Global Heterogeneity Observed In Dual Combination Therapy for Hypertension

March 24, 2022
Connor Iapoce

Connor Iapoce is an associate editor for HCPLive and joined the MJH Life Sciences team in April 2021. He graduated from The College of New Jersey with a degree in Journalism and Professional Writing. He enjoys listening to records, going to concerts, and playing with his cat Squish. You can reach him at

Large variations were observed in the transition between monotherapy and dual combination therapy for hypertension across countries and demographic group.

A significant variation in the transition between monotherapy and dual combination therapy for hypertension across countries and by demographic group was observed in a recent cohort study.

Investigators noted that since current guidelines do not provide recommendations for the preferred choice of a second agent added to monotherapy as a result of a lack of data from randomized controlled trials, this large variation may be due to a trial-and-error approach.

“The heterogeneity of treatment pathways of hypertension across data sources and countries reflects the failure of the field to converge on an effective and consistent treatment-escalation algorithm for hypertension,” wrote study author Hua Xu, PhD, University of Texas Health Science Center at Houston. “It is plausible that not all combination therapies have the same risks and benefits.”

From 11 electronic health record (EHR) databases, the study consisted of adult patients with prior antihypertensive monotherapy who newly initiated escalated treatment with 1 of 56 drug ingredients that constituted 4 major drug classes from 2000 - 2019.

The 4 drug classes included:

  • angiotensin-converting enzyme inhibitor [ACEI] or angiotensin receptor blocker [ARB]
  • calcium channel blocker [CCB]
  • Β-blocker
  • thiazide or thiazide-like diuretic

A total of 970,335 patients with hypertension who newly initiated dual combinations of antihypertensive agents after escalating from monotherapy were included in the final analysis. This included 11,494 patients from Australia, 6890 patients from South Korea, 2096 patients from Singapore, 7008 patients from China, 8544 patients from Taiwan, 103,994 patients from France, 76,082 patients from Italy, and 754,137 patients from the US.

The mean age of patients varied across data sources, ranging from 57.6 years in China to 67.7 years in Singapore and the proportion of patients by sex ranged from 24,358 (36.9%) women in Italy to 408,964 (54.3%) women in the US.

Investigators observed significant variation in use across countries and patient subgroups across 12 dual combinations of antihypertensive drug classes commonly used.

Starting an ACEI or ARB monotherapy followed by a CCB (ACEI or ARB + CCB) was the most commonly prescribed combination in Australia (698 patients in ePBRN SWSLHD [31.7%] and 3842 patients in Australia LPD [41.4%]), as well as Singapore (216 patients in KTPH [25.7%] and 439 patients in NUH [35.0%]).

In Western countries, the proportion of patients treated with ACEI or ARB + diuretic ranged from 123,940 patients (16.4%) in the US to 508 patients (23.1%) in Australia.

Further, among Western countries, the proportion of patients treated with CCB + ACEI or ARB ranged from 54,297 patients in the US (7.2%) to 15,749 patients in France (15.1%), while the proportion among Asian countries ranged from 133 patients in Singapore (10.6%) to 3312 patients in China (47.3%).

Additionally, investigators observed the distribution of 12 dual combination therapies were significantly different by age and sex in almost all databases.

They highlighted the use of ACEI or ARB + CCB varied from 873 of 3737 patients ages 18 to 64 years (23.4%) to 343 of 2292 patients aged 65 years or older (15.0%) in the South Korea Ajou University database.

Moreover, the use of ACEI or ARB + CCB varied from 2121 of 4718 (44.8%) men to 1721 of 4549 (37.7%) women in Australian LPD (P for drug combination distributions by sex < .001).

Investigators additionally observed the treatment patterns of dual combination therapies were significantly different by history of CVD in all databases (P <.001). The US database howed the proportion of patients receiving ACEI or ARB + β-blocker was 37,663 of 169,687 patients with a history of CVD (22.2%) and 72,916 of 584,450 patients without a history of CVD (12.5%).

The study, “Analysis of Dual Combination Therapies Used in Treatment of Hypertension in a Multinational Cohort,” was published in JAMA Network Open.