Other factors considered by the Work Group for this recommendation included the improved outcomes of blood pressure reduction and blood pressure goal attainment, which outweighed the small risk of adverse events. There was some variation in patient values and preferences. Overall, the strength of the evidence and substantial effect sizes within the two SRs contributed to the Strong for recommendation.[75,76] Recommendation 11. We suggest offering nurse-led interventions as an option for patients treated for hypertension. (Weak for | Reviewed, New-replaced) Discussion Nurse-led interventions for the management of HTN encompass a wide variety of treatment approaches including cardiovascular risk assessment, education, counseling on lifestyle modification, goal setting, action planning, and the initiation and titration of antihypertensive medications using established protocols. When compared with usual care, nurse-led interventions have been found to reduce SBP and DBP, improve adherence to medication therapy, and improve quality of life metrics in patients with HTN.[82-88] All studies reviewed by the Work Group contained multiple components of nurse-led intervention, some paired with other co-interventions. Our evidence review found one SR, by Parappilly et al. (2018), that compared nurse-led interventions to usual care.[88] It was based on 16 RCTS and enrolled a total of 3,568 participants diagnosed with a previous stroke or transient ischemic attack. The researchers observed no statistically significant difference in SBP and DBP changes between nurse-led interventions and usual care. However, the authors indicated that one RCT was found to be an outlier. After removing this study from the meta-analysis, the models demonstrated a statistically significant effect on reducing SBP and DBP in favor of nurse-led interventions when compared to usual care. The authors reported a mean difference in SBP reduction of 2.84 mm Hg and a MD in DBP reduction of 2 mm Hg, favoring nurse-led intervention. All studies included in the SR contained multiple nurse-led components including education, lifestyle changes, providing feedback, appointment scheduling, and medication review and compliance.[88] The Work Group identified two additional RCTs that had results consistent with the SR by Parappilly et al. (2018) (i.e., favoring the nurse- led intervention group).[82,84] One found a reduction in DBP similar to the SR by Parappilly et al. (2018) (i.e., favoring the nurse-led intervention).[82] Three additional RCTs reported more frequent hypertension control or achieving a blood pressure goal of <140/90 mm Hg in the nurse-led intervention group when compared to the usual care control group.[83,85,87] No significant harms were found with nurse-led interventions in studies that reported on the outcome. Medication adherence is a critical component in chronic disease management for HTN. The SR by Parappilly et al. (2018) reported a statistically significant difference between nurse-led intervention and usual care in the change in medication adherence at follow-up.[88] Our evidence review found one RCT reporting a statistically significant difference in medication adherence in favor of nurse-led intervention.[87] Another RCT, by Zhu et al. (2018), found no statistically significant difference between nurse-led intervention and usual care in the change in medication adherence at follow-up.[82] Two additional RCTs found no statistically significant difference between nurse-led intervention and usual care when coupled with co-interventions such as electronic health record (EHR) tools and mobile health technologies.[83,85] These two RCTs had small sample sizes and may have been underpowered to detect the true intervention effect. Two RCTs found a statistically significant change in quality of life metrics favoring the nurse-led intervention group versus usual care.[82,87] However, a third RCT, by Persell et al. (2018), found no quality of life impact when using EHR tools alone or EHR tools plus nurse-led education with usual care or when interventions were compared with one another.[83] Despite general consistency in the evidence supporting the notion that nurse-led interventions inform the management of HTN, there is some variability in provider and patient preferences. The patient focus group revealed that some patients did not feel that their providers offered the full range of management strategies available and prioritized pharmacologic interventions. This highlights an opportunity to utilize nurse-led interventions for lifestyle modification. Additionally, the patient focus group found that patients would like to be offered verbal education as well as educational materials, such as pamphlets. Some patients reported that they did not receive information on the sequelae of high blood pressure and that their providers did not consider individual patient characteristics that could impact their high blood pressure and management strategies. A common theme highlighted in the patient focus group was the desire for ongoing communication and education from providers to patients. This is a potential area in which nurse-led intervention can fill current gaps in care. In general, nurse-led intervention is well received by patients and most providers. Patients often appreciate nurse-led intervention due to increased accessibility to care and time efficiency. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation identified in the evidence review conducted as part of this guideline update.[82-88] The Work Group s confidence in the quality of the evidence is very low for all included studies due to the lack of objectivity of outcome assessment, incomplete outcome data, selective reporting, small sample size, lack of blinding, and recruitment bias. The body of evidence had some limitations including confounders in the analysis.[82-88] Other considerations regarding this recommendation included the benefits of improved blood pressure and medication adherence outweighing the potential harms (none identified). Patient values and preferences were somewhat varied. Thus, the Work Group decided upon a Weak for recommendation. More research is needed to evaluate the effectiveness of nurse-led intervention to manage HTN in specific subgroups (e.g., age, ethnicity, comorbidities). Additionally, more research is needed to evaluate the effectiveness of nurse-led intervention, such as evaluating initiation and titration of antihypertensive medications using established protocols. Recommendation 12. We suggest offering registered dietitian-led nutrition interventions as an option for patients with hypertension who are or are not on medication. (Weak for | Reviewed, New-replaced) Discussion Registered dietitian-led nutrition interventions, such as education about low sodium diets, weight loss, and increasing consumption of fresh fruits and vegetables, have been found to result in modest but statistically significant lowering of SBP and DBP in treated and untreated hypertensive individuals.[89] The current recommendation is based on low quality evidence from an SR by Reigel et al. (2018), which included 4,491 patients across 13 studies, in which nutrition-based interventions resulted in lower SBP (MD -2.82 mm Hg) and lower DBP (MD -1.37 mm Hg), as compared with the usual care.[89] However, when studies were grouped based on whether the nutrition intervention was delivered by a registered dietitian versus other practitioners, significant reductions in SBP (MD -3.5 mm Hg) and DBP (MD -1.37 mm Hg) were only seen in the registered dietitian-led nutrition intervention group. In addition, blood pressure reductions were more pronounced with interventions longer than six months. No significant harms were found with nutrition interventions. Focus group participants highlighted that patients and caregivers strongly valued dietary interventions to lower blood pressure. Although not systematically reviewed in this guideline update, it is generally accepted that comprehensive dietitian-led intervention can positively impact other aspects of cardiovascular health, such as blood lipid and glucose levels, weight loss, and alcohol cessation. However, there may be barriers in obtaining healthy food choices for some patients. Service Members frequently do not get a choice regarding where they are going, what they are doing, or where they will eat in a deployed/training environment. Food sources may vary (e.g., Meals Ready to Eat (MREs), items received in care packages, training area or forward operating base (FOB)/central operating base (COB) dining facilities). Depending on what area of responsibility the Service Member is deployed to/training in, these rations may be high in sodium and fat. These nutritional factors may impact HTN management and necessitate counseling related to diet. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed the relevant evidence identified in the evidence review conducted as part of this guideline update.[89] The Work Group s confidence in the quality of the evidence is low. The body of evidence showed overall modest effect size, although statistically significant, and had some limitations including small size, inadequate allocation concealment and blinding, and inclusion of dietary approach as a part of multidisciplinary intervention in some individual studies. Other considerations regarding this recommendation included patients preferences. The potential benefit of nutritional intervention to improve global cardiovascular health outweighs potential adverse events and burden, which were not found. Thus, the Work Group decided upon a Weak for recommendation. More research is needed to evaluate intensity and duration of dietitian-led interventions to improve blood pressure control and effectiveness of registered dietitian-led nutritional intervention to manage HTN in specific subgroups (e.g., different ages, ethnicities). Recommendation 13. We suggest technology-based interventions (e.g., e-counseling, electronic transmission of data, telemonitoring, mobile applications) for improving control of hypertension. (Weak for | Reviewed, New-replaced) Discussion Several key words are defined to better understand this recommendation and its impact. Telehealth refers to data communicated between the patient and provider in ways other than face-to-face interactions. This is accomplished through a variety of methods to include use of computers, mobile devices, or mobile applications. In contrast, telemonitoring is the use of information and communication technologies to monitor and transmit items related to patient health status between geographically separated individuals, which permits home monitoring of patients to include nursing or residential care homes using external electronic devices. Methods may include e-counseling, real-time consults, electronic transmission of data and interventions, mobile interventions, and/or interactive digital interventions. Additionally, mHealth is defined as mobile health. The World Health Organization defines it as the use of mobile applications and wireless technology to support the achievement of health goals.[90] In the development of this recommendation, the Work Group considered whether concurrent treatment impacted outcomes. The Work Group considered whether the intervention of interest was provided instead of, or in addition to, usual care (in-person visits). Some of the possible interventions may include mobile applications, telehealth monitoring, telehealth visits with primary care or a subspecialty. The impact of the intervention of interest and any concurrent treatment on the following outcomes was considered: reduction in blood pressure, change in blood pressure from baseline, achievement of lower blood pressure goals and adherence to therapy, and percentage of patients taking medication. In examining instead of or in addition to usual care (in-person visits) , two RCTs, Liu et al. (2018) [91] and Nolan et al. (2018),[92] compared an e-counseling intervention with usual care or control. Liu et al. observed a not statistically significant difference in SBP change between user-driven e-counseling and control, while a statistically significant change was noted with expert-driven e-counseling.[91] Nolan et al. (2018) reported a not statistically significant difference between e-counseling plus usual care for SBP and DBP at four months.[92] Two SRs compared mobile applications or mobile health technology with usual care or control. Alessa et al. (2018) indicated that applications had either a positive or statistically significant positive effect on SBP and DBP as compared to usual care or control.[93] Four of the 12 RCTS in Xiong et al. (2018) reported a statistically significant change in either SBP or DBP in favor of mHealth interventions as compared to usual care.[94] Marquez Contreras et al. (2018) reported a statistically significant difference in SBP change in favor of the mobile application as compared to usual care.[95] Twelve of 21 RCTs in Xiong et al. 2018) reported a significant improvement in medication adherence in the intervention group compared to controls.[94] In looking at telehealth monitoring, one SR by McLean et al. (2016) included seven RCTs comparing interactive digital interventions with usual care. McLean et al. (2016) observed statistically significant changes in SBP and DBP in favor of interactive digital interventions compared to usual care.[96] This recommendation looked at a variety of topics that include web-based interventions and telemonitoring. Two SRs [97,98] and two RCTs [99,100] compared telehealth visits with usual care or control. Chen et al. (2019) and Beishuizen et al. (2016) reported statistically significant differences in favor of web-based interventions for changes in SBP and DBP.[99,100] In contrast, one RCT included in Vargas et al. (2017) reported a not statistically significant difference in SBP change at three months.[98] Similarly, an additional RCT (not included in one of the above four SRs) by McManus et al. (2018) observed no statistically significant differences in SBP or DBP at six months.[52] One RCT included in Vargas et al. examined medication adherence and found no statistically significant difference in medication adherence between short message service (SMS) and control.[98] However, an additional RCT (not included in one of the above four SRs) by Pan et al. compared home telemonitoring with usual care and observed statistically significant differences in favor of home telemonitoring for SBP and DBP.[101] Given these conflicting results, additional studies need to examine possible effectiveness of mHealth.[90] Additional considerations include the confidentiality and security of all Health Insurance Portability and Accountability Act (HIPAA)-related health information, variation in use between age population groups, and variation in access to internet or technologies due to financial considerations. Primary HTN continues to be a concern. Emerging technologies should be considered as a possible additional intervention between the provider and patient to address HTN, thereby giving the provider additional tools to teach and evaluate the patient s progress. This recommendation s strength is Weak for. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed the relevant evidence for this recommendation identified in the evidence review conducted as part of this guideline update.[52,91-101] The overall confidence in the quality of the evidence is very low to low. While the balance of desirable and undesirable outcomes shows that benefits slightly outweigh harms/burden, there is a large variation of patient values and preferences. It cannot be understated that this recommendation has a broad scope with general findings that may show a modest benefit for those patients and providers who choose to utilize this medium. Technologies continue to evolve at a rapid pace and new capabilities are continually emerging. Additional studies should consider the effectiveness, safety, adherence, and overall quality of life impact on decreasing blood pressure. C. Non-pharmacological Management a. Weight Reduction The following recommendations are directed towards patients with HTN and overweight/obesity. There are benefits to weight reduction outside of treating for HTN. The various interventions may be more or less effective for other outcomes than for the treatment of HTN. Providers may refer to the VA/DoD Clinical Practice Guideline for Screening and Management of Obesity and Overweight for further discussion of treatment methods for patients with overweight/obesity.11 Recommendation 14. We suggest advising patients with hypertension and overweight/obesity to lose weight to improve blood pressure. (Weak for | Reviewed, Amended) Discussion As part of lifestyle modification, weight loss has been found to improve blood pressure in patients with HTN and overweight/obesity. Overall, reduction in weight or BMI had a positive effect on blood Therefore, the Work Group suggests advising patients with HTN and overweight/obesity to lose weight to reduce blood pressure. Although the confidence in the quality of the evidence is very low,[102-109] the Work Group believes the benefits outweigh the harms. As far as specific interventions for weight loss, the Work Group suggests offering diet directed at weight loss for treatment of HTN 11 See the VA/DoD Clinical Practice Guideline for Screening and Management of Obesity and Overweight. Available at: https://www.healthquality.va.gov/guidelines/CD/obesity/. (see Recommendation 15).[106-108] Additionally, the Work Group recommends neither for nor against weight loss medications for the treatment of HTN (see Recommendation 16).[103] Lastly, there is insufficient evidence to recommend for or against bariatric surgery for the treatment of HTN in patients with obesity and HTN (see Recommendation 17).[104,105] As Recommendation 14 is a Reviewed, Amended recommendation, the Work Group systematically reviewed evidence related to this recommendation identified in the evidence review conducted as part of this guideline update.[102-109] The confidence in the quality of the evidence supporting dietary and lifestyle interventions for blood pressure reduction through weight loss was low to very low. The Work Group believes that the benefits of diet and lifestyle modifications outweigh the harms. There will be variability in patient values and preferences, as not all patients will want to lose the weight or be accepting of a lifestyle modification. Thus, the Work Group decided upon a Weak for recommendation. Recommendation 15. For patients with hypertension and overweight/obesity, we suggest offering a diet directed at weight loss for the treatment of hypertension. (Weak for | Reviewed, New-added) Discussion The Work Group reviewed evidence on the effects of various weight loss interventions, including diet directed at weight loss which has been found to improve blood pressure in patients with HTN. One SR [108] and two RCTs [106,107] comprised the evidence base for diets directed at weight loss therapy. One SR, by Semlitsch et al. (2016), assessed the long-term effects of weight-reducing diets in people with HTN.[108] Three of the studies included in the SR by Semlitsch et al. (2016) examined the impact of diet versus no diet on SBP and DBP reduction (n=731);[108] there was further blood pressure reduction in the diet intervention group. One study included in the SR by Semlitsch et al. (2016) demonstrated significantly reduced cardiovascular morbidity in the diet intervention group. While the study was small, there was a large effect.[110] An RCT, by Kucharska et al. (2018), found that the Dietary Approaches to Stop Hypertension (DASH) diet reduced blood pressure in patients with overweight/obesity and HTN.[107] Another RCT, by Tay et al. (2014), studied the effects of a low-carbohydrate, high-unsaturated/low- saturated fat diet (LC) versus a high unrefined carbohydrate, low-fat diet (HC) on blood pressure reduction in patients with type 2 diabetes; results were inconclusive.[106] Confidence in the quality of the evidence is very low due to serious study limitations and imprecision. While SBP and DBP did decrease in the intervention groups for several studies, it was not clear whether it was a clinically meaningful reduction in As the recommendation on a diet directed at weight loss is Reviewed, New-added, the Work Group systematically reviewed evidence related to this recommendation identified in the evidence review conducted as part of this guideline update.[106-108] The Work Group had very low confidence in the quality of evidence supporting dietary interventions for weight loss for the treatment of HTN; there were serious limitations and a high risk of bias. While the data was somewhat limited, the effect sizes in the evidence were reasonably large. The benefits outweigh the harms, as only a few harms were associated with the interventions. There is a large variation in patient preferences as there are various versions of diet, and providers would need to get the patient to agree to participate in the dietary intervention. Some patients would not accept the intervention. Thus, the Work Group decided upon a Weak for recommendation. Recommendation 16. For the treatment of hypertension, there is insufficient evidence for or against offering weight loss medications for patients with obesity and hypertension. (Neither for nor against | Reviewed, New-added) Discussion The Work Group also looked at the evidence for offering weight loss medications for patients with obesity and HTN. There was insufficient evidence in the studies reviewed by the Work Group to recommend for or against offering weight loss medications for the treatment of HTN. An SR by Siebenhofer et al. (2016) compared weight loss medications (orlistat and phentermine/topiramate) to placebo in patients with HTN.[103] There were statistically significant improvements in SBP and DBP for individuals taking either orlistat (four studies with 2,058 patients) or phentermine/topiramate (one study with 1,305 patients) compared to placebo. The study that compared phentermine/topiramate to placebo found a high rate of low-severity side effects with use of phentermine/topiramate (85.4% for low-dose, 88.8% for high-dose) compared to placebo (77.3%), but a low rate of serious adverse events with use of phentermine/topiramate (3.4% for low-dose and 3.7% for high-dose) compared to placebo (4.2%).[103] The harms slightly outweighed the benefits. Evidence on other medications was not found and therefore not reviewed. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation identified in the evidence review conducted as part of this guideline update.[103] The confidence in the quality of the evidence was low due to risk of bias concerns and the small effect size. The harms slightly outweigh the benefits; there were gastrointestinal (GI) and musculoskeletal side effects with orlistat and relatively modest benefits. There is large variation in patient preferences regarding this medication because of the side effects. Patients may not want to take the medication, and there is the potential for taking the medication for life. Therefore, the Work Group decided upon a Neither for nor against recommendation. Recommendation 17. For the treatment of hypertension, there is insufficient evidence to suggest for or against bariatric surgery for patients with obesity and hypertension. (Neither for nor against | Reviewed, New-added) Discussion The Work Group also looked at the evidence for offering bariatric surgery for the treatment of HTN for patients with obesity and HTN. There was insufficient evidence in the studies reviewed by the Work Group to recommend for or against offering bariatric surgery for the treatment of HTN. The evidence for this recommendation was based on one SR [105] and one RCT.[104] In the RCT, by Schiavon et al. (2018), patients with a BMI of 30 to 39.9 kg/m2 were followed for 12 months after surgical intervention and demonstrated a greater reduction in anti-hypertensive medication usage as compared to patients treated with medications (from an average of three medications to zero to one). There were adverse events reported when patients were medically or surgically treated.[104] Schiavon et al. (2018) reported no differences in reduction of SBP and DBP between medical or surgical treatment groups.[104] The SR by Yan et al. (2016) followed the patients receiving medical treatment or bariatric surgery for 12 to 60 months; the highest BMI was 43 kg/m2 .[105] Yan et al. (2016) found only a statistically significant decrease in SBP in the bariatric surgery treatment group.[105] The confidence of the quality of the evidence is very low, and benefits and harms were balanced. As this is a Reviewed, New-added, the Work Group systematically reviewed evidence related to this recommendation identified in the evidence review conducted as part of this guideline update.[104,105] The confidence in the quality of the evidence was very low. The benefit and harms of bariatric surgery are balanced. The potential for positive outcomes was balanced with the risk of adverse events from surgery. There was large variation in the patient values and preferences regarding whether to have the surgery or avoiding surgery and committing to a lifestyle change. Not everyone would or should accept surgery as an intervention due to personal values and the inherent risks of any surgery, including bariatric surgery. The necessary medications and cost of surgery also need to be considered. Most of the evidence focused on patients with comorbid HTN and diabetes. Based on all these considerations, the Work Group determined that there was insufficient evidence for or against recommending bariatric surgery to treat HTN. b. Exercise/Physical Activity Recommendation 18. We suggest offering individual or group-based exercise for the treatment of hypertension to reduce blood pressure. (Weak for | Reviewed, Amended) Discussion The evidence in support of this recommendation was strongest for combined aerobic and resistance exercise interventions and for group/team-based sports. Other interventions reviewed included aerobic dance training, water-based exercise, yoga, traditional Chinese exercises such as Tai Chi and Qigong, and digital interventions to reduce sedentary time. Aerobic and resistance exercise interventions, both individually and in combination, have been shown to reduce blood pressure. Herrod et al. (2018) conducted an SR of RCTs comparing non-pharmacologic strategies to non-intervention controls.[111] The included studies had mean participant ages of at least 65; intervention duration ranged from four weeks to one year. The researchers found statistically significant improvements favoring each type of exercise intervention for both SBP and DBP. MDs in SBP and DBP for combined aerobic/resistance exercise versus control were -5.9 mm Hg and -3.5 mm Hg, respectively. A 2016 meta-analysis by Corso et al. (2016) also examined the efficacy of combining aerobic and resistance exercise interventions of similar duration for blood pressure reduction in slightly younger (mean age across studies 56 years) prehypertensive adults.[112] Statistically significant reductions of -3.2 mm Hg (SBP) and - 2.5 mm Hg (DBP) were seen for concurrent aerobic and resistance training versus control. Herrod et al. (2018) also reported data favoring separate aerobic, resistance, and isometric exercise interventions over control.[111] MDs in SBP and DBP for aerobic exercise versus control were -5.1 mm Hg and -2.2 mm Hg, respectively, while MDs in SBP and DBP for resistance exercise versus control were -5.5 mm Hg and -2.0 mm Hg, respectively. Only two studies included in the SR looked at isometric exercise versus control; MDs of -9.1 mm Hg (SBP) and -3.0 mm Hg (DBP) were reported. Additional data on aerobic exercise comes from a 2016 RCT comparing aerobic dance training to non-exercise controls in participants on two antihypertensive agents.[113] Statistically significant differences in both SBP and DBP favored dance training. A larger proportion of participants in the dance group were able to reduce their number of blood pressure medications; however, control participants were older and had a higher BMI at baseline. Recreational group sports may offer similar blood pressure reductions as combination aerobic/resistance exercise, as well as improving other cardiovascular risk factors. Bellissimo et al. (2018) conducted an SR and meta-analysis to estimate the pooled effects of community-based, recreational-level group sports on cardiometabolic risk factors and fitness parameters in adults.[114] Included trials compared group sports interventions against exercise and/or non-exercise controls; the majority used soccer as the group sports intervention. Intervention groups averaged 134 min/week of physical activity; the average intervention duration was roughly six months. Statistically significant differences favored recreational group sports for both SBP (MD -5.7 mm Hg) and DBP (MD -3.4 mm Hg). Improvements in total cholesterol, low-density lipoprotein (LDL) cholesterol, and BMI were also seen with intervention groups; statistically significant differences favored recreational group sports. An SR by Reichert et al. (2018) examined the blood pressure effects of aquatic-based exercise versus land training or non-exercise controls in adults and elderly individuals.[115] Aquatic interventions included aerobic, resistance, or combined aerobic/resistance training, but were limited to exercise performed in an upright position due to potentially beneficial physiological changes associated with hydrostatic pressure from immersion. Improvements in blood pressure for aquatic-based exercise versus control reached statistical significance only with sensitivity analyses for individuals with HTN (SBP and DBP) or for individuals with prehypertension (DBP only). Evidence reviewed did not suggest meaningful differences between higher and lower intensities of exercise or digital interventions to reduce sedentary time versus control. The strength of evidence reviewed for yoga and traditional Chinese exercise was rated low or very low quality and showed either no benefit for intervention versus control or inconsistent findings for critical outcomes.[116-119] As this is a Reviewed, Amended recommendation, the Work Group systematically reviewed evidence related to this recommendation identified in the evidence review conducted as part of this guideline update.[111-119] Quality of the evidence reviewed was affected by the inherent difficulty of blinding participants to exercise interventions. Some studies also lacked blinding (or reporting of blinding) of assessors to interventions or had meaningful differences in baseline characteristic between intervention groups. The Work Group s confidence in the quality of the evidence for exercise overall is low, but varied across types of interventions, with the strongest evidence (moderate quality) found for combined aerobic/resistance exercise and for recreational group sports. Patient preferences regarding exercise may vary considerably; some may dislike exercise, while others may value it as a means to potentially limit pill burden. Preferences for different types of exercise may also vary. Patients who dislike traditional exercise may be more likely to engage in group sports due to social or competitive aspects. The benefits of exercise outweigh the harms, particularly given the wide range of other health parameters positively affected by physical activity. Recommendation 19. We recommend a target for aerobic exercise of at least 120 minutes per week for reduction in blood pressure. (Strong for | Not Reviewed, Amended) Discussion As this is a Not Reviewed, Amended recommendation, the Work Group did not systematically review new evidence related to this recommendation. Two meta-analyses of RCTs studying the effects of aerobic exercise on blood pressure were reviewed during the 2014 VA/DoD HTN CPG update and provide evidence that the quantity of aerobic exercise influences its efficacy in blood pressure reduction.[120,121] Whelton et al. (2002) showed statistically significant improvements in blood pressure for interventions involving at least 120 minutes/week of aerobic exercise; magnitude of effect was clinically meaningful for SBP and DBP.[121] Kelley et al. (2001) also showed statistically significant improvements in blood pressure; furthermore, a meta-regression showed that increased minutes of exercise per session were associated with greater reductions in blood pressure.[120] Based on the assessment of the quality of the evidence put forth in the 2014 VA/DoD HTN CPG,[120,121] the Work Group determined the confidence in the quality of evidence is moderate for SBP and low for DBP. Benefits clearly outweigh the harms, although some patients may dislike, or have limited ability to, exercise. c. Dietary Modifications Recommendation 20. We recommend a dietitian-led Dietary Approaches to Stop Hypertension Diet for the treatment or prevention of hypertension for patients with hypertension or interested patients with other cardiovascular risk factors. (Strong for | Not Reviewed, Amended) Discussion Clinical trials on supplements frequently produce different or even opposite results than those expected based on epidemiologic data showing associations between food constituents and health outcomes. As individuals consume whole foods rather than isolated nutrients, it is more useful to confirm that a pattern of whole foods confers benefit, rather than that a micro/macronutrient is beneficial dependent on context. Fiber and various micronutrients such as potassium, magnesium, and calcium are thought to improve blood pressure based on epidemiologic data. The DASH trial represents the first major clinical trial to test a dietary pattern for the prevention and/or management of HTN. The DASH trial emphasized inclusion of these nutrients via commonly consumed foods rather than supplements.[122] This approach allows for the detection of potential additive and/or synergistic effects of these nutrients which might individually be too small to detect. The DASH diet has been shown to reduce SBP and DBP in both hypertensive and normotensive adults, whether at dietary sodium intakes similar to the average daily consumption [123] or in combination with varying degrees of sodium restriction.[122] Combining the DASH diet with sodium restriction consistently produces larger decreases in blood pressure than either intervention alone across As this is a Not Reviewed, Amended recommendation, the Work Group did not systematically review new evidence related to this recommendation. However, confidence in the quality of the evidence systematically reviewed for the 2014 VA/DoD HTN CPG is high.[122-124] Benefits outweigh harms, though patient preferences regarding dietary modification may vary. Some patients may be resistant to changing eating patterns or face geographical or financial barriers to accessing certain types of healthy foods. Others may have high levels of motivation to improve diet quality in an effort to reduce pill burden. Patient focus group participants indicated that initial referral to a dietitian is common but expressed the desire for spouses/caregivers to be included in nutrition interventions when possible. The current guideline continues to recommend the DASH diet based on the existing body of evidence to support its use in lowering blood pressure. Recommendation 21. In patients with hypertension, we recommend that sodium intake be limited to no more than 2,300 mg/day (100 mmol/day), with referral to a dietitian or other support as appropriate. (Strong for | Not Reviewed, Not Changed) Discussion Many national and international organizations recommend reducing sodium intake for the prevention and management of HTN, with the ultimate goal of reducing associated morbidity and mortality. New evidence was not reviewed as part of this CPG update; evidence reviewed during the 2014 VA/DoD HTN CPG update is summarized below. There is a strong body of evidence from animal studies and human observational and experimental studies noting a dose-dependent relationship between dietary sodium intake and blood pressure in both normotensive and hypertensive individuals, though there is known variation in salt sensitivity both within and across populations. It should be noted that recommendations for dietary sodium reduction to reduce cardiovascular risk generally rely on surrogate markers (e.g., blood pressure) rather than clinical outcomes. The current guideline recommends a reduction to 2300 mg/day. There is strong clinical evidence from the DASH sodium trial that a reduction from 3400 mg (average daily intake of U.S. adults) to 2300 mg (the previously defined tolerable upper intake level [UL] [125])12 improves blood pressure in the short term.[126] Limited observational research suggests that CVD event rates also decrease with reductions in sodium intake Two relevant RCTs addressing blood pressure and/or mortality outcomes for reducing sodium intake were reviewed during the 2014 VA/DoD HTN CPG update. The Trials of Hypertension Prevention Phase II (TOHP II) 12 There is no longer a defined UL for sodium, as there is no toxicological indicator specific to excessive sodium intake. The 2019 Dietary Reference Intakes now include a new category, the Chronic Disease Risk Reduction Intake (CDRR), or intake above which intake reduction is expected to reduce chronic disease risk in an apparently healthy population. The value of the new CDRR for adults (2300 mg) is the same as the previous UL for sodium. study compared counseling on sodium reduction to usual care in overweight adults.[128] The intervention group achieved greater mean net decreases in SBP and DBP at both 18 and 36 months. The effect was statistically significant when compared with controls for SBP at both times and for DBP at 18 months only. Shea et al. (2011) presented mortality outcome data from a post-hoc analysis of the Trial of Non- pharmacologic Interventions in the Elderly (TONE).[129] Despite the TONE trial achieving clinically and statistically significant improvements in blood pressure,[110] no change in all-cause mortality was found for the intervention group when compared to usual care.[129] Both TOHP II and TONE were lifestyle interventions in free-living cohorts rather than controlled feeding trials. Thus, the low percentage of intervention group participants who met the studies goal of <80 mmol/day (1840 mg) average sodium intake (21% in TOHP II, roughly 40% in TONE) represents the inherent difficulty of lifestyle modification compounded by the ubiquity of sodium in the present U.S. food supply. The studies support reducing sodium intake as a means to lower blood pressure, but do not justify a lower goal than 2300 mg or confirm that clinical outcomes are improved. It is possible that an effect on mortality would have been detected had TONE intervention participants been more successful in lowering sodium intake. Several organizations recommend or suggest lower targets for daily sodium intake. The 2017 ACC/AHA CPG recommends sodium reduction for adults with elevated blood pressure and lists <1500 mg as an optimal goal. [4] The 2015-2020 Dietary Guidelines for Americans recommends daily sodium intake <2300 mg for adults, but note that those with HTN or prehypertension may benefit from further reduction The average daily sodium intake in the U.S. is over 3400 mg/day excluding table salt, well above this guideline s recommendation of 2300 mg/day.[131] Disagreement regarding the exact cut-point at which risks outweigh benefits should not distract from a unified public health message that a reduction in sodium intake from current levels is desirable. As this is a Not Reviewed, Not Changed recommendation, the Work Group did not systematically review new evidence related to this recommendation. The Work Group s confidence in the quality of the evidence remains high based on evidence reviewed during the 2014 VA/DoD HTN CPG update.[126,128,129] The benefits of reducing daily dietary sodium intake to 2300 mg outweigh the harms. As dietary sodium recommendations rely heavily on research on surrogate markers, additional research is warranted to confirm that reducing blood pressure via reducing sodium intake has the predicted effect on morbidity and mortality. Future research is also needed to determine the efficacy and safety of lower sodium targets. Since the majority of sodium consumed by Americans comes from processed and prepared foods (versus added table salt), recommended intake levels would be attained most feasibly with changes to the food supply in addition to individual dietary modification. The U.S. Food and Drug Administration (FDA) has solicited comments on, but has not yet released, voluntary sodium reduction targets for food manufacturers and restaurants. Patients desire and ability to reduce sodium intake may vary; some may find low sodium diets unpalatable, and others, such as deployed military, may have limited access to fresh/unprocessed foods. Referral to a dietitian can help interested patients incorporate this recommendation into the broader context of a healthful diet. Per the patient focus group, inclusion of spouses/caregivers in nutrition interventions may provide additional benefit, as they may be responsible for household food shopping and/or preparation. Recommendation 22. In patients with additional cardiovascular risk factors, such as dyslipidemia, we suggest considering a dietitian-led Mediterranean Diet as an alternative to the Dietary Approaches to Stop Hypertension Diet. (Weak for | Not Reviewed, Not Changed) Discussion Epidemiologic data has long suggested a cardio-protective effect of a Mediterranean-style diet. Despite known variation in the cuisine of Mediterranean countries, certain characteristic features are commonly used to describe a traditional Mediterranean diet: high intake of vegetables, fruits, nuts, unrefined grains, and olive oil; moderate intake of fish and poultry; low or moderate intake of wine; and low intake of red meat, processed meat, dairy, and sweets. New evidence was not reviewed as part of the current CPG update. Evidence reviewed during the 2014 VA/DoD HTN CPG update is summarized below. Toledo et al. evaluated the effects of a Mediterranean diet on blood pressure in the PREDIMED (PREvenci n con DIeta MEDiterr nea) trial in Spain, which included a large cohort of men and women at high cardiovascular risk.[132] The two intervention groups received individual and group education on an energy-unrestricted Mediterranean diet from registered dietitians, as well as regular supplies of either extra-virgin olive oil or mixed nuts. The control group received a similar format of education on a low-fat diet. Statistically significant improvements in DBP, but not SBP, were found for both intervention groups when compared to controls at four years.[132] Furthermore, the two groups randomized to the Mediterranean diet experienced a significant 28-30% reduction in major cardiovascular events (MI, stroke, or death from cardiovascular causes).[133] The PREDIMED trial was subsequently retracted and republished in 2018 due to issues with the randomization process.[134] One site enrolled household members without randomization. Another assigned entire clinics to an intervention group rather than individual participants. A third site reported inconsistent use of randomization tables. In the republished paper, data was reanalyzed to account for correlations within families or clinics. The authors also reported a reanalysis of data after exclusion of participants known or suspected to have been improperly randomized. Reported results were similar after these corrections. As this is a Not Reviewed, Not Changed recommendation, the Work Group did not systematically review new evidence related to this recommendation as part of this guideline update. Confidence in the quality of evidence is low based on evidence put forth in the 2014 VA/DoD HTN CPG.[132] Issues with the randomization process of the PREDIMED trial were reported, but the corrected results were similar to those initially published.[134] Additional research is warranted to confirm these results, as well as to test the Mediterranean diet in RCTs of more diverse populations and against controls with more dissimilar baseline characteristics and intervention dietary patterns. Based on the available evidence, the benefits of this intervention outweigh the harms. Patient preferences vary regarding dietary modification; interested patients may prefer one dietary pattern over another. A Mediterranean-style dietary pattern may be beneficial to patients with HTN. It presents a viable alternative to the DASH diet for those who find lower fat diets unpalatable, have additional cardiovascular risk factors, or otherwise prefer the Mediterranean dietary pattern. Referral to a registered dietitian, when available, may help patients achieve the desired changes. D. Pharmacological Treatment a. For Hypertension Recommendation 23. We recommend offering a thiazide-type diuretic, calcium channel blocker, or either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker as primary pharmacologic therapy for hypertension for reduction in composite cardiovascular outcomes. (Strong for | Reviewed, New-replaced) Discussion The effects of the various antihypertensive drug classes on reducing composite cardiovascular outcomes, and not just differences in blood pressure lowering effect, were the focus for the recommendation. The SR and meta-analysis of 50 RCTs by Thomopoulos et al. (2015) was the key body of evidence reviewed to recommend these four main drug classes as initial therapy for HTN.[135] Head-to-head comparisons of different antihypertensive drug classes were made for the critical and important outcomes. The components of the critical outcome from the SR included the composite of fatal or nonfatal stroke and CHD events (coronary death and nonfatal MI), both with and without hospitalizations for heart failure. In patients with HTN, the SR found that angiotensin-converting enzyme inhibitors (ACEIs) were equivalent to angiotensin II receptor blockers (ARBs); ACEIs were equivalent to thiazide-type diuretics; and calcium channel blockers (CCBs) were equivalent to thiazide-type diuretics for composite cardiovascular outcomes. No significant differences in the critical outcome were found for the comparisons of ACEIs and CCBs or ARBs and CCBs. This does not imply equivalency, only that a conclusion could not be determined. No critical outcomes were noted for ARBs versus thiazide-type diuretics.[135] The Work Group did not make a formal recommendation for other outcomes such as stroke or heart failure reduction alone. However, there were an extensive number of comparisons that addressed other outcomes. Notable findings were that thiazide-type diuretics were superior to the other drug classes for preventing CHF outcomes, CCBs were superior to the other drug classes for reducing all-cause mortality, and CCBs were inferior to other drug classes at preventing CHF outcomes.[135] ACEIs and ARBs are not used concomitantly, due to well-recognized safety risks, as discussed in Recommendation 26. Although the evidence was not supportive of a recommendation, providers can consider beta blockers as an alternative to the four main antihypertensive classes for patients with compelling indications, including those with underlying CAD, following MI, and in heart failure with reduced ejection fraction. Patients who are intolerant to the four main antihypertensive drug classes may also consider a beta blocker. The SR found beta blockers were equivalent to ARBs for the composite cardiovascular outcomes and reported no significant difference between beta blockers and CCBs or thiazide-type diuretics. There were no critical outcomes reported for beta blockers compared to ACEIs. Some important outcomes showed beta blockers were inferior to the other drugs classes, particularly for stroke reduction.[135] Beta blockers are not recommended as initial antihypertensive therapy, as the evidence is mixed as to whether there is a clear benefit in reducing cardiovascular events. Thomopoulos et al. (2015) did not evaluate differences in adverse events.[135] However, the Work Group determined that the benefits of the reduction in composite cardiovascular outcomes outweighed the harms, including both the AEs associated with pharmacologic therapy (e.g., orthostatic hypotension, increases in serum creatinine, hyperkalemia, other metabolic concerns) and the alternative of not receiving drug treatment. Although the four main drug classes for initial therapy were supported by the evidence base, there is still some variation, as individual patients may show differences in personal choices, including tablet burden and frequency of medication administration. Additionally, patient-to-patient variation in tolerability of AEs can be a factor when choosing a particular antihypertensive drug class. This variability was also supported by the patient focus group, during which some of the patients indicated that providers focused on pharmacological therapies, rather than providing information and education on non-pharmacologic treatments. An important implication in terms of resource use is cost. Drug copayments for VA and TRICARE beneficiaries vary depending on factors such as dispensing venue (e.g., military treatment facilities [MTF] versus mail order) and whether a generic versus branded formulation is dispensed. Cost may be less of an issue for active duty personnel, who receive their medications at no cost. The Work Group agreed on a Strong for recommendation due to the robust and extensive body of evidence from RCTs, meta-analyses, and SRs supporting use of the four main antihypertensive drug classes.[135] This is considered a Reviewed, New-replaced recommendation, as new evidence from the SR focused on composite cardiovascular outcomes, in contrast to the 2014 VA/DoD HTN CPG recommendation for which the primary literature was evaluated to recommend thiazide-type diuretics as first-line. The confidence in the quality of evidence was moderate, as the authors of the SR adjusted outcomes so that the blood pressure reductions in each drug class were similar.[135] This led to the conclusion that antihypertensive drugs from the same classes have the same blood pressure lowering effect, which may or may not be true. Thomopoulos et al. (2015) did not include the same individual components of the critical outcome in the SR as the guideline-defined composite cardiovascular outcome (which was comprised of cardiovascular and all-cause mortality, stroke, CHF, kidney function, safety and blood-pressure lowering).[135] However, overall, the consensus of the Work Group was that the critical outcome results supported that the four antihypertensive drug classes produced similar effects on reducing composite cardiovascular events. Recommendation 24. In African American patients with hypertension, we recommend against using an angiotensin- converting enzyme inhibitor or angiotensin II receptor blocker as monotherapy. (Strong against | Not Reviewed, Not Changed) Discussion In addition to being recommended as primary pharmacologic therapy for HTN for reduction in composite cardiovascular outcomes in this CPG (see Recommendation 23), a thiazide-type diuretic or CCB are appropriate initial choices for African Americans with HTN.[136] Of the 33,357 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial, 35% were African American.[137] A subgroup analysis of this patient population found that the ACEI (lisinopril) was less effective in lowering blood pressure than the thiazide-type diuretic (chlorthalidone) or the long-acting dihydropyridine (LA DHP) CCB (amlodipine).[136] Although there was no significant difference between an ACEI or thiazide-type diuretic in the primary outcome of combined fatal CHD or nonfatal MI, the subgroup analysis of African American patients found that those participants randomized to the ACEI versus the thiazide-type diuretic were at a 40% greater risk of stroke, 30% greater risk of heart failure, 19% greater risk of CVD, and 15% greater risk of combined CHD.[136] There was no difference in major CVD outcomes between the thiazide-type diuretic and the LA DHP CCB in the subgroup of African American patients, other than a higher incidence of heart failure with the CCB.[136] The ALLHAT study also found that African American patients randomized to the LA DHP CCB (amlodipine) had greater adherence to treatment and required fewer medications to reach the blood pressure goal than those randomly assigned to the ACEI (lisinopril).[138] Additionally, the Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study reported that African Americans prescribed a beta-blocker (atenolol) had better cardiovascular outcomes than those prescribed an ARB (losartan).[139] In the African American Study of Kidney Disease and Hypertension (AASK), ACEIs were found to be more effective than beta-blockers or LA DHP CCBs in slowing glomerular filtration rate (GFR) decline among African American patients with proteinuria.[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. 