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COMPASS vs PEGASUS approach in a comparative budget impact analysis.

Published:October 10, 2020DOI:https://doi.org/10.1016/j.ejim.2020.10.002

      Keywords

      The treatment of coronary artery disease (CAD), peripheral artery disease (PAD) and ischemic heart disease (IHD), has been radically modified in the recent past by the implementation of the results of two randomized controlled studies. The PEGASUS-TIMI-54 trial, showing as 60mg ticagrelor/BID may significantly reduce the incidence of the primary composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), or stroke [
      • Bonaca MP
      • Bhatt DL
      • Cohen M
      • Steg PG
      • Storey RF
      • Jensen EC
      • Magnani G
      • Bansilal S
      • Fish MP
      • Im K
      • Bengtsson O
      • Oude Ophuis T
      • Budaj A
      • Theroux P
      • Ruda M
      • Hamm C
      • Goto S
      • Spinar J
      • Nicolau JC
      • Kiss RG
      • Murphy SA
      • Wiviott SD
      • Held P
      • Braunwald E
      • Sabatine MS
      PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction.
      ], was the first study to demonstrate a clinical benefit of prolonged dual anti-platelet therapy (DAPT), beyond the first year after an acute MI (AMI), although with a reduced dose of second additional anti-platelet drug. The COMPASS trial explored a novel alternative approach for the treatment of CAD and PAD, with a dual anti-thrombotic therapy (DATT, anti-platelet plus low-dose anti-coagulant drug) [
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • Dagenais GR
      • Hart RG
      • Shestakovska O
      • Diaz R
      • Alings M
      • Lonn EM
      • Anand SS
      • Widimsky P
      • Hori M
      • Avezum A
      • Piegas LS
      • Branch KRH
      • Probstfield J
      • Bhatt DL
      • Zhu J
      • Liang Y
      • Maggioni AP
      • Lopez-Jaramillo P
      • O'Donnell M
      • Kakkar AK
      • Fox KAA
      • Parkhomenko AN
      • Ertl G
      • Störk S
      • Keltai M
      • Ryden L
      • Pogosova N
      • Dans AL
      • Lanas F
      • Commerford PJ
      • Torp-Pedersen C
      • Guzik TJ
      • Verhamme PB
      • Vinereanu D
      • Kim JH
      • Tonkin AM
      • Lewis BS
      • Felix C
      • Yusoff K
      • Steg PG
      • Metsarinne KP
      • Cook Bruns N
      • Misselwitz F
      • Chen E
      • Leong D
      • Yusuf S
      COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease.
      ].
      Previous analyses of large observational registries showed a large potential overlap of clinical indication between DAPT (PEGASUS) and DATT (COMPASS) approaches [
      • Darmon A
      • Bhatt DL
      • Elbez Y
      • Aboyans V
      • Anand S
      • Bosch J
      • Branch KR
      • Connolly SJ
      • Dyal L
      • Eikelboom JW
      • Fox KAA
      • Keltai K
      • Probstfield J
      • Yusuf S
      • Abtan J
      • Sorbets E
      • Eagle KA
      • Ducrocq G
      • Steg PG
      External applicability of the COMPASS trial: an analysis of the reduction of atherothrombosis for continued health (REACH) registry.
      ,
      • Schiele F
      • Puymirat E
      • Ferrières J
      • Simon T
      • Fox KAA
      • Eikelboom J
      • Danchin N
      FAST-MI investigators. The FAST-MI 2005-2010-2015 registries in the light of the COMPASS trial: The COMPASS criteria applied to a post-MI population.
      ]. A choice between these possible approaches (DAPT vs DATT) can be based on differences in indications and contra-indications characterizing each study [
      • Brunetti ND
      • De Gennaro L
      • Di Biase M
      • Caldarola P
      Double antiplatelet therapy vs association of antiplatelet and low dose of anticoagulant therapy: PEGASUS or COMPASS?.
      ].
      Prior studies have shown that both PEGASUS and COMPASS solutions may be cost/effective [
      • Ademi Z
      • Zomer E
      • Tonkin A
      • Liew D
      Cost-effectiveness of rivaroxaban and aspirin compared to aspirin alone in patients with stable cardiovascular disease: An Australian perspective.
      ,
      • Magnuson EA
      • Li H
      • Wang K
      • Vilain K
      • Shafiq A
      • Bonaca MP
      • Bhatt DL
      • Cohen M
      • Steg PG
      • Storey RF
      • Braunwald E
      • Sabatine MS
      • Cohen DJ
      PEGASUS-TIMI 54 Trial Investigators.Cost-Effectiveness of Long-Term Ticagrelor in Patients With Prior Myocardial Infarction: Results From the PEGASUS-TIMI 54 Trial.
      ]. A further comparative assessment, however, could be based not exclusively on indications and contra-indications, but also on relative outcomes and from a budget impact analysis (BIA) perspective. We therefore aimed to compare the “economic” efficacy of PEGASUS vs COMPASS approach and to analyze profiles of BIA convenience according to relative cost differences between drugs in case of patients eligible for both treatments.
      A comparison between PEGASUS and COMPASS trials is given in Figure-1a). Considering that the PEGASUS study had a mean follow-up of 33 months and the COMPASS of 23 months, the ARR for the primary and secondary endpoints was standardized at 1 year. The number-needed-to-treat and -to-avoid primary and every secondary endpoint was therefore calculated and used to estimate the relative cost per event saved. Relative costs per event saved were plotted according to possible relative costs between drugs (COMPASS vs PEGASUS) In the derived plot, areas on the right indicate a relative cost of COMPASS higher than PEGASUS, areas on the left a relative cost of COMPASS lower than PEGASUS. The top areas of the plot indicate a more favorable cost/efficacy profile with COMPASS approach (cost per event saved reduction), bottom areas a more favorable profile with PEGASUS.
      After plotting the possible range of relative costs of COMPASS over PEGASUS, three zones can be identified (Figure 1b). If the price of COMPASS approach is lower than 30-40% compared to PEGASUS, the former is favorable in terms of costs/efficacy for all the primary and secondary endpoints. If the price of COMPASS approach ranges between less than 30-40% and not more than 40-45% of PEGASUS, the former is favorable in preventing stroke and CV mortality, the latter in preventing MI and composite endpoint of CV death/MI/stroke. Finally, if the price of COMPASS approach is higher than 40-45% of PEGASUS, the COMPASS approach is favorable only for preventing stroke events. The COMPASS approach is always favorable in preventing stroke outcome.
      Figure 1
      Figure 1a) Comparison between PEGASUS and COMPASS trial ARR for the different endpoints. b) Relative cost reduction per event saved according to relative cost between drugs: comparison between Rivaroxaban (COMPASS study) and Ticagrelor (PEGASUS study). Legend. ARR absolute risk reduction, NNT number needed to treat, CV cardiovascular, CHD coronary heart disease, MI myocardial infarction
      In this study we therefore show for the first time, with a comparative BIA, preferable treatment approaches between PEGASUS and COMPASS, according to the relative drug cost profile and different outcome. After analysis of saved events according to relative costs, is evident that, in the case of potential overlap in drug prescription, the relative cost may drive the choice between alternative treatments. If the cost of COMPASS approach is relevantly lower than PEGASUS, DATT with aspirin and rivaroxaban 2.5mg bid could be preferred. In case of substantial equivalence of costs, DATT can be more efficient in reducing stroke and CV mortality, DAPT in preventing MI and the composite endpoint. When, finally, the cost of COMPASS is relevantly higher than PEGASUS, DATT can be preferred exclusively in reducing stroke.
      The cost/effectiveness of both DATT and DAPT has been already evaluated in the recent past. Compared to aspirin, rivaroxaban in combination with aspirin is likely to be cost-effective in preventing recurrent CV events in patients with stable atherosclerotic vascular disease [
      • Ademi Z
      • Zomer E
      • Tonkin A
      • Liew D
      Cost-effectiveness of rivaroxaban and aspirin compared to aspirin alone in patients with stable cardiovascular disease: An Australian perspective.
      ]; compared to aspirin alone, rivaroxaban plus aspirin was associated to ICERs of AUD$ 23,560/YoLS and AUD$ 31,436/QALY gained, with a threshold of AUD$ 50,000/QALY gained assumed to signify cost-effectiveness.
      For patients with a history of MI >1 year previously, long-term treatment with ticagrelor 60mg+ low-dose ASA yields a cost-effectiveness ratio suggesting intermediate value based on current guidelines [
      • Magnuson EA
      • Li H
      • Wang K
      • Vilain K
      • Shafiq A
      • Bonaca MP
      • Bhatt DL
      • Cohen M
      • Steg PG
      • Storey RF
      • Braunwald E
      • Sabatine MS
      • Cohen DJ
      PEGASUS-TIMI 54 Trial Investigators.Cost-Effectiveness of Long-Term Ticagrelor in Patients With Prior Myocardial Infarction: Results From the PEGASUS-TIMI 54 Trial.
      ]. Ticagrelor appears to provide higher value for patients in several recognized high-risk subgroups. Over a lifetime horizon, ticagrelor was associated with an ICER of $94,917/QALY gained [
      • Magnuson EA
      • Li H
      • Wang K
      • Vilain K
      • Shafiq A
      • Bonaca MP
      • Bhatt DL
      • Cohen M
      • Steg PG
      • Storey RF
      • Braunwald E
      • Sabatine MS
      • Cohen DJ
      PEGASUS-TIMI 54 Trial Investigators.Cost-Effectiveness of Long-Term Ticagrelor in Patients With Prior Myocardial Infarction: Results From the PEGASUS-TIMI 54 Trial.
      ]. Several high-risk groups, however, had more favorable ICERs, including patients with >1 prior MI, multivessel disease, diabetes, renal dysfunction (all with ICERs $50,000 to $70,000/QALY gained), patients age <75 years (ICER=$44,779/QALY gained), and PAD patients (ICER=$13,427/QALY gained).
      Less, however, is known in comparative cost/effectiveness analysis and in BIA. BIA should be considered as an economic evaluation conducted according to the budget holders’ perspective, with a short time horizon (<3 years) and within a clearly specified setting, where results are expressed as undiscounted cost differences between the new scenario (including the new technology or drug) and the current/reference scenario, taking account of the potential trade-offs in healthcare resources induced by the effectiveness of the new technology/drug, and easy to understand by budget holders [
      • Garattini L
      • van de Vooren K
      Budget impact analysis in economic evaluation: a proposal for a clearer definition.
      ]; the approach is radically different from a cost-effectiveness analysis.
      In this comparative BIA we identified different favorable treatments according to relative cost, representing alternative options for both clinicians and policy makers responsible for great health care services, both in the private and the public sector. Patients at higher risk of stroke could be treated with DATT rather than DAPT, patients at higher risk of MI with DAPT rather than DATT.
      Several points, however, should be considered for a balanced BIA. The structural designs of each trial and the risk profile of the patient population (exclusively MI in PEGASUS vs. about 2/3 MI in COMPASS) are not completely comparable. PEGASUS tested prolonged DAPT one year after MI, while COMPASS tested aspirin plus low-dose anticoagulant in patients with stable chronic CAD and/or PAD. COMPASS patients were likely higher-risk given the far greater density of PAD (almost 5-fold that in PEGASUS), were treated later with study drug, and were in a prematurely terminated study. Early termination of COMPASS trial could have reduced absolute risk reduction achieved with DATT against aspirin. Differences in terms of efficacy found in terms of stroke vs MI reduction should consider that both represent secondary endpoint, not preliminary established for sample sizing and study design. It's important to note that no head-to-head comparison of DAPT versus DATT has occurred to permit definitive statements of relative efficacy in mitigating MACE. This is a theoretical BIA based on several assumptions (constant incidence of adverse events, comparable risk profiles between studies, etc.). Finally, how to identify subject with and increased risk of stroke rather than MI still remains an unresolved issue.
      In conclusion, relative cost may influence the BIA superiority in a direct comparison of COMPASS vs PEGASUS approach in patients eligible for both. COMPASS approach could be preferable in preventing stroke, PEGASUS in preventing MI. Less pronounced differences were found with regard to CVD and MACE.

      Declaration of Competing Interest

      None to disclose.

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