Bridging the Gap Between RCTs and RWE Through Endpoint Selection.

This commentary is authored by several industry real-world evidence (RWE) experts, with support from IQVIA, as part of the 'RWE Leadership Forum': a group of Industry Leaders who have come together as non-competitive partners to understand and respond to RWD/E challenges and opportunities with a single expert voice. Here, the forum discusses the value in bridging the industry disconnect between RTCs and RWE, with a view to promoting the use of RWE in the RCT environment. RCT endpoints are explored along several axes including their clinical relevance and their measure of direct patient benefit, and then compared with their real-world counterparts to identify suitable paths, or gaps, for assimilating RWE endpoints into the RCT environment.

Strengthening pharma's contract with society: the value of trusted partnerships between pharma and healthcare facilitated by real-world data.

This White Paper is authored by 11 industry real-world evidence (RWE) experts, with support from IQVIA, as part of the 'RWE Leadership Forum': a group of industry leaders who come together as noncompetitive partners to understand and respond to internal or external RWD/E challenges and opportunities with a single expert voice. Herein we aim to clarify the rules of engagement between pharma and healthcare in order to establish trust-based partnerships, which will unlock unique value for society, including the medical community and the ultimate beneficiary, the patient.

Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation.

OBJECTIVE: To assess the cost-effectiveness of dabigatran etexilate, a new oral anticoagulant, versus warfarin and other alternatives for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation (AF). METHODS: A Markov model estimated the cost-effectiveness of dabigatran etexilate versus warfarin, aspirin or no therapy. Two patient cohorts with AF (starting age of <80 and ≥80 years) were considered separately, in line with the UK labelled indication. Modelled outcomes over a lifetime horizon included clinical events, quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs). RESULTS: Patients treated with dabigatran etexilate experienced fewer ischaemic strokes (3.74 dabigatran etexilate vs 3.97 warfarin) and fewer combined intracranial haemorrhages and haemorrhagic strokes (0.43 dabigatran etexilate vs 0.99 warfarin) per 100 patient-years. Larger differences were observed comparing dabigatran etexilate with aspirin or no therapy. For patients initiating treatment at ages <80 and ≥80 years, the ICERs for dabigatran etexilate were £4831 and £7090/QALY gained versus warfarin with a probability of cost-effectiveness at £20 000/QALY gained of 98% and 63%, respectively. For the patient cohort starting treatment at ages <80 years, the ICER versus aspirin was £3457/QALY gained and dabigatran etexilate was dominant (ie, was less costly and more effective) compared with no therapy. These results were robust in sensitivity analyses. CONCLUSIONS: This economic evaluation suggests that the use of dabigatran etexilate as a first-line treatment for the prevention of stroke and systemic embolism is likely to be cost-effective in eligible UK patients with AF.

Quality of INR control and outcomes following venous thromboembolism.

INTRODUCTION: The objective of this study was to evaluate the pattern of anticoagulation after venous thromboembolism (VTE) in actual clinical practice. MATERIAL AND METHODS: This study used the General Practice Research Database. Individuals aged 18+ years with VTE were matched to 3 controls. RESULTS: Of the 46 335 patients with VTE and 138 024 controls, 70.2% of cases and 86.6% of controls had no obvious risk factors. The mortality risk was increased substantially around the time of diagnosis (relative hazard rate [RR] around 21) but remained elevated for a further 4 years (RRs around 1.5-2.0). The mean percentage of time spent within the therapeutic range for international normalized ratio (INR) was 57.0%. The lowest rate of VTE recurrence occurred in patients with ≥70% time spent within therapeutic range (RR of 0.50, 95% CI 0.39-0.63 compared to <30%). CONCLUSIONS: Higher time spent within therapeutic INR range was associated with lower risks of VTE recurrence and death due to VTE.

Treatments for stroke prevention in atrial fibrillation: a network meta-analysis and indirect comparisons versus dabigatran etexilate.

Patients with atrial fibrillation at moderate to high risk of stroke are not always anticoagulated despite a lack of contraindications to vitamin K antagonists (VKAs) like warfarin. These patients are treated with aspirin, aspirin-clopidogrel combination therapy or even receive no thromboprophylaxis. The oral direct thrombin inhibitor, dabigatran etexilate 150 mg BID and 110 mg BID, might represent an alternative for these patients; however, no head-to-head clinical trial data exist versus these alternative treatments. A network meta-analysis (NMA) was performed to indirectly compare dabigatran etexilate with antiplatelets and placebo. Compared with placebo, dabigatran etexilate 150 mg BID was estimated to significantly reduce the risk of any stroke (ischaemic and haemorrhagic) by 75% (relative risk [RR] 0.25; 95% confidence interval [CI] 0.12-0.51), ischaemic stroke by 77% (RR 0.23; 95% CI 0.14-0.38), systemic embolism by 83% (RR 0.17; 95% CI 0.05-0.50) and mortality by 36% (RR 0.64; 95% CI 0.45-0.91). Dabigatran etexilate 150 mg BID was estimated to significantly reduce the risk of any stroke compared with aspirin monotherapy by 63% (RR 0.37; 95% CI 0.20-0.69) and aspirin plus clopidogrel by 61% (RR 0.39; 95% CI 0.21-0.72). Trends toward reduced risk with both dabigatran etexilate regimens were found for most clinical outcomes. Relative risk estimates of dabigatran etexilate versus adjusted-dose VKAs within the NMA were consistent with results from the head-to-head randomised trial of these two strategies. Indirect evidence suggests treatment with dabigatran etexilate offers benefit for the prevention of stroke, systemic embolism and mortality over antiplatelets and placebo. There was no indication of increased intracranial or extracranial haemorrhage with dabigatran etexilate compared to antiplatelet agents.

Cost-effectiveness of warfarin: trial versus "real-world" stroke prevention in atrial fibrillation.

BACKGROUND AND PURPOSE: Previous cost-effectiveness analyses analyzed warfarin for stroke prevention in randomized trial settings. Given the complexities of warfarin treatment, cost-effectiveness should be examined within a real-world setting. METHODS: Our model followed patients with atrial fibrillation at moderate to high risk of stroke through primary and recurrent ischemic stroke, hemorrhages--intracranial and extracranial, and the resulting disability. Four scenarios were examined: (1) all patients start on warfarin with perfect control, that is, international normalized ratio (INR) values always within range; (2) all patients start on warfarin with trial-like control, where INR can fall outside the recommended range; (3) all patients start on warfarin with real-world INR control; and (4) real-world prescription (and control) of warfarin, aspirin, or neither for warfarin-eligible patients. Reported warfarin discontinuation rates were used. Main outcomes were total number of events, quality adjusted life years, and costs in a US setting. RESULTS: The total number of primary and recurrent ischemic strokes in a 1,000-patient cohort (age 70 years, lifetime analysis) was 626, 832, 984, and 1,171 in scenarios 1 to 4, respectively. The corresponding mean quality adjusted life years per patient were 7.21, 6.92, 6.75, and 6.67 for scenarios 1 to 4, respectively. Costs per patient were $68,039, $77,764, $84,518, and $87,248 in scenarios 1 to 4, respectively. If "perfect" adherence to warfarin was assumed, except for discontinuations for clinical reasons, strokes would decrease to 503, 737, 909, and 1,120 in scenarios 1 to 4, respectively. CONCLUSIONS: Clinical and cost outcomes are strongly dependent on the quality of anticoagulation and rates of warfarin discontinuation. Clinicians should work to improve both. Policy makers should use real-world INR control and warfarin discontinuation rates when assessing cost-effectiveness.

How effective are dose-adjusted warfarin and aspirin for the prevention of stroke in patients with chronic atrial fibrillation? An analysis of the UK General Practice Research Database.

The objective of this study was to evaluate the rate of stroke associated with aspirin and warfarin in routine clinical practice. The study included patients aged 40+ with chronic atrial fibrillation (cAF) registered in the UK General Practice Research Database. The outcome was the rate of stroke during current, past and no use of aspirin and warfarin. The study included 51,807 cAF patients. There was no difference in the rate of stroke between current and past use of aspirin (relative rate [RR] = 1.04 [95% confidence interval (CI) 0.94 - 1.15]), while the rate of stroke was reduced during current warfarin use compared to past use (RR = 0.62 [95% CI 0.54 - 0.71]). For warfarin, a pattern of lower rates of stroke during current exposure and higher rates with past exposure was seen only in patients treated for at least 6-12 months. For aspirin, no changes in the rates of stroke were observed with discontinuation of aspirin. The effectiveness of warfarin was dependent on the level of anticoagulation, with optimal risk reduction occurring within the recommended international normalised ratio (INR) range of 2.0 to 3.0. The proportion of patients achieving a stable INR within the target therapeutic range was at its lowest during the first three months of warfarin treatment. In conclusion, the results of this study support the effectiveness of warfarin treatment to reduce the rate of stroke in cAF patients in the general clinical practice setting, however the risk reduction is lower than that reported in clinical trials.

Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism after total knee and hip replacement surgery.

OBJECTIVE: This was an evaluation of the cost-effectiveness of oral dabigatran etexilate compared with subcutaneous low-molecular-weight heparin (enoxaparin) for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR) and total hip replacement (THR) surgery from the perspective of the UK National Health Service. METHODS: Dabigatran etexilate (220 mg once daily) was compared with enoxaparin (40 mg once daily) in patients undergoing TKR (duration of prophylaxis, 6-10 days) and THR (duration of prophylaxis, 28-35 days). The 10-week acute postsurgical phase was modeled using a decision tree. A Markov process (1-year cycle length) was used to model long-term events (recurrent VTE, postthrombotic syndrome, and consequences of intracranial hemorrhage) for patients' remaining lifetimes. Relative risks for VTE and bleeding events were derived from 2 Phase III studies that compared dabigatran etexilate with enoxaparin 40 mg once daily. The probabilities of long-term events were estimated using data from published longitudinal studies. RESULTS: Rates of VTE and bleeding events did not differ significantly between dabigatran etexilate and enoxaparin. Dabigatran etexilate was less costly than enoxaparin in TKR and substantially less costly in THR, primarily due to differences in administration costs. The cost of prophylaxis for THR patients, including drugs and administration costs, was estimated at pound 137 for dabigatran etexilate and pound 237 for enoxaparin ( pound 7 for nursing time during the hospital stay, pound 91 for nurse home visits for administration after hospital discharge, and an additional pound 2 in drug costs). At a willingness-to-pay threshold of pound 20,000 per quality-adjusted life-year, the probability of cost-effectiveness for dabigatran etexilate was 75% in TKR and 97% in THR. These results were robust across a range of sensitivity analyses. CONCLUSION: From the perspective of the UK National Health Service, thromboprophylaxis with dabigatran etexilate was cost-saving compared with enoxaparin 40 mg once daily, with comparable efficacy and safety profiles.

Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis.

Dabigatran etexilate has been investigated in three phase III trials for the prevention of venous thromboembolism (VTE). Health technology assessment agencies increasingly require meta-analyses of all relevant evidence for an intervention, if appropriate. The objective of this study was to perform a meta-analysis of efficacy and safety data for the recommended dose of dabigatran etexilate, 220 mg once daily (od), for VTE prophylaxis after total knee arthroplasty (TKA) and total hip arthroplasty (THA), and discuss the appropriateness of combining the data. Risk ratios (RR) for VTE and bleed end-points were estimated using fixed and random effects meta-analysis. Analyses were performed combining RE-MODEL and RE-NOVATE, which compared dabigatran etexilate with enoxaparin 40 mg od after TKA and THA, respectively, and also including RE-MOBILIZE, which compared dabigatran etexilate with enoxaparin 30 mg twice daily after TKA. Tests for statistical heterogeneity were performed using the Chi-squared statistic. No significant differences were detected between dabigatran etexilate and enoxaparin in any of the end-points analysed, either in the two trial analysis (all p > 0.15), or when all three trials were combined ( all p > 0.30). RRs (random effects) for the composite end-point total VTE and all-cause mortality were 0.95 [95% confidence intervals 0.82 - 1.10] and 1.05 [0.87 - 1.26] in the two and three trial analyses, respectively. Meta-analysis of RE-MODEL and RE-NOVATE supported the conclusions of the individual trials that dabigatran etexilate is non-inferior to enoxaparin 40 mg od, with a similar safety profile. Meta-analysis of all three trials found no significant differences between treatments in any of the end-points analysed. Heterogeneity between the trials cannot be ruled out.

Warfarin treatment in patients with atrial fibrillation: observing outcomes associated with varying levels of INR control.

INTRODUCTION: We aimed to determine the level of INR control associated with reduced stroke and mortality. MATERIAL AND METHODS: The study used a retrospective cohort design using linked inpatient, haematology and mortality data from Cardiff and the Vale of Glamorgan, UK. Anonymised patients admitted with a diagnosis of non-valvular atrial fibrillation (NVAF) were defined as warfarin or non-warfarin treated by number of repeated International Normalised Ratio (INR) tests. Warfarin treated patients (>5 INR tests) categorised as at moderate or high risk of stroke (CHADS2 score > or = 2) with varying levels of INR control were compared to those who did not receive warfarin treatment using Cox proportional hazards models controlling for age, sex and CHADS2 score. Outcome measures were time to stroke and mortality. RESULTS: 6,108 patients with NVAF were identified. 2,235 (36.6%) of these patients had five or more INR readings and of these 486 (21.7%) had CHADS2 score > or = 2. There was significant improvement in time to stroke event in those patients with INR control of greater than 70% of time in therapeutic range (2.0 to 3.0) compared with the non-warfarin treatment group. Overall survival was significantly improved for all warfarin treated groups with INR control of greater than 40% of time in range. CONCLUSIONS: Patients with INR control of above 70% of time in range had a significantly reduced risk of stroke. Patient suitability for warfarin treatment should be continuously assessed based on their ability to maintain a consistently therapeutic INR.

Cost-utility analysis comparing meropenem with imipenem plus cilastatin in the treatment of severe infections in intensive care.

This study compared the cost-effectiveness of meropenem with that of imipenem plus cilastatin in the treatment of severe infections in hospital intensive care in the UK. A Markov model was constructed to model lifetime costs and quality-adjusted life years (QALYs) of using meropenem and imipenem plus cilastatin for the treatment of severe infections in intensive care. Estimates of effectiveness, utility weights and costs were obtained from the published literature. Probabilistic sensitivity analysis was conducted to assess the robustness of the results. Estimated treatment costs for the patient cohort were pound 14,938 with meropenem and pound 15,585 with imipenem plus cilastatin. QALYs gained were 7,495 with meropenem and 7,413 with imipenem plus cilastatin. Probabilistic sensitivity analysis showed meropenem to be significantly less costly (-pound 636.47, 95% CI -pound 132.33 to -pound 1,140.62) and more effective (0.084, 95% CI 0.023 to 0.144). Meropenem thus appears significantly more effective and less expensive than imipenem plus cilastatin and should therefore be considered the dominant treatment strategy.