Objective The purpose of this study is to describe recent mortality trends from aortic stenosis (AS) among eight high-income countries.
Methods We analysed the WHO mortality database to determine trends in mortality from AS in the UK, Germany, France, Italy, Japan, Australia, the USA and Canada from 2000 to 2020. Crude and age-standardised mortality rates per 100 000 persons were calculated. We calculated age-specific mortality rates in three groups (<64, 65–79 and ≥80 years). Annual percentage change was analysed using joinpoint regression.
Results During the observation period, the crude mortality rates per 100 000 persons increased in all the eight countries (from 3.47 to 5.87 in the UK, from 2.98 to 8.93 in Germany, from 3.84 to 5.52 in France, from 1.97 to 4.33 in Italy, from 1.12 to 5.49 in Japan, from 2.14 to 3.38 in Australia, from 3.58 to 4.22 in the USA and from 2.12 to 5.00 in Canada). In joinpoint regression of age-standardised mortality rates, trend changes towards a decrease were observed in Germany after 2012 (−1.2%, p=0.015), Australia after 2011 (−1.9%, p=0.005) and the USA after 2014 (−3.1%, p<0.001). Age-specific mortality rates in age group ≥80 years had shifts towards decreasing trends in all the eight countries in contrast to other younger age groups.
Conclusions While crude mortality rates increased in the eight countries, shifts towards decreasing trends were identified in age-standardised mortality rates in three countries and in the elderly aged ≥80 years in the eight countries. Further multidimensional observation is warranted to clarify the mortality trends.
- aortic stenosis
- global health
Data availability statement
Data are available in a public, open access repository. Processed data are available upon reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Aortic stenosis (AS) is a critical disease without structural treatment. The annual number of patients undergoing surgical or transcatheter treatment is increasing, and reports suggest that surgical and interventional outcomes are improving over time; however, the impact of these improvements on overall mortality trends from AS across countries remains unclear.
WHAT THIS STUDY ADDS
While crude mortality rates of AS increased in eight studied countries (G7 plus Australia) during the two decades, age-standardised mortality rates were converted to decreasing trends in Germany from 2012, Australia from 2011 and the USA from 2014. All the eight countries had shifts towards decreasing trends in the age group of ≥80 years during the observation period.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These findings provide evidence of national impacts which may be associated with treatment progress for AS. Further multidimensional observation is warranted to clarify the relationship between mortality trends and treatment progress.
Aortic stenosis (AS) is the most common type of valvular heart disease referred for treatment in industrialised countries.1 2 Epidemiological data on AS from the USA and Europe estimates a prevalence of approximately 2% in patients between 70 years and 80 years of age, with a significant association with increasing age.3 AS most commonly develops as a result of degenerative remodelling of a normal tricuspid aortic valve.1 3 Other risk factors for AS include a bicuspid valve or other congenital abnormalities, in addition to rheumatic heart disease, although this is relatively rare in industrialised countries.2 With an ageing population across many industrialised countries, the burden of AS is projected to increase.4
In symptomatic patients, average survival with severe AS without treatment is approximately 2 years, with a 1-year mortality rate as high as 50%.5–7 Aortic valve replacement (AVR) is the standard of care in these patients and traditionally has been performed through open heart surgery.1 Over the past two decades, transcatheter aortic valve implantation (TAVI) has emerged as a less invasive treatment option for AS, especially in these patients who may be poor candidates for surgical aortic valve replacement (SAVR) due to advanced age or additional comorbidities.8 9 Guidelines about which patients should be referred for TAVI as opposed to SAVR vary between industrialised countries and have evolved over time.8 10
There is an increasing annual number of patients undergoing surgical/transcatheter AVR, and surgical/interventional outcomes have been reported to be improving over time11 12; however, the impact of these improvements on overall mortality trends from AS across countries remains unclear. The purpose of this study is to describe temporal mortality trends from AS among eight high-income countries (the UK, the USA, Canada, Germany, France, Italy, Japan and Australia). We hypothesised that mortality outcomes would be improved over time as surgical and procedural techniques evolved, with a particular improvement in patients with advanced age (≥80 years old) with the emergence of TAVI over the past two decades.
Material and methods
The WHO Mortality Database13 receives official national statistics directly from the competent authorities of the contributing countries. Deaths in the database are recorded with underlying cause of death, which is defined as the disease which initiated the train of morbid events leading directly to death, according to the International Classification of Diseases. This database has been widely used for epidemiological research on variety of diseases, including cardiothoracic diseases.14 15 We identified trends in mortality from AS from 2000 onward. International Classification of Diseases, 10th Revision, codes were used to determine the cause of death (I350 for non-rheumatic AS). Data on the age distribution of the countries’ populations at midyear were obtained from the United Nations World Population Prospects 2019.16 Patients or the public were not involved in the design, conduct, reporting or dissemination plans of our research.
Crude mortality rates were calculated by dividing the number of deaths from AS by the number of persons in a country. Age-specific mortality rates were calculated by dividing the number of deaths by the number of persons in each age group (≤64, 65–79 and ≥80 years). The number of deaths were categorised into the same age groups and summarised in figures. The proportion of deaths in those aged ≥80 years within the entire number of deaths in the first and last observation years were compared using χ2 tests. Using the WHO World Standard Population,17 we estimated age-standardised mortality rates with 95% CIs by using formulas developed by Tiwari et al.18 We conducted joinpoint regression analysis to assess trends of age-specific and age-standardised mortality rates by estimating average annual percentage change (APC) at country levels.19 Monte Carlo permutation method with 4499 randomly permuted data sets was used to identify an optimal joinpoint model with its 95% CIs. The average APC and its 95% CIs were computed as a weighted average of APC from the joinpoint model. The trend was considered significantly increasing or decreasing when both limits of the 95% CI of an average APC were both positive or negative. Years with missing data were excluded from the analysis. Statistical analyses were performed using the Stata V.17 statistical software and Joinpoint Regression Program (Statistical Research and Applications Branch, National Cancer Institute, Maryland, USA). A p value of <0.05 was considered statistically significant.
Number of deaths and age groups
The mortality data were analysed from 2001 to 2019 in the UK, from 2000 to 2020 in Germany and Australia, from 2000 to 2016 in France, from 2003 to 2017 in Italy, and from 2000 to 2019 in Japan, the USA and Canada based on the availability. The number of deaths from AS increased in all the eight countries during the observation period (from 2049 to 3963 in UK, from 2429 to 7486 in Germany, from 2267 to 3571 in France, from 1134 to 2625 in Italy, from 1430 to 6971 in Japan, from 406 to 862 in Australia, from 10 088 to 13 876 in the USA and from 650 to 1870 in Canada), which were mainly from the increase in the mortality in the age group of ≥80 years (figure 1 and online supplemental table S1). The proportion of deaths in ≥80 years was significantly increased in all the eight countries (p<0.0001).
Crude mortality rates
Crude mortality rates per 100 000 persons in the most recent year are summarised in table 1. Crude mortality rates of AS was lowest in Australia and highest in Germany in the last observation year. During the observation period, the crude mortality rates per 100 000 persons increased in all the eight countries (from 3.47 to 5.87 in the UK, from 2.98 to 8.93 in Germany, from 3.84 to 5.52 in France, from 1.97 to 4.33 in Italy, from 1.12 to 5.49 in Japan, from 2.14 to 3.38 in Australia, from 3.58 to 4.22 in the USA and from 2.12 to 5.00 in Canada) (figure 2). The average APC of crude mortality rate in joinpoint regression showed significantly increasing trends in all the countries except for Australia, whose average APC indicated a constant trend.
Age-standardised mortality rates
Age-standardised mortality rates, average APC and fitted trend lines of joinpoint regressions are summarised in table 1 and figure 2. In the last observation year, Japan had the lowest age-standardised mortality rate, while Germany had the highest (figure 3). Overall age-standardised mortality rates during the observation period were significantly increasing trends in UK, Germany, Italy, Japan and Canada (p<0.001) and constant trends in France, Australia and the USA (table 1). In joinpoint regression, age-standardised mortality rates were converted to decreasing trends in Germany from 2012, in Australia from 2011 and in the USA from 2014 (table 2). In the UK from 2015 and in Canada from 2015, the age-standardised mortality rates were converted to constant from increasing trends. In Japan, the increasing trends of the age-standardised mortality rates were attenuated after 2011.
Age-specific mortality rates
Age-specific mortality rates of AS per 100 000 persons in each age group in the eight countries and their trends are summarised in table 3, figure 4, online supplemental tables S2–S4 and online supplemental figures S1 and S2. The overall age-specific mortality trends in those aged ≤64 years were significantly decreasing in France and Australia, while those in the USA were increasing. A change in trends in those aged ≤64 years was not found except for the UK and Germany. The overall age-specific mortality trends in 65–79 years were decreasing in France and the USA, while those in Germany and Japan were increasing. In Germany from 2013 and in Australia from 2010, the age-specific mortality rates in 65–79 years were converted to decreasing trends. In contrast to the previous two age groups, no countries have decreasing overall trends of age-specific mortality rates in ≥80 years; however, the rates were converted to decreasing trends in Germany from 2013, in Australia from 2017 and in the USA from 2014. The age-specific mortality rates in ≥80 years were converted from increasing trends to constant trends in the UK from 2015, in France from 2010, in Italy from 2011 and in Canada from 2015. In Japan, the increasing trends of the age-specific mortality rates in ≥80 years were attenuated after 2011.
In this study, we demonstrated the recent trends in crude, age-standardised and age-specific mortality from AS in the eight high-income countries. Crude mortality rates of AS demonstrated increasing trends in the UK, Germany, France, Italy, Japan, the USA and Canada over the past decades, and after age standardisation, these increasing trends persisted in the UK, Germany, Italy, Japan and Canada. Age-standardised mortality rates were converted to decreasing trends in Germany from 2012 (−1.2%, p=0.015), Australia from 2011 (−1.9%, p=0.005) and the USA from 2014 (−3.1%, p<0.001). In contrast to that of the other age groups, no countries had decreasing overall trends in age-specific mortality rates of the age group of ≥80 years; however, all the eight countries had shifts towards decreasing trends during the observation period in this age group. Age-specific mortality rates in age ≥80 years were converted to decreasing trends in Germany, Australia and the USA and were converted from increasing trends to constant trends in the UK, France, Italy and Canada, and attenuated increasing trends were found in Japan.
AS is associated with a poor prognosis if it is left untreated, and the average survival in those with symptomatic AS may be as low as 2 years.1 Historically, SAVR was the only modality available for definitive treatment of patients with AS. While rates of postoperative complications and mortality have been improving over time even though the baseline risk and comorbidities of patients undergoing this procedure may be increasing,9 11 20 common reasons for conservative management of AS have been advanced age, comorbidities, dementia, frailty and prohibitive surgical risk,21 and the emergence of TAVI has extended therapeutic options to previously untreatable patients.
This analysis evaluated mortality trends across eight developed countries in four continents (the UK, the USA, Canada, Germany, France, Italy, Japan, and Australia). After TAVI first gained Conformité Européenne approval in 200722, approval by the Food and Drug Administration (FDA) in the USA was granted in 2011, and in Japan, TAVI has been available since 2013.8 23 Guidelines and eligibility around the world have continued to evolved with the emergence of trials in intermediate and low-risk patients with AS; in the USA for example, sequential FDA approval was granted for TAVI first for inoperable patients in 2011, followed by patients at high surgical risk, patients at intermediate surgical risk in 2016 and finally patients at low surgical risk in 2019.8 24 Thus, the use of TAVI has increased dramatically since the introduction.12 25–28 Other important factors which may engender regional differences in temporal trends of mortality in patients with AS include differences in population demographics, age distribution as well as comorbid conditions in addition to differences between national healthcare systems and funding models (single-payer compared with private insurance) which may alter coverage and availability of different types of interventional management.12 22 Additionally, the increasing prevalence of AS, which may be related to an increase in diagnosis, could also influence on AS mortality trends29 . Therefore, the adoption of a standardised approach to diagnosis and treatment (TAVI and SAVR) in the G7 countries and Australia may need to be further investigated through additional studies.
In this analysis, we stratified mortality trends in patients with AS based on age, which is a key criteria involved in procedural selection24 ; in those under 65 years of age, surgical procedures may include congenital cardiac operations and the Ross procedure30, in addition to mechanical (or bioprosthetic) SAVR. In those aged 65–79, bioprosthetic SAVR has been the mainstay of treatment, and TAVI is being recommended especially for those with short longevity. In patients with AS above 80 years of age, the past 20 years have been a period of major change with TAVI quickly becoming the standard of care10 . It was in this age range (≥80 years), compared with younger patients, where we observed shifts towards decreasing trends in mortality in all the eight countries, signalling improving care and survival in the oldest subgroups.
Limitations to this analysis include the following. The prevalence of comorbid factors which may influence mortality in patients with AS could not be determined and thus adjusted for based on the data available within the WHO database. Another limitation is the lack of information on treatment modality for patients; there was no data available on mortality rates according to treatment modality (conservative treatment vs SAVR vs TAVI). In addition, the degree of information bias in clinical and administrative processes may differ among countries, and within country over the study period. Improvements in diagnosis of AS may influence on increase in mortality rates, rather than an actual increase in the number of people dying from AS; however, the value of the study database has been appreciated widely in epidemiological research as it provides one of the best contemporary country-level estimates of disease burden.14 15 In some countries, recent observations were missing, which may have prevented us from detecting any recent trend changes. Lastly, mortality trends can be influenced by differences in base mortality rates, even though our goal is to present a descriptive analysis of the trends.
In conclusion, our review of WHO data suggests that while the overall trends in crude and age-standardised mortality rates of AS were increasing or remaining constant in the eight countries over the observation period, shifts towards decreasing trends were identified in the age group≥80 years. Given that different surgical and procedural treatment approaches may be required for each age group, further observation of AS mortality trends in each age group is warranted.
Data availability statement
Data are available in a public, open access repository. Processed data are available upon reasonable request.
Patient consent for publication
Ethics approval was deemed waived as all the data were anonymous and aggregated without any personal information.
We are thankful for the data publicly made available by WHO. We are solely responsible for the analyses, interpretations or conclusions of this publication.
Twitter @HibinoMDMPH, @AuneDagfinn, @BobbyYanagawa, @DLBHATTMD, @GuiAttizzaniMD, @MarcPPelletier, @SubodhVermaMD
Presented at Presented in the American Heart Association Scientific Sessions 2022, Chicago, November 6, 2022.
Contributors We confirmed that each of the authors listed in our manuscript contributed to the study with satisfying the criteria for the authorship. MH is responsible for the overall content as guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests SV holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals and the Toronto Knowledge Translation Working Group; he is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organisation. DLB discloses the following relationships: advisory board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences and Stasys; board of directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; chair: Inaugural Chair, American Heart Association Quality Oversight Committee; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, Rutgers University (for the NIH-funded MINT Trial); honoraria: American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim, AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor and associate editor), K2P (cochair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees), Wiley (steering committee); other: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), VA CART Research and Publications Committee (chair); patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital received any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, 89Bio; royalties: Elsevier (editor, Braunwald’s Heart Disease); site coinvestigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, Svelte, Vascular Solutions; Trustee: American College of Cardiology; unfunded research: FlowCo, Takeda.
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