Cost-Effectiveness Analysis of Rivaroxaban in the Secondary Prevention of Acute Coronary

ONLINE APPENDIX

Cost-effectiveness Analysis of Rivaroxaban in the Secondary Prevention of Acute Coronary Syndromes in Sweden

Najida Begum • Stephanie Stephens • Olaf Schoeman • Anina Fraschke • Bodo Kirsch • Jean-Baptiste Briere • Freek W.A. Verheugt • Ben A. van Hout

To inform the design of the model and specify model inputs, formal systematic literature reviews of economic evaluations, clinical data from epidemiological studies and clinical trials, quality of life data, and costs and resource use were performed. The search was conducted from a global perspective, and hence also covered local sources of information, not directly applicable to Sweden. All data identified through theses searches were considered and the most relevant data for the Swedish setting was applied to the model.

The details of the search are provided below.

LITERATURE DATABASES

For the original review, the literature search was conducted on May 5, 2011 using the following electronic databases:

MEDLINE and MEDLINE In-Process (using the PubMed platform), not limited by date (from 1948 to 5 May 2011)
EMBASE (using the Dialog Platform), not limited by date (from 1947 to 5 May 2011)
EconLit (using the Dialog platform), performed on 25 April 2011, with the date limits: January 2000 to 25 April 2011
The Cochrane Library, not limited by date (from 1946 to 5 May 2011), which includes the following:

–The Cochrane Database of Systematic Reviews

–The Cochrane Central Register of Controlled Trials

–Database of Abstracts of Reviews of Effectiveness

Inside Conferences (using the Dialog Platform), not limited by date (from October1993 to 5 May 2011)

For the review update, the literature search was conducted using the same literature databases, with date limits:

MEDLINE and MEDLINE In-Process (using the PubMed platform), limited by Entrez date (i.e., date added to database) (from 5 February 2011 to 5 July 2012)
EMBASE (using the Dialog Platform), limited by Entrez date (i.e., date added to database) (from 5 February 2011 to 5 July 2012)
EconLit (using the Dialog platform), limited by Entrez date (i.e., date added to database) (from 25 January 2011 to 5 July 2012)
The Cochrane Library, not limited by date (from 1946 to 5 July 2012), which includes the following:

The Cochrane Database of Systematic Reviews

The Cochrane Central Register of Controlled Trials

Database of Abstracts of Reviews of Effectiveness

Inside Conferences (using the Dialog Platform), limited by Entrez date (i.e., date added to database) (from 5 February 2011 to 5 July 2012)

The search was limited to articles published in English, French, German, Italian, Spanish, Japanese, Chinese, and Portuguese.

INTERNET SITES AND OTHER RESOURCES

The searches were conducted for 2008 to July 2012, to identify the most recent abstracts, where abstracts were available online and free of charge. Any relevant older abstracts are likely to have been published as a manuscript since being presented as an abstract. The following Web sites were searched:

American Heart Association (AHA) Scientific Sessions: 2008-2012
American Heart Association Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke Conference (AHA QCOR): 2010-2012
European Society of Cardiology (ESC): 2008-2011
American College of Cardiology (ACC): 2009-2012
American College of Chest Physicians (ACCP): 2008-2012
International Society for Pharmacoeconomics and Outcomes Research (ISPOR): 2009-2012

We also searched the following Web sites for relevant health technology appraisals and related documents, with no limits on publication date:

NICE
Scottish Medicines Consortium (SMC)
Institute for Quality and Efficiency in Healthcare (IQWiG)
Haute Autorité de santé (HAS)

Bibliographic reference lists of any included systematic reviews and meta-analyses were searched for relevant randomised controlled trials (RCTs) that were not identified in the initial literature searches.

Specific search terms depended on the nature of the search facilities on each Web site and were drawn from the intervention and disease terms used in the database searches. A log of Internet searches, including the date of the search, the URL of the site searched, and the search terms used, was maintained. Potentially relevant resources obtained via the Internet were saved as PDF files to maintain a record of information in case the electronic source changes or is removed in the future.

SEARCH TERMS

Search terms included combinations of Title/Abstract free-text terms and Subject Index Headings (e.g., Medical Subject Headings [MeSH]). The following types of search terms were used:

Search terms relating to the health condition of interest (e.g.,"Acute Coronary Syndrome"[MeSH], “Myocardial Infarction”[MeSH], “Unstable Angina”[MeSH])
Study type(s): terms for clinical studies (e.g.,“randomised clinical trial," “prospective studies," “observational studies”; the search terms for study design were adapted from search filters published by the Scottish Intercollegiate Guidelines Network [SIGN] [
Study type (s): terms for economic evaluations (e.g., “cost-effectiveness," “cost-utility," “economic models”; the search terms were adapted from search filters published by SIGN [ and the Centre for Reviews and Dissemination [CRD] [
Search terms relating to quality of life, and utility values (e.g.,"Quality of Life"[MeSH], “EQ-5D," “health related quality of life”; the search terms were adapted from search filters published by SIGN [ and the CRD [
Search terms relating to cost and resource use (e.g.,“Cost of Illness”[MeSH], Economics, medical [MeSH], “resource use”; the search terms were adapted from search filters published by SIGN [ and the CRD [
Search terms for risk factors for ACS (e.g.,“Risk Factors”[MeSH])
Search terms for epidemiology (e.g.,“Incidence”[MeSH], “Prevalence”[MeSH])
Search terms for registry studies (e.g.,“Epidemiologic Studies”[Majr], “Registries”[Majr])
Search terms for clinical guidelines (e.g.,“Practice Guideline”[Publication Type])
Search terms relating to interventions (e.g.,“clopidogrel”[Substance Name], “prasugrel”[Substance Name], “rivaroxaban”[Substance Name]).

The full search strategies are presented below for the original review (denominated as A-#) and the update (denominated as B-#).

CLINICAL SEARCH STRATEGIES

Table A-1.Search Strategy to Identify Clinical Studies of ACS Patients in the Electronic Databases: MEDLINE and MEDLINE In-Process, Using the PubMed Platform (search conducted on 5 May 2011; not limited by date [1948 to 5 May 2011])

Table A-2.Search Strategy to Identify Clinical Studies of ACS Patients in the Electronic Databases: Cochrane (search conducted on 5 May 2011; not limited by date [1946 to 5 May 2011])

Note: Specifically, the search included three Cochrane databases: The Cochrane Database of Systematic Reviews, The Cochrane Central Register of Controlled Trials, and Database of Abstracts of Reviews of Effectiveness.

Table A-3.Search Strategy to Identify Clinical Studies of ACS Patients in the Electronic Databases: EMBASE, Using the Dialog Platform (search conducted on 5 May 2011; not limited by date [1947 to 5 May 2011])

Term Group / Search Terms / No. of Articles
Population / #1 / Acute()Coronary()Syndrome/de OR Heart Infarction! OR Unstable Angina Pectoris! OR myocardial()infarct?/ti,ab OR unstable()angina/ti,ab OR heart()attack/ti,ab OR ACS/ti,ab OR heart()event?/ti,ab OR heart()arrest?/ti,ab OR cardiac()arrest?/ti,ab OR acute()coronary()syndrome?/ti,ab OR heart()infarction/ti,ab OR STEMI/ti,ab OR NSTEMI/ti,ab OR NON()STEMI/ti,ab OR NONSTEMI/ti,ab OR (acute/ti,ab AND coronary/ti,ab) OR (coronary/ti,ab AND syndrome?/ti,ab) OR non()ST()segment()elevation()myocardial()infarction/ti,ab OR ST()segment()elevation()myocardial()infarction/ti,ab / 304177
Intervention / #2 / Warfarin/de OR Acetylsalicylic()Acid/de OR rivaroxaban/de OR clopidogrel/de OR prasugrel/de OR Ticagrelor/de OR rivaroxaban/ti,ab OR clopidogrel/ti,ab OR prasugrel/ti,ab OR Ticagrelor/ti,ab OR warfarin/ti,ab OR aspirin/ti,ab OR ticlopidine/ti,ab,de OR acetylsalicylic()acid/ti,ab OR Phenprocoumon/de OR Decarboxyprothrombin/de OR Phenprocoumon/ti,ab OR vitamin()K()antagonist/ti,ab / 182114
Clinical Trials / #3 / Randomized()Controlled()Trial/de OR Controlled Clinical Trial! OR randomized/ti,ab OR placebo?/ti,ab,de OR Clinical()Trial/de OR randomly/ti,ab OR trial?/ti OR randomized()controlled()trial?/ti,ab OR randomised()controlled()trial?/ti,ab OR randomized()clinical()trial?/ti,ab OR randomised()clinical()trial?/ti,ab OR randomized()trial?/ti,ab OR randomized()trial?/ti,ab OR random()allocation/ti,ab OR “single blind procedure”/de OR “double blind procedure”/de OR double()blind()method/ti,ab OR single()blind()method/ti,ab OR ((singl?/ti,ab OR doubl?/ti,ab OR treb?/ti,ab OR tripl?/ti,ab) AND (blind?/ti,ab OR mask?/ti,ab)) OR random()assignment?/ti,ab OR open()label()trial?/ti,ab OR Phase()2()Clinical()Trial/de OR Phase()3()Clinical()Trial/de OR Phase()4()Clinical()Trial/de OR randomization/ti,ab,de OR randomisation/ti,ab OR Double()blind()procedure OR Single()blind()procedure OR crossover()procedure/de / 1247780
Other clinical studies (prospective studies) / #4 / Cohort()Analysis/de OR cohort?/ti OR longitudinal/ti OR Follow()Up/de OR evaluation()stud?/ti OR Prospective()Study/de OR Meta()Analysis/de OR systematic()review/ti,ab,de OR systematic()literature()review/ti OR meta()analysis/ti,ab OR meta()analysis/ti,ab / 799382
All clinical studies / #5 / #1 AND #2 AND (#3 OR #4) / 16202
Exclusion terms – exclude animals / #6 / /human / 15952
Exclusion terms – study type / #7 / (Comment?/ti OR dt=Letter OR dt=Editorial OR Case()Report/de OR Case()Study/de OR Phase()1()Clinical()Trial/de OR case()stud?/ti,ab OR case()report?/ti,ab OR case()series/ti,ab OR diet/ti OR Retrospective()Study/de OR retrospective/ti,ab OR dt=review NOT (Meta()Analysis/de OR systematic()review/ti,de OR systematic()literature()review/ti OR meta()analysis/ti,ab OR meta()analysis/ti,ab) / 4845532
All relevant studies / #8 / #6 NOT #7 / 10254
Limit by language / #9 / #8 with language limits: la=(English OR French OR German OR Spanish OR Chinese OR Japanese OR Portuguese OR Italian) / 10033
Limit population / #10 / #9 AND (Acute()Coronary()Syndrome/maj OR Heart Infarction!/maj OR Unstable Angina Pectoris!/maj OR myocardial()infarct?/ti OR unstable()angina/ti OR heart()attack/ti OR ACS/ti OR heart()event?/ti OR heart()arrest?/ti OR cardiac()arrest?/ti OR acute()coronary()syndrome?/ti OR heart()infarction/ti OR STEMI/ti OR NSTEMI/ti OR NON()STEMI/ti OR NONSTEMI/ti OR (acute/ti AND coronary/ti) OR (coronary/ti AND syndrome?/ti) OR non()ST()segment()elevation()myocardial()infarction/ti OR ST()segment()elevation()myocardial()infarction/ti) / 4863

Table A-4.Search Strategy to Identify Clinical Studies of ACS Patients in the Electronic Databases: Inside Conferences, Using the Dialog Platform (search conducted on 5 May 2011; not limited by date [October 1993 to 5 May 2011])

Term Group / Search Terms / No. of Articles
Population / #1 / Acute()Coronary()Syndrome? OR Unstable()Angina OR myocardial()infarct? OR heart()attack OR ACS OR heart()event? OR heart()arrest? OR cardiac()arrest? OR heart()infarction OR STEMI OR NSTEMI OR NON()STEMI OR NONSTEMI OR (acute AND coronary) OR (coronary AND syndrome?) OR non()ST()segment()elevation()myocardial()infarction OR ST()segment()elevation()myocardial()infarction / 40970
Intervention / #2 / warfarin OR aspirin OR rivaroxaban OR clopidogrel OR prasugrel OR ticagrelor OR ticlopidine OR acetylsalicylic()acid OR Phenprocoumon OR acarboxyprothrombin OR vitamin()K()antagonist / 1025
All clinical studies / #3 / #1 AND #2 / 38

ECONOMIC SEARCH STRATEGIES

Table A-5.Search Strategy to Identify Economic and Utility Studies of ACS Patients in the Electronic Databases: MEDLINE and MEDLINE In-Process, Using the PubMed Platform (search conducted on 25 April 2011; date limits: January 2000 to 25 April 2011)

Term Group / Search Terms / No. of Articles
Population / #1 / "Acute Coronary Syndrome"[MeSH] OR "Myocardial Infarction"[MeSH] OR "Angina, Unstable"[MeSH] OR myocardial infarct*[Title/Abstract] OR "unstable angina"[Title/Abstract] OR "heart attack"[Title/Abstract] OR "ACS"[Title/Abstract] OR heart event*[Title/Abstract] OR heart arrest*[Title/Abstract] OR cardiac arrest*[Title/Abstract] OR acute coronary syndrome*[Title/Abstract] OR "heart infarction"[Title/Abstract] OR STEMI[Title/Abstract] OR NSTEMI[Title/Abstract] OR “NON-STEMI”[Title/Abstract] OR NONSTEMI[Title/Abstract] OR “NON STEMI”[Title/Abstract] OR (acute[Title/Abstract] AND coronary[Title/Abstract]) OR (coronary[Title/Abstract] AND syndrome*[Title/Abstract]) OR "non ST segment elevation myocardial infarction"[Title/Abstract] OR "ST segment elevation myocardial infarction"[Title/Abstract] / 222305
Economic models / #2 / "Costs and Cost Analysis"[MeSH] OR “Cost-Benefit Analysis”[MeSH] OR “Economics, hospital”[MeSH] OR "Economics, medical"[MeSH] OR "Economics, nursing"[MeSH] OR “Economics, pharmaceutical”[MeSH] OR “cost analysis”[Title/Abstract] OR “cost-analysis”[Title/Abstract] OR cost effective*[Title/Abstract] OR cost-effective*[Title/Abstract] OR “cost utility”[Title/Abstract] OR “cost-utility”[Title/Abstract] OR "Models, Economic"[MeSH] OR economic model*[Title/Abstract] OR “costminimization”[Title/Abstract] OR “costminimisation”[Title/Abstract] OR “cost-minimisation”[Title/Abstract] OR “cost-minimization”[Title/Abstract] OR (model*[Title/Abstract] AND (cost*[Title/Abstract] OR economic*[Title/Abstract] OR pharmacoeconomic*[Title/Abstract])) / 243546
Interventions / #3 / "Warfarin"[MeSH] OR "Aspirin"[MeSH] OR "rivaroxaban"[Substance Name] OR "clopidogrel"[Substance Name] OR "prasugrel"[Substance Name] OR "Ticagrelor"[Substance Name] OR rivaroxaban[Title/Abstract] OR clopidogrel[Title/Abstract] OR prasugrel[Title/Abstract] OR Ticagrelor[Title/Abstract] OR warfarin[Title/Abstract] OR aspirin[Title/Abstract] OR ticlopidine[Title/Abstract] OR “acetylsalicylic acid’”[Title/Abstract] OR "Phenprocoumon"[MeSH] OR "acarboxyprothrombin" [Supplementary Concept] OR “Phenprocoumon”[Title/Abstract] OR “vitamin K antagonist”[Title/Abstract] / 68463
Economic models of specific interventions / #4 / #2 AND #3 / 1096
Economic and resource-use studies / #5 / ("Cost of Illness"[MeSH] OR "Health Expenditures"[MeSH] OR “Economics, hospital”[MeSH] OR "Economics, medical"[MeSH] OR "Economics, nursing"[MeSH] OR “Economics, pharmaceutical”[MeSH] OR "Health Resources/utilization"[MeSH] OR "Fees and Charges"[MeSH] OR "Health Care Costs"[MeSH] OR healthcare cost*[Title/Abstract] OR health care cost*[Title/Abstract] OR health-care cost*[Title/Abstract] OR economic*[Title] OR pharmacoeconomic*[Title/Abstract] OR "resource use"[Title/Abstract] OR "resource utilization"[Title/Abstract] OR "resource utilisation"[Title/Abstract] OR direct cost*[Title/Abstract] OR indirect cost*[Title/Abstract] OR medication cost*[Title/Abstract] OR physician cost*[Title/Abstract] OR hospitalisation cost*[Title/Abstract] OR hospitalization cost*[Title/Abstract] OR hospital cost*[Title/Abstract] OR "cost of illness"[Title/Abstract] OR "burden of illness"[Title/Abstract]) NOT (model*[Title] OR cost-effective*[Title] OR cost effective*[Title] OR “cost-utility”[Title] OR “cost utility”[Title]) / 132313
Studies on utility and impact on patient life / #6 / "Quality of Life"[MeSH] OR "quality of life"[Title/Abstract] OR "QoL"[Title/Abstract] OR "hrqol"[Title/Abstract] OR "hqol"[Title/Abstract] OR patient report*[Title/Abstract] OR "health utility"[Title/Abstract] OR "health utilities"[Title/Abstract] OR "standard gamble"[Title/Abstract] OR "time trade off"[Title/Abstract] OR “time trade-off” OR "TTO"[Title/Abstract] OR "EuroQol"[Title/Abstract] OR "EQ5D"[Title/Abstract] OR "EQ 5D"[Title/Abstract] OR "EQ-5D"[Title/Abstract] OR "quality of well being"[Title/Abstract] OR "quality of well-being"[Title/Abstract] OR "HUI"[Title/Abstract] OR "SF-6D"[Title/Abstract] OR "QALY"[Title/Abstract] OR quality adjusted life year*[Title/Abstract] OR quality-adjusted life year*[Title/Abstract] OR quality adjusted life-year*[Title/Abstract] OR quality-adjusted life-year*[Title/Abstract] OR "SF-36"[Title/Abstract] OR "SF36"[Title/Abstract] OR "sickness impact profile"[Title/Abstract] OR sf6*[Title/Abstract] OR sf 6*[Title/Abstract] OR short form 6*[Title/Abstract] OR shortform 6*[Title/Abstract] OR “sf six” [Title/Abstract] OR “sfsix”[Title/Abstract] OR “shortform six” [Title/Abstract] OR “short form six”[Title/Abstract] OR “sf 36”[Title/Abstract] OR “short form 36”[Title/Abstract] OR “shortform 36”[Title/Abstract] OR “sf thirtysix”[Title/Abstract] OR “sf thirty six”[Title/Abstract] OR “shortform thirtysix”[Title/Abstract] OR “shortform thirty six”[Title/Abstract] OR “short form thirty six”[Title/Abstract] OR “short form thirtysix”[Title/Abstract] OR “short form thirty six”[Title/Abstract] OR “Short Form Health Survey”[Title/Abstract] OR “willingness to pay”[Title/Abstract] OR (utilit*[Title/Abstract] AND score*[Title/Abstract]) OR (utilit*[Title/Abstract] AND weight*[Title/Abstract]) OR “Rosser”[Title/Abstract] OR (health[Title/Abstract] AND utilit*[Title/Abstract]) OR (utilit*[Title/Abstract] AND value[Title/Abstract]) OR disutility[Title/Abstract] OR health* year equivalent*[Title/Abstract] OR "Health Status Indicators"[MeSH] / 306617
All studies / #7 / #1 AND (#4 OR #5 OR #6) / 8626
Exclusion terms – exclude animals / #8 / "Animals"[MeSH] NOT "Humans"[MeSH] / 3554374
Exclusion terms – study type / #9 / "Comment"[Publication Type] OR "Letter"[Publication Type] OR "Editorial"[Publication Type] OR "Case Reports"[Publication Type] OR "Clinical Trial, Phase I"[Publication Type] OR "case study"[Title/Abstract] OR "case studies"[Title/Abstract] OR “case report”[Title/Abstract] OR “case reports”[Title/Abstract] OR “case series”[Title/Abstract] OR "Retrospective Studies"[MeSH] OR “retrospective”[Title/Abstract] OR "Review Literature as Topic"[MeSH] OR "Review"[Publication Type] / 4401602
All relevant studies / #10 / #7 NOT (#8 OR #9) / 5386
Limit by language, and to publications from 2000 onwards / #11 / #10 with language limits: English, French, German, Spanish, Chinese, Japanese, Italian, Portuguese, published from 2000 onwards / 3853

Table A-6.Search Strategy to Identify Economic and Utility Studies of ACS Patients in the Electronic Databases: Cochrane (search conducted on 25 April 2011; date limits: January 2000 to 25 April 2011)