An indirect comparison, via enoxaparin, of rivaroxaban with dabigatran in the prevention of venous thromboembolism after hip or knee replacement

Abstract

Objective:

To compare the efficacy, in the prevention of venous thromboembolism (VTE), and safety, of rivaroxaban and dabigatran relative to the common comparator enoxaparin.

Methods:

Two randomized clinical trials of dabigatran, one after total hip replacement (THR), RE-NOVATE, and one after total knee replacement (TKR), RE-MODEL, were identified as using the same enoxaparin regimen (40 mg once daily given the evening before surgery) and being of comparable duration to two rivaroxaban trials, RECORD1 and RECORD3. Indirect comparisons were performed on both efficacy and safety endpoints. To enable comparisons, symptomatic VTE results were based on the total study duration period, i.e. including the follow-up period. Major bleeding included surgical-site bleeding events.

Results:

After THR, rivaroxaban 10 mg once daily significantly reduced total VTE and symptomatic VTE relative to dabigatran 220 mg once daily (relative risk 0.34 and 0.19, respectively). After TKR, rivaroxaban significantly reduced total VTE versus dabigatran (relative risk 0.53); symptomatic VTE was not different between dabigatran and rivaroxaban. There was no significant difference in the rates of major bleeding for patients receiving rivaroxaban or dabigatran.

Conclusions:

Based on the indirect comparisons, rivaroxaban was estimated to be more efficacious than dabigatran in the prevention of total VTE after THR and TKR. Our analysis relied upon published data for dabigatran and did not have the advantages of more detailed comparative data obtained directly from a randomized trial, as was the case with rivaroxaban. Further comparative research may be of value, but until available our conclusions represent the best available evidence.

Key words::

• Dabigatran
• Enoxaparin
• Hip/knee replacement
• Rivaroxaban
• Thromboprophylaxis
• Venous thromboembolism

Introduction

In 2003, an estimated 12 million US hospital patients were predicted to be at risk of venous thromboembolism (VTE): the composite of deep vein thrombosis (DVT) and pulmonary embolism (PE)1. Another study estimated the incidence of symptomatic VTE at approximately 760,000 cases per year across six European countries2. First-year costs per patient for all-cause VTE are high: $10,800 or more in the US, especially for PE ($16,644)3, and up to €4000 in Europe4. Those at particular risk are patients undergoing procedures such as total hip replacement (THR) or total knee replacement (TKR) surgery. In the US, a VTE occurring during the index surgical admission can increase index admission costs by more than $25,000 after THR or $9000 after TKR5. Thromboprophylaxis has been shown to reduce the incidence of VTE; however, prophylaxis is often underused and a number of US organizations have developed quality improvement initiatives to improve clinical practice and reduce VTE-related morbidity and mortality6.

Rivaroxaban is an oral, direct Factor Xa inhibitor approved in more than 100 countries worldwide for the prevention of VTE in adult patients after elective hip or knee replacement surgery7,8. Dabigatran is an oral, direct thrombin inhibitor that has similarly been approved in many countries worldwide for the prevention of VTE in adult patients after elective hip or knee replacement surgery9. These approvals were based on a number of studies, in which the efficacy of rivaroxaban or dabigatran was compared with the current standard of care, enoxaparin.

Rivaroxaban and dabigatran are now used in many countries for the prevention of VTE after THR and TKR. It is important that clinicians, and other decision makers such as reimbursement authorities, understand the efficacy and safety of rivaroxaban relative to this other prophylactic option. In the absence of direct comparative randomized controlled trial (RCT) data for rivaroxaban against dabigatran, the most appropriate method for assessing the relative efficacy and safety of rivaroxaban versus dabigatran is an indirect comparison based on published RCTs10.

An adjusted indirect comparison assesses the efficacy and safety of drugs that have not been compared in a head-to-head clinical trial by analyzing the efficacy and safety of each drug relative to a common comparator – in this case, enoxaparin. This approach is recommended by the National Institute for Health and Clinical Excellence (NICE) in the UK11. Given that it is not feasible to conduct additional clinical trials, a rigorous indirect analysis with validated statistical tools is considered the most appropriate approach to assessing the relative efficacy of rivaroxaban to dabigatran. Because the primary audiences for the comparisons reported here are clinical decision makers and reimbursement authorities outside the US, the analyses were restricted to the enoxaparin regimen generally used in Europe and elsewhere, namely enoxaparin 40 mg once daily (od). Indirect comparisons of rivaroxaban and dabigatran using the common comparator of enoxaparin 30 mg twice daily (bid; RECORD4 and RE-MOBILIZE) will be reported separately.

Methods

Eligible study criteria

To be eligible for inclusion in the indirect comparison, studies needed to be double-blind RCTs in patients undergoing THR or TKR using the same enoxaparin regimen: 40 mg od given the evening before surgery, as the standard of care comparator.

Studies of rivaroxaban and dabigatran after THR/TKR

The rivaroxaban phase III RECORD program consisted of four phase III trials of rivaroxaban compared with both commonly used enoxaparin regimens (REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism [RECORD]1–4^12–15). In THR patients, RECORD1 compared the efficacy of extended prophylaxis (35 days) with rivaroxaban 10 mg od versus enoxaparin 40 mg od. RECORD2 compared the efficacy of extended prophylaxis (35 days) with rivaroxaban 10 mg od, versus short-term prophylaxis (10–14 days) with enoxaparin 40 mg od followed by placebo. In patients undergoing TKR, RECORD3 evaluated rivaroxaban 10 mg od versus enoxaparin 40 mg od, initiated preoperatively, for 10–14 days, and RECORD4 compared the efficacy of rivaroxaban 10 mg od versus enoxaparin 30 mg bid, initiated postoperatively, for 10–14 days. The primary efficacy outcome in each trial was total VTE: the composite of DVT (either symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal PE, and all-cause mortality. Secondary efficacy outcomes included major VTE (proximal DVT, non-fatal PE, or VTE-related death) and symptomatic VTE. The primary safety outcome was major bleeding, defined as bleeding that was fatal, occurred in a critical organ or required reoperation, or clinically overt extra-surgical-site bleeding associated with a fall in hemoglobin of at least 2 g/dl (1.24 mmol/l), or that required transfusion of 2 or more units of whole blood or packed cells12–15. The results of these trials consistently showed a significant reduction in total VTE with rivaroxaban, with no significant differences in rates of major bleeding12–15.

The phase III program for dabigatran for the prevention of VTE after THR/TKR consisted of three large-scale, non-inferiority studies that compared two doses of dabigatran (150 and 220 mg od) with standard enoxaparin regimens16–18. The primary efficacy outcome for all three studies was a composite of total VTE (asymptomatic and symptomatic) and all-cause mortality while receiving the study drug. Comparison of dabigatran with enoxaparin 40 mg od demonstrated that both doses of dabigatran were non-inferior to enoxaparin for the prevention of VTE after TKR (RE-MODEL) and THR (RE-NOVATE). However, in the RE-MOBILIZE study conducted in patients undergoing TKR, comparing dabigatran with enoxaparin 30 mg bid started 12–24 hours after surgery, both doses of dabigatran failed to demonstrate non-inferiority compared with enoxaparin18, possibly due to the more intense and prolonged dosing of the latter. In all three studies, there were no significant differences between the major bleeding rates associated with dabigatran and enoxaparin.

Duration of prophylaxis

An important factor in comparative RCTs is the duration of prophylaxis. The choice of which data to include in each indirect comparison was based upon the treatment duration for the common comparator enoxaparin. In THR, the indirect comparison was against a comparator that had used 35 days’ enoxaparin in its trials; the RE-NOVATE17 and RECORD1¹² studies were used as the source of the data for dabigatran and rivaroxaban, respectively. For the same reason, in TKR, the RE-MODEL16 and RECORD3¹⁴ studies were used as the source of the data for dabigatran and rivaroxaban, respectively. Essentially, the comparisons performed for rivaroxaban versus dabigatran are, therefore, drug-versus-drug comparisons. In these comparisons, there were only small differences in the duration of prophylaxis and the doses of the common comparator were consistent.

Studies compared

Therefore, for THR, RECORD1 was compared with RE-NOVATE, and for TKR, RECORD3 was compared with RE-MODEL Details of the trials are given in Table 1. The original intent was to perform a formal meta-analysis with sensitivity testing, but because of the limited studies with acceptable similarities this was not possible.

Table 1.  Summary of clinical trials included in the analyses.

Study reference	Study intervention	Patient number/characteristics	Dose and duration of intervention	Primary endpoint(s)
THR studies
Eriksson et al. 20079 RECORD1	Rivaroxaban	4541 patients randomized. Mean age = 63.2 years, 45.5% male	10 mg, 6–8 hours postoperatively then daily for 35 days	Total VTE (composite of any DVT or non-fatal PE) and all-cause mortality
Eriksson et al. 200714 RE-NOVATE	Dabigatran	3494 patients. Mean age = 64 years, 43.7% male	150 mg or 220 mg with half dose 1–4 hours after surgery/full dose if day after surgery, followed by full dose daily for 28–35 days	Total VTE (composite of any DVT or symptomatic PE) and all-cause mortality
TKR studies
Lassen et al. 200811 RECORD3	Rivaroxaban	2531 patients randomized. Mean age = 67.6 years, 31.8% male	10 mg, 6–8 hours postoperatively then daily for 10–14 days	Total VTE (composite of any DVT or non-fatal PE) and all-cause mortality
Eriksson et al. 200713 RE-MODEL	Dabigatran	2076 patients. Mean age = 68 years, 34.0% male	150 or 220 mg with either half dose 1–4 hours after surgery/full dose if day after surgery, followed by full dose daily for 6–10 days	Total VTE (composite of any DVT or symptomatic PE) and all-cause mortality

DVT, deep vein thrombosis; PE, pulmonary embolism; THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism.

Efficacy and safety endpoints

Indirect comparisons were performed on both efficacy and safety (bleeding) endpoints. Symptomatic VTE results were based on the total study duration period, i.e. including follow-up; in addition, symptomatic VTE results for the treatment duration period are provided. All outcomes were assessed by central independent adjudication committees.

Efficacy analyses

For efficacy endpoints, analyses were performed for total VTE and for symptomatic VTE. Total VTE is a venography-dependent endpoint comprising any DVT, non-fatal PE, and all-cause mortality, and was assessed in the modified intention-to-treat (mITT) populations, i.e. the populations evaluable for the primary efficacy outcome. Total VTE was the primary efficacy endpoint in all trials included in these indirect comparisons. Venographies were performed at the end of the protocol-defined treatment period.

Bleeding events

These indirect analyses also estimated the impact of rivaroxaban on major bleeding relative to dabigatran. However, there are differences between the studies in the definition of major bleeding. In the pivotal rivaroxaban RCTs12–15, major bleeding was defined as bleeding that was fatal, involved a critical organ, or that required reoperation, as well as clinically overt bleeding outside the surgical site associated with a decrease in the hemoglobin level of ≥2 g/dl (1.24 mmol/l) or requiring infusion of ≥2 units of blood. In contrast, the definition of major bleeding in the dabigatran RCTs16,17 included surgical-site bleeding events. However, the rivaroxaban studies also collected data that allowed estimates of major bleeding rates based on definitions similar to those in the dabigatran trials. Hence, results from the RECORD RCTs for major bleeding with surgical-site bleeding were used to perform the indirect safety comparisons of rivaroxaban versus dabigatran. Major bleeding with surgical-site bleeding has been presented previously in a pooled analysis of the four RECORD studies19. It should be noted that major bleeding with surgical-site bleeding was not adjudicated and was not the primary safety endpoint in the RECORD RCTs.

Analysis of dabigatran data

To enable like-for-like analyses of rivaroxaban versus dabigatran, only results for the primary dose of dabigatran (220 mg od) were extracted. Moreover, dabigatran trials presented symptomatic DVT and symptomatic PE separately16,17. Because other trials reported symptomatic VTE (patients with a symptomatic DVT or PE), it was necessary to make an assumption regarding the number of patients who would have both symptomatic DVT and PE in order to determine the rate of symptomatic VTE in the dabigatran studies. Published data for the RE-MODEL16 and RE-NOVATE17 trials indicate that there was no overlap, i.e. no patients in these trials appear to have suffered both a DVT and a PE9. This observation is consistent with reported incidence data from the Global Orthopaedic Registry (GLORY), which showed no coincident DVTs and PEs for the 239 events reported in patients undergoing THR or TKR20. Hence, for this analysis, it was assumed that no patients who received dabigatran and sustained either a symptomatic DVT or PE actually had both events.

Statistical analysis

Statistical analyses were run in Stata SE version 8.2 and Microsoft Excel.

Outcomes and measures

The analyses focused upon total VTE, symptomatic VTE during treatment and follow-up, and major bleeding. Collectively, these endpoints combine overall measures of efficacy and safety with clinically relevant symptomatic endpoints, and are included in the majority of comparative phase III studies12–18.

Indirect comparison: rivaroxaban versus dabigatran

Indirect comparisons were performed using the adjusted indirect comparison methodology developed by Bucher et al.10. This method derives the indirect estimates by comparing the effects of each treatment versus the common comparator, and retains the benefits of randomization from the original trial data. This approach is in line with the conclusions from a comprehensive review of published indirect comparisons commissioned by the NHS R&D Health Technology Assessment Programme, which highlighted the need to use an adjusted indirect comparison to minimize bias and the drawing of overly precise conclusions21.

Results

Indirect comparisons: total hip replacement

Extended prophylaxis with rivaroxaban (10 mg od) versus extended prophylaxis with dabigatran (220 mg od)

This analysis is based on a comparison of one trial against the common comparator, enoxaparin 40 mg od, for each intervention, namely the RECORD1 and RE-NOVATE trials. Cumulative event rates and relative risks (RRs) are shown in Table 2. Symptomatic VTE results were taken from the total study duration, including follow-up. The derived indirect comparisons indicated that rivaroxaban significantly reduced both total VTE and symptomatic VTE relative to dabigatran 220 mg od. Results for symptomatic VTE during the treatment duration gave a RR of 0.20 (95% confidence interval [CI] 0.04–0.90) for rivaroxaban versus dabigatran.

Table 2.  Indirect comparison of extended prophylaxis with rivaroxaban (10 mg od) versus extended prophylaxis with dabigatran (220 mg od) in total hip replacement.

Events	RECORD1		RE-NOVATE		Indirect comparison RR (95% CI)
	Rivaroxaban	Enoxaparin	Enoxaparin	Dabigatran
Total VTE*†	1.1 (0.7–1.8)	3.7 (2.8–4.8)	6.7 (5.1–8.3)	6.0 (4.5–7.6)	0.34 (0.18–0.64)
	18/1595	58/1558	60/897	53/880
RR (95% CI)	0.30 (0.18–0.51)		0.90 (0.63–1.29)
Symptomatic VTE‡$	0.3 (0.1–0.7)	0.7 (0.4–1.1)	0.4 (0.1–1.0)	1.1 (0.5–1.8)	0.19 (0.05–0.77)
	7/2193	15/2206	5/1142	12/1137
RR (95% CI)	0.47 (0.19–1.15)		2.41 (0.85–6.82)
Major bleeding including surgical site¶	1.8 (1.3–2.5)	1.5 (1.0–2.1)	1.6 (0.9–2.5)	2.0 (1.3–3.0)	0.95 (0.44–2.03)
	40/2209	33/2224	18/1154	23/1146
RR (95% CI)	1.22 (0.77–1.93)		1.29 (0.70–2.37)

Indirect comparison shows RR for rivaroxaban vs dabigatran. For differences that are statistically significant, the 95% CI for the RR excludes 1.0.

CI, confidence interval; mITT: modified intention-to-treat; od, once daily; RR, relative risk against enoxaparin; VTE, venous thromboembolism.

*Results shown as percent incidence (95% CI), number of patients with event/number of patients over the treatment duration period/number of patients.

†mITT population, evaluable for primary efficacy outcome.

‡Results shown as percent incidence (95% CI), number of patients with event/number of patients over the total study duration, including follow up/number of patients.

$Safety population who underwent surgery.

¶Safety population.

The results of the indirect comparison also indicate that there is no significant difference in the rates of major bleeding, including surgical-site bleeding, for patients receiving rivaroxaban or dabigatran after THR. There was a wide CI, with the point estimate close to 1 (Table 2).

Indirect comparisons: total knee replacement

Short-term prophylaxis with rivaroxaban (10 mg od) versus short-term prophylaxis with dabigatran (220 mg od)

This indirect comparison was based on the data for RECORD3 and RE-MODEL for the rivaroxaban and enoxaparin treatment groups, and the results are presented in Table 3. Symptomatic VTE results were taken from the total study duration, including follow-up (see below). Rivaroxaban significantly reduced total VTE by 47% versus dabigatran (95% CI 29–61%). Symptomatic VTE was not different between dabigatran and rivaroxaban. During the treatment duration, excluding the follow-up period, the analysis yielded a numerical but non-significant increase in symptomatic VTE with rivaroxaban versus dabigatran (RR 3.00, 95% CI 0.33–27.35). However, it is important to note that this result is based on only one treatment-emergent symptomatic venous thromboembolic event (a DVT) with 220 mg dabigatran16. This is also reflected in the extremely wide CI (83-fold geometric range), which demonstrates clearly that this result cannot be construed as an actual difference. Such an interpretation is also consistent with the significant reduction in total VTE observed with rivaroxaban (Table 3), as well as the previously described reductions with rivaroxaban after THR. In order to substantiate this conclusion, an analysis was performed, in which symptomatic VTE over the treatment and follow-up periods was indirectly compared for rivaroxaban and the 220 mg dose of dabigatran. This included five further symptomatic events for rivaroxaban14 and three further symptomatic events for dabigatran16. This analysis yielded a RR of 1.08 (95% CI 0.28–4.15) for rivaroxaban versus dabigatran, which was consistent with the conclusion that there is no significant difference in rates of symptomatic VTE between rivaroxaban and dabigatran.

Table 3.  Indirect comparison of short-term prophylaxis with rivaroxaban (10 mg od) versus short-term prophylaxis with dabigatran (220 mg od) in total knee replacement.

Events	RECORD3		RE-MODEL		Indirect comparison RR (95% CI)
	Rivaroxaban	Enoxaparin	Enoxaparin	Dabigatran
Total VTE*†	9.6 (7.7–11.8)	18.9 (16.4–21.7)	37.7 (33.5–41.9)	36.4 (32.2–40.6)	0.53(0.39–0.71)
	79/824	166/878	193/512	183/503
RR (95% CI)	0.51 (0.39–0.65)		0.97 (0.82–1.13)
Symptomatic VTE‡$	1.08 (0.6–1.8)	2.2 (1.5–3.2)	1.31	0.59	1.08 (0.28–4.15)
	13/1201	27/1217	9/685	4/675
RR (95% CI)	0.49 (0.25–0.94)		0.45 (0.14–1.46)
Major bleeding including surgical site¶	1.7 (1.1–2.6)	1.4 (0.8–2.2)	1.3 (0.6–2.4)	1.5 (0.7–2.7)	1.10 (0.37–3.31)
	21/1220	17/1239	9/694	10/679
RR (95% CI)	1.25 (0.67–2.37)		1.14 (0.46–2.78)

Indirect comparison shows RR for rivaroxaban vs dabigatran. For differences that are statistically significant, the 95% CI for the RR excludes 1.0.

*Results shown as percent incidence (95% CI), number of patients with event/number of patients over the treatment duration period/number of patients.

†mITT population.

‡Including follow-up period.

$Safety population who underwent surgery.

¶Safety population.

CI, confidence interval; od, once daily; RR, relative risk against enoxaparin; VTE, venous thromboembolism.

With respect to major bleeding, the indirect comparison showed a similar result to that for THR, with no statistical difference between rivaroxaban and dabigatran. The CI was again very wide, with the point estimate again close to 1 (RR 1.10, 95% CI 0.37–3.31, Table 3).

No meta-analyses were performed due to the fact that only two studies after THR and two studies after TKR were included in this comparison.

Discussion

Based on the indirect comparisons, rivaroxaban was found to be more efficacious than dabigatran in the prevention of VTE after THR and more efficacious than dabigatran in the prevention of total VTE after TKR. After THR, rivaroxaban 10 mg od significantly reduced total VTE and symptomatic VTE relative to dabigatran 220 mg od. After TKR, rivaroxaban significantly reduced total VTE versus dabigatran; symptomatic VTE was not different between dabigatran and rivaroxaban. There was no significant difference in the rates of major bleeding.

With respect to symptomatic VTE, it should also be noted that there were fewer treatment-emergent events with enoxaparin in the RE-MODEL trial (1.3%; 9/685)16 than in RECORD3 (2.0%; 24/1217)14, even though prophylaxis was administered for a longer period in RECORD3 (9–13 days)14 than in RE-MODEL (6–10 days)16. Rivaroxaban significantly reduced the incidence of treatment-emergent symptomatic VTE versus enoxaparin in RECORD3 (p = 0.005)14; conversely p-values were not reported in the RE-MODEL trial. Additional evidence suggesting that rivaroxaban is more efficacious than dabigatran after TKR comes from the results of the RE-MOBILIZE18 and RECORD4¹⁵ studies. Dabigatran failed to attain non-inferiority versus the North American enoxaparin regimen (30 mg bid) for the primary endpoint (total VTE, as defined above)18, whereas rivaroxaban demonstrated superiority for the same endpoint against the same enoxaparin regimen and was the first new oral anticoagulant to do so15. These results are consistent with those presented here with respect to the 40 mg od enoxaparin regimen. In regard to symptomatic events in these trials, there were seven symptomatic DVTs and six PEs in 618 patients who received dabigatran 220 mg od, compared with five symptomatic DVTs and five PEs in 668 patients treated with enoxaparin 30 mg bid after TKR18. Conversely, there were fewer symptomatic events with rivaroxaban 10 mg od (11/1526 patients) compared with enoxaparin 30 mg bid (18/1508 patients), respectively, although the difference did not reach statistical significance (p = 0.187)15.

Analyses of major bleeding, including surgical site bleeding, showed no significant difference after either THR or TKR for rivaroxaban versus dabigatran, despite the fact that rivaroxaban was administered for a slightly longer period compared with dabigatran (see Table 1).

A limitation of this study is that the results of an indirect comparison cannot replicate the results from a comparative RCT. However, trials utilizing evidence-based guideline-recommended durations of prophylaxis22 are nonetheless of interest to reimbursement authorities, and this remains an appropriate and useful comparison. A further limitation of the analysis relates to the need to rely upon published data for the efficacy and safety data for dabigatran. Although access to more detailed comparative data would improve the precision of these results, enough data were available to perform these basic analyses.

Separate analyses were required depending upon the duration of enoxaparin after THR and the enoxaparin regimen after TKR to ensure that no bias resulted from these differences. This reduced the power of the statistical analyses and prevented the more appropriate meta-regression technique being used for all analyses.

A recent paper has reported the results of an exploratory indirect comparison of rivaroxaban and dabigatran23. The authors conducted meta-analyses to obtain pooled treatment effects of each drug compared with enoxaparin. There are a number of differences between the Trkulja and Kolundzic paper and the current paper. Unlike the approach in the current paper of using just the primary dose of dabigatran 220 mg od, Trkulja and Kolundzic combined both doses of dabigatran for their analysis. They also used the RECORD data for their analysis of ‘major or non-major clinically relevant bleeding’, which does not accord with the bleeding definition of ‘major bleeding including surgical site’ in the current paper. Trkulja and Kolundzic also included results from RECORD4 in their analyses; these were not included in the current paper because the focus was on using the enoxaparin regimen used outside the US as the comparator. They stated that they could not readily compare rivaroxaban and dabigatran for primary and secondary efficacy events or bleeding rates, because of different adjudication performed by different committees. They concluded that their analysis suggested that the existing clinical data did not allow claims of one drug being superior to the other.

An even more recent article24 using an adjusted indirect comparison of a larger number of trials than the current article, concluded that rivaroxaban was superior to dabigatran in preventing VTE (RR 0.50, 95% CI 0.37–0.68) but with a slight trend towards increased bleeding (RR 1.14, 95% CI 0.80–1.64).

Despite the potential drawbacks of the current analysis, indirect comparisons are a means of approximating the relative efficacy and safety of prophylaxes that have not been compared directly in a head-to-head clinical trial. The results of the analysis where trials using the 30 mg bid dose of enoxaparin were compared will be reported separately. Finally, the results of these analyses could be used to populate an economic model to estimate the cost effectiveness of rivaroxaban versus dabigatran. Such economic analyses are important to reimbursement and formulary decision makers to assist in informing analyses of the value for money of rivaroxaban relative to a wider range of existing prophylaxes used currently. The ideal study for comparison, a randomized trial, is not available and may never be performed. As such, a carefully conducted indirect comparison, as we have performed, represents the best available evidence.

Transparency

Declaration of funding

This study was supported by Bayer Schering Pharma AG and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Declaration of financial/other relationships

M.L. is an employee of Bayer HealthCare plc., N.S. is an employee of Johnson & Johnson, L.L.C., A.D. and F.R. are employed by IMS Consulting as consultants for Bayer HealthCare plc, and C.L. is an independent statistician for Bayer HealthCare plc.

Acknowledgments

The authors would like to acknowledge Seamus McMillan and Chris Thomas who provided editorial support, with funding from Bayer Schering Pharma AG and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.