Key Points
Question
What is the potential number of lives saved with optimal implementation of quadruple guideline-directed medical therapy (GDMT) on a global level?
Findings
Globally, an estimated 1.19 million deaths (95% CI, 0.77 million to 1.91 million) per year could be prevented with optimization of GDMT, with more than 1 million lives saved in the Eastern Mediterranean and African, Southeast Asian, and Western Pacific regions combined.
Meaning
Improving utilization of GDMT could lead to considerable mortality benefits on a global level. Even partial improvements in the use of GDMT has the potential to result in a substantial number of lives saved.
Abstract
Importance
Guideline-directed medical therapy (GDMT) remains underutilized on a global level, with significant disparities in access to treatment worldwide. The potential global benefits of quadruple therapy on patients with heart failure with reduced ejection fraction (HFrEF) have not yet been estimated.
Objective
To assess the projected population-level benefit of optimal GDMT use globally among patients with HFrEF.
Design, Setting, and Participants
Estimates for HFrEF prevalence, contraindications to GDMT, treatment rates, and the number needed to treat for all-cause mortality at 12 months were derived from previously published sources. Potential lives saved from optimal implementation of quadruple therapy among patients with HFrEF was calculated globally and a sensitivity analysis was conducted to account for uncertainty in the existing data.
Main Outcomes and Measures
All-cause mortality.
Results
Of an estimated 28.89 million people with HFrEF worldwide, there were 8 235 063 (95% CI, 6 296 020-10 762 972) potentially eligible for but not receiving β-blockers, 20 387 000 (95% CI, 15 867 004-26 184 996) eligible for but not receiving angiotensin receptor–neprilysin inhibitors, 12 223 700 (95% CI, 9 376 895-15 924 973) eligible for but not receiving mineralocorticoid receptor antagonists, and 21 229 170 (95% CI, 16 537 400-27 242 688) eligible for but not receiving sodium glucose cotransporter-2 inhibitors. Optimal implementation of quadruple GDMT could potentially prevent 1 188 277 (95% CI, 767 933-1 914 561) deaths over 12 months. A large proportion of deaths averted were projected in Southeast Asia, Eastern Mediterranean and Africa, and the Western Pacific regions.
Conclusions and Relevance
Improvement in use of GDMT could result in substantial mortality benefits on a global scale. Significant heterogeneity also exists across regions, which warrants additional study with interventions tailored to country-level differences for optimization of GDMT worldwide.
This study examines the projected population-level benefit of optimal guideline-directed medical therapy use globally among patients with heart failure with reduced ejection fraction.
Introduction
Guideline-directed medical therapy (GDMT) remains underutilized globally, despite data demonstrating its efficacy and mortality benefits, with numbers needed to treat ranging from 28 to 80 in just 1 year.1 Although prior studies have estimated mortality benefits for individual components of GDMT, nearly all studies have focused on the US.2,3,4 The projected benefits of global optimization of GDMT remain unknown, despite lower- and middle-income countries experiencing increasing rates of heart failure, contributing to significant morbidity and mortality as well as increasing health care costs.5
Methods
All data were obtained from previously published sources (eTable 1 in Supplement 1). The number of patients eligible for GDMT therapy was calculated based on estimates of heart failure prevalence from the Global Burden of Disease study.6 Patients with an ejection fraction of less than 40% were included, while patients with New York Heart Association class I heart failure and those receiving hospice, comfort care, or advanced therapies were excluded. Due to the limited availability of global data, previously reported US estimates were used to determine the number of patients receiving hospice and comfort care and those receiving advanced therapies.7 The proportion of patients with contraindications to GDMT were also estimated from US registries and applied globally.8 Treatment rates by modified World Health Organization region were obtained from the REPORT-HF registry for evidence-based β-blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs).9 Data for angiotensin receptor-neprilysin inhibitors (ARNIs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) were estimated using a multinational cohort from Sweden, Japan, and the US as well as a separate US registry data.10,11
Estimates for the number of treated and untreated patients as well as potential lives saved were calculated based on methods previously described.2,3,4 The number needed to treat, which was standardized to 1 year and previously derived from large clinical trial data, is shown in eTable 2 in Supplement 1 and was used to calculate the projected number of lives saved for each component of GDMT. For ARNIs, the estimated benefit was calculated based on a scenario in which all patients were prescribed an ARNI and those already receiving an ACEI/ARB were subsequently switched to an ARNI. A multilevel sensitivity analysis was performed using the analysis-of-extremes method to determine the 95% CI for the estimated number of lives saved as previously described (eMethods in Supplement 1).12 The mortality benefits resulting from implementation of successive therapies were considered to be fully additive, consistent with findings of prior cross trial comparative analyses.13 The projected number of lives saved for each GDMT component as well as quadruple therapy were displayed using a heat map based on countries with available data in the REPORT-HF registry.9 All analyses, including creation of heat maps, were performed using Stata version 18.0 (StataCorp).
Results
There are 29 million people estimated to have HFrEF globally, largely concentrated in the Eastern Mediterranean and African, Southeast Asian, and the Western Pacific regions (Table 1). A total of 13.7% to 25.8% of patients were excluded due to contraindications or intolerance to the individual components of quadruple GDMT therapy based on previously published data. Across all regions, rates of β-blocker prescriptions were the highest, followed by ACEI/ARB and then MRA. SGLT2i and ARNI use was low, at approximately 9.4% and 10.9%, respectively. North America and Western Europe had the highest rates of β-blocker use, whereas Southeast Asia and the Western Pacific had the lowest rates (eFigure in Supplement 1). North America had comparatively low rates of ACEI/ARB and MRA use, while Eastern Europe had the highest rates globally. Table 2 shows the number of eligible patients not receiving GDMT. Globally, this number ranged from roughly 8.24 million for β-blockers to 21.23 million for SGLT2is.
Table 1. Projected Global HFrEF Prevalence and Eligible Patients for Guideline-Directed Medical Therapies.
| Outcome | No. (95% CI) | |||||||
|---|---|---|---|---|---|---|---|---|
| Global | Central and South America | Eastern Europe | Eastern Mediterranean and Africa | North America | Southeast Asia | Western Europe | Western Pacific | |
| HFrEF prevalence | 28 886 010 (22 859 744-36 496 076) | 1 799 747 (1 261 566-2 543 190) | 728 227 (526 963-988 277) | 7 149 210 (5 117 480-9 821 189) | 2 364 600 (1 739 513-3 163 141) | 6 932 491 (4 966 721-9 719 644) | 1 390 100 (1 085 157-1 758 448) | 8 327 453 (5 802 678-11 852 419) |
| Treatment rates | ||||||||
| β-Blocker | 0.67 (0.66-0.68) | 0.67 (0.65-0.69) | 0.76 (0.74-0.78) | 0.68 (0.66-0.70) | 0.78 (0.76-0.80) | 0.47 (0.45-0.49) | 0.78 (0.77-0.79) | 0.57 (0.55-0.59) |
| ACEI/ARB | 0.59 (0.58-0.60) | 0.61 (0.59-0.63) | 0.69 (0.67-0.71) | 0.63 (0.61-0.65) | 0.53 (0.50-0.56) | 0.44 (0.42-0.46) | 0.64 (0.62-0.66) | 0.55 (0.53-0.57) |
| ARNI | 0.109 (0.108-0.110) | 0.109 (0.108-0.110) | 0.109 (0.108-0.110) | 0.109 (0.108-0.110) | 0.111 (0.109-0.113) | 0.109 (0.108-0.110) | 0.146 (0.142-0.150) | 0.100 (0.098-0.101) |
| MRA | 0.43 (0.42-0.44) | 0.45 (0.44-0.46) | 0.52 (0.50-0.54) | 0.32 (0.30-0.34) | 0.35 (0.32-0.38) | 0.27 (0.25-0.29) | 0.47 (0.45-0.49) | 0.50 (0.48-0.52) |
| SGLT2i | 0.094 (0.093-0.095) | 0.094 (0.093-0.095) | 0.094 (0.093-0.095) | 0.094 (0.093-0.095) | 0.202 (0.199-0.206) | 0.094 (0.093-0.095) | 0.208 (0.203-0.213) | 0.057 (0.056-0.058) |
| Patients eligible for GDMT therapies | ||||||||
| β-Blocker | 24 954 736 (19 515 526-31 901 246) | 1 526 762 (1 046 184-2 205 877) | 658 332 (469 143-907 004) | 6 077 060 (4 258 786-8 523 426) | 2 147 802 (1 543 833-2 938 941) | 5 904 178 (4 125 591-8 482 221) | 1 172 407 (895 012-1 515 813) | 7 229 634 (4 944 715-10 479 838) |
| ARNI | 22 877 834 (17 829 254-29 345 278) | 1 397 360 (953 123-2 027 768) | 605 972 (430 271-837 791) | 5 563 032 (3 881 290-7 835 609) | 1 977 787 (1 415 516-2 717 414) | 5 405 732 (3 759 215-7 801 516) | 1 072 459 (814 965-1 392 662) | 6 630 891 (4 516 675-9 649 765) |
| MRA | 21 445 088 (16 679 753-27 560 072) | 1 308 093 (889 686-1 903 367) | 569 852 (403 773-789 450) | 5 208 431 (3 623 958-7 355 205) | 1 860 503 (1 328 045-2 562 689) | 5 061 881 (3 509 464-7 326 078) | 1 003 510 (760 398-1 306 648) | 6 217 849 (4 224 888-9 070 004) |
| SGLT2i | 23 438 222 (18 280 624-30 040 704) | 1 432 275 (978 033-2 076 228) | 620 100 (440 676-856 623) | 5 701 726 (3 982 335-8 022 750) | 2 023 660 (1 449 863-2 777 687) | 5 540 223 (3 857 284-7 986 722) | 1 099 427 (836 391-1 426 169) | 6 792 443 (4 631 250-9 875 611) |
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter-2 inhibitor.
Table 2. Untreated Patients and Potential Lives Saved From Optimal Implementation of Guideline-Directed Medical Therapies.
| Outcome | No. (95% CI) | |||||||
|---|---|---|---|---|---|---|---|---|
| Global | Central and South America | Eastern Europe | Eastern Mediterranean and Africa | North America | Southeast Asia | Western Europe | Western Pacific | |
| Eligible patients not receiving GDMT | ||||||||
| β-Blocker | 8 235 063 (6 296 020-10 762 972) | 503 831 (324 150-772 409) | 158 000 (104 705-232 933) | 1 944 659 (1 267 700-2 917 851) | 472 516 (305 591-711 391) | 3 129 214 (2 095 589-4 682 619) | 257 929 (183 607-355 998) | 3 108 743 (2 036 225-4 697 083) |
| ARNI | 20 387 000 (15 867 004-26 184 996) | 1 245 222 (848 225-1 809 391) | 539 997 (382 916-747 567) | 4 957 354 (3 454 123-6 991 769) | 1 758 337 (1 255 826-2 420 941) | 4 817 181 (3 345 484-6 961 347) | 915 860 (692 493-1 195 242) | 5 970 515 (4 059 510-8 704 431) |
| MRA | 12 223 700 (9 376 895-15 924 973) | 719 451 (483 369-1 059 599) | 273 529 (185 870-394 462) | 3 541 733 (2 385 999-5 160 443) | 1 209 327 (829 313-1 731 195) | 3 695 173 (2 492 860-5 492 178) | 531 860 (389 435-715 852) | 3 108 925 (2 034 170-4 703 041) |
| SGLT2i | 21 229 170 (16 537 400-27 242 688) | 1 297 283 (884 769-1 882 846) | 561 656 (398 653-776 836) | 5 164 339 (3 602 584-7 275 504) | 1 614 496 (1 151 580-2 225 904) | 5 018 057 (3 489 457-7 242 832) | 871 035 (658 549-1 136 882) | 6 404 275 (4 360 749-9 323 699) |
| Potential lives saved | ||||||||
| β-Blocker | 294 109 (187 382-480 490) | 17 994 (9647-34 483) | 5643 (3116-10 399) | 69 452 (37 729-130 261) | 16 876 (9095-31 759) | 111 758 (62 369-209 046) | 9212 (5464-15 893) | 111 027 (60 602-209 691) |
| ARNI | 350 016 (229 361-556 148) | 20 993 (12 187-37 267) | 8434 (5092-14 279) | 82 036 (48 702-141 392) | 31 790 (19 453-53 179) | 93 907 (55 461-166 166) | 14 619 (9495-23 121) | 106 733 (61 697-190 591) |
| MRA | 207 181 (132 442-337 394) | 12 194 (6827-22 449) | 4636 (2625-8357) | 60 029 (33 701-109 331) | 20 497 (11 713-36 678) | 62 630 (35 210-116 360) | 9015 (5500-15 166) | 52 694 (28 731-99 641) |
| SGLT2i | 336 971 (218 749-540 530) | 20 592 (11 703-37 358) | 8915 (5273-15 413) | 81 974 (47 653-144 355) | 25 627 (15 233-44 165) | 79 652 (46 157-143 707) | 13 826 (8711-22 557) | 101 655 (57 682-184 994) |
| Total | 1 188 277 (767 933-1 914 561) | 71 772 (40 365-131 557) | 27 628 (16 107-48 448) | 293 491 (167 785-525 340) | 94 789 (55 494-165 780) | 347 946 (199 197-635 278) | 46 671 (29 170-76 738) | 372 108 (208 712-684 917) |
Abbreviations: ARNI, angiotensin receptor–neprilysin inhibitor; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter-2 inhibitor.
Optimal implementation of quadruple GDMT therapy globally resulted in an estimated 1 188 277 (95% CI, 767 933-1 914 561) lives saved in 12 months, with a large contribution from prevention of cardiovascular mortality (eTable 3 in Supplement 1). Benefits were seen in Southeast Asia and the Western Pacific, with 720 054 deaths averted combined, as well as in the Eastern Mediterranean and African region, with 293 491 lives saved with optimal GDMT (Figure). Notably, ARNIs and SGLT2i accounted for the largest proportion of deaths averted, at 29.5% and 28.4%, respectively. Optimal use of β-blockers resulted in 24.8% of total lives saved globally and MRAs resulted in 17.4% of total lives saved globally.
Figure. Projected Deaths Averted.
Discussion
Optimal implementation of quadruple GDMT therapy would lead to a projected 1.19 million lives saved globally over the course of 1 year. Significant benefits would be achieved with GDMT optimization in Southeast Asia and the Western Pacific, as well as in Eastern Mediterranean and African countries. These differences are mostly driven by the fact that a large proportion of the global HFrEF population resides in these regions coupled with relatively low current treatment rates. These findings highlight the heterogeneity of GDMT treatment worldwide as well as the magnitude of potential deaths averted with improvements in GDMT utilization.
Although this study demonstrates the substantial benefits of optimal GDMT use in reduction of heart failure mortality worldwide, there remains significant challenges to implementation in real-world practice, including patient hesitancy, provider inertia, and systemic factors such as health care access and cost of care.14 Significant disparities have also been reported in low- and middle-income countries given inequities in access to diagnostic tools and therapies. In particular, use of GDMT may be limited given lack of availability and affordability with previous reports, suggesting that β-blockers may only be used in one-third of patients in low- and middle-income countries.5 Efforts toward reducing barriers to the administration of these beneficial drugs are needed. This includes addressing the social determinants of health that create disparities in quality health care, more universal coverage for life-enhancing therapies, development of polypills, and earlier implementation of treatments.
This study is limited by the scarcity of available data globally on GDMT eligibility and treatment. The majority of the data on treatment rates were derived from the REPORT-HF registry, which included 44 countries across 6 continents.9 Notably, only 5 countries in Africa were included: Algeria, Egypt, Morocco, South Africa, and Tunisia. Estimates on GDMT contraindications were also derived from US data and applied globally. Additionally, data on use of ARNIs and SGLT2i were estimated from the Get With the Guidelines-Heart Failure and EVOLUTION-HF registries, which only include data from the US, Sweden, and Japan and may overestimate or underestimate the true level of utilization. As a result, the benefits of optimal ARNI and SGLT2i treatment may be different than estimated here. Relative risk reductions were also based on the tolerability and adherence achieved in key clinical trials, although they have been previously shown to be similar to results found in large meta-analyses.2 In light of these limitations, a multilevel sensitivity analysis was performed to produce 95% CIs that may account for some of the uncertainty in the available data.
Conclusions
This study highlights significant population-level mortality benefits with optimization of GDMT quadruple therapy on a global level and provides insights on regional differences that may better inform worldwide efforts for heart failure management. Although future studies are needed to better understand the heterogeneity that exists within each region and potential interventions targeted to different settings, these findings demonstrate the urgent need for improved implementation of GDMT therapies worldwide.
Supplemental Methods
eTable 1. Data Sources
eTable 2. NNT
eTable 3. Cardiovascular Mortality
eFigure 1. Treatment Rates
eReferences
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Methods
eTable 1. Data Sources
eTable 2. NNT
eTable 3. Cardiovascular Mortality
eFigure 1. Treatment Rates
eReferences
Data sharing statement