The aim of this study was to examine trends of clinical outcome and to clarify surrogate markers when titrating ß-blocker in heart failure patients with reduced left ventricular ejection fraction (HFrEF, LVEF <50%). METHODS AND RESULTS: Consecutive HFrEF patients starting on ß-blocker were divided into 2 groups according to time of dose fixation attainment: before 31 December 2005 (group 1, n=108) or after 1 January 2006 (group 2, n=119). There were no significant differences in patient characteristics between the 2 groups at baseline. Beta-blocker fixed dose was higher with lower resting heart rate in group 2 (6.2±5.7mg/day vs. 9.5±9.1mg/day in carvedilol equivalent dose, P=0.001; 74.2±11.1beats/min vs. 70.2±9.7beats/min, P=0.004). The rate of HF hospitalization and/or all-cause death after 36 months was lower in group 2 than in group 1 (22% vs. 38%, P=0.011; hazard ratio, 0.90; P=0.012). Cox regression analysis showed that ß-blocker ≥10mg/day and achieved heart rate ≤71beats/min predicted a better outcome (both P<0.05). CONCLUSIONS: Recent improvement of clinical outcome among HFrEF patients may be attributable to the up-titration policy accompanying lowered heart rate. Resting heart rate ≤71beats/min and ß-blocker ≥10mg/day (ie, 50% of the target dose for Japanese patients) could be surrogate markers when titrating ß-blocker.

Novel criteria of urine osmolality effectively predict response to tolvaptan in decompensated heart failure patients--association between non-responders and chronic kidney disease.

BACKGROUND: A newly-developed vasopressin type 2 receptor antagonist, tolvaptan (TLV), has a unique feature of diuresis, but the response to this drug can be unpredictable. METHODS AND RESULTS: Data were collected from hospitalized patients with decompensated congestive heart failure who were administered TLV at 3.75-15 mg/day (n=61). A responder/non-responder to TLV was determined as having any increase/decrease in urine volume (UV) during the next 24h after TLV treatment on the first day. Logistic regression analyses for increases in UV were performed, and independent predictors of the responder were the following: C1, baseline urine osmolality (U-OSM) >352 mOsm/L; and C2, %decrease in U-OSM >26% at 4-6h after TLV administration. Criteria consisting of C1 and C2 had a good predictability for responders by receiver-operating characteristic analysis (area under the curve=0.960). Kidneys of the non-responders no longer had diluting ability (%decrease of U-OSM at 4-6h=2.7 ± 14.6%*), but also barely kept concentrating ability (baseline U-OSM=296.4 ± 68.7*mOsm/L) with markedly reduced estimated glomerular filtration ratio (35.5 ± 29.4 m l · min(-1) · 1.73 m(-2)*) (*P<0.05 vs. patients who had at least 1 positive condition [n=42]). CONCLUSIONS: More than 26% decrease in U-OSM from a baseline >352 mOsm/L for the first 4-6h predicts responders to TLV. Unresponsiveness to TLV is attributable to nephrogenic diabetes insipidus complicated by chronic renal disease.

Urine osmolality estimated using urine urea nitrogen, sodium and creatinine can effectively predict response to tolvaptan in decompensated heart failure patients.

BACKGROUND: Urine osmolality (U-OSM) is valuable to predict response to tolvaptan (TLV) in decompensated heart failure patients, but measurement of U-OSM is not always available on site. METHODS AND RESULTS: Data were collected from 66 hospitalized patients with decompensated heart failure who had received TLV at 3.75-15 mg/day. U-OSM, which was estimated using the following formula: 1.07×{2×[(urine sodium (mEq/L)]+[urine urea nitrogen (mg/dl)]/2.8+[urine creatinine (mg/dl)]×2/3}+16, was well correlated with the actual measurement (r=0.938, P<0.001). Criteria consisting of C1 (estimated baseline U-OSM>358 mOsm/L) and C2 (%decrease in estimated U-OSM>24% at 4-6 h after the first TLV dose) significantly discriminated responders from non-responders (P<0.05). CONCLUSIONS: Response to TLV can be predicted using U-OSM, which can be estimated using urine urea nitrogen, sodium, and creatinine concentration data.

Preoperative levels of bilirubin or creatinine adjusted by age can predict their reversibility after implantation of left ventricular assist device.

BACKGROUND: It is often difficult to predict reversibility of liver or renal function after left ventricular assist device (LVAD) implantation in patients with stage D heart failure. METHODS AND RESULTS: Data were obtained for 69 patients who had received a LVAD (18 continuous-flow, 51 pulsatile). Persistent hepatic or renal dysfunction was defined as levels of total bilirubin (TB) or creatinine (Cre) >1.5mg/dl at 6 months after LVAD implantation. TB score or Cre score was calculated: 0.15 × age+1.1 × (preoperative TB) or 0.2 × age+3.6 × (preoperative Cre), in which coefficients were determined on the basis of odds ratios for persistent hepatic or renal dysfunction, respectively. Receiver-operating characteristics analyses showed good predictabilities for persistent end-organ dysfunction (area under curve: 0.794 for TB score and 0.839 for Cre score). High-risk strata of TB score (>11.0 points) or Cre score (>14.1 points) were associated with persistently higher levels of TB or Cre (TB, 1.32 ± 0.51; Cre, 1.23 ± 0.41 mg/dl; both P<0.001 vs. low-risk strata). CONCLUSIONS: Reversibility of end-organ function with LVAD implantation can be well predicted by our new risk scoring system that consists of the preoperative TB or Cre level adjusted by the patient's age. The scoring system would be beneficial, especially in considering the indication of a bridge to candidacy.

Volumetric and functional assessment of ventricles in pulmonary hypertension on 3-dimensional echocardiography.

BACKGROUND: Non-invasive assessment of volume and function on the right ventricle (RV) for pulmonary hypertension (PH) is limited. METHODS AND RESULTS: Patients with PH (n=23) underwent 3-dimensional (D) echocardiography (3DECHO), with cardiac magnetic resonance imaging to confirm its precision, and right heart catheterization. On linear regression analysis the RV end-systolic volume index (ESVI) was positively correlated with pulmonary vascular resistance (PVR) and mean pulmonary arterial pressure (mPAP; R=0.42 and 0.46, P=0.03 and 0.03, respectively). The RV end-diastolic volume index (EDVI) was positively correlated with mPAP (R=0.41, P<0.05). The left ventricular (LV) EDVI was inversely correlated with PVR (R=-0.48, P=0.02). The RV ejection fraction was inversely correlated with PVR and mean right atrial pressure (mRAP; R=-0.57, and -0.45, P=0.004, and 0.03, respectively). RVEDVI/LVEDVI and RVESVI/LVESVI (the diastolic and systolic remodeling indices, respectively) had a significantly positive linear relationship with PVR (R=0.67 and 0.55, P=0.0005 and 0.006, respectively), and the former had a significantly positive linear relationship with mRAP (R=0.42, P<0.05). During the recovery process in 1 specific case, the remodeling indices maintained a significant linear relationship with the hemodynamic parameters. CONCLUSIONS: Novel indices provided by 3DECHO may be utilized as alternative indicators of hemodynamic changes in PH patients.

Successful weaning from the DuraHeart with a low left ventricular ejection fraction.

We report a case in which the DuraHeart (Terumo Heart, Ann Arbor, MI, USA) was successfully removed despite a low ejection fraction. A 33-year-old man who suffered from dilated cardiomyopathy underwent implantation of the DuraHeart. The assist flow decreased to less than 1.0 l/min 3 months after the implantation. Echocardiography demonstrated a low left ventricular ejection fraction (26 %) and left ventricular dilatation (64 mm). Right heart catheterization revealed a cardiac index of 2.9 l/min/m(2) with a DuraHeart flow of 0.7 l/min. The patient underwent DuraHeart explantation without cardiopulmonary bypass. He was stable at 10 months post-explant.

Bosentan improved persistent pulmonary hypertension in a case after implantation of a left ventricular assist device.

No medical treatment has been established to ameliorate pulmonary hypertension (PH) due to left heart disease. Heart transplantation (HTx) is thus far the definitive therapy for stage D heart failure, but concomitant PH is one of the major risk factors for death after HTx. Recently, implantation of a left ventricular assist device (LVAD) has been reported to improve PH and has become a major bridge tool for HTx. We experienced a rare case with persistent PH even after the implantation of a continuous-flow LVAD. The administration of an endothelin receptor antagonist, bosentan, significantly decreased pulmonary vascular resistance. Combination therapy with LVAD implantation and anti-PH medication may be useful for patients with stage D heart failure complicated with severe PH.

Acute pulmonary vasoreactivity test with sildenafil or nitric monoxide before left ventricular assist device implantation.

There has been no established medical therapy to ameliorate pulmonary hypertension (PH) owing to left heart disease (LHD-PH). It has recently been shown that the left ventricular assist device (LVAD) can improve LHD-PH and therefore has the potential to become a major bridge tool for heart transplantation (HTx). However, some patients still have persistent PH even after LVAD treatment. It is essential to demonstrate the reversibility of end-organ dysfunction, including PH, prior to implantable LVAD treatment, especially in Japan, because implantable LVAD treatment is indicated only as bridge to transplantation. Here we report a patient with LHD-PH whose PH was demonstrated to be reversible by the acute pulmonary vasoreactivity test (APVT) with nitrogen monoxide (NO) and the phosphodiesterase-5 inhibitor sildenafil. Both inhaled NO and sildenafil reduced pulmonary vascular resistance, but pulmonary capillary wedge pressure was increased by NO, which was conversely decreased under increased cardiac output by sildenafil. After the patient was listed as an HTx recipient, pulmonary vascular resistance recovered down to an acceptable range with LVAD treatment. Based on these findings, we suggest that the APVT with sildenafil may be a useful and safe tool to predict improvement of PH after LVAD treatment.

Successful conversion from thiazide to tolvaptan in a patient with stage d heart failure and chronic kidney disease before heart transplantation.

Chronic kidney disease (CKD) is often complicated with advanced heart failure because of not only renal congestion and decreased renal perfusion but also prolonged use of diuretics at higher doses, which sometimes results in hyponatremia. Preoperative CKD is known to be associated with poor prognosis after heart transplantation (HTx). We experienced a stage D heart failure patient with CKD and hyponatremia who was switched from trichlormethiazide to tolvaptan. His hyponatremia was normalized, and his renal function was improved after conversion to tolvaptan. In patients with stage D heart failure, it may be useful to administer tolvaptan with a concomitant reduction in the dose of diuretics in order to preserve renal function and avoid hyponatremia before HTx.

Insufficient self-care is an independent risk factor for adverse clinical outcomes in Japanese patients with heart failure.

Self-care is a cornerstone for the successful management of heart failure (HF). The purpose of this study was to examine the impacts of HF self-care on prognosis in Japanese patients with HF. A total of 283 HF outpatients (age 64 ± 14, 70% male, 52% HFrEF) were enrolled. We asked patients to answer about their adhevence to 5 self-care behaviors (medication, eating a low-sodium diet, regular exercise, daily weight check, and treatment seeking behavior). On the basis of the results, we classified patients into a good self-care group and a poor self-care group. The primary outcome was HF hospitalization and/or cardiac death. In total, 65% of patients were classified into the poor self-care group. During a median follow-up of 2 years, cardiac events occurred more frequently in the poor self-care group (22% versus 9.6%, P = 0.013). Poor self-care was an independent risk factor for cardiac events in Cox regression analysis adjusted for clinical parameters (hazard ratio = 2.86, P = 0.005). Poor self-care was also associated with an increased number of HF hospitalizations as well as an extended length of hospital stay for HF. Poor knowledge about HF was an independent determinant for poor self-care in multivariate logistic regression analysis (odds ratio = 0.92, P = 0.019). Insufficient self-care is an independent risk factor for cardiac events in Japanese patients with HF.

A case with recovery of response to tolvaptan associated with remission of acute kidney injury and increased urine osmolality.

Tolvaptan (TLV), a vasopressin type 2 receptor antagonist, has been demonstrated to be effective in patients with decompensated heart failure (HF) refractory to incremental doses of diuretics, but the responsiveness has not always been predictable. We have recently proposed that urine osmolality (U-OSM) is a valuable parameter for the prediction of responses to TLV, because U-OSM reflects the activity of the collecting ducts, where TLV plays its unique role. Acute kidney injury (AKI) is often associated with severe tubular dysfunction, including the collecting ducts, and in such cases a response to TLV may not be expected. We here experienced a patient with HF and AKI in whom TLV was not effective during AKI. We also observed recovery of responsiveness to TLV along with remission of AKI as well as increased U-OSM later on. We believe that this is the first report on the reversibility of the TLV response in relation to U-OSM.