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Treatment-Resistant Hypertension: A PragmaticManagement Approach
Treatment-Resistant Hypertension: A Pragmatic
Management Approach
Brent M Egan
Care Coordination Institute, Greenville Health System, GreenvilleSouth Carolina, USA; Department of Medicine, University of SouthCarolina School of Medicine, Columbia, South Carolina, USA
Corresponding Author: Brent M Egan, Vice-President, CareCoordination Institute, Greenville Health System, GreenvilleSouth Carolina, USA; Department of Medicine, University ofSouth Carolina, School of Medicine, Columbia, South CarolinaUSA
Phone: +8645222261
e-mail: began@ccihealth.org
Treatment-resistant hypertension (TRH) is defined as officeblood pressure (BP) uncontrolled on ≥3 or controlled on ≥4antihypertensive medications at optimal doses. Apparent (a)TRH, a term used when medication dose, patient adherence,and out-of-office BP are unknown, impacts ∼30% of treated,uncontrolled hypertensives. Approximately 50% of uncontrolledaTRH patients were not prescribed optimal therapydefined as ≥50% of maximum recommended doses of threedifferent BP medication classes. Suboptimal adherenceoccurs in ∼10 to 60% of aTRH cases. Out-of-office readingsare nonhypertensive in roughly one-third of aTRH patients.Only ∼30 to < 50% of aTRH patients are truly treatment resistant."Office" TRH has a favorable prognosis, underlining theimportance of out-of-office BP. Suboptimal regimens andadherence with hypertension outside the office are likely associatedwith poor outcomes. Standardized treatment algorithmscan improve appropriate prescribing. The BP self-monitoring,single-pill combinations, inexpensive medications, and shareddecision making can improve adherence. Controlled TRHdoes not produce the expected reduction of cardiovascularevents, suggesting that greater attention to other vascularrisk factors and subclinical target organ change is important.The TRH patients have secondary hypertension more oftenthan non-TRH patients, especially primary aldosteronism,yet most will not have an identifiable secondary cause. ManyTRH patients are volume expanded and respond to intensifieddiuretic therapy, dietary sodium restriction, dual calciumchannel blocker therapy, or addition of α1-adrenoceptorantagonists. Plasma renin activity or hemodynamics can alsoinform successful and more personalized therapy. Referralto a hypertension specialist can be helpful if the approachesnoted do not control BP in TRH.
Keywords: Cardiovascular disease, Nonadherence, Officeresistance, Pseudoresistant hypertension, Spironolactone,Treatment-resistant hypertension.
How to cite this article: Egan BM. Treatment-ResistantHypertension: A Pragmatic Management Approach. HypertensJ 2017;3(3):125-130.
Source of support: Nil
Conflict of interest: None


Treatment-resistant hypertension is defined as BP uncontrolledon ≥3 or controlled on ≥4 different classes antihypertensivemedications at optimal doses and preferablyincluding a diuretic.1 Apparent TRH is often used, sincemeasurement artifacts, suboptimal treatment regimens,i.e., contributors to pseudoresistance, are not assessed inmany epidemiological studies.2 In the USA, the prevalenceof aTRH among all adults hypertensives rose from∼6 to 11% and from 16 to 28% in treated uncontrolledhypertensives between 1988 to 1994 and 2007 to 2010.

The rising prevalence of aTRH partially reflects moreintensive treatment.2-4 More intensive treatment is akey factor in improving hypertension control, but leadsto higher percentages of controlled patients on four ormore and uncontrolled patients on three or more BPmedication classes. Insulin resistance is also linked withTRH.5 Thus, aging of many population groups globallycombined with the epidemic of obesity and diabetes islikely to increase the worldwide prevalence of aTRHover time.6-8 An effective global strategy to amelioratethe adverse effects of access to excess calories, sugar, fat,salt, labor-saving devices, and passive entertainment aswell as more effective antihypertensive medications areinterventions that could limit the expected rise in prevalenceof aTRH globally.

Clinically Important Subsets of aTRH

Measurement artifacts are common, affecting 30 to50% of aTRH patients.9-11 Thus, it is important to obtainaccurate BP values, which are representative of usualvalues outside the office. With regard to accuracy, mostBP values in the majority of clinical settings are not measuredaccording to established protocol and reflect errorsinherent with the flawed methodology.12,13 Yet, BP canbe measured accurately in the office setting by trainedindividuals adhering to a standardized measurementprotocol and still not represent out-of-office values due toan "office" or "white coat" effect. Automated office BP, inwhich a series of BP values are obtained with the patientalone in the examination room, minimizes the officeeffect and better approximates usual daytime readings.14The Canadian Hypertension Guidelines recommendautomated office BP pressure as the preferred in-officemeasurement method.15

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Suboptimal Treatment Regimens

Our group reported that ∼50% of patients with uncontrolledaTRH were not prescribed optimal therapydefined as three different antihypertensive medications,including a diuretic at ≥50% of the maximum recommendedor approved doses, e.g., hydrochlorothiazide25 mg, lisinopril 20 mg, and amlodipine 5 mg daily.16While not all patients with aTRH tolerate optimal therapy,it is likely that >50% would be able to tolerate suchtreatment if prescribed. Thus, clinicians appear to haveopportunities to improve BP control by optimizing dosesof prescribed antihypertensive medications in patientswith aTRH who have sustained hypertension outsidethe office setting.

Inadequate adherence, or failing to take ≥75% of prescribedmedication, impacts ∼10 to 60% of aTRH.1,2 Directquestions, such as "Are you taking your medications?"often elicit the socially desirable response. Invitingpatients to share any concerns about costs, side effects,or other barriers is more likely to elicit clinically usefulinformation. Any admission of nonadherence is oftenassociated with taking < 75% of prescribed medication.17

Medication possession ratio (MPR) or the percentage(fraction) of days the patient possesses the medicationduring a given time period, e.g., 6 to 12 months, is a reasonableproxy for adherence.18 A discussion with the dispensingpharmacist or examining pill bottles to assess thenumber of prescription refills relative to initial prescriptionand visit dates provide useful, although imperfectassessment of MPR. Medications that are "automatically"mailed to the patient's home provide less useful informationwith regard to MPR as a proxy for adherence.

Clinical tactics to enhance adherence in patientswith uncontrolled hypertension include self-monitoredBP, reducing pill burden with single-pill combinations,refill consolidation to minimize visits to the pharmacyrequired to obtain medications, shared decision making,in which patients participate in therapeutic decisions,reminders, and pill organizers.18-21

Prognosis in aTRH

In patients with aTRH based on office BP, the subsetwith nonhypertensive out-of-office BP values has a more favorable prognosis.10,11 Patients trained in BP self-monitoringwho use an accurate device can provide reliable out-ofofficereadings.19 Using an accurate, validated ambulatoryBP monitor is another method for obtaining useful BPvalues outside the office setting.9-11 Both self-monitoredBP and ambulatory BP monitoring provide prognosticallyimportant information beyond office BP.22 The prognosisof patients with uncontrolled aTRH and suboptimalregimens or adherence has not been specifically studied.However, the magnitude of adverse outcomes in aTRHis unlikely to be explained only by the subset withoutpseudoresistance, i.e., true treatment resistance.
The benefits of hypertension control in patients withcontrolled aTRH appear to be significantly less than inadults without TRH (Table 1). The Reasons for geographicand racial differences in stroke (REGARDS) trial observeda lower rate of coronary heart disease (CHD) but a similarincidence of stroke in adults with controlled than uncontrolledaTRH.23 Neither International verapamil trandoliprilstudy (INVEST) nor Treat to new targets (TNT)observed differences in overall cardiovascular outcomesbetween the controlled and uncontrolled aTRH groups.24,25

In our South Carolina practice network, amongpatients without aTRH, the composite cardiovascularoutcome of stroke, CHD, and chronic heart failure (CHF)was 31% lower in the group controlled to < 140/< 90 mmHg than in the group with higher BP values (hazardratio, 0.69; 95% confidence interval, 0.65-0.74).26 In contrast,among patients with aTRH, the group controlled to< 140/< 90 had 13% fewer composite cardiovascular events(hazard ratio, 0.87; 95% confidence interval, 0.82-0.93)than the group with higher BP values. The significantdifference in the benefit of BP control between the aTRHand non-aTRH groups occurred, despite the fact that theabsolute difference in BP between the controlled anduncontrolled groups was virtually identical.

Unlike REGARDS and TNT,23,25 BP control was similarlyeffective for reducing stroke in hypertensive adultswith and without aTRH (41 vs 45%, p = not significant) in the South Carolina analysis.26 While BP control significantlyreduced myocardial infarction and acute coronarysyndrome in patients with aTRH, the benefit was marginallyless than in patients without aTRH (20 vs 32% reduction,p = 0.06). However, BP control was not beneficial forreducing emergency department and hospital admissionsfor CHF in patients with as compared with those withoutaTRH (0 vs 23%, p < 0.01).

Table 1: Cardiovascular outcomes in patients with controlled vsuncontrolled aTRH
Treatment-Resistant Hypertension: A PragmaticManagement Approach
CVD: Cardiovascular disease; CHD: Coronary heart disease;CHF: Chronic heart failure; ALLHAT: Antihypertensive lipid loweringheart attack trial;REGARDS: Reasons for geographic and racialdifferences in stroke; INVEST : International verapamil trandoliprilstudy; TNT : Treat to new targets; SC: South Carolina;  : Nochange;  : Increase/higher; ↓ : Decrease/lower; NA : Not applicable

Treatment-Resistant Hypertension: A Pragmatic Management Approach

Table 2: For uncontrolled aTRH, an exemplary base regimen and potential drug changes based on clinical situation are shown
Treatment-Resistant Hypertension: A PragmaticManagement Approach
All drug doses in mg/day. Specific antihypertensive medications are provided for illustrative purposes. For example, indapamide 1.25 to2.5 mg daily could be prescribed rather than chlorthalidone and ramipril 10 to 20 mg daily, perindopril 4 to 8 mg, valsartan 160 to 320mg could be prescribed a renin-angiotensin system blockers. Nitrendipine and felodipine are examples of calcium channel blockersthat could be substituted for amlodipine. †With renin-guided therapy, reductions in BP med number can be realized in some patients;PRA: Plasma renin activity

Pharmacotherapy of aTRH

In hypertensive patients without compelling indicationsfor ß-blockers, a thiazide-type diuretic, angiotensin receptorblocker and calcium channel antagonist will comprisea commonly prescribed three-drug regimen.16 Anexemplary regimen that provides three different classesof antihypertensive medications at half- and maximaldoses are provided in Table 2. Half-maximal and maximalrecommended doses are shown.

Adding a low-dose aldosterone antagonist, e.g., 12.5to 50 mg daily spironolactone, lowers BP in many TRHpatients. In fact, several studies in patients with uncontrolledTRH found that spironolactone at doses averaging∼25 mg daily lowered BP 20-25/10-12 mm Hg, whichis roughly double the response to several other drugclasses.1,27 Of interest, Guyton and Hall28 modeling ofthe circulation >50 years ago indicated that aldosteroneplayed a growing role in BP regulation over time(Graph 1). Over time aldosterone was projected to playa greater role in BP regulation than renin/angiotensinvasoconstriction, baroreceptors, and chemoreceptors.If patients are not ideal candidates for spironolactone,e.g., baseline serum K+ >4.5 or estimated glomerularfiltration rate (eGFR) < 45 to 50 mL/1.73 m2/min,29 thenchanging from hydrochlorothiazide to chlorthalidone ora long-acting loop diuretic, e.g., torsemide, can lower BP.Chlorthalidone is more likely than hydrochlorothiazide to be effective with eGFR 30 to 44 [Stage 3B chronic kidneydisease (CKD)].1 Patients with eGFR < 30 mL/1.7 m2/minmay require a loop diuretic, e.g., torsemide, to improvevolume control and lower BP. Patients with eGFR < 15often require dialysis for volume and BP control.

Treatment-Resistant Hypertension: A PragmaticManagement Approach
Graph 1: BP regulation over the short-, intermediate-, and longterm. BP is a complex variable with multiple inputs as shown. Inresponse to an acute change in arterial BP, the time course andpotency of the various inputs to BP homeostasis are shown. Thekidney is the major regulator of BP. Factors intrinsic or extrinsic tothe kidney which raise or lower the threshold for pressure natriuresisare critical in determining the long-term BP set point. Adapted fromdata in Guyton and Hall28

In patients with progesterone and antiandrogeniceffects of spironolactone, eplerenone is an alternativealdosterone antagonist devoid of sex steroid effects. Sincealdosterone raises BP in significant part by increasingthe number and activity of epithelial sodium channels(ENaC), amiloride, which blocks the ENaC, is also effective.However, amiloride does not block the adverseeffects of aldosterone on target organs, e.g., the heartand kidney. Monitoring for hyperkalemia is important with both aldosterone antagonists and ENaC inhibitors.Aldosterone antagonists and ENaC inhibitors have a lowrisk when started at modest doses in individuals witheGFR >45 and serum potassium < 4.6 mmol/L. Whilethese agents can be used cautiously when essential inindividuals with lower eGFR or higher serum potassium,beginning at very low doses and frequent monitoring(e.g., ≤7 days), for adverse effects is warranted wheninitiating treatment or increasing doses.

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An important practical concern raised by clinicianscaring for patients in very hot climates is the potentialfor volume depletion, hypotension, and possibly heatstroke with aggressive diuretic therapy. In low-renin,presumably volume-expanded patients living in very hotclimates, this concern may be mitigated by using drugclasses other than diuretics, e.g., dual calcium channelblockade, which are effective antihypertensive agentsin patients with low-renin values.30-32 It is importantto note the lack of proven safety advantage for thisapproach among hypertensive patients subject to prolongedhigh ambient temperatures.

Evidence suggests that low-renin patients have abetter BP response to diuretics, aldosterone antagonists,α1-adrenoceptor blockers, and calcium antagonists than torenin/angiotensin system and ß-blockers.31,32 Conversely,high-renin patients can have more robust BP responses torenin/angiotensin and ß-adrenoceptor blockers.

For patients with neurogenic hypertension, alphaand/or beta-receptor blockade or central sympatholytics,e.g., guanfacine, can lower BP. Heart rates of ∼80 beats/minute and higher have been associated with increasedcardiovascular morbidity and mortality, especiallysudden death in treated and untreated hypertensivepatients.33 ß-blockers, which lower heart rate, reducecardiovascular morbidity and mortality in patients withclinical CHD and heart failure. The benefits of ß-blockersfor primary prevention have been debated, althoughevidence supports their use as initial antihypertensivetherapy in adults < 60 years old.15

In the absence of compelling indications, renin/angiotensinand ß-blockers may be withdrawn from low-reninand diuretics from high-renin patients, while retainingBP control.31,32 In other words, renin-guided therapy canimprove BP control without increasing the number ofantihypertensive medications in a substantial proportionof patients. Medium-renin patients respond well to bothgroups of medications with preference given to the groupnot prescribed. For example, in a patient with mediumreninvalues on a ß-adrenoceptor blocker and angiotensinreceptor blocker, a diuretic or nondihydropyridine calciumantagonist would be preferred, whereas if the patient weretaking a diuretic and calcium channel antagonist, a renin/angiotensin system or ß-blocker would be preferred.

Prognosis in Patients with Controlled and
Uncontrolled TRH and Implications for
Clinical Management

Hypertension guidelines generally recommend addingand uptitrating antihypertensive medications until goalBP is achieved. The implied assumption is that the benefitsof treating hypertension are mainly related to BPlowering irrespective of the number of antihypertensivemedications required to achieve BP reduction. However,as summarized in Table 1, this assumption may notalways be valid.

Thus, in patients uncontrolled on three or more orcontrolled on four or more medications, it is importantfor clinicians to recognize that these individuals likelyremain at higher risk for cardiovascular events thanpatients prescribed fewer medications with comparableBP values. To mitigate risk for atherosclerotic cardiovascularevents, clinicians are encouraged to optimizecontrol of other cardiovascular risk factors with specialattention to prescription of evidence-based statin dosesin statin-eligible patients.34,36 Even moderate statin doses,e.g., atorvastatin 10 mg daily in the Anglo-ScandinavianOutcomes Trial (ASCOT), were associated with a 36%reduction in coronary events and less aTRH.35 This isconsistent with other evidence, suggesting a modest BPlowering effect of statins, which appears to be greater inadults with rather than without hypertension. Cliniciansare also encouraged to use antihypertensive medicationswith compelling indications37 in patients with CKD,CHF, and cardiovascular disease, which amplify risk forincident cardiovascular events.

In summary, aTRH is a common condition. Usingthe pragmatic approach outlined in this update and ourprevious pragmatic review,21 clinicians can identify andaddress pseudoresistance, screen for secondary hypertension,and initiate changes to lifestyle and pharmacotherapyto improve BP control. It is likely that ≥80% ofaTRH patients can be successfully managed in primarycare. For complex cases of secondary hypertension andtruly refractory hypertension, referral to a hypertensionspecialist is warranted for further management andconsideration of device-based therapies.

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