Novel approaches for treating hypertension

Introduction

Blood pressure is considered to be elevated at hypertensive levels when systolic blood pressure (SBP) is ≥140 mmHg and/or diastolic blood pressure is ≥90 mmHg. Hypertension is generally considered to be one of the strongest modifiable risk factors for cardiovascular disease. Its asymptomatic clinical presentation means that there is a long exposure time that contributes to cardiovascular complications and ultimately leads to a detrimental impact on global health.

Pharmacological treatment of hypertension decreases the likelihood of cardiovascular events such as heart attack, heart failure, and stroke occurring^1–3, although blood pressure and associated cardiovascular diseases are still on the increase, particularly with our ageing population. The importance of blood pressure lowering can be seen with the outcomes from the recently published SPRINT trial⁴. When SBP was intensively controlled to a target of <120 mmHg compared with the standard treatment target of <140 mmHg, intensive anti-hypertensive treatment resulted in ~25% reduction in primary composite outcome of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death. Because of the striking findings, the trial was stopped ahead of time after a median follow-up of 3.3 years. While there is ongoing debate as to the applicability of such findings given the usually less rigorous clinical practice settings occurring in the general community, together with key patient exclusions (e.g. diabetes mellitus and stroke)⁵, the high relevance of blood pressure control for organ protection is clearly evident. These findings are consistent with previous meta-analysis data on one million adults that demonstrated an association between increasing cardiovascular risk and blood pressure⁶.

Many anti-hypertensive therapies are currently being used when lifestyle and behavioural changes are not sufficient. As our undergraduate students quickly learn, the “ABCD” of commonly prescribed anti-hypertensive agents (i.e. A=inhibitors of angiotensin [Ang] such as Ang-converting enzyme [ACE] inhibitors and Ang type I [AT₁] receptor antagonists; B=β1-adrenoceptor antagonists; C=calcium channel antagonists; D=diuretics) are likely to be key initial choices. However, these drugs do not always adequately control blood pressure or are not appropriate in all hypertensive patients who usually exhibit various co-morbidities. Notwithstanding important issues such as noncompliance, it is still estimated that 10–15% of hypertensive patients are resistant to current treatment options, where blood pressure is uncontrolled with three or more different classes of anti-hypertensives, including a diuretic^7,8. Therefore, the need for new treatment strategies to treat the multi-faceted nature of hypertension, including organ protection, is still an area of intensive research. This short review will discuss emerging novel approaches currently being investigated to treat hypertension.

Combination therapies

Owing to the known clinical efficacy of inhibiting the renin-Ang system (RAS), one could speculate that additive multi-site therapy would result in maximal RAS blockade leading to enhanced anti-hypertensive effects and reduced end organ damage. Indeed, dual RAS blockade did show positive results from short-term studies using blood pressure and albuminuria as surrogate outcomes^9–11, but subsequent longer-term trials measuring clinical outcomes have consistently shown that excessive RAS suppression causes adverse effects. For example, the ONTARGET¹², ALTITUDE¹³, VA NEPHRON-D¹⁴, and ATMOSPHERE¹⁵ trials have confirmed, in a variety of high-risk patients with cardiovascular disease and/or diabetes or heart failure, that combination therapies that simultaneously inhibit a combination of renin, ACE, or AT₁ receptors do not provide additional benefit and in fact exhibit adverse effects such as hypotension, hyperkalaemia, and renal dysfunction. The less favourable risk-benefit ratio of such dual RAS inhibition argues against this therapeutic strategy, and current hypertension guidelines do not recommend combined RAS inhibitor treatment¹.

Perhaps reflecting the need for rigorous blood pressure management, in an era of relatively few first-in-class anti-hypertensive agents, there have been numerous fixed double- and triple-dose combinations approved by the FDA this millennia, as recently reviewed¹⁶.

Re-purposing older drugs: mineralocorticoid receptor antagonists for treatment-resistant hypertension

There have been two mineralocorticoid receptor antagonists available for many decades. The second-generation compound eplerenone has reduced affinity for androgen and progesterone receptors compared with the first-generation antagonist spironolactone, but it is also less potent than spironolactone at blocking aldosterone receptors, hence the greater anti-hypertensive potency exhibited by spironolactone¹⁷. Just as the RALES trial¹⁸ led to a resurgence in the use of spironolactone and later eplerenone for the treatment of severe heart failure, there is renewed interest in the use of mineralocorticoid receptor antagonists for treatment-resistant hypertension (TRH), if this is caused by aldosterone breakthrough in patients already being treated with an ACE inhibitor or an AT₁ receptor antagonist, leading to sodium retention¹⁷.

While there have been a number of short-term (4–24 weeks’ duration) placebo-controlled trials that have shown beneficial effects of spironolactone in TRH¹⁷, the strongest evidence for the use of spironolactone in TRH has recently been obtained from the PATHWAY-2 trial¹⁹. All patients who were already receiving A+C+D medications were randomised to receive 12-week sequential treatments of placebo, spironolactone, the α₁-adrenoceptor antagonist doxazosin, and the β₁-adrenoceptor antagonist bisoprolol. In this study, spironolactone reduced home blood pressure recordings by approximately double that of other active treatment arms and showed for the first time a direct drug comparison in the same TRH patients. There was also a significant inverse correlation between plasma renin and blood pressure reduction by spironolactone, suggesting that sodium retention contributed to TRH. In this study¹⁹ and earlier studies¹⁷, there was a low incidence of adverse effects. While it has been argued that these results should influence treatment guidelines¹⁹, it will be of great interest to determine long-term TRH outcomes in this particular cohort, including potential adverse outcomes, given the combined use of an ACE inhibitor or an AT₁ receptor antagonist together with mineralocorticoid receptor blockade. Of interest, newer nonsteroidal mineralocorticoid receptor antagonists, such as finerenone, have been developed to target the heart and are being trialled in heart failure²⁰.

Recent clinical advances

Emerging therapies

Renal denervation

Of the non-pharmacological methods being investigated to lower blood pressure²⁰, the effects of renal denervation are highly relevant and very topical. This interventional treatment was aimed at ablating the effects of augmented sympathetic drive to the kidney, which contributes to the pathogenesis of hypertension primarily owing to sympathetic activation and the release of renin. To this end, Symplicity HTN-1⁴⁹ and Symplicity HTN-2⁵⁰ trials used a minimally invasive catheter-based radiofrequency strategy to cause renal nerve denervation in an attempt to lower blood pressure in patients with TRH. These trials were very successful, with the reductions in blood pressure maintained for up to 3 years in many cases^51,52. However, procedural concerns were raised about the study design (including lack of blinding or true resistant hypertension⁵³), which prompted the large multi-centre, sham-controlled, blinded Symplicity HTN-3 trial⁵⁴. Surprisingly, no significant blood pressure reductions were observed between the renal denervation and the sham groups after 6 months of follow-up⁵⁴, which has resulted in considerable controversy in the field of renal denervation. This discrepancy from earlier trials has been attributed to incomplete ablation after renal denervation, since later analysis revealed that complete renal denervation was rarely achieved in patients in Symplicity HTN-3⁵⁵, most likely related to the inexperience of many trial operators and lack of procedural checks^55,56. Recently, it has been cogently argued that the rationale for renal denervation for TRH remains valid⁵⁶. However, “smarter” renal denervation trials, with respect to design, location of ablation energy delivery, and testing of achieved denervation⁵⁶, are awaited with intense interest. The devil will be in the detail as to how this field, which holds great promise, progresses.

Conclusions

Despite the effectiveness of the currently available anti-hypertensive medications, there is always a need for novel treatment strategies that are more effective in particular hypertensive patient groups and to provide additional resources to tackle TRH. Most of the newer drugs mentioned, including the emerging therapies, are likely to be useful for lowering blood pressure and/or limiting hypertension-related target organ damage.