Hypertension (elevated blood pressure) is the leading preventable risk factor for cardiovascular disease (CVD) and associated mortality, with more than 1 billion people living with the condition worldwide1 [1]. Recent studies have indicated that Russia and other Eastern European countries are responsible for a large proportion of the global burden of hypertension, and that its control remains insufficient despite numerous attempts to raise awareness of the condition [2][3]. Indeed, a 2017 evaluation of four regions in Russia (Krasnodar, Omsk and Ryazan, and the Republic of Karelia) estimated that the age-standardized prevalence of hypertension to be 44%, with 33% of patients living with blood pressure values ≥140/90 mm Hg [2]. Moreover, only 50% of patients who were prescribed antihypertensive therapy were estimated to be achieving effective treatment [2]. Further published data has indicated that the probabilities of being hypertensive, being hypertensive and receiving treatment, and being hypertensive and having controlled blood pressure are low in in Russia [4-6]. The economic burden associated with hypertension is also substantial, accounting for 1% of Russian gross domestic product (GDP) in 2016, higher than any other major chronic non-communicable disease [7][8].

Overcoming the burden of hypertension is limited by inefficiencies in management of the condition. Inefficiencies can manifest in the identification of underlying causes and risk factors, lifestyle modification, and prescription of appropriate multimodal therapy, with a majority (70%) of hypertensive individuals requiring at least two antihypertensive agents to achieve target blood levels [9][10]. Indeed, a 2017 regional study in Russia indicated that improved diagnosis and control of hypertension can lead to marked improvements in blood pressure control rate, reductions in the percentage of patients with a systolic blood pressure (SBP) ≥180 mm Hg, and reductions in stroke incidence rate [3]. However, combination therapy increases the burden of self-administration on antihypertensive individuals, which has been associated with reduced adherence and, consequently, reduced blood pressure control [9]. Indeed, data from four Russian regions have indicated that only 25% of patients achieve blood pressure control [2]. Moreover, a review of studies evaluating antihypertensive treatment in Russia found that adherence varied from 11-44% (when measured using the Morisky Medication Adherence Scale (MMAS-4)) [11]. Improving adherence to antihypertensive agents and, consequently, blood pressure control, could therefore elucidate substantial clinical benefits for individuals with hypertension in Russia [1].

Recommendations for the treatment of hypertension in Russia follow the recent guidance published by the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) [12]. These guidelines recommended initiation of an antihypertensive treatment with a two-drug combination, preferably in a single pill combination (SPC), with exceptions in frail, older patients and those with grade 1 hypertension (e.g., SBP <150 mm Hg) [11]. This is in contrast to traditional treatment strategies recommended in previous guidelines, such as single drug with dosage titration first, then sequential addition of other agents (start low and go slow (SLGS)), which was recommended in its "stepped care" variant by JNC-1 in 1977 and the first ESC/ESH guidelines in 2003; and free choice combination with multiple pills (FCC), which was previously specified as an intensification treatment option but has now been indicated as an essential option when SPC therapy is not available by the International Society of Hypertension (ISH) [13-15]. Moreover, the updated guidance placed strong emphasis on the importance of evaluating treatment adherence as a major cause of poor blood pressure control.

In the absence of data from long-term clinical trials, which can be difficult to perform due to financial, practical and ethical concerns, modeling studies can help to inform decision making around hypertensive treatment strategies by projecting the impacts of different therapies on blood pressure and the incidence of associated clinical events. Previous modeling studies have evaluated the long-term clinical outcomes associated with the management of hypertension, including an analysis projecting outcomes for different therapies in five countries (Italy, China, South Korea, Mexico and Russia) and a study investigating the effects of different treatment programs on cardiovascular outcomes in Russia [16][17]. However, the present paper aimed to focus on bespoke, 10-year projections for the Russian setting, alongside additional and complementary data, to better emphasize the findings of the analysis and provide pertinent information for physicians and healthcare payers in the country. The aim of this specific analysis was therefore to model and estimate the long-term clinical outcomes associated with different treatment pathways for hypertension in the Russian setting, with a particular focus on the effects of adherence with SPC versus multiple pill combinations.

The long-term effects of antihypertensive agents can be difficult to evaluate in real-world practice or clinical trials. A 10-year study enrolling thousands of people with hypertension is associated with substantial practical and financial challenges, as well as ethical implications of continuing use of regimens associated with poor adherence and, consequently, poor outcomes. In absence of long-term clinical trial data or real-world evidence assessing different antihypertensive agents, a microsimulation modeling approach was deemed the best way of evaluating the long-term effects of antihypertensive agents over 10 years. Computer simulation modeling can be a valuable tool for projecting health and economic outcomes for populations receiving different interventions, particularly when informed by the best available data.

The microsimulation approach has been previously utilized to estimate the long-term clinical outcomes of antihypertensive pathways in five different countries [15]. A microsimulation model was specifically developed by the Institute for Health Metrics and Evaluation (IHME) to leverage population health data generated from the Global Burden of Disease, Risk Factors, and Injuries (GBD) study, to project outcomes related to health intervention scenarios and provide decision-makers with guidance on how to optimize healthcare in the Russian setting2. For each simulation, the model was used to generate a population of simulated individuals based on age, gender and health characteristics (SBP, history of ischemic heart disease (IHD), intracerebral or subarachnoid hemorrhage (stroke), chronic kidney disease (CKD) and disability) from Russia-specific data from the GBD 2017. In the model, simulants were exposed to a risk of background mortality, and could transition between health states in the model based on probabilities of developing complications associated with each simulated patient’s risk factor profile. Transition probabilities for the model (based on rates of IHD incidence and excess mortality, CKD incidence and excess mortality, stroke incidence and excess mortality, and background mortality) were also derived from the GBD 2017. Simulants included non-hypertensive individuals, hypertensive but controlled individuals, and hypertensive not-controlled individuals, with hypertension defined as SBP >140 mm Hg in untreated individuals. Simulations were designed to evaluate patient-level clinical outcomes for individuals aged ≥40 years over 10 years (run in 28-day time steps) according to four different treatment pathways (see Modeled interventions). A 10-year time horizon was used to demonstrate sufficient differences in mortality, cardiovascular and renal outcomes between treatment pathways.

Clinical input data were primarily based on data from the GBD 2017, for which the analytic process has been previously described [18-20]. Utilized data included age and gender distributions, mortality rates, health status, SBP, rates of stroke, IHD, CKD and associated mortality, treatment attributes and healthcare services utilization rates. Transition probabilities between states in the model were also derived from the GBD 2017. Adherence was defined in terms of the percentage of patients who took medication for hypertension on ≥80% of the days they were prescribed, with different adherence rates for each treatment pathway based on published data (Table 1) [4][10][21]. Adherence values were included as annual probabilities, where zero would be complete non-adherence and 1 would be perfect adherence in the population each year.

Modeled treatments for simulated individuals were designed to capture a range of interventions, comprising both single and multiple drug combinations. Captured medication classes included angiotensin converting enzyme inhibitors (ACE-inhibitors), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), beta-blockers and diuretics.

Four different treatment pathways were modeled: current treatment practices (CTP) based on treatment pattern data from the GBD 2017, single drug with dosage titration first then sequential addition of other agents (start low and go slow, SLGS), free choice combination with multiple pills (FCC) and combination therapy in the form of a single pill (SPC). The four pathways are described in detail in Table 1.

Included clinical outcomes captured mean SBP of the treated population, percentage of patients with controlled blood pressure, percentage of patients who were adherent over the treatment period, all-cause mortality, and clinical events, which encompassed stroke events (ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage), IHD events (acute myocardial infarction, angina and heart failure), and CKD. Clinical events also comprised stroke-, IHD- and CKD-related mortality. Clinical outcomes were used to estimate disability-adjusted life years (DALYs), a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death3.

Compliance with ethics guidelines. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

SPC, FCC and SLGS were all projected to improve health outcomes compared with CTP over 10 years, with SPC therapy demonstrating the largest clinical benefits due to the greatest number of simulated individuals achieving blood pressure control (Figure 1). At population level, the average number of days taken to achieve blood pressure control after initiating treatment was also lowest with SPC, with patients achieving control after 827 days. Patients receiving CTP took an average of 833 days to achieve control, while patients receiving FCC and SLGS took an average of 856 and 1,031 days, respectively. Average SBP was lowest with SPC over the duration of the analysis, followed by FCC (Figure 2). CTP was associated with the highest average SBP after 10 years, but lower than SLGS for the first 4 years of the analysis (Figure 2). Reductions in SBP and time to achieve control with all treatment pathways, particularly initially, were mitigated by the addition of newly diagnosed but not yet treated simulated hypertensive individuals throughout the analysis.

Reductions in SBP led to reductions in clinical events in all pathways. The percentage of individuals experiencing a clinical event (stroke, IHD or CKD) was lowest with SPC (10.4%), followed by FCC (10.7%), SLGS (11.0%) and CTP (11.4%). SPC, FCC and SLGS were associated with reductions in the incidence of clinical events of 227, 164 and 99 events per 100,000 person-years, respectively, versus CTP. SPC, FCC and SLGS were therefore associated with reductions in the incidence of clinical events of 9.2%, 6.6% and 4.0%, respectively, versus CTP (Figure 3).

Mortality was also influenced by reductions in SBP and the incidence of clinical events. Mortality associated with clinical events was substantially reduced with SPC therapy, with 62 deaths averted per 100,000 person-years versus CTP. FCC and SLGS were also associated with reduced mortality, with 45 and 26 deaths averted per 100,000 person-years, respectively, versus CTP. Mortality was therefore projected to be 4.9%, 3.5% and 2.1% lower with SPC, FCC and SLGS, respectively, versus CTP (Figure 3).

Combining the incidence of clinical events and early mortality showed that SPC was associated with 1,193 DALYs averted per 100,000 person-years versus CTP. FCC and SLGS were associated with 834 and 476 DALYs averted per 100,000 person-years, respectively, versus CTP. Projected DALYs were therefore estimated to be 5.2%, 3.6% and 2.1% lower with SPC, FCC and SLGS, respectively, versus CTP (Figure 3). Consistently improved outcomes with SPC were due to the improved adherence, and consequent improved blood pressure, versus FCC, SLGS and CTP.

Based on long-term projections, SPC therapies are likely to improve clinical outcomes for people with hypertension versus CTP in Russia. SPC, FCC, and even SLGS regimens that are no longer recommended by current guidelines, are likely to improve blood pressure control versus CTP and thereby reduce the risk of adverse clinical events and associated DALYs and mortality. The high number of days to achieve blood pressure control following treatment initiation was due to new untreated patients continually entering the model over the course of the analysis — but this outcome was still lowest with SPC therapy.

Hypertension in Russia is responsible for a substantial proportion of the global clinical burden, with an estimated age-standardized prevalence of 44% and 33% of individuals living with blood pressure values ≥140/90 mm Hg [2]. However, with only 50% of patients who are prescribed antihypertensive therapy estimated to be achieving effective treatment, and only 25% of patients achieving blood pressure control, there is significant scope for improving health outcomes for hypertensive individuals in Russia [2]. The present analysis has shown that SPC and FCC were associated with the greatest improvements in SBP, with improved adherence a key driver of the projected clinical benefits, and a differentiating factor versus FCC. Adherence was highlighted as having a large scope for improvement in a recent Russian study that found adherence varied between 11-44% on the MMAS-4 scale, a widely used, generic, medication-taking behavior scale originally developed for individuals with hypertension [10][22]. With combination therapy often required in hypertensive individuals, and the benefits associated with blood pressure control, the present analysis has shown that therapies that can reduce the burden on patients by combining efficacious compounds in the form of a single pill (thereby improving adherence) can have a marked impact on blood pressure control, incidence of complications and associated DALYs [3][8][9]. Use of SPC therapies could therefore decrease non-adherence and elucidate substantial clinical benefits for individuals with hypertension in Russia [1].

That acknowledged, improvements in adherence are possible beyond use of SPC that would further benefit populations with hypertension in Russia, and this unmet need should be the focus of future research in the country. Indeed, a 2020 systematic review of Russian studies indicated that the most effective ways to improve adherence are patient education and the use of medications in fixed combinations [22]. A recent population-based study in Russia also found that a high prevalence of untreated hypertension, particularly in men [23]. Moreover, a large proportion of untreated, hypertensive individuals were unaware of their condition. Recommended initiatives from this study included an annual general health check for individuals aged ≥40 years and extending healthcare professional hours to allow increased contact time with patients, as well as indicating that more effective strategies could be employed to better detect hypertensive individuals and improve adherence to antihypertensive therapies [24]. While developments in healthcare accessibility could help to improve diagnosis, SPC treatments could offer solutions to individuals with uncontrolled blood pressure due to adherence-related issues, and future studies should evaluate the impact of increased prescription of these medications to hypertensive populations in Russia.

Current treatment guidelines with Russia follow recommendations published by the ESC/ESH in 2018, which indicate SPC therapy as an essential therapy in non-frail and non-elderly individuals [11]. The present analysis has indicated that wider provision of SPC therapy would greatly improve health outcomes for people with hypertension in Russia. Even wider use of more traditional treatment strategies, such as SLGS or FCC, was shown to substantially improve health outcomes. These findings demonstrate the importance of appropriate prescription of medications and implementing methods to regularly evaluate and maintain adherence levels, as indicated in the ESC/ESH guidelines and shown by both the results of the present analysis and numerous published studies [3][8][9][11].

DALYs are a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death, and are a way of combining morbidity and mortality into a single outcome measure. For example, a person with a BMI <25 kg/m² has 1.04 fewer DALYs than a person with a BMI >30 kg/m², or a person receiving a kidney transplant is associated with 1.4 fewer DALYs compared with chronic dialysis [25][26]. Use of DALYs puts the findings of the present study into context and allows comparison across disease areas, demonstrating the magnitude of the clinical benefits associated with SPC therapy.

A previous publication has evaluated the long-term outcomes associated with different treatment strategies for hypertension in five countries, including Russia [15]. The present study aims to build on that analysis by illustrating and discussing outcomes specifically for the Russian setting, and to provide pertinent information for physicians, patients, and healthcare payers in the country, with novel data in the present analysis capturing the time to achieving blood pressure control and average SBP levels over time with the four evaluated treatment strategies. Discussing these results specifically for Russia, particularly given the large prevalence of hypertension and the unmet treatment need in the country, provides a better background for contextualizing outcomes in terms of the improvements available to the hypertensive population in the Russian setting.

A limitation of the study was that the GBD 2017, as well as additional searches in the published literature, did not elucidate data relating to dosing for the CTP scenario, or precise adherence data for the different treatment regimens. Adherence in the analysis was also modeled as a binary outcome, which may not reflect clinical practice where patients can have varying levels of adherence. However, data limitations are often inherent in all modeling analyses, and in absence of long-term clinical trial data (which are often highly costly and associated with substantial ethical dilemmas such as non-intensification of poorly controlled individuals), modeling studies arguably represent the best basis for decision making by healthcare payers and professionals.

Based on long-term projections, the present analysis indicates that combination therapies (including SPC and FCC) are likely to reduce the burden of hypertension compared with conventional treatment options in Russia. Improved adherence was the key driver of benefits, with SPC therapies associated with the greatest overall benefits in terms of improving SBP and reducing clinical events, DALYs and mortality compared with other treatment pathways.

Acknowledgements. Data extraction and the modeling analysis was performed by the institute for health metrics and evaluation at the University of Washington and supported by funding from Sanofi. Medical writing support was provided by William Valentine and Samuel Malkin at Ossian health economics and communications GMBH (Basel, Switzerland), supported by funding from Sanofi.

The authors would like to thank Daniela Deroche-Chidebi at Sanofi for her support throughout the project.

Relationships and Activities: none.

1. World Health Organization. Hypertension Fact Sheet, September 13, 2019. Available at: https://www.who.int/news-room/fact-sheets/detail/hypertension. Accessed on March 20, 2020. 2. Institute for Health Metrics and Evaluation Global Burden of Disease (GBD) 2017. Available at: http://www.healthdata.org/gbd/gbd-2017-resources. Accessed on March 20, 2020. 3. World Health Organization: Health statistics and information systems. Available at: https://www.who.int/healthinfo/global_burden_disease/metrics_daly/en/. Accessed on April 9, 2020.