Resistant hypertension and cardiovascular disease mortality in the US: results from the National Health and Nutrition Examination Survey (NHANES)

Hypertension affects 29% of the US adult population, corresponding to approximately 90 million Americans [1]. Hypertension is a risk factor for a number of adverse cardiovascular outcomes, including stroke, coronary heart disease, and heart failure [2]. Treatment of hypertension prevents and reduces cardiovascular morbidity, notably a 40% reduction in risk of stroke and 15% reduction in risk of myocardial infarction [3, 4]. Recent data suggest that hypertension awareness has improved with a reduction in the proportion of untreated hypertensive patients; however, the percentage of patients on multiple antihypertensive medications has progressively risen [5].

Apparent treatment-resistant hypertension (aTRH) is defined as hypertension that remains uncontrolled (≥140/≥90 mmHg) despite treatment with ≥3 antihypertensive medications or hypertension that is controlled (< 140/90 mmHg) on ≥4 antihypertensives [6]. In comparison with non-aTRH hypertensive patients, patients with aTRH, regardless of blood pressure (BP) control, have a higher risk of coronary artery disease, cardiovascular disease, heart failure, end-stage renal disease (ESRD), and all-cause mortality [7‐10]. With the rise in prevalence of hypertensive patients with aTRH from 5.5% in 1988 to 11.8% in 2008, aTRH has become a common condition within the US population [5]. However, the risk of cardiovascular mortality associated with aTRH in the US population is unknown.

The goal of our study was to assess the risk of cardiovascular mortality amongst individuals with aTRH in the US using data from the National Health and Nutrition Examination Survey. Furthermore, we sought to compare the risk of cardiovascular mortality amongst aTRH subgroups, stratified by BP control.

In this U.S. nationally-representative study, we found that 7.6 million US adults with diagnosed and treated hypertension had aTRH, which was associated with 47% higher risk of cardiovascular mortality compared to people without aTRH. Those with controlled aTRH and uncontrolled aTRH had 66 and 43% higher risk of cardiovascular death, compared with the non-aTRH group. Among participants without aTRH, those on 3 antihypertensive medications had a trend toward higher risk of cardiovascular mortality than those on < 3 antihypertensive medications. Our findings suggest that patients with aTRH and non-aTRH requiring 3 medications for BP control represent high cardiovascular disease risk groups and should be considered as targets for risk reduction interventions.

Hypertension increases the risk of coronary artery disease, myocardial infarction, stroke, accelerated atherosclerosis, congestive heart failure, and ESRD [13]. While microvascular changes play a role in the pathogenesis of hypertension, uncontrolled hypertension is known to cause further microvascular structural and functional alterations, notably smooth muscle cell hypertrophy and collagen deposition in resistance arterioles [14]. Hypertension is also associated with conditions, such as obesity and diabetes mellitus, that further alter and damage microvasculature in presence of an inflammatory milieu [15], resulting in impaired endothelial insulin signaling and insulin-stimulated nitric oxide synthesis [16]. Similarly, the aTRH participants in our study were more likely to have diabetes (39.5% vs. 24.5%) and CVD (40.1% vs. 18.9%) than the non-aTRH participants. These comorbidities may have influenced the hypertensive disease burden and blood pressure control in aTRH participants. It is important to consider the differences in the baseline characteristics between the aTRH and non-aTRH groups when interpreting our results. However, the baseline characteristics seen in our study are representative of that of the US population, thus the findings of our study are applicable to general practice.

Over the past three decades, significant efforts have been focused on improving awareness, treatment, and control of hypertension. According to Egan et al., the percentage of hypertensive patients with uncontrolled hypertension decreased from 73.2% in 1988 to 52.5% in 2008 [5]. However, with the reduction in uncontrolled hypertension and increased awareness of treatment, there has been an increase in the prevalence of aTRH. Between 1988 and 2008, the percentage of hypertensive patients on 1 or 2 medications remained relatively constant, while the percentage of patients on ≥3 medications increased progressively [5]. It is generally assumed that once the BP is at goal, regardless of the number of medications being used, the risk of cardiovascular disease is mitigated. However, our study demonstrates that despite adequate blood pressure control, people with aTRH are at an increased risk of cardiovascular mortality.

In prior studies, aTRH was found to be associated with higher risk of ESRD, ischemic cardiac events, congestive heart failure, and stroke in comparison to patients with non-resistant hypertension [7, 17]. Importantly, cardiovascular disease risk remains elevated amongst patients with aTRH, regardless of BP control [7, 17]. In a study by Muntner et al., 14,684 ALLHAT trial participants were categorized as having aTRH or non-resistant hypertension. There was a higher risk of coronary heart disease, stroke, all-cause mortality, heart failure, and ESRD in those with aTRH [7]. Similarly, in a study by Irvin et al., a higher risk of coronary heart disease, stroke, and all-cause mortality was noted among those with aTRH [18]. Our study similarly demonstrates increased risk of CVD mortality amongst people with aTRH, therefore extending the findings from prior studies with data generalizable to the US population. However, unlike prior studies [8‐10, 18], our study did not show a significantly increased risk of all-cause mortality in the aTRH group in comparison to the non-aTRH group. This suggests that individuals with aTRH are at greater risk of cardiovascular-related mortality but overall have similar risk of all-cause mortality.

Although the pathophysiology of aTRH is not well-understood, it is known that patients with aTRH have higher levels of brain-type and natriuretic peptides as well as aldosterone [19]. Additional contributing factors to aTRH may include non-adherence with lifestyle changes, including diet and exercise, and inadequate pharmacologic therapy [20]. Pharmacologic management of apparent treatment-resistant hypertension should include therapeutic optimization of antihypertensive dosages, systematic measurement of BP response to treatment, and assistance in overcoming barriers to adherence. Our study shows that even with medication prescription and BP control, aTRH patients remain at a higher risk of cardiovascular outcomes, suggesting a need for further risk mitigation strategies. The ongoing TRIUMPH trial (Clinicaltrials.gov no. NCT02342808) is evaluating the efficacy of lifestyle intervention using sodium restriction, DASH diet, exercise, weight management, and patient instruction and education in the treatment of aTRH [21]. Experimental treatments include renal denervation and electrical carotid baroreceptor stimulation using implantable devices; however, further studies are necessary for determination of efficacy and safety for use in treatment of aTRH [22, 23].

The observed associations between aTRH and cardiovascular mortality in our study provides some interesting insights (Table 2). In the unadjusted model (Model 1), aTRH was associated with a 2.5-fold higher risk of cardiovascular mortality, compared to the non-aTRH group. Adjusting for age, sex, and race (Model 2) reduces the magnitude of this association, reflecting the confounding effects of these variables. The association is further attenuated by adjusting for additional confounders in Model 3, in particular baseline diabetes and cardiovascular disease which had higher prevalence in the aTRH group as compared to the non-aTRH group. In Model 4, adjusting for kidney function (estimated glomerular filtration rate and albuminuria), further attenuates the association. It is likely that some of these adjustment factors, such as baseline cardiovascular disease and kidney function mediate the observed association between aTRH and outcomes. The higher systolic BP in the aTRH group (144 mmHg) as compared to the non-aTRH group (122 mmHg) could be contributing to higher prevalence of cardiovascular and kidney disease noted at the baseline in the aTRH group (Table 1). At baseline 40.1% of those in the aTRH group had cardiovascular disease, compared to 18.9% in the non-aTRH group. Similarly, the aTRH group had lower estimated glomerular filtration rate (68 ml/min|1.73 m²) as compared to the non-aTRH group (82 ml/min|1.73 m²). Clinical implication of these findings is that in patients with aTRH (whether controlled or uncontrolled) careful attention must be paid to reducing cardiovascular risk and preserving kidney function. From a population health perspective, aTRH identifies a patient population at 2.5-fold higher risk of cardiovascular mortality. This high-risk population can be easily identified using electronic health records, and population health management strategies could target this population for focused interventions such as lifestyle modification, and use of medications with cardioprotective and renoprotective effects.

Several limitations of our study deserve mention. First, we only had participant reported prescriptions and did not have information on prescription adherence which limits our ability to differentiate between true treatment-resistant hypertension and uncontrolled hypertension as the result of medication noncompliance [24]. Second, medications are assessed at a single timepoint due to the cross-sectional nature of NHANES. A time-updated analysis could account for changing patterns of comorbidities, medications, and BP over time and may find different associations. Third, we did not have information on medication doses. Physician prescription patterns, such as the use of low dose combination antihypertensive medications, may incorrectly assign participants to the aTRH category and bias the observed associations. Fourth, we only assessed cardiovascular mortality and did not have information on cardiovascular events. These limitations of our study are balanced by its strengths including its large sample size representative of the U.S. population, inclusion of racial/ethnic minorities, broad age range, rigorous data collection and extensive information on covariates, large number of events, and near-complete mortality follow-up using the NDI. The results of our study are generalizable to non-institutionalized U.S. adults.

In conclusion, in the US population, aTRH is common with 7.6 million affected adults and is associated with higher risk of cardiovascular disease mortality. In particular, the risk of cardiovascular disease mortality remains high among those with controlled BP on 3 medications (non-aTRH) or ≥ 4 medications (controlled aTRH), groups not generally considered at high risk. Future risk reduction interventions should consider focusing on these high-risk groups.