Anticoagulation in Atrial Fibrillation
Jacobs, Maartje
DOI:
10.33612/diss.132895541
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2020
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Jacobs, M. (2020). Anticoagulation in Atrial Fibrillation: Consideration for treatment and health economic
aspects. University of Groningen. https://doi.org/10.33612/diss.132895541
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Chapter
Principal findings and clinical implications
The disease burden related to atrial fibrillation (AF) has been acknowledged for many years. An overall prevalence of 3% in the adult population might not be perceived as high, however if this is related to the actual number of individuals affected worldwide: 33.5 million individuals in 2010, the scale becomes much more tangible.(1,2) The population of AF patients world-wide is almost twice the current population of the Netherlands. The life time risk to develop AF is around 25% at age 40 years, so one in four would develop AF.(3) Taking in mind that disease detection is suboptimal, especially in low- and middle-income countries, the true prevalence of AF is probably much higher. Dedicated guidelines have been developed to guide the treatment of AF, nonetheless there is still room for improvement.
The stroke risk is increased in AF patients and AF is unknown in around 30% of the patients admitted with an ischaemic stroke. Stroke prevention is very effective to reduce stroke and mortality in AF if prescribed and used correctly. The introduction of NOACs was a great improvement in stroke prevention because these drugs are more patient friendly to use and they are at least as effective as VKAs. Improvement doesn’t necessarily have to come from innovation only. Early detection of AF and early initiation of stroke prevention, regardless of which oral anticoagulant is used, can already have a great impact. Also, putting more focus on co-morbidities and a patient’s overall well-being could contribute to a more tailored therapy.
Detection of patients with AF by screening
Screening on a large scale, also labeled organized or systematic screening, poses many challenges. Screening programmes can be worth the investment relative to the benefits if organized in an efficient manner. Systematic screening programmes that have been implemented on a large scale mostly focus on cancer, including breast cancer, cervical cancer, colorectal cancer and prostate cancer. Selecting subjects for screening is straightforwardly based on age and gender. Systematic screening is less common in cardiovascular disease, which is surprising since it is known that cardiovascular disease are also one of the leading causes of death.(4) Screening has the potential to prevent the targeted disease and therewith reduce the disease burden and morbidity. Screening specifically for atrial fibrillation is referred to in clinical guidelines and age is mentioned as a good selection criterion since AF prevalence increases with age.(1) However, the approach advocated is an opportunistic approach since the inclusion is based on the patient’s initiative to visit a doctor. Systematic screening would in theory reach a broader population and should lead to a higher overall detection, also detecting asymptomatic patients. The earlier the diagnosis, the higher the likelihood of preventing an adverse outcome. In Chapter 2 and 4, a single time point systematic screening for
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AF was evaluated from a health economic perspective. Both studies included the costs of screening and subsequent costs of stroke prevention treatment. Interestingly, the study in the Netherlands (Chapter 2) showed that the yield of screening, referring to the numbers of patients newly diagnosed, was of marginal influence on the cost-effectiveness of screening.(5) This result was mainly related to the averted high impact of stroke on quality of life and health care costs. The finding of this study would imply that AF screening is already worth the investment if a limited number of new patients would be detected and initiated oral anticoagulation. Of course, the overall value also depends on the diagnostic accuracy, the investment necessary to organize the screening and the detection rate in general practice. The disadvantage of a single time point screening is that paroxysmal AF could be overseen. The numbers of studies that evaluated AF screening in randomized, controlled setting is unfortunately limited. Both opportunistic screening and systematic setting were both considered effective in a systematic review, but opportunistic screening was more likely to be cost-effective.(6) This is only valid if uptake of opportunistic screening in randomized controlled trials is comparable in clinical practice. Systematic screening and opportunistic screening were both considered a cost-effective use of resources. Screening can be based on different techniques, including pulse palpation, blood pressure monitoring and single lead ECG screening.
More innovative detection methods were developed the last years that could contribute to AF detection. The first-generation applications were based on a single-lead ECG device that could be linked to an app on a mobile phone. Examples are devices that use a finger pad sensor (AliveCor®) or finger photoplethysmography (CardioRhythm®,
FibriCheck®).(7) These technologies have a good sensitivity (>93%) and specificity
(88-98%). Another example is the MyDiagnostick®, a single-lead ECG device with USB
connectivity that was used in the evaluation in Chapter 2. An interesting example is the use of smartwatches that have the function to detect an irregular pulse. A large-scale assessment to identify AF was performed with the Apple Watch.(8) Of the 419,297 participants that were enrolled in the Apple Heart study, 0,52% had an irregular pulse notification and more specifically 3.2% of the participants aged 65 years and over. The low notification in all participants was mainly due to the relatively low mean age of the study population (41 years). After irregular pulse detection, patients could return an ECG patch for further analysis. Within the participants that returned the ECG patch, the AF yield was 34% (153 patients identified). The positive predictive value of the watch was 71% and only 60% in the group aged 65 years and over. Digital alerts encourage people in engaging with health care providers. The Apple Heart Study showed that 76% of the participants contacted a health care provider. The newest generation of smartwatches (Apple Watch 4 and newer) have the possibility to record an ECG. This enables the physician to confirm a possible AF diagnosis, without the need for further diagnostic procedures. Therefore,
smartwatches could contribute to AF detection, especially if the older population can be motivated to wear these devices.
The prevalence of AF can differ depending on geography and population characteristics. Chapter 3 is a systematic review that describes AF prevalence in Sub-Saharan Africa (SSA). Numbers that approached a population prevalence were only 0,3-0,7% in patients aged 50 and 70 years and over which is much lower than the prevalence in Europe. This review showed that AF seems to be underreported in the African region, with patients being generally younger compared to high-income countries. The lower numbers of AF patients could be and underestimate due to more restricted access to health care and less routine monitoring with ECGs. Screening for AF could be a good approach to determine the true AF prevalence in the AF region. The World Heart Federation (WHF) developed a roadmap for diagnosis and treatment of nonvalvular AF.(9) The WHF suggests two strategies for screening: pulse palpation for patients presenting with AF symptoms and secondly opportunistic screening of patients 65+ years, also with pulse palpation. The WHF acknowledges that early detection and treatment can reduce morbidity and mortality in AF patients. Opportunistic pulse palpation has a high number of false positives that can result in unnecessary ECGs. An optimal screening method should be fairly cheap to perform and has to have a high specificity and sensitivity. Inexpensive smartphone- or smartwatch-based rhythm monitoring could have a potential application in low- and middle-income countries (LMICs) to detect AF. The main hurdle for large-scale screening is the low availability of specially trained staff for ECG analysis. In Chapter 4 of this thesis a study is included that explores AF screening feasibility in Sub-Saharan Africa. Nigeria was chosen as a case study. This health economic modelling study evaluated a single AF screening session combined with subsequent initiation of stroke prevention therapy. Articles that were included in the systematic review in Chapter 4 were also used as model input for this evaluation, if appropriate. The anticoagulants evaluated as stroke prevention strategy included warfarin, a NOAC and a 1:1 case-mix of NOAC:warfarin. The evaluation showed that AF screening has the potential to be cost-effective in Nigeria with an incremental cost-effectiveness ratio of $986 per QALY gained with 100% warfarin use. The ICER rose to $12,210 per QALY gained due to high cost of a NOAC. In line with results from the AF screening evaluation in Chapter 2, cost-effectiveness of screening in Sub-Saharan Africa was sensitive to stroke probability and stroke-related quality of life. Cost-effectiveness had a low sensitivity to AF prevalence, which was also the case in the evaluation conducted for the Netherlands. Main difference in the evaluation in Sub-Saharan Africa was the impact of treatment cost, since the stroke prevention therapy made up the vast majority of all included health care costs. As the stroke prevention treatment costs are high compared to event-related costs, the AF screening session costs are of marginal influence. This implies that AF screening can
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be worth the investment if screening is set up in an efficient and not too costly manner and the costs of stroke prevention treatment shouldn’t be too high and still affordable for the population.
Optimizing stroke prevention in patients with AF
Oral anticoagulants are very effective in lowering the risk of stroke and mortality, stroke risk can be reduced by up to two-third. Guidance to initiate stroke prevention in AF patients has been well established over the years. The decision to initiate an anticoagulant in AF patients is mainly based on the stroke risk, calculated with the CHA2DS2-VASc score. The prescription of oral anticoagulation has increased over the last decade, nonetheless there are also still patients untreated or treated with antiplatelet therapy. Guideline recommended oral anticoagulation use is around 75-80% in clinical practice.(10,11,12) In Africa the percentage of clinically eligible patients receiving oral anticoagulants was alarmingly low at less than 20%.(13) There is still room to improve stroke prevention initiation, not just in LMIC regions such as Africa but surely also in high-income countries. The initiation of an anticoagulant also depends on the factors that the prescriber takes into account when they decide to initiate therapy. A study exploring factors relevant to decision making showed a wide range of factors that are taken into account, in the end leading to 16 consensus factors that the health care providers valued important.(14) This shows that stroke prevention initiation also depends on prescribers personal considerations.
The application of the CHA2DS2-Vasc stroke risk score is developed and validated in a general AF population.(15) It is not fully clear if the stroke risk score is also applicable in specific settings, for example in new-onset AF that develop in the critically ill phase and/or after surgery, to determine the necessity of stroke prevention therapy. Chapter 9 of this thesis describes the incidence and treatment of new-onset AF at the ICU. Based on the CHA2DS2-Vasc score, only 56.3% of the patients with new-onset AF received an
anticoagulant at hospital discharge. Unfortunately, this study was not powered to detect differences in clinical outcomes compared to patients without AF or with previously diagnosed AF. Other studies showed that the thromboembolic risk of new-onset AF patients was lower compared to patients without new-onset AF post-surgery and also compared to matched nonvalvular AF patients.(16,17) Evidence in the general population suggested that the stroke risk is still increased after restoration of sinus rhythm.(18,19) However, also considering the newer evidence, it can be debated if that principle also applies to AF that developed in the critically ill phase or after surgery since there could be provoking factors for developing an arrhythmia. It remains unclear if stroke prevention should be initiated in new-onset AF that developed in the critically ill phase or for
example after surgery and if duration and/or transient nature of the arrhythmia should determine the necessity to initiate oral anticoagulation in this specific population.
The efficacy of VKAs depends on the time in therapeutic range (TTR), as measured by the international normalized ratio (INR). With NOACs, routine monitoring is not necessary because of the fixed dosing regimen that has a proven efficacy. NOAC therapy is at least as effective and safe as warfarin/VKAs as shown in the clinical trials. The four major NOAC trials had a varying range of TTRs for the VKA arm (56-68%). Although no heterogeneity across TTR quartiles was reported, the individual studies were underpowered to detect differences based on the TTR.
The correct dose and correct use by the patients are crucial elements to warrant the efficacy and safety of NOACs. Chapter 5 concluded that at least 10% of the patients received an inappropriate NOAC dose at initiation with a fairly equal distribution of overdosing and underdosing. A UK population-based study found comparable results as described in Chapter 5. Underdosing occurred more frequently than overdosing in apixaban and rivaroxaban users, overdosing was more frequent in dabigatran users. Underdosing was more than twice as common in apixaban users.(20) There seems to be a trend in more underdosing in apixaban prescriptions, which could be related to the ‘two out of three’ dosing rule for apixaban. Apixaban has 3 items related to dosing: Age ≥ 80 year, body weight ≤60 kg and/or serum creatinine ≥ 1.5 mg/dL (133µmol/l). If two or three items are present in the patient, the lower dose of 2,5 mg twice daily has to be used. Often the reduced dose of 2.5 mg is already prescribed if a patients fulfills only one of the three criteria. In general, overdosing increases the risk of bleeding whereas underdosing increases the risk of stroke. Prescription errors can be prevented by better education, full availability of patient information and also by more advanced electronic support in prescribing. A meta-analysis that explored the results of the NOAC randomized clinical trials concluded that patient eligible for the reduced dose NOAC, according to patient and clinical factors, were at elevated risk for thromboembolic and hemorrhagic complications compared to patients eligible for a full-dose NOACs.(21). A large registry confirmed that a reduced dose NOAC is often inappropriately prescribed. In the patients with a reduced dose NOAC prescription, 57% was reduced inconsistently from the FDA label. Patients with an inappropriate reduced NOAC dose had a higher unadjusted rate of thromboembolic events (2.11 vs 1.35 in patients with appropriate reduced dose) and a higher death rate (6.77 vs 2.70). After adjustment there was no significant difference, nonetheless this shows a clear trend and numerical difference.(22) Another nationwide cohort study also found a trend towards higher rates of ischemic stroke and systemic embolism for apixaban 2.5 mg compared to warfarin.(23) These results confirm that more focus needs to be put on prescribing the correct NOAC dose.
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Treatment adherence is an important aspect to take into account during treatment initiation and in patients that are already on treatment. Non-adherence can lead to increased health care costs.(24) As described in Chapter 6, adherence seems to be higher in NOACs with a once-daily regimen compared to a twice-daily regimen. Although this study is focused on secondary adherence, this preliminary finding is interesting and could be incorporated in decision making. Prescribers should understand the reason for non-adherence to tailor a patient’s needs and preferences. Monitoring treatment adherence during the treatment can also be established with the help of digital solutions. Telemonitoring can be easily implemented with a medication bottle that records the time and date of opening and transfers this information to a server to compare the pattern to the expected pattern. A clinical study in AF patients showed that telemonitoring with NOAC leads to a high treatment adherence. In this study apixaban was used and treatment adherence based on pill counts was 97.9% and even 99.0% if direct patient-feedback was applied.(25) Costs for telemonitoring were high and did not outweigh the costs of strokes averted as shown in the cost-effectiveness analysis of this study. Since this analysis only took into account a limited number of outcomes/health effects and high costs for telemonitoring, the intervention could be cost-effective in specific high-risk population. Digital adherence tools already provide sustainable solutions, although they are not so commonly used in daily practice. A wide variety of non-digital and digital adherence devices is already on the market.(26) Digital solutions to support a patient should be integrated in healthcare, ideally by providing digital solutions on prescription and reimbursing these solutions for patients groups that could benefit, i.e. polypharmacy patients, patients with an irregular lifestyle and the elderly.
Balancing bleeding and stroke risk in specific populations of AF patients
The extent of under- and over-treatment is also relevant in AF patients undergoing a percutaneous coronary intervention (PCI). There is an ongoing discussion whether dual antiplatelet therapy in combination with anticoagulation is really necessary in this specific subpopulation with AF. It is known that a combination of warfarin with antiplatelet therapy leads to a threefold increased risk for non-fatal and fatal bleeding. (27) The pitfall in this combination therapy is to unnecessarily give a reduced dose oral anticoagulant that is suboptimal for stroke prevention in AF. In chapter 8 of this thesis, the conclusion was that (N)OAC with single antiplatelet therapy, clopidogrel, seemed to be the optimal choice. As stated in that chapter, what seemed wise at that point in time might be obsolete now. A few studies on OAC + (D)APT have been published after that review article was published. The ENTRUST AF PCI study results were published in 2018 which also demonstrated non-inferiority in bleeding without significant differences in ischemic events for endoxaban+ a P2Y12 inhibitor. The AUGUSTUS trial had a 2x2 factorial design
where apixaban or a VKA and aspirin or matching placebo were given on top of a P2Y12 inhibitor.(28) A regimen with apixaban plus clopidogrel, without aspirin, resulted in less bleeding (major or clinically relevant non-major bleeding) and fewer hospitalizations without a significant difference in the incidence of ischemic events (stroke, MI and stent thrombosis). This study confirms the previous conclusion that single antiplatelet therapy is the preferred choice in AF patients with ACS. The study was not powered for differences in ischemic outcomes, it does however show a clear trend towards a beneficial effect. The strength of this study was that the used doses of apixaban were those with proven efficacy in stroke prevention, and the dose was only reduced if patients met the dose reduction criteria. The PIONEER AF-PCI study used a rivaroxaban dose not approved for stroke prevention and the RE-DUAL PCI trial randomized patients to the reduced dose dabigatran of 110 mg twice daily.(29)(30). It is now clear that the use of a NOAC + a P2Y12 inhibitor reduces the risk of bleeding, but a trial providing convincing, statistically significant results on ischemic endpoint is unfortunately still lacking. Apixaban is the NOAC associated with the lowest bleeding rate when combined with a P2Y12 inhibitor. (31) Omitting aspirin is certainly not disadvantaging AF patients undergoing PCI. The use of aspirin beyond hospital discharge should only be used in a small group of patients with a high ischemic risk an low bleeding risk, now substantiated in the North American perspective.(32) A network meta-analysis of the Cochrane Group showed no superiority for one NOAC over another, for any of the outcomes. Evidence was classified very low- to moderate-certainty and this suggested no meaningful difference between NOACs and VKAs following PCI in patients with non-valvular AF. However, NOACs probably do reduce the risk of recurrent hospitalizations for adverse events compared with VKAs.(33) Another patient group where an optimal efficacy-safety balance is relevant, are patients that undergo an intervention. VKAs are generally interrupted since they increase the risk of bleeding. Low-molecular weight heparins (LMWHs) have a much shorter half-life and can be initiated to bridge this period of interruption. In Chapter 10, bridging anticoagulation was evaluated for AF patients on VKAs. Using a mathematical model we demonstrated that only a limited patient group where the stroke risk is high and the bleeding risk is low would benefit from bridging. This conclusion is only valid for VKAs.(34) NOACs have a rapid onset of action and a short half-life. Therefore, these drugs can be easily used around an intervention. VKAs have a longer half-life and need to be interrupted multiple days before the intervention. Even more challenging is the need to titrate the VKA dose after discontinuation and therewith a longer period with suboptimal stroke prevention efficacy. NOACs are usually interrupted 24 — 48 hours before surgery and restarted 24 — 48 hours thereafter. A recent study suggests that AF patients receiving LMWH bridging have a higher risk of early ischemic recurrence and hemorrhagic transformation compared to non-bridged patients.(35) In the non-bridging
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group, there was a statistically significant difference in the rate of ischemic events in the patients treated with NOACs versus VKAs: 2,5% versus 5,5%. There was no difference in the hemorrhagic events.(35) Bridging therapy (LMWH use) with NOACs was associated with a higher risk of ischemic events compared with patients receiving NOACs alone. In patients undergoing AF ablation, NOACs can even be continued periprocedural without compromising safety and efficacy.(36) This approach was already described in clinical guidelines, but was substantiated with this first randomized trial.(1,37)
Elective electrical cardioversion (ECV) is an example of an intervention often used in AF patients where an anticoagulant is specifically initiated for the intervention. The peri-procedural risk for stroke and systemic embolism (SE) is increased due to the temporary stasis of the blood. Inadequate anticoagulation prior to ECV poses a risk for bleeding if the INR is too high and a risk for stroke and/or SE if the INR is too low. Inadequate anticoagulation could be as high as 50%, which may also create an economical burden due to ECVs being postponed and a higher risk for complications during the procedure.(38) Since NOACs have a predictable pharmacokinetic and -dynamic profile, these anticoagulants have a potential benefit to use with ECV. Time to cardioversion is shorter and fewer cardioversions need to be rescheduled. A small real-world study with dabigatran showed comparable total costs for warfarin and dabigatran users with almost half the time to cardioversion (34 days versus 67 days for dabigatran and warfarin, respectively).(39) Rates of thromboembolism and bleeding were low (<1%).(40,41,42) Guidelines of the American College of Cardiology, American Heart Association Heart Rhythm Association and Anesthesiologists have upgraded the evidence to use NOACs before and after cardioversion.(34,43) The shorter time to cardioversion and fewer reschedules can be translated in a benefit on patients’ quality of life. NOACs therefore seem a preferable option to use with electrical cardioversion. In Chapter 11 of this thesis it was shown that rivaroxaban could lead to a gain in quality-adjusted life years with only limited additional cost: 0.23 QALY gained per patient costing €1.83 per patient treated compared to VKA use. The gain in QALYs was related to the shorter period before ECV in the rivaroxaban group. In the period before ECV, patients were in a symptomatic AF state with a lower quality of life. In this modelling study a pre-ECV treatment period of 22 days was used for the NOAC. An even shorter NOAC treatment period before the ECV procedure, which would be possible based on the pharmacokinetic profile, could lead to even higher health gains and cost-savings.
Costs associated with stroke prevention in AF patients
The AF population that would be eligible for treatment with NOACs is large. The AF population in the Netherlands was already estimated at 260,000 patients back in 2012 in the first reimbursement process.(44) A treatment should ideally be effective and also
cost-effective. Drug assessment for reimbursement takes into account cost-effectiveness alongside clinical effectiveness in the Netherlands. The NOACs are cost-effective but are associated with a high budget impact due to the large number of AF patients that would be eligible for treatment. The NOACs dabigatran and rivaroxaban were actually the first drugs in The Netherlands where a new approach was used to control drug spending. The Ministry of Health started ‘a new integrated approach that focuses on the appropriate use of resources and provides for acceptable expenditure development’.(45) A price-volume agreement was the basis for conditional reimbursement approval for the first 3 years. Agreements were made about a lower initial price, followed by further decreasing prices as the volume would increase. Moreover, it was agreed that in the event of a patient volume higher than expected in advance, the additional costs would remain limited. The initial unit price that was mentioned by Boehringer Ingelheim in their cost-effectiveness dossier was €2.50 per day for both dabigatran 110 mg and 150 mg. The financial arrangement was initially for 3 years, nonetheless all NOACs on the Dutch market are all still in a financial arrangement with conditional reimbursement (conditional for the indication where it can be used for). The Ministry of Health is thus far not willing to break open these arrangements, unless the list price would be voluntarily lowered to an acceptable price. The price has to be balanced by the health care costs that the NOAC use can avert. In Chapter 7 of this thesis, the real-world health care costs were compared in patients initiating dabigatran versus the VKA acenocoumarol. This cost analysis indicated that the use of dabigatran was an indicator for lower hospital care costs and more specifically lower in-hospital cardiology care costs.(46). A population-based study with a time-driven activity-population-based costing method showed that warfarin use incurs costs comparable to NOACs in the primary care setting.(47) Around 52% of the patients was not stable on warfarin treatment, this introduced additional costs due to INR monitoring and additional health care provider time. A Danish study showed that the total costs per patient per year are lower for apixaban, dabigatran and edoxaban compared to warfarin from a societal perspective.(48) This was calculated also taking into account health care costs averted due to the efficacy of the drugs. The total annual costs for NOACs were $2,006-$2,557 compared to $2,358-2,636 for warfarin.
In high-income countries the discussion is focused around controlling health care expenditures and more specifically also reducing drug expenditures. In low- and middle-income countries (LMICs) the discussion is of a different order. NOACs are there considered as expensive, especially compared to VKAs, and those costs raise a barrier for patient access. For example, in Nigeria dabigatran costs around $900 for a year of treatment. NOACs are rarely used in low- and middle-income countries while they would undoubtedly have added value in countries with a less organized health care system. As discussed before, VKA efficacy depends on the TTR. Anticoagulation with
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VKA drug therapy that is not properly and routinely monitored can lead to ineffective stroke prevention and also an increase in bleeding events. Especially in rural areas, access to health care is limited. NOACs do not need routine monitoring if patients are educated how to take their drug. The use of NOACs would be a good solution to overcome several challenges in stroke treatment in low- and middle-income countries. In the light of drug use in LMICS, the WHO publishes a core list of essential medicines. The core list presents a list of minimum medicine needs for a basic health-care system, listing the most efficacious, safe and cost–effective medicines for priority conditions.(49) In 2015, the WHO committee decided not to add NOACs to the list because 1) further research was first needed to explore the unmet need in anticoagulation 2) Safety was a concern because there was no specific antidote to reverse the anticoagulant effect and 3) there was a large difference in cost between NOACs and warfarin disproportional to the observed incremental benefit.(50) Dabigatran has nevertheless been added to this list in 2019. The main issue in implementing the use of NOACs in lower income countries is the high drug costs. Is has been shown that the four cardiovascular disease medicines (aspirin, beta blockers, ACE inhibitors and statins) were already potentially unaffordable for 33% of the lower middle-income countries and even in 60% of low-income countries.(51) These CVD drugs are much cheaper than NOACs with median monthly costs around $17 in low-income countries. Considering the fact that a high percentage of households can’t afford this $17 per month for CVD drugs, NOACs would be unaffordable for most of the patients. The capacity to pay is only $89 per month among low-income households and $243 in low middle-income countries compared to $4,238 per month in high-income countries.(51) In comparison, in Nigeria warfarin is only around $35 per year without monitoring costs and $65 also taking into account monitoring costs.
Generic NOACs could offer a solution to reduce the price level of these drugs. The primary patent of dabigatran already expired in 2018 in LMICs, the other patents will expire in 2020, 2022 and 2023 for rivaroxaban, apixaban and rivaroxaban, respectively. (13) There are some secondary patents that could delay generic entry. The World Heart Federation also highlighted the need for generic medication in their 2017 Roadmap for Nonvalvular Atrial Fibrillation. A generic version of dabigatran is already on the Indian market for $26 per month compared to around $70 per month for the originator. This shows that NOACs could still be manufactured with profit for fairly low costs, and most probably the price can be even lower. In Chapter 4 of this thesis, screening with subsequent initation of stroke prevention would be cost-effective with NOAC drug costs ≤ US$86 per 6 months and would be cost-saving with NOAC drug costs ≤US$14 per 6 months. This price was calculated for an AF screening setting and based on a willingness-to-pay at the GDP per capita for Nigeria (roughly $2,000 per QALY). The NOAC price of $86/6 months (roughly $14/ month) seems feasible from a ‘capacity to pay’ perspective
and also from a profitability standpoint for the pharmaceutical industry. Introducing a lower priced NOAC could lead to such an improvement in stroke treatment in LMIC that it is almost an ethical obligation to introduce generics that have a fair price or to lower the NOACs price in LMICs to an affordable level.
Future perspectives
The introduction of the NOACs already lead to an improvement in stroke prevention for AF patients. These drugs are more convenient to use and show additional benefit on specific outcomes compared to the VKAs, which were the former gold standard. The treatment of AF is already well established, especially in high-income countries, wherefore improvements is more focused on the organization of health care. Optimizing AF detection is one of the items where there is still room for optimization. Also, more focus should be put on guiding the NOAC treatment initiation and treatment adherence to assure appropriate use and dosing. In low- and middle-income countries there is still considerable room for improvement to reach the level of care for AF patients in high-income countries. Non-communicable diseases (NCDs), including AF were understandably not the diseases to primarily focus on. Now that welfare is increasing in lower- and middle-income countries, the NCDs seem to cause a big challenge to population health. There is no specific focus on AF because it might not seem the biggest threat at this point in time. If a more systematic approach would be used to screen for AF, this could show that the prevalence of AF is presumably much higher than currently known. Screening can be easily organized, especially if mobile devices are used in areas where health care is less accessible. The other issue is that NOACs are not readily available in many countries due to the high costs. This is a disadvantage, because these drugs could really contribute to improving stroke prevention. With no necessity to monitor NOAC treatment with tests such as INR monitoring, patient education should suffice to highly reduce the risk for a first or second stroke. Generic NOACs could contribute to increasing access to stroke prevention strategies if they would be offered at a fair price that patients can afford.
Looking towards the future, there is a new interesting group of drugs being studied. Although NOACs show a better safety profile compared to VKAs, there is still a remaining risk for hemorrhages. Selective inhibition of Factor XI and XII could be an interesting target in the coagulation pathway as these factors contribute to pathologic thrombosis. Factors XI and XII are components of the intrinsic pathway of coagulation and are upstream of the targets of the available anticoagulants. The drugs currently under development (preclinical and phase 1) include small molecules, antibodies and an antisense drug.(52) The drugs target catalytic activity of activated factor XI, factor XI activation mediated by activated factor XII and one drug inhibits factor XI synthesis
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in the liver. Most are administered intravenously or subcutaneously and some have the benefit of a once-monthly administration. Results thus far show a good safety profile, nonetheless it is too early to tell if there is a potential to lower the hemorrhagic risk without compromising on anticoagulation efficacy.
Health economics can contribute to show the value of future improvement in disease detection and stroke prevention in AF by confirming that the costs are worth the health gains. Health economics can not only be applied to drugs but also to devices, interventions and even in a broader context when talking about optimizing treatment pathways. That is the point where health economics meets value-based healthcare. A patient-centered, integrated healthcare system should be developed where we pay for a care bundle instead of one specific disease or diagnosis. Focusing on AF, this would mean: more collaboration between the cardiologist and GP, delivering the care in a way that fits the patients’ needs, registering patient outcomes while adapting treatment choices to these outcomes and integrating cardiovascular risk management in the AF treatment. Health care costs are increasing in high-income countries and therefore we need a new way of delivering our health care more efficiently at lower costs, while also improving patient outcomes. Since stroke opposes such a high economic burden to society, AF treatment is a good place to start the optimization.
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