Resistant, refractory hypertension are not alike; new ‘hope’ for treating uncontrolled BP
Click Here to Manage Email Alerts
Key takeaways:
- Resistant and refractory hypertension represent distinct disease states requiring different treatments.
- A ‘deluge’ of procedural and pharmacologic options offer hope for those with uncontrolled high BP.
A speaker reported that improved differentiation of resistant vs. refractory hypertension is essential in choosing optimal antihypertensive treatment, as the two represent different disease states of elevated blood pressure.
Additionally, with the many novel pharmacologic therapies on the horizon in clinical trials and the FDA approval of two renal denervation devices, there is renewed hope for the treatment of resistant and refractory hypertension.
Source: Adobe Stock
“[Resistant and refractory hypertension] actually represent two somewhat different disease states, and therefore we may have to change our conventional approaches to the treatment of resistant and refractory hypertension, understanding their pathophysiology,” Norman E. Lepor, MD, FACC, clinical professor of medicine at the Geffen School of Medicine at UCLA and attending cardiologist at Smidt Heart Institute of Cedars-Sinai, said during a presentation. “It's been a long time since the last innovation in hypertension, angiotensin receptor blockers. ... All of the sudden in the last 2 or 3 years, we're seeing a rash of important developments that have implications.”
Lepor defined resistant hypertension as elevated BP above goal despite concurrent use of three or more antihypertensive medications of different classes at maximal or maximally tolerated doses. The diagnosis of resistant hypertension required the exclusion of risk factors for falsely resistant hypertension, including improper BP measurement technique, white coat hypertension, clinical inertia and nonadherence to antihypertensive medication.
Refractory hypertension was defined as elevated BP despite concurrent use of five or more antihypertensive medications, including a long-acting thiazide-like diuretic and spironolactone, according to the presentation.
“Make sure that the patients are on these three classes, assuming there's no issues with intolerance or allergy as such. They're typically on a diuretic, usually a thiazide-like diuretic, [a renin-angiotensin-aldosterone system] blocker and a calcium channel blocker,” Lepor said during the presentation. “If their blood pressure is not optimized on that type of regimen, make sure you're checking either home blood pressures or ambulatory blood pressure in order to assess true blood pressures. You certainly don't want to count on that one singular blood pressure taken in the physician's office. You want to make sure they're adherent.”
In addition to monitoring antihypertensive medication adherence, physicians should ensure patients are not taking any other medication that could exacerbate their hypertension, such as NSAIDs, and discuss with them the benefits of eating a low-sodium diet, limiting alcohol intake and engaging in physical activity, Lepor stated.
In patients whose BP remains above target despite adherence to a calcium channel blocker, renin-angiotensin-aldosterone system inhibitor and diuretic — ruling out the other barriers to effective BP reduction — Lepor stated that a mineralocorticoid receptor antagonist (MRA) such as spironolactone may be considered as the fourth class of resistant hypertension treatment, barring the presence of hyperkalemia or stage 4 or 5 chronic kidney disease.
Other add-on treatments for patients with resistant hypertension could include beta-blockers, central sympatholytics, alpha-blockers, hydralazine and minoxidil, according to the presentation.
“[Aldosterone synthase inhibitors are] going to be one innovation that perhaps may have implications for the treatment of the resistant hypertensive patient,” Lepor said. “Looking at the renin-angiotensin-aldosterone system in terms of those patients that are difficult to control, what we find here is when we look at patients with resistant hypertension and they're on three drugs, we say, 'what's the fourth drug that we should use?' Oftentimes, if they truly have resistant hypertension, it's a volume-mediated effect. So therefore, using a drug that has a diuretic effect, such as spironolactone, actually leads to greater blood pressure reduction than a beta-blocker or an alpha-blocker.”
However, for patients with refractory hypertension, fluid retention is not an issue, according to the presentation.
In November 2023, two procedural options for the treatment of resistant/refractory hypertension received FDA approval: ultrasound renal denervation (Paradise, Recor Medical) and radiofrequency renal denervation (Symplicity Spyral, Medtronic).
“Basically, what they're doing is destroying both the afferent and efferent limbs of the sympathetic innervation of the kidney,” Lepor said. “Past trials, early on, were not very positive because we probably did not do a very good job of ablating enough of the innervation of the kidney to effect significant blood pressure changes ... We've been talking about denervation since 2011. This is something that's not particularly new, and it dropped off after negative trials. But now we've had a host of positive trials and they've led to the FDA approval.”
Fourth and fifth pharmaceutical antihypertensive options currently in clinical trials for treatment of resistant/refractory hypertension include:
- ocedurenone (Novo Nordisk) and esaxerenone (AdisInsight, Daiichi Sankyo), both nonsteroidal MRAs;
- aprocitentan (Idorsia), a dual endothelin antagonist;
- baxdrostat (AstraZeneca), a aldosterone synthetase inhibitor;
- M-atrial natriuretic peptide (MANP), an ATP analog developed by Mayo Clinic; and
- IONIS-AGT-L (Ionis) and zilebesiran (Alnylam), both attenuators of hepatic angiotensinogen.
“Making the diagnosis of true resistant/refractory hypertension can be tedious, but it's important,” Lepor said. “With refractory hypertension, we're more likely to push sympathetic blocking drugs vs. in resistant hypertension. Affecting volume, maximize dosing of combination ACE inhibitors/angiotensin receptor blockers, thiazide-like diuretics and calcium channel blockers is really important because if you're really good at it and you could really convince your patient, they're likely to have their blood pressure controlled. Spironolactone should be the fourth drug in the appropriate patient in the clinical setting.
“We discussed a variety of pharmacologic and device-based approaches for treatment that I think really lend itself to very exciting times now,” he said. “After 20 years of drought, suddenly, we're getting a deluge with all these innovations. There's now hope for enhancing the treatment of those patients who suffer from resistant and refractory hypertension.”
Collapse
Lepor NE. Refractory HTN and new drugs & procedures in the future. Presented at: World Congress Insulin Resistance Diabetes & Cardiovascular Disease Conference; Dec. 7-9, 2023; Los Angeles.
Click Here to Manage Email Alerts