Should Race be Used as a Factor in Hypertensive Treatment?
The origin of Race-based Guidelines for Hypertension:
Race-based diagnosis and treatment in medicine has become an increasingly contentious topic in the past few years, from re-evaluating the use of race-modified GFR in calculating renal function to use of racial categorization in pulmonary function testing of lung function. In the above areas, poor study design and essentialist racist assumptions led to adoption and perpetuation of different scales for White and African American patients without a sound scientific basis. For instance, the initial studies suggesting that African Americans had higher Creatinine levels (and therefore lower GFR) were potentially confounded by the muscle mass of the patients in the sample, and thus, not related to race, but to class and occupation. The case of treating hypertension with different medications based on race is more contemporary, and relies on a more well-designed study.
The ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) was a double-blind study of over 30,000 patients comparing the effects of Chlorthalidone, Amlodipine, and Lisinopril over 4-8 years with the outcome measures of combined fatal CHD (coronary heart disease) or non-fatal myocardial infarction, and subgroup analysis of black patients.
The ALLHAT found the following:
Higher relative risk of stroke and combined CVD with Lisinopril compared to Chlorthalidone for black patients
Mean follow-up systolic blood pressure of 4 mm HG higher in blacks with Lisinopril compared to Chlorthalidone
Per the authors, these changes reflect “poorer BP response with ACE inhibitors in black patients.” Overall, the authors concluded that thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and recommended this as first-line anti-hypertensive therapy.
These findings were replicating among other large studies. The AASK study (African American Study of Kidney Disease and Hypertension) found ACE inhibitors were not as effective at lowering blood pressure in black patients, though they did prevent progression of kidney disease. As a result of these two major trials, as recently as 2017 the ACC/AHA (American College of Cardiology/American Heart Association) recommended black patients with no comorbidities receive either a thiazide or CCB as initial therapy, and non-black patients can receive ACE, thiazide or CCB as initial therapy. The JNC8 (Eight Joint National Committee in 2014) and ISHB (International society on Hypertension in Blacks) similarly recommended a race-based approach to hypertension treatment. In short, these societies targeted their recommendations to optimize treatment for black patients based on scientific data.
Investigating the underlying biology of racial differences
Is there a biological basis for potential increased response of black patients to thiazide or CCB monotherapy, and worse response to ACE inhibitors? There numerous studies pointing to a distinct hypertensive phenotype in African Americans. One key hypothesis is that African American patients are more prone to salt retention (i.e. higher salt-sensitivity), and as a result, have lower circulating levels of renin.
The story goes, less renin, less ability of ACE inhibitors to work on the renin-angiotensin-aldosterone system (RAS) to lower blood pressure. This begs the question: what is the origin of this particular subtype of hypertension? Here are a few hypotheses and the underlying pathophysiology that could explain them:
Historical – One speculative hypothesis is that the slave trade led to “limited access to water favoring the survival of persons who were avid sodium retainers and accelerating gene selection for sodium retention.” There is at best, mixed data to support this hypothesis[1], and lack of access to data to determine salt environments in Africa or the Americas between the 16th -19th centuries. The proposed mechanism would be as follows:
Salt sensitive individual (due to geography in salt-poor environments or due to historical factors such as slave trade): Salt load --> Increase in Norepinephrine --> Activation of renin --> RAS activation
Over time, the body would reach a different set point for RAS activation, and the increase activation would lower renin levels in the blood.
Non-biologic – Obesity is a known driver of hypertension, which may confound the relationship between hypertension and race
Obesity --> Insulin resistance --> Salt-sensitivity
Genetic – Polymorphisms for the ACE gene and the angiotensinogen (ATG) gene, as well as other genetic variations have been shown to explain some differences in rates of hypertension between BAA and non-BAA. Similarly, there are genes related to the Atrial natrurietic peptide (ANP) and renal sodium channel that may play a role in increase salt-sensitivity among African Americans.
Suppose that there are differences in salt-sensitivity among black and non-black patients, from a combination of acquired and genetic factors. Does it follow that ACE inhibitors would not help African Americans as much? Turns out that even in patients with low-renin levels, while ACE inhibitors may not do as well lowering blood pressure, they still exert important effects such as endothelial dysfunction, attenuate proteinuria, and reduce renal injury. In brief, according to Williams (2014), “there is no evidence of reduced efficacy for ACEI or ARB therapy on clinical outcomes in African Americans.” As recently as 2014, the author recommended dual therapy for initial BP management for African Americans.
From theory to clinical practice
Do the benefits of thiazide or CCB monotherapy hold up in real practice? A retrospective observational study sought to answer this question by comparing prescribing differences and HTN control in BAA (Black African American) vs. non-BAA patients aged 18 to 85 on 1- or 2-drug regimens. What were the findings?
More BAA were prescribed thiazides as monotherapy, in keeping with the guidelines.
BAA had worse control of hypertension compared with non-BAA for both 1- and 2-drug regimens.
More frequent follow-up was associated with better hypertension control among BAA
As an observational study, it is hard to completely eliminate confounding variables. Still, the authors raise the important question: given the higher fourfold higher prevalence of CKD among BAA, might delayed use of ACE/ARB medications in early CKD lead to persistence of such a disparity?
The editorial by Flack and Buhnerkempe offers a thoughtful synthesis of the data with attention to the realities of practice.
The JNC8 offers the following tool for titrating combination therapy.
Summary:
Many scientific studies have found distinct physiological differences in salt-sensitivity and response to blood pressure treatment between White and African American patients. Such differences likely represent a combination of social, genetic, and environmental causes. In regards to treatment, the largest study (ALLHAT) found thiazides less harmful than ACE inhibitors in African Americans, but only for monotherapy. However, in clinical practice, there are more differences within racial groups than between racial groups on multiple medications. Given the higher prevalence of CKD in African Americans, guidelines are moving in the direction of starting most patients with hypertension on combination therapy with both ACE/ARB (for renal protection) and CCB or combination ACE/ARB and diuretic for those with BP greater than 20/10mm Hg above goal.
Guideline summary from Different Associations:
The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) blood pressure guideline recommends calcium channel blockers and thiazide diuretics as first-line agents for Non-Hispanic African American adults with hypertension who do not have heart failure or renal disease, along with an added emphasis for the use of antihypertensive medications from two or more different classes
The International Society of Hypertension in Blacks (ISHIB) recommends combination therapy with a CCB plus a renin-angiotensin blocking agent (preferably angiotensin receptor blocker [ARB]) as first-line treatment for NH Black patients with hypertension
For Black adults with hypertension, the JNC 8 recommended a thiazide-type diuretic or CCB as initial treatment.
References:
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group; The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997. doi:10.1001/jama.288.23.2981
Flack JM, Buhnerkempe MG. Race and Antihypertensive Drug Therapy: Edging Closer to a New Paradigm. Hypertension. 2022 Feb;79(2):349-351. doi: 10.1161/HYPERTENSIONAHA.121.18545. Epub 2022 Jan 12. PMID: 35020461.
Holt HK, Gildengorin G, Karliner L, Fontil V, Pramanik R, Potter MB. Differences in Hypertension Medication Prescribing for Black Americans and Their Association with Hypertension Outcomes. J Am Board Fam Med. 2022 Jan-Feb;35(1):26-34. doi: 10.3122/jabfm.2022.01.210276. PMID: 35039409.
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Richardson SI, Freedman BI, Ellison DH, Rodriguez CJ. Salt sensitivity: a review with a focus on non-Hispanic blacks and Hispanics. J Am Soc Hypertens. 2013 Mar-Apr;7(2):170-9. doi: 10.1016/j.jash.2013.01.003. Epub 2013 Feb 19. PMID: 23428408; PMCID: PMC4574876.
Verdecchia P, Grossmann E, Whelton P. 2023 ESH Guidelines. What are the main recommendations? Eur J Intern Med. 2023 Oct;116:1-7. doi: 10.1016/j.ejim.2023.07.034. Epub 2023 Aug 1. PMID: 37537030.
Williams SF, Nicholas SB, Vaziri ND, Norris KC. African Americans, hypertension and the renin angiotensin system. World J Cardiol. 2014 Sep 26;6(9):878-89. doi: 10.4330/wjc.v6.i9.878. PMID: 25276290; PMCID: PMC4176798.
[1] Per the authors, “In question are the key tenets of the theory which implicate salt deficiency in the areas of Africa from which slaves originated, the trauma of the slave trade, and conditions in the Americas as triggers for unnatural genetic selection for renal sodium-retainers.”