[140] The AASK trial would suggest that African Americans with CKD should be placed on an ACEI, but the ALLHAT study reported that chlorthalidone was superior to lisinopril for CVD outcomes in African Americans.[141] Therefore, for African American patients with CKD on monotherapy with an ACEI or an ARB, the addition of a thiazide-type diuretic would be appropriate as additional therapy to augment the cardiovascular protection of diuretics to the kidney protection of ACEIs or ARBs. Providers may refer to the VA/DoD Clinical Practice Guideline for the Management of Chronic for further discussion of use of an ACEI or ARB in patients with CKD. In addition, the potential for increased risk of AEs with blood pressure medication was a concern noted among the participants in the patient focus group. Although not included in the previous evidence review, the Work Group noted the potential for harm with an ACEI in African American patients due to an increased risk for angioedema reported to be up to five times greater than in white patients. Of the patients randomized to an ACEI in ALLHAT, angioedema was reported as a serious adverse event more frequently in the subgroup of African American patients (0.72%) compared to non-African American patients (0.31%), and more frequently than African American patients receiving treatment with a thiazide- type diuretic (0.04%) or a LA DHP CCB (0.06%).[136] Per FDA product information, angioedema has been reported rarely in patients treated with an ARB. Additional research is needed to determine the risk in African American patients and/or patients who have previously experienced angioedema while on an ACEI. Additional considerations include potential compelling indications for use of an ACEI or ARB in patients with HTN and comorbidities. As this is a Not Reviewed, Not Changed recommendation, the Work Group did not systematically review evidence related to this recommendation. Based on the evidence review from the 2014 VA/DoD HTN CPG, See the VA/DoD Clinical Practice Guideline for the Management of Chronic Kidney Disease. Available at: https://www.healthquality.va.gov/guidelines/cd/ckd/index.asp the Work Group s confidence in the quality of the evidence is high.[136-141] Other considerations regarding this recommendation include the potential for harm (from a rare but serious adverse event) as well as reduced benefit in this patient population (i.e., reduced outcome benefit and less blood pressure reduction compared to alternative treatments). Patient values and preferences were considered to be similar. Thus, the Work Group decided to carry forward the Strong for recommendation against use of an ACEI or ARB as monotherapy in African American patients with HTN. It is appropriate to add an ACEI or ARB to a thiazide-type diuretic and/or a CCB for this population. Recommendation 25. In hypertensive patients 65 years and over, we suggest a thiazide-type diuretic for reduction in composite cardiovascular outcomes. (Weak for | Reviewed, New-added) Discussion In hypertensive patients over the age of 65, treatment with a thiazide-type diuretic compared to other treatment options has been shown to reduce a composite cardiovascular outcome which included heart failure and stroke.[142] In this same meta-analysis, beta-blockers performed worse than all other therapies and CCBs, ACEIs, and ARBs had no significant difference in the composite outcome for patients over the age of 65 compared to other therapies. It is important to note that the age of 65 is an arbitrary cut-off that was used in this single meta-analysis. Individual trials have used various age cut-offs for enrollment. Furthermore, this meta-analysis reported similar outcomes with an age cut-off of 60, as compared to 65. Large RCTs are consistent with this recommendation, specifically ALLHAT which is especially pertinent to VA/DoD providers due to the more than 7,000 Veterans included in the study.[137] Of note, ALLHAT enrolled patients age 55 and over and demonstrated improved CVD outcomes with chlorthalidone compared to amlodipine or lisinopril. Harms of thiazide-type diuretics versus other therapies were considered, but a meta-analysis of adverse events did not demonstrate any significant difference between thiazide-type diuretics and other therapies.[142] In general, the evidence supports the use of thiazide-type diuretics in older patients with HTN over other classes of medication. While there is strong evidence that thiazide-type diuretics in general reduce a composite cardiovascular outcome, there is significant variability between agents in the thiazide-type diuretic class. The strongest trial evidence for improved CVD outcomes with thiazide-type diuretics involves chlorthalidone and indapamide, from ALLHAT and the Hypertension in the Very Elderly Trial (HYVET), respectively.[137,143] In Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), ACEI/CCB combination was favored over an ACEI/thiazide-type diuretic combination.[144] The dose and type of the thiazide-type diuretic in ACCOMPLISH (hydrochlorothiazide [HCTZ] 12.5-25 mg/day) was lower than equipotent doses of chlorthalidone or indapamide. For initial or add-on treatment of HTN, chlorthalidone and indapamide result in greater decreases of blood pressure compared to low doses (12.5-25 mg/day) of HCTZ. For these reasons, chlorthalidone or indapamide is preferred over HCTZ when choosing a thiazide-type diuretic. Patient preferences may vary based on the requirement for laboratory monitoring with thiazide-type medications. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation.[137,142-144] The Work Group s confidence in the quality of the evidence is moderate. The body of evidence had some limitations including an assumption of class effect between all thiazide-type diuretics, inconsistent results across different composite outcomes, and an age cut-off that did not match the primary study evidence.[137,142-144] Other considerations regarding this recommendation included the benefits, primarily in the composite cardiovascular outcome, outweighing the potential harm of adverse events, which was insignificant compared to other therapies. Patient values and preferences were somewhat varied. Thus, the Work Group decided upon a Weak for recommendation. More research is needed into the comparative effectiveness of different medications in the thiazide-type diuretic class. Recommendation 26. We recommend against more than one of the following three drug classes together in the same patient: angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or direct renin inhibitors. (Strong against | Not Reviewed, Not Changed) Discussion Despite the potential for additional blood pressure reduction with combination therapy of agents that act at the renin-angiotensin system (ACEIs, ARBs, and direct renin inhibitors [DRIs]), data from clinical trials have reported an increased risk for harm (including hypotensive symptoms, kidney dysfunction or acute kidney injury events, or hyperkalemia) without long-term cardiovascular or kidney outcome benefit in patients treated with combination therapy with any two of these three classes compared to monotherapy.[145-147] Although these trials primarily studied high-risk patients (those with at least one of the following conditions: vascular disease, diabetes, CKD, or diabetic nephropathy), the majority of patients either had a diagnosis of HTN or were being treated with antihypertensive medications.[145-147] As this is a Not Reviewed, Not Changed recommendation, the Work Group did not systematically review evidence related to this recommendation. Based on the evidence reviewed during the 2014 VA/DoD HTN CPG update, the Work Group s confidence in the quality of the evidence was moderate.[147] Two additional studies that were not part of the 2014 VA/DoD HTN CPG evidence review, but were included in the previous discussion, provide support for the lack of benefit and potential harm with combination therapy.[145,146] Other considerations regarding this recommendation include the potential harm of adverse events, which was significant, and lack of outcome benefit, outweighing the minimal potential benefit of additional blood pressure reduction. Patient values and preferences were considered to be similar. The Work Group decided to carry forward the Strong against recommendation against use of combination therapy with an ACEI, ARB, or DRI, so as to inform providers of the rationale against this practice. Recommendation 27. For the treatment of hypertension, there is insufficient evidence to recommend for or against initiating combination therapy over initiating monotherapy with the sequential addition of another medication. (Neither for nor against | Reviewed, New-replaced) Discussion Combination therapy for treating HTN is common. The ACCOMPLISH study confirmed that combination therapy is safe and effective.[144] Patients in ALLHAT often utilized combination therapy,[137] with only 26% of participants reaching goal blood pressure (<140/90 mm Hg) with monotherapy.[148] Generally speaking, larger reductions of blood pressure (e.g., 20/10 mm Hg or more) often require at least two medications to achieve blood pressure control, and initiating therapy with two drugs is effective and well tolerated, apart from a slight increase in dizziness incidence for some combination dosing, in most However, evidence is lacking on the effect of various treatment approaches on important primary outcomes (e.g., mortality, cardiovascular events, stroke). Specifically, additional studies are needed on initiating therapy with one drug and sequentially titrating agents compared to starting two drugs simultaneously and titrating as necessary. The systematic evidence review conducted for this CPG update did not identify any studies that met inclusion criteria. From a practical perspective, providers and patients depending on their preferences as well as a patient s comorbid conditions and the anticipated magnitude of blood pressure lowering may wish to consider combination therapy when selecting initial therapy. Initial combination therapy may reduce the number of titrations and visits to achieve blood pressure goal. Patients with a compelling indication for more than one class of antihypertensive agent may benefit from initial combination therapy, as well. Additionally, combination pills, when available, may reduce medication co-payments for some patients. Whether using sequential or initial combination therapy, providers should attempt to achieve dosing ranges that have been found to impact important clinical outcomes. As this is a Reviewed, New-replaced recommendation, the Work Group systematically searched for evidence related to this recommendation in the evidence review conducted as part of this guideline update; however, no evidence met inclusion criteria. Therefore, this recommendation is based on evidence cited in the 2014 VA/DoD HTN CPG.[137,144,149] The Work Group determined there is some variation in patient values and preferences as some patients may prefer reducing the number of pills but fixed-dose combination therapy may not always be available (e.g., in the desired drug combination or strength) or prescribed. b. For Resistant Hypertension Recommendation 28. For patients with resistant hypertension (defined as those who are not adequately controlled with maximally tolerated dose of triple therapy [i.e., a thiazide-type diuretic, calcium channel blockers, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker]), we suggest adding spironolactone in those patients without contraindications. (Weak for | Reviewed, New-replaced) Discussion The mineralocorticoid receptor antagonist (MRA) spironolactone more effectively reduced SBP and DBP compared to placebo when added as the fourth agent to the treatment regimen of patients with resistant HTN (RHT).[150,151] In patients with a history of hyperkalemia and diminished renal function, spironolactone should be used cautiously and with frequent monitoring of potassium and renal function in RHT patients, and should be avoided altogether in patients with eGFR less than 30 ml/min/1.73M2 or a serum potassium greater than 5.0 mEq/L. Since spironolactone has both antiandrogenic and endocrine effects, it should also be used cautiously in patients with menstrual irregularities, breast pain or gynecomastia. Two SRs that included five RCTs of 662 patients with RHT and four RCTs of 553 patients with RHT, respectively, compared spironolactone to placebo or to ramipril.[150,151] Compared to placebo, spironolactone reduced office SBP/DBP by an average of 15.73/6.21 mm Hg and 24-hour ambulatory or home SBP/DBP by 8.70/4.12 mm Hg.[150] More limited studies of another MRA, eplerenone,[152] and an epithelial sodium channel blocker, amiloride,[153] suggest that they have qualitatively similar effects on blood pressure as spironolactone in patients with RHT. Compared with clonidine or spironolactone, the addition of other antihypertensive drugs (notably candesartan, doxazosin, bisoprolol, ramipril, atenolol, or alpha methyldopa) to the three-drug regimen of patients with RHT were less effective in reducing blood pressure.[150,154] It should be noted, however, that there are no studies which directly compare either amiloride or eplerenone with spironolactone in patients with RHT. From a safety perspective, spironolactone, eplerenone, and amiloride all consistently resulted in a modest increase in serum potassium. The longest period of evaluation of the effect of spironolactone, another antihypertensive drug, or placebo on blood pressure in these RCTs was 24 weeks. Thus, it was not possible to determine the effect of the drugs on cardiovascular outcomes. However, one RCT, the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT), included patients who met the criteria for RHT.[155] A subset of 403 of the study participants from the Americas (U.S., Canada, Argentina, and Brazil) had RHT; 1,361 patients without RHT served as the comparator group. Patients were treated for an average of 2.92 years with either spironolactone or placebo in addition to their three-drug therapy. SBP in the spironolactone group was lower than in the placebo group at four weeks and remained significantly lower for at least eight months. The significantly greater reduction in the primary endpoint in spironolactone- versus placebo-treated patients was comparable in those with and without RHT. The evidence on which this recommendation is made is derived from three SRs and two independent RCTs that were not included in the SRs.[150-152,154,155] A third open-label study documented the blood pressure lowering effect of amiloride in a subset of 146 RHT patients who had already been treated with spironolactone, placebo, bisoprolol, or doxazosin in the Pathway-2 RCT.[153] The results of this substudy were not included in the three SRs since it was published later. The Work Group did not consider this substudy in its development of the recommendation or determination of the confidence in the quality of the evidence. Among the five RCTs included in the SR by Liu et al. (2017) spironolactone consistently lowered office and ambulatory or home SBP and DBP in the pooled analysis.[150] In this analysis, spironolactone also lowered SBP by 4.5 mm Hg compared to atenolol, candesartan, or alpha methyldopa, a statistically significant effect. The strength of evidence to support the efficacy of spironolactone to lower both SBP and DBP compared to either placebo or other drugs previously listed was considered to be high with a low risk of bias. Similar conclusions were reached after review of the SR by Wang et al. (2016).[151] In contrast, the strength of the evidence represented by the 19 studies of 2,758 patients with RHT in the SR by Makai et al. (2017) was very low.[152] Studies of both spironolactone and eplerenone (MRAs) were combined for this analysis so it was impossible to determine if the efficacy of each was equivalent to the other. Furthermore, the collective risk of bias among the studies was considered to be a serious limitation even though 24-hour SBP and DBP were significantly reduced when assessed by ABPM but not by office DBP. When Krieger et al. (2018) compared the effects of clonidine on office and 24-hour blood pressure with those of low-dose spironolactone in patients with RHT with multiple comorbidities excluded, there were no significant differences but there was considerable variability in the responses of the patients.[154] Collectively, there was sufficient concern about either imprecision or risk of bias among the SRs and RCT supporting the addition for adding spironolactone as the preferred fourth agent in patients with RHT still not controlled on three drugs to make only a Weak for recommendation. Although of considerable clinical interest, the findings that spironolactone reduced cardiovascular outcomes in the TOPCAT cohort with preserved ejection fraction heart failure and RHT similarly to those without RHT was not considered in the above assessment because of the serious limitations of the study design as well as serious imprecision.[155] In addition, it is likely that this population of preselected patients with heart failure are phenotypically different from other patients with RHT. Before adding a fourth drug to the treatment regimen, medication adherence should be assessed and the benefits of non-pharmacologic therapy should be reinforced in every patient who meets the criteria for RHT. Because of the frequency with which medication non-adherence occurs in this population, the term apparent treatment resistant hypertension has appeared in the literature with increasing frequency. If addition of spironolactone is being considered, it should be remembered that spironolactone will interfere with the tests that are ordered as part of the evaluation for hyperaldosteronism, a secondary form of HTN. If a secondary HTN workup is planned, initiation of therapy with spironolactone should be delayed until that workup is complete. Drugs other than spironolactone may be more appropriate for the RHT patient who has a history of hyperkalemia, has significantly impaired kidney function, sexual dysfunction, or has developed either mastodynia or gynecomastia upon exposure to this drug in the past. A number of different drugs are available for the RHT patient whose blood pressure remains uncontrolled. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed the evidence related to this recommendation. The following three SRs or meta-analyses [150-152] and two RCTs [154,155] identified in the evidence review conducted as part of this guideline update were evaluated in detail. The strengths and weakness of the data in this literature are summarized above. The benefits of taking once-daily spironolactone outweighs the potential for AEs when the RHT patient is chosen carefully and monitored closely as therapy is initiated. Epidemiologically, patients who meet the criteria for RHT are at increased risk for fatal and non-fatal cardiovascular events. Yet there are no outcome data to guide the clinical practitioner on which fourth-line drug will have the greatest effect on cardiovascular events. Furthermore, little is known about the impact of age, gender, and comorbidities like diabetes, CKD, CAD, or prior stroke on the response to specific medications in patients with RHT. VIII. Research Priorities During the development of the 2020 VA/DoD HTN CPG, the Work Group identified numerous areas for future research, including areas requiring stronger evidence to support current recommendations as well as research exploring new areas to guide future CPGs. A. Automated Office Blood Pressure and Out-of-office Blood Pressure Out-of-office blood pressure measurements were shown to be superior to routine office blood pressure measurements in predicting cardiovascular events; therefore, future studies should focus on impact of blood pressure management based on out-of-office blood pressure measurements on clinically relevant outcomes in hypertensive individuals. Further research is also needed to evaluate whether patient-related outcomes can be improved with management of HTN in the general population based on blood pressure targets obtained with AOBP that is being increasingly recognized as equivalent to out-of-office blood pressure. Additionally, variation in appropriate management for blood pressure variation by time of day and season should be included in future studies to determine the clinical significance. B. Self-monitoring of Blood Pressure Areas of research include the development of protocols allowing for self-management and self-adjustment of antihypertensive medications by hypertensive individuals, based on home self-monitoring of blood pressure and provider guidance. Furthermore, it is important to identify what specific hypertensive populations (demographic characteristics and comorbidities) would benefit the most from self-monitoring of blood pressure and what outcomes (blood pressure control, adherence, cardiovascular outcomes) may be improved with self-monitoring of blood pressure. C. New Technology Future research on application of new technology in management of HTN should include incorporation of telemonitoring using smartphone applications and other technology to improve patients adherence to medications and enable communication with healthcare providers to maximize access to treatment. D. Interdisciplinary Approaches HTN treatment requires a complex approach combining prescription drug management, implementation of a healthy lifestyle and diet, and monitoring of adherence to these interventions. Therefore, high quality randomized trials are needed to evaluate cost-effectiveness and impact on patient-related clinical outcomes of protocolized nurse-led and pharmacist-led antihypertensive medication titration programs, and the role of registered dietitian-led interventions targeting healthy lifestyle changes and diet, and adherence monitoring for improving blood pressure control and patient-centered outcomes. E. Diet and Exercise Most of the evidence supports modest reduction in blood pressure with low sodium diets; however, clinical trials are needed to evaluate whether long-term cardiovascular outcomes can be also affected by low sodium diets, and whether it is the low sodium diet itself or low sodium intake as a part of an overall healthy dietary pattern which leads to improved clinical end-points. Despite general belief that a reduction in sedentary time results in lowering of blood pressure, there is a paucity of clinical data about optimal duration, frequency and specific type(s) of exercise that would result in improved patient outcomes. Clinical trials are required to address these research questions. F. Obesity and Hypertension Growing rates of obesity call for additional research on blood pressure lowering as well as cardiovascular benefits of weight loss interventions, including pharmacological therapy and bariatric surgery in obese hypertensive individuals. Trials with long-term follow up are especially important to evaluate sustainability and impact of weight-lowering interventions in patients with obesity and HTN. G. Pharmacotherapy Combination antihypertensive therapy may allow for use of lower doses of individual agents and, therefore, minimize adverse drug effects. However, clinical trials are needed to evaluate whether (and which specific) combination of antihypertensive agents and at what doses are more effective than a maximum-level dose of a single agent for blood pressure control and medication adherence. Clinical trials should also focus on comparative effectiveness of (1) equivalent doses of chlorthalidone and hydrochlorothiazide, and (2) newer antihypertensive agents, such as vasodilatory beta-blockers in essential HTN. Management of RHT is a rapidly expanding area and future studies with long-term follow-up that would allow evaluation of clinical outcomes are needed to establish optimal fourth-line antihypertensive agents in RHT and whether variations in patient characteristics may necessitate differential approaches to a fourth-line agents for RHT. H. Screening for Asymptomatic Hypertension-mediated Target Organ Damage Despite clinically sound concerns about target organ damage resulting from HTN and routine screening for asymptomatic CVD and kidney disease that is done by many general practitioners, there is a paucity of evidence to support this practice. Future studies are needed to evaluate cost effectiveness and clinical impact of routine screening for asymptomatic target organ damage in hypertensive individuals. For example, coronary artery calcification (CAC) score carries prognostic value in hypertensive patients. However, additional research should address whether CAC scores can direct initiation of antihypertensive therapy and dictate individualization of blood pressure management and goals. Appendix A: Evidence Review Methodology A. Developing the Scope and Key Questions The CPG Champions, along with the Work Group, were tasked with identifying KQs to guide the systematic review of the literature on HTN. These questions, which were developed in consultation with the Lewin Team, addressed clinical topics of the highest priority for the VA and DoD populations. The KQs follow the population, intervention, comparison, outcome, timing and setting (PICOTS) framework for evidence questions, as established by the Agency for Healthcare Research and Quality (AHRQ). Table A-1 provides a brief overview of the PICOTS typology. PICOTS Element Description Population, Patients, or Problem A description of the patients of interest. It includes the condition(s), populations or sub- populations, disease severity or stage, co-occurring conditions, and other patient characteristics or demographics. Intervention or Exposure Refers to the specific treatments or approaches used with the patient or population. It includes doses, frequency, methods of administering treatments, etc. Comparison Describes the interventions or care that is being compared with the intervention(s) of interest described above. It includes alternatives such as placebo, drugs, surgery, lifestyle changes, standard of care, etc. Outcome Describes the specific results of interest. Outcomes can include short, intermediate, and long-term outcomes, or specific results such as quality of life, complications, mortality, morbidity, etc. Timing, if applicable Describes the duration of time that is of interest for the particular patient intervention and outcome, benefit, or harm to occur (or not occur). Setting, if applicable Describes the setting or context of interest. Setting can be a location (such as primary, specialty, or inpatient care). Abbreviation: PICOTS: population, intervention, comparison, outcome, timing and setting The Champions, Work Group, and evidence review team carried out several iterations of this process, each time narrowing the scope of the CPG and the literature review by prioritizing the topics of interest. Due to resource constraints, all developed KQs were not able to be included in the systematic evidence review. Thus, the Champions and Work Group determined which questions were of highest priority, and those were included in the review. Table A-2 contains the final set of KQs used to guide the SR for this CPG. Once the KQs were finalized, the Work Group rated and prioritized the outcomes they had defined for each KQ based on how important the Work Group judged each outcome to be. Rating outcomes by their relative importance can help focus attention on those outcomes that are considered most important for clinical decision making when making judgements regarding the overall quality of the evidence to support Using GRADE methodology, the Work Group rated each outcome on a 1-9 scale (7-9, critical for decision making; 4-6, important, but not critical, for decision making; and 1-3, of limited importance for decision making). Critical and important outcomes were included in the evidence review (see Outcomes); however, only outcomes judged to be critical were used to determine the overall quality of evidence (see Grading Recommendations). a. Population(s) Adult patients ( 18 years of age) with (management) or without (screening, primary prevention) HTN Including women of childbearing age, women with a history of preeclampsia, pregnant women, deployed Service Members, and patients with comorbidities (e.g., diabetes, CKD) Note: Although evidence on pregnant women was included in the search, no evidence in this population was identified in the evidence review; see the VA/DoD Clinical Practice Guideline for the Management of Pregnancy for additional information regarding HTN in Excluding children, adolescents, and patients with unusual causes of secondary HTN (e.g., pheochromocytoma, aldosteronism) b. Interventions Key Question 1 Interventions to diagnose and manage HTN, including white coat HTN, masked HTN, undiagnosed masked HTN Home measure (self-measure), 24-hour ambulatory monitoring (daytime, nighttime, and Different approaches to physician office manual blood pressure measurement Key Question 2 Home measure (self-measure), 24-hour ambulatory monitoring (daytime, nighttime, and 24-hour), telemonitoring, night-time home measurement Key Question 3 Bariatric surgery Obesity medications approved for chronic weight management (phentermine/topiramate, lorcaserin, orlistat, naltrexone/bupropion, liraglutide) Lifestyle interventions to reduce weight (only weight loss diet studies designed to reduce HTN), including dietary changes, physical activity, decrease in sedentary activities, and including intervention using behavioral modification methods Key Question 4 Lifestyle modification that involves exercise Aerobic exercise, non-aerobic exercise Interventions intended to reduce sedentary time Weight training/ resistance (e.g., hand grip) 14 See the VA/DoD Clinical Practice Guideline for the Management of Pregnancy. Available at: https://www.healthquality.va.gov/guidelines/WH/up/ Tai Chi, Qigong, yoga Key Question 5 Antihypertensive pharmacologic therapy to a specific systolic blood pressure goal or range or with the goal of reduction in blood pressure Key Question 6 Antihypertensive pharmacologic therapy to a specific diastolic blood pressure goal or range or with the goal of blood pressure reduction Key Question 7 Initial therapy: thiazide-type diuretics, ACEIs, ARBs, CCBs, beta blockers Add-on therapy: a drug/class from list above that is other than the initial therapy, or other drugs/classes (e.g., spironolactone, a MRA, aka aldosterone antagonist [AA], etc.) could be used as add-on therapy Key Question 8 Initial therapy various combinations of: thiazide-type diuretic + ACEI, thiazide-type diuretic + ARB, thiazide-type diuretic + ARB, thiazide-type diuretic + beta blocker, thiazide-type diuretic + CCB, ACEI + CCB, ARB + CCB Note: Interventions were not limited to combination within one tablet Key Question 9 Addition of a fourth drug (any) Initial three medications should include (all in maximum tolerated doses): long-acting dihydropyridine CCB, renin-angiotensin system blocker (ACEI or ARB), thiazide-type diuretic Key Question 10 Telehealth visit with primary care or sub-specialty Telehealth monitoring Mobile apps Instead of or in addition to usual care (in-person visits) Key Question 11 Clinical provider other than prescribers, such as clinical pharmacists, nurses, etc. (In-person or via telehealth) Instead or in addition to usual care (in-person visits) Key Question 12 Screening for asymptomatic CKD with eGFR and urine protein (albumin) measurement Screening for asymptomatic CAD with electrocardiogram (ECG) and calcium score Screening for asymptomatic left ventricular hypertrophy (LVH) with ECG and echocardiogram (ECHO) Screening for asymptomatic peripheral vascular disease (PVD) with carotid ultrasound (US) and ankle-brachial index (ABI) At diagnosis and whether should be repeated at certain intervals c. Comparators Key Question 1 Other method of blood pressure measurement Key Question 2 No monitoring Standard of care office blood pressure Other forms of monitoring listed in intervention Key Question 3 Standard care No intervention Wait list Active intervention unrelated to weight or blood pressure Other intervention listed in intervention column Placebo Sham surgery Different frequency or amount Key Question 4 Standard of care No intervention Wait list Active intervention unrelated to blood pressure Other intervention listed in intervention column Different frequency or amount Key Question 5 Comparator group has a different systolic blood pressure goal or range (i.e., study arms did not need to have the same blood pressure goal or the comparator was a placebo) Usual care Placebo No treatment No goal Key Question 6 Comparator group has a different diastolic blood pressure goal or range (i.e., study arms did not need to have the same blood pressure goal or the comparator was a placebo) Usual care Placebo No treatment No goal Key Question 7 Initial therapy (where comparator is from a different class than the Intervention): thiazide- type diuretics, ACEIs, CCBs, beta blockers Add-on therapy: a drug/class from list above other than initial therapy, or other drugs/ classes (e.g., MRA) could be used as add-on therapy Key Question 8 Initial therapy: thiazide-type diuretics, ACEIs, CCBs, beta blockers With second drug added in at a later time from list above Key Question 9 Placebo A different fourth drug (any) Key Question 10 Usual care No intervention Wait list Active intervention unrelated to blood pressure Another telemonitoring method from intervention list with a different intensity Key Question 11 Usual care No intervention Wait list Active intervention unrelated to blood pressure Another intervention from intervention list with a different intensity Key Question 12 No screening d. Outcomes Key Question 1 Critical outcomes: specificity, sensitivity, positive predictive values (PPV), negative predictive values (NPV), area under curve (AUC), etc. to diagnose and manage HTN, including white coat HTN, masked HTN, undiagnosed masked HTN Key Question 2 Critical outcomes: Reduction in blood pressure, change in blood pressure from baseline, achievement of lower blood pressure goals, HTN control; adherence to therapy, percentage of patients taking medications Important outcomes: composite cardiovascular (CV) outcomes; CV and all-cause mortality; strokes; reduction in CV risks; time to blood pressure control, number of office visits to achieve control Key Question 3 Critical outcomes: Reduction in blood pressure, change in blood pressure from baseline, achievement of lower blood pressure goals, HTN control Important outcomes: composite CV outcomes; CV and all-cause mortality; coronary events; strokes; safety; reduction in antihypertensive medications, number of antihypertensive medications Key Question 4 Critical outcomes: Reduction in blood pressure, change in blood pressure from baseline, achievement of lower blood pressure goals, HTN control Important outcomes: composite CV outcomes; CV and all-cause mortality; coronary events; strokes; CHF; reduction in CV risks Key Questions 5 and 6 Critical outcomes: composite CV outcomes Important outcomes: CV and all-cause mortality; coronary events; strokes; CHF; renal function; safety Key Question 7 Critical outcomes: composite CV outcomes Important outcomes: CV and all-cause mortality; strokes; CHF; renal function; safety; reduction in blood pressure, change in blood pressure from baseline, achievement of lower blood pressure goals, HTN control Key Question 8 Critical outcomes: reduction in blood pressure, change in blood pressure from baseline, achievement of lower blood pressure goals, HTN control Important outcomes: composite CV outcomes; safety; time to blood pressure control, number of office visits to achieve control; adherence to therapy, percentage of patients taking medications Key Question 9 Critical outcomes: safety; reduction in blood pressure, change in blood pressure from baseline, achievement of lower blood pressure goals, HTN control Important outcomes: composite CV outcomes; strokes; CHF; renal function Key Questions 10 and 11 Critical outcomes: Reduction in blood pressure, change in blood pressure from baseline, achievement of lower blood pressure goals, HTN control; adherence to therapy, percentage of patients taking medications Important outcomes: patient quality of life; safety, AEs/adverse events Key Question 12 Critical outcomes: composite outcomes Important outcomes: CV and all-cause mortality; strokes, renal function; reduction in CV risk; diagnosis of masked HTN; dosing and drug selection decisions for antihypertensive drugs B. Conducting the Systematic Review Based on the decisions made by the Champions and Work Group members regarding the scope, the KQs, and the PICOTS statements, the Lewin Team produced an SR protocol prior to conducting the review. The protocol was reviewed and approved by the Champions and Work Group members. It described in detail the final set of KQs, the methodology to be used during the SR process, and the inclusion/exclusion criteria to be applied to each potential study, including, but not limited to, study type, sample size, and PICOTS criteria. Extensive literature searches identified 16,492 citations potentially addressing the KQs of interest to this evidence review. Of those, 11,050 were excluded upon title review for clearly not meeting inclusion criteria (e.g., not pertinent to the topic, not published in English, published prior to study inclusion publication date). Overall, 5,442 abstracts were reviewed with 4,723 of those being excluded for the following reasons: not an SR or an accepted study design (see the General Criteria for Inclusion in Systematic Review and Key Question Specific Criteria), did not address a KQ of interest to this review, did not report on an outcome of interest, or published outside cut-off publication dates. A total of 719 full- length articles were reviewed. Of those, 405 were excluded at a first pass review for the following: not addressing a KQ of interest, not enrolling the population of interest, not meeting inclusion criteria for clinical study or SR, not meeting inclusion criteria for any KQ, or being a duplicate publication. A total of 314 full-length articles were thought to address one or more KQs and were further reviewed. Of these, 217 were ultimately excluded and reasons for their exclusion are presented in Figure A-1. Overall, 97 studies addressed one or more of the KQs and were considered as evidence in this review. Table A-2 indicates the number of studies that addressed each of the questions. Figure A-1. Study Flow Diagram Abbreviations: KQ: key question; SR: systematic review Alternative Text Description of Study Flow Diagram Figure A-1. Study Flow Diagram is a flow chart with nine labeled boxes linked by arrows that describe the literature review inclusion/exclusion process. Arrows point down to boxes that describe the next literature review step and arrows point right to boxes that describe the excluded citations at each step (including the reasons for exclusion and the numbers of excluded citations). 1. Box 1: 16,492 citations identified by searches a. Right to Box 2: 11,050 citations excluded at the title level i. Citations excluded at this level were off-topic, not published in English, or published prior to inclusion date b. Down to Box 3 a. Right to Box 4: 4,723 citations excluded at the abstract level i. Citations excluded at this level were not an SR or clinical study, clearly did not address a KQ, did not report on an outcome of interest, or were outside cutoff publication dates b. Down to Box 5 a. Right to Box 6: 405 citations excluded at 1st pass full article level i. Articles excluded at this level did not: address a key question of interest, enroll the population of interest, meet inclusion criteria for clinical study or SR, meet inclusion criteria for any key question, or were a duplicate b. Down to Box 7 a. Right to Box 8: 217 citations excluded at 2nd pass KQ level i. 81 not a study design, setting, or population of interest ii. 73 superseded by more comprehensive review or included in an SR iii. 13 not an intervention of interest iv. 10 inadequate or unclear follow-up v. 7 inadequate or unclear reporting of data vi. 5 not an outcome of interest vii. 2 not a comparison of interest viii. 26 other (e.g., not published in English, not a clinical trial or SR, published outside date range) b. Down to Box 9 Table A-2. Evidence Base for KQs Question Number Question Number of Studies and Type of Studies 1 What is the optimal method for accurately measuring blood pressure? 6 SRs 2 What is the impact of blood pressure monitoring on adherence to therapy and achievement of blood pressure goals? 3 What is the effectiveness of obesity or overweight treatment (including lifestyle modifications, medications, surgery) to prevent or treat HTN? 4 What is the effectiveness of lifestyle modification that involves exercise (including aerobic exercise, Tai Chi or Qigong) to prevent or treat HTN? What is the optimal amount of these exercises necessary to prevent or treat HTN? 5, 6 For adult outpatients being treated for HTN, what is the systolic (KQ5) or diastolic (KQ6) blood pressure goal that is associated with improved health outcomes? 7 For adult outpatients with HTN, what are the comparative effectiveness and harms of the antihypertensive drug classes thiazide-type diuretics, ACEIs, ARBs, CCBs, and beta blockers (as initial therapy, with or without add-on therapy)? 8 For adult outpatients with HTN, what is the effectiveness and comparative effectiveness and harms of initiating a combination of two or more drug classes versus initiating one drug and adding a second drug later on in selected patients? No evidence 9 For adult patients with resistant or difficult to control HTN, what is the effectiveness and comparative effectiveness and harms of adding any antihypertensive drug to an existing drug regimen of three or more drugs? 10 What are the effectiveness, comparative effectiveness, and harms of telehealth, mobile applications, or other new technologies to improve blood pressure control in adults with HTN? 1 cluster RCT 11 What are the effectiveness, comparative effectiveness, and harms of less conventional forms of HTN care delivery, such as clinical pharmacists-run clinic, nurses-run clinic, using established protocols? 5 cluster RCTs 12 For adult outpatients with HTN and prehypertension, should screening for asymptomatic HTN-mediated end-organ damage by performed? 2 prospective cohort studies Total Evidence Base 97 studies Abbreviations: HTN: hypertension; RCT: randomized controlled trial; SR: systematic review a. General Criteria for Inclusion in Systematic Review SRs or clinical studies published on or after December 15, 2013 to March 25, 2019. If multiple SRs addressed a KQ, we selected the most recent and/or comprehensive review. SRs were supplemented with clinical studies published subsequent to the SR. Studies must have been published in English. Publication must have been a full SR or clinical study; abstracts alone were not included. Similarly, letters, editorials, and other publications that were not full-length clinical studies were not accepted as evidence. SRs must have searched MEDLINE or EMBASE for eligible publications, performed a risk of bias assessment of included studies, and assessed the quality of evidence using a recognizable rating system, such as GRADE or something compatible (e.g., the one used by the AHRQ Evidence-based Practice Centers). If an existing review did not assess the overall quality of the evidence, evidence from the review must have been reported in a manner that allowed us to judge the overall risk of bias, consistency, directness, and precision of evidence. We did not use an existing review as evidence if we were not able to assess the overall quality of the evidence in the review. Intervention studies must have assessed pharmacological or non-pharmacological treatment and have been a prospective, RCT with an independent control group. Crossover trials were not included. Study must have enrolled at least 30 patients (15 per study group) unless otherwise noted (see Key Question Specific Criteria below). Study must have enrolled at least 85% of patients who met the study population criteria: adults aged 18 years or older who have or might be at risk for developing HTN. Study must have had follow-up data for at least 85% of enrolled participants. Study must have reported on at least one critical or important outcome of interest. b. Key Question Specific Criteria For all KQs, SRs of clinical study types appropriate for the respective key question (as outlined below) were the first line of evidence KQ 1: RCTs and diagnostic cohort studies that reported on the diagnostic characteristics of the screening test (e.g., sensitivity, specificity, repeatability) KQ 2: RCTs or non-randomized, prospective comparative studies KQ 3, 4: RCTs, overall sample size 30 KQ 9: RCTs or non-randomized, prospective comparative trials, total sample size 100; retrospective comparative trials total sample size 400 (minimum 200/arm) KQ 10, 11: RCTs KQ 12: RCTs, non-randomized comparative trials, and diagnostic cohort studies c. Literature Search Strategy Information regarding the bibliographic databases, date limits, and platform/provider can be found in the table below. Additional information on the search strategies, including topic-specific search terms and search strategies can be found in Appendix J. Table A-3. Bibliographic Database Information Name Date Limits Platform/Provider Cochrane Database of Systematic Reviews (Cochrane Reviews) Cochrane Central Register of Controlled Trials December 15, 2013 to March 25, 2019 Wiley Database of Abstracts of Reviews of Effects December 15, 2013 to March 25, 2019 Wiley EMBASE (Excerpta Medica) December 15, 2013 to March 25, 2019 Elsevier Health Technology Assessment Database (HTA) December 15, 2013 to March 25, 2019 Wiley PubMed (In-process and Publisher records) December 15, 2013 to March 25, 2019 National Library of Medicine C. Convening the Face-to-face Meeting In consultation with the COR, the Champions, and the Work Group, the Lewin Team convened a three and one half day face-to-face meeting of the CPG Champions and Work Group members on June 3 6, 2019. These experts were gathered to develop and draft the clinical recommendations for an update to the 2014 VA/DoD HTN CPG. The Lewin Team presented findings from the evidence review in order to facilitate and inform the process. Under the direction of the Champions, the Work Group members were charged with interpreting the results of the evidence review and were asked to categorize and carry forward recommendations from the 2014 VA/DoD HTN CPG, modifying the recommendations as necessary. The members also developed new clinical practice recommendations not presented in the 2014 VA/DoD HTN CPG based on the evidence review conducted as part of this guideline update. The Work Group members were divided into three smaller subgroups at this meeting. As the Work Group members drafted clinical practice recommendations, they also assigned a grade for each recommendation based on a modified GRADE and USPSTF methodology. Each recommendation was graded by assessing the quality of the overall evidence base, the associated benefits and harms, the variation in values and preferences, and other implications of the recommendation. In addition to developing recommendations during the face-to-face meeting, the Work Group members also began to revise the 2014 VA/DoD HTN CPG algorithms to reflect the new and amended recommendations. They discussed the available evidence as well as changes in clinical practice since 2014, as necessary, to update the algorithms. D. Grading Recommendations This CPG uses the GRADE methodology to assess the quality of the evidence base and assign a strength for each recommendation. The GRADE system uses the following four domains to assess the strength of each Balance of desirable and undesirable outcomes Confidence in the quality of the evidence Values and preferences Other implications, as appropriate, Resource use Equity Acceptability Feasibility Subgroup considerations The following sections further describe each domain. Balance of desirable and undesirable outcomes refers to the size of anticipated benefits (e.g., increased longevity, reduction in morbid event, resolution of symptoms, improved quality of life, decreased resource use) and harms (e.g., decreased longevity, immediate serious complications, adverse event, impaired quality of life, increased resource use, inconvenience/hassle) relative to each other. This domain is based on the understanding that the majority of clinicians will offer patients therapeutic or preventive measures as long as the advantages of the intervention exceed the risks and AEs. The certainty or uncertainty of the clinician about the risk-benefit balance will greatly influence the strength of the recommendation. Some of the discussion questions that fall under this domain include: Given the best estimate of typical values and preferences, are you confident that the benefits outweigh the harms and burden or vice versa? Are the desirable anticipated effects large? Are the undesirable anticipated effects small? Are the desirable effects large relative to undesirable effects? Confidence in the quality of the evidence reflects the quality of the evidence base and the certainty in that evidence. This second domain reflects the methodological quality of the studies for each outcome variable. In general, the strength of recommendation follows the level of evidence, but not always, as other domains may increase or decrease the strength. The evidence review used for the development of recommendations, conducted by ECRI, assessed the confidence in the quality of the evidence base using GRADE methodology and assigned a rating of High, Moderate, Low, or Very Low. The outcomes judged to be critical were used to determine the overall quality of evidence. Per GRADE, if the quality of evidence differs across the critical outcomes, the lowest quality of evidence for any of the relevant critical outcomes determines the overall quality of the evidence for a recommendation; the overall confidence cannot be higher than the lowest confidence in effect estimates for any outcome that is determined to be critical for clinical decision making.[24,157] The elements that go into the confidence in the quality of the evidence include: Is there high or moderate quality evidence that answers this question? What is the overall certainty of this evidence? Values and preferences is an overarching term that includes patients perspectives, beliefs, expectations, and goals for health and life. More precisely, it refers to the processes that individuals use in considering the potential benefits, harms, costs, limitations, and inconvenience of the therapeutic or preventive measures in relation to one another. For some, the term values has the closest connotation to these processes. For others, the connotation of preferences best captures the notion of choice. In general, values and preferences increase the strength of the recommendation when there is high concordance and decrease it when there is great variability. In a situation in which the balance of benefits and risks are uncertain, eliciting the values and preferences of patients and empowering them and their surrogates to make decisions consistent with their goals of care becomes even more important. A recommendation can be described as having similar values, some variation, or large variation in typical values and preferences between patients and the larger populations of interest. Some of the discussion questions that fall under the purview of values and preferences include: Are you confident about the typical values and preferences and are they similar across the target population? What are the patient s values and preferences? Are the assumed or identified relative values similar across the target population? Other implications consider the practicality of the recommendation, including resource use, equity, acceptability, feasibility and subgroup considerations. Resource use is related to the uncertainty around the cost-effectiveness of a therapeutic or preventive measure. For example, statin use in the frail elderly and others with multiple co-occurring conditions may not be effective and, depending on the societal benchmark for willingness to pay, may not be a good use of resources. Equity, acceptability, feasibility, and subgroup considerations require similar judgments around the practically of the recommendation. The framework below (Table A-4) was used by the Work Group to guide discussions on each domain. Table A-4. GRADE Evidence to Recommendation Framework Decision Domain Questions to Consider Judgment Balance of desirable and undesirable outcomes Given the best estimate of typical values and preferences, are you confident that the benefits outweigh the harms and burden or vice versa? Are the desirable anticipated effects large? Are the undesirable anticipated effects small? Are the desirable effects large relative to undesirable effects? Benefits outweigh harms/burden Benefits slightly outweigh harms/ burden Benefits and harms/burden are balanced Harms/burden slightly outweigh benefits Harms/burden outweigh benefits Confidence in the quality of the evidence Is there high or moderate quality evidence that answers this question? What is the overall certainty of this evidence? High Moderate Low Very low Values and preferences Are you confident about the typical values and preferences and are they similar across the target population? What are the patient s values and preferences? Are the assumed or identified relative values similar across the target population? Similar values Some variation Large variation Other implications (e.g., resource use, equity, acceptability, feasibility, subgroup considerations) Are the resources worth the expected net benefit from the recommendation? What are the costs per resource unit? Is this intervention generally available? Is this intervention and its effects worth withdrawing or not allocating resources from other interventions? Is there lots of variability in resource requirements across settings? Various considerations The strength of a recommendation is defined as the extent to which one can be confident that the desirable effects of an intervention outweigh its undesirable effects and is based on the framework above, which combines the four domains.[158] GRADE methodology does not allow for recommendations to be made based on expert opinion alone. While strong recommendations are usually based on high or moderate confidence in the estimates of effect (quality of the evidence) there may be instances where strong recommendations are warranted even when the quality of evidence is low.[18] In these types of instances where the balance of desirable and undesirable outcomes and values and preferences played large roles in determining the strength of a recommendation, this is explained in the discussion section for the recommendation. The GRADE of a recommendation is based on the following elements: Four decision domains used to determine the strength and direction (described above) Relative strength (Strong or Weak) Direction (For or Against) The relative strength of the recommendation is based on a binary scale, Strong or Weak. A strong recommendation indicates that the Work Group is highly confident that desirable outcomes outweigh undesirable outcomes. If the Work Group is less confident of the balance between desirable and undesirable outcomes, they present a weak recommendation. Similarly, a recommendation for a therapy or preventive measure indicates that the desirable consequences outweigh the undesirable consequences. A recommendation against a therapy or preventive measure indicates that the undesirable consequences outweigh the desirable consequences. Occasionally, instances may occur when the Work Group feels there is insufficient evidence to make a recommendation for or against a specific therapy or preventive measure. This can occur when there is an absence of studies on a particular topic that met evidence review inclusion criteria, studies included in the evidence review report conflicting results, or studies included in the evidence review report inconclusive results regarding the desirable and undesirable outcomes. Using these elements, the grade of each recommendation is presented as part of a continuum: Strong For (or We recommend offering this option ) Weak For (or We suggest offering this option ) No recommendation for or against (or There is insufficient evidence ) Weak Against (or We suggest not offering this option ) Strong Against (or We recommend against offering this option ) Note that weak (For or Against) recommendations may also be termed Conditional, Discretionary, or Qualified. Recommendations may be conditional based upon patient values and preferences, the resources available, or the setting in which the intervention will be implemented. Recommendations may be at the discretion of the patient and clinician or they may be qualified with an explanation about the issues that would lead decisions to vary. E. Recommendation Categorization a. Recommendation Categories and Definitions A set of recommendation categories was adapted from those used by NICE.[21,22] These categories, along with their corresponding definitions, were used to account for the various ways in which recommendations could have been updated from the 2014 VA/DoD HTN CPG. The categories and definitions can be found in Table A-5. Table A-5. Recommendation Categories and Definitions* Evidence Reviewed* Recommendation Category Definition Reviewed New-added New recommendation following review of the evidence New-replaced Recommendation from previous CPG that has been carried over to the updated CPG that has been changed following review of the evidence Not changed Recommendation from previous CPG that has been carried forward to the updated CPG where the evidence has been reviewed but the recommendation is not changed Amended Recommendation from the previous CPG that has been carried forward to the updated CPG where the evidence has been reviewed and a minor amendment has been made Deleted Recommendation from the previous CPG that has been removed based on review of the evidence Not reviewed Not changed Recommendation from previous CPG that has been carried forward to the updated CPG, but for which the evidence has not been reviewed Amended Recommendation from the previous CPG that has been carried forward to the updated CPG where the evidence has not been reviewed and a minor amendment has been made Deleted Recommendation from the previous CPG that has been removed because it was deemed out of scope for the updated CPG *Adapted from the NICE guideline manual (2012) [21] and Garcia et al. (2014) [22] Abbreviation: CPG: clinical practice guideline b. Categorizing Recommendations with an Updated Review of the Evidence Recommendations were first categorized by whether or not they were based on an updated review of the evidence. If evidence had been reviewed, recommendations were categorized as New-added, New- replaced, Not changed, Amended, or Deleted. Reviewed, New-added recommendations were original, new recommendations that were not in the 2014 VA/DoD HTN CPG. Reviewed, New-replaced recommendations were in the previous version of the guideline, but were modified to align with the updated review of the evidence. These recommendations could have also included clinically significant changes to the previous version. Recommendations categorized as Reviewed, Not changed were carried forward from the previous version of the CPG unchanged. The Reviewed, Not Changed category was used for recommendations carried forward to the updated CPG with review of the evidence and where no changes were deemed necessary to the recommendation language. For recommendations carried forward to the updated CPG with review of the evidence and slightly modified wording, the Reviewed, Amended recommendation category was used. This allowed for the wording of the recommendation to reflect GRADE methodology as well as for any other non- substantive (i.e., not clinically meaningful) language changes deemed necessary. The evidence used to support these recommendations was carried forward from the previous version of the CPG and/or was identified in the evidence review for the update. Recommendations could have also been designated Reviewed, Deleted. These were recommendations from the previous version of the CPG that were not brought forward to the updated guideline after review of the evidence. This occurred if the evidence supporting the recommendations was out of date, to the extent that there was no longer any basis to recommend a particular course of care and/or new evidence suggests a shift in care, rendering recommendations in the previous version of the guideline obsolete. c. Categorizing Recommendations without an Updated Review of the Evidence There were also cases in which it was necessary to carry forward recommendations from the previous version of the CPG without an updated SR of the evidence. Due to time and budget constraints, the update of the HTN CPG could not include a review of all available evidence on management of HTN; instead, the KQs were focused on areas of new or updated scientific research or areas that were not previously covered in the CPG. For areas of research that have not changed, and for which recommendations made in the previous version of the guideline were still relevant, recommendations could have been carried forward to the updated guideline without an updated SR of the evidence. The support for these recommendations in the updated CPG was thus also carried forward from the previous version of the CPG. These recommendations were categorized as Not reviewed. If evidence had not been reviewed, recommendations could have been categorized as Not changed, Amended, or Deleted. Not reviewed, Not changed recommendations refer to recommendations from the previous version of the HTN CPG that were carried forward unchanged to the updated version. The category of Not reviewed, Amended was used to designate recommendations that were modified from the 2014 VA/DoD HTN CPG with the updated GRADE language, as explained above. Recommendations could also have been categorized as Not reviewed, Deleted if they were determined to be out of scope. A recommendation was out of scope if it pertained to a topic (e.g., population, care setting, treatment, and condition) outside of the scope for the updated CPG as defined by the Work Group. The categories for the recommendations included in the 2020 version of the guideline are noted in the Recommendations. The categories for the recommendations from the 2014 VA/DoD HTN CPG are noted in Appendix D. F. Drafting and Submitting the Final Clinical Practice Guideline Following the face-to-face meeting, the Champions and Work Group members were given writing assignments to craft discussion sections to support each of the new recommendations and/or to update discussion sections from the 2014 VA/DoD HTN CPG to support the amended carried forward recommendations. The Work Group also considered tables, appendices, and other sections from the 2014 VA/DoD HTN CPG for inclusion in the update. During this time, the Champions and Work Group also made additional revisions to the algorithms, as necessary. After developing the initial draft of the updated CPG, an iterative review process was used to solicit feedback on and make revisions to the CPG. Once they were developed, the first two drafts of the CPG were posted on a wiki website for a period of 14-20 business days for internal review and comment by the Work Group. All feedback submitted during each review period was reviewed and discussed by the Work Group and appropriate revisions were made to the CPG. Draft 3 of the CPG was made available for peer review and comment. This process is described in the section titled Peer Review Process. After revisions were made based on the feedback received during the peer review and comment period, the Champions presented the CPG to the EBPWG for their approval. Changes were made based on feedback from the EBPWG and the guideline was finalized. The Work Group also produced a set of guideline toolkit materials which included a provider summary, pocket card, and patient summary. The final 2020 VA/DoD HTN CPG was submitted to the EBPWG in March 2020. Appendix B: Patient Focus Group Methods and Findings A. Methods As part of the effort to update this CPG, VA and DoD Leadership held a patient focus group. The patient focus group was held on January 23, 2019, at the Naval Medical Center in San Diego, CA. The aim of the focus group was to further understand and incorporate the perspective of patients with HTN and who are covered and/or receiving their care through the VA and/or DoD healthcare systems, as these patients are most affected by the recommendations put forth in the CPG. The focus group delved into the patients perspectives on a set of topics related to their HTN management, including their priorities, challenges they have experienced, the information they received regarding their care, as well as the impacts of their care on their lives. Participants for the focus group were recruited by VA and DoD Leadership as well as by the HTN CPG Champions. Patient focus group participants were not intended to be a representative sample of VA and DoD patients. However, recruitment focused on eliciting a range of perspectives likely to be relevant and informative in the guideline development process. Patients were not incentivized for their participation or reimbursed for travel expenses. The HTN CPG Champions and Work Group, with support from Lewin, developed a set of questions to help guide the focus group. The focus group facilitator led the discussion using the previously prepared questions as a general guide to elicit the most important information from the patients regarding their experiences and views about their treatment and overall care. 