Ivabradine is cost-effective in thetreatment of chronic heart failureStephen Morris,1 Rachael Hunter2

The SHIFT study showed that addingivabradine to standard heart failure medi-cation can improve prognosis, reduce hos-pitalisations, and improve quality of life inpeople with chronic heart failure and sys-tolic dysfunction. These health andhealthcare benefits need to be balancedagainst the costs of using the drug, whichmay be considerable with lifetime treat-ment, but up until now there has been noevidence on the combined costs and con-sequences of ivabradine in heart failure.

Griffiths et al1 used data from SHIFT toevaluate the cost-effectiveness of ivabra-dine. They developed a complex economicmodel to compare the lifetime costs andbenefits of ivabradine plus standard careversus standard care alone in a subgroupof patients in the SHIFT trial with baselineresting heart rate ≥75 bpm (the licensedindication in Europe). Their base caseincremental cost per quality adjusted lifeyear (QALY) gained was £8498, which isbelow the £20 000 cost-effectivenessthreshold recommended in England. Theyundertook many sensitivity analyses to seehow robust the findings were to the modelparameters and assumptions and found theresults did not change appreciably—thecost-effectiveness of ivabradine remainedbelow the cost-effectiveness threshold invirtually all scenarios.

It is worth noting that the economicmodel constructed by Griffiths et al wasused in the manufacturer’s submission tothe National Institute for Health and CareExcellence (NICE) as part of its technologyappraisal of ivabradine in people withchronic heart failure.2 An electronic versionof the economic model was submitted,which was scrutinised in microscopic detailby an Evidence Review Group (ERG) aspart of the appraisal process.3 Close inspec-tion of the model plus associated documen-tation provided a more rigorous reviewthan is possible within the peer reviewprocess for a manuscript submitted to a

journal, providing additional quality assur-ance. The ERG were content with the ana-lysis, concluding ‘[o]verall, the ERG issatisfied that the model developed by themanufacturer to assess the relative cost-effectiveness of the addition of ivabradineto standard care is robust.’3 The ERG alsopointed out that some of the specific mod-elling assumptions made in the analysiswere likely to be biased in favour of stand-ard treatment alone, and therefore Griffithset al are likely to have underestimated thecost-effectiveness of ivabradine. The upshotis that evidence for the cost-effectiveness ofivabradine seems clear.As well as evidence of its cost-

effectiveness there is also evidence aboutthe budgetary implications of using ivabra-dine, which is important to commis-sioners. NICE produced a costing reportto calculate the budget impact of using thedrug according to its recommendations,estimating that the additional annual costof using ivabradine would be £2.3 millionannually across the whole of England(£4400 per 100 000 population).4 This isa small budgetary impact for commis-sioners compared with some other drugs,partly reflecting the modest number ofpatients suitable for ivabradine treatment.5

The study by Griffiths et al throws upsome interesting health economics issues.First, their analysis accounts for costsincurred by the English National HealthService. It is known that heart failureincurs a large amount of healthcareresources and that emergency hospitalisa-tions are the main cost driver. Given theblurring of boundaries between healthand social care, the inclusion of personaland social services resources use in theNICE reference case, and the care andsupport needed for people with heartfailure outside of the National HealthService, a wider perspective could havebeen taken, for example, accounting fornursing and residential home costs andcosts of end of life care. It is ambiguouswhat impact inclusion of these costswould have on the cost-effectiveness ratiofor ivabradine. On the one hand, reducingmorbidity and improving quality of lifeare likely to reduce social care needs andso including these costs would improvethe cost-effectiveness of ivabradine; buton the other, demand may increase with

extended survival, reducing ivabradine’scost-effectiveness.

Second, standard treatment for chronicheart failure in the SHIFT population wasβ-blocker therapy in addition to ACE inhi-bitors, diuretics, aldosterone antagonists,angiotensin receptors blockers and cardiacglycosides. Unfortunately, patients regularlydo not take adequate doses of β-blockersand it is believed there is some reluctanceby clinicians to uptitrate patients to therecommended dose. This was a particularproblem with the SHIFT trial, as even withsignificant efforts made by investigators toensure that participants were receivingadequate doses of β-blocker therapy priorto enrolment in the trial, only 23% ofpatients managed to achieve the targetdose.6 A supplementary analysis of SHIFTdata found that the effects of ivabradinewere not significantly impacted byβ-blocker dose,7 but questions remain as towhether more should be done to improvecompliance with β-blockers and whether ornot this is cost-effective. The results of a USstudy of an intervention to increase the pro-portion of patients who take the recom-mended dose of their clinically indicatedpharmacotherapy following a myocardialinfarction was that if the interventionachieved full compliance it was both cost-saving and resulted in better patient out-comes.8 A subgroup analysis by Griffithset al showed that ivabradine was still cost-effective in people receiving target doseβ-blocker therapy, but there is the risk thatby making ivabradine available to cliniciansit is considered as an alternative to the extraeffort required to achieve adequate doses ofβ-blocker therapy.

Third, ivabradine is an interesting casestudy because sometimes when evaluatingcost-effectiveness there is clear evidencethat an intervention is clinically effective,but the costs of the intervention are suchthat cost-effectiveness is uncertain. In thecase of ivabradine, the situation is reversedbecause there is some uncertainty surround-ing the health benefits, but the cost-effectiveness evidence—accounting foruncertainty in costs and benefits—is morecompelling. In the SHIFT trial, ivabradinetherapy significantly reduced the number ofprimary composite endpoint events com-pared with standard care, but while it sig-nificantly reduced the risk of hospitalisation(HR 0.74; 95% CI 0.66 to 0.83) there wasno significant impact on the risk of cardio-vascular death (HR 0.91; 95% CI 0.80 to1.03). In terms of uncertainty in the cost-effectiveness of ivabradine, Griffiths et alcarried out a probabilistic sensitivity ana-lysis that simultaneously accounted foruncertainty in model parameters for both

1Department of Applied Health Research, UniversityCollege London, London, UK; 2Research Department ofPrimary Care & Population Health, University CollegeLondon, London, UK

Correspondence to Professor Stephen Morris,Department of Applied Health Research, UniversityCollege London, 1-19 Torrington Place, London WC1E7HB, UK; steve.morris@ucl.ac.uk

Morris S, et al. Heart July 2014 Vol 100 No 13 991

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costs and benefits and found that ivabradinehad a greater than 0.95 probability of beingcost-effective at a cost-effectiveness thresh-old of £20 000 per QALY gained.

Fourth, given the significant cost of ran-domised controlled trials, there remainsthe question of whether or not additionalresearch to further establish the costs andbenefits of ivabradine over and abovecurrent best practice is worthwhile. A pos-sible future step might be to conduct an‘extra value of perfect information’ ana-lysis, something that is relatively straight-forward once the cost-effectiveness modelhas been designed and probabilistic sensi-tivity analyses have been run. This wouldprovide information about what valueadditional research might provide giventhe prevalence of the condition in thepopulation and the level of uncertainty. Ifthe cost of research is greater than thevalue that the additional research wouldprovide, it would be considered prudentto implement ivabradine based on thecurrent information available.

Overall, Griffiths et al have demon-strated that ivabradine is cost-effective ineligible heart failure patients. The factthat such a comprehensive analysis was

undertaken was made possible by the col-lection of rich health economic datawithin SHIFT. This provides a goodmodel for other studies with an interest ineconomic as well as health outcomes.

Contributors SM and RH both wrote the first draft ofthe editorial. Both authors contributed significantly tothe final draft.

Competing interests None.

Provenance and peer review Commissioned;internally peer reviewed.

To cite Morris S, Hunter R. Heart2014;100:991–992.

Received 19 March 2014Accepted 22 March 2014Published Online First 15 April 2014

▸ http://dx.doi.org/10.1136/heartjnl-2013-304598

Heart 2014;100:991–992.doi:10.1136/heartjnl-2014-305684

REFERENCES1 Griffiths A, Paracha N, Davies A, et al. The cost

effectiveness of ivabradine in the treatment of chronicheart failure from the UK National Health Serviceperspective. Heart 2014;100:1031–6.

2 NICE. Ivabradine in chronic heart failure: NICEtechnology appraisal guidance 267. NICE, 2012.http://www.nice.org.uk/TA267 (accessed 18 Mar2014).

3 BMJ Technology Assessment Group. Ivabradine for thetreatment of chronic heart failure (ID484). BMJ TAG,2012. http://www.nets.nihr.ac.uk/__data/assets/pdf_file/0006/82599/ERGReport-11-39-01.pdf (accessed18 Mar 2014).

4 NICE. Ivabradine for treating chronic heart failure:costing template. NICE, 2012. http://guidance.nice.org.uk/TA267/CostingTemplate/xls/English (accessed18 Mar 2014).

5 Cullington D, Goode K, Cleland J, et al. Limited rolefor ivabradine in the treatment of chronic heart failure.Heart 2011;97:1961–6.

6 Teerlink J. Ivabradine in heart failure—no paradigmSHIFT…yet. Lancet 2010;376:9744.

7 Swedberg K, Komajda M, Bohm M, et al. Effects onoutcomes of heart rate reduction by ivabradine inpatients with congestive heart failure: is there aninfluence of beta-blocker dose? J Am Coll Cardiol2012;59:1938–45.

8 Choudry N, Patrick A, Antman E, et al.Cost-effectiveness of providing full drug coverage toincrease medication adherence in post-myocardialinfarction Medicare beneficiaries. Circulation2008;117:1261–8.

992 Morris S, et al. Heart July 2014 Vol 100 No 13

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doi: 10.1136/heartjnl-2014-305684 2014 100: 991-992 originally published online April 15, 2014Heart

 Stephen Morris and Rachael Hunter of chronic heart failureIvabradine is cost-effective in the treatment

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