Treating Resistant Hypertension Today: Test Your...

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Treating Resistant Hypertension Today:Test Your Skills Supported by an independent educational grant from Arbor Pharmaceuticals, Inc.


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Treating Resistant Hypertension Today: Test Your Skills

Target AudienceThis activity is intended for cardiologists, primary care physicians, emergency medicine physicians, and all clinicians interested in the care of patients with resistant hypertension.

GoalThe goal of this activity is to improve physicians’ ability to screen for and manage resistant hypertension.

Learning ObjectivesUpon completion of this activity, participants will Have greater competence related to: • The assessment of patients to rule in or rule out resistant hypertension • Making appropriate selections of antihypertensive strategies in patients with resistant hypertension • Escalating therapy in a patient with hypertension in order to achieve treatment goals

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CME Released: 2/15/17; Valid for credit through: 2/15/18


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Faculty Information and Disclosure Statements

FacultyDavid S. Kountz, MD, MBAProfessor of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey

Disclosure: David S. Kountz, MD, MBA, has disclosed the following relevant financial relationships:

Received grants for clinical research from: Boehringer Ingelheim Pharmaceuticals, Inc.

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CME ReviewerRobert Morris, PharmDAssociate CME Clinical Director, Medscape, LLC

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The following cases are modeled on the interactive grand rounds approach. The questions within the activity are designed to test your current knowledge. After each question, you will be able to see whether you answered correctly and read evidence-based information that supports the most appropriate answer choice. The questions are designed to challenge you; you will not be penalized for answering the questions incorrectly. At the end of the activity, there will be a short post-test assessment based on the material presented.

Case 1: Patient BackgroundJoan, a 72-year-old black woman presents to her primary care physician (PCP) for her scheduled appointment. She has longstanding hypertension of about 30 years, diabetes, and osteoarthritis. At diagnosis at the age of 42, her hypertension (150/90 mm Hg) was initially managed with lifestyle modifications as she had no other cardiovascular risk factors at that time (diabetes and osteoarthritis developed later in her life). When lifestyle management alone was insufficient, she was treated with hydrochlorothiazide at an initial dose of 25 mg/day. Soon after the dose was titrated to 50 mg/day, which she did not tolerate, and she discontinued the medication. She was then prescribed a calcium channel blocker (CCB), amlodipine. Initiated at 2.5 mg/day and titrated to 10 mg/day over time, amlodipine has remained as her base drug for the last 20 years. Occasionally, a second antihypertensive agent has been added to her regimen but, for the most part, she has been on amlodipine alone. She takes an active interest in her health and keeps her scheduled medical appointments. She is socially active and regularly takes part in gatherings in her community. She is also physically active and plays with her grandchildren, despite her age and arthritis.

About 18 months ago, her PCP noticed that her blood pressure (BP) was gradually drifting away from her target of 140/90 mm Hg. At her request, her PCP did not add a second antihypertensive agent to her regimen. She pledged to adhere to lifestyle changes to bring her pressure back under control. Six months later, her office BP reading was 156/100 mm Hg. This time, she agreed with her doctor’s recommendations to add a second medication. An angiotensin converting enzyme (ACE) inhibitor, ramipril 2.5 mg/day, was added to her regimen and titrated to 10 mg/day. For the next 3 to 4 months, she continued on ramipril and amlodipine. Her BP neither improved nor worsened. At her next office visit, 6 months after the addition of ramipril, her office reading was 162/102 mm Hg. Her home BP measurements taken from time to time indicated readings in the range of 156/98 to 160/100 mm Hg.

QUESTION 1 (LO1)

Does Joan have resistant hypertension?

Answer Choices:

Yes, because her blood pressure (BP) was previously controlled

Yes, because diabetes predisposes to resistant hypertension

Yes, because older age predisposes to resistant hypertension

No, she has not yet failed ≥3 concurrent antihypertensive agents

Answer Explanation: Resistant hypertension is defined as the failure to reach target BP despite treatment with optimal doses of 3 concurrent antihypertensive medications. Patient characteristics, including older age, diabetes, and obesity, are associated with an increased risk of developing resistant hypertension. Although Joan’s age and her diabetes place her at increased risk for developing resistant hypertension, at present she cannot be diagnosed as having resistant hypertension. Per the definition of resistant hypertension, she has not failed 3 concurrent antihypertensive medications.

x

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The seventh Joint National Committee (JNC 7) and the 2008 American Heart Association (AHA) position statements define resistant hypertension as the failure to reach target BP despite treatment with 3 concurrent antihypertensive medications.[1,2] Both JNC 7 and AHA require that each medication should be from a different class of antihypertensive medications, with 1 medication from the diuretic class, and that all medications should have been optimally dosed. The AHA definition, in addition, includes hypertension that is controlled on ≥4 medications.[2] Although the AHA acknowledges that the number of medications is arbitrary, it is nonetheless important to set a definition in order to identify individuals with resistant hypertension as they are at a high risk of adverse outcomes.

Despite a standardized definition, the prevalence and incidence of resistant hypertension has proved difficult to estimate. Data from large clinical trials of antihypertensive therapy place the prevalence at 13% to 54%,[3-8] although this might be an overestimate. Patients in clinical trials often represent a preselected population with higher risk profiles and comorbidities. Estimates from observational studies of the general population of hypertensive individuals, in contrast, place the prevalence at 10% to 20%, which might be a more realistic estimate.[9-11] There are limited data on the incidence of resistant hypertension. A rigorously conducted longitudinal study utilizing patient data collected over a 4-year period from insurance databases has estimated the incidence of resistant hypertension among individuals presenting with incident hypertension to be 1.9%.[10]

The implications of uncontrolled BP in individuals with resistant hypertension are much more profound than those in patients without resistant hypertension. Individuals with resistant hypertension have a significantly higher risk of adverse cardiovascular and renal outcomes, including stroke, myocardial infarction, congestive heart failure, and chronic kidney disease.[10,11] The excess cardiovascular and renal risk in these individuals may be high as 50%.[10] The reason for the heightened cardiovascular and renal risk is unknown, although elevated levels of aldosterone may be a contributing factor.[12,13] Given the potential for a poorer outcome in individuals with resistant hypertension, clinicians need to be vigilant in identifying and properly managing these patients.

A number of patient characteristics are known to be associated with resistant hypertension, particularly older age, obesity, chronic kidney disease, and diabetes (Table 1).[2,10] The presence of these risk factors per se, however, should not be used to diagnose resistant hypertension.

Table 1. Patient Characteristics Associated With Resistant Hypertension[2,10]

Joan’s age and her diabetes would place her at an increased risk for developing resistant hypertension, but at present, she cannot be diagnosed as having resistant hypertension. Per the definition of resistant hypertension, she has not failed 3 concurrent, optimally dosed, antihypertensive medications.


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QUESTION 2 (LO1)

Which of the following would be a reasonable cause of action for Joan at this time?

Answer Choices:

Order ambulatory BP monitoring (ABPM)

Assess for medication adherence

Add another antihypertensive agent to her regimen

Refer for echocardiography to asses cardiovascular risk

Answer Explanation: In individuals who are unable to control their BP, underlying reasons for this failure need to be evaluated before further treatment considerations. Nonadherence to prescribed medications and the white coat syndrome are the 2 main reasons for failure to control BP. White coat syndrome can be ruled out as Joan’s home BP readings are consistent with the office measurement. ABPM is, thus, not necessary. It would be prudent to assess for nonadherence in Joan, although she takes an active interest in her health and keeps to scheduled appointments. In the absence of cardiac symptoms, a referral for echocardiography for cardiovascular risk assessment is not indicated.

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An estimated 80 million adults in the United States have high BP, representing a third of the adult population.[14] Data from the National Health and Nutrition Examination Survey 2011-2012 indicate that approximately 75% of individuals with hypertension are being treated with antihypertensive medication, and 50% have their BP controlled.[14] Most individuals with hypertension require 2 or more medications to achieve their BP target.[15] Approximately 80% achieve their target BP on 2-drug combinations.[16]

Individuals who are unable to reach their BP targets on treatment have uncontrolled hypertension, which is not synonymous with resistant hypertension.[2] Uncontrolled hypertension is a broader term that encompasses individuals with true resistant hypertension as well as patients who are poorly adherent to BP medications or who are suboptimally treated. Thus, reasons for the failure to control BP need to be evaluated in these individuals before further treatment considerations.[2,17]

Medication nonadherence is one of the main reasons for failure to achieve BP targets and is a major problem among antihypertensive individuals. An estimated 25% to 50% of individuals are totally or partially nonadherent to their prescribed antihypertensive treatments.[18-20] Clinicians can monitor adherence using patient self-reports, pill counts, prescription refill rates through electronic medical records, or assessment of serum levels of antihypertensive medications. Patient self-reports and pill counts, however, tend to overestimate adherence.[21,22] When inquiring about adherence, nonconfrontational approaches are more likely to produce a truthful response from the individual. For example, consider saying “Occasionally missing medications is quite normal considering our hectic lives. I am wondering if you ever miss taking your medications” as opposed to “I better not hear that you miss taking your medications.” Hence, good clinician-patient communication skills are important, with attention to nonjudgmental or nonconfrontational approaches to questioning. Assessment of adherence through prescription refill rates using electronic medical records is a more objective means of assessing adherence. However, it only tracks prescription filling but not medication consumption. Measurement of serum levels of antihypertensive medications, in contrast, is not only an objective but also an accurate means of monitoring adherence.[23] In the United States, laboratory assays to measure serum levels of most antihypertensive medications (thiazide diuretics, beta-blockers, CCBs, and spironolactone) are available and are covered by health insurance.[23]

When nonadherence is established, the underlying reason(s) should be assessed and addressed, if possible. Many factors are known to contribute to nonadherence, including patient-related factors (eg, health literacy, forgetfulness, psychosocial factors, and incompatibility with daily routine), medication-related (eg, adverse effects of medications and complex drug regimens), clinician-related (eg, poor clinician-patient encounters), and system-related (eg, financial reasons and medical insurance) factors.[24-27] As each individual’s situation is unique and may also change over time, strategies to address nonadherence should be individualized.

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White coat syndrome is another major contributor to uncontrolled BP. This syndrome is defined by an office BP reading that is persistently >140/90 mm Hg but normal (<130/80 mmHg) when measured in an out-of-office setting.[2] It is present in up to 40% of individuals with uncontrolled hypertension.[28] White coat syndrome can be ruled out by performing 24-hour ambulatory BP monitoring (ABPM) or home BP monitoring.[2] Although ABPM is a reliable, objective means of measuring an individual’s BP,[29] it may not be practical from a patient perspective. Arm discomfort and sleep disturbance at night due to scheduled readings may affect adherence to the monitor and result in erroneous readings.[30] ABPM is often not used in clinical practice. Home BP measurements are patient-friendly and a less costly alternative to ABPM. Individuals, however, need to be trained on properly using the monitor and performing BP measurements to obtain accurate home BP measurements. The accuracy of the monitor also needs to be validated against an office monitor.

Certain lifestyle behaviors and concomitant medications/substances can also interfere with BP control.[2,17,31] Excessive dietary salt and alcohol consumption as well as nonsteroidal anti-inflammatory drugs (NSAIDs), sympathomimetic agents (eg, decongestants, diet pills, and cocaine), and stimulants (eg, methylphenidate, dexmethylphenidate, dextroamphetamine, amphetamine, methamphetamine, and modafinil) can all elevate BP.

In Joan, white coat syndrome can be ruled out, as she performs home monitoring and her readings are consistent with the office measurement. ABPM is, thus, not necessary. It would be prudent to assess for nonadherence in Joan, although she takes an active interest in her health and keeps to scheduled appointments. She does take ibuprofen daily for relief of arthritic pain, which could potentially interfere with BP control. In the absence of cardiac symptoms, a referral for echocardiographic assessment of cardiovascular risk is not indicated in Joan.

Case 1 (cont): Assessment for Possible Reasons for Elevated BPJoan admitted that she might have missed taking her antihypertensive medications occasionally, but for the most part she has been adherent. She does not consume alcohol and follows the Dietary Approaches to Stop Hypertension (DASH) diet. She denies taking sympathomimetic agents or stimulants, but she does take ibuprofen daily for relief of arthritis pain. Her PCP had advised her to switch from ibuprofen to acetaminophen several months ago. Although she did follow his advice, her knee pain worsened and she switched back to ibuprofen. She did not provide this information to her physician. At this point, her PCP decides to add another medication to her antihypertensive regimen.

QUESTION 3 (LO3)

Which of the following would be an appropriate addition to her regimen?

Answer Choices:

Atenolol (beta-blocker)

Chlorthalidone (diuretic)

Doxazosin (α-adrenergic receptor blocker)

Valsartan (angiotensin receptor blocker [ARB])

Answer Explanation: The first 3 agents recommended by treatment guidelines for the management of hypertension include a diuretic, a CCB, and an ACE inhibitor or an ARB, either as monotherapy or as combination therapy. Joan is currently taking an ACE inhibitor and a CCB. When adding a third agent, the recommended option would be a diuretic. She is, however, intolerant to hydrochlorothiazide; thus, other diuretics should be considered. Chlorthalidone is more effective in reducing BP than hydrochlorothiazide is and would be a reasonable choice as a diuretic. Beta-blockers or alpha blockers may be used as fourth agents after inadequate BP control on CCB + ACE inhibitor + diuretic combination therapy. An ACE inhibitor and an ARB should not be used in combination as they belong to the same class of drugs. Using agents from the same class may not necessarily increase efficacy, but is likely to increase the risk of adverse effects.

x


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The JNC 8 and the American Society of Hypertension/International Society of Hypertension (ASH/ISH) guidelines recommend (in no particular order) a thiazide or thiazide-like diuretic, a CCB, and a renin-angiotensin system (RAS) inhibitor (an ACE inhibitor or an angiotensin II receptor blocker [ARB]) as the initial 3 medications for the management of hypertension, either as monotherapy or in combination.[16,32] In individuals with Stage 1 hypertension, guidelines recommend therapy initiation with a single agent, while in individuals with Stage 2 hypertension, the recommendation is to initiate combination therapy with 2 agents (Figure 1).[16] The choice of initial medications is influenced by age, ethnicity/race, and the presence of comorbid conditions (diabetes, chronic kidney disease, and coronary artery disease). Therapy is intensified with the addition of another agent when maximal doses of initial monotherapy or combination therapy fail to achieve BP target.

Figure 1. ASH/ISH Algorithm for the Management of Hypertension[16]

In black individuals with stage 1 hypertension who have no other comorbidities, irrespective of age, a CCB is the preferred initial agent, although a thiazide diuretic is also an option. Joan was first treated with a thiazide diuretic and then switched to a CCB when she did not tolerate the diuretic. When the CCB was no longer adequate to control her BP, an ACE inhibitor was added. As her BP is still not under control, the addition of a diuretic is indicated according to the guidelines.[16] Because Joan was previously intolerant to hydrochlorothiazide at 50 mg/day, reinstituting hydrochlorothiazide may not be the best option. The use of other thiazide or thiazide-like diuretics, particularly chlorthalidone, should be considered. At equivalent doses, chlorthalidone is a more effective BP-reducing agent than hydrochlorothiazide.[33,34] It also has a longer duration of action.[16] Beta-blockers may be used as a fourth agent after inadequate BP control with a diuretic, CCB, and an ACE inhibitor or ARB.[16,32] An ACE inhibitor and an ARB should not be used in combination as they belong to the same class of drugs, targeting RAS. They are both beneficial in patients with kidney disease, but when used together may increase the risk of renal events without an increase in benefit.[35-37] Moreover, in individuals not controlled on an ARB, adding a diuretic or CCB has been shown to be more effective than adding an ACE inhibitor,[38] underscoring the rationale for using agents from different classes.

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Case 1 (cont): Therapy EscalationJoan initiated treatment with chlorthalidone at 12.5 mg/day, and her amlodipine dose was titrated up to 20 mg/day. She returned 6 weeks later and her office BP reading was 140/80 mm Hg. Her home readings ranged from 140/80 to 145/85 mm Hg. She complained of peripheral edema.

QUESTION 4 (LO3)

How would you balance efficacy vs safety in this patient?

Answer Choices:

Discontinue ramipril as this is causing her peripheral edema

Discontinue chlorthalidone as this is causing her peripheral edema and increase ramipril dose to 20 mg/day

Reduce amlodipine dose to 10 mg/day and discontinue chlorthalidone

Reduce amlodipine dose to 10 mg/day and increase chlorthalidone dose to 25 mg/day, if needed

Answer Explanation: Peripheral edema is a dose-dependent adverse effect of CCBs. Joan has been on 10 mg of amlodipine for many years without tolerability issues. Therefore, reducing the dose back to 10 mg would resolve her edema. If reducing the dose of amlodipine affects her BP control, increasing the chlorthalidone dose to 25 mg/day or ramipril dose to 20 mg/day should be considered.

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Balancing efficacy and safety is an important consideration when using multiple agents to manage hypertension. At standard recommended doses, antihypertensive agents (diuretics, CCBs, ACE inhibitors, ARBS, and beta-blockers) produce similar reductions in BP.[39] When used in combinations, the efficacy of the agents is additive but the adverse effects are not. One agent, thus, does not potentiate the adverse effects of another. The adverse effects of diuretics, CCBs, and beta-blockers are dose-dependent while those of ACE inhibitors and ARBs are not. Hence, reducing the dose of the agents from the recommended doses may help mitigate the adverse effect burden of combinations. This was demonstrated in a meta-analysis of placebo-controlled trials where half-doses of CCBs and diuretics had significantly fewer adverse effects than the recommend doses.[39] Efficacy, on the other hand, was not significantly compromised. At half-doses, efficacy was reduced by 20%. Thus, when using multiple agents, low-to-moderate doses may help to achieve an adequate balance between efficacy and safety.

Clinicians may also consider titrating the dose of the agents to a patient-specific tolerable dose, to individualize the dose. Each class of agents has a specific adverse effect profile.[16] The most frequent adverse effects of diuretics are fatigue and excessive urination. With CCBs, peripheral edema, is a frequently reported adverse effect, especially at higher doses. Fatigue, lowering of heart rate, dizziness from low heart rate, reduced sexual function, and reduced exercise tolerance are notable adverse effects of beta-blockers. Cough is the main adverse effect reported with ACE inhibitors. ARBs do not cause coughs. Angioedema occurs rarely with ACE inhibitors and ARBs. Based on the adverse effects, clinicians should be able to identify the agent responsible when using multiple agents and adjust the dose appropriately.

In this patient, the higher dose of CCB is the cause of her peripheral edema. She has been on the 10 mg/day dose for many years without tolerability issues. Reducing the dose of amlodipine back to 10 mg/day would eliminate her peripheral edema. If reducing the dose of amlodipine affects her BP control, increasing her chlorthalidone dose to 25 mg/day or ramipril dose to 20 mg/day should be considered and adverse effects associated with dose increases monitored.

Case 1: ConclusionAmlodipine dose was reduced to 10 mg/day while maintaining chlorthalidone at 12.5 mg/day and ramipril at 10 mg/day. At her next scheduled visit, 4 weeks later, Joan reported the resolution of her peripheral edema. Her office BP reading was 142/83 mm Hg and her home readings were in that range as well.


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Case 2: Patient BackgroundAllen is a 48-year-old white man with a 10-year history of hypertension and a strong family history of hypertension. His father and uncle are hypertensive and have had cardiac events in their 60s. Allen is a busy executive and reports being under tremendous stress at work and at home. Allen is highly motivated to get his BP under control. He maintains a healthy lifestyle and is not overweight. He is an avid runner (runs half marathons), pays great attention to his diet, and avoids high sodium sports drinks. He is frustrated because even with these lifestyle measures, he has difficulty maintaining his BP target. His office BP is 154/94 mm Hg. His home readings are in the same range. He has no palpitations, chest pain, or other symptoms. His laboratory results are normal. He is on 2 antihypertensive agents, azilsartan 40 mg/day and amlodipine 5 mg/day. His PCP discussed adding chlorthalidone to his regimen but he opted not to as he has read that chlorthalidone is not as widely used as hydrochlorothiazide. His PCP added hydrochlorothiazide 12.5 mg/day to his regimen. Three months later at his next visit, his BP remains at 150/96 mm Hg.

QUESTION 5 (LO3)

According to the ASH/ISH clinical practice guidelines, what is a reasonable BP treatment goal for this young patient with a family history of hypertension and cardiac events?

Answer Choices:

<140/90 mm Hg

<150/90 mm Hg

<130/80 mm Hg

<120/80 mm Hg

Answer Explanation: All current treatment guidelines recommend a BP target of <140/90 mm Hg for most individuals with hypertension. In elderly individuals, the BP target is <150/90 mm Hg. For young individuals (<50 years), the ASH/ISH guidelines suggest a more aggressive goal of <130/80 mm Hg is reasonable and can be considered.

x

Various organizations have set treatment goals for systolic and diastolic BPs (Table 2).[16,31,32,40,41] For most individuals with hypertension, a BP goal of <140/90 mm Hg is recommended. In elderly individuals, defined as ≥60 years or ≥80 years depending on the organization, a higher BP goal of <150/90 mm Hg is recommended. In individuals with diabetes, chronic kidney disease, and coronary artery disease (CAD), previous guidelines endorsed a lower target of <130/80 mm Hg. However, there is insufficient evidence to support this lower treatment target and most guidelines now recommend <140/90 mm Hg as the BP goal. For individuals <50 years, there is currently no clinical trial evidence regarding BP targets. Although most guidelines recommend the <140/90 mm Hg goal, the ASH/ISH guidelines suggest that in these young individuals it is reasonable to consider a more aggressive BP goal of <130/80 mm Hg.[16] A treatment goal of <130/80 mm Hg is, thus, reasonable in Allen, who is 48 years old and has a family history of hypertension with cardiac events.

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Table 2. Hypertension Goals[16,31,32,40,41]

Organization Blood Pressure Goal (mm Hg)

General Diabetes Mellitus Chronic Kidney Disease

ASH/ISH <140/90≥80 yr: <150/90

<140/90 <140/90Albuminuria: <130/80

AHA/ACC/ASH <140/90 <140/90 <140/90

ESH/ESC <140/90>80 yr: 140-150/90

<140/85Proteinuria: <130/85

<140/90

JNC 8 <140/90≥60 yr: <150/90

<140/90 <140/90

ACP/AAFP ≥60 yr: SBP <150 ≥60 yr: SBP <140 ≥60 yr: SBP <140

AAFP = American Academy of Family Physicians; ACC = American College of Cardiology; ACP = American College of Physicians; AHA = American Heart Association; ASH = American Society of Hypertension; ESC = European Society of Cardiology; ESH = European Society of Hypertension ISH = International Society of Hypertension; JNC = Joint National Committee; SBP = systolic blood pressure.

QUESTION 6 (LO1)

What is the most reasonable next course of action for Allen?

Answer Choices:

Evaluate underlying reasons for not achieving BP goal

Add another agent from a different class

Increase the dose of his current agents

Refer for diet and exercise counseling

Answer Explanation: Allen has failed to control his BP on 3 concurrent antihypertensive medications, and resistant hypertension should be suspected. The evaluation of an individual with suspected resistant hypertension begins with assessment for pseudoresistance. Pseudoresistance may arise secondary to poor BP measurement technique, poor adherence to antihypertensive medications, white coat syndrome, or suboptimal dosing of medications.

x

Allen has failed to control his BP on 3 concurrent antihypertensive medications and resistant hypertension should be suspected.[1,2] Once resistant hypertension is suspected, the individual should be thoroughly evaluated to rule out pseudoresistance, or apparent resistance. Pseudoresistance may arise secondary to poor BP measurement technique, poor adherence to antihypertensive medications, white coat syndrome, or suboptimal dosing of medications.[2,17,31]

The correct measurement of office BP requires the individual to be seated and at rest and is performed using an appropriately sized cuff. Using cuffs that are too small for the arm can overestimate BP. Medication nonadherence and white coat syndrome are highly prevalent among individuals with resistant hypertension. Therapeutic monitoring (serum assays of hypertensive medications) indicates that up to 50% of individuals with resistant hypertension are poorly adherent[42] and based on 24-hour ABPM, up to 40% have white coat syndrome.[28] Thus, in individuals with suspected resistant hypertension, evaluation for medication adherence and ensuring BP readings are correctly assessed and are precise are critical. It is also important to ensure that antihypertensive medications are optimally dosed. Suboptimal dosing due to clinician’s failure to titrate medications to recommended doses or tolerable doses is a common finding in clinical practice. A community-based, practice network study that included more than 200 clinics and nearly 470,000 hypertensive individuals, found that approximately 14% of all patients with uncontrolled hypertension and 50% of patients with uncontrolled apparent treatment-resistant hypertension were treated with optimal doses of ≥3 BP medications.[43]

In Allen, a thorough evaluation for possible pseudoresistance should be undertaken before making any management decisions.


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Case 2 (cont): Assessing for PseudoresistanceThe office reading is repeated, paying particular attention to technique, but there was little change in Allen’s BP reading. Allen denies nonadherence to his medical regimen. He reassures his commitment to getting his BP under control. White coat syndrome can also be ruled out, as his home readings corroborate the office readings. His PCP reviews his medications with him and notes that he could increase the dose of amlodipine to 10 mg/day and hydrochlorothiazide to 25 mg/day. Three months later, Allen’s BP remains essentially unchanged at 149/95 mm Hg. He is diagnosed as having resistant hypertension.

QUESTION 7 (LO2,3)

In further managing Allen, all of the following measures are reasonable except_______.

Answer Choices:

Switch hydrochlorothiazide to chlorthalidone

Investigate for secondary hypertension as clinically indicated

Assess sodium intake

Increase hydrochlorothiazide dose to 50 mg/day

Answer Explanation: Resistant hypertension may arise due to lifestyle factors such as excessive dietary sodium or alcohol consumption, consumption of medications/substances that interfere with BP control, or secondary causes of hypertension. Accordingly, management of individuals with resistant hypertension begins with a review of the individual’s history (including lifestyle characteristics and comorbid conditions and medications taken) and physical examination and laboratory tests to assess for secondary causes of hypertension. As occult volume overload is common in individuals with resistant hypertension, pharmacologic management begins with optimizing diuretic therapy. This often involves switching from hydrochlorothiazide to chlorthalidone. Chlorthalidone is the preferred diuretic, as it is more potent than hydrochlorothiazide. Increasing hydrochlorothiazide dose to 50 mg/day is likely to be futile, as increasing the dose from 12.5 mg/day to 25 mg/day had little effect on BP.

x

Lifestyle factors such as excessive dietary sodium or alcohol consumption, consumption of medications/substances that interfere with BP control, or secondary hypertension may all lead to the development of resistant hypertension.[2,17,31] Excessive dietary sodium and alcohol cause systemic vasoconstriction and promote water and sodium retention, thereby mitigating the BP-lowering effect of antihypertensive agents. As mentioned in case 1, many nonhypertensive medications and substances directly increase BP and/or reduce the BP-lowering effect of antihypertensive medications (Table 3).[2,17] Secondary hypertension, caused by a potentially correctable condition, is present in 5% to 10% of all individuals with hypertension.[44] Some forms of secondary hypertension, however, are more common in individuals with resistant hypertension, including obstructive sleep apnea, chronic kidney disease, primary aldosteronism, and renal artery stenosis.[2,17]

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Table 3. Medications/Substances That Can Interfere With Blood Pressure Control[2,17]

Medications SubstancesAntidepressants (eg, bupropion, tricyclic antidepressants, selective serotonin reuptake inhibitors, venlafaxine, monoamine oxidase inhibitors)

Oral contraceptives Dietary (eg, alcohol, bitter orange, licorice)

Corticosteroids Stimulants (eg, methylphenidate, dexmethylphenidate, dextroamphetamine, amphetamine, methamphetamine, modafinil)

Herbal supplements (eg, ginseng, ephedra, mahuang)

Cyclosporine Sympathomimetic agents (eg, decongestants, diet pills, cocaine)

Erythropoietin TacrolimusNonsteroidal antiinflammatory agents (eg, ibuprofen, naproxen, aspirin, cyclooxygenase-2 inhibitors)

The management of individuals with resistant hypertension usually begins with a review of the individual’s history, including lifestyle characteristics and comorbid conditions and medications taken, and physical examination and laboratory tests to assess for secondary causes of hypertension.[2,17,31] In some instances, eliminating the interfering lifestyle factor or medication or treating the underlying secondary cause of hypertension can lead to BP control. A low-sodium diet is the number one lifestyle modification that is recommended to all individuals with resistant hypertension. A low-sodium diet decreases systolic BP by 4 to 7mm Hg and diastolic BP by 1 to 3 mm Hg in individuals with hypertension.[45-47] In individuals with resistant hypertension, reduction of BP is more pronounced. and can be as high as 23/9 mm Hg.[48]

Pharmacologic management of resistant hypertension begins with optimizing diuretic therapy.[2,17,31] Occult volume overload is common in individuals with resistant hypertension, and may be due to a high sodium diet and/or chronic kidney disease. The increase in extracellular volume may not manifest as overt peripheral edema. Although hydrochlorothiazide is the most commonly used thiazide diuretic, it’s BP-reducing effect is inferior to that of chlorthalidone.[33,34] Chlorthalidone is at least twice more potent than hydrochlorothiazide.[49] Chlorthalidone is, thus, the preferred diuretic for the management of resistant hypertension.[2,17] Hence, optimizing diuretic therapy in individuals with resistant hypertension may entail switching from hydrochlorothiazide to chlorthalidone.

In Allen, increasing his hydrochlorothiazide dose to 50 mg/day, which is the maximum dose, is likely to be futile, as increasing the dose from 12.5 mg/day to 25 mg/day had essentially no effect on BP.


Pg.15

Case 2 (cont): Therapy EscalationAllen’s PCP convinced him to switch from hydrochlorothiazide to chlorthalidone, which is initiated at 12.5 mg/day and then titrated up to 25 mg/day. He also reduces the dose of amlodipine back to 5 mg/day, considering the lack of an effect with the higher dose. After these changes, at his next visit, his BP is now at 140/94 mm Hg. As he is not at his goal of <130/80 mm Hg, his PCP decides to add another antihypertensive agent.

QUESTION 8 (LO2,3)

Which of the following agents could be added to Allen’s regimen?

Answer Choices:

Carvedilol

Doxazosin

Hydralazine

Spironolactone

Answer Explanation: Mineralocorticoid receptor antagonists (MRAs), spironolactone or eplerenone, are often recommended as the fourth agent in individuals with resistant hypertension. When MRAs fail to control BP or are contraindicated, other classes of pharmacologic agents may be considered, including beta-blockers (eg, carvedilol), direct vasodilators (hydralazine), a centrally acting agent (clonidine), or alpha-adrenergic receptor blockers (eg, doxazosin).

x

Optimizing diuretic therapy in individuals with resistant hypertension helps in reducing BP, but most individuals will require more than 3 agents to achieve control.[31] Mineralocorticoid receptor antagonists (MRAs), spironolactone or eplerenone, are often recommended as the fourth agent in these individuals.[2,17,31] The addition of MRAs provides significant antihypertensive benefit. Spironolactone can reduce systolic BP by 10 to 20 mm Hg and diastolic BP by 3 to 10 mm Hg.[50,51] Up to one-fifth of individuals with resistant hypertension have primary aldosteronism,[12,52,53] which provides the rationale for using MRAs in these individuals. Risk of hyperkalemia is a concern with MRAs, especially in older individuals and in patients with diabetes and/or chronic kidney disease. The risk is also heightened when MRAs are coadministered with ACE inhibitors, ARBs, and/or NSAIDs.[2] Serum potassium levels of individuals taking an MRA should thus be monitored every 3 months for at least the first year of treatment. When MRAs fail to control BP or are contraindicated, other classes of pharmacologic agents may be considered, including beta-blockers (eg, carvedilol), direct vasodilators (eg, hydralazine), a centrally-acting agent (eg, clonidine), or alpha-adrenergic receptor blockers (eg, doxazosin).[16,17]

Case 2 (cont): Follow-Up After Therapy EscalationThree months after the addition of spironolactone 12.5/day, Allen’s office BP reading drops to 135/90 mm Hg. Spironolactone is titrated up to 25 mg/day and 3 months later, Allen’s BP drops to 130/83 mm Hg. His serum potassium levels remain in the normal range at both 3 and 6 months after spironolactone initiation and he reports no adverse effects. Now that his BP is under control, he asks whether he can discontinue one of his antihypertensive agents to simplify his regimen.

Pg.16


QUESTION 9 (LO2)

How can Allen’s PCP respond to his request?

Answer Choices:

Discontinue amlodipine

Discontinue azilsartan

Use a single-pill combination therapy

Advise him that he should maintain his regimen

Answer Explanation: Allen’s BP has been controlled only in the past 3 months; hence, it would be prudent to continue his current regimen. However, his regimen can be simplified by substituting single-pill combinations for free-combinations, whenever possible.

x

Individuals with resistant hypertension require 4 or more antihypertensive agents to adequately control their BP to target levels.[31] Use of multiple agents may, however, pose a barrier to treatment adherence. Simplifying the treatment regimen by using single-pill combinations, in contrast, is associated with significantly better adherence/persistence than using free combinations.[54] Single-pill combinations may also be more effective than equivalent free-combinations in controlling BP, at least when used as initial therapy in individuals with hypertension.[55] A number of single-pill combinations are available in the United States (Table 4).[56]

Question type: Confidence

QUESTION 10

How difficult was this patient management decision for you to make? (Select ranking from 1 [Difficult] to 5 [Easy])

Answer Choices:

1 – Difficult

2

3

4

5 – Easy


Pg.17

Table 4. Single-Pill Combinations [56]

FDA-Approved Combination Products to Treat Hypertension

Amlodipine-Based Combinations* HCTZ-Based Combinations* Other Combinations*

Aliskiren:amlodipine Aliskiren:HCTZ Fosinopril:HCTZ Olmesartan:HCTZ Aliskiren:valsartan

Benazepril:amlodipine Amiloride:HCTZ Irbesartan:HCTZ Propranolol:HCTZ Atenolol:chlorthalidone

Olmesartan:amlodipine Benazepril:HCTZ Lisinopril:HCTZ Quinapril:HCTZ Azilsartan:chlorthalidone

Telmisartan:amlodipine Bisoprolol:HCTZ Losartan:HCTZ Spironolactone:HCTZ Bendroflumethiazide:nadolol

Valsartan:amlodipine Candesartan:HCTZ Methyldopa:HCTZ Telmisartan:HCTZ Chlorthalidone:clonidine

Aliskiren:amlodipine:HCTZ† Captopril:HCTZ Metoprolol:HCTZ

(extended release) Triamterene:HCTZ Trandolapril:verapamil

Amlodipine:HCTZ:olmesartan† Enalapril:HCTZ Metoprolol:HCTZ Valsartan:HCTZ

Amlodipine:HCTZ:valsartan† Eprosartan:HCTZ Moexipril:HCTZ

HCTZ = hydrochlorothiazide.*Generic names; †Triple-combination therapy is not recommended for initial treatment of hypertension.

Allen’s BP has been controlled only in the past 3 months; hence, it would be prudent to continue his current regimen. However, his regimen can be simplified by substituting the single-pill combination of azilsartan/chlorthalidone 40/25 for the free combination of azilsartan 40 mg/day and chlorthalidone 25 mg/day.

Case 2: ConclusionThe free combination of azilsartan and chlorthalidone is discontinued and the single-pill combination of azilsartan/chlorthalidone 40/25 is initiated in Allen. Spironolactone 25 mg/day and amlodipine 5 mg/day are continued. At his last follow-up, a year after the addition of spironolactone, his BP remains at or close to his target of <130/80 mm Hg.

Pg.18


Abbreviations

AAFP = American Academy of Family Physicians

ABPM = ambulatory blood pressure monitoring

ACC = American College of Cardiology

ACE = angiotensin converting enzyme

ACP = American College of Physicians

AHA = American Heart Association

ARB = angiotensin receptor blocker

ASH = American Society of Hypertension

BP = blood pressure

CAD = coronary artery disease

CCB = calcium channel blocker

DASH = Dietary Approaches to Stop Hypertension

ESC = European Society of Cardiology

ESH = European Society of Hypertension

HCTZ = hydrochlorothiazide

ISH = International Society of Hypertension

JNC = Joint National Committee

MRA = mineralocorticoid receptor antagonist

NSAID = non-steroidal anti-inflammatory drug

PCP = primary care physician

RAS = renin-angiotensin system

SBP = systolic blood pressure

Related LinksLinear Relationship Between Sodium Consumption and Mortality www.medscape.org/viewarticle/870674

Treat the Risk, Not Just the Numbers, for Hypertension http://www.medscape.org/viewarticle/870664

Incorporating Oral Prostanoids Into Practice: Who Is the Right Candidate? http://www.medscape.org/viewarticle/867874

What Is the Optimal Sodium Intake to Reduce CV Risk http://www.medscape.org/viewarticle/863684


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