Network Meta-Analysis of Randomized Trials Evaluating the Comparative Efficacy of Lipid-Lowering Therapies Added to Maximally Tolerated Statins for the Reduction of Low-Density Lipoprotein Cholesterol.

Background Lowering low-density lipoprotein cholesterol (LDL-C) levels decreases major cardiovascular events and is recommended for patients at elevated cardiovascular risk. However, appropriate doses of statin therapy are often insufficient to reduce LDL-C in accordance with current guidelines. In such cases, treatment could be supplemented with nonstatin lipid-lowering therapy. Methods and Results A systematic literature review and network meta-analysis were conducted on randomized controlled trials of nonstatin lipid-lowering therapy added to maximally tolerated statins, including statin-intolerant patients. The primary objective was to assess relative efficacy of nonstatin lipid-lowering therapy in reducing LDL-C levels at week 12. Secondary objectives included the following: LDL-C level reduction at week 24 and change in non-high-density lipoprotein cholesterol and apolipoprotein B at week 12. There were 48 randomized controlled trials included in the primary network meta-analysis. All nonstatin agents significantly reduced LDL-C from baseline versus placebo, regardless of background therapy. At week 12, evolocumab, 140 mg every 2 weeks (Q2W)/420 mg once a month, and alirocumab, 150 mg Q2W, were the most efficacious regimens, followed by alirocumab, 75 mg Q2W, alirocumab, 300 mg once a month, inclisiran, bempedoic acid/ezetimibe fixed-dose combination, and ezetimibe and bempedoic acid used as monotherapies. Primary end point results were generally consistent at week 24, and for other lipid end points at week 12. Conclusions Evolocumab, 140 mg Q2W/420 mg once a month, and alirocumab, 150 mg Q2W, were consistently the most efficacious nonstatin regimens when added to maximally tolerated statins to lower LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B levels and facilitate attainment of guideline-recommended risk-stratified lipoprotein levels.

Exploring the treatment gap among patients with osteoporosis-related fractures in France.

The use of anti-osteoporosis treatment following a diagnosis of osteoporosis with fracture or a relevant fragility fracture remains low in France. Initiating an anti-resorptive may reduce the incidence of a subsequent fracture by 60%. PURPOSE: To describe real-world osteoporosis treatment patterns in individuals with a fragility fracture in France and to explore the impact of initiating treatment on the risk of subsequent fracture. METHODS: A retrospective cohort study, using the national French Health Insurance claims database. Males and females 50 years and over, with a hospital discharge diagnosis of osteoporosis with fracture or a relevant fragility fracture between 2011 and 2014, were included and followed until death or the end of 2016, whichever came first. The primary outcome was the proportion of patients receiving anti-osteoporosis treatments prior to and post-index fracture. Change in fracture rates before and after treatment initiation was assessed in an exploratory analysis. RESULTS: A total of 574,133 patients (138,567 males, 435,566 females) had a qualifying index fracture. The proportion of patients receiving any anti-osteoporosis treatment increased pre-index fracture to post-index fracture from 2.2 to 5.6% among males, and from 11.8 to 18.2% among females. Oral bisphosphonates were the most prescribed anti-osteoporosis treatment for both males and females among post-index fractures (60.6% and 68.8% of patients initiating treatment). Following initiation of anti-resorptives, the incidence of subsequent fracture was reduced by 60% (rate ratio (RR): 0.40, 95% confidence interval [CI]: 0.34-0.45). CONCLUSION: Anti-osteoporosis treatment following an index fracture in France remains low. Improved identification and pharmacologic management of patients at risk of fragility fractures are necessary to reduce the risk of subsequent fractures.

Fractures in untreated patients with osteoporosis in Germany: an InGef healthcare insurance database analysis.

Osteoporosis is a skeletal disease that may result in low-trauma fracture if untreated. Among men and women ≥ 70 years untreated for osteoporosis, 30% (43,514) sustained at least one post-index fracture. Care for patients with osteoporosis diagnosis directly contributed to a cost burden of €786 million. INTRODUCTION: Osteoporosis is a skeletal disease that manifests as bone mineral density loss and low-trauma fractures. This database analysis describes the characteristics of untreated osteoporosis patients, and their rate of fractures, health resource utilization, and cost burden. METHODS: From the InGef database (2011-2016), eligible patients (≥ 70 years) untreated for osteoporosis were identified via a recorded diagnosis of osteoporosis (ICD-10 codes M80/M81) or an initial fragility fracture (index point). All patients were followed up for fractures post index. Direct costs included inpatient, outpatient, pharmacy, and ancillary care costs. RESULTS: A total of 144,752 patients (mean age 79 years; 73% female, median follow-up of 3.2 years) met the eligibility criteria; 23% had a history of fractures. Forty-eight percent of patients had cardiac diseases, 32% diabetes, and 27% cerebrovascular disease. Thirty percent (43,514) of patients had at least one post-index fracture; two or more post-index fractures were experienced in 7% (10,262) of patients. Median time from index date to first fracture was 145.5 days. Bisphosphonates were the most prescribed osteoporosis treatment following a first fracture post-index (n = 4102, 9.2%). There was a total of 107,055 patients (74.0%) who had at least one all-cause hospital stay. The total number of fracture-related admissions was 63,595 and that of outpatient visits was 323,460. A total of 34,764 (24%) patients died during follow-up. Costs for fracture-related care for patients directly contributed to a cost burden of €786 million. CONCLUSIONS: Osteoporosis patients and patients who sustain a fragility fracture remain undertreated for osteoporosis, increasing their risk of future fractures. Diagnosing and treating this group of patients should remain a priority to alleviate the clinical and economic burden of osteoporosis-related fractures.

Real-world treatment patterns of PCSK9 inhibitors among patients with dyslipidemia in Germany, Spain, and the United Kingdom.

OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 antibody inhibitors (PCSK9i) are approved as adjuncts to maximal tolerated statin therapy to lower low-density lipoprotein cholesterol (LDL-C). This study describes real-world use, characteristics of PCSK9i users and non-users, and factors influencing treatment choice. METHODS: A physician and patient survey was conducted in Germany, Spain, and the UK from December 2016 to April 2017 through the Adelphi Dyslipidemia Disease Specific Program. Physicians reported patients' lipid-lowering therapy (LLT) history and characteristics. PCSK9i users were systematically over-sampled. Results were summarized using frequencies and proportions. RESULTS: The study included 110, 123, and 117 physicians from Germany, Spain, and the UK, respectively, providing data on 3,073 patients (mean age = 62 years; 60% male). Most patients (63-73%) had prior statin and/or ezetimibe use. Compared to patients receiving other LLT (n = 2686), PCSK9i users (222 in Germany, 97 in Spain, 68 in the UK) were, on average, 5-7.5 years younger and had LDL-C at diagnosis averaging 23-53 mg/dl higher. Familial hypercholesterolemia (FH), coronary heart/artery disease, myocardial infarction, and acute coronary syndrome were more common among PCSK9i users than non-users. PCSK9i users were also more likely to use high-intensity statins in their current LLT regimen (64-89% vs 28-50%). Physicians commonly reported PCSK9i benefits on LDL-C and total cholesterol as reasons for initiating these agents, and PCSK9i users reported good knowledge of cardiovascular disease and treatment options. CONCLUSIONS: Results indicate that physicians are prescribing PCSK9i to patients with high cardiovascular risk in accordance with European guidelines and reimbursement requirements.

Systematic Review and Network Meta-Analysis on the Efficacy of Evolocumab and Other Therapies for the Management of Lipid Levels in Hyperlipidemia.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab substantially reduce low-density lipoprotein cholesterol (LDL-C) when added to statin therapy in patients who need additional LDL-C reduction. METHODS AND RESULTS: We conducted a systematic review and network meta-analysis of randomized trials of lipid-lowering therapies from database inception through August 2016 (45 058 records retrieved). We found 69 trials of lipid-lowering therapies that enrolled patients requiring further LDL-C reduction while on maximally tolerated medium- or high-intensity statin, of which 15 could be relevant for inclusion in LDL-C reduction networks with evolocumab, alirocumab, ezetimibe, and placebo as treatment arms. PCSK9 inhibitors significantly reduced LDL-C by 54% to 74% versus placebo and 26% to 46% versus ezetimibe. There were significant treatment differences for evolocumab 140 mg every 2 weeks at the mean of weeks 10 and 12 versus placebo (-74.1%; 95% credible interval -79.81% to -68.58%), alirocumab 75 mg (-20.03%; 95% credible interval -27.32% to -12.96%), and alirocumab 150 mg (-13.63%; 95% credible interval -22.43% to -5.33%) at ≥12 weeks. Treatment differences were similar in direction and magnitude for PCSK9 inhibitor monthly dosing. Adverse events were similar between PCSK9 inhibitors and control. Rates of adverse events were similar between PCSK9 inhibitors versus placebo or ezetimibe. CONCLUSIONS: PCSK9 inhibitors added to medium- to high-intensity statin therapy significantly reduce LDL-C in patients requiring further LDL-C reduction. The network meta-analysis showed a significant treatment difference in LDL-C reduction for evolocumab versus alirocumab.

Health state utilities associated with major clinical events in the context of secondary hyperparathyroidism and chronic kidney disease requiring dialysis.

BACKGROUND: Patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT) who require dialysis are at increased risk for cardiovascular events and bone fractures. To assist in economic evaluations, this study aimed to estimate the disutility of these events beyond the impact of CKD and SHPT. METHODS: A basic one-year health state was developed describing CKD and SHPT requiring dialysis. Further health states added acute events (cardiovascular events, fractures, and surgical procedures) or chronic post-event effects. Acute health states described a year including an event, and chronic health states described a year subsequent to an event. General population participants in Canada completed time trade-off interviews from which utilities were derived. Pairwise comparisons were made between the basic state and event, and between comparable health states. RESULTS: A total of 199 participants (54.8% female; mean age = 46.3 years) completed interviews. Each health state had ≥130 valuations. The mean (SD) utility of the basic health state was 0.60 (0.34). For acute events, mean utility differences versus the basic state were: myocardial infarction, -0.06; unstable angina, -0.05; peripheral vascular disease (PVD) with amputation, -0.33; PVD without amputation, -0.11; heart failure, -0.14; stroke, -0.30; hip fracture, -0.14; arm fracture, -0.04; parathyroidectomy, +0.02; kidney transplant, +0.06. Disutilities for chronic health states were: stable angina, -0.09; stroke, -0.27; PVD with amputation, -0.30; PVD without amputation, -0.12; heart failure, -0.14. CONCLUSIONS: Cardiovascular events and fractures were associated with lower utility scores, suggesting a perceived decrease in quality of life beyond the impact of CKD and SHPT.