Characterizing Dual Combination Therapy Use in Treatment Escalation of Hypertension: Real-World Evidence from Multinational Cohorts

Background: Over one billion adults have hypertension globally, of whom 70% cannot achieve hypertension control goal with monotherapy alone. Data are lacking on patterns of dual combination therapies prescribed to patients who escalate from monotherapy. Methods: Using eleven electronic health record databases that 118 million patients across eight countries/regions, we characterized the initiation of antihypertensive dual combination therapies for patients with hypertension. In each database, we first constructed cohorts of patients who newly initiate dual combination therapy of the four most commonly used antihypertensive drug classes (angiotensin-converting enzyme inhibitor [ACEi] or angiotensin receptor blocker [ARB]; calcium channel blocker [CCB]; beta-blocker; and thiazide diuretic) after escalating from monotherapy, and then described treatment utilization using these cohorts. Findings: We identified 980,648 patients with hypertension who newly initiated dual combination therapy: 12,541 from Australia, 6,980 from South Korea, 2,096 from Singapore, 7,008 from China, 16,663 from Taiwan, 103,994 from France, 76,082 from Italy, and 754,137 from the United States (US). Significant variations in treatment utilization existed across databases and patient subgroups. In Australia and Singapore databases, starting an ACEi/ARB monotherapy followed by a CCB was most common while in South Korea, China and Taiwan databases, starting a CCB monotherapy followed by an ACEi/ARB was most common. In Italy, France, and US databases, sequential use of an ACEi/ARB monotherapy followed by a diuretic was most common. Younger patients were more likely to be prescribed ACEi/ARB then a CCB or a diuretic compared with older patients. Women were more likely to be prescribed diuretics then an ACEi/ARB or a CCB compared with men. Interpretation: Large variation in the transition between monotherapy and dual combination therapy for hypertension was observed across countries and by demographic groups. These results highlight the need for future research to identify which dual combination therapy is most effective in practice. Funding: This study was supported by the National Research Foundation Singapore under its AI Singapore Programme (Award Number: AISG-GC-2019-002), National Medical Research Council (NMRC) under the Open Fund - Large Collaborative Grant (OF-LCG) - NMRC/OFLCG/001/2017 and Center Grant (CG) schemes - NMRC/CG/C016/2017, the Bio Industrial Strategic Technology Development Program (20003883, 20005021), the Ministry of Trade, Industry & Energy (MOTIE, Korea), a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), the Ministry of Health &Welfare, Republic of Korea (grant number: HR16C0001), the Australian Government National Health and Medical Research Council (NHMRC Grant Number: APP1192469). Declaration of Interest: JL, XW, CR MVZ are employees of IQVIA. YL reports grants from the National Heart, Lung, and Blood Institute (K12HL138037) and the Yale Center for Implementation Science. She was a recipient of a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion. HMK received expenses and/or personal fees from UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, the Siegfried and Jensen Law Firm, Arnold and Porter Law Firm, Martin/Baughman Law Firm, F-Prime, and the National Center for Cardiovascular Diseases in Beijing. He was a co-founder of Refactor Health and HugoHealth and had grants and/or contracts from the Centers for Medicare & Medicaid Services, Medtronic, the U.S. Food and Drug Administration, Johnson & Johnson, and the Shenzhen Center for Health Information. MAS reports grants from US National Science Foundation, grants from US National Institutes of Health, grants from the US Department of Veterans Affairs, grants from IQVIA, and personal fees from Janssen Research & Development and Private Health Management. SCY reports grants from Korean Ministry of Health & Welfare, grants from Korean Ministry of Trade, Industry & Energy. RWP reports grants from Korean Ministry of Health & Welfare, grants from Korean Ministry of Trade, Industry & Energy. The other co-authors report no potential competing interests. Ethical Approval: Use of TMUCRD data has been approved by theTMU-Joint Institutional Review Board (Project number: TMU-JIRB N202011003).