Tackle resistant hypertension. Learn when it is pseudo resistant hypertension, and how to treat this pesky condition when it is true resistant hypertension. Dr. Jordy Cohen (@jordy_bc) leads us through her approach to keeping the BP where it should be (University of Pennsylvania).
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While there is still conflict regarding the definition of hypertension, it is generally agreed that hypertension is a systolic blood pressure (BP) ≥ 130mm Hg and/or a diastolic BP ≥ 80 mmHg (2017 ACC/AHA Guidelines), while other groups have a higher threshold to define hypertension, 140/90 (ACP/AAFP guidelines). Dr. Cohen reminds that in most patients a BP >140/90 is not acceptable and should be addressed even if they are already on multiple agents.
Bottom line: Hypertension = systolic blood pressure (BP) ≥ 130mm Hg and/or a diastolic BP ≥ 80 mmHg
Essential hypertension, also called primary hypertension, is hypertension without a clear secondary cause, and it is often the result of multiple processes. However, essential hypertension can be thought about in terms of two primary contributory mechanisms, renin-angiotensin-aldosterone system (RAAS)-driven or sympathetic-driven hypertension (Hallow et al 2014 and Guyton et al 1975).
The RAAS-driven mechanism is more likely salt sensitive, and the problem is primarily volume, even if there are no signs of edema. These patients are more likely to benefit from a thiazide diuretic (Maaliki et al 2022).
The alternative is sympathetic driven hypertension, which occurs in people who have a more active fight-or-flight process. Sympathetic-driven hypertension, in patients with more active fight-or-flight response, can be linked to anxiety and may be more susceptible to drugs like caffeine (DeLalio et al 2020). Sympathetic-drive hypertension may be more symptomatic with the patients experiencing headaches and palpitations.
Patients may be exposing themselves to a larger dose of caffeine than they were 10 or 20 years ago. A Starbucks “venti” coffee has 400 mg of caffeine, and that’s not counting extra shots (Starbucks). When asking a patient how much coffee they drink a day, three cups could mean three large drinks from Starbucks totaling over a gram of caffeine, which could be contributing to hypertension especially in sympathetic driven disease (Mesas et al 2011).
Vascular aging resulting in arterial stiffness also contributes to hypertension (Mitchell 2014). This phenomenon is closely linked with salt intake and environmental exposure, as demonstrated by studying the Yanomami tribe, an isolated community without exposure to the western diet or modern life. Members of the Yanomami tribe have minimal salt intake and do not have any increase in blood pressure with age (INTERSALT Trial: Carvalho et al 1998 and Mueller et al 2018). Chronic kidney disease and diabetes are also associated with early vascular aging (Dai et al 2020 and Ryder et al 2020). Recent work by Dr. Cohen suggests that there could be a reciprocal relationship between vascular aging and metabolic conditions, high blood pressure and large artery stiffness are associated with an increased risk of developing diabetes (Cohen et al 2022).
Structural racism continues to drive health disparities and hypertension is no different (Churchwell et al 2020). Racism and the consequences of racist policies like redlining are associated with hypertension. The Jackson Heart Study generated data that showed that racism leads to elevated blood pressure (Forde et al 2020) and low socioeconomic status (SES) during childhood can lead to high blood pressure even after an individual obtains a higher SES (Glover et al 2020). There is also data showing that a transient increase in violent crime can be linked to a rise in blood pressure (Tung et al 2019).
Bottom Line: RAAS-driven and sympathetic-driven hypertension are drivers of essential hypertension. RAAS-driven is salt sensitive and responds well to thiazide diuretics like chlorthalidone, and sympathetic-driven hypertension is often more susceptible to substances like caffeine.
Patients should be treated with all three first line agents before second line agents are added. Dr. Cohen talks at more length on choosing an initial blood pressure agent in episode #321. First line agents are (2017 ACC/AHA Guidelines):
ARBs/ACEi, angiotensin receptor blockers (ARBs) and ACE (angiotensin-converting enzyme) inhibitors like losartan or lisinopril
Thiazide diuretics like chlorthalidone or hydrochlorothiazide
Calcium channel blockers, specifically dihydropyridines like amlodipine
Second line agents include other diuretics (loop diuretics like furosemide, potassium sparing diuretics like amiloride, and aldosterone antagonists like spironolactone), beta blockers like carvedilol, alpha-1 blockers like prazosin, alpha-2 agonists like clonidine, and direct vasodilators like hydralazine and minoxidil.
Dr. Cohen taught us that citalopram could be considered another second line antihypertensive agent for patients with anxiety; she often reaches for citalopram before thinking about beta blockers. While there is mixed data about the effect of citalopram on blood pressure (Calvi et al 2021), Dr. Cohen finds that citalopram is useful in lowering blood pressure in patients with comorbid treatment resistant hypertension and anxiety. Individual studies of citalopram have shown it to be effective at lowering blood pressure in patients with chronic posttraumatic stress disorder or patients already on amlodipine (Tucker et al 2003 and Fu et al 2015). This could be due to an effect on the sympathetic nervous system; selective serotonin reuptake inhibitors (SSRIs) like citalopram decrease sympathetic control of the heart (Licht et al 2012). Dr. Cohen noted that some of these patients with anxiety and a history of trauma presented to her clinic with borderline elevated metanephrines. This observation is supported by literature showing that children with a history of abuse and adults with PTSD have altered blood chemistry (Pitman et al 2012 and De Bellis et al 1994). Building trust and learning about a history of trauma and/or anxiety may identify patients who would benefit from citalopram.
Bottom line: Start with the three first line agents for blood pressure treatment and consider citalopram if your patient has comorbid anxiety.
Dr. Cohen encourages us to have a low threshold for adding a third agent in a patient who is still hypertensive despite already being on two antihypertensive agents. While we want to avoid polypharmacy, using multiple antihypertensive agents at a lower dose can achieve blood pressure control with fewer side effects (Bennett et al 2017). Your patient doesn’t need to be taking three antihypertensive pills to be on three medications, there are triple fixed dose combination pills available that are often inexpensive and covered by insurance, olmesartan-amlodipine-hctz and valsartan-amlodipine-hydrochlorothiazide. Each additional antihypertensive agent can lower blood pressure 5-15 mmHg (Manisty and Hughs 2012). An exception to this rule is spironolactone, the addition of spironolactone to a patient already on maximum tolerated doses of three antihypertensive medications can lead to a 20 mmHg drop in blood pressure (Chen et al 2020). Dr. Cohen avoids prescribing an MRA if the serum potassium is > 4.5 mEq/L in a patient with chronic kidney disease, and the drug insert for spironolactone uses > 5 mEq/L as a threshold (Spironolactone Drug Insert).
When a beta blocker is not otherwise indicated (atrial fibrillation, heart failure with reduced ejection fraction, or migraines), beta blockers should not be used for first line blood pressure control, even if there is a significant contribution from anxiety. Beta blockers can be associated with an elevated cardiac risk; one of Dr. Cohen’s studies (among several other studies in other patient populations) showed that patients with HIV who were treated using a beta blocker as a first line agent had an increased risk of developing major cardiac events (Rethy et al 2021). Patients with anxiety induced hypertension benefit from control of their anxiety with citalopram (Tucker et al 2003 and Fu et al 2015). Dr. Cohen would be more likely to prescribe a clonidine patch or guanfacine over a beta blocker for hypertension linked with anxiety–only the patch, she never prescribes the clonidine in pill form because of high likelihood of nonadherence using drugs dosed multiple times a day coupled with rebound hypertension (Geyskes et al 1979). Guanfacine is also indicated for ADHD (Iwanami et al 2020), so Dr. Cohen uses this for patients with ADHD and hypertension. Prazosin not a very potent antihypertensive medication but is useful for patients with benign prostatic hyperplasia (BPH) and hypertension. While they can be helpful in some patients, Dr. Cohen finds herself stopping beta blockers much more often than prescribing them. When discontinuing beta blockers, they may need to be weaned due to withdrawal precipitated when they are stopped quickly among patients on a moderate or higher dose (Frishman 1987). She suggests weaning off beta blockers by cutting the dose in half every two weeks, and she sometimes uses clonidine patches to help the process. Hydralazine is not a common antihypertensive for Dr. Cohen. By the time someone gets to needing a potent vasodilator like hydralazine or minoxidil, we are likely missing volume overload or another etiology of their hypertension, and they are more likely to benefit from optimization of their diuretic regimen first. Lastly, Dr. Cohen has never prescribed minoxidil and only stopped it.
Are all thiazides created equal? While a recent study conducted in the Department of Veterans Affairs health system found no cardiovascular benefit of switching from hydrochlorothiazide to chlorthalidone (Ishani et al 2022), this study was not in very high risk patients and there seem to have been differences in adherence across the groups, so Dr. Cohen still uses chlorthalidone in many patients with resistant hypertension or hypertension with chronic kidney disease due to its favorable pharmacokinetics; hydrochlorothiazide has a half life of 9-12 hours (Beermann and Groschinsky-Grind 1977), but chlorthalidone’s half life is longer than 40 hours (Riess et al 1977). Practically, this means that someone who takes hydrochlorothiazide in the morning may not have effective salt clearance during their evening meal. Chlorthalidone is available in 25 mg or 50 mg tablets, but it does not divide well, often breaking into uneven pieces. Due to its long half life, patients can take a half-ish-dose one day and the other half-ish-dose the next, or chlorthalidone can be prescribed every other day for a patient who will remember (Chlorthalidone Drug Insert). Chlorthalidone is notoriously hard to compound, but there is a azilsartan-chlorthalidone combo pill (not currently available as a generic). Prescribing practices in countries differ greatly and favor certain drugs, although hydrochlorothiazide is pervasive in America, its prevalence is more a function of clinical inertia than drug superiority (Messerli and Bangalore 2011 and McNally et al 2019). Lastly, don’t forget about indapamide, which is available in 1.25 mg and 2.5 mg long acting formulations.
Bottom Line: Have a low threshold for adding a third agent in a persistently hypertensive patient. Low dose triple combination pills are a great way to lower blood pressure while avoiding side effects, and beta blockers are not great options for blood pressure until after you’ve exhausted first and other second line agents.
Laboratory evaluation for hypertension should include a basic metabolic panel, a lipid profile, and urinalysis looking for proteinuria (2017 ACC/AHA Guidelines). For hard to control hypertension, renin and aldosterone should also be tested. Dr. Cohen’s research of testing and prescribing data from the VA shows that renin and aldosterone are tested in less than 2% of eligible patients, and testing is associated with a 4-fold higher likelihood of initiating MRA therapy (Cohen et al 2021). Episode #386 with Dr. Matt Luther takes a deep dive into primary aldosteronism. Testing for renin and aldosterone doesn’t just uncover primary aldosteronism, suppressed renin with normal aldosterone is a “Liddle-like” syndrome that can be treated with amiloride, typically starting at 5 mg or 2.5 mg if there is fear of hyperkalemia (Monticone, 2018).
Check for sleep apnea in patients with a thick neck, obesity, morning headaches, daytime sleepiness, a history of snoring, and/or witnessed apnea. Good adherence to continuous positive airway pressure (CPAP) is associated with a reduction in blood pressure (Hoshide et al 2022).
Pheochromocytoma is a very rare cause of hypertension (0.2-0.6%), and they tend to cause symptoms like palpitations, headaches, and diaphoresis. Pheochromocytomas lead to plasma metanephrines above 2-3 times the reference range. Borderline elevated plasma metanephrines may indicate a temporary sympathetic surge (e.g., due to stress from an acute hospitalization) or history of trauma (Pitman et al 2012 and De Bellis et al 1994). Don’t order 24h collections, catecholamines, or dopamine that’s not the correct answer in your practice or on the test.
Bottom Line: If they have hard to control blood pressure, you should measure renin and aldosterone levels. It’s probably not a pheochromocytoma, but if you have to (e.g., if they’re symptomatic), order plasma metanephrines.
A patient has resistant hypertension when they are on the optimally tolerated doses of three first line antihypertensive agents and still have a blood pressure above goal. To diagnose resistant hypertension, you must first rule out pseudo resistant hypertension (Carey et al 2018).
Pseudo resistant hypertension is the appearance of resistant hypertension, but it is instead due to medication non-adherence, white-coat effect, inaccurate blood pressure measurement, or under-treatment. First and foremost, the blood pressure must be measured correctly to diagnose resistant hypertension. Episodes #254 and #321 cover accurately measuring blood pressure in more depth. However, in short, blood pressure should be an average of 3 readings using an automated device taken after the patient has rested for 5 minutes, and has their feet flat on the floor, back supported, and their bare arm supported at about the level of their heart (2017 ACC/AHA Guidelines).
White coat effect (i.e., isolated elevated office blood pressure with normal blood pressure out of the office, among people with treated hypertension) can be uncovered by incorporating home blood pressure measurements into patient evaluation. Additionally, getting three readings can help uncover white coat effect because subsequent readings tend to be lower in this population. A meta-analysis has shown that white coat effect is not associated with elevated cardiovascular risk, so it should be diagnosed but not treated (Franklin et al 2016 and Cohen et al 2019).
Nonadherence is a common cause of pseudo resistant hypertension, and it is more prevalent than we expect. Research comparing pharmacy fill data to serum drug levels shows that constantly filling prescriptions does not mean that a patient is consistently taking their prescriptions (Osula et al 2022). Physician assessment of patient medication adherence is also not accurate (Pandey et al 2015). Dr Cohen suggests that we address nonadherence by partnering with patients using phrases like “are there any side effects that I can help you with?” or “is there anything bugging you about these drugs or making it hard for you to take them that I can help make it better?” Fixed dose combination pills can be a tool to fight against nonadherence (Parati et al 2021).
Bottom line: Pseudo resistant hypertension is the appearance of resistant hypertension, but it is instead due to another cause: medication non-adherence, white-coat effect, inaccurate blood pressure measurement, or under treatment.
Pharmaceuticals, chemotherapeutic agents, and herbal supplements can all cause hypertension, and their potential influence should be evaluated in suspected resistant hypertension. Ibuprofen, oral contraceptives with estrogen, immunosuppressive drugs, antidepressants (SNRIs), amphetamines, sympathomimetic, and glucocorticoids are just some of the medications that can cause hypertension (Carey et al 2018). Tizanidine, a central alpha agonist used to treat pain, can cause severe pharmaceutical induced hypotension and rebound hypertension (Luther et al 2019).
Cancer therapies like VEGF inhibitors and tyrosine kinase inhibitors can cause severe acute hypertension (2017 ACC/AHA Guidelines). Chemotherapeutic induced hypertension is often treated with antihypertensive agents, and rebound hypotension when these chemotherapeutic agents are being held can be dangerous. If pro-hypertensive chemotherapeutic agents are being held, the antihypertensive agents must also be held while closely monitoring blood pressure (Cohen et al 2023).
Causes of hypertension can also be hidden in the social history. Drugs, alcohol, cigarettes, and herbal supplements (arnica, ginkgo, ginseng, st john’s wort, licorice, and Ma huang aka ephedra) can all cause hypertension (Jalini et al 2013 and Carey et al 2018). Consumption patterns for these substances can change over time and should be continually reevaluated. Another non-pharmaceutical cause of hypertension that may win you a point in Quizzo is black licorice from outside the US (Penninkilampi et al 2017).
Bottom line: Pharmaceuticals, chemotherapeutic agents, and herbal supplements can all cause hypertension. Their potential influence should be evaluated in suspected resistant hypertension. Furthermore, if chemotherapeutic agents are being held, the antihypertensive agents must also be held while closely monitoring blood pressure to avoid dangerous hypotension.
Dr. Cohen has received research grants from the NIH and has written for UpToDate. The Curbsiders report no financial disclosures.
Gorth DJ, Cohen J, Williams PN, Watto MF. “390 Resistant Hypertension”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast Final publishing 17th April, 2023.
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