Safety and Effectiveness of Elotuzumab in Japanese Patients with Relapsed/Refractory Multiple Myeloma: A Post-marketing Surveillance Study.

Objective Elotuzumab plus lenalidomide and dexamethasone (ELd) was approved in Japan in 2016 for the treatment of relapsed/refractory multiple myeloma (RRMM). This post-marketing surveillance study evaluated the safety and effectiveness of ELd in RRMM patients during routine clinical practice in Japan. Methods Elotuzumab safety was assessed by evaluating adverse drug reactions (ADRs), and effectiveness was assessed primarily by the best overall response. Patients The study enrolled patients with RRMM who received ELd therapy between November 18, 2016, and June 18, 2017. The safety and effectiveness analysis sets included 831 and 755 patients, respectively. Results In the safety analysis set, patients received a median (range) of 12 (1-40) elotuzumab administrations over 108 (1-728) days of treatment. The relative dose intensity of elotuzumab was ≥90% in 74.1% of patients. ADRs and serious ADRs were reported in 41.2% and 15.2% of the patients, respectively. The most common ADR was infection (12.0%), followed by lymphocytopenia (10.1%), infusion reactions (7.5%), secondary malignancies (e.g. gastric cancer and pancreatic carcinoma), cataracts, and interstitial lung disease (0.2% each). While most patients with ADRs recovered, 71 discontinued treatment, and 14 deaths were reported. The presence of comorbidities, particularly cardiovascular disorders, significantly affected the safety. The overall response rate was 41.1%. Conclusion This all-case post-marketing surveillance study showed that ELd had an acceptable tolerability profile and promising clinical activity in Japanese patients with RRMM.

Postmarketing surveillance evaluating the safety and effectiveness of golimumab in Japanese patients with rheumatoid arthritis.

OBJECTIVES: The purpose of this study was to evaluate the real-world safety and effectiveness of golimumab (GLM) in Japanese patients with rheumatoid arthritis. METHODS: A postmarketing surveillance of 5154 patients was conducted with a follow-up duration of at least 24 weeks. Patients were divided into four groups based on the initial treatment: 50 mg or 100 mg of GLM with concomitant use of methotrexate (MTX) and 50 mg or 100 mg of GLM monotherapy. Patient characteristics at baseline, safety and effectiveness were assessed for each group. RESULTS: Over 70% of patients received 50 mg of GLM with concomitant MTX, and approximately, 20% received monotherapy. The incidence rate of adverse events was 45.40 per 100 patient-years. The incidence of adverse events including serious adverse events was comparable across all groups. The proportion of patients showing remission or low disease activity increased from 13.69% to 46.21% at the final evaluation, and no differences were observed in the percentage of remission across the four groups. Concomitant MTX use was associated with higher probability of continuing therapy. CONCLUSIONS: GLM showed effectiveness in Japanese rheumatoid arthritis patients with an acceptable safety profile.

Percutaneous stenting of bilateral central venous occlusions in a hemodialysis patient.

Upper-extremity central venous obstruction is often first recognized when an arteriovenous fistula is made for hemodialysis at an ipsilateral site. We encountered a case of markedly expanded edema after making an arteriovenous fistula in the left forearm. Systemic venography showed that the bilateral brachiocephalic veins and right subclavian vein were occluded. Implantation of a self-expandable stent in the left brachiocephalic vein relieved the edema. However, recurrence of similar edema and occlusion of the left brachiocephalic vein were noted after 1.5 years. The left brachiocephalic vein was then recanalized by ballooning and additional stent implantation, and a stent was implanted between the superior vena cava and right subclavian vein. Simultaneous reconstruction of the bilateral central venous obstruction by percutaneous intervention rather than surgical repair was suitable for this patient because of previous thoracoplasty. We also believe that this method can provide an opportunity to select the suitable forearm for making an arteriovenous fistula, in which the ipsilateral central vein will exhibit little restenosis.

Incomplete stent apposition in a left main bifurcated lesion after kissing stent implantation.

We present the case of a 75-year-old female who developed restenosis after the deployment of kissing sirolimus-eluting stents at the left main coronary artery (LMCA) bifurcation. Restenosis occurred at the left circumflex (LCx) artery ostium, where a stent deployed from the LMCA to the LCx arteries overlapped another stent deployed from the LMCA to the left anterior descending (LAD) artery. We investigated the stent expansion and deformation after kissing stent implantation using a phantom three-dimensional model depicting a LMCA bifurcation. Stent overlap was detected at the distal LMCA whether the LAD stent was positioned over the left circumflex (LCx) stent or vice versa. Stent overlap created a gap beneath the overlapped portion of the stent. Thus, we found that kissing stent implantation using different-sized stents produced compression of the LCx stent at the distal LMCA. Incomplete stent apposition caused by stent overlap and stent deformation is thought to be the main mechanism for restenosis after kissing stent implantation procedures.

Detection of patency of internal mammary artery grafts to the left anterior descending artery by transthoracic Doppler echocardiography.

BACKGROUND: To determine whether a coronary artery bypass graft (CABG) is patent, we examined the flow of the left internal mammary artery (LIMA) to the left anterior descending artery (LAD) by transthoracic Doppler echocardiography (TTDE). PATIENTS AND METHODS: Eighty-seven patients with CABG (LIMA to distal LAD) were enrolled in the study. The flows from each subject were analyzed by three criteria: mosaic flow at the anastomosis site, distal anterograde flow (ante flow), and proximal retrograde flow (retro flow). RESULTS: On angiography, 79 grafts were patent and eight were not. TTDE study of 79 patent grafts demonstrated mosaic, ante, and retro flow in 63 (79.7%), 74 (93.7%), and 35 grafts (49.4%), respectively. The averaged diastolic peak velocity of ante flow was 26.3 +/- 11.0 cm/sec, significantly higher than that (4.8 +/- 7.1 cm/sec, P < or = 0.0001) in eight patients without patent grafts. These eight patients had no mosaic or retro flow and only three had ante flow. The accuracies to predict patency were 81.6%, 90.8%, and 49.4% for mosaic, ante, and retro flows, respectively. CONCLUSIONS: The existence of mosaic, retro, or sufficient ante flows strongly indicated the patency of LIMA to the LAD. When symptoms are possible to be derived from the occlusion of CABG to LAD, TTDE is a promising method to examine whether a LIMA to LAD bypass is patent.

Experimental hyperhomocysteinemia impairs coronary flow velocity reserve.

BACKGROUND: Hyperhomocysteinemia has been identified as an independent risk factor for coronary artery disease. One mechanism is considered to be deteriorated endothelial function that is recovered by vitamin C. However, its direct action on coronary circulation has yet to be examined. This study was designed to test the hypothesis that experimental acute hyperhomocysteinemia would impair coronary flow velocity reserve (CFR) by increasing oxidative stress. METHODS: Eleven healthy male volunteers (aged 23.3+/-0.9 years) were enrolled. CFR induced by intravenous 5'-adenosine triphosphate infusion was measured by transthoracic-Doppler echocardiography. Measurements were taken before and 4 h after administration of a placebo, oral methionine (L-methionine 0.1 g/kg) or oral methionine plus vitamin C (2 g) on 3 separate days. RESULTS: The baseline average diastolic peak velocity (APV) was similar in all 3 groups. In the methionine group, plasma homocysteine increased (12.9+/-7.0 to 32.1+/-9.4 nmol/ml, p<0.0001), while APV under hyperemic conditions (APV-hyp) and CFR significantly decreased (87.2+/-11.4 cm/sec and 4.02+/-0.70 to 73.2+/-10.2 cm/sec and 3.35+/-0.52, p=0.0022 and 0.0030, respectively). Moreover, there was a significant inverse correlation between the plasma homocysteine and CFR (r=-0.620, p=0.0021). However, upon simultaneous administration of vitamin C, APV-hyp and CVR did not decrease despite an elevation in plasma homocysteine. CONCLUSIONS: Experimentally induced acute hyperhomocysteinemia significantly decreased CFR, and this decrease was significantly reversed by vitamin C administration. Oxidative stress is suggested to play a major role in the deleterious effects of homocysteine on the coronary microcirculation.

Vascular endoscopic and macroscopic observations after crush stenting of coronary artery bifurcations in pigs.

The crush stent technique has recently been proposed to limit the development of restenosis between drug-eluting stents implanted at coronary artery bifurcations. We studied the stent expansion, apposition to the vessel, and aspect of the overlapping stents after in vivo crush stent implantation. Crush stent implantation was performed at coronary bifurcations in anesthetized swines. The treated sites were examined using intravascular ultrasound and a vascular endoscope. The stents removed from the vessel were analyzed macroscopically. After final kissing balloon inflation, an adequate apposition of the stent to the vessel wall was confirmed by vascular endoscopy and visual inspection. However, the side-branch stent was narrowed at the site of stent overlap, and the overlapping stents in the main branch created a metal mass, which could promote the development of thrombosis. The technique of crush stent implantation with additional kissing balloon inflation is feasible and promising. However, it may be limited by thrombosis and restenosis at the carina because of stent overlapping and potential incomplete apposition. Additional studies are needed to confirm the safety and long-term clinical results of this technique.

Evaluation of improved coronary flow velocity reserve using transthoracic Doppler echocardiography after single LDL apheresis.

UNLABELLED: The purpose of this study was to clarify whether coronary flow velocity reserve (CFVR), evaluated by adenosine 5'-triphosphate-induced hyperemia, is improved by single low-density lipoprotein (LDL) apheresis. Lipid lowering therapy is known to improve endothelium-dependent vasodilatation in forearm or coronary resistant vessels. However, few reports have studied the effect of acute LDL reduction on CFVR. METHODS: Seven patients with familial hypercholesterolemia and significant coronary stenosis except in the left anterior descending artery (LAD) were enrolled in this study. Coronary flow velocity reserve was estimated before and after LDL apheresis using transthoracic Doppler echocardiography (TTDE), which detects the flow velocity at the distal site of the LAD. Although the averaged diastolic peak velocity (ADPV) during ATP-induced hyperemia was similar before and after LDL apheresis, the ADPV at baseline decreased from 30.69 to 25.56 cm/s, resulting in an increased CFVR from 1.78 to 2.10 (P < 0.001). Plasma bradykinin and 6 keto PGF1alpha increased while fibrinogen and plasma viscosity decreased after apheresis. Single LDL apheresis improves CFVR according to TTDE analysis because of the decreasing ADPV at baseline, which is thought to be induced by epicardial coronary artery dilatation and improved microvessel function. This is the result of various factors, such as changes in plasma LDL cholesterol, bradykinin and PGI2 levels with LDL apheresis.

Effect of water immersion on renal sympathetic nerve activity and arterial baroreflex in conscious rabbits with heart failure.

Several studies have indicated an interaction between cardiopulmonary mechanoreflex and arterial baroreflex. However, the contribution of cardiopulmonary mechanoreflex to an abnormal arterial baroreflex in chronic heart failure (CHF) has not been fully investigated. We examined the effect of the activation of cardiopulmonary mechanoreceptors induced by head-out water immersion (WI) on the arterial baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in conscious rabbits with CHF induced by myocardial infarction. The arterial baroreflex sensitivity (BRS) of both HR and RSNA were decreased in CHF. WI induced a small decrease in RSNA in CHF compared to a sham-operated group (Sham), despite a similar increase in central venous pressure. WI did not affect BRS of HR or RSNA in either Sham or CHF. By averaging rectified RSNA recordings, we found that miniature RSNA in the control in CHF was higher than that in Sham. WI decreased the synchronized RSNA without changing miniature RSNA in either group. These results suggest that cardiopulmonary mechanoreflex control of RSNA is reduced in CHF, and that cardiopulmonary mechanoreflex has little effect on arterial baroreflex. An increase in miniature RSNA may reflect sympatho-excitation in CHF.