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Dapagliflozin and Cardiac, Kidney, and Limb Outcomes in Patients With and Without Peripheral Artery Disease in DECLARE-TIMI 58.
Bonaca, MP, Wiviott, SD, Zelniker, TA, Mosenzon, O, Bhatt, DL, Leiter, LA, McGuire, DK, Goodrich, EL, De Mendonca Furtado, RH, Wilding, JPH, et al
Circulation. 2020;(8):734-747
Abstract
BACKGROUND Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis. METHODS A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer. RESULTS Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97-1.56], P=0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21-2.12], P=0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 - 2.03], P=0.0058), and limb adverse events (adjusted HR, 8.37, P<0.001). The relative risk reductions with dapagliflozin for CV death/HHF (HR, 0.86, PAD; HR, 0.82, no-PAD; P-interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P-interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90-1.26]) and amputation (HR, 1.09 [95% CI, 0.84-1.40]), with no significant interactions by a history of PAD versus not (P-interactions=0.30 and 0.093, respectively). CONCLUSIONS Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01730534.
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Efficacy and safety of loxoprofen sodium topical patch for the treatment of pain in patients with minor acute traumatic limb injuries in Brazil: a randomized, double-blind, noninferiority trial.
Fujiki, EN, Netto, NA, Kraychete, DC, Daher, MT, Tardini, R, Nakamoto, A, Lopes, DG
Pain. 2019;(7):1606-1613
Abstract
Posttraumatic injury pain is commonly treated with oral nonsteroidal anti-inflammatory drugs. However, oral nonsteroidal anti-inflammatory drugs cause several adverse events, with topical formulations arising as an important alternative. Therefore, we aimed at evaluating the efficacy and safety of loxoprofen patch (LX-P) in the treatment of patients with posttraumatic pain. This phase III, randomized, double-blind, noninferiority study enrolled Brazilian patients aged 18 to 65 years diagnosed with lower and upper limb posttraumatic injury who were experiencing moderate or severe pain. Patients were assigned to active LX-P or to loxoprofen tablet (LX-T), and pain intensity was measured based on a visual analog scale score variation after 7 days of treatment. Data on clinical symptoms, rescue medication use, and adverse events were also collected. Visual analog scale score variation was compared using a 10% noninferiority margin. Two hundred forty-two patients were randomly assigned to LX-P (n = 123) or to LX-T (n = 119). The results showed a reduction in pain after 7 days of treatment: -49.96 (n = 118; SE 1.7) in the LX-P and -47.71 (n = 117; SE 1.6) in the LX-T groups (difference of -2.25; 95% CI: -5.97 to 1.47; P = 0.23). On the safety analysis, the LX-T group presented twice as many patients with treatment-emergent adverse events as the LX-P group (30.8% and 14.2%, respectively). A sensitivity analysis demonstrated that rescue medication use has not affected the primary end point. This study showed that LX-P has a comparable efficacy to LX-T, but with a better safety profile, being a therapeutic option for the treatment of posttraumatic injury pain.
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Dexmedetomidine for prevention of skeletal muscle ischaemia-reperfusion injury in patients with chronic limb ischaemia undergoing aortobifemoral bypass surgery: A prospective double-blind randomized controlled study.
Kundra, TS, Thimmarayappa, A, Dhananjaya, M, Manjunatha, N
Annals of cardiac anaesthesia. 2018;(1):22-25
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Abstract
BACKGROUND Dexmedetomidine is a selective α-2 agonist used for sedation. It has also been shown to have myocardial protective effect and prevent ischemia-reperfusion injury in off-pump coronary artery bypass patients. The aim of our study was to assess the effect of dexmedetomidine for prevention of skeletal muscle ischemia-reperfusion injury in patients undergoing aortobifemoral bypass surgery. METHODOLOGY Sixty adult patients (Group dexmedetomidine n = 30, Group normal saline n = 30) undergoing aortobifemoral bypass surgery were recruited over 3 months. Randomization was done using a computer-generated random table. The attending anesthesiologist would be blinded to whether the drug/normal saline was being administered. He would consider each unlabeled syringe as containing dexmedetomidine and calculate the volume to be infused via a syringe pump accordingly. Dexmedetomidine infusion (1 mcg/kg) over 15 minutes was given as a loading dose, followed by maintenance infusion of 0.5 mcg/kg/h till 2 h postprocedure in Group dexmedetomidine (D) while the same volume of normal saline was given in the control Group C till 2 h postprocedure. Creatine phosphokinase (CPK) values were noted at baseline (T0), 6 h (T1), 12 h (T2), and 24 h (T3) after the procedure. Hemodynamic variables (heart rate [HR] and mean blood pressure [MAP]) were recorded at T0, T1, T2, and T3. Results were analyzed using unpaired Student's t-test, P < 0.05 was considered statistically significant. RESULTS MAP and HR significantly decreased in Group D as compared to control group (P < 0.05). However, the decrease was never <20% of the baseline. The CPK values at 6, 12, and 24 h were statistically significant between the two groups. CONCLUSION Dexmedetomidine prevents skeletal muscle ischemia-reperfusion injury in patients undergoing aortobifemoral bypass surgery.
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Limb ischemic preconditioning reduces heart and lung injury after an open heart operation in infants.
Zhou, W, Zeng, D, Chen, R, Liu, J, Yang, G, Liu, P, Zhou, X
Pediatric cardiology. 2010;(1):22-9
Abstract
Open heart surgery supported by cardiopulmonary bypass is associated with heart and lung ischemia-reperfusion injury (IRI). Limb remote ischemic preconditioning (RIPC) reduces injury caused by ischemia-reperfusion in multiple distant organs. We conducted a prospective clinical trial (randomized and controlled) to test the feasibility and safety of limb RIPC, as well as its protective effects against myocardial and pulmonary IRI for infants undergoing repair of simple congenital heart defects. Infants undergoing repair of ventricular septal defects were enrolled in our study and randomly assigned to one of two treatment groups: limb RIPC or control. RIPC was induced twice (24 h and 1 h preoperatively) via three 5-min cycles of ischemia and reperfusion on the left upper arm using a blood pressure cuff. Lung compliance, respiratory index (RI), and cardiac inotropic score (IS) were calculated for each patient. Serum concentrations of the following factors were measured perioperatively: interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha; lactate dehydrogenase (LDH), creatine kinase (CK), and its isoenzyme (CK-MB), and troponin I (TnI); malondialdehyde (MDA) and superoxide dismutase (SOD). The expression of heat shock protein 70 (HSP 70) in cardiomyocytes was analyzed by Western blot. Surgical outcomes, including limb movement and sensory function, were recorded in detail. Sixty infants weighting less than 7 kg were studied, with 30 patients in the RIPC group and 30 in the control group. Within 6 months of discharge from the hospital, no limb disability, sensory disturbance, or other surgical complications were found in any patient. Compared with the control group, patients in the RIPC group had higher Cs and Cd, along with lower RI and IS at various postoperative phases. At the beginning of the operation, serum concentrations of IL-6, IL-8, IL-10, TNF-alpha, LDH, CK, and TnI were higher in the RIPC group than the control group. Postoperatively, release of cytokines and leakage of heart enzymes were attenuated in the RIPC group; serum concentrations of cytokines and heart enzymes were lower in the RIPC group at some, but not all, postoperative time points. Furthermore, the RIPC group had lower coronary sinus venous concentrations of MDA and higher concentrations of SOD. Similarly, the expression of HSP 70 was upregulated in cardiomyocytes from the RIPC group. Limb RIPC can be applied safely and easily in infants, can attenuate systemic inflammatory response syndrome, and can increase systemic tolerance to IRI, imparting a protective effect against myocardial and pulmonary IRI. The expression of HSP 70 has an important role in the mechanism of action for RIPC.
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Cost effectiveness analysis of intravenous ketorolac and morphine for treating pain after limb injury: double blind randomised controlled trial.
Rainer, TH, Jacobs, P, Ng, YC, Cheung, NK, Tam, M, Lam, PK, Wong, R, Cocks, RA
BMJ (Clinical research ed.). 2000;(7271):1247-51
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Abstract
OBJECTIVES To investigate the cost effectiveness of intravenous ketorolac compared with intravenous morphine in relieving pain after blunt limb injury in an accident and emergency department. DESIGN Double blind, randomised, controlled study and cost consequences analysis. SETTING Emergency department of a university hospital in the New Territories of Hong Kong. PARTICIPANTS 148 adult patients with painful isolated limb injuries (limb injuries without other injuries). MAIN OUTCOME MEASURES Primary outcome measure was a cost consequences analysis comparing the use of ketorolac with morphine; secondary outcome measures were pain relief at rest and with limb movement, adverse events, patients' satisfaction, and time spent in the emergency department. RESULTS No difference was found in the median time taken to achieve pain relief at rest between the group receiving ketorolac and the group receiving morphine, but with movement the median reduction in pain score in the ketorolac group was 1.09 per hour (95% confidence interval 1.05 to 2.02) compared with 0.87 (0.84 to 1.06) in the morphine group (P=0.003). The odds of experiencing adverse events was 144.2 (41.5 to 501.6) times more likely with morphine than with ketorolac. The median time from the initial delivery of analgesia to the participant leaving the department was 20 (4.0 to 39.0) minutes shorter in the ketorolac group than in the morphine group (P=0.02). The mean cost per person was $HK44 ( pound4; $5.6) in the ketorolac group and $HK229 in the morphine group (P<0.0001). The median score for patients' satisfaction was 6.0 for ketorolac and 5.0 for morphine (P<0.0001). CONCLUSION Intravenous ketorolac is a more cost effective analgesic than intravenous morphine in the management of isolated limb injury in an emergency department in Hong Kong, and its use may be considered as the dominant strategy.