Expert insights on tackling resistant hypertension

By Naveed Saleh, MD, MS | Medically reviewed by James Beckerman, MD, FACC
Published May 4, 2023

Key Takeaways

  • Resistant hypertension (RH) is defined as uncontrolled blood pressure after treatment with either three antihypertensive medications (including one diuretic) or four medications, according to the 2017 AHA/ACC hypertension guidelines. 

  • RH raises the risk of cardiovascular disease events independent of high blood pressure readings and should be identified and treated early.

  • Spironolactone is the preferred add-on agent in cases of RH.

The clinical importance of hypertension can never be understated, as this condition is one of the main causes of death worldwide, according to a paper in the Journal of Human Hypertension (JHH).[] Even though antihypertensive drugs and treatment strategies are widely applied, some patients still don’t attain target blood pressure levels. 

This condition is called resistant hypertension (RH). It is linked to an increased risk of hypertension-mediated organ damage, such as chronic kidney disease (CKD) and premature cardiovascular disease (CVD). However, early identification and management can improve hypertension and decrease the associated morbidity and mortality.

When does hypertension become “resistant”?

RH refers to hypertension that is uncontrolled after treatment with either three antihypertensive medications (including one diuretic) or four medications, according to 2017 hypertension guidelines from the American Heart Association (AHA) and American College of Cardiology (ACC).[]

About 13% of patients treated for hypertension have RH, according to an analysis by the American College of Cardiology (ACC).[] Factors related to RH include left ventricular hypertrophy, chronic kidney disease, obesity, and diabetes. 

“Refractory” hypertension refers to hypertension that is uncontrolled following the use of five or more antihypertensive medications of different classes, such as a diuretic and a mineralocorticoid antagonist, according to the analysis.

RH patients are at greater risk for cardiovascular disease events than those with nonresistant hypertension or white-coat hypertension. 

Therefore, it is imperative to closely monitor patients with RH to better control their blood pressure and other risk factors, and lower the occurrence of adverse outcomes. 

Patients with RH are also more likely to be identified with secondary hypertension (eg, renal disease), note the authors of the analysis. Causes of secondary hypertension should be identified as they can increase the risk of CVD events or death independent of increased blood pressure. Resolution of secondary causes of hypertension can improve blood pressure control, as well as resolving hypertension itself in some cases.

Accurate blood pressure readings

When considering a diagnosis of RH, it’s necessary to obtain highly accurate blood pressure readings. Pseudo-resistant hypertension refers to elevated readings in the clinic that are not secondary to the failure of antihypertensives. 

Cardiologist Vincent F. Carr, DO, in an exclusive interview with MDLinx, described the correct technique for measuring blood pressure. 

“In these times of limited office visit time it is tremendously important that the office blood pressure determinations follow the protocol of using the correct blood pressure cuff, and not putting the cuff over a shirt sleeve,” he said. “This may suggest the patient is hypertensive when they are not, and lead to unnecessary prescribing and adverse effects.”  

"Secondly, patient compliance with their medications is vitally important, and an emphasis on discussing compliance and acknowledging the fatigue and other symptoms is necessary."

Vincent F. Carr, DO

The ACC analysis offered the following recommendations for assessing blood pressure:

  • Make sure the brachial cuff is the right size, as a tighter cuff can alter blood pressure readings.

  • Have the patient sit still for 5 minutes with the feet planted on the ground, back supported, and upper extremity supported before the first measurement.

  • Evaluate blood pressure during two visits, and on each visit, take an average of two to three readings. 

  • Check blood pressure of both arms and select the higher reading.

If the difference in readings between both arms is greater than 10 mmHg, vascular abnormalities, which can be a secondary cause of hypertension, should be considered. 

Ambulatory blood pressure measurements should be used in patients suspected of having white-coat hypertension. As noted in the ACC analysis, one study indicated that 37% of patients diagnosed with RH had within-normal blood pressure readings when checked by an ambulatory monitor.

The most frequent cause of uncontrolled hypertension is medication non-adherence, which can be challenging to assess and improve in certain patients.  

“Although rates of nonadherence appear to be lower in RH than in the general population with [hypertension], steps should be taken to maximize patient adherence through simplification of treatment regimens, education, and behavioral strategies,” wrote the authors of the ACC analysis.

Comprehensive H&P

RH is defined as blood pressure readings consistently over 130/80 despite the prescription of three antihypertensives (including one diuretic) at maximally tolerated doses.

Patients being evaluated for RH should receive a robust H&P, with a deep dive in anthropomorphic measures, medication history, and use of recreational or illicit drugs. 

Medications: Sometimes drugs like acetaminophen, NSAIDs, and decongestants (ie, sympathomimetics) can raise the blood pressure or lower the response to antihypertensive medications. Other possible offenders include immunosuppressants and monoamine oxidase inhibitors.

When hypertension is due to drug interactions, decisions on seeking the optimal doses or considering discontinuation should be explored with the patient on an individual basis.

End-organ damage: Patients should be evaluated for possible end-organ damage by means of a basic metabolic panel and an ECG or echo to determine left ventricular hypertrophy. A fundoscopic exam can detect hypertensive retinopathy.

Secondary hypertension: Physicians should consider secondary hypertension in cases of accelerating hypertension, malignant hypertension, or similar situations. About 10% of hypertension cases are characterized as secondary, with the most common causes being renal parenchymal disease, renovascular disease, primary hyperaldosteronism, obstructive sleep apnea, and drug-induced hypertension.

If signs such as hypokalemia, abdominal bruits, or unequal readings between the arms are noted, secondary causes of hypertension should be explored.

For example, primary aldosteronism is a secondary cause that should be assessed via a plasma aldosterone/renin level. Patients should discontinue aldosterone antagonists for at least 4 weeks—with potassium level correcting—before testing for aldosterone/renin levels. 

If BUN and creatinine levels are increased, the patient should be evaluated for renal parenchymal disease using a renal ultrasound and urinalysis.

Dr. Carr commented on the myriad of causes for secondary hypertension and RH. “Secondary hypertension involving over-the-counter non-steroidal anti-inflammatory pain medicines and other prescribed medications needs to be considered, along with thyroid and adrenal disease, which should be part of the differential diagnosis in patients with difficult-to-control or highly variable blood pressure control.”

Treating RH through lifestyle modification

As Dr. Carr noted, there are numerous investigational treatments for resistant hypertension. However, he said, it is important to understand that most hypertension can be adequately controlled following the accepted ACC guidelines, which specify prescribing three antihypertensive medications to the maximal or maximally tolerated doses, with one drug being a diuretic. In addition, he stated, the clinician should be “looking for pseudo-hypertension and drug-induced hypertension and other secondary causes.” Principles of treatment for RH are also presented in a review published in Circulation Research.[]

The initial treatment approach, per the ACC, is aggressive lifestyle modification, with weight loss, increased exercise, and a diet plan (eg, DASH) as all-important. Part of this lifestyle modification includes decreased sodium intake and decreased alcohol intake. Decreasing potassium intake may be helpful in patients who do not have baseline hypokalemia. 

Treating RH with medication

Medication adherence is a must and can be facilitated with the prescription of fixed-dose combinations. 

Behavioral interventions include adherence feedback to the patient, motivational interviewing, and syncing adherence behaviors with daily habits.

In patients with RH, in addition to the standard blood pressure regimen, aldosterone antagonists such as spironolactone are the preferred add-on therapy, per the ACC. 

This type of drug should be used only in individuals without hyperkalemia or impaired kidney function. 

Writing in the JHH, the authors specified that pharmacological treatments should include “combinations of at least three different agents (a long-acting thiazide diuretic, a long-acting calcium channel blocker, and a renin-angiotensin system blocker with further addition of a low dose of mineralocorticoid receptor antagonist (spironolactone).”

Other approaches. Hypertension specialists can advise on the appropriate use of other agents. Device-based interventions—all of which are still in development—include renal denervation, carotid baroreceptor stimulators, and central arteriovenous fistula, as discussed by the JHH authors.

Renal denervation, for instance, involves ablation of the renal sympathetic supply using specialized catheters. Outcomes of this intervention are equivocal, despite many randomized trials, as discussed in a StatPearls review.[] Importantly, a Cochrane 2021 review found no impact of renal denervation on major adverse cardiac events but did show decreases in blood pressure readings in the office.

As for carotid baroreceptor stimulators, the technology is promising but requires further study, per Dr. Carr. Moreover, creating a venous fistula to treat chronic pulmonary hypertension in hemodialysis patients is also investigational and applies only to a small population of hemodialysis patients.

Multidisciplinary teams and consultations with hypertension specialists may be helpful in patients with RH.

“Inter-professional communication is of prime importance,” say the StatPearls authors, especially in detecting cases of resistant or difficult-to-treat hypertension, when referral and an inter-specialty approach will benefit a patient the most. The inter-professional team includes nursing staff and a nurse practitioner, the primary referring physician, and a cardiologist, nephrologist, and pharmacist. Inter-professional communication with this type of team is essential for ensuring blood pressure control. 

“This team can also monitor for adequate patient compliance as well as potential toxicities and adverse effects, all of which will result in minimizing future complications and reducing health care costs as well as improving patient outcomes,” the StatPearls authors added.

What this means for you

Resistant hypertension is challenging to diagnose and treat. Care provided by multidisciplinary teams and hypertension specialists is often recommended. Patients should also be advised on stringent lifestyle changes, exercise, stress reduction, and medication compliance. Spironolactone is the preferred add-on agent to antihypertensive regimens, per the ACC/AHA.

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