Guideline-Driven Management of Hypertension

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Circulation Research is available at www.ahajournals.org/journal/res

Correspondence to: Robert M. Carey, MD, P.O. Box 801414, University of Virginia Health System, Charlottesville, VA. Email [email protected] The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCRESAHA.121.318083.

For Sources of Funding and Disclosures, see page 841.

HYPERTENSION COMPENDIUM

Guideline-Driven Management of Hypertension

An Evidence-Based Update

Robert M. Carey , Jackson T. Wright Jr, Sandra J. Taler, Paul K. Whelton

ABSTRACT: Several important findings bearing on the prevention, detection, and management of hypertension have been reported since publication of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline. This review summarizes and places in context the results of relevant observational studies, randomized clinical trials, and meta-analyses published between January 2018 and March 2021. Topics covered include blood pressure measurement, patient evaluation for secondary hypertension, cardiovascular disease risk assessment and blood pressure threshold for drug therapy, lifestyle and pharmacological management, treatment target blood pressure goal, management of hypertension in older adults, diabetes, chronic kidney disease, resistant hypertension, and optimization of care using patient, provider, and health system approaches. Presenting new information in each of these areas has the potential to increase hypertension awareness, treatment, and control which remain essential for the prevention of cardiovascular disease and mortality in the future.

Key Words: American Heart Association ◼ antihypertensive agents ◼ blood pressure ◼ cardiovascular disease ◼ hypertension ◼ mortality

G

lobally, high blood pressure (BP) is the leading risk factor for cardiovascular disease (CVD) morbidity and mortality.¹ In the United States, high BP ranks first among modifiable risk factors in population attributable to CVD risk, accounting for the largest proportion of coronary heart disease, heart failure, and stroke events.² In adults with hypertension, control of BP with antihypertensive medication reduces the risk of CVD and all- cause mortality.^3,4 Thus, hypertension is one of the most consequential and remediable threats to the health of individuals and society.

Although BP-lowering interventions can be used to prevent CVD events and mortality, this can only be achieved by preventing high BP and recognizing, treating, and controlling hypertension.⁵ The first step in managing hypertension is accurate diagnosis. Once hypertension has been confirmed, lifestyle modification and pharmacological treatment can be initiated to reduce BP and CVD risk. Titration of nonpharmacological and medication interventions to maximum tolerable effectiveness and long-term persistence with the treatment regimen are essential for optimal BP control and CVD risk reduction.

In the United States, progress in the quest to reduce population BP over the past several decades has been quantified as trends in hypertension awareness, treatment, and control to a systolic BP (SBP)/diastolic BP (DBP) <140/90 mm Hg. In an analysis of National Health and Nutrition Examination Survey data, hypertension (SBP ≥140 mm Hg, DBP ≥90 mm Hg, or taking antihypertensive medication) awareness and treatment increased significantly in all age groups between 1999 to 2004 and 2011 to 2016 (≈85 and 79%, respectively, for adults ≥65 years in 2011–2016). However, the improvements primarily occurred between 1999 to 2004 and 2005 to 2010.⁶ Hypertension awareness and treatment rates in 2011 to 2016 were relatively high, providing limited opportunity for improvement. In contrast, National Health and Nutrition Examination Survey analyses identify markedly suboptimal rates of BP control.^6,7 Among all adults with hypertension, the proportion with BP controlled to an SBP/DBP <140/90 mm Hg increased from 31.8% in 1999 to 2000 to 48.5% in 2007 to 2008, peaked at 53.8% in 2013 to 2014, and then declined to 43.7% in 2017 to 2018.⁷ Among adults

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HYPERTENSION COMPENDIUM

taking antihypertensive medication, the prevalence of SBP/DBP control to <140/90 mm Hg increased from 53.4% in 1999 to 2000 to 68.3 % in 2007 to 2008, peaked at 72.2% in 2013 to 2014, and then declined to 64.8% in 2017 to 2018, such that control rates in 2017 to 2018 were similar to those in 2005 to 2006.⁷ From a public health perspective, the substantial reduction in BP control from 2013 to 14 to 2017 to 18 is alarming.

In December 2013, the panel members appointed to the eighth Joint National Committee (JNC-8) published a report recommending a higher BP goal (SBP/DBP

<150/90 mm Hg) for adults ≥60 years compared with the 2003 JNC-7 recommended target (SBP/DBP <140/90 mm Hg).^8,9 A minority report from 5 of the 17 JNC-8 panel members warned that relaxation of the BP goal would reduce the intensity of antihypertensive drug therapy and

level of BP control.¹⁰ In March 2017, a clinical practice guideline from the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) also recommended initiation of antihypertensive treatment in adults ≥60 years with an SBP persistently ≥150 mm Hg to achieve an SBP <150 mm Hg, with the possibility of a lower initiation and target SBP of 140 mm Hg in those with a history of stroke, a transient ischemic attack, or other evidence of high CVD risk.¹¹ It is conceivable that the JNC-8 panel members and ACP/AAFP guideline reports may be responsible for the diminution in hypertension control.

In November 2017, the American College of Cardiology (ACC)/American Heart Association (AHA) in partner- ship with 9 other professional societies published a BP guideline that redefined hypertension as a persistent average SBP ≥130 mm Hg or DBP ≥80 mm Hg (SBP ≥130 mm Hg for those ≥65 years of age), lowered the drug treatment threshold to an average SBP ≥ 130 mm Hg or DBP

≥80 mm Hg for adults with a 10-year atherosclerotic CVD (ASCVD) risk ≥10%, and reduced the SBP/DBP goal of therapy to <130/80 mm Hg (SBP<130 mm Hg for those

≥65 years).¹² These changes were prompted by data showing a ≈2-fold increase in CVD events and mortality in adults with BP 130 to 139/80 to 89 mm Hg compared with those with normal BP (<120/80 mm Hg), attributable risk estimates that this category of BP accounts for >20% of the BP-related CVD events, the results of multiple randomized clinical trials (including the PREVER- Prevention Trial [Prevention of Cardiovascular Events in Patients with Hypertension and Pre-hypertension Study trial] and SPRINT [Systolic BP Intervention Trial]), and meta-analyses of trials showing reduced CVD events and death with goal BP <130/80 mm Hg.¹² Although the ACP and AAFP¹¹ failed to endorse the 2017 ACC/AHA Guide- line recommendations for a lower BP goal, the Guideline has been embraced by most professional societies with an interest in BP and by US governmental agencies, including the National Center for Health Statistics that oversees the National Health and Nutrition Examination Survey. Adop- tion of the ACC/AHA recommendations has the potential to increase hypertension awareness, treatment, and control, both by increasing the proportion of adults taking antihypertensive medication and by treatment intensification for those with BP levels above target.

A substantial worldwide decline in population BP has occurred since the initiation of hypertension prevention, detection, treatment, and control programs in the 1960s and 1970s.¹³ These BP reductions have been noted in high-risk, socioeconomically disadvantaged populations, including in the Southeastern region of the United States, where population SBP levels declined by as much as 18 mm Hg over a 40-year period.¹⁴ This seems to have resulted from a downward shift in average BP across the entire distribution of BP, suggesting an effect of lifestyle changes in addition to pharmacological antihypertensive treatment.

Nonstandard Abbreviations and Acronyms

AAFP American Academy of Family Physicians

ABPM ambulatory blood pressure monitoring ACC American College of Cardiology ACCORD Action to Control Cardiovascular Risk

in Diabetes

ACCORD-BP Action to Control Cardiovascular Risk in Diabetes Blood Pressure

ACE angiotensin-converting enzyme ACP American College of Physicians ADVANCE Action in Diabetes and Vascular

Disease

AHA American Heart Association ARR aldosterone/renin ratio

ASCVD atherosclerotic cardiovascular disease

BP blood pressure

CARDIA Coronary Artery Risk Development in Young Adults

CVD cardiovascular disease DASH Dietary Approaches to Stop

Hypertension

DBP diastolic blood pressure DM diabetes mellitus

FU follow up

HBPM home blood pressure monitoring

HR hazard ratio

JNC Joint National Committee

MH masked hypertension

MRA mineralocorticoid receptor antagonist

OR odds ratio

RCT randomized controlled trial RH resistant hypertension SBP systolic blood pressure

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HYPERTENSION COMPENDIUM This review focuses on the prevention, detection, and

management of hypertension with emphasis on new information since the publication of the 2017 ACC/AHA BP Guideline.¹²

BP Measurement and the Diagnosis of Hypertension

The ability to measure BP accurately remains a major challenge for providers managing patients with hypertension. Office BP measurements for clinical care are meant to be similar to those utilized in the observational cohort studies that have documented risk at a given BP level and the antihypertensive clinical outcome trials that have documented the benefit of BP lowering.^12,15 However, the time required for staff training and the need for effi- ciencies in provider workflow patterns continue to com- promise the validity of office BP measurements used for diagnosing hypertension and assessing success in achieving hypertension treatment targets.^15,16

The 2017 ACC/AHA BP Guideline supports use of oscillometric devices to obtain automated office BP measurements and recommends out-of-office BP readings to confirm high BPs in the office and to recognize masked hypertension (MH) and white coat hypertension.¹² The Euro- pean Society of Hypertension recommended out-of-office BP in 2007 as a complement to office BP measurement.¹⁷ The National Institute for Health and Care Excellence clinical guideline in 2010 was the first to recommend confir- mation of the hypertension diagnosis using out-of-office measurements, although this was primarily to exclude overtreatment of patients with white coat hypertension.¹⁸ Since the publication of the 2017 ACC/AHA Guideline, other national guidelines have also recommended the use of out-of-office readings to exclude white coat hypertension and MH, although these readings were recommended to be complementary rather than preferred to office readings.^19,20 Differences between office BP, automated office BP, home blood pressure monitoring (HBPM), and ambulatory blood pressure monitoring (ABPM) are summarized in Figure I in the Data Supplement.

Automated office BP monitors that can be pro- grammed to measure multiple BP readings automati- cally after the recommended rest period were also promoted by the 2017 ACC/AHA Guideline and 2019 AHA Scientific Statement.^12,15 Although earlier data suggested that BP varied with the presence or absence of staff during BP measurement with these devices,²¹ more recent studies have refuted this concern when the core recommendations for accurate measurement are respected.^22–24 However, less active staff involvement can result in less staff time per reading compared with manual measurement (and potential cost savings).²⁵ A challenge to the use of oscillometric devices in place of mercury and aneroid sphygmomanometers in clinical practice and research is the lack of independent

validation of many such devices and the lack of require- ment for validation of devices sold in most countries, including the United States.^15,26 Unfortunately, only 1 in 5 automated devices are validated for accuracy.²⁷ Online listing of validated devices, including the newly released US Blood Pressure Validated Device Listing, are now readily available.^28,29 Although well-designed com- parisons of ABPM and HBPM are not available, some helpful reports have been published during the last 2 years. In a study of participants (N=333) with office BP<140/90, ABPM was more sensitive in detecting MH than HBPM, with an MH prevalence of 25.8% overall and 11.1% at home, with 29% to 29.5% showing MH by both techniques.³⁰ In another study, HBPM was as effective as ABPM in predicting left ventricular mass index.³¹ A comparison of office and out-of-office BP measuring techniques is shown in Table 1.

Despite its lower sensitivity in detecting MH, HBPM remains the most practical option for recognition of MH and white coat hypertension as well as for BP monitoring, especially during medication titration and monitoring of treatment BP levels. However, careful attention to patient education is required in order for providers to have confidence in accepting HBPM data over office readings to determine BP control (Table 2).^12,32,33 In a study of community-dwelling adults (N=318), 2 readings taken in the morning and evening for a minimum of 3 days have proven sufficient for reliable estimation of out-of-office BP and for confirming the diagnosis of hypertension.³⁴ HBPM has been particularly useful with the increasing need for virtual visits to manage hypertension during the coronavirus disease 2019 (COVID-19) pandemic.

Newer technologies for BP measurement that are less intrusive and provide a more complete profile of BP are on the horizon.³⁵ These will require both validation for accuracy and their capacity to predict clinical outcomes.

The ability to measure and compare central to brachial BP was proposed as a better way to predict CVD risk.³⁶ However, a recent study in a large cohort (N=13 461) suggested that measurement of central BP using the Sphygmocor device was no more predictive of CVD outcomes than automated office BP readings obtained with the Omron 907 device.³⁷

PATIENT EVALUATION: SCREENING FOR SECONDARY HYPERTENSION

The 2017 ACC/AHA Guideline provides detailed guidance on historical, physical, and laboratory features that may suggest secondary hypertension and merit additional testing.¹² It is particularly important to consider an evaluation for secondary causes when the patient is young or the hypertension is resistant to treatment. Identification of a secondary cause may cure hypertension, or improve BP control if a cure is not feasible. The approaches to

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management of renovascular hypertension and primary aldosteronism have recently been modified.

Renovascular Hypertension

Several randomized controlled trials (RCTs) of renal artery interventions in ASCVD renovascular hypertension have failed to demonstrate an improvement in mortality or renal survival.³⁸ A recent systematic review of 8 major RCTs reported reduction in DBP and the number of antihypertensive medications needed, but no differences in SBP or renal function after angioplasty.³⁹

Even when significant ASCVD renal artery stenosis is confirmed, the optimal course of treatment is not clear, particularly with unilateral lesions.⁴⁰ In most cases, unilateral lesions can be managed using medical therapy (renin-angiotensin system blockade) with periodic sur- veillance to ensure adequate perfusion of the contra- lateral nonstenotic kidney. However, for some patients, particularly those who are younger, have sudden onset of hypertension, or have radiological features that suggest fibromuscular dysplasia, direct intervention is often sen- sible (Table 3).⁴¹ For fibromuscular dysplasia this should consist of angioplasty without stents, whereas stents are needed for most atherosclerotic lesions to maintain long- term patency. For patients with bilateral hemodynamically significant stenosis, defined as a stenosis >75%, intra- arterial intervention should be considered with careful assessment of patient risk for complications, especially renal atheroembolic events. In patients at high risk for complications from intra-arterial intervention, a trial of renin-angiotensin system blockade is an appropriate first step with careful monitoring of kidney function. If creatinine rises >30% or the patient develops sudden (flash) pulmonary edema, this will suggest the need for an inva- sive approach. Patients with severe bilateral stenosis were not included in the RCTs and require careful individualized decision-making with consideration of intervention to pre- serve kidney function.

Primary Aldosteronism

New evidence suggests that primary aldosteronism is part of a spectrum of aldosterone excess states. Recent publications suggest aldosterone excess plays a role in primary hypertension or intermediate conditions of rela- tive aldosterone excess, a forme fruste of the full primary aldosteronism state. Data from Brown et al⁴² support consideration of primary aldosteronism even when the plasma aldosterone/renin ratio (ARR) screening test is negative. In an analysis of patient cohorts at 4 centers, including participants with normal BP, untreated stage 1 and stage 2 hypertension, and treated resistant hypertension (RH), ARR was compared with urinary aldosterone excretion measured after oral salt loading.

Using a urinary aldosterone level >12 µg/24 hours as the threshold for diagnosis, primary aldosteronism was present in 11.3% of normotensive patients, and up to 22% of those with hypertension, with increasing prevalence associated with greater severity of hypertension.

The ARR had poor sensitivity and negative predictive value, particularly when renin was suppressed.⁴² Cohen et al⁴³ reported very low (1.6%) utilization of ARR screening for patients with RH in the Veterans Admin- istration system suggesting that many cases of primary aldosteronism are missed. These findings suggest that aldosterone excess may play a role even in primary hypertension and may be unrecognized as a contribu- tor to RH (Figure). For hypertensive patients with suppressed renin levels, especially those with uncontrolled or RH, it is important to go beyond the ARR to measure urinary aldosterone excretion under salt-loading conditions. Furthermore, the concept of a spectrum of aldosterone excess mediated mechanisms may explain the effectiveness of mineralocorticoid receptor antago- nists (MRAs) observed in the PATHWAY-2 trial (Spi- ronolactone versus Placebo, Bisoprolol and Doxazosin to Determine an Optimal Treatment for Drug-Resistant Hypertension trial) of RH.⁴⁴

Table 1. Comparison of Office BP, Automated Office BP, ABPM, and HBPM Characteristic

Standard of-

fice BP AOBP ABPM HBPM

Measurement parameter(s) Resting office BP

Resting office BP

Dynamic daytime BP (responses to exercise, meals, drugs); BP pattern (NH, nocturnal BP dipping, early AM BP surge)

Resting home BP

Detects WCH No No Yes Yes

Detects MH No No +++ ++

Sensitivity for estimating CVD event risk

+ + +++ ++

Sensitivity for estimating LVH

risk − − ++ ++

Use with BP telemonitoring No No ++ +++

ABPM indicates ambulatory BP monitoring; AOBP, automated office BP; BP, blood pressure; CVD, cardiovascular disease;

HBPM, home BP monitoring; LVH, left ventricular hypertrophy; MH, masked hypertension; NH, nocturnal hypertension; and WCH, white coat hypertension.

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CARDIOVASCULAR RISK ASSESSMENT AND BP THRESHOLD FOR DRUG

THERAPY

The 2017 ACC/AHA BP Guideline based decisions regarding initiation of medication on level of BP and estimation of ASCVD risk, supported by evidence from clinical trials and meta-analyses.¹² The ACC/AHA risk

calculator provides guidance for patients age 40 to 79 years but does not apply to younger patients where data are lacking. Based on average risk in the landmark antihypertensive drug trials, a 10-year ASCVD ≥10% was identified as the cut point for definition of high risk.

Treatment of Hypertension in Young Adults

With rising rates of overweight and obesity, in the United States and globally, the prevalence of hypertension and diabetes mellitus (DM) resulting from insulin resistance has increased and may carry greater risk in the context of multiple CVD risk factors, even in the young.¹ For young patients with isolated hypertension, lifetime risk of ASCVD is high. As the overall distribution of BP has shifted to a lower average value in the community, more CVD events are occurring at lower BP levels.^14,45 This was recently shown to be true for young adults with hypertension who have earlier onset of coronary heart disease, heart failure, stroke, transient ischemic attacks, and peripheral arterial disease requiring intervention. In the CARDIA (Coronary Artery Risk Development in Young Adults) longitudinal study of 3851 young adults followed over a median of 18.8 years, only 4% were taking medication for hypertension.⁴⁶ Adjusted hazard ratios (HRs) for CVD events were 1.67 (95% CI, 1.01–2.77), 1.75 (95% CI, 1.22–2.53), and 3.49 (95% CI, 2.42–5.05), for elevated BP, and ACC/AHA stage 1 and stage 2 hypertension, respectively, compared with controls with normal BP.⁴⁶ Supplemented by evidence for target organ damage (TOD), including left ventricular hypertrophy⁴⁷ and brain volume and white matter changes,⁴⁸ high BP in the young may no longer be considered benign. Therefore, it may not be appropriate to delay antihypertensive pharmacological treatment, even while lacking event-based RCT evidence for prevention of ASCVD. Young patients are reported to have lower awareness, slower time to diagnosis, and poorer BP control than older patients.

Concerns raised by providers relate to labeling of young adults with illness, medication safety concerns, especially in women of childbearing age, concerns related to potential misdiagnosis, and impact on life insurance rates. Both DBP and SBP are important for prediction of CVD risk in young adults. In a recently reported risk analysis conducted in almost 6.5 million Koreans, aged 20 to 39 years at baseline, who were followed for a median of 13.2 years, ACC/AHA stage 1 isolated systolic hypertension, isolated diastolic hypertension, and systolic/

diastolic hypertension were associated with multivariate- adjusted hazard ratios of 1.36, 1.32, and 1.67, respectively, compared with normal BP.⁴⁹

The evidence suggests treatment of hypertension in the young using lifestyle modification with the addition of BP-lowering medications when lifestyle interventions are inadequate. Allowing a period of 6 to 12 months to institute lifestyle modification is reasonable but only in

Table 2. Procedures for Use of HBPM Instructions to staff

Patient training should occur under medical supervision and include Information about hypertension

Advice in selection of BP monitor

Acknowledgment that individual BP readings may vary substantially Interpretation of results

Devices

Verify use of validated automated devices. Use of auscultatory devices (mercury, aneroid, or other) is not generally useful for HBPM because patients rarely master the technique required for measurement of BP with auscultatory devices.

Monitors with provision for storage of readings in memory are preferred.

Verify use of appropriate cuff size to fit the arm

Verify that left/right inter-arm differences are insignificant. If differences are significant, instruct patient to measure BPs in the arm with higher readings.

Instructions provided to patients Instructions on HBPM procedures

Avoid smoking, caffeinated beverages, or exercise within 30 min before BP measurements.

Ensure ≥5 min of quiet rest before BP measurements.

Sit correctly

Back straight and supported

Sit with feet flat on the floor and legs uncrossed.

Arm supported on a flat surface (such as a table), with the upper arm at heart level.

Bottom of the cuff placed above the antecubital fossa (bend of the elbow).

Remain still during BP measurement Take multiple readings

At least 2 readings 1 min apart in morning before taking medications and in evening.

Measure and record BP daily during week before a clinic visit and when instructed.

Record all readings accurately

Monitors with built-in memory should be brought to all clinic appoint- ments.

BP should be based on an average of readings on ≥2 occasions for clinical decision-making.

Note: We encourage training and certification through PAHO or American Heart Association (AHA)/AMA Target BP virtual courses. AHA indicates Ameri- can Heart Association; AMA, American Medical Association; BP, blood pressure;

HBPM, home blood pressure monitoring; and PAHO, Pan American Health Or- ganization.

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the absence of TOD. There is an urgent need for hypertension treatment event-based RCTs in the young which will likely require measuring TOD end points rather than only cardiovascular events and death.

LIFESTYLE MANAGEMENT: THE

CORNERSTONE OF PREVENTION AND TREATMENT

Numerous environmental factors are associated with BP, especially components of diet, physical activity, and alcohol consumption. In many instances, changes in exposure to these factors have led to a corresponding change in BP, with the best-proven interventions being a healthy diet, reduced sodium intake, weight loss, augmentation of potassium intake, physical activity, and abstinence or moderation in alcohol consumption.^12,50 These 6 interventions are effective for prevention of hypertension, treatment of hypertension, enhancing the effect of antihypertensive medication, and reducing the number of drugs needed to control BP (Table 4).

A recent meta-analysis confirmed the efficacy of nonpharmacological interventions for prevention of hypertension in trials that were conducted in low- and middle-income countries.⁵¹ Fu et al⁵² conducted a series of clinical trials network meta-analyses to estimate the comparative effectiveness of 22 different interventions for lowering BP in 2 groups of adults (those with an SBP ≥140 mm Hg, DBP ≥90 mm Hg, or taking antihypertensive medication, and those with an SBP 120–139 mm Hg or DBP 80–89 mm Hg). Based on the BP-lowering effects in pooled analyses and the GRADE estimated quality of the underlying data,⁵³ they concluded that an intervention based on the Dietary Approaches to

Stop Hypertension (DASH) was superior to usual care and all other nonpharmacological interventions in lowering SBP. Unfortunately, differences in study design, intervention methods, the samples studied, and other aspects of the clinical trials that were compared make it difficult to conduct a fair comparison. The greatest impediment to accepting the conclusion that the DASH diet provides superior BP lowering compared with the other interventions recommended in the 2017 ACC/AHA Guideline is that the DASH diet trials included in the Fu et al⁵² meta-analyses were feeding studies, whereas most of the other interventions were evaluated in trials that employed behavior change interventions. Feeding studies provide a very efficient means to change diet, but they are expensive and the efficacy in such studies is not generalizable. In clinical practice, behavior change and pill supplementation are the only practical approaches to implementing nonpharmacological recommendations, with behavior change being the preferred approach.¹² In a 3-arm behavioral change trial (N=810; baseline mean SBP/DBP=134.9/84.8 mm Hg) that compared usual care, an established BP-lowering intervention (weight loss, sodium reduction, increased physical activity, and limited alcohol intake) and addition of the DASH diet to the established intervention, both active interventions were effective compared with usual care (≈4 mm Hg SBP net difference), but addition of the DASH diet to the established diet provided no additional statistically significant lowering of SBP (P=0.43).⁵⁴ It may be better to accept that each of the nonpharmacological interventions recommended in the 2017 ACC/AHA Guideline is effective and use of ≥2 interventions is likely to result in a more substantial effect.⁵⁵ Likewise, each of the interventions has greater efficacy at higher starting levels of BP. A pragmatic approach in clinical and public

Table 3. Clinical Approaches to Renovascular Hypertension Evaluation and Treatment Cause Patient characteristics Risk factors

Screening, initial approaches

Confirmatory

testing Management options Fibromuscular

dysplasia

Female prevalence, age of onset 30–50 s, association with smoking, some with family history

Smoking CT angiography Renal angiography Angioplasty without stenting (rarely recurs) vs medical therapy with renin-angiotensin blockade

MR angiography if CT not an option, Doppler US at spe- cialized centers Atherosclerotic

disease

Male prevalence, older age of onset associated with atherosclerosis in multiple vascular beds, association with smoking, hyperlipidemia

CVD risk factors including smoking, hyperlipidemia

Doppler US Renal angiography if intervention indicated

Unilateral disease: Medical therapy using renin-angiotensin blockade and management of CVD risk factors with interval monitoring of renal function and perfusion CT or MR angiog-

raphy

Bilateral disease: Medical therapy using renin-angiotensin blockade and management of CVD risk factors with interval monitoring of renal function and perfusion, vs angioplasty with stenting with careful assessment of risks of intervention Aortic

coarctation

Onset of hypertension before age 30 y, claudication symptoms

Bicuspid aortic valve

Measurement of brachial and popliteal BP

CT angiography Referral to congenital heart disease or vascular medicine specialist

CT angiography

BP indicates blood pressure; CT, computed tomography; CVD, cardiovascular disease; MR, magnetic resonance; and US, ultrasound.

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health practice is to decide which of the proven interventions are likely to be of greatest benefit based on an individual’s or population’s lifestyle and their perceived willingness to embrace the interventions. Specifically, is overweight, excessive sodium or alcohol consumption, or unhealthy diet the biggest problem, and which of the possible interventions is likely to be embraced with the most enthusiasm?

The greatest potential for a population-wide nonpharmacological intervention is gradual reduction in the addition of sodium during food processing and preparation.⁵⁶ Resolve to Save Lives, the World Health Organization, the World Hypertension League, and others are collaborat- ing to achieve the goal of sodium reduction globally.^57–60 A new biostatistical method, which facilitates aggre- gation of data from 2-armed RCTs, the most common type of experimental contrast, has made estimation of the dose-response relationship between sodium and BP more feasible.⁶¹ Filippini et al⁶² used this method to conduct a sodium-BP dose-response meta-analysis based on 81 clinical trials with a minimal duration of 4 weeks.

They identified a substantially linear dose-response relationship between sodium intake and BP across the entire range of exposure, with a 100 mmol/d reduction in sodium being associated with a 5.43 mm Hg reduction in SBP. The results were similar for those with or without hypertension, except that the former group exhibited a steeper decrease in BP following sodium reduction.

These findings support the lower sodium intake target (<1500 mg/d) recommended by the AHA,⁶³ compared with the <2300 mg/d target endorsed by the 2019 National Academies of Sciences, Engineering, and Medi- cine Dietary Reference Intakes Review Committee,⁶⁴ or the <2000 mg/d target advocated in 2012 by the World Health Organization.⁶⁵ However, the findings also suggest benefit from any reduction in sodium intake that can be achieved.

In a separate analysis of 32 RCTs, Filippini et al⁶⁶ reported a U-shaped pattern for the dose-response relationship between potassium intake and BP, with the optimal BP-lowering effect occurring for potassium intakes in the range of 90 to 150 mmol/d. The BP-lowering

Figure. Schematic representation of the mechanisms of autonomous aldosterone production in primary hypertension.

Aldosterone production from the adrenal zona glomerulosa is independent of the renin-angiotensin system and is not suppressible with dietary sodium loading. Excess aldosterone expands extracellular fluid volume by augmenting sodium reabsorption in the renal cortical collecting duct. Expanded fluid volume leads to hypertension and suppression of renin and the entire renin-angiotensin cascade. Increased aldosterone production is abnormal in the face of renin suppression but plasma aldosterone concentrations are lower than those of patients with classical overt primary aldosteronism. Dashed line and grey tone indicates suppression. ACE indicates angiotensin-converting enzyme; Ang, angiotensin;

and AT₁, angiotensin type-1.

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effect was greater in participants with compared with those without hypertension and for those at higher levels of sodium intake.

Several reports have confirmed the errors associated with use of spot urines to estimate 24-hour urinary sodium intake.^67–70 Spot urines provide systematically biased estimates of 24-hour urinary excretion, with overestimation at lower intakes of sodium and under- estimation at higher intakes.⁶⁷ Likewise, use of spot urines to estimate 24-hour urinary sodium intake yields a J-shaped relationship with mortality, whereas the relationship is linear when 24-hour urine collections are used to assess the relationship.⁶⁷ The World Hypertension League published a position paper on use of spot urines, short-duration timed collections, and 24-hour collections to assess dietary sodium intake.⁷¹ The position paper endorsed use of a single 24-hour urine measurement over a series of days from a representative population sample for estimation of a population’s current 24-hour dietary sodium ingestion and an average of at least 3 nonconsecutive 24-hour urinary collections was recommended for estimation of current usual dietary sodium intake in individuals. Despite the well-documented errors resulting from use of spot urines to estimate average intake of dietary sodium, leading peer-reviewed journals

continue to publish manuscripts in which dietary sodium intake has been estimated using spot urines.^72–74

PHARMACOLOGICAL MANAGEMENT

The 2017 ACC/AHA Guideline and other recent guidelines continue to recommend thiazide or thiazide-type diuretics, calcium channel blockers, ACE (angiotensin- converting enzyme) inhibitors, and angiotensin receptor blockers as initial drug choices, and for subsequent add- on therapy, based on their efficacy in reducing BP and documented benefit in reducing clinical outcomes.^12,19,75 Beta-blockers are generally not recommended as first- line agents in patients without coronary heart disease or heart failure due to lesser benefit on stroke reduction compared with agents from the other recommended classes.12,20,75,76 Spironolactone or eplerenone are recommended for BP control in patients with RH.^12,77

Chlorthalidone and indapamide, thiazide-like diuretics, have a longer duration of action compared with thiazide diuretics and are the preferred diuretics for management of hypertension. HCTZNetwork meta-analyses have shown benefit of chlorthalidone over HCTZ (hydrochlorothiazide) on clinical outcomes, although a large (N=730 225) retrospective, nonrandomized observational

Table 4. Six Best-Proven Nonpharmacological Recommendations for Prevention and Management of Hypertension

Recommendation Intervention Regimen and dosage

Approximate SBP lowering, mm Hg

Hypertension No hypertension Healthy diet DASH diet is the best-

studied/proven healthy diet for BP lowering

Fruits, vegetables, whole grains, low-fat dairy products, with reduced satu-

rated and total fat content. Limited dose-response information. −5 −3

Weight loss Calorie reduction and

physical activity Optimal goal is to achieve ideal body weight but any weight loss is desirable. Linear dose-response relationship. Expect about 1 mm Hg reduction in SBP for every 1 kg weight loss.

−5 −3

Reduced dietary sodium intake

Dietary change Optimal dietary intake goal is <1500 mg sodium/day, but any reduction is desirable. Linear dose-response relationship. Expect about 1–3 mm Hg reduction in SBP for a 1000 mg reduction in sodium intake in adults with/

without hypertension

−5 −3

Increased dietary

potassium intake Dietary change (preferred over pill supplementation)

Optimal goal of 3500–5000 mg potassium/day. Greater BP lowering was identified in those consuming more dietary sodium. Nonlinear U-shaped dose-response relationship. Quality of evidence was lower than for sodium reduction.

−5 −3

Physical activity Aerobic exercise (best evidence)

Exercise such as brisk walking, 5–7×/wk (30–60 min/session), aiming for at least 150 min/wk. Gradual start-up. Warm-up at start and cool down at end of each session.

−5 −3

Dynamic resistance exercise (evidence-less robust)

Exercise such as weight-lifting or circuit training, at least 2–3×/wk. Gener- ally requires guidance/supervision by exercise professional. Often used as a supplement to aerobic exercise.

−4 −2

Isometric resistance exercise (evidence least robust)

Exercise such as hand-grip training regimens, at least 3–4×/wk. −4 −2

Moderation in alco-

hol intake Reduction in alcohol

consumption In adults who drink alcohol, intake goal −4 −3

Men: ≤2 standard drinks/d Women: ≤1 standard drink/d

BP indicates blood pressure; DASH, dietary approaches to stop hypertension; and SBP, systolic BP.

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HYPERTENSION COMPENDIUM study of new users of chlorthalidone (N=36 918) com-

pared with HCTZ from administrative databases failed to document a significant difference in effectiveness.⁷⁸ The Veterans Administration (VA) Diuretic Comparison Proj- ect, randomized comparison of chlorthalidone and HCTZ effects on clinical outcomes in 13 500 patients, is sched- uled for completion by the end of 2022.⁷⁹

Some glucose-lowering agents, particularly GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT-2 (sodium-glucose cotransporter-2) inhibitors significantly improve CVD and kidney outcomes, especially in diabetic patients with and without hypertension. They also reduce BP significantly, with SGLT-2 inhibitors seeming to have the largest effect.^80,81 The magnitude of BP lowering (2–

4 mm Hg on 24-hour ABPM) with these agents is less than with most first-line antihypertensive agents. Given this and their greater cost, SGLT-2 inhibitors should be prescribed primarily for glucose lowering rather than for treatment of high BP.

Despite the lower BP targets recommended in the 2017 ACC/AHA Guideline, hypertension control rates in the US remain suboptimal even by the higher JNC-7 BP treatment targets, largely due to undertreatment, especially in Black patients.⁸² Quality improvement interventions have increased BP control overall and in race-ethnic subgroups, but a 5% to 10% difference in control rates persists between Black and non-Black adults. Clinician inertia and patient nonadherence to the prescribed treatment continue as major contributors to inadequate BP control. A recent report from a quality improvement proj- ect aimed at more accurate BP measurement, reducing therapeutic inertia, and increasing treatment adherence over 6 months demonstrated sustained SBP lowering of 12.7 mm Hg for an additional 6 months compared with a 5 mm Hg SBP decline during the baseline period in patients with uncontrolled BP, P<0.0001.⁸³ However, clinician inertia was only reduced from 52% to 49.5%.

No race/ethnic difference in BP control was noted with the BP regimen utilized in SPRINT even in the <120 mm Hg arm where chlorthalidone, the primary diuretic, and amlodipine, the primary calcium channel blocker were provided at no cost to the study participants.⁸⁴ The effectiveness, safety, and cost-effectiveness of 90 compared with 30-day prescription refills in improving adherence has also been demonstrated.⁸⁵ The major elements of an effective antihypertensive drug treatment program are provided in Table 5.

BP Goal

RCTs have demonstrated that the risk of CVD can be greatly reduced with effective antihypertensive therapy.^3,4 Choice of an optimal goal for BP treatment should be based on a balance between the best level for CVD prevention and the risk of untoward side effects resulting from the treatment.

On the basis of new evidence, the 2017 ACC/AHA Guideline reduced the SBP/DBP goal from that recommended in the 2003 JNC-7 (<140/90 mm Hg for most adults but <130/80 mm Hg for those with DM or chronic kidney disease [CKD]) to <130/80 mm Hg for most adults but an SBP <130 mm Hg for noninstitutionalized ambulatory community-dwelling adults

≥65 years of age.¹² Evidence supporting this guideline change included results of SPRINT as well as multiple systematic reviews and meta-analyses, as summarized in several post-guideline reports.^86–88 In addition, a recent direct meta-analysis by Sakima et al⁸⁹ restricted to 19 trials in which adults with hypertension were ran- domly assigned to a different BP target, reported a significant reduction in major CVD events, MI, and stroke in those assigned to more versus less intensive treatment and in subgroup analysis identified a BP target of

<130/80 mm Hg as optimal for CVD protection. Like- wise, a meta-analysis of 4 RCTs conducted in patients with prior stroke documented a significant reduction in recurrent stroke among those randomized to more intensive BP reduction.⁹⁰

Concerns have been raised that the CVD and all- cause mortality benefit of intensive BP control in SPRINT might have been offset by an increased rate of treatment adverse effects. This concern was largely assuaged by the recent demonstration that intensive BP control is not associated with other causes of hos- pitalization.⁹¹ Another widespread concern, especially in older adults, had been that more intensive antihypertensive treatment might increase the frequency or severity of orthostatic hypotension, leading to falls, syncope, or CVD events. This concern was put to rest by 2 reports by Juraschek et al^92,93 examining SPRINT data and the aggregated individual patient data from multiple clinical trials for association of intensive treatment with orthostatic hypotension. In SPRINT, orthostatic hypotension was more common in the standard treatment group and was not associated with a higher rate of CVD events or

Table 5. Keys to Effective Blood Pressure Control in Adults With Hypertension

1. Agree (patient and provider) on blood pressure target 2. Use fixed-dose combinations

3. Substitute long-acting chlorthalidone for hydrochlorothiazide (alternatively indapamide)

4. Use long-acting amlodipine as first-line calcium channel blocker 5. Monthly visits until blood pressure target achieved

6. Replace prescription of 30 d with 90-d refills, if allowed 7. Use telehealth strategies to augment office-based management 8. Enhance connectivity between patient, provider, and electronic health

record for better feedback and communication

9. Screen for social determinants of health and consideration of obstacles to care

10. Use multidisciplinary team-based care to enhance lifestyle and medication adherence and to solve social issues

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HYPERTENSION COMPENDIUM with syncope, electrolyte abnormalities, injurious falls, or acute renal failure.^92,94 In the Juraschek et al⁹³ meta-analysis of 18 466 participants, including those in SPRINT, intensive BP-lowering treatment also reduced the risk of orthostatic hypotension, possibly due to improvement in baroreflex function and diastolic filling while reducing left ventricular hypertrophy or arterial stiffness. Thus, asymp- tomatic orthostatic hypotension during hypertension treatment should not trigger automatic down-titration of therapy, even in the setting of a lower BP goal.

The AHA’s Life’s Simple 7 focuses on cardiovascular health factors for primordial or primary prevention of CVD (smoking, body mass index, physical activity, total choles- terol, diet, BP, and fasting glucose).^95,96 The AHA Life’s Simple 7 online survey tool increases patient awareness of their BP and other related comorbidities such as DM, obesity, and high sodium intake.^97. Treating hypertension to goal aims to achieve ideal cardiovascular health.

OLDER ADULTS

Professional societies provide conflicting advice on best practices for management of hypertension in older adults. The 2017 ACC/AHA Guideline recommends a treatment goal of <130 mm Hg for noninstitutionalized ambulatory community-dwelling older adults (≥65 years of age) and an individualized team-based approach, based on clinical judgment and patient preference, for those with a high burden of comorbidity and limited life expectancy.¹² In adults at high risk for CVD, including older adults, Hypertension Canada 2020 recommends initiation of antihypertensive medication in those with an SBP ≥130 mm Hg and treatment to an SBP goal <120 mm Hg.⁹⁸ The National Heart Foundation of Australia hypertension guideline recommends initiating antihypertensive drug therapy in “patients at moderate absolute CVD risk (10-15% 5-year risk) with persistent systolic BP ≥140 mm Hg or diastolic BP ≥ 90 mmHg and an initial SBP/DBP target of <140/90 mm Hg or lower, if tolerated, with an SBP goal of <120 mm Hg in older adults (>75 years), if tolerated.⁹⁹ At the other extreme, the ACP and AAFP recommend that adults ≥60 years with a persistent SBP ≥150 mm Hg should be treated with antihypertensive medication to achieve a target SBP of <150 mm Hg, with consideration of a <140 mm Hg target in those with a history of stroke, transient ischemic attack, or other unspecified evidence of high risk for CVD.¹¹

Population modeling studies^100,101 have suggested substantial health benefits from implementation of the 2017 ACC/AHA Guideline recommendations compared with those in the 2003 JNC-7 Report⁹ or the 2014 JNC-8 Panel Members Report.⁸ In US adults ≥40 years, Bundy et al¹⁰⁰ estimated that in comparison to the 2014 JNC-8 Panel Members Report recommendations, implementation of the 2017 ACC/AHA Guideline recommendations would result in an annual reduction

of 340 000 CVD events and 157 000 deaths (Table 6).

In an analysis confined to adults ≥60 years, Jaeger et al¹⁰² identified a high 10-year risk of ASCVD (18.0%) in adults for whom the ACC/AHA but not the ACP/AAFP Guideline recommends antihypertensive drug therapy.

Among adults already taking antihypertensive medication, the 10-year risk of ASCVD in those recommended intensification of therapy by the ACC/AHA, but not the ACP/AAFP, was also high (18.2%). Thus, the ACC/

AHA Guideline is more effective than the ACP/AAFP Guideline in identifying adults ≥60 years of age at high CVD risk for the initiation and intensification of antihypertensive drug therapy.

During the past 2 years, several additional original research papers and meta-analyses have contributed to our understanding of the management of hypertension in older adults.^103–106 In an analysis of the overall SPRINT cohort (N=9361; mean age=67.9 years; median follow- up [FU]=3.34 years), mild cognitive impairment (MCI) was detected in 239 of the 4678 participants (16.2 per 1000 person-years) randomized to intensive antihypertensive treatment (SBP target <120 mm Hg) compared with 284 of the 4683 participants (19.4 per 1000 person-years) randomized to standard antihypertensive

Table 6. Simulation Study by Bundy et al¹⁰⁰ Comparing Estimated Annual Prevention of CVD Events and Deaths by Adhering to 2014 JNC-8 Panel Recommendations or the 2017 American College of Cardiology (ACC)/American Heart Asso- ciation (AHA) BP Guideline

Basis for estimation

(1) Estimation of proportion of US adults in BP categories using NHANES (2) Incidence of major CVD events & all-cause mortality by modeling 4

large community-based cohort studies (ARCS, CV Health, Framingham, MESA)

(3) Network meta-analysis (42 RCTs) to estimate HRs for outcomes and determine population-attributable risks and events reduced.

Characteristic 2014 evidence-

based guideline 2017 ACC/AHA guideline BP threshold (mm Hg) for

initiation of antihypertensive drugs

≥140/90 (<age 60 years)

≥140/90 (general population)

≥150/90 (≥age 60

years) ≥130/80 (high

CVD risk) BP goal (mm Hg) of treatment <140/90 (<age 60

years)

<130/80

<150/90 (≥age 60 years)

Annual CVD event reduction

(≥age 40 years) 270 000 610 000

(NNT=70) Annual reduction in death

(≥age 40 years) 177 000 334 000

(NNT=129) Note: Sensitivity analysis determined that, even if 100% implementation of the 2017 guideline were not achieved, the CVD event and death reductions would still be significantly larger compared with the 2014 guideline. ACC indicates American College of Cardiology; AHA, American Heart Association; ARCS, Ath- erosclerosis Risk in Communities Study, BP, blood pressure; CV, cardiovascular;

CVD, cardiovascular disease; JNC, Joint National Committee; MESA, Multi-Eth- nic Study of Atherosclerosis; NHANES, National Health and Nutrition Examina- tion Survey; NNT, number needed to treat; and RCT, randomized controlled trial.

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HYPERTENSION COMPENDIUM treatment (SBP target <140 mm Hg), resulting in an HR

(95% CI) of 0.83, 0.70 to 0.99.¹⁰³ In a randomized comparison of participants with a median FU of 5.11 years (trial and extended post-trial FU), there was a significant difference in both MCI (HR, 0.81 [95% CI, 0.69–0.95];

P=0.007) and the composite of dementia and MCI (HR, 0.85 [95% CI, 0.74–0.97]; P=0.01) and a nonsignificant trend for benefit in dementia per se (HR, 0.83 [95% CI, 0.67–1.04]).¹⁰³ During FU, CVD events occurred much earlier than dementia indicating the need for trials with a longer period of treatment and FU than occurred in SPRINT where the trial was stopped prematurely due to CVD and all-cause mortality benefit after a median FU of only 3.26 years.

In a subset of 670 SPRINT participants (mean age, 67.3 years) who were evaluated with brain magnetic resonance imaging at baseline and after 4 years of FU (N=449), randomization to intensive treatment was associated with a smaller increase in cerebral white matter lesion volume, an independent risk factor for cognitive decline and dementia, compared with standard treatment during trial FU.¹⁰⁴ Similar apparent magnetic resonance imaging benefits were noted in the INFINITY trial (Inten- sive versus Standard Ambulatory Blood Pressure Low- ering to Prevent Functional Decline in the Elderly trial) and during extended FU in the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes).^105,106

In a secondary analysis, confined to SPRINT participants who were ≥80 years at baseline (N=1167;

mean age, 83.5 years), those randomized to intensive and standard treatment achieved a mean SBP of 123.9 mm Hg and 135.3 mm Hg, respectively, resulting in a somewhat smaller mean difference between the 2 groups (11.5 mm Hg)¹⁰⁷ than the average difference (14.8 mm Hg) noted in the overall trial cohort (N=9361).^94,103 Despite this and the smaller sample size, randomization to intensive treatment lowered the risk of major CVD events (HR, 0.67 [95% CI, 0.50–0.90]), all-cause mortality (HR, 0.67 [95% CI, 0.48–0.93]), and MCI (HR, 0.72 [95% CI, 0.53–0.98]) compared with standard treatment.¹⁰⁷ The CVD and mortality benefits resulting from intensive therapy were similar to those reported in an earlier subgroup analysis confined to participants ≥75 years (N=2636).¹⁰⁸ In SPRINT participants ≥80 years, there was no evidence that gait speed modified the treatment effect on major CVD events or all-cause mortality, but the participants with higher baseline Montreal Cognitive Assessment scores experienced significantly better CVD and all- cause mortality outcomes compared with their coun- terparts with lower Montreal Cognitive Assessment scores (0.01 and 0.003, respectively).¹⁰⁷

In a meta-analysis that included 14 RCTs (N=96158;

mean age=69 years), BP lowering (12 trials; N=92 135;

mean FU=4.1 years) resulted in a small but significant reduction in the risk of dementia or cognitive impairment

(odds ratio, 0.93 [95% CI, 0.88–0.98]).¹⁰⁹ There was no convincing evidence for the superiority of any class of antihypertensive medication in the prevention of dementia or cognitive decline in a meta-analysis of 21 cohort studies (N=43 049) and 8 clinical trials (N=13 817), 2 of which were treated as cohort studies in the analysis, where the mean age of most participants was between 70 and 79 years.¹¹⁰

Several ongoing SPRINT-like RCTs are being conducted in Brazil and China in patients with hypertension and diabetes and with hypertension and stroke.¹¹¹ These trials are utilizing study designs that allow for continued treatment and trial assessment of dementia should a convincing difference in CVD events occur before the planned end of the trial. Collectively, they will contribute to our understanding of the optimal SBP treatment target for prevention of CVD, all-cause mortality, MCI, and dementia, overall and in subgroups, including in older adults.

DIABETES MELLITUS

High BP and type 2 DM frequently coexist, with hypertension being reported in ≈80% of patients with DM. In cohort studies, the combination of hypertension and DM has been repeatedly shown to dramatically increase the risk of CVD compared with either risk factor on its own.¹¹² Lifestyle modification is central to prevention and management of both DM and hypertension, with an emphasis on weight loss and physical activity for prevention and control of DM.^113,114 Addition of antihypertensive drug therapy is recommended because most patients with the combination of hypertension and DM are at high risk for ASCVD.¹² In addition, most surveys suggest that clini- cians do not formally estimate CVD/ASCVD risk even when recommended by guidelines.¹¹⁵ The benefits of antihypertensive drug therapy for management of hypertension in patients with DM have been extensively demonstrated in individual RCTs and meta-analyses of clinical trials.^3,116 All recommended classes of antihypertensive drug therapy, including diuretics, are similarly effective for prevention of CVD, except in those with heavy protein- uria or advanced kidney disease where renin-angiotensin system inhibitors are indicated.¹² Typically, a combination of 2 or 3 agents is required to achieve BP targets.

There is substantial guideline concordance for an SBP goal of <130 mm Hg in most adults with hypertension and DM.^12,19,117 For example, in 95.7% of adults on antihypertensive medication who remain above their recommended BP goal both the ACC/AHA BP Guideline and American Diabetes Association Position Statement recommend intensification of therapy.¹¹⁸ The ACCORD BP (Action to Control Cardiovascular Risk in Diabetes BP Trial) was based on a factorial design, in which the planned analysis assumed no interaction between the different treatments being studied (BP lowering and

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HYPERTENSION COMPENDIUM glycemic control).¹¹⁹ The ACCORD BP results indicate this assumption was not realized, with the consequence that the planned analysis yielded results that are unreli- able.¹¹⁹ In a secondary post hoc analysis, the participants randomized to intensive BP lowering (SBP target <120 mm Hg) and standard glycemic control derived CVD prevention benefits that were comparable to those seen with intensive BP lowering in SPRINT.¹²⁰ There was no evidence of CVD benefit in the participants randomized to intensive BP lowering and intensive glycemic control.

However, after the intensive glycemic intervention was discontinued, due to harm, CVD prevention in those randomized to intensive BP lowering changed to a pattern like that seen in SPRINT.¹²⁰ In a secondary analysis of 10 948 ADVANCE (Action in Diabetes and Vascular Dis- ease) RCT participants, all of whom had DM at baseline, treatment with a perindopril-indapamide combination significantly reduced mortality and major CVD (macro- vascular and microvascular) events compared with placebo, irrespective of baseline SBP or a 10-year ASCVD risk <20% or ≥20%.¹²¹ In those with a baseline SBP

<140 mm Hg, most of the active therapy benefit resulted from treatment in the group with a baseline SBP 130 to 139 mm Hg—a finding that supports the 2017 ACC/

AHA Guideline recommendation to treat such individuals with a combination of nonpharmacological therapy and antihypertensive medication, especially those with a 10-year ASCVD risk ≥10%.¹²

CHRONIC KIDNEY DISEASE

The inclusion and careful renal disease monitoring of patients with stage 3 to 4 CKD in SPRINT has expanded our understanding of the kidney function changes that occur with intensive BP control. Subgroup analysis yielded similar benefits for prevention of CVD and all- cause mortality compared with what was identified in the full cohort, with very low rates of the main renal end point in those with CKD at baseline (halving of estimated glomerular filtration rate or development of end-stage renal disease). When lesser degrees of kidney function decline were considered, there was a higher risk of ≥30%

decline in estimated glomerular filtration rate and lower albumin excretion rates with intensive therapy compared with standard therapy reported for both patients with and without CKD at baseline. Intensive treatment was associated with higher rates of reported acute kidney injury serious adverse events.^122,123 However, additional analyses suggest these changes were hemodynamic and were not associated with urinary biomarkers of kidney damage which were lower in the intensive treatment group.¹²⁴ Similar findings were reported for a substudy of ACCORD participants.¹²⁵ These results supporting a benign hemodynamic process rather than permanent injury as the mechanism for a rise in serum creatinine

remain preliminary, covering only the first 1 to 2 years of treatment; thus, additional longer-term data will be needed to confirm the findings.

An updated Kidney Disease Improving Global Out- comes BP guideline has been released.¹²⁶ The report recommends standardized office BP measurements, preferably using an automated device, and intensive antihypertensive therapy with a target SBP of <120 mm Hg for all patients with CKD not on dialysis, including those with and without DM.

RESISTANT HYPERTENSION

Resetting the general BP goal for antihypertensive therapy to <130/80 mm Hg by the 2017 ACC/AHA guideline de facto changed the definition of treatment RH.¹² This change was reconfirmed by the 2018 AHA Scientific Statement on RH⁷⁷ which formally defined the disorder as BP that remains uncontrolled above goal in spite of the concurrent use of 3 antihypertensive drugs of different classes. These pharmacological classes commonly include a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (ie, ACE [angiotensin-converting enzyme] inhibitor or angiotensin receptor blocker) and a diuretic, and all 3 agents should be administered at maximum or maximally tolerated doses and at the appropriate dosing interval. RH also includes patients whose BP is controlled at or below goal but requiring ≥4 antihypertensive agents of different classes to achieve target.⁷⁷

A critical change in the definition of RH in the 2018 AHA Scientific Statement was that pseudo-resistance (ie, error in BP measurement, the white coat effect, or suboptimal adherence to the antihypertensive drug regimen) now must be excluded before a patient can be labeled as having RH.⁷⁷ Exclusion of pseudo-resistance before making the diagnosis of RH was also recommended by the 2018 European Society of Cardiology/European Society of Hypertension BP guideline.¹⁹ Although the new goal for BP control in the office is now <130/80 mm Hg, it is important to remember that office BP should be confirmed using out-of-office measurements and that the 24-hour ABPM goal is now <125/75 mm Hg as recently validated.12,15,77,127

Under the new definition of RH using the 130/80 mm Hg cutoff, its prevalence was expected to escalate dramatically, placing an exponential burden on the health care system. However, population modeling studies have estimated that this change would result in only about a 2% increase in the prevalence of RH (from 17.7% to 19.7%) in the United States.¹²⁸

The importance of RH is its association with higher CVD and kidney disease risk compared with hypertension without resistance, but the prognosis of RH using the current definition had not been studied.⁷⁷ The first