Management of Hypertension
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  • 1 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota

Learning Objectives

  1. Describe the effect of lower blood pressure targets on the risk of progression to ESRD or acute kidney injury
  2. Describe the effect of lower blood pressure targets on the risk of cognitive impairment and dementia
  3. Explain the most effective initial agents for treatment of hypertension based on recent studies
  4. Summarize the outcomes of combination drug therapy compared with a stepped care approach
  5. Discuss additional drug choices after the first 3 agents for patients with resistant hypertension
  6. Summarize recent studies on the role of nonadherence and implementation strategies to address it
  7. Outline the use of the atherosclerotic cardiovascular disease (ASCVD) risk calculator in deciding whether to initiate hypertension drug therapy

Management of Hypertension

The management of hypertension includes detection, monitoring, and the selection of the dose and timing of medication that is effective and well tolerated to achieve recommended BP targets. We discuss the 2017 ACA/AHA Blood Pressure Guideline and important publications that inform hypertension medication selections and combinations and time of dosing, along with limited progress on strategies to improve management.

2017 ACC/AHA Blood Pressure Guideline

The 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/AphA/ASH/ASPC/NMA Blood Pressure Guideline (the American College of Cardiology / American Heart Association [ACC/AHA] guideline) for the prevention, detection, evaluation, and management of high BP in adults was announced and released in late 2017 (1). This document was developed by a panel of BP experts at the request of the National Heart, Lung, and Blood Institute to replace the Seventh Joint National Committee BP guideline for the United States. In recent years, an explosion of guidelines published by primary and subspecialty societies in the United States has generated confusion among clinicians and led to differences between generalists and specialist providers with respect to BP definitions and targets. This topic has been widely debated at national and international meetings inasmuch as other countries have also published guidelines. The recent release of an updated European Society of Hypertension/European Society of Cardiology guideline (2), an updated United Kingdom National Institute for Health and Care Excellence guideline (3), and continued updates from the Canadian Society of Hypertension (4) have further fueled the controversy.

The initial reaction from primary care providers was to reject the lower targets. In a December 2017 article in the AAFP News, published by the American Academy of Family Physicians (AAFP), that organization decided not to endorse the 2017 ACC/AHA high BP guideline but to stay with the BP targets recommended in the 2014 evidence-based guideline published by the panel appointed to the Eighth Joint National Committee (5), which was officially disbanded by the National Heart, Lung, and Blood Institute prior to publication of the document. In that guideline, which was never adopted on a national level, the BP target for patients ≥60 years old was <150/90 mmHg. The AAFP listed several reasons for their decision, including concerns regarding use of a nonvalidated cardiovascular disease (CVD) risk calculator, lack of individual quality ratings for each systematic review in the data analyses, concern for undue influence of SPRINT data on the BP targets, and lack of AAFP representation on the expert panel inasmuch as the AAFP could not reach agreement with ACC/AHA on their requirements for participation. Shortly thereafter, the American College of Physicians and the AAFP jointly published a clinical practice guideline on pharmacologic treatment of hypertension in adults ≥60 years old to recommend targeting systolic BP <150 mmHg for most adults ≥60 years old, with a lower target of <140 mmHg for those with prior stroke or at high cardiovascular (CV) risk (6). Recently, a more accepting attitude has evolved, as reflected by an “In the Clinic” summary of hypertension published in 2019 (7), which endorses and explains the ACC/AHA 2017 high BP guideline. Table 4 lists current BP guidelines demonstrating the multitude of sponsoring organizations and highlighting their similarities and differences.

Table 4.

Current blood pressure guidelines and sponsoring organizations, highlighting similarities and differences

GuidelineYounger TargetOlder TargetDiabetes TargetCKD Target
2017 American College of Cardiology/American Heart Association High BP Guideline<130/80 mmHg<130/80 mmHg with consideration for comorbidities<130/80 mmHg<130/80 mmHg
2018 European Society of Cardiology/European Society of Hypertension (1)<140/90 for all, <130/80 for most if well tolerated, 120-129 systolic for most patients age <65 years130-139 systolic for age ≥65, 130-139 systolic for age >80 years if treatment well toleratedTarget 130 systolic, <130 if tolerated but not <120 mmHgTarget 130-139 mmHg systolic
Diastolic BP <80 should be considered for allTarget <80 diastolic but not <70 mmHg
NICE – National Institute for Health and Care Excellence (2)Age <80 years, Clinic BP <140/90 mmHg, ABPM/HBPM <135/85 mmHgAge ≥80 years, Clinic BP <150/90 mmHg, ABPM/HBPM <145/85 mmHg<130/80 mmHg<140/90 mmHg; if CKD with diabetes or ACR ≥70 mg/mmol to <130/80 mmHg
American Diabetes Association Standards of Medical Care in Diabetes (3)Not includedNot included<130/80 mmHg for those at higher CV risk (existing ASCVD or 10-year ASCVD risk ≥15%) if it can be safely attained<130/80 mmHg for those at higher CV risk (existing ASCVD or 10-year ASCVD risk ≥15%) if it can be safely attained
<140/90 for those at lower CV risk<140/90 for those at lower CV risk
2018 Hypertension Canada: 2018 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults and Children (4)<140/90 mmHg without compelling indications<130/80 mmHg<140/90 mmHg
<120 mmHg systolic if high risk for CV disease
2017 American College of Physicians/American Association of Family Practice (5)Not indicatedAge ≥ 60 years: <150 mmHg systolic, consider <140 mmHg systolic for history of TIA or stroke or at high CV riskAge ≥ 60 years: <150 mmHg systolic, consider <140 mmHg systolic for history of TIA or stroke or at high CV riskAge ≥ 60 years: <150 mmHg systolic, consider <140 mmHg systolic for history of TIA or stroke or at high CV risk
2020 Kidney Disease Improving Global Outcomes Clinical Practice Guideline on the Management of Blood pressure in Chronic Kidney DiseaseUnder review, due in 2020

Adapted with permission from Taler SJ. Initial Treatment of Hypertension. N Engl J Med 78: 636–644, 2018, with updating for ESC/ESH, NICE, ADA, Hypertension Canada, KDIGO

ABPM, ambulatory BP monitoring; ACR, albumin-creatinine ratio; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; HBPM, home BP monitoring; TIA, transient ischemic attack.

References

Williams B, et al. Eur Heart J (2018) 00, 1–98.

National Institute for Health and Care Excellence: Hypertension in adults: Diagnosis and management, published August 2019

American Diabetes Association. 10. Cardiovascular disease and risk management: standards of Medical Care in Diabetes-2020. Diabetes Care 43(Suppl.1):S111–S134, 2020.

Nerenberg KA, et al.: Hypertension Canada's 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children. Can J Cardiol 34:506–525, 2018.

Qaseem A, et al.: Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 166:430–437, 2017.

The authors and editors of this publication agree with the 2017 ACC/AHA guideline, which establishes official definitions and targets for the United States. The ACC/AHA guideline was developed and endorsed by 11 stakeholder and professional organizations and was based on the most recent and complete evidence available and without commercial support or influence. Such practice guidelines are intended to clarify and simplify the evidence and to guide decisions to provide the highest quality of patient care. Updates are expected as additional evidence becomes available.

The guideline is graded with respect to the strength of recommendations (strong, moderate, weak) and the strength of the evidence (A, B-R, B-NR, C-LD, C-EO) reflecting the spectrum from high-quality randomized controlled trials to expert opinion. An evidence review committee was commissioned to perform a systematic review addressing three critical questions to be incorporated into the guideline (8): 1) the value of self-measurement of BP compared with office-based measurements for achieving better control and for preventing adverse clinical outcomes, 2) the optimal target for BP lowering, and 3) benefits and harms of specific antihypertensive agents by drug class as first-line therapy. This evidence review, which included trials up to the Systolic Blood Pressure Intervention Trial (SPRINT) in November 2015 and the Secondary Prevention of Small Subcortical Strokes Trial for the optimal target analysis, reported transient improvement in BP at 6 months using self-measurement that was not sustained at 12 months, supported a target of systolic <130 mmHg to reduce CV events, and indicated equivalent benefits from angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), β-blockers, and thiazide and thiazide-type diuretics. The guideline addresses risk factors, definitions, evaluation, and treatment of high BP in adults in general, and in the setting of multiple comorbid conditions. It is designed to serve as an online reference, allowing easy movement to topic sections and relevant references with a simple mouse click.

The definitions of normal BP, elevated BP, and hypertension stages 1 and 2 were revised to lower thresholds based on epidemiologic and trial data that address the risks and benefits of treatment. According to the ACC/AHA guideline, normal BP is defined as <120/80 mmHg, elevated BP as systolic pressure 120 to 129 mmHg and diastolic pressure as <80 mmHg, stage 1 hypertension as systolic pressure 130 to 139 mmHg or diastolic pressure 80 to 89 mmHg, and stage 2 hypertension as systolic pressure ≥140 mmHg or diastolic pressure ≥90 mmHg. The diagnosis is based on two or more readings at two or more visits.

In an effort to keep recommendations simple, the guideline maintains the same thresholds for initiation of treatment and for BP targets. Decisions on when to initiate medication are based on BP level and on the individual patient’s CV risk. The rationale for adding calculation of risk is based on an analysis of pooled individual level trial data for >50,000 participants in 11 trials indicating a consistent reduction in risk ratio across all risk groups, with progressively greater absolute risk reduction for those with the highest CVD risk (9). Patterns of larger absolute risk reduction with treatment for those at progressively higher CVD risk were observed for stroke, coronary heart disease, heart failure, and CVD-associated death. For further coverage of this topic, the reader is referred to an excellent discussion by Muntner and Whelton (10). In a similar manner, SPRINT investigators selectively enrolled patients with a high CV risk (10-year risk >15% for a CVD event using Framingham risk score) to demonstrate event-free and overall survival benefit from more intensive BP treatment. As recommended in the ACC/AHA guideline, for those between 40 and 64 years of age, CV risk should be estimated using the Pooled Cohorts equation http://www.cvriskcalculator.com/).

Lifestyle modifications are recommended as an integral part of therapy for all patients with elevated BP or higher whether medication is recommended or not. Lifestyle modifications include sodium restriction to <1500 mg sodium daily, weight reduction to <20% above ideal weight, and 30 minutes of daily aerobic exercise. Other options include use of the Dietary Approaches to Stop Hypertension (DASH) diet, increasing potassium intake, and limits on alcohol use. Earlier initiation of pharmacologic therapy is indicated for patients with stage 1 hypertension and preexisting CVD, chronic kidney disease (CKD) or diabetes mellitus (DM), or high estimated 10-year CV risk. Medications are divided by first tier and additional agents with recommendations regarding drug selection and combination.

The guideline contains additional extensive recommendations for drug selection for patients with specific comorbidities, including DM, CKD, several cardiac diseases (ischemic heart disease, heart failure with preserved or reduced ejection fraction, atrial fibrillation, valvular heart disease and others), cerebrovascular disease including hemorrhagic and ischemic stroke, and by demographic characteristics including black race, elderly age, and others, based on evidence where available. For black adults with hypertension but without heart failure or CKD, including those with DM, initial antihypertensive treatment should include a thiazide-type diuretic or CCB, based on better outcomes in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (11). For patients with CKD and macroalbuminuria, initial therapy should include an ACE inhibitor or ARB; this approach could be considered even in patients with microalbuminuria. To consider demographic predictors and comorbidities, one can click to the dedicated section for each condition to get concise recommendations with a single mouse click. Specific references are collated after each section to pursue additional information.

To address concerns regarding overtreatment of the elderly, the guideline offers substantial room for individual consideration of the patient’s general health and longevity. For those patients with a high burden of comorbidity and limited life expectancy, clinical judgment, patient preference, and a team-based approach to assess risk/benefit are advised for decisions regarding intensity of BP lowering and choice of medication.

Ancillary SPRINT Studies

The results from the SPRINT trial contributed heavily to the guideline recommendations. SPRINT was a randomized trial that included 9351 participants and was stopped early after demonstrating a CV and all-cause mortality benefit from intensive treatment (i.e., systolic BP target <120 mmHg) compared with standard treatment (i.e. systolic BP target <140 mmHg) (12). Whereas the primary trial was discussed in the previous Neph-SAP, including results for the elderly and CKD subgroups, a multitude of additional substudies have been published since. Two topics are of particular interest: the effect of tight BP control on kidney function for those with and without pre-existing CKD and the effects of tight BP control on the risks for developing dementia or mild cognitive impairment.

Effects of Intensive Treatment on Kidney Function

The SPRINT Research Group reported the results of intensive BP control on CKD for a prespecified subgroup of SPRINT participants with stage 3 to 4 CKD (estimated GFR [eGFR] 20–59 mL/min per 1.73 m2), less than 1 gram/day proteinuria, no polycystic kidney disease, and meeting all other inclusion and exclusion criteria for SPRINT (13). CKD subgroup patients were randomized 1:1 to intensive versus standard BP targets and constituted 28.3% of the full SPRINT cohort (n = 2646). Systolic BP separation occurred early and was maintained throughout the trial, as in the full cohort. Whereas rates of the primary outcome of CVD events did not differ between the intensive and standard therapy groups, the trend was consistent with benefits seen in the full SPRINT cohort, and the rate for all-cause death was significantly lower in the intensive treatment group. In contrast, the rates of halving of eGFR or development of ESRD were low in both study arms and did not differ (Figure 2). When lesser degrees of eGFR decline were considered, intensive treatment was associated with a higher risk of ≥30% decline in eGFR, whereas albumin-to-creatinine ratios were lower in the intensive treatment group. The eGFR decline was thought to be due to an acute hemodynamic effect, which resolved after the first 6 months of the trial; even so, there was a slightly higher rate of eGFR decline that persisted in the intensive treatment group (Figure 3).

Figure 2.
Figure 2.

Kaplan-Meier curves for pre-specified outcomes in SPRINT participants with CKD. Panel A shows the primary cardiovascular outcome, defined as the composite of myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, and death from cardiovascular causes. Panel B shows the all-cause death outcome. Panel C shows the main kidney outcome, defined as the composite of a decrease in eGFR of ≥50% from baseline (confirmed by repeat testing ≥90 days later) or the development of ESRD. The broken lines depict the intensive group; the solid lines depict the standard group. Reprinted with permission from reference 13 (Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, et al.: Effects of Intensive BP Control in CKD. J Am Soc Nephrol 28: 2812–2823, 2017).

Citation: Nephrology Self-Assessment Program nephsap 19, 1; 10.1681/nsap.2020.19.1.3

Figure 3.
Figure 3.

Changes in estimated GFR in standard care (upper line) and intensive care (lower line) groups in SPRINT chronic kidney disease cohort. Reprinted with permission from reference 13 (Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, et al.: Effects of Intensive BP Control in CKD. J Am Soc Nephrol 28: 2812–2823, 2017).

Citation: Nephrology Self-Assessment Program nephsap 19, 1; 10.1681/nsap.2020.19.1.3

Beddhu et al. (14) evaluated changes in eGFR and risk for AKI for SPRINT participants without kidney disease at enrollment (n = 6662). There was a 3.5-fold higher hazard of developing incident CKD (defined as at least 30% reduction to eGFR <60 mL/min per 1.73 m2) during the trial if assigned to the intensive treatment group. Patients in the intensive treatment arm had eGFR 3.32 mL/min per 1.73 m2 lower at 6 months and 4.50 mL/min per 1.73 m2 lower at 18 months, which then plateaued at 4.83 mL/min per 1.73 m2 lower at month 30 and 4.71 mL/min per 1.73 m2 lower at month 42 (Figure 4); 4.2% versus 1.1% had a ≥30% decline event to reach eGFR <60 mL/min per 1.73 m2. The final status of participants who developed incident CKD is shown in Figure 5. No patient in either study arm reached ESRD. In the intensive treatment arm, 26% had resolution of CKD, 14% had a <30% eGFR decline, and 50% had a 305 to 50% eGFR decline, whereas the corresponding rates for the standard treatment arm were 10%, 15%, and 60%. In total, there were 12 patients in the intensive treatment group (8.6% of those with any degree of AKI) and 5 in the standard group (12.5% of those with any degree of AKI) with >50% decline in eGFR at the end of the trial. For the subgroup of patients who developed incident CKD during SPRINT, Zhang et al (15). measured nine urinary biomarkers of kidney damage (collected at baseline and 1 year after enrollment) in 162 patients (128 in the intensive treatment group and 34 in the standard group) and 162 control individuals matched by demographics and randomization group. Patients who developed incident CKD in the intensive treatment arm had decreases rather than increases in biomarkers of kidney damage, supporting a benign hemodynamic process rather than intrinsic and permanent injury.

Figure 4.
Figure 4.

Change in estimated GFR in standard and intensive treatment groups without chronic kidney disease at enrollment, looking at fasting or nonfasting status. From Annals of Internal Medicine, Beddhu S, Rocco MV, Toto R, et al., for the SPRINT Research Group. Effects of Intensive Systolic Blood Pressure Control on Kidney and Cardiovascular Outcomes in Persons Without Kidney Disease: A Secondary Analysis of a Randomized Trial. 2017;167:375–383 ©2020 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.

Citation: Nephrology Self-Assessment Program nephsap 19, 1; 10.1681/nsap.2020.19.1.3

Figure 5.
Figure 5.

Final status of SPRINT non—chronic kidney disease (CKD) participants who met the criteria for incident CKD during follow-up in the intensive (top) and standard (bottom) treatment groups. From Annals of Internal Medicine, Beddhu S, Rocco MV, Toto R, et al., for the SPRINT Research Group. Effects of Intensive Systolic Blood Pressure Control on Kidney and Cardiovascular Outcomes in Persons Without Kidney Disease: A Secondary Analysis of a Randomized Trial. 2017;167:375–383 ©2020 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.

Citation: Nephrology Self-Assessment Program nephsap 19, 1; 10.1681/nsap.2020.19.1.3

Recently, Malhotra et al. (16) reported on changes in five urine markers of tubule injury, inflammation, and repair in association with kidney function outcomes for the CKD subgroup in SPRINT. The highest risk of reaching a kidney outcome event was associated with the highest quartiles for urinary KIM-1, MCP-1, and YKL-40, and urinary IL-18 was associated with eGFR decline. The lack of association of these markers with nonCKD patient outcomes and the associations seen in patients with pre-existing CKD suggest that most of the eGFR changes reported in SPRINT were hemodynamic.

The SPRINT Alzheimer’s, Seniors, and Kidney Study (SPRINT ASK) was approved as an extension to SPRINT to collect additional data on kidney function of SPRINT patients. That study has been completed, and the data are under analysis but have not been released.

A New KDIGO Guideline on the Way

Kidney Disease: Improving Global Outcomes (KDIGO) updated their 2012 BP guideline in 2017. A controversies conference proceeding (17) laid out the issues. Topics to be re-examined included office and out-of-office BP measurement methods; classifications of masked, sustained, and white coat hypertension; BP treatment and target thresholds; the effects of lower targets on kidney parameters; and choice of antihypertensive agents in patients with CKD and comorbidities. A final draft of the guideline is currently under international peer review and is expected to be made public this year.

Effects of Intensive Treatment on Dementia and Mild Cognitive Impairment

SPRINT MIND was a substudy designed to evaluate the effects of tightened BP control on brain function outcomes and has been presented at multiple forums. The primary results were published by Williamson et al. in 2019 (18). Among all 9361 participants randomized to intensive or standard treatment goals over a median intervention period of 3.34 years and with follow-up over 5.11 years, there were fewer cases of probable dementia in the intensive treatment group (149 in the intensive treatment group versus 176 in the standard treatment group), which did not reach statistical significance (hazard ratio [HR], 0.86; 95% confidence interval [95% CI], 0.67 to 1.04). The study was underpowered for the dementia endpoint because of early termination and fewer than expected patients in the full cohort. However, the risk of mild cognitive impairment was significantly reduced in the intensive treatment group versus the standard treatment group (287 versus 353, HR, 0.81; 95% CI, 0.69 to 0.95), as was the combined endpoint of mild cognitive impairment and probable dementia (HR, 0.85; 95% CI, 0.74 to 0.97).

Cognitive function was ascertained using a three-step process by centrally trained and certified examiners at each site, including a test of global cognitive function, learning and memory, and processing speed. For those scoring lower on the cognitive assessment, a preidentified proxy was administered the functional activities questionnaire or an extended cognitive battery. Additional data collected included a standardized measurement of depressive symptoms, perceived health status, and quality of life.

Whereas technically negative for the primary outcome of probable dementia, the trial provides reassurance that intensive BP control did not increase the risk for dementia and suggests a protective effect of intensive treatment. The effect difference was likely diminished by the drift of BP levels upward in the intensive treatment group once the treatment aspect of the trial was ended. Subsequent analyses of SPRINT MIND reported smaller increases in cerebral white matter hyperintensity volumes, considered a harbinger of future cognitive impairment and dementia, but also noted greater decreases in total brain volume with intensive treatment. A similar reduction in total brain volume was noted in the ACCORD intensive treatment group, and it is thought that this may reflect reduced hydration status such as may be observed with more aggressive diuretic therapy (19). This issue requires further investigation.

A second randomized trial, How intensively should we treat blood PRESsure in established cERebral small VEssel disease? (PRESERVE) (20) compared the intensive BP target of <125 mmHg systolic with the standard target of 130 to 140 mmHg systolic for a small group of 70 patients with hypertension. MRI confirmed symptomatic lacunar infarct and confluent white matter intensities. Analyzable data from 29 patients in the intensive group and 33 in the standard group (with systolic BP declines of 27 ± 17 mmHg and 8 ± 12 mmHg, respectively, and with 38% of the intensive treatment group not achieving their BP target) showed no differences in global perfusion or in gray or white matter changes related to BP lowering. Adverse events did not differ between groups. These data, although not definitive, support the safety of BP lowering in patients with small vessel disease of the brain.

  • Largely based on SPRINT, the ACC/AHA Blood Pressure Guideline lowered the BP definition and treatment targets.
  • Lower targets are associated with a greater early decline in GFR, which appears to be hemodynamic and does not alter CV or all-cause mortality benefit.
  • Lower targets do not worsen and may reduce the risk for mild cognitive impairment and dementia.

Medication Dosing

Selection of Initial Agents

Whereas current guidelines, including the 2017 ACC/AHA guideline, promote initial drug selection from one of four drug classes, the decision to select one class over another has often been made somewhat at random. The provider may select an ACE inhibitor, an ARB, or alternatively select a CCB first rather than a thiazide-type diuretic to avoid the need for electrolyte measurements or to alleviate concerns regarding potential change in GFR. Patients with albuminuria or heart failure are preferentially treated with an ACE inhibitor or an ARB. Black patients are first treated with a CCB or a thiazide-type diuretic. Patients with asthma or chronic obstructive pulmonary disease are usually not prescribed ACE inhibitors, owing to concern for cough. Few randomized controlled trials have compared one agent with another, with the strongest data coming from ALLHAT, which enrolled subjects from 1994 to 1998 and compared a single agent from each of several classes only (11). Other trials included only small cohorts and lacked long-term event outcomes.

In this void, we now have data. In a recent publication from Lancet, Suchard et al. (21) in the Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Hypertension (LEGEND-HTN) study describe a new framework that uses real-world big data to provide comparative effectiveness and safety information from millions of patients while minimizing publication and other inherent biases. The investigators used six administrative claims and three electronic health record (EHR) databases across four countries and restricted inclusion to individuals with at least 1 year of prediagnosis medical care, a new diagnosis of hypertension, and pharmacy fills of a first-line antihypertensive medication. This study retrospectively compiled a cohort of patients receiving initial antihypertensive therapy and compared subsequent clinical event outcomes and safety endpoints. With five drug classes, 55 outcomes, two time-at-risk definitions, and two propensity score adjustment approaches, this generated 22,000 effect estimate combinations.

Although the methods are complex, the results are striking and extremely useful. In a population cohort of 4,893,591 patients, of whom 48% were started on an ACE inhibitor, 17% on a thiazide or thiazide-like diuretic, 16% on a dihydropyridine CCB, 15% on an ARB, and 3% on a nondihydropyridine CCB, significant outcomes of myocardial infarction (MI) and of hospitalization for heart failure and stroke were reduced in individuals treated with a thiazide or thiazide type-diuretic compared with each of the other drug classes. Nondihydropyridine CCBs were inferior to each of the other drug classes.

As expected, thiazide or thiazide-like diuretics had higher risks of hypokalemia and hyponatremia and a lower risk of hyperkalemia than other drug classes, and ACE inhibitors had higher risks of angioedema and cough than other agents.

The major strength of the study is the use of large-scale clinical data to compare real-world effectiveness across drug classes regarding initial drug therapy of hypertension. Weaknesses relate to the retrospective nature of the data and lack of randomization. Furthermore, BP values were not available for the majority of the cohort. It is thus possible that physicians chose thiazides or thiazide-type diuretics rather than alternative agents for patients with lower baseline BP, which could then have biased the risk estimate in favor of thiazides. However, in a substudy using data from one claims provider where BP data were available, median BPs were highest among thiazide users, which supported the main findings and confirmed the superiority of thiazide diuretics over the other drug classes.

A more recent network meta-analysis published in JAMA Cardiology provides somewhat conflicting results (22). Wei et al. (22) compared CV event rates in patients with hypertension and no substantial comorbidities who were enrolled in randomized clinical trials comparing different antihypertensive medications. The data were pulled from 46 clinical trials including 248,887 participants. Compared with placebo, ACE inhibitors, dihydropyridine CCBs, and thiazide diuretics were similarly effective in reducing overall CV events, CV death, and stroke. When compared with other agents, ACE inhibitors were most effective in reducing risk of MI, and diuretics were most effective in reducing revascularization (Figure 6). Each 10-mmHg systolic reduction and 5-mmHg diastolic reduction in BP was significantly associated with the lower risk of CV death, stroke, and overall CV events. One would assume these populations were similar since Suchard et al. (21), included patients with a new diagnosis of hypertension started on initial therapy, and Wei et al. (22) included patients enrolled in clinical trials comparing one agent with placebo or with another agent. Differences may relate to study design and the potential for new findings using the large-scale LEGEND-HTN approach, which would avoid publishing biases but may introduce other limitations.

  • Thiazides and thiazide-like diuretics are good first-line agents for most patients. An ACE inhibitor or an ARB is preferred for patients with proteinuria.
  • Fixed-dose drug combinations provide effective therapy.
  • Nonadherence or suboptimal adherence remains a major reason for inadequate BP control.

Figure 6.
Figure 6.

Network meta-analysis comparing single class of antihypertension medications with placebo for treatment of cardiovascular events. Effectiveness of different drug classes in reducing overall cardiovascular (CV) events, myocardial infarction, stroke, CV revascularization, and overall CV events. ACE, indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; DH CCB, dihydropyridine calcium channel blocker; and error bars, 95% CI. Reprinted with permission from reference 22 (Wei J, Galaviz KI, Kowalski AJ, et al.: Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications: A Systematic Review and Network Meta-analysis. JAMA Netw Open 2020;3(2):e1921618), which is available under the terms of the Creative Commons Attribution License.

Citation: Nephrology Self-Assessment Program nephsap 19, 1; 10.1681/nsap.2020.19.1.3

Use of Combination Agents

Rea et al. (23) studied 100,982 patients started on a single agent and 24,653 patients started on a two-drug fixed combination agent to determine how many ended up on combination therapy, and the timing of treatment escalation. For the patients started on monotherapy 22%, 27%, 32%, and 36% were taking combination therapy at 6 months and at 1, 2, and 3 years later, respectively, and in the fixed combination group 85%, 82%, 79%, and 78% were taking combination therapy. The initial combination therapy tactic was associated with 20% lower mortality and 16% lower hospitalizations for CV events, with significant reductions in multiple CV outcomes (Figure 7). These results suggest that therapeutic inertia may prevent proper drug titration and contribute to low hypertension control rates. Inertia may result from loss to follow-up and patients’ unwillingness to take additional medications, and from providers’ failure to actively engage in intensifying treatment.

Figure 7.
Figure 7.

Protective effect of combination therapy over monotherapy in reducing cardiovascular outcomes. Used with permission from Reference 23. (Rea F, Corrao G, Merlino L, et al.: Initial Antihypertensive Treatment Strategies and Therapeutic Inertia. Hypertension 72: 846–853, 2018).

Citation: Nephrology Self-Assessment Program nephsap 19, 1; 10.1681/nsap.2020.19.1.3

In another combination therapy trial, Ojji et al. (24) reported a unique single-blind randomized trial of three different combination therapy agents administered to black African patients with uncontrolled hypertension in six African countries. They randomized 728 black patients to amlodipine/hydrochlorothiazide, amlodipine/perindopril, or perindopril/hydrochlorothiazide drug combinations using a lower-dose combination tablet for 2 months followed by titration to a higher-dose combination tablet for an additional 4 months. For the 621 patients who completed the trial and underwent 24-hour ambulatory BP monitoring at baseline and at 6 months, those receiving amlodipine/hydrochlorothiazide or amlodipine/perindopril had lower 24-hour ambulatory systolic BP compared with those taking perindopril/hydrochlorothiazide, with a difference of about 3 mmHg. Similar differences were noted in office BP and ambulatory diastolic BP readings.

These results conflict with the previously held belief that there is a synergistic effect from the combination of a renin-angiotensin-aldosterone system blocker with a diuretic leading to greater BP declines. The results are concordant with an earlier trial, ACCOMPLISH, which demonstrated greater BP reductions and lower CV event rates using the combination amlodipine/benazepril compared with benazepril/hydrochlorothiazide. In both of these trials, the concern has been raised that hydrochlorothiazide effects are short acting. Whether the outcomes would be different with a long-acting thiazide-like diuretic such as chlorthalidone is unclear.

In a second publication from the LEGEND-HTN observational cohort study, Hripcsak et al. (25) compared CV and safety outcomes of first-time users of chlorthalidone and hydrochlorothiazide from 2001 to 2018 based on administrative claims from two claims databases and one collection of EHRs. Of 730,225 patients, 36,918 were prescribed chlorthalidone and 693,337 were prescribed hydrochlorothiazide. There were no significant differences in outcomes, including MI, hospitalization for heart failure, or ischemic or hemorrhagic stroke; however, chlorthalidone was associated with a higher risk for hypokalemia, hyponatremia, acute kidney failure, CKD, and type 2 diabetes mellitus. Although this study does not support initial therapy with chlorthalidone, it does not shed light on the use of chlorthalidone for more difficult or resistant patients with hypertension. It is not surprising that the more potent agent also had greater risk for potency-associated side effects.

Moving beyond two-drug combinations, in the Triple Pill versus Usual Care Management for Patients with Mild-to-Moderate Hypertension (TRIUMPH) study, Webster et al. (26) enrolled 700 patients from 11 urban hospitals in Sri Lanka in an open-label trial of a once-daily triple BP therapy combination (telmisartan, amlodipine, chlorthalidone with low-dose and high-dose versions to allow drug titration) for 349 patients compared with usual care for 351 patients. Over the subsequent 5 to 20 months, 675 (96%) completed the trial. The proportion achieving their target BP was higher in the combination therapy group (70% versus 55%), with a mean BP of 125/76 mmHg versus 134/81 mmHg for usual care at 6 months. An improved response was evident as early as 6 weeks after initiation of treatment. Adverse events were similar (38.1 versus 34.8% in usual care), with no significant differences in patient withdrawal rates between groups. In subgroup analysis, triple combination therapy was beneficial for younger patients, for those with more severe hypertension, and across education and income levels.

This study demonstrates the utility of a fixed-dose combination containing inexpensive, effective medications combined appropriately even in settings with limited resources. Triple therapy combinations are being promoted in the 2018 European Society of Cardiology/European Society of Hypertension Arterial Blood Pressure Guideline. This study provides evidence that should stimulate greater efforts to market these agents in the United States, because at this time they are not generally available. Rational combinations would likely include a renin-angiotensin system blocker with a CCB and a thiazide/thiazide-like diuretic.

Putting all of these studies together, the data still support initial treatment with a thiazide or thiazide-type diuretic including hydrochlorothiazide, chlorthalidone, or indapamide for most patients. An approach favored by the author is to choose indapamide as a gentler thiazide-type diuretic and reserve chlorthalidone for patients with more resistant or severe hypertension, including those for whom hydrochlorothiazide is unsuccessful. For patients with albuminuria, an ACE inhibitor or ARB (preferred for the patient with asthma, chronic obstructive pulmonary disease, or chronic cough) should be selected first. If a thiazide-type diuretic is ineffective or not tolerated, change to or addition of an ACE inhibitor, ARB, or CCB is appropriate. There is a generally unmentioned potential risk of a drug reaction associated with combination therapies, particularly among patients with multiple drug sensitivities. In such cases it would be difficult to identify the single inciting agent, thereby removing multiple agents as treatment options. However, use of double or triple combination agents has been demonstrated to shorten the time to achieve and increase the percentage of patients who achieve BP targets.

Timing of Medication

There have been several publications over the past 2 years on the timing of medication dosing. Hermida et al. (27) claimed that bedtime dosing resulted in significant reductions in nocturnal BP measurements, return of normal circadian BP reductions at night, and substantial reductions in CV endpoints. The prospective Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events (MAPEC) study randomized 2156 hypertensive patients (1380 with untreated hypertension and 776 with resistant hypertension) who were taking ≥1 hypertension medication to take all of their medications in the morning or take ≥1 medication at night (27). A 48-hour ABPM was performed at each clinic visit and at least annually. After a median follow-up of 5.6 years, subjects ingesting ≥1 BP-lowering medications at bedtime had significantly lower risk of total CV events than those ingesting all medications upon awakening (0.39 [0.29–0.51]; number of events 187 versus 68; P<0.001), and lower risk of major events including CVD, MI, ischemic stroke, and hemorrhagic stroke (0.33 [0.19–0.55]; number of events: 55 versus 18; P<0.001). There was additional randomization to ensure balanced testing of different drug classes administered at night, and providers could add medications if BP was not controlled to goal after 3 months or could move additional medications to nighttime dosing. The only diuretic included in the trial was torsemide. By the end of the study, 502/1072 (46.8%) of the bedtime dosing arm were taking all of their medications at night. Note that the event-free survival curves separated early (within the first 6 months) and continued to diverge substantially throughout the trial. Relative risks were extremely favorable to evening dosing. It is also of note that daytime BP by clinic or ABPM measurements did not differ by time of dose administration, and all differences in outcomes were attributed to lower nighttime BP.

These claims were thought to be inflated and without confirmation by others, and they were not generally adopted. Recently, Poulter et al. (28) questioned this concept in the Hellenic-Anglo Research into Morning or Night Antihypertensive Drug Delivery (HARMONY) trial, which evaluated the differential effects of morning versus evening dosing on mean 24-hour ambulatory BP levels. In that trial, 103 patients aged 18 to 80 years with reasonable BP control to ≤150/≤90 mmHg on stable therapy with ≥1 agent were recruited and randomized to take their usual therapy in the morning or in the evening for 12 weeks, then to cross over to the alternative timing for another 12 weeks. Clinic BP and ABPM were taken at baseline, 12 and 24 weeks. For the 95 patients who completed all three 24-hour recordings, mean 24-hour, daytime, and nighttime systolic and diastolic BP did not differ between daytime and evening dosing, nor were there differences in clinic BP levels. A larger trial, Treatment in the Morning Versus Evening (TIME), has enrolled the planned cohort of 21,113 patients comparing morning versus evening dosing for major CV outcomes over a mean period of 4 years, which will extend to 2021. However, this study does not use ABPM.

Hermida et al. (29) have now published the Hygia Chronotherapy Trial, a prospective endpoint trial of 19,084 hypertensive patients assigned 1:1 to ingest all (≥1) antihypertensive medications at bedtime or on awakening in the morning. A 48-hour ABPM was performed at each clinic visit and at least annually. After 6.3 years median follow-up, 1752 patients experienced a primary CV outcome of death, MI, coronary revascularization, heart failure, or stroke. After adjustment for age, sex, diabetes status, CKD, smoking, prior CVD events, and others, bedtime administration was associated with a lower hazard ratio of 0.55 for the primary outcome and 0.44 to 0.66 for each of the other single outcomes.

Such a large-scale study using extended ABPM on large cohorts is difficult to replicate. The extreme benefits observed from adjustment of time of administration—without medication or dosage changes, and the extreme reductions in endpoints associated with only nighttime BP reductions—has raised doubts in the hypertension community regarding the validity of these results. Dramatic reductions in nighttime BPs could precipitate cardiac or cerebral ischemia, particularly in patients with generalized vascular disease.

At this time, we do not know whether nighttime dosing of medication provides significant benefits over morning dosing (30). The topic has reached the general public and will not infrequently require discussion with individual patients.

Implementation Strategies for Hypertension Control

Nonadherence or suboptimal adherence to antihypertensive medications is thought to be one of the main reasons for inadequate BP control. Studies have shown that only about 50% of patients with hypertension adhere to their medication, defined as taking ≥80% of their medications (31). Efforts to address this problem include additional education, using resources from EHRs, coaching sessions, or smartphone apps. Two recently published trials were both negative for their primary outcome of improved BP control (32,33).

In a randomized trial by Persell et al. (32), 794 patients with hypertension taking ≥3 medications for any purpose were randomly assigned by their clinic to EHR-based medication management tools (medication review sheets, lay medication information sheets), EHR tools plus nurse-led medication management support, or usual care. After 12 months, systolic BP was higher and control rates lower in the EHR-alone group and comparable between the EHR plus education and usual care groups. Investigators observed medication reconciliation improvement in both EHR groups, and greater understanding of medications and dosing in the EHR plus education group, compared with usual care. Based on BP readings, the addition of EHR without and with additional education did not appear to improve medication adherence.

Morawski et al. (33) recruited 411 subjects with uncontrolled hypertension taking one to three medications for participation in a smartphone app trial for the Medisafe app. Outcomes were BP based on home BP readings and adherence based on self-assessment using the Morisky Medication Adherence Scale (MMAS) after 12 weeks. Systolic BP declined in both groups equally by 10.6 mmHg in the intervention group and by 10.1 mmHg in the control group. The mean MMAS score improved by 0.4 points only in the intervention group, but the improvement was thought to be too small to translate into improvements in BP, with the minimal effect difference felt to be 2 points. The authors did note that the greatest improvement in adherence was seen in those with the lowest levels at baseline; thus, there may be some benefit from the effort.

Resistant Hypertension

The American Heart Association release of a new Scientific Statement on Resistant Hypertension in 2018 is discussed earlier in this nephSAP issue (34). Beyond modification of the definition for resistant hypertension, additional recommendations cover drug therapy adjustments in detail, with a focus on choice of agents for the fourth, fifth, or sixth agent added to the regimen. Volume excess is common, especially in patients with CKD; thus, chlorthalidone should be used for eGFR down to 30 mL/min with consideration of a loop diuretic, particularly the longer-acting loop diuretic torsemide, for lower levels of renal function. Beyond inclusion of an ACE inhibitor or an ARB, a CCB, and an appropriately dosed diuretic, the addition of a mineralocorticoid receptor antagonist is indicated using either spironolactone or eplerenone (35). Additional steps include consideration of a β-blocker, then a direct vasodilator such as hydralazine or minoxidil for men. There is a short summary of the current status of device-based therapies, none of which are currently approved by the US Food and Drug Administration.

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  • View in gallery

    Kaplan-Meier curves for pre-specified outcomes in SPRINT participants with CKD. Panel A shows the primary cardiovascular outcome, defined as the composite of myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, and death from cardiovascular causes. Panel B shows the all-cause death outcome. Panel C shows the main kidney outcome, defined as the composite of a decrease in eGFR of ≥50% from baseline (confirmed by repeat testing ≥90 days later) or the development of ESRD. The broken lines depict the intensive group; the solid lines depict the standard group. Reprinted with permission from reference 13 (Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, et al.: Effects of Intensive BP Control in CKD. J Am Soc Nephrol 28: 2812–2823, 2017).

  • View in gallery

    Changes in estimated GFR in standard care (upper line) and intensive care (lower line) groups in SPRINT chronic kidney disease cohort. Reprinted with permission from reference 13 (Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, et al.: Effects of Intensive BP Control in CKD. J Am Soc Nephrol 28: 2812–2823, 2017).

  • View in gallery

    Change in estimated GFR in standard and intensive treatment groups without chronic kidney disease at enrollment, looking at fasting or nonfasting status. From Annals of Internal Medicine, Beddhu S, Rocco MV, Toto R, et al., for the SPRINT Research Group. Effects of Intensive Systolic Blood Pressure Control on Kidney and Cardiovascular Outcomes in Persons Without Kidney Disease: A Secondary Analysis of a Randomized Trial. 2017;167:375–383 ©2020 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.

  • View in gallery

    Final status of SPRINT non—chronic kidney disease (CKD) participants who met the criteria for incident CKD during follow-up in the intensive (top) and standard (bottom) treatment groups. From Annals of Internal Medicine, Beddhu S, Rocco MV, Toto R, et al., for the SPRINT Research Group. Effects of Intensive Systolic Blood Pressure Control on Kidney and Cardiovascular Outcomes in Persons Without Kidney Disease: A Secondary Analysis of a Randomized Trial. 2017;167:375–383 ©2020 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.

  • View in gallery

    Network meta-analysis comparing single class of antihypertension medications with placebo for treatment of cardiovascular events. Effectiveness of different drug classes in reducing overall cardiovascular (CV) events, myocardial infarction, stroke, CV revascularization, and overall CV events. ACE, indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; DH CCB, dihydropyridine calcium channel blocker; and error bars, 95% CI. Reprinted with permission from reference 22 (Wei J, Galaviz KI, Kowalski AJ, et al.: Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications: A Systematic Review and Network Meta-analysis. JAMA Netw Open 2020;3(2):e1921618), which is available under the terms of the Creative Commons Attribution License.

  • View in gallery

    Protective effect of combination therapy over monotherapy in reducing cardiovascular outcomes. Used with permission from Reference 23. (Rea F, Corrao G, Merlino L, et al.: Initial Antihypertensive Treatment Strategies and Therapeutic Inertia. Hypertension 72: 846–853, 2018).

  • 1.

    Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, .: 2017 guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A Report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension 71: e13e115, 2018 PubMed

    • Search Google Scholar
    • Export Citation
  • 2.

    Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, .: ESC Scientific Document Group: 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 39: 30213104, 2018 PubMed

    • Search Google Scholar
    • Export Citation
  • 3.

    Hypertension in adults: diagnosis and management. National Institute for Health and Care Excellence website. https://www.nice.org.uk/guidance/ng136. NICE guideline [NG136]. Published August 28, 2019. Accessed April 6, 2020

  • 4.

    Nerenberg KA, Zarnke KB, Leung AA, Dasgupta K, Butalia S, McBrien K, .; Hypertension Canada: Hypertension Canada’s 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children. Can J Cardiol 34: 506525, 2018 PubMed

    • Search Google Scholar
    • Export Citation
  • 5.

    James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, .: 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311: 507520, 2014 PubMed

    • Search Google Scholar
    • Export Citation
  • 6.

    Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA; Clinical Guidelines Committee of the American College of Physicians and the Commission on Health of the Public and Science of the American Academy of Family Physicians: Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 166: 430437, 2017 PubMed

    • Search Google Scholar
    • Export Citation
  • 7.

    Byrd JB, Brook RD: Hypertension. Ann Intern Med 170: ITC65ITC80, 2019 PubMed

  • 8.

    Reboussin DM, Allen NB, Griswold ME, Guallar E, Hong Y, Lackland DT, .: Systematic Review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 71: 21762198, 2018 PubMed

    • Search Google Scholar
    • Export Citation
  • 9.

    Sundstrom J, .; Blood Pressure Lowering Treatment Trialists’ Collaboration: Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 384: 591598, 2014 PubMed

    • Search Google Scholar
    • Export Citation
  • 10.

    Muntner P, Carey RM, Gidding S, Jones DW, Taler SJ, Wright JT Jr, .: Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. J Am Coll Cardiol 69: 24462456, 2017 PubMed

    • Search Google Scholar
    • Export Citation
  • 11.

    ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 288: 29812997, 2002 PubMed

    • Search Google Scholar
    • Export Citation
  • 12.

    Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, .; SPRINT Research Group: A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 373: 21032116, 2015 PubMed

    • Search Google Scholar
    • Export Citation
  • 13.

    Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, .; SPRINT Research Group: Effects of intensive BP control in CKD. J Am Soc Nephrol 28: 28122823, 2017 PubMed

    • Search Google Scholar
    • Export Citation
  • 14.

    Beddhu S, Rocco MV, Toto R, Craven TE, Greene T, Bhatt U, .; SPRINT Research Group: Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in persons without kidney disease: a secondary analysis of a randomized trial. Ann Intern Med 167: 375383, 2017 PubMed

    • Search Google Scholar
    • Export Citation
  • 15.

    Zhang WR, Craven TE, Malhotra R, Cheung AK, Chonchol M, Drawz P, .; SPRINT Research Group: Kidney damage biomarkers and incident chronic kidney disease during blood pressure reduction: a case-control study. Ann Intern Med 169: 610618, 2018 PubMed

    • Search Google Scholar
    • Export Citation
  • 16.

    Malhotra R, Katz R, Jotwani V, Ambrosius WT, Raphael KL, Haley W, .: Urine markers of kidney tubule cell injury and kidney function decline in SPRINT trial participants with CKD. Clin J Am Soc Nephrol 15: 349358, 2020 PubMed

    • Search Google Scholar
    • Export Citation
  • 17.

    Cheung AK, Chang TI, Cushman WC, Furth SL, Ix JH, Pecoits-Filho R, .; Conference Participants: Blood pressure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference. Kidney Int 95: 10271036, 2019 PubMed

    • Search Google Scholar
    • Export Citation
  • 18.

    Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G, Cheung AK, .; SPRINT MIND Investigators for the SPRINT Research Group: Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA 321: 553561, 2019 PubMed

    • Search Google Scholar
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