Resistant Hypertension: The 2018 Update

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It was the last day of ASN Kidney Week and I decided to walk to the convention center to catch a bit of downtown San Diego on the way. I was listening to a podcast that featured one of my heroes, Atul Gawande, and he happened to mention how undertreated hypertension is, despite there being numerous inexpensive medications to manage it. As I arrive to the conference room- the topic was serendipitously “Resistant Hypertension: Taming the Beast”, and the room was packed.

Recent changes to the definition of Resistant Hypertension: The definition of resistant hypertension, as per the most recent scientific statement published in Hypertension in 2018, is blood pressure of a patient with hypertension that remains elevated above goal despite the concurrent use of 3 antihypertensive agents of different classes, commonly including a long-acting calcium channel blocker (CCB), ACE inhibitor or ARB and a diuretic.

It is important to stress that a diuretic should be part of the 3 drug regimen if possible, before diagnosing a patient with resistant hypertension. (*this is listed on 2008 statement and not discussed in detail in 2018 update) All agents should be administered at maximum or maximally tolerated doses and at the appropriate dosing frequency . Patients on greater than or equal to 4 antihypertensive medications with controlled blood pressure are termed having controlled resistant hypertension.

The definition of resistant hypertension has been modified from that of the 2008 AHA scientific statement in 4 important ways:

  1. BP should be measured and the BP threshold for diagnosis and treatment goals should be in accord with current clinical practice guidelines.
  2. Patients should be taking ≥3 antihypertensive agents, commonly including a long-acting CCB, a blocker of the renin-angiotensin system (ACE inhibitor or ARB), and a diuretic at maximum or maximally tolerated dose
  3. Patients with the white-coat effect should not be included in the definition of resistant hypertension
  4. The diagnosis of resistant hypertension requires the exclusion of antihypertensive medication nonadherence.

Apparent treatment-resistant hypertension (aTRH)- confounding true prevalence? The term aTRH is used when ≥1 of the following data elements are missing: medication dose, adherence, or out-of-office BP; thus, pseudoresistance cannot be excluded.

With regards to population based studies, percentage of patients with aTRH in the NHANES  (National Health and Nutrition Examination Survey) and REGARDS (Reasons for Geographic and Racial Differences in Stroke) database was 14.5 and 14.1% respectively.

Data on prognosis: Observational and prospective data have demonstrated that patients with resistant hypertension have worse outcomes. Daugherty via a retrospective cohort study (>200,000 patients) showed that patients with resistant hypertension were 47% more likely to suffer the combined outcomes of death, myocardial infarction, heart failure, stroke, or CKD over the median 3.8 years of follow-up.

Latest on association of metabolic derangements- The Copeptin Angle and The Obesity-Aldosterone Axis: Apart from the previous links to aldosterone excess  and suppressed renin levels – plasma osmolality adjusted copeptin concentrations, a surrogate marker for vasopressin release, are twice as high in patients with resistant hypertension compared with those with nonresistant controlled BP. Additionally, investigators have recently demonstrated that obesity, particularly the abdominal obesity typical of men, contributes to excess aldosterone in patients with resistant hypertension.

Look out for the anti-depressants: The usually touted culprit medications for contributing to uncontrolled HTN are NSAIDS, oral contraceptives and sympathomimetics. Some of the overlooked ones can be antidepressants that include: tricyclic antidepressants, venlafaxine and fluoxetine.

The Sleep and Hypertension association: There is growing evidence that poor sleep contributes to elevated BP via activation of both the sympathetic nervous system and renin-angiotensin-aldosterone system. SBP, diastolic BP, and heart rate increase the day after a sleep-deprived night compared with the day after a normal sleep; urinary excretion of norepinephrine is also increased.

With regards to OSA- prevalence rates can be 70-90% in patients with resistant hypertension. However, it is important to note that treatment with CPAP only has mild improvement in systolic BP of only 2-5 mm Hg.

The Secondary Causes: Among the secondary causes of resistant hypertension, renal artery stenosis has some recent data on revascularization. Observational series have shown improved BP control and mortality after successful revascularization, especially in patients with high risk clinical presentations (eg. flash pulmonary edema). Post hoc analysis of Cardiovascular Outcomes with Renal Artery Lesions (CORAL) trial suggests a mortality benefit with revascularization compared to medical therapy for atherosclerotic renal artery stenosis in patients without proteinuria.

Secondary Cause Prevalence Screening Test
Primary hyperaldosteronism 8-20% Blood aldosterone to renin ratio, 24 hour urine aldosterone
Renovascular disease 5-24% Atherosclerosis related RAS: Duplex ultrasonography

Fibromuscular dysplasia: CT/MR angiogram

Drug or alcohol induced 2-4% Urinary drug screen
Kidney parenchymal disease 1-2% Kidney ultrasound (kidney biopsy)
Pheochromocytoma 0.1-0.6% Plasma metanephrines or 24 hr urine for fractionated metanephrines
Aortic coarctation 0.1% Echocardiogram, CT or MR angiogram
Cushing’s syndrome <0.1% Dexamethasone suppression test, 24 hr urine cortisol
Monogenetic disorders (eg. Liddle) Rare Specific genetic testing based on clinical suspicion

Treatment options: pharmacologic and devices: Ample evidence now exists that mineralocorticoid receptor blockade has demonstrated significant improvement in BP in patients with resistant hypertension, with the most convincing data arising from the PATHWAY 2 trial  and meta-analyses by Wang and Zhao.

Three sub-studies emanating from the PATHWAY 2 done to assess mechanisms underlying this superiority of spironolactone and pathogenesis of resistant hypertension, have shown that the disease is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension.

Device therapy still remains in nascent stages. Despite methodological concerns regarding study, SYMPLICITY HTN-3 has spawned new catheters and trial designs. SPYRAL HTN-OFF MED study provided more extensive renal denervation and showed significant reduction in BP. Similarly, the RADIANCE-HTN showed that endovascular ultrasound renal denervation reduced ambulatory blood pressure at 2 months. Most importantly, in both studies, patients enrolled did not have resistant hypertension.

Lastly, the CALM-FIM_EUR has recently demonstrated, in patients with resistant hypertension, that endovascular baroreflex amplification substantially reduced BP with an acceptable safety profile.

To conclude: While we have come far to elucidate mechanisms and risk factors for resistant hypertension, lifestyle changes and pharmacologic treatment with emphasis on adherence remain the mainstay of therapy. The onus is now on nephrology, to help tackle one of the most ominous issues of modern medicine which is responsible for the biggest impact on years of life lost globally.

High Yield Resources

2018 AHA Scientific Statement on Resistant Hypertension

2017 ACC/AHA Etc Hypertension Guidelines

Resistant Hypertension: Incidence, Prevalence, and Prognosis- Circulation

Hypertension trials cheat sheet

Primary Hyperaldosteronism: Practical Approach to Diagnosis and Management

Post by Sam Kant, MD (@kantsmd)
Chief Resident, Internal Medicine
University of Maryland Medical Center, Midtown Campus

1 comment

  1. Dr. Kant a highly informative capsule on a common problem which probably is not getting enough attention. There are a couple of things I wanted to comment upon
    1. From what I remember the definition of resistant requires “Optimal” dosing which is considered to be 50% of maximum permissible dose, and not maximal dosing.
    2. ACC AHA in the same guidelines also forwarded the term Refractory Hypertension (BP not controlled by 5 drugs of which one is spironolactone or other MRA).
    The proposed pathophysiology of refractory hypertension is sympathetic nervous system overactivitiy (reflected by elevated basal heart rates and 24 HR urinary norad levels) rather than fluid retention due to Aldosterone overaction in resistent HTN.

    Please do correct me if I understood the topic wrong.

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