Insights into treatment-resistant and refractory hypertension

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Refractory hypertension (RfH) is a high-risk hypertension phenotype that was previously classed alongside treatment-resistant hypertension (TRH) in studies. Dr Michael G. Buhnerkempe and Dr John Flack, from Southern Illinois University School of Medicine, aimed to identify the health outcomes of RfH patients using data from a chronic kidney disease cohort. It was found that RfH patients had a significantly greater risk of chronic kidney disease progression and cardiovascular events, but no increase in mortality rates when compared to TRH patients. Further studies are needed in other patient populations to support their findings.

Hypertension, or high blood pressure (measurement of >130/80mm Hg), affects nearly half of all Americans, which is approximately 108 million individuals. When your blood pressure is higher than normal, it can damage your heart and put you at risk of heart disease and stroke, which are the leading causes of death in the United States. In 2018, nearly half a million deaths in the US were attributed to hypertension, and only about 20% of individuals affected by hypertension have the condition under control.

Phenotypes of hypertension

Treatment-resistant hypertension (TRH) can be defined in two ways. Uncontrolled TRH is when an individual’s blood pressure is still high after treatment with three or more antihypertensives. Controlled TRH is when an individual’s blood pressure is normal after treatment with four or more antihypertensives. The National Institute for Health and Care Excellence (NICE) guidelines noted that the treatments should include an angiotensin-converting enzyme (ACE) inhibitor, which works by relaxing blood vessels; a calcium channel blocker, which widens blood vessels; and a diuretic, to remove excess water and salt from the body. All medication should be administered at a maximal or maximally tolerated level so is titrated (i.e. medication is started at a low dose and gradually raised until the maximum effective dose is achieved). At present, clinicians cannot predict TRH in individuals with high blood pressure at the time of increasing the dose of titrations. Therefore, understanding the risk factors is important to remain continually cautious and to determine treatment options for individuals with high risk factors.

Another type of TRH is called refractory hypertension (RfH). It is defined as uncontrolled blood pressure when taking five or more antihypertensive medications, including a diuretic. The prevalence of RfH differs across various sources of literature, from 3% to 31% of individuals originally diagnosed with TRH, and from 0.5% to 1.4% of the general population of treated hypertensive patients. As a separate observation of extreme hypertensive treatment failure, it is important to discern the prevalence, cause, and prognosis of TRH as separate from RfH.

“Health outcomes of individuals
with refractory hypertension alone have not been previously studied.”

The difference, however, between TRH and RfH is not fully understood, especially those differences pertaining to patients’ prognosis. Previous studies of TRH have included RfH patients within its definition. These studies identified that individuals who are treatment-resistant are associated with higher risks of mortality, kidney failure, and cardiovascular diseases, including stroke, myocardial infarction, and congestive heart failure, compared to non-resistant hypertension. Health outcomes of individuals with RfH alone have not been previously studied. In population studies, risk factors for RfH include individuals with obesity, diabetes, and chronic kidney disease. Black individuals are also more likely to have RfH.

High blood pressure affects nearly half of all Americans – around 108 million individiuals.

Difference between treatment-resistant and refractive hypertension

Dr Michael G. Buhnerkempe and Dr John Flack, from Southern Illinois University School of Medicine, evaluated the relationship between RfH and patient prognosis, especially with regards to renal and cardiovascular functions and mortality outcomes. Data from the Chronic Renal Insufficiency Cohort (CRIC) was used, as previous studies have correlated poor renal function with a higher prevalence of RfH.

CRIC is an ongoing, multicentre, prospective cohort study across the United States, established to examine the risk factors for the progression of chronic kidney disease and cardiovascular disease in patients with decreased renal function. After accounting for inclusion and exclusion criteria, data from 3,147 participants were analysed. This study, published in the journal Hypertension in 2021, is highly novel, as it is the first study to determine the long-term health impacts of RfH and to provide context for its diagnosis in comparison to TRH. Dr Buhnerkempe also aimed to provide corrected prognosis risk estimates as well as risk factors for patients with TRH, as previous studies included RfH patients in the inclusion criteria of participants.

Of the 3,147 participants, 1,005 (31.9%) had TRH and 136 (4.3%) had RfH. The higher prevalence of RfH individuals in this chronic kidney disease cohort compared to previous estimations in the general population (at 0.5% to 1.4%) can be attributed to chronic kidney disease patients being at higher risk of RfH. The figure of 4.3% is also more in line with estimates from hypertension specialty clinics, which report 2.7% to 9.5% individuals having RfH, because chronic kidney disease is a common comorbidity found in these patients.

The study focused on a chronic kidney disease population.

As expected, patients with TRH have poorer health outcomes compared to patients with responsive hypertension (non-TRH/RfH). Participants with TRH were more likely to have lower glomerular filtration rate (lower kidney function), higher BMI, higher cholesterol and reports of a history of diabetes, cardiovascular disease, stroke, congestive heart failure, atrial fibrillation, and chronic obstructive pulmonary disease. TRH participants were also more likely to be Black and older than responsive hypertensive participants. This supports previous hypotheses and longitudinal studies that have found similar correlations between increased cardiovascular, renal, and all-cause mortality in TRH patients.

“This study supports the proposition that RfH is a high-risk hypertension phenotype.”

After separating out RfH from TRH participants, it was observed that patients with RfH have a significantly greater risk of chronic kidney disease progression and cardiovascular events without an increase in mortality rates compared to patients with TRH. RfH participants were also more likely to be Black. This study supports the proposition that RfH is a high-risk hypertension phenotype. It also supports previous studies that identified Black individuals as being at greater risk of experiencing hypertension. This has implications for the prevention and management of RfH in Black communities and further highlights the racial disparities in hypertension rates and health outcomes.

Previous population studies had identified age, sex, BMI, albuminuria (presence of albumin protein in the blood), and diabetes to be significantly different between TRH and RfH individuals. The patient population in this study was restricted to individuals with chronic kidney disease, which may have introduced selection bias and eliminated some demographic and clinical characteristics that were found outside of chronic kidney disease populations.

The CRIC provides robust longitudinal data on long-term health outcomes for the different hypertension phenotypes.

Previous studies had also found that uncontrolled TRH is more analogous to RfH than controlled TRH because cardiovascular risk was greater in the former, with no significant difference in mortality rates between uncontrolled and controlled TRH. This mirrors the finding in this paper, and suggests caution should be applied when distinguishing between RfH and TRH.

There is a conjecture that hypertension severity lies on a strict continuum of blood pressure levels, because previous observations showed that individuals with RfH have significantly higher blood pressure levels than TRH patients. However, this study found similar risk profiles if hypertension, TRH, and RfH were defined using updated blood pressure guidelines of 130/80 mm Hg. Therefore, the specific blood pressure threshold does not impact the difference in prognosis between TRH and RfH, and other identifiers and risk factors should be considered instead. Blood pressure thresholds may only be able to identify individual outcome risks within hypertension phenotypes and not between phenotypes, such as TRH and RfH.

This study has several strengths. There was a large sample size of 3,147 participants. As RfH is a relatively rare phenotype of hypertension, a much larger sample size would be required in the general population to gather statistically significant data and analysis. The duration of follow-up in the CRIC is long, with participants conducting yearly visits for up to 10 years. This provides robust longitudinal data on long-term health outcomes for the different hypertension phenotypes. However, despite the large sample size, this study only focused on a chronic kidney disease population. Further studies on other patient populations are needed to support the findings in this paper.


In conclusion, it is important to identify individuals who are at high risk of developing RfH even though its prevalence is very rare, so clinicians can better monitor and mitigate other long-term risks by identifying alternative treatment strategies.

What other patient populations are you interested to study to determine the health outcomes of RfH patients?

We are interested in studying RfH in all patient populations to increase the value of this research across clinical settings. However, the association of RfH with co-morbid conditions like chronic kidney disease, obesity, or diabetes makes studying health outcomes in these specific populations especially important. By comparing across these populations we can observe how RfH interacts with co-morbid conditions to determine patient health risks. In addition, patients with secondary causes of hypertension, like sleep apnoea or primary aldosteronism, are at increased risk for TRH and RfH and are crucial to our understanding of the health outcomes associated with RfH.



  • Buhnerkempe, M. G., Prakash, V., Botchway, A., Adekola, B., et al. (2021). Adverse health outcomes associated with refractory and treatment-resistant hypertension in the chronic renal insufficiency cohort. Hypertension, 77, 72-81.
  • Buhnerkempe, M. G., Botchway, A., Prakash, V., Al-Akchar, M., et al. (2019). Prevalence of refractory hypertension in the United States from 1999 to 2014. Journal of Hypertension, 37 (9), 1797-1804. Available at: 10.1097/HJH.0000000000002103
  • Buhnerkempe, M. G., Botchway, A., Morales, C. E. N., Prakash, V., et al. (2018). Predicting the risk of apparent treatment-resistant hypertension: a longitudinal, cohort study in an urban hypertension referral clinic. Journal of the American Society of Hypertension, 12 (11), 809-817.
  • Centers for Disease Control and Prevention (CDC). (2020). High blood pressure. [online] CDC. Available at: [Accessed 26 June 2021].

Research Objectives

Dr Michael G. Buhnerkempe and Dr John Flack study refractory hypertension using data from a chronic kidney disease cohort.


The CRIC study, from which data for this study was taken, was funded under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases


  • Albert Botchway, PhD
  • Carlos E. Nolasco Morales, MD
  • Vivek Prakash, MS
  • Lowell Hedquist, BS
  • All CRIC study personnel and collaborators.


Michael Buhnerkempe, PhD, is a biostatistician whose research focuses on the development and application of cutting-edge statistical and mathematical tools to clinical data.

John Flack, MD, MPH is an Internal Medicine specialist as well as a practicing Hypertension Specialist who also is Chair of the department of Medicine at Southern Illinois University.

Center for Clinical Research
201 E. Madison, Springfield IL 62702

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