Plan utarbeidet 10.4.2012, publisert 20.4.2012
Kort beskrivelse/sammendrag (norsk)
Atrieflimmer er en rytmeforstyrrelse i hjertet. På grunn av uregelmessige elektriske impulser, trekker forkamrene og hjertekamrene
seg ikke sammen synkront slik de normalt skal gjøre. Dette medfører ujevn blodflyt og økt risiko for dannelse av blodpropper.
Blodproppene kan bli ført med blodstrømmen og forårsake hjerneslag eller systemisk emboli andre steder i kroppen. For å forebygge
dette er det anbefalt at pasienter med atrieflimmer og moderat til høy risiko for hjerneslag får blodfortynnende behandling.
I dette prosjektet vil vi undersøke effekt og kostnadseffektivitet av nye antikoagulanter til slagforebygging hos pasienter
med atrieflimmer sammenliknet med warfarin.
Project Plan (English)
The Norwegian Medicines Agency (NoMa) requested NOKC to assess whether any of the new anticoagulants are cost-effective in
comparison with existing alternatives to prevent stroke in patients with atrial fibrillation.
To calculate the cost-effectiveness of the new anticoagulants (apixaban, dabigatran and rivaroxaban) relative to each other
and to warfarin for prevention of stroke in patients with atrial fibrillation.
To compare the efficacy of new anticoagulants with warfarin in preventing morbidity and mortality for patients with atrial
To construct a model which calculates remaining quality adjusted life expectancy for patients with atrial fibrillation and
disease -related costs along the clinical pathway.
Atrial fibrillation (AF) is the most common irregularity of the heart rhythm. The atria contract at a more rapid pace than
the ventricles, causing suboptimal filling of the ventricles and impaired blood circulation. This typically causes some degree
of fatigue, and increases the risk of blood clotting especially in the atria. The blood clots may then be transported by the
bloodstream to the brain and cause strokes, or through the body resulting in systemic embolisms.
Given an increased risk of stroke for patients with atrial fibrillation, patients usually receive drugs intended to prevent
blood clotting. Several different classes of drugs, with different points of action, are used. The choice between these drugs
depends on an overall assessment based on the age of the patient, prior strokes, co-medication, risk factors and more.
Today, warfarin is the standard treatment to prevent clotting for patients with atrial fibrillation and additional risk factors
(Risøe 2004, You 2012). Warfarin is considered to be an effective treatment, reducing the risk of stroke and myocardial infarction
(Aguilar 2011). Warfarin treatment does, however, require regular follow-up (INR-measurements) to ensure proper use as it
is sensitive to interaction with food and other medications. INR-measurements are commonly performed by doctors, but self
management in selected patients have recently shown to produce even better results, but is only sporadically used in Norway
(Ringerike 2010). Warfarin is also known to increase the risk of bleeding, particular intracranial bleeds. New drugs with
less need for monitoring have been developed recently or are under development (dabigatran, rivaroxaban, apixaban, edoxaban).
New anticoagulants are usually first developed and tested in persons undergoing orthopaedic surgery. NOKC has previously published
a report on dabigatran and rivaroxaban compared to warfarin in this setting (Ringerike 2011). NOKC has also published several
reports within (primary and secondary) prevention of cardiovascular disease (Håheim 2008, Wisløff 2008, Hamidi 2010, Wisløff
2010). Experiences from these previous model analyses will be important in this HTA.
We will perform a health technology assessment (HTA) consisting of at least the three elements efficacy, safety and health
economic evaluation. The HTA will be performed in accordance with the guidelines for Norwegian HTA reports (Kunnskapssenteret
2011). Efficacy and safety will be evaluated through a systematic review, and the economic evaluation will be performed through
a modelling exercise.
The inclusion criteria for the systematic review (SR) are defined by the following PICO:
Population: Patients with non-valvular atrial fibrillation at moderate and high risk of stroke (CHADS2≥1)
Interventions: Dabigatran (110 mg x2 or 150 mg x2)
Rivaroxaban (20 mg x 1)
Apixaban (5 mg x 2)
Control: Warfarin to INR 2.5 (2.0-3.0)
Dabigatran (110 mg x2 or 150 mg x2)
Rivaroxaban (20 mg x 1)
Apixaban (5 mg x 2)
Outcome: Mortality (all cause)
Ischemic stroke or systemic embolism
Hemorrhagic stroke / intracranial bleeding
Acute myocardial infarction (AMI)
Major gastrointestinal (GI) bleeding
Major bleeding (not GI or intracranial)
Quality of life (EQ5D, 15D, SF6D, SF36, HUI)
Study design: Systematic reviews, HTA reports, randomized controlled trials
Languages: No limitations in languages during the search, but we will only include articles in English, articles with
English abstract or articles in Scandinavian.
A systematic search strategy will be constructed by the lead reviewers in collaboration with an information specialist/librarian.
The strategy will include both subject headings (MeSH, Emtree) and text words. We will firstly search for systematic reviews
and HTA reports. We will additionaly search for recently published randomized controlled trials not included in the available
systematic reviews and HTA reports to ensure the inclusion of the most recent documentation.
We plan to search the following databases:
- The Cochrane Library
- Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1948 to present
- EMBASE 1980 to present
- Centre for Reviews and Dissemination (CRD)
We will search for HTA reports at http://www.crd.york.ac.uk/CRDWeb/SearchPage.asp and on websites of selected HTA organizations.
We are aware that the Canadian Agency for Drugs and Technologies in Health (CADTH) posted at draft called “Safety and Effectiveness
of New Oral Anti-coagulants Compared to Warfarin in Preventing Stroke and Other Cardiovascular Events in Patients with Atrial
Fibrillation” for consultation in February 2012. This will probably be published in a final version within a few months. We
will contact CADTH to avoid duplicating their work.
The Norwegian Medicines agency and the pharmaceutical companies with marketing authorization for the included interventions
will be contacted. They will be given the opportunity to supplement us with non-identified articles or data matching our inclusion
Selection of publications
Two persons will independently review all citations generated by the search to identify potentially relevant publications
based on title and/or abstract. We will obtain full text versions for articles that appear to meet our inclusion criteria
or in cases where sufficient information was not available to make a decision. Two persons will independently assess whether
the publication is relevant or not according to our list of inclusion criteria. We will solve disagreements by discussion
or by consulting a third reviewer.
Publications meeting the predefined inclusion criteria will be assessed for quality according to a check list for systematic
reviews or for risk of bias for randomized controlled trials (Kunnskapssenteret 2011). All assessments will be performed and
agreed upon by two persons.
We will collect data from the systematic reviews or from randomized controlled trials and present the data as they appear
in the publications. In cases where data are pooled into composite endpoints or mixed populations, we will try to identity
and extract data to fit our outcomes. We will extract subgroup data for the following categories, if reported; age, previous
stroke or different CHADS2 score. If it is impossible to disentangle data for appropriate subgroups, we will use the overall effect estimate.
If appropriate, we will perform meta-analyses using a random effects model. As far as possible our analyses of efficacy will
be performed according to the principle of “intention-to-treat”. Direct comparisons will be analysed using the software program
It is likely that not all our comparisons of interest have been performed in head-to-head comparison trials. Consequently,
we will most likely additionally analyse the results in a network meta-analysis using the program WinBUGS.
Grading the quality of evidence
Two reviewers will assess overall confidence in the results for each outcome by using GRADE (Grading of Recommendations, Assessment,
Development and Evaluation, www.gradeworkinggroup.org). The method is based on the study design used and involves an evaluation of eight criteria for each outcome. Limitations
in any of five criteria may lower the quality: study quality/risk of bias, consistency between trials, directness (in how
similar the population, intervention, and outcomes are between the trials and the stated objectives of this report), precision
of the estimates and reporting bias. The three criteria to evaluate an increase in quality are: large effect, presence of
a dose-response gradient and plausible confounding that would change (lower) the effect. For outcomes based on indirect comparisons,
we will downgrade one level due to low confidence in the results originating from different studies.
The economic evaluation will be based on efficacy data, as well as data on side-effects and health related quality of life
summarised within the project (see previous section). If data on HRQoL is not retrieved through the systematic review, we
will search for quality of life weights for the events and health states in the model. We will develop a model mainly based
on the NorCaD model (Wisløff 2008) to simulate life-time health effects and costs of the different possible interventions.
Modifications of this model will depend on which outcomes that actually have been reported in trials. The main idea is however
to include both cardiovascular outcomes and reported side effects. The PICO for this economic evaluation are:
Population: Patients with atrial fibrillation aged 65 and 75 who now are recommended to use warfarin (CHADS2 >= 1). Separate analyses will be performed for different CHADS2 score.
Interventions: apixaban, dabigatran and rivaroxaban
Outcome: Cost per QALY, Cost per life year, net health benefit, probability of being cost-effective
Study design: Probabilistic Markov model
Perspective: Health care provider
The model will be made probabilistic, which means that all parameters which are uncertain will be included as probability
distributions into the model. These probability distributions are supposed to reflect the uncertainty relating to these parameters.
Quality of included parameters is considered part of this uncertainty.
Activities and schedule
- Search for literature on efficacy
- Search for inputs to health economic model (health related quality of life weights, incidence, morbidity, mortality and costs)
- Include literature according to inclusion/exclusion criteria
- Evaluate methodological quality (checklist on SR or HTA, RoB on RCT)
- Build model based on NorCaD
- Extract data on efficacy
- Extract data for model and fill in as probability distributions
- Network meta-analysis on RCT’s
- GRADE evaluation for each important outcome
- Run model for different (pre-specified) subgroups
- Write report and get it peer-reviewed, revised, approved and published
The end product will be an HTA report from NOKC. We also plan to publish a network meta-analysis and the economic evaluation
as scientific articles if similar analyses are not published before we are finished. Results will be submitted to some of
the following conferences depending on how newsworthy the results are: HTAi, SMDM, Cochrane, International Stroke conference.
The Norwegian Medicines Agency (NOMA) is the commissioner of this project. Hence, the HTA report will be sent to NOMA and
external reviewers simultaneously (scheduled August 2012).
Indexing for home page
Atrial fibrillation, stroke, anticoagulants, dabigatran, rivaroxaban, apixaban, warfarin, health technology assessment.
 We will search for health related quality of life weights as input for the model only if no efficacy data on health related
quality of life is retrieved.