Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE.

BACKGROUND: Semuloparin is a novel ultra-low-molecular-weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. OBJECTIVES: Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE-KNEE), elective hip replacement (SAVE-HIP1) and hip fracture surgery (SAVE-HIP2). PATIENTS/METHODS: All studies were multinational, randomized and double-blind. Semuloparin and enoxaparin were administered for 7-10 days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non-fatal pulmonary embolism or all-cause death. Safety outcomes included major bleeding, clinically relevant non-major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). RESULTS: In total, 1150, 2326 and 1003 patients were randomized in SAVE-KNEE, SAVE-HIP1 and SAVE-HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE-HIP1. In SAVE-HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE-KNEE and SAVE-HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. CONCLUSIONS: Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles

CPAP increases physical activity in obstructive sleep apnea with cardiovascular disease

STUDY OBJECTIVES:Uncertainty exists over whether continuous positive airway pressure (CPAP) treatment improves moderate to vigorous physical activity levels in those with obstructive sleep apnea. We aimed to determine effects of CPAP on moderate to vigorous physical activity among participants with co-occurring cardiovascular disease and obstructive sleep apnea. METHODS:The Sleep Apnea cardioVascular Endpoints (SAVE) trial recruited participants with confirmed cardiovascular disease history and obstructive sleep apnea, 45–75 years old. The 2,687 participants (1,346 randomized to CPAP plus usual care and 1,341 to usual care alone) were followed up for a mean of 3.7 years. Self-reported physical activity was recorded at baseline, 6, 24, and 48 months using the Godin-Shepard Leisure Time Exercise Questionnaire (LTEQ). We also determined effects on any limitation of physical activity reported on the physical functioning subscale of the 36-item short form questionnaire (SF-36) and proportions of participants reaching guideline recommended physical activity levels. RESULTS:Among 2,601 participants with available data, those in the CPAP group reported significantly more physical activity compared to the usual care group, with approximately 20% higher reported moderate activities on the LTEQ during follow-up (adjusted mean 95% confidence interval) scores: 8.7, 7.5–9.9 vs 7.3, 6.1–8.5; P = .003). Those in the CPAP group also reported less limitation in physical activity (adjusted between-group difference in SF-36 physical functioning subscale score 1.66, 95% confidence interval 0.87–2.45; P < 0.001), and more reported sufficient levels of physical activity to meet recommendations. CONCLUSIONS:CPAP has positive effects on improving physical activity levels, consistent with long-term health benefits. CLINICAL TRIAL REGISTRATION:Registry: ClinicalTrials.gov; Name: Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea to Prevent Cardiovascular Disease (SAVE); URL: https://clinicaltrials.gov/ct2/show/NCT00738179; Identifier: NCT00738179; and Registry: Australian New Zealand Clinical Trials Registry; Name: Sleep Apnea cardioVascular Endpoints study—An investigation of continuous positive airway pressure for the treatment of obstructive sleep apnea to prevent cardiovascular disease; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=83062&isReview=true; Identifier: ACTRN12608000409370. CITATION:Stevens D, Loffler KA, Buman MP, et al. CPAP increases physical activity in obstructive sleep apnea with cardiovascular disease. J Clin Sleep Med. 2021;17(2):141–148

Low Prognostic Value of Novel Nocturnal Metrics in Patients With OSA and High Cardiovascular Event Risk: Post Hoc Analyses of the SAVE Study

Background: Traditional methods for the quantification of OSA severity may not encapsulate potential relationships between hypoxemia in OSA and cardiovascular risk. Research Question: Do novel nocturnal oxygen saturation (SpO2) metrics have prognostic value in patients with OSA and high cardiovascular event risk? Study Design and Methods: We conducted post hoc analyses of the Sleep Apnea Cardiovascular Endpoints (SAVE) trial. In 2687 individuals, Cox proportional hazards models that were stratified for treatment allocation were used to determine the associations between clinical characteristics, pulse oximetry-derived metrics that were designed to quantify sustained and episodic features of hypoxemia, and cardiovascular outcomes. Metrics included oxygen desaturation index, time <90% SpO2, average SpO2 for the entire recording (mean SpO2), average SpO2 during desaturation events (desaturation SpO2), average baseline SpO2 interpolated across episodic desaturation events (baseline SpO2), episodic desaturation event duration and desaturation/resaturation-time ratio, and mean and SD of pulse rate. Results: Neither apnea-hypopnea index, oxygen desaturation index, nor any of the novel SpO2 metrics were associated with the primary SAVE composite cardiovascular outcome. Mean and baseline SpO2 were associated with heart failure (hazard ratio [HR], 0.81; 95% CI, 0.69-0.95; P = .009; and HR, 0.78; 95% CI, 0.67-0.90; P = .001, respectively) and myocardial infarction (HR, 0.86; 95% CI, 0.77-0.95; P = .003; and HR, 0.81; 95% CI, 0.73-0.90; P < .001, respectively). Desaturation duration and desaturation/resaturation time ratio, with established risk factors, predicted future heart failure (area under the curve, 0.86; 95% CI, 0.79-0.93). Interpretation: Apnea-hypopnea index and oxygen desaturation index were not associated with cardiovascular outcomes. In contrast, the pattern of oxygen desaturation was associated with heart failure and myocardial infarction. However, concomitant risk factors remained the predominant determinants for secondary cardiovascular events and thus deserve the most intensive management