Drug-based, device-based approaches can safely treat resistant hypertension
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Key takeaways:
- Clinicians must carefully rule out other conditions before diagnosing resistant hypertension.
- Drug- and device-based approaches can safely treat elevated blood pressure.
PHILADELPHIA — A variety of pharmacologic and device-based approaches provides hope for effective and safe treatment of resistant hypertension, which can be “tedious but important” to diagnose, according to a speaker.
There are several types of uncontrolled hypertension; resistant hypertension is defined as a BP exceeding 130/80 mm Hg when a person is prescribed at least three antihypertensive medications, 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 at the Heart in Diabetes CME Conference. Those medications are typically an ACE inhibitor or angiotensin receptor blocker, a thiazide diuretic and a long-acting calcium channel blocker.
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“Making the diagnosis of resistant hypertension can be tedious but important,” Lepor said. “It is important to maximize dosing of the combination ACE or [angiotensin receptor blocker], thiazide-like diuretic and calcium channel blocker. Spironolactone should be the fourth drug in the appropriate patient, and we now have a variety of pharmacologic and device-based approaches, providing hope for effective and safe treatment.”
Approximately 20% of people with hypertension do not know they have elevated BP, whereas only half of those with hypertension have controlled BP and about one-third of patients with so-called resistant hypertension could have their BP controlled with the addition of a fourth drug, such as a mineralocorticoid receptor antagonist (MRA), Lepor said.
“You want to make sure you are optimizing therapy and considering the ‘four D’s’ — drug dose, duration and diuretic choice, “ Lepor said. “You certainly want to assess for [medication] adherence and confirm that the patient has resistant hypertension.”
Beware of ‘pseudoresistant hypertension’
Lepor said clinicians should understand the many factors that contribute to resistant hypertension and that proper assessment for those factors could help lower elevated BP without additional pharmacology. It is also important to rule out other common conditions that may resemble resistant hypertension, such as primary aldosteronism, thyroid disease, obstructive sleep apnea, or less common but possible conditions such as pheochromocytoma, Cushing’s syndrome or coarctation of the aorta, Lepor said.
“You want to assess the patient’s BP correctly and make sure they are on the three [recommended] classes of medicines,” Lepor said. “You want to make sure patients are adherent to these treatments, and then evaluate for secondary causes of hypertension. I routinely ask patients if they are taking NSAIDs ... as well as herbs, especially herbs of a licorice type.”
Several common factors can contribute to what Lepor called “pseudoresistant hypertension,” including a poor relationship between the clinician and patient or the patient not taking medications as prescribed due to issues such as cost, adverse effects, a complicated dosing schedule, and memory or psychiatric problems. Physician inertia when it comes to titrating dosing is another issue, Lepor said.
“Before we call people resistant hypertensives, you certainly want to exclude the ‘white coat hypertension’ effect with a 24-hour BP monitor,” Lepor said. “Assessing for compliance is a huge issue. I do not really count pills, but certainly educating patients [about taking medications] is important. And make sure the BP is taken properly. In many settings, it can be an untrained medical assistant taking a BP when the patient is not in the correct position.”
Drug therapies
The American Heart Association scientific statement on resistant hypertension calls for adding an MRA such as spironolactone for patients whose BP is uncontrolled despite use of renin-angiotensin system blockers, calcium channel blockers and diuretics, Lepor said.
“We often see beta-blockers prescribed to these patients as second, third or fourth drugs,” Lepor said, noting that spironolactone has been shown to be much more effective at reducing BP in uncontrolled hypertension.
“That is something important we need to remind ourselves of before utilizing these other agents,” he said.
Beyond MRAs, clinical trials for other agents will provide several “new and exciting therapies” for resistant hypertension, each with their own unique mechanism of action, Lepor said. A phase 3 trial is currently underway for a novel nonsteroidal MRA, KBP-5074, also known as ocedurenone (KBP Biosciences) for uncontrolled hypertension in people with advanced chronic kidney disease (CKD). In the BLOCK-CKD trial of patients with uncontrolled BP despite taking two to four agents and poor kidney function, ocedurenone lowered systolic BP by a placebo-subtracted 6.5 mm Hg and 10.9 mm Hg, depending on dose, compared with placebo at 84 days; hyperkalemia was not a significant reason for withdrawal from the trial.
“This allows us potentially to use an MRA in patients where we avoid them, those with class IIIb and class IV CKD,” Lepor said. “Traditional MRAs are not used in this population because of the propensity for hyperkalemia.”
Despite the use of MRAs, a high unmet medical need remains, Lepor said. Also coming soon is aprocitentan (Idorsia), a joint endothelin A/endothelin B receptor antagonist, which is being evaluated for treatment of resistant hypertension in the PRECISION trial, Lepor said.
IONIS-AGT-LRX (Ionis) is an antisense inhibitor of angiotensinogen in development that is administered by one injection every 6 months, and a small phase 2 study showed the agent was safe, well tolerated, lowered angiotensinogen and in an exploratory outcome lowered BP.
Baxdrostat (Cincor Pharma/AstraZeneca), a selective aldosterone synthase inhibitor, demonstrated in trials significant reductions in aldosterone and increases in plasma renin activity compared with placebo, as well as a 10 mm Hg placebo-subtracted reduction of BP measured with 24-hour BP monitoring, Lepor said.
“Compared with placebo, [baxdrostat] was well tolerated; a few patients in a small study did develop hyperkalemia, so that is certainly possible,” Lepor said.
Role for renal denervation
High-quality studies now demonstrate that both radiofrequency and ultrasound renal denervation are associated with BP lowering over 24 hours in patients with mild to moderate, severe and resistant hypertension, Lepor said, and renal denervation did not result in any significant long-term increase in renal artery stenosis or worsening of renal function. The BP-lowering effect of renal denervation was sustained for up to 3 years in trials, providing the benefit equivalent of a single medication with a roughly 5 mm Hg to 10 mm Hg BP reduction, Lepor said.
“This may be an option for patients unable to tolerate long-term medications at the necessary doses or who cannot tolerate medications at all,” Lepor said. “Renal denervation should be offered mainly to patients with high global CV risk, for whom intensive BP treatment may have a particularly pronounced benefit.”
References:
- Bakris G, et al. Hypertension. 2021;doi:10.1161/HYPERTENSIONAHA.121.17073.
- Barbato E, at al. Eur Heart J. 2023;doi:10.1093/eurheartj/ehad054.
- Schlaich MP, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)02034-7.
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Lepor NE, et al. Session 12 – Hot Topics in Cardiometabolic Health. Presented at: Heart in Diabetes CME Conference; June 9-11, 2023; Philadelphia.
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