Is There a Sex-Related Difference in Response to Renal Denervation?

Renal denervation (RDN) in the treatment of hypertension continues to evolve, with new evidence emerging regarding its safety and efficacy. This evidence is reinforced by the recognition of hypertension as a major contributor to cardiovascular morbidity and mortality and, therefore, the need for adjunct therapy aside from medication to help achieve better blood pressure (BP) control. Hypertensive women have been found to have worse cardiovascular outcomes than their male counterparts. Furthermore, female-specific factors can complicate the management of hypertension and are implicated in the overall increase in cardiovascular risks. As a result, concerns regarding the need for sex-specific consideration in the management of hypertension have been raised previously. With some studies reporting variable BP response to antihypertensives based on sex, an interesting question remains: Does the sex of a patient have an effect on response to RDN? To date, data regarding sex-related differences in response to RDN are limited, and further studies addressing this issue are warranted.

RDN was developed as a treatment option for patients with uncontrolled hypertension despite lifestyle modification and pharmacotherapy.¹ Early randomized trials demonstrated a significant reduction in office BP after RDN.^1-5 However, the first sham-controlled trial, SYMPLICITY HTN-3, showed no difference in BP reduction between the RDN and sham control arms.⁶ Nonetheless, more recent studies demonstrated a significant, although less pronounced, reduction in office and 24-hour ambulatory BP.^7-11 Hypertension remains an important risk factor for cardiovascular disease in both men and women. Globally, it affects 30% of the adult population, with an estimated prevalence of resistant hypertension at 14% to 20%.^12-14 A dose-dependent relationship was found between BP and mortality from cardiovascular and cerebrovascular disease.¹⁵ Thus, even a modest reduction in BP can lead to better outcomes with regard to cardiovascular morbidity and mortality.¹⁶ Recently, Mahfoud et al demonstrated that RDN significantly increased time in therapeutic range (TTR), defined as the proportion of time the patient spends within a predetermined BP (< 140 mm Hg for office systolic BP and < 130 mm Hg for ambulatory systolic BP).¹⁷ TTR was shown to be an independent predictor of cardiovascular events in hypertensive patients.¹⁸ In the study reported by Mahfoud et al, a 10% increase in TTR through 6 months post-RDN was associated with a significant reduction in cardiovascular events at 6 through 36 months.¹⁷

Hypertension in women carries a greater burden on cardiovascular health compared to men.¹⁹ Several sex-specific factors are implicated in the mechanism of hypertension in women, including hormones, pregnancy-related factors, and sympathetic activity. Although some evidence regarding sex-related variation in response to antihypertensives is available, data regarding differences in response to RDN between men and women are limited. In this article, we highlight issues that are specific to hypertension in women. Furthermore, we summarize the available data on sex-related differences in hypertension treatment, including the response to medication as well as RDN.

HYPERTENSION IN WOMEN

Overall, hypertension is more prevalent in men compared to women (52% vs 43% for United States adults aged 20 years or older). However, in adults aged 65 years or older, the prevalence is higher in women.¹³ Women are more likely to be aware of their condition, under treatment, or in control of their hypertension.¹³ The risk of cardiovascular disease was shown to be higher in women for every 10-mm Hg increase in systolic BP.¹⁹ Moreover, life expectancy was found to be shorter by approximately 5 years in hypertensive compared to normotensive women.²⁰ Hypertension control resulted in a greater reduction in cardiovascular mortality among women compared to men and was found to have the highest impact on reducing cardiovascular mortality compared to all other risk factors.¹⁶

Sex-specific factors are implicated in the development and pathogenesis of hypertension in women. Estrogen has a protective effect in premenopausal women. It plays an important role in endothelial function and causes vasodilatation as a result of increased synthesis of nitric oxide and inhibition of sympathetic activity and renin-angiotensin-aldosterone system.²¹ Therefore, a sharp reduction in estrogen level after menopause results in activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, which in turn increases risk of hypertension in older women.²¹ Moreover, an increase in endothelin level in postmenopausal women due to lack of its inhibition by estrogen can further implicate the development of hypertension by increasing renal vasoconstriction and salt reabsorption. Additionally, sex hormones can influence vascular function and are linked to arterial elasticity,²² the lack of which during menopause leads to an increase in arterial stiffness and decrease in arterial compliance. Whereas hypertensive women have a lower level of central sympathetic activity than men, there is a more dramatic increase in muscle sympathetic nerve activity (marker for central synthetic activity) in women with age that increases their risk of developing hypertension in older age.²³ Hypertension is one of the most common conditions complicating pregnancy. Gestational hypertension affects 6% to 7%, and preeclampsia affects 10% of pregnancies.²⁴ Both are associated with an increased risk of developing chronic hypertension.²⁵ Combined hormonal contraception is associated with a small increase in BP that usually resolves after discontinuation of therapy, the mechanism of which is not fully understood.²⁶ This risk increases with longer duration of use and in the presence of other cardiovascular risk factors, including smoking and obesity.²⁷

Data regarding the effect of hormone replacement therapy on the development of hypertension in postmenopausal women is conflicting and, if present, it only leads to a mild increase in BP.^28-31 Fibromuscular dysplasia as a secondary cause of hypertension is more common in women and should be considered in young hypertensive women.³²

SEX-RELATED DIFFERENCES IN ANTIHYPERTENSIVES

Sex-related differences in hypertension treatment—including class of medications prescribed, treatment response, side effects, and pharmacokinetics—have been reported across several studies. In a large cross-sectional survey including a hypertensive United States population, women were more likely to be on treatment compared to men (61.4% vs 56.8%, respectively). Furthermore, the use of diuretics and angiotensin receptor blockers (ARBs) was more common in women (31.6% vs 22.3% for diuretic and 11.3% vs 8.7% for ARBs, in women and men, respectively). For those who were receiving antihypertensive medications, men were more likely to use ≥ 3 drugs, especially in the older population (60-69 years, 12.3% vs 19.8%; 70-79 years, 18.6% vs 21.2%; and ≥ 80 years, 18.8% vs 22.8%, in women and men, respectively).³³ In other studies, women were prescribed thiazide more often than men, which could be explained by the added benefit of thiazide on bone density in postmenopausal women as a result of reduced renal calcium excretion and subsequent reduction of fracture risk.^34,35 Furthermore, after adjustment for baseline variables, amlodipine was found to be associated with a better decline in diastolic BP in women with mild to moderate hypertension when compared to men (91.4% vs 83%; P ≤ .001).³⁶

Regarding pharmacokinetics, sex variation in response to Β-blockers has been described. It has been shown that men have a quicker absorption rate of metoprolol, whereas women have slower drug clearance and smaller volume of distribution. Thus, a 50% dose reduction of metoprolol was recommended when used in healthy young women compared to men.³⁷

Additionally, women were reported to experience more frequent adverse effect to most antihypertensives compared to men, with the exception of mineralocorticoid recepto antagonists.^38,39

With regard to the BP-lowering effect on clinical outcomes, no significant difference was found between men and women in the occurrence of major adverse cardiovascular events.^40,41

SEX-RELATED DIFFERENCES IN RESPONSE TO RDN

Data regarding sex-related difference in response to RDN are limited. A meta-analysis including 15 studies evaluated the efficacy of RDN in 857 patients with resistant hypertension at 6 months compared to medical therapy and/or sham procedure; it revealed that patient sex does not impact either 24-hour systolic blood pressure (meta-regression coefficient, –0.0119; 95% CI, –0.0481 to 0.0242; P = .5174) or 24-hour diastolic blood pressure (meta-regression coefficient, –0.0061; 95% CI, –0.0421 to 0.0299; P = .7407) after RDN.⁴²

In another meta-analysis assessing the impact of RDN on renal outcomes, a univariable mixed effects meta-regression analysis performed on 48 cohorts showed that female sex was not a predictor for change in estimated glomerular filtration rate (coefficient of 0.57; CI, 0.40-1.54; P = .25).⁴³

RADIANCE-HTN TRIO, a randomized single-blinded trial that assessed the impact of ultrasound RDN on daytime ambulatory systolic BP at 2 months in patients with resistant hypertension, demonstrated no difference in change in daytime ambulatory systolic BP according to patient sex (P = .69).⁴⁴ Similar results were found in the REQUIRE and SYMPLICITY HTN-3 trials.^6,45

SPYRAL-HTN OFF MED, a single-blinded randomized sham-controlled trial, recruited patients with mild to moderate hypertension on no medical therapy to evaluate the impact of RDN on baseline-adjusted difference in 24-hour systolic BP. In the prespecified subgroup analysis, the change in 24-hour systolic BP at 3 months for RDN and the sham group were similar for women and men (–2.5[–6.8 to 1.8] versus –4.8 [–7.4 to –2.2]; P = .35, respectively).⁸

RADIANCE-HTN SOLO, another United States RDN study, recruited patients with resistant hypertension and had a primary outcome of change in daytime ambulatory systolic BP at 12 months. A multivariate model analysis showed that male sex was a predictor for average real variability in home systolic BP after RDN (P = .003).⁴⁶

In a prospective cohort involving a Chinese population with resistant hypertension and assessing the effect of RDN on mean systolic and diastolic BP reduction at 3 months, women had a better response in systolic BP reduction after RDN (Β –0.31; P = .005), whereas sex had no impact on diastolic BP response to RDN (Β –0.243; P = .051).⁴⁷

Analysis from the extended GLOBAL SIMPLICITY DEFINE registry (n = 2,872 patients, 42% women), showed no difference in office systolic or ambulatory 24-hour systolic BP reduction in women versus men (–18.4 vs –15.5, P = .13 for systolic BP for women and men, respectively; and –8.8 vs –9.3, P = .14 for ambulatory 24-hour systolic BP, respectively).⁴⁸ Table 1A, Table 1B, and Table 1C^{3,5,6,8-10,44-59} summarizes the outcomes from RDN studies, including subgroup analysis by patient sex when included.

PERSPECTIVE

Hypertension is a major contributor to cardiovascular health in women, especially in the older population. Therefore, using all available resources to adequately control BP in hypertensive women is of paramount importance. RDN is a potential option for hypertension treatment, with new studies showing positive results. Although current guidelines have no sex-specific recommendation for hypertension treatment, awareness and understanding of factors that impact hypertension and its management in women are important to improve outcomes. The currently available data on sex-related differences in response to hypertension treatment (medication or RDN) have limitations, the reasons for which include underrepresentation of women in hypertension trials, small sample size, inclusion of heterogeneous population in meta-analyses, and differences in clinical trials designs and protocols (Figure 1). Therefore, little evidence can be generated from the existent literature, and addressing these limitations in future studies trials will help to derive a patient-centered therapeutic approach (Figure 1).

Figure 1. An illustration that summarizes sex-related differences in hypertension and currently available information regarding RDN in women, with suggestions made for future clinical trials. HR, heart rate; HRT, hormone replacement therapy; MACE, major adverse cardiovascular events; OCP, oral contraceptive pills; RCT, randomized controlled trial.

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